Loss of LBP triggers lipid metabolic disorder through H3K27 acetylation-mediated C/EBPβ-SCD activation in non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease(NAFLD)is associated with mutations in lipopolysaccharide-binding protein(LBP),but the underlying epigenetic mechanisms remain understudied.Herein,LBP^(-/-)rats with NAFLD were established and used to conduct integrative targetingactive enhancer histone H3 lysine 27 acetylation(H3K27ac)chromatin immunoprecipitation coupled with high-throughput and transcriptomic sequencing analysis to explore the potential epigenetic pathomechanisms of active enhancers of NAFLD exacerbation upon LBP deficiency.Notably,LBP^(-/-)reduced the inflammatory response but markedly aggravated high-fat diet(HFD)-induced NAFLD in rats,with pronounced alterations in the histone acetylome and regulatory transcriptome.In total,1128 differential enhancer-target genes significantly enriched in cholesterol and fatty acid metabolism were identified between wild-type(WT)and LBP^(-/-)NAFLD rats.Based on integrative analysis,CCAAT/enhancer-binding proteinβ(C/EBPβ)was identified as a pivotal transcription factor(TF)and contributor to dysregulated histone acetylome H3K27ac,and the lipid metabolism gene SCD was identified as a downstream effector exacerbating NAFLD.This study not only broadens our understanding of the essential role of LBP in the pathogenesis of NAFLD from an epigenetics perspective but also identifies key TF C/EBPβand functional gene SCD as potential regulators and therapeutic targets.

Reorganization of 3D genome architecture provides insights into pathogenesis of early fatty liver disease in laying hens

Background Fatty liver disease causes huge economic losses in the poultry industry due to its high occurrence and lethality rate.Three-dimensional(3D)chromatin architecture takes part in disease processing by regulating tran-scriptional reprogramming.The study is carried out to investigate the alterations of hepatic 3D genome and H3K27ac profiling in early fatty liver(FLS)and reveal their effect on hepatic transcriptional reprogramming in laying hens.Results Results show that FLS model is constructed with obvious phenotypes including hepatic visible lipid deposi-tion as well as higher total triglyceride and cholesterol in serum.A/B compartment switching,topologically associat-ing domain(TAD)and chromatin loop changes are identified by high-throughput/resolution chromosome conforma-tion capture(HiC)technology.Targeted genes of these alternations in hepatic 3D genome organization significantly enrich pathways related to lipid metabolism and hepatic damage.H3K27ac differential peaks and differential expres-sion genes(DEGs)identified through RNA-seq analysis are also enriched in these pathways.Notably,certain DEGs are found to correspond with changes in 3D chromatin structure and H3K27ac binding in their promoters.DNA motif analysis reveals that candidate transcription factors are implicated in regulating transcriptional reprogram-ming.Furthermore,disturbed folate metabolism is observed,as evidenced by lower folate levels and altered enzyme expression.Conclusion Our findings establish a link between transcriptional reprogramming changes and 3D chromatin struc-ture variations during early FLS formation,which provides candidate transcription factors and folate as targets for FLS prevention or treatment.

Wedelolactone attenuates sepsis-associated acute liver injury by regulating the macrophage M1/M2 polarization balance through the PI3K/AKT/NF-κB signalling pathway

Background:Liver injury caused by sepsis seriously impairs the normal physiology of the liver.Wedelactone(WED)has an obvious anti-inflammatory effect against liver damage caused by various factors.Nevertheless,further research is needed to determine if WED might mitigate acute liver damage linked to sepsis by influencing macrophage polarization.Methods:We first assessed the effect of WED on lipopolysaccharides-triggered liver injury by biochemistry assay and tissue staining.Inflammatory factors were assessed using the ELISA kits.The expression of Cluster of Differentiation 86(CD86)and Cluster of Differentiation 206(CD206)was measured by immunofluorescence assay.The protein levels of inducible nitric oxide sythase(iNOS),Arginase 1(Arg-1),phosphatidylinositol 3-kinase(PI3K),protein kinase B(AKT),PI3K phosphorylation(p-PI3K),AKT phosphorylation(p-AKT),inhibitor of kappa B kinase(IKK),inhibitor of kappa B(IκB),and nuclear factor kappa-B(NF-κB)p65 were quantified by western blot analysis.Results:WED decreased the level of alanine aminotransferase(ALT),aspartate aminotransferase(AST),alkaline phosphatase(ALP)and malondialdehyde,and increased the activity of superoxide dismutase(SOD)and glutathione peroxidase(GSH-PX).Moreover,WED exerted effective anti-inflammatory effects by decreasing the level of Tumor necrosis factor-α(TNF-α)and Interleukin 6(IL-6)and increasing the level of Interleukin 10(IL-10)in serum and cells.WED not only decreased CD86 and iNOS expression but also increased CD206 and Arg-1 expression.WED also downregulated the increased expression of PI3K,AKT,p-PI3K,p-AKT,IKK,and NF-κB p65 induced by lipopolysaccharides,while up-regulated the decreased expression of IκB.Besides,LY294002 with WED decreased the expression of protein PI3K,AKT,p-PI3K,p-AKT,IKK and NF-κB p65,and raised the expression of IκBα.Conclusion:Wedelolactone could attenuate sepsis-associated acute liver injury,and its mechanism may be associated with balancing pro-inflammatory and anti-inflammatory by the regulation of M1/M2 macrophage polarization via the PI3K/AKT/NF-κB signaling pathway.

