Correlation between CAT polymorphism and susceptibility to DMAc-induced abnormal liver function: a case-control study of Chinese population

Context: Acute or chronic exposure of N,N-dimethylacetamide (DMAc) is responsible for abnormal liver function. It appears that DMAc is mainly metabolized by cytochrome P450 in the liver and thereby produces reactive oxygen species (ROS). The elimination of ROS and the repairing of ROS-induced DNA damage are relevant to the ultimate toxicity of DMAc.

Objective: To investigate whether the polymorphisms in the CAT (rs564250, rs769214 and rs7943316), hOGG1 (rs2072668 and rs159153) and XRCC1 (rs25487 and rs1799782) genes are associated with susceptibility to DMAc-induced abnormal liver function in Chinese population.

Methods: Samples were obtained from 108 workers with DMAc-induced abnormal liver function and 108 workers with normal liver function.

Results: Subjects with the CAT rs769214 GA/GG genotypes had a reducing risk of abnormal liver function, which was more evident in the subgroups exposed to DMAc?<10?years, exposed to DMAc?<5?mg/m³, never smoked and never drank.

Conclusions: CAT rs769214 (-844?G?>?A) polymorphism may be associated with DMAc-induced abnormal liver function in Chinese population.     

MiRNAs roles in the diagnosis,prognosis and treatment of colorectal cancer

ABSTRACT

Introduction: The liver is the main location for metastasization in stage IV colorectal cancers.

Areas covered: This review intends to comprehensively present the most important studies conducted in the past few years concerning the role of miRNAs in colorectal cancer liver metastases, trying to clarify some aspects regarding tumor biology and favorite liver metastasization site.

Expert commentary: Recent advances in tissue and serum RNA extraction has considerably improved the field of microRNAs studies. These molecules known to play a crucial role in the metastatic stage indicate a starting point in the development of clinical biomarkers with a possible role in the stratification of high-risk patients for adequate treatment.     

超声弹性成像与超声造影对肝肿瘤的诊断效果对比

目的:分析超声弹性成像与超声造影对肝肿瘤的诊断效果。方法:收集我院2015年3月至2016年3月收治的肝肿瘤患者76例,术前均行超声弹性成像和超声造影检查,比较超声弹性成像和超声造影与病理诊断(黄金标准)的结果。结果:超声弹性成像与病理检查结果比较无统计学差异(P0.05);超声造影与病理检查结果无统计学差异(P0.05);超声弹性成像和超声造影的敏感性、特异性、准确性无统计学差异(P0.05)。结论:超声弹性成像、超声造影对肝肿瘤诊断中均有重要价值,建议二者联合检测,提高肝肿瘤检出准确率。     

Deceased-Donor Apolipoprotein L1 Renal-Risk Variants Have Minimal Effects on Liver Transplant Outcomes

BackgroundApolipoprotein L1 gene (APOL1) G1 and G2 renal-risk variants, common in populations with recent African ancestry, are strongly associated with non-diabetic nephropathy, end-stage kidney disease, and shorter allograft survival in deceased-donor kidneys (autosomal recessive inheritance). Circulating APOL1 protein is synthesized primarily in the liver and hydrodynamic gene delivery of APOL1 G1 and G2 risk variants has caused hepatic necrosis in a murine model.MethodsTo evaluate the impact of these variants in liver transplantation, this multicenter study investigated the association of APOL1 G1 and G2 alleles in deceased African American liver donors with allograft survival. Transplant recipients were followed for liver allograft survival using data from the Scientific Registry of Transplant Recipients.ResultsOf the 639 liver donors evaluated, 247 had no APOL1 risk allele, 300 had 1 risk allele, and 92 had 2 risk alleles. Graft failure assessed at 15 days, 6 months, 1 year and total was not significantly associated with donor APOL1 genotype (p-values = 0.25, 0.19, 0.67 and 0.89, respectively).ConclusionsIn contrast to kidney transplantation, deceased-donor APOL1 G1 and G2 risk variants do not significantly impact outcomes in liver transplantation.     

