Liver fibrosis and hepatic stellate cells: Etiology, pathological hallmarks and therapeutic targets

Liver fibrosis is a reversible wound-healing process aimed at maintaining organ integrity, and presents as the critical pre-stage of liver cirrhosis, which will eventually progress to hepatocellular carcinoma in the absence of liver transplantation. Fibrosis generally results from chronic hepatic injury caused by various factors, mainly viral infection, schistosomiasis, and alcoholism; however, the exact pathological mechanisms are still unknown. Although numerous drugs have been shown to have antifibrotic activity in vitro and in animal models, none of these drugs have been shown to be efficacious in the clinic. Importantly, hepatic stellate cells(HSCs) play a key role in the initiation, progression, and regression of liver fibrosis by secreting fibrogenic factors that encourage portal fibrocytes, fibroblasts, and bone marrow-derived myofibroblasts to produce collagen and thereby propagate fibrosis. These cells are subject to intricate cross-talk with adjacent cells, resulting in scarring and subsequent liver damage. Thus, an understanding of the molecular mechanisms of liver fibrosis and their relationships with HSCs is essential for the discovery of new therapeutic targets. This comprehensive review outlines the role of HSCs in liver fibrosis and details novel strategies to suppress HSC activity, thereby providing new insights into potential treatments for liver fibrosis.

Iron and liver fibrosis: Mechanistic and clinical aspects

Liver fibrosis is characterised by excessive deposition of extracellular matrix that interrupts normal liver functionality. It is a pathological stage in several untreated chronic liver diseases such as the iron overload syndrome hereditary haemochromatosis, viral hepatitis, alcoholic liver disease, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis and diabetes. Interestingly, regardless of the aetiology, iron-loading is frequently observed in chronic liver diseases. Excess iron can feed the Fenton reaction to generate unquenchable amounts of free radicals that cause grave cellular and tissue damage and thereby contribute to fibrosis. Moreover, excess iron can induce fibrosis-promoting signals in the parenchymal and non-parenchymal cells, which accelerate disease progression and exacerbate liver pathology. Fibrosis regression is achievable following treatment, but if untreated or unsuccessful, it can progress to the irreversible cirrhotic stage leading to organ failure and hepatocellular carcinoma, where resection or transplantation remain the only curative options. Therefore,understanding the role of iron in liver fibrosis is extremely essential as it can help in formulating iron-related diagnostic, prognostic and treatment strategies. These can be implemented in isolation or in combination with the current approaches to prepone detection, and halt or decelerate fibrosis progression before it reaches the irreparable stage. Thus, this review narrates the role of iron in liver fibrosis. It examines the underlying mechanisms by which excess iron can facilitate fibrotic responses. It describes the role of iron in various clinical pathologies and lastly,highlights the significance and potential of iron-related proteins in the diagnosis and therapeutics of liver fibrosis.

Correlation of MRI-determined small bowel Crohn’s disease categories with medical response and surgical pathology

AIM: To determine whether magnetic resonance imaging (MRI) can be used to categorize small bowel Crohn's disease (SB CD) into groups that correlate with response to medical therapy and surgical pathology.METHODS: Data was collected from all patients with MRI evidence of SB CD without significant colonic disease over a 32-mo period. Two radiologists, blinded to clinical findings, evaluated each MRI and grouped them based on bowel wall thickness and wall enhancement. These categories were: (1) "fibrosis", (2) "mild segmental hyper-enhancement and mild wall thickening", (3) "mild segmental hyper-enhancement and marked wall thickening", (4) "marked segmental transmural hyper-enhancement". Patient response to additional medical therapy post-MRI was prospectively determined at 8-wk. Non-responders underwent endoscopy and were offered therapeutic endoscopy or surgery. Surgical pathology was assessed against the MRI category. RESULTS: Fifty-five patients were included. Females and category "2" patients were more likely, and patients with luminal narrowing and hold-up less likely, to respond to medical therapy (P < 0.05). Seventeen patients underwent surgery. The surgical pathologicalfindings of fibrosis and the severity of inflammation correlated with the MRI category in all cases.CONCLUSION: Our fi ndings suggest that SB CD can be grouped by the MRI f indings and that these groups are associated with patients more likely to respond to continued medical therapy. The MRI categories also correlated with the presence and level of intestinal inflammation and fibrosis on surgical pathology, and may be of prognostic use in the management of CD patients.