Better performance of PIVKA-II for detecting hepatocellular carcinoma in patients with chronic liver disease with normal total bilirubin

BACKGROUND Serum protein induced by vitamin K absence or antagonist-Ⅱ(PIVKA-Ⅱ) is a promising biomarker for hepatocellular carcinoma(HCC) surveillance.AIM To identify the contributing factors related to the abnormal elevation of PIVKA-Ⅱ level and assess their potential influence on the performance of PIVKA-Ⅱ in detecting HCC.METHODS This study retrospectively enrolled in 784 chronic liver disease(CLD) patients and 267 HCC patients in Mengchao Hepatobiliary Hospital of Fujian Medical University from April 2016 to December 2019. Logistic regression and the area under the receiver operating characteristic curve(AUC) were used to evaluate the influencing factors and diagnostic performance of PIVKA-Ⅱ for HCC, respectively.RESULTS Elevated PIVKA-Ⅱ levels were independently positively associated with alcohol-related liver disease, serum alkaline phosphatase(ALP), and total bilirubin(TBIL) for CLD patients and aspartate aminotransferase(AST) and tumor size for HCC patients(all P < 0.05). Serum PIVKA-Ⅱ were significantly lower in patients with viral etiology, ALP ≤ 1 × upper limit of normal(ULN), TBIL ≤ 1 × ULN, and AST ≤ 1 × ULN than in those with nonviral disease and abnormal ALP, TBIL, or AST(all P < 0.05), but the differences disappeared in patients with early-stage HCC. For patients with TBIL ≤ 1 × ULN, the AUC of PIVKA-Ⅱ was significantly higher compared to that in patients with TBIL > 1 × ULN(0.817 vs 0.669, P = 0.015), while the difference between ALP ≤ 1 × ULN and ALP > 1 × ULN was not statistically significant(0.783 vs 0.729, P = 0.398). These trends were then more prominently perceived in subgroups of patients with viral etiology and HBV alone.CONCLUSION Serum PIVKA-Ⅱ has better performance in detecting HCC at an early stage for CLD patients with normal serum TBIL.

Diagnostic and prognostic performances of GALAD score in staging and 1-year mortality of hepatocellular carcinoma: A prospective study

BACKGROUND The GALAD score has improved early hepatocellular carcinoma(HCC)detection rate.The role of the GALAD score in staging and predicting tumor characteristics or clinical outcome of HCC remains of particular interest.AIM To determine the diagnostic/prognostic performances of the GALAD score at various phases of initial diagnosis,tumor features,and 1-year mortality of HCC and compare the performance of the GALAD score with those of other serum biomarkers.METHODS This prospective,diagnostic/prognostic study was conducted among patients with newly diagnosed HCC at the liver center of Vajira Hospital.Eligible patients had HCC staging allocation using the Barcelona Clinic Liver Cancer(BCLC)categorization.Demographics,HCC etiology,and HCC features were recorded.Biomarkers and the GALAD score were obtained at baseline.The performance of the GALAD score and biomarkers were prospectively assessed.RESULTS Exactly 115 individuals were diagnosed with HCC.The GALAD score increased with disease severity.Between BCLC-0/A and BCLC-B/C/D,the GALAD score predicted HCC staging with an area under the curve(AUC)of 0.868(95%CI:0.80–0.93).For identifying the curative HCC,the AUC of GALAD score was significantly higher than that of Alpha-fetoprotein(AFP)(0.753)and Lens culinaris agglutinin-reactive fraction of AFP-L3(0.706),and as good as that of Protein induced by vitamin K absence-II(PIVKA-II)(0.897).For detecting aggressive features,the GALAD score gave an AUC of 0.839(95%CI:0.75–0.92)and significantly outperformed compared to that of AFP(0.761)and AFP-L3(0.697),with a trend of superiority to that of PIVKA-II(0.772).The performance to predict 1-year mortality of GALAD score(AUC:0.711,95%CI:0.60–0.82)was better than that of AFP(0.541)and as good as that of PIVKA-II(0.736).The optimal cutoff value of GALAD score was≥6.83,with a specificity of 72.63%for exhibiting substantial reduction in the 1-year mortality.CONCLUSION The GALAD model can diagnose HCC at the curative stage,including the characteristic of advanced disease,more than that by AFP and AFP-L3,but not PIVKA-II.The GALAD score can be used to predict the 1-year mortality of HCC.