Network pharmacology-based identification of significant pathway for protection of Yinhuang granule in a mice model of metabolic-associated fatty liver disease

BackgroundMetabolic-associated fatty liver disease (MAFLD) is a spectrum of liver disorders. Nonalcoholic steatohepatitis (NASH) is defined as a more serious process of MAFLD with liver inflammation.PurposeThis study aims to observe the alleviation of Yinhuang granule (YHG), a Chinese patent medicine, on methionine and choline-deficient diet (MCD)-induced MAFLD in mice.MethodsNetwork pharmacology was used to analyze the improving effect of YHG on MAFLD and possible targets. MAFLD was induced in mice by MCD diet feeding for 6 weeks. In the last 2 weeks, the mice were orally given with YHG (400, 800 mg/kg) every day. Biochemical parameters of serum and liver, as well as hepatic gene expression were detected.ResultsNetwork pharmacology showed that YHG could improve MAFLD, inflammation, liver fibrosis, and oxidative stress. In animal experiments, YHG reduced hepatocellular damage and hepatic lipids accumulation which induced by MCD. In terms of liver inflammation, YHG attenuated MCD-induced liver inflammation in mice. YHG also inhibited the activation of hepatic stellate cells (HSCs) and alleviated liver fibrosis in MCD-fed mice. Through nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway, YHG alleviated liver oxidative stress injury in mice which induced by MCD.ConclusionYHG ameliorated MCD-induced MAFLD in mice by reducing hepatic lipids accumulation, alleviating liver oxidative, inflammatory injury and attenuating hepatic fibrosis.     

一种非酒精性脂肪性肝病的超声影像人工智能辅助诊断系统开发

摘要 目的：结合人工智能方法设计针对肝脏超声影像的辅助诊断系统，辅助医生对大样本肝脏超声影像数据的标准化和高效化诊断，实现基于肝脏超声图像的非酒精性脂肪性肝病的精准诊断。方法：通过开发肝脏超声影像的识别与分类、脂肪肝分级分析和肝脏脂肪含量定量分析三个模块，建立一套非酒精性脂肪性肝病的超声影像人工智能辅助诊断系统，该系统能够自动区分输入到系统中不同采样视野的超声影像类型，并对肝脏超声图像进行数字化分析，给出待测超声图像是否呈现脂肪肝以及其肝脏脂肪含量的百分比值。结果：本研究中的超声图像识别分类模块可高通量区分出肝肾比图像和衰减率图像的两类超声影像，其分类的准确率达100%。脂肪肝分级分析模块在测试集数据的准确率达到84%，展现出可胜任辅助医生诊断的能力。基于人工肝脏脂肪含量定量方法开发的肝脏脂肪含量定量分析模块的准确率达到67.74%。结论：本研究已开发出一套基于肝脏超声影像的智能辅助诊断系统，可以辅助医生快速、简单、无创地筛选出潜在患有脂肪肝的患者，虽然现阶段实现肝脏脂肪定量分析仍有难度，但已展现出较大的临床应用潜力。     

Synthesis,in vitro and in vivo antitumor and antiviral activity of novel 1-substituted benzimidazole derivatives

Abstract

A novel series of 5-nitro-1H-benzimidazole derivatives substituted at position 1 by heterocyclic rings was synthesized. Cytotoxicity and antiviral activity of the new compounds were tested. Compound 3 was more active than doxorubicin against A-549, HCT-116 and MCF-7. However, compound 3 showed no activity against human liver carcinoma Hep G-2 cell line. Compounds 9 and 17b (E) showed potency near to doxorubicin against the four cell lines. The acute toxicity of compound 9 on liver cancer induced in rats was determined in vivo. Interestingly, it showed restoration activity of liver function and pathology towards normal as compared to the cancer-bearing rats induced by DENA. Compounds 17a (Z), 17b (E) and 18a (Z) were the most promising compounds for their antiviral activity against rotavirus Wa strain.     