The relationship between staging of hepatic fibrosis and the levels of serum biochemistry

Objective: To study the relationship between the de- gree of hepatic fibrosis and serum fibrosis markers. Methods: Liver biopsies were performed in 67 pa- tients with hepatitis. The sections were stained with hematoxylin eosin and immunohistochemical stain. Staging of hepatic fibrosis was made microscopically. The serum levels of hyaluronic acid (HA), type Ⅲ procollagen (PC-Ⅲ), laminin (LN), and type Ⅳ collagen (Ⅳ-C) were measured by radioimmunoas- say. Results: The serum levels of HA, PC-Ⅲ, LN and Ⅳ-C were elevated from S1 to S4 because of the in- crease of hepatic fibrosis. The serum concentrations of HA, PC-Ⅲ, LN and Ⅳ-C were increased with the progress of disease, with the highest concentration at the stage of cirrhosis. Conclusion: The stages of hepatic fibrosis are corre- lated with the serum levels of HA, PC-Ⅲ, LN and Ⅳ-C, which as markers may play a role in detecting the degree of hepatic fibrosis.

Hierarchical and selective roles of galectins in hepatocarcinogenesis, liver fibrosis and inflammation of hepatocellular carcinoma

Hepatocellular carcinoma(HCC)represents a global health problem.Infections with hepatitis B or C virus,non-alcoholic steatohepatitis disease,alcohol abuse,or dietary exposure to aflatoxin are the major risk factors to the development of this tumor.Regardless of the carcinogenic insult,HCC usually develops in a context of cirrhosis due to chronic inflammation and advanced fibrosis.Galectins are a family of evolutionarily-conserved proteins defined by at least one carbohydrate recognition domain with affinity forβ-galactosides and conserved sequence motifs.Here,we summarize the current literature implicating galectins in the pathogenesis of HCC.Expression of"proto-type"galectin-1,"chimera-type"galectin-3 and"tandem repeat-type"galectin-4 is up-regulated in HCC cells compared to their normal counterparts.On the other hand,the"tandemrepeat-type"lectins galectin-8 and galectin-9 are downregulated in tumor hepatocytes.The abnormal expression of these galectins correlates with tumor growth,HCC cell migration and invasion,tumor aggressiveness,metastasis,postoperative recurrence and poor prognosis.Moreover,these galectins have important roles in other pathological conditions of the liver,where chronic inflammation and/or fibrosis take place.Galectin-based therapies have been proposed to attenuate liver pathologies.Further functional studies are required to delineate the precise molecular mechanisms through which galectins contribute to HCC.

Multiparameter magnetic resonance imaging of liver fibrosis in a bile duct ligation mouse model

BACKGROUND Bile duct ligation(BDL)in animals is a classical method for mimicking cholestatic fibrosis.Although different surgical techniques have been described in rats and rabbits,mouse models can be more cost-effective and reproducible for investigating cholestatic fibrosis.Magnetic resonance imaging(MRI)has made great advances for noninvasive assessment of liver fibrosis.More comprehensive liver fibrotic features of BDL on MRI are important.However,the utility of multiparameter MRI to detect liver fibrosis in a BDL mouse model has not been assessed.AIM To evaluate the correlation between the pathological changes and multiparameter MRI characteristics of liver fibrosis in a BDL mouse model.METHODS Twenty-eight healthy adult male balb/c mice were randomly divided into four groups:sham,week 2 BDL,week 4 BDL,and week 6 BDL.Multiparameter MRI sequences,included magnetic resonance cholangiopancreatography,T1-weighted,T2-weighted,T2 mapping,and pre-and post-enhanced T1 mapping,were performed after sham and BDL surgery.Peripheral blood and liver tissue were collected after MRI.For statistical analysis,Student’s t-test and Pearson’s correlation coefficient were used.RESULTS Four mice died after BDL surgery;seven,six,five and six mice were included separately from the four groups.Signal intensities of liver parenchyma showed no difference on TI-and T2-weighted images.Bile duct volume,ΔT1 value,T2 value,and the rate of liver fibrosis increased steadily in week 2 BDL,week 4 BDL and week 6 BDL groups compared with those in the sham group(P<0.01).Alanine aminotransferase and aspartate transaminase levels initially surged after surgery,followed by a gradual decline over time.Strong correlations were found between bile duct volume(r=0.84),T2 value(r=0.78),ΔT1 value(r=0.62),and hepatic fibrosis rate(all P<0.01)in the BDL groups.CONCLUSION The BDL mouse model induces changes that can be observed on MRI.The MRI parameters correlate with the hepatic fibrosis rate and allow for detection of cholestatic fibrosis.