血清甲胎蛋白、PIVKA-Ⅱ、GGT、GGT/ALT检测对早期原发性肝癌的诊断价值

目的 研究血清甲胎蛋白、异常凝血酶原(PIVKA-Ⅱ)、γ-谷氨酰转移酶(GGT)、GGT/丙氨酸氨基转移酶(GGT/ALT)在早期原发性肝癌诊断中的临床价值。方法 研究方法为前瞻性分析,观察对象为2020年1月至2023年1月攀枝花市中西医结合医院的80例疑似早期原发性肝癌患者,将细胞学、病理学活检诊断结果作为本次研究的金标准划分两组,分别命名为恶性组(n=53)与良性组(n=27)。分别采集血液样本检测血清甲胎蛋白、PIVKA-Ⅱ、GGT、ALT水平,并计算GGT/ALT比值;比较两组患者血清甲胎蛋白、PIVKA-Ⅱ、GGT、GGT/ALT表达水平。比较两组患者血清甲胎蛋白、PIVKA-Ⅱ、GGT、GGT/ALT阳性情况。所有患者均进行细胞学、病理学活检,分析血清甲胎蛋白、PIVKA-Ⅱ、GGT、GGT/ALT单一指标、联合指标诊断原发性肝癌与病理学诊断结果的一致性。采用受试者工作特征(ROC)曲线评估血清甲胎蛋白、PIVKA-Ⅱ、GGT、GGT/ALT 4项指标单一与联合对原发性肝癌的诊断效能。结果 恶性组患者的血清甲胎蛋白、PIVKA-Ⅱ、GGT、GGT/ALT表达水平分别为(1 118.82±67.85) ng/mL、(582.43±197.17) mAU/mL、(102.06±9.47) U/L、3.19±1.71,均明显高于良性组[(9.30±4.76) ng/mL、(31.18±7.34) mAU/mL、(71.64±21.98) U/L、1.61±0.64],差异均有统计学意义(P<0.05)。恶性组患者血清甲胎蛋白、PIVKA-Ⅱ、GGT、GGT/ALT单一及联合指标阳性率分别为73.58%、88.68%、100.00%、54.72%、100.00%,均明显高于良性组(40.74%、14.81%、70.37%、18.52%、33.33%),差异均有统计学意义(P<0.05)。血清甲胎蛋白与组织病理学诊断之间的一致性系数Kappa=0.320(P=0.004),血清PIVKA-Ⅱ与组织病理学诊断之间的一致性系数Kappa=0.725(P<0.001),血清GGT与组织病理学诊断之间的一致性系数Kappa=0.358(P<0.001),血清GGT/ALT与组织病理学诊断之间的一致性系数Kappa=0.309(P=0.002),联合诊断与组织病理学诊断之间的一致性系数Kappa=0.385(P=0.001)。ROC曲线显示,甲胎蛋白、PIVKA-Ⅱ、GGT、GGT/ALT诊断早期原发性肝癌的曲线下面积(AUC)分别为0.842、0.943、0.908、0.899、0.997。结论 在早期原发性肝癌诊断中,血清PIVKA-Ⅱ水平检测的诊断价值优于甲胎蛋白、GGT、GGT/ALT,AFP、PIVKA-Ⅱ、GGT、GGT/ALT 4项指标联合检测的价值优于单一指标检测。