Schisandrol B promotes liver enlargement via activation of PXR and YAP pathways in mice

BackgroundSchisandrol B (SolB) is one of the bioactive components from a traditional Chinese medicine Schisandra chinensis or Schisandra sphenanthera. It has been demonstrated that SolB exerts hepatoprotective effects against drug-induced liver injury and promotes liver regeneration. It was found that SolB can induce hepatomegaly but the involved mechanisms remain unknown.PurposeThis study aimed to explore the mechanisms involved in SolB-induced hepatomegaly.MethodsMale C57BL/6 mice were injected intraperitoneally with SolB (100 mg/kg) for 5 days. Serum and liver samples were collected for biochemical and histological analyses. The mechanisms of SolB were investigated by qRT-PCR and western blot analyses, luciferase reporter gene assays and immunofluorescence.ResultsSolB significantly increased hepatocyte size and proliferation, and then promoted liver enlargement without liver injury and inflammation. SolB transactivated human PXR, activated PXR in mice and upregulated hepatic expression of its downstream proteins, such as CYP3A11, CYP2B10 and UGT1A1. SolB also significantly enhanced nuclear translocation of PXR and YAP in human cell lines. YAP signal pathway was activated by SolB in mice.ConclusionThese findings demonstrated that SolB can significantly induce liver enlargement, which is associated with the activation of PXR and YAP pathways.     

肝癌小鼠外周血及脾脏T淋巴细胞亚群的变化及其意义

目的:观察小鼠原位肝癌模型外周血以及脾脏T淋巴细胞亚群与正常小鼠之间的差异变化,探讨其差异变化的意义。方法:在正常KM小鼠肝脏种植H22细胞,建立小鼠原位模型。采用流式细胞术,以健康正常小鼠为对照,检测肝癌小鼠外周血以及脾脏T淋巴细胞亚群的变化。结果:与健康正常小鼠相比,肝癌小鼠外周血CD4~+T淋巴细胞、CD4~+/CD8~+比例有显著性降低,CD8~+T淋巴细胞显著性升高;脾脏CD3~+、CD4~+T淋巴细胞有显著性降低。结论:小鼠原位肝癌模型外周血以及脾脏T淋巴细胞亚群发生异常,免疫系统紊乱,可以反映小鼠肝癌的发生、发展。     

Cidea和Cidec促进肝脏中脂类的积累

目的:探讨Cidea和Cidec对肝脏中脂滴大小和脂类积累的影响。方法:首先,检测ob/ob肥胖小鼠的脂肪肝中Cidea和Cidec的表达情况。然后,采用腺病毒系统在野生型小鼠肝脏中过表达Cidea和Cidec,以及在ob/ob小鼠肝脏中基因沉默Cidea和Cidec,检测肝脏中脂滴大小和脂积累情况。结果:Cidea和Cidec在脂肪性肝脏中高表达。肝脏细胞中过表达Cidea和Cidec促进大脂滴的形成并能促进小鼠肝脏中的脂积累,且二者有协同作用。在脂肪肝中沉默Cidea和Cidec能缓解脂肪肝的程度,且脂合成基因的下调,线粒体活性增加。Cidea和Cidec的共沉默能进一步降低肝脏中的脂类积累。结论:Cidea和Cidec在促进肝脏的脂积累中起重要作用,并且二者有协同作用。     

Betaine chemistry,roles, and potential use in liver disease

BackgroundBetaine is the trimethyl derivative of glycine and is normally present in human plasma due to dietary intake and endogenous synthesis in liver and kidney. Betaine is utilized in the kidney primarily as an osmoprotectant, whereas in the liver its primary role is in metabolism as a methyl group donor. In both organs, a specific betaine transporter mediates cellular uptake of betaine from plasma. The abundance of both betaine and the betaine transporter in liver greatly exceeds that of other organs.Scope of reviewThe remarkable contributions of betaine to normal human and animal health are summarized together with a discussion of the mechanisms and potential beneficial effects of dietary betaine supplements on liver disease.Major conclusionsA significant amount of data from animal models of liver disease indicates that administration of betaine can halt and even reverse progression of the disruption of liver function. Betaine is well-tolerated, inexpensive, effective over a wide range of doses, and is already used in livestock feeding practices.General significanceThe accumulated data indicate that carefully controlled additional investigations in humans are merited. The focus should be on the long-term use of betaine in large patient populations with liver diseases characterized by development of fatty liver, especially non-alcoholic fatty liver disease and alcoholic liver disease.     

线粒体E3泛素连接酶MARCH5表达上调促进肝癌生长

目的:膜相关锌指蛋白MARCH5(membrane-associated RING-CH 5)是定位于线粒体外膜的E3泛素连接酶,在调控线粒体分裂融合相关蛋白的表达中发挥重要作用。以往研究在多种肿瘤中证实了线粒体分裂融合的异常,但目前MARCH5在肝癌中的表达与生物学作用均不清楚。本研究旨在探讨MARCH5在肝癌组织与细胞系中的表达及其在肿瘤生长中的调控作用。方法:1).利用免疫组化实验检测62对肝癌癌与癌旁组织中MARCH5表达,以明确MARCH5在肝癌中的表达是否发生了异常改变。2).利用qRT-PCR与Western blot实验检测4株肝癌细胞(SNU-354、SNU-368、HLE与HLF)与1株正常肝细胞HL7702中MARCH5表达,进一步分析MARCH5在肝癌细胞系中的表达改变。3).下调肝癌细胞中MARCH5表达后,利用EDU实验与克隆形成实验分析对肝癌细胞增殖与克隆形成能力的影响。结果:1).MARCH5在肝癌组织中表达显著高于癌旁组织。2). MARCH5在4株肝癌细胞中的表达均显著高于正常肝细胞。3).下调MARCH5表达可显著抑制肝癌细胞的增殖与克隆形成。结论:MARCH5在肝癌中表达显著上调并通过诱导增殖与克隆形成而促进肝癌的生长。     

Protective effect of wild Corni fructus methanolic extract against acute alcoholic liver injury in mice

Background: In Chinese folk medicine, Corni fructus (C. fructus) has traditionally been used to improve liver function, although the mechanism underlying its activity remains unclear. The aim of the present study was to evaluate the protective effects of wild C. fructus methanolic extract against acute alcoholic liver injury.

Methods: Alcohol was administered to mice for three consecutive days, either alone or in combination with C. fructus methanolic extract (50, 100, or 200?mg/kg body weight/d). Serum and liver tissue were collected from the animals and subjected to biochemical and histopathological analyses.

Results: C. fructus signi?cantly alleviated alcohol-induced liver injury by reducing serum alanine aminotransferase, aspartate aminotransferase, and thiobarbituric acid reactive species, inhibiting hydroxyl radicals (?OH), and increasing total superoxide dismutase, glutathione peroxidase, and glutathione in the liver (P?C. fructus treatment inhibited the expression and activity of cytochrome P450 2E1 (P?Conclusions: C. fructus could be a promising natural substance for ameliorating acute alcohol-induced oxidative stress and hepatic injury.     

G-CSF promotes the viability and angiogenesis of injured liver via direct effects on the liver cells

Background

Presently, liver transplantation is the only treatment strategy for liver failure (LF). Although granulocyte-colony stimulating factor (G-CSF) exhibits protective functions in LF, it is not clear whether it directly affects the liver cells.

Methods and Results

We established an injured liver cell model and observed that G-CSF treatment promoted cell viability and enhanced Ki67 and VEGF-A expression. Thereafter, human umbilical vein endothelial cells (HUVECs) were cultured in a conditioned medium collected from the G-CSF-treated injured liver cells. HUVECs’ proliferation and tubule formation were promoted. Furthermore, in an injured liver mouse model, confirmed via haematoxylin–eosin staining, we evaluated serum alanine aminotransferase activity, Ki67 expression, and microvessel density (MVD). G-CSF treatment significantly relieved liver injury, upregulated Ki67 expression, and enhanced MVD in the injured mouse liver tissue. Additionally, AKT and ERK signal targets were explored, and it was demonstrated that the effects of G-CSF on injured liver cells were mediated through the AKT and ERK signalling pathways.