血清PIVKA-Ⅱ、AFP与HBV-DNA联合检测对HBV所致肝癌的诊断及预后预测价值

目的探究血清异常凝血酶原Ⅱ(PIVKA-Ⅱ)、甲胎蛋白(AFP)与乙肝病毒脱氧核糖核酸(HBV-DNA)联合检测对HBV所致肝癌(HCC)的诊断及预后预测价值。方法选取2018年8月至2020年7月在本院接受治疗的98例HCC患者作为研究对象(肝癌组),另取同期95例体检健康人群作为健康组,95例肝硬化患者作为肝硬化组,观察3组受试者血清PIVKA-Ⅱ、AFP与HBV-DNA表达水平和一般资料差异。根据肝癌组3年内预后情况将患者分为生存组(57例)和死亡组(41例)。比较肝癌组一般资料和血清PIVKA-Ⅱ、AFP与HBV-DNA水平关系;多因素Logistic和COX回归分析分别分析影响受试者患肝癌和患者预后不良的影响因素;四格表法计算血清PIVKA-Ⅱ、AFP与HBV-DNA水平对HCC的预测价值;ROC曲线分析评估血清PIVKA-Ⅱ、AFP与HBV-DNA水平对HCC患者预后的预测价值。结果肝癌组患者血清PIVKA-Ⅱ、AFP与HBV-DNA水平显著高于健康组和肝硬化组(P<0.05);HCC发病与血清PIVKA-Ⅱ、AFP与HBV-DNA水平有关,且是危险因素(P<0.05)。HCC患者预后不良与血清PIVKA-Ⅱ、AFP与HBV-DNA水平以及肿瘤数量有关(P<0.05),且是危险因素。血清PIVKA-Ⅱ、AFP与HBV-DNA水平以及3项联合诊断HCC发病的准确度分别为77.43%、72.57%、77.43%和84.72%。血清PIVKA-Ⅱ、AFP与HBV-DNA水平以及3项联合诊断HCC预后不良的AUC分别为0.823、0.841、0.824和0.958,3项联合诊断效能优于单一诊断(P<0.05)。结论血清PIVKA-Ⅱ、AFP与HBV-DNA水平在HCC患者和预后不良患者中呈高表达,且3项联合可有效预测HCC发病和HCC患者预后情况。

原发性肝癌患者血清PIVKA-Ⅱ、AFP表达水平及其临床意义

目的探讨原发性肝癌患者血清维生素K缺乏或拮抗剂-Ⅱ诱导的蛋白质(PIVKA-Ⅱ)、甲胎蛋白(AFP)水平变化及其临床意义。方法回顾性分析温州医科大学附属苍南医院2019年1月至2023年10月接诊的68例原发性肝癌患者的临床资料,作为肝癌组,并选择同期接诊的50例乙型肝炎肝硬化患者作为肝硬化组、50例慢性乙型肝炎患者作为肝炎组、50例健康人群作为对照组。比较四组血清PIVKA-Ⅱ、AFP水平,比较肝癌组不同病理特征患者血清PIVKA-Ⅱ、AFP水平。结果肝癌组血清PIVKA-Ⅱ、AFP水平均高于肝硬化组、肝炎组及对照组,有统计学意义(P<0.05),肝硬化组、肝炎组、对照组血清PIVKA-Ⅱ比较,无统计学意义(P>0.05),肝硬化组、肝炎组血清AFP比较,无统计学意义(P>0.05);肝癌组不同TNM分期、肝功能Child分级、肿瘤直径、病灶数量、淋巴结转移、微血管侵犯患者比较,均有统计学意义(P<0.05)。结论原发性肝癌患者血清PIVKA-Ⅱ、AFP均明显升高,可反映患者病情程度,有较好的临床应用价值。

Embryonic liver fordin is involved in glucose glycolysis of hepatic stellate cell by regulating PI3K/Akt signaling

AIM To investigate the role of embryonic liver fordin(ELF) in liver fibrosis by regulating hepatic stellate cells(HSCs) glucose glycolysis.METHODS The expression of ELF and the glucose glycolysisrelated proteins were evaluated in activated HSCs. si RNA was used to silence ELF expression in activated HSCs in vitro and the subsequent changes in PI3K/Akt signaling and glucose glycolysis-related proteins were observed.RESULTS The expression of ELF increased remarkably in HSCs of the fibrosis mouse model and HSCs that were cultured for 3 wk in vitro. Glucose glycolysis-related proteins showed an obvious increase in the activated HSCs, such as phosphofructokinase, platelet and glucose transporter 1. ELF-si RNA, which perfectly silenced the expression of ELF in activated HSCs, led to the induction of glucose glycolysis-related proteins and extracellular matrix(ECM) components. Moreover, p Akt, which is an important downstream factor in PI3K/Akt signaling, showed a significant change in response to the ELF silencing. The expression of glucose glycolysisrelated proteins and ECM components decreased remarkably when the PI3K/Akt signaling was blocked by Ly294002 in the activated HSCs. CONCLUSION ELF is involved in HSC glucose glycolysis by regulating PI3K/Akt signaling.