Conclusions

G-CSF promotes injured liver viability and angiogenesis by directly affecting injured liver cells via the AKT and ERK signalling pathways. These findings improve our understanding of the role of G-CSF in recovery from LF.

     

Suppression of endoplasmic reticulum stress reverses hindlimb unloading-induced hepatic cellular processes in mice

BackgroundThe Hindlimb unloaded mouse, an animal model of simulated microgravity demonstrates significant metabolic and hepatic derangements. However, cellular and molecular mechanisms driving liver dysfunction in Hindlimb unloaded mice are poorly characterized.MethodsWe investigated the possible contribution of dysregulated protein homeostasis by endoplasmic reticulum, endoplasmic reticulum stress, to liver dysfunction during HU. C57BL/6j male mice were grouped into ground-based controls or Hindlimb unloaded groups treated daily with vehicle or 4-phenylbutyrate (4-PBA), a potent inhibitor of endoplasmic reticulum stress. Following three weeks of HU, mice were sacrificed, and liver tissues were dissected for further analysis.ResultsHindlimb unloaded was associated with hepatic atrophy and elevated endoplasmic reticulum stress, which was restored by 4-PBA treatment. The Gene Ontology analysis revealed the downregulation of genes primarily involved in liver metabolic and Wingless-related integration site (WNT) signaling pathways, while those related to cytochrome P450, and liver fibrosis were upregulated. The Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed downregulation of several genes involved in metabolic pathways following treatment with 4-PBA, induced by HU.ConclusionsWe report several differential and uniquely expressed genes associated with microgravity-induced elevated ER stress and liver injury. Our data has translational potential in unraveling novel molecular targets for pharmaceutical therapies of liver diseases.General significanceOur novel findings show a pathogenic role for elevated ER stress in liver injury in microgravity conditions.     

Synthesis and cellular bioactivities of novel isoxazole derivatives incorporating an arylpiperazine moiety as anticancer agents

In our endeavour towards the development of effective anticancer therapeutics, a novel series of isoxazole-piperazine hybrids were synthesized and evaluated for their cytotoxic activities against human liver (Huh7 and Mahlavu) and breast (MCF-7) cancer cell lines. Within series, compounds 5l-o showed the most potent cytotoxicity on all cell lines with IC₅₀ values in the range of 0.3–3.7?μM. To explore the mechanistic aspects fundamental to the observed activity, further biological studies with 5m and 5o in liver cancer cells were carried out. We have demonstrated that 5m and 5o induce oxidative stress in PTEN adequate Huh7 and PTEN deficient Mahlavu human liver cancer cells leading to apoptosis and cell cycle arrest at different phases. Further analysis of the proteins involved in apoptosis and cell cycle revealed that 5m and 5o caused an inhibition of cell survival pathway through Akt hyperphosphorylation and apoptosis and cell cycle arrest through p53 protein activation.     

Liquiritigenin suppresses the activation of hepatic stellate cells via targeting miR-181b/PTEN axis

BackgroundLiquiritigenin (LQ), an aglycone of liquiritin in licorice, has demonstrated antioxidant, anti-inflammatory and anti-tumor activities. Previously, LQ was found to inhibit liver fibrosis progression.PurposePhosphatase and tensin homolog (PTEN) has been reported to act as a negative regulator of hepatic stellate cell (HSC) activation. However, the roles of PTEN in the effects of LQ on liver fibrosis have not been identified to date.MethodsThe effects of LQ on liver fibrosis in carbon tetrachloride (CCl₄) mice as well as primary HSCs were examined. Moreover, the roles of PTEN and microRNA-181b (miR-181b) in the effects of LQ on liver fibrosis were examined.ResultsLQ markedly ameliorated CCl₄-induced liver fibrosis, with a reduction in collagen deposition as well as α-SMA level. Moreover, LQ induced an increase in PTEN and effectively inhibited HSC activation including cell proliferation, α-SMA and collagen expression, which was similar with curcumin (a positive control). Notably, loss of PTEN blocked down the effects of LQ on HSC activation. PTEN was confirmed as a target of miR-181b and miR-181b-mediated PTEN was involved in the effects of LQ on liver fibrosis. LQ led to a significant reduction in miR-181b expression. LQ-inhibited HSC activation could be restored by over-expression of miR-181b. Further studies demonstrated that LQ down-regulated miR-181b level via Sp1. Collectively, we demonstrate that LQ inhibits liver fibrosis, at least in part, via regulation of miR-181b and PTEN.ConclusionLQ down-regulates miR-181b level, leading to the restoration of PTEN expression, which contributes to the suppression of HSC activation. LQ may be a potential candidate drug against liver fibrosis.     