Yu Gan Long Ameliorates Hepatic Fibrosis by Inhibiting PI3K/AKT,Ras/ERK and JAK1/STAT3 Signaling Pathways in CCl4-induced Liver Fibrosis Rats

Yu Gan Long(YGL)is a Chinese traditional herbal formula which has been reported to attenuate liver fibrosis for many years and we have explored its anti-fibrotic mechanism through blocking transforming growth factor(TGF-β)in the previous study.But the mechanisms associated with platelet-derived growth factor(PDGF)-BB remain obscure.In this study,we further investigated the mechanism of YGL reducing carbon tetrachloride(CCl4)-induced liver fibrosis in rats.Our results showed that YGL suppressed CCl4-induced upregulation of collagen IV(Col IV),type HI precollagen(PCHI),hyaluronuc acid(HA)and laminin(LN),which are implicated in liver fibrosis.Also,YGL reduced theα-smooth muscle actin(α-SMA)expression,which acts as the indicator of liver fibrosis.Furthermore,YGL decreased the serum levels of hepatic stellate cell(HSC)mitogen PDGF-BB and inflammation cytokines,including TNF-α,IL-1β,IL-6.Markers involved in liver fibrosis,such as Ras,p-Raf-1,p-ERK1/2,p-JNK,p-P38,p-PI3K,p-AKT,p-JAKl,p-STAT3 were downregulated significantly after treatment with YGL.Our results indicated that YGL ameliorated CCl4-induced liver fibrosis by reducing inflammation cytokines production,and suppressing Ras/ERK,PI3K/AKT,and JAK1/STAT3 signaling pathways,which provided further evidence towards elucidation of the anti-fibrotic mechanism of YGL.

Beneficial effects of adenosine triphosphate-sensitive K^+ channel opener on liver ischemia/reperfusion injury

AIM: To investigate the effect of diazoxide administration on liver ischemia/reperfusion injury.

Application of DDG-3300K Liver Reserve Function Analyzer and Relevant Nursing Procedures at the Department of Infectious Diseases

Objective: To discuss some key points about nursing in the use of DDG-3300K liver reserve function analyzer in patients at the department of infectious diseases. Method: DDG-3300K liver reserve function analyzer was applied to 5464 patients at the department of infectious diseases. The reasons for failed detection and complications related to the detection were analyzed, and the measures for improving the nursing procedures were proposed. Result: Among the 5464 patients, the detections were successful at the first attempt in 5458 patients;2 patients had leakage of liquid;2 patients were poorly prepared, and 1 case failed because of mistaken selection of CO mode, which led to adverse drug reactions;1 case did not finish the detection due to anaphylactic shock;8 patients had nausea and 6 patients had skin rash on the four limbs and torso during the detection. Conclusion: It is necessary to formulate the nursing procedures for the use of DDG-3300K liver reserve function analyzer. Moreover, preparatory work, health education, refined nursing procedures and skillful operations are closely related to the success rate and accuracy of the detection.

Localization of ATP-sensitive K^+ channel subunits in rat liver

BACKGROUND ATP-sensitive K^+(KATP)channels were originally found in cardiac myocytes by Noma in 1983.KATP channels were formed by potassium ion-passing poreforming subunits(Kir6.1,Kir6.2)and regulatory subunits SUR1,SU2A and SUR2B.A number of cells and tissues have been revealed to contain these channels including hepatocytes,but detailed localization of these subunits in different types of liver cells was still uncertain.AIM To investigate the expression of KATP channel subunits in rat liver and their localization in different cells of the liver.METHODS Rabbit anti-rat SUR1 peptide antibody was raised and purified by antigen immunoaffinity column chromatography.Four of Sprague-Dawley rats were used for liver protein extraction for immunoblot analysis,seven of them were used for immunohistochemistry both for the ABC method and immunofluorescence staining.Four of Wistar rats were used for the isolation of hepatic stellate cells(HSCs)and Kupffer cells for both primary culture and immunocytochemistry.RESULTS Immunoblot analysis showed that the five kinds of KATP channel subunits,i.e.Kir6.1,Kir6.2,SUR1,SUR2A,and SUR2B,were detected in liver.Immunohistochemical staining showed that Kir6.1 and Kir6.2 were weakly to moderately expressed in parenchymal cells and sinusoidal lining cells,while SUR1,SUR2A,and SUR2B were mainly localized to sinusoidal lining cells,such as HSCs,Kupffer cells,and sinusoidal endothelial cells.Immunoreactivity for SUR2A and SUR2B was expressed in the hepatocyte membrane.Double immunofluorescence staining further showed that the pore-forming subunits Kir6.1 and/or Kir6.2 colocalized with GFAP in rat liver sections and primary cultured HSCs.These KATP channel subunits also colocalized with CD68 in liver sections and primary cultured Kupffer cells.The SUR subunits colocalized with GFAP in liver sections and colocalized with CD68 both in liver sections and primary cultured Kupffer cells.In addition,five KATP channel subunits colocalized with SE-1 in sinusoidal endothelial cells.CONCLUSION Observations from the present study indicated that KATP channel subunits expressed in rat liver and the diversity of KATP channel subunit composition might form different types of KATP channels.This is applicable to hepatocytes,HSCs,various types of Kupffer cells and sinusoidal endothelial cells.

Qishen decoction suppresses liver fibrosis by downregulating PI3K/Akt/mTOR signal pathway

Objective:To observe the effect of Qishen decoction on PI3K/Akt/mTOR signal pathway in rats with liver fibrosis;Methods:40 SD rats were randomly divided into four groups: the control group, the model group, Qishen decoction group, and Colchicine group. Except the control group, the remaining three groups were used to establish liver fibrosis model by intraperitoneal injection of carbon tetrachloride. At the end of modeling, Qishen decoction and colchicine group were given corresponding drug gavage treatment, rats in the model group and the control group were treated with equal volume distilled water for 8 weeks. At the end of the treatment, the blood and liver tissues of rats in each group were collected, the liver function indexes and hydroxyproline content were detected by ELISA, the pathological morphology of liver tissue was detected by HE and Masson staining. Immunohistochemical method was used to detect α-SMA protein expression and Western blot was used to detect the expression of α-SMA, Col-I, Col-Ⅲ and key proteins in PI3K/Akt/mTOR signaling pathway.Results: Compared with the model group, Qishen decoction significantly reduced the levels of AST, ALT, and TBIL in serum, and reduced Hyp content, inflammatory score, fibrosis score, and collagen staining area in liver tissue, differences were statistically significant (P<0.05). At meanwhile, Qishen decoction significantly reduce the expression level of α-SMA, CoL-I and Col-Ⅲ in liver tissue(P<0.05). In addition, compared with the model group, Qishen decoction significantly down-regulated the expressions of p-PI3K, p-Akt and p-mTOR in liver tissue, difference were statistically significant (P<0.05).Conclusion: Qishen decoction suppresses liver fibrosis and inhibits the deposition of collagen in liver tissue by down-regulating PI3K/Akt/mTOR signal pathway.

Analysis of the Relationship between PI3K/Akt Signaling Pathway and Insomnia of Liver Depression Syndrome

Some studies have shown that the co-morbidity of insomnia and anxiety and depression is very prominent, among which 70% of anxiety patients are accompanied by sleep disorders, which is commonly referred to as insomnia of liver depression syndrome in traditional Chinese medicine. The etiology and pathogenesis of traditional Chinese medicine is liver-qi discomfort, and soothing liver and relieving depression should be taken as the basic treatment method and treatment principle. By sorting out the relevant literature on PI3K/Akt signaling pathway, the relationship between PI3K/Akt signaling pathway and depression and insomnia was sorted out, and the possible mechanism of Liver-soothing and Depression-Relieving therapy for insomnia of liver-depression syndrome was found.

Protective effect of fu-qi granule on carbon tetrachloride-induced liver fibrosis in rats

AIM： To investigate the effcacy of fu-qi granule （FQG） on carbon tetrachloride （CCl4） induced liver fbrosis in rats and the underlying mechanisms. METHODS： Sixty rats were randomly divided into six groups： normal control group, CCl4 induced liver fbrosis group, AnluoHuaxianWan group and three treatment groups of FQG. Treatment of rats with intraperitoneal injection of carbon tetrachloride solution at 0.3 mL per 100 g body weigh twice a week for 8 wk. The normal control group the rats were given the media （olive oil） at the same time. In the frst 2 wk, rats were raised with feedstuff （80% corn meal, 20% lard, 0.5% cholesterol）. Serum samples were collected for alanine transaminase, aspartate aminotransferase, alkaline phosphatase, albumin, total protein assay and typical histopathological changes was observed in Hematoxylin-eosin staining sections. Smooth muscle alpha actin （α-SMA） was analyzed with immunohistochemistry. Mammalian target of rapamycin （mTOR） and hypoxia-inducible factor-1 （HIF-1α） expressions were detected by Western blot-ting. Tissue inhibitor of matrix metalloproteinases-1 （TIMP-1） and matrix metalloproteinases-9 （MMP-9） were measured with semi-quantitative reverse transcriptase-polymerase chain reaction.RESULTS： FQG significantly reduced the serum levels of alanine transaminase, aspartate aminotransferase, alkaline phosphatase and increased the serum contents of albumin, total protein in rats with liver fibrosis. Moreover, FQG promoted extracellular matrix degradation by increasing MMP-9 and inhibiting TIMP-1 and α-SMA. mTOR and HIF-1α expression in liver significantly decreased in the rats treated with FQG. CONCLUSION： The results indicated that FQG signi-fcantly reverse fbrosis induced by CCl4, which should be developed as a new and promising preparation for the prevention of liver fbrosis.