肝脱细胞基质溶液包被对HepG2细胞增殖及基质金属蛋白酶活性的影响

目的:建立由猪肝组织制备肝脱细胞基质溶液的新方法,并研究基质溶液包被对人肝癌细胞HepG2增殖及基质金属蛋白酶活性的影响。方法:对猪肝脏进行脱细胞处理,经研磨、冻干及胃蛋白酶消化制备肝脱细胞基质溶液,利用此基质溶液包被聚苯乙烯培养表面,进行HepG2细胞体外培养,并使用CCK-8、实时定量PCR、明胶酶谱等检测细胞增殖以及基质金属蛋白酶的基因表达和活性。结果:建立了由猪肝组织制备肝脱细胞基质溶液的新方法。与未包被组相比,脱细胞基质溶液包被培养显著促进HepG2细胞增殖,其细胞周期蛋白cyclin D1的基因表达增高,为未包被组的1.95倍(P0.01)。此外,脱细胞基质溶液包被组HepG2细胞的MMP14基因表达为未包被组的2.01倍(P0.05),明胶酶谱检测基质溶液包被组细胞的MMP9活性为未包被组的6.66倍(P0.01)。结论:肝脱细胞基质溶液包被培养可显著促进HepG2细胞增殖并提高其MMP9的活性,在构建模拟肝癌微环境培养体系中具有一定的应用潜力。     

Safety of co-administration of herbal and conventional medicines on liver and kidney function in stroke patients: A single-center retrospective study

BackgroundAlthough herbal medicines (HMs) are widely used worldwide, information concerning their interactions with conventional medicines (CMs) is sparse. In particular, stroke affects a high proportion of elderly people with impaired hepatic and renal function. Stroke is often accompanied by various complications and is commonly treated via the co-administration of HMs and CMs in Asia.PurposeWe aimed to investigate the effects of co-administration of HMs and CMs on liver and kidney function in patients with stroke. We estimated the prevalence of drug-induced liver injury (DILI) or herb-induced liver injury (HILI) and drug-induced acute kidney injury (DIAKI) or herb-induced acute kidney injury (HIAKI) in patients co-administered HMs and CMs.Study designThis was a retrospective study that reviewed the electronic medical records of 401 patients with stroke in a single hospital.MethodsThe prevalence of DILI or HILI and types of liver injury was examined according to abnormal increases in liver tests. The probable causality between drug or herb administration and liver injury was assessed using the Roussel Uclaf Causality Assessment Method. In addition, the prevalence of DIAKI or HIAKI was estimated using the Kidney Disease Improving Global Outcomes acute kidney injury stage criteria and related medical records.ResultsOut of a total of 401 patients, only four (1.0%) developed liver injury. Two cases of DILI (0.5%) and two cases of HILI (0.5%) were reported. Moxifloxacin and ebastine were the CMs that caused hepatotoxicity. Chungpyesagan-tang and Yeoldahanso-tang were the HMs that caused liver toxicity. Even in cases showing severe liver damage, alkaline phosphatase levels remained less than five times the normal value, and liver function test values recovered within 14 days. There were no cases of DIAKI or HIAKI in this cohort.ConclusionThese results suggest that if appropriately prescribed by experts, the co-administration of CMs and HMs is safe and does not adversely affect liver and kidney function in patients with stroke. To support these results, further large-scale multicenter prospective studies and toxicological studies based on the interaction between HMs and CMs are warranted.