基于神经网络的超声背散射零差K成像脂肪肝评价方法研究

目的 :针对传统超声背散射零差K模型参数估计方法存在复杂度较高的问题,提出一种基于神经网络的超声背散射零差K模型参数估计方法,并在此基础上提出一种基于神经网络的超声背散射零差K成像脂肪肝评价方法。方法:首先,利用蒙特卡罗仿真得到模拟的超声背散射包络信号样本,然后提取特征参数并输入到训练好的神经网络模型中,即可得到零差K模型参数的估计结果。其次,利用滑动窗口法估计窗口内局部背散射包络信号的零差K模型参数值,对零差K模型参数估计值矩阵进行扫描变换、颜色映射和感兴趣区域设置,将感兴趣区域内的参数图像叠加显示到B超图像中,实现超声背散射零差K成像。最后,通过计算机仿真实验验证基于神经网络的超声背散射零差K模型参数估计方法的估算精度,通过临床实验验证基于神经网络的超声背散射零差K成像评价脂肪肝的性能。结果:计算机仿真实验结果表明,基于神经网络的超声背散射零差K模型参数估计方法估计零差K模型lg α参数、k参数的相对均方根误差分别为0.505和0.408,相比传统估计方法整体上提高了估算精度。临床实验结果表明,基于神经网络的超声背散射零差K模型参数αNN、kNN诊断脂肪肝≥S1、≥S2、≥S3的AUC值分别为0.77、0.84、0.87和0.77、0.84、0.84,相比基于传统超声背散射零差K成像提高了脂肪肝评估性能。结论:提出的基于神经网络的超声背散射零差K成像脂肪肝评价方法能够较好地评估脂肪肝,可为定量超声评价脂肪肝提供一种新手段。

血清PIVKA-Ⅱ、AFP、AFP-L3%联合检测在原发性肝癌诊断中的应用价值

目的 研究原发性肝癌诊断中血清异常凝血酶原(PIVKA-Ⅱ)、甲胎蛋白(AFP)、甲胎蛋白异质体比率(AFP-L3%)联合检测的应用价值。方法 选取150例健康体检者、100例慢性乙型肝炎(乙肝)患者、87例原发性肝癌患者,分别设为对照组、肝炎组、肝癌组。所有研究对象均进行PIVKA-Ⅱ、AFP、AFP-L3检测,对比三组肿瘤标志物的检测结果及阳性检出率,肿瘤标志物单项检测与联合检测的诊断效能。结果 对照组PIVKA-Ⅱ为(2.76±0.41)mAU/ml、AFP为(3.05±0.64)μg/L、AFP-L3%为(3.01±0.52)%;肝炎组PIVKA-Ⅱ为(14.32±2.18)mAU/ml、AFP为(18.67±2.11)μg/L、AFP-L3%为(10.14±2.13)%;肝癌组PIVKA-Ⅱ为(9750.59±17934.97)mAU/ml、AFP为(23865.92±69102.40)μg/L、AFP-L3%为(16.72±17.66)%。对照组、肝炎组、肝癌组的PIVKA-Ⅱ、AFP、AFP-L3%呈升高趋势,且各组间对比,差异有统计学意义(P<0.05)。肝癌组PIVKA-Ⅱ、AFP、AFP-L3%单项检测阳性检出率与联合检测阳性检出率分别为73.56%、65.52%、62.07%、87.36%,均高于对照组的0、0、0、0与肝炎组的4.00%、8.00%、10.00%、6.00%,且肝炎组高于对照组,差异有统计学意义(P<0.05)。在原发性肝癌中,PIVKA-Ⅱ单项检测敏感度为73.56%、特异度为96.00%、准确性为85.56%、阳性预测值为94.12%、阴性预测值为80.67%;AFP单项检测敏感度为65.52%、特异度为92.00%、准确性为79.68%、阳性预测值为87.69%、阴性预测值为75.41%;AFP-L3%单项检测敏感度为62.07%、特异度为90.00%、准确性为77.01%、阳性预测值为84.38%、阴性预测值为73.17%;PIVKA-Ⅱ、AFP、AFP-L3%联合检测敏感度为91.95%、特异度为98.00%、准确性为95.19%、阳性预测值为97.56%、阴性预测值为93.33%。PIVKA-Ⅱ、AFP、AFP-L3%联合检测的敏感度、准确性以及阴性预测值均高于PIVKA-Ⅱ、AFP、AFP-L3%单项检测,特异度高于AFP-L3%单项检测,阳性预测值高于AFP、AFP-L3%单项检测,差异有统计学意义(P<0.05)。结论 联合检测血清PIVKA-Ⅱ、AFP、AFP-L3能够促进原发性肝癌诊断效能的提升,并可将其与其他肝病进行鉴别区分。

超声造影肝脏影像报告和数据管理系统分类联合血清热休克蛋白90α、异常凝血酶原鉴别肝细胞癌和肝内胆管细胞癌

目的 探讨血清热休克蛋白90α(HSP90α)、异常凝血酶原(PIVKA-Ⅱ)联合超声造影肝脏影像报告和数据管理系统(LIRADS)分类在肝细胞癌和肝内胆管细胞癌中的鉴别诊断价值。方法 选取绵阳市中心医院2020年5月至2021年11月确诊的35例肝内胆管细胞癌(ICC)病人为ICC组,另选取105例肝细胞癌病人为肝细胞癌组。采用全自动发光免疫分析仪检测血清PIVKA-Ⅱ水平,采用ELISA法检测血清HSP90α水平,对所有病人进行超声造影检查,根据LI-RADS分类系统收集各超声特征;受试者操作特征(ROC)曲线分析超声造影LI-RADS-M(简称LR-M)类特征(动脉期环状高增强、门脉早期消退、显著消退)、血清HSP90α、PIVKA-Ⅱ及三者联合诊断ICC的价值。结果 与肝细胞癌组[(8.89±1.63)μg/L,(526.18±83.75)mAU/mL,16.19%,10.48%,15.24%,6.67%,48.57%,21.90%]相比,ICC组血清HSP90α(12.15±2.56)μg/L、PIVKA-Ⅱ(679.42±95.74)mAU/mL水平及胆管扩张(60.00%)、肿瘤边界模糊(60.00%)、形态不规则(62.86%)、动脉期环状高增强(51.43%)、门脉早期消退(94.29%)、显著消退(65.71%)比例显著较高(P<0.05)。超声造影LR-M类特征、血清HSP90α、PIVKA-Ⅱ及三者联合诊断ICC的曲线下面积(AUC)及其95%CI分别为0.80(0.72,0.88)、0.78(0.71,0.90)、0.78(0.68,0.87)、0.90(0.82,0.98),其中联合诊断效能最佳。结论超声造影LR-M类特征和血清HSP90α、PIVKA-Ⅱ联合后对ICC有较高的诊断性能,可有效鉴别诊断肝细胞癌和ICC。

Macrophage-derived SHP-2 inhibits the metastasis of colorectal cancer via Tie2-PI3K signals

This research aimed to explore the influence of Src homology-2 containing protein tyrosine phosphatase(SHP-2)on the functions of tyrosine kinase receptors with immunoglobulin and EGF homology domains 2(Tie2)-expressing monocyte/macrophages(TEMs)and the influence of the angiopoietin(Ang)/Tie2-phosphatidylinositol-3-kinase(PI3K)/protein kinase B(Akt)/mammalian target of rapamycin(mTOR)(Ang/Tie2-PI3K/Akt/mTOR)signaling pathway on the tumor microvascular remodeling in an immunosuppressive microenvironment.In vivo,SHP-2-deficient mice were used to construct colorectal cancer(CRC)liver metastasis models.SHP-2-deficient mice had significantly more metastatic cancer and inhibited nodules on the liver surface than wild-type mice,and the high-level expression of p-Tie2 was found in the liver tissue of the macrophages’specific SHP-2-deficient mice(SHP-2MACKO)+planted tumor mice.Compared with the SHP-2 wild type mice(SHP-2WT)+planted tumor group,the SHP-2MAC-KO+planted tumor group experienced increased expression of p-Tie2,p-PI3K,p-Akt,p-mTOR,vascular endothelial growth factor(VEGF),cyclooxygenase-2(COX-2),matrix metalloproteinase 2(MMP2),and MMP9 in the liver tissue.TEMs selected by in vitro experiments were co-cultured with remodeling endothelial cells and tumor cells as carriers.It was found that when Angpt1/2 was used for stimulation,the SHP-2MAC-KO+Angpt1/2 group displayed evident increases in the expression of the Ang/Tie2-PI3K/Akt/mTOR pathway.The number of cells passing through the lower chamber and the basement membrane and the number of blood vessels formed by cells compared with the SHP-2WT+Angpt1/2 group,while these indexes were subjected to no changes under the simultaneous stimulation of Angpt1/2+Neamine.To sum up,the conditional knockout of SHP-2 can activate the Ang/Tie2-PI3K/Akt/mTOR pathway in TEMs,thereby strengthening tumor micro angiogenesis in the microenvironment and facilitating CRC liver metastasis.