Study on key genes and pathways of myocardial fibrosis and prediction of effective traditional Chinese medicine

Objectives:Bioinformatics was applied to screen the key genes of Myocardial fibrosis,explore its pathogenesis and predict the potential traditional Chinese medicines for the treatment of Myocardial fibrosis.Methods:Based on raw data of gene chip GSE59437 from gene expression database(GEO),myocardial tissue samples from 3 control mice and 3 mice treated with angiotensin II-induced myocardial fibrosis were included.Using R language processing data and screening of gene express significant differences(DEG),use a database of DAVID and the R language finish Gene Ontology(GO)annotation and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment for differences gene,using the STRING database structure protein protein interactions(PPI)networks,using Cytoscape software visualization and use the MCODE plug-in screening key function modules in the network.Coremine Medical database was used to map the key genes,construct the gene-Chinese medicine network,and screen the traditional Chinese medicines for the treatment of myocardial fibrosis.Results:208 DEGs were screened,94 of which were up-regulated and 114 were down-regulated.DEGs is mainly involved in a variety of biological processes such as extracellular matrix remodeling,collagen fiber deposition and lipid metabolism disorders.KEGG pathway enrichment involves Platelet activation,Oxytocin signaling pathway,Insulin secretion,ECM-receptor interaction,GnRH signaling pathway,TNF signaling pathway and other signaling pathways.Key modules of PPI network including:CTGF,TIMP1,SPP1,SERPINE1,COL3A1,POSTN and FOS.The potential traditional Chinese medicines for the treatment of myocardial fibrosis are Astragalus membranaceus(Fisch.),Lepidium apetalum Willd and Salvia miltiorrhiza Bge.Conclusion:Myocardial fibrosis is a complex pathological process,and the genes related to the imbalance of extracellular matrix synthesis and degradation and excessive deposition of collagen fibers play an important role in this process.This study provides a scientific reference for further exploring the pathogenesis of myocardial fibrosis,looking for therapeutic targets and potential therapeutic traditional Chinese medicines.

NEGATIVE REGULATORY EFFECT OF SOMATOSTATIN ON EXPERIMENTAL RAT HEPATIC FIBROSIS

Objective To clarify the actions of somatostatin （SST） on the hepatic fibrogenesis in experimental rats. Methods Seventy five Sprague-Dawley rats were divided into 5 groups at random, including normal control, model control, SST-treated model groups of high, medium and low doses （200 μg·kg^-1·d^-1 , 100μg·kg^ 1 ·d^-1and 50 μg·kg^ 1 ·d^-1, respectively） （ n = 15, in each group）. All rats, except for the normal controls, were injected with 40% carbon tetrachloride （ CCI4 ） subcutaneously for 8 weeks to establish hepatic fibrosis. Meanwhile, rats of SST-treated model groups were given different doses of SST twice a day in the same way. Then the liver function, serum levels of hyaluronic acid （HA）, laminin （ LM） , and collagen type IV （CIV） were tested. The collagen types I and III, and pathological changes in liver tissue were assessed. Results Being compared with the model control group, SST-treated groups, especially the medium and low dose ones, exhibited significantly improved indices of liver function, including alanine minotransferase （ALT）, aspartate aminotrans- ferase （AST）, albumin （ALB）, total bilirubin （TBIL） and alkaline phosphatase （ALP）. Markedly lowered expres- sion of serum HA, LM and tissular collagen types I, III were also detected radioimmunologically and immunohisto- chemically in the low dose SST-treated model group. Moreover, pathological findings, such as lessened fibrous septa, decreased hepatic stellate cells （HSCs）, alleviated hepatic steatosis and attenuated inflammation, confirmed the significant improvement in fibrotic degree under the treatment of low dose rather than other doses of SST. Conclusion SST exerts the negative modulatory effect on hepatic fibrosis with a pathophysiological basis of extra- cellular matrixes （ECM） decreasing and hepatocyte protection. Low dose of SST （50 μg·kg^ 1 ·d^-1 ） maY be the optimum one among all doses.

Optimization of Tetrandrine Treatment in Rat Hepatic Fibrosis Model

Objective To optimize the therapeutic dosage of tetrandrine (Tet) in rat hepatic fibrosis model. Methods 50 Wistar ratswere divided into 5 groups at random including normal control, model control, Tet-treated model groups of 10 mg.kg-1.d-1, 5 mg.kg-1.d-1and 2.5 mg.kg-1.d-1(n=10 in each group). All rats, except for the normal controls, were injected with axenic porcine serum(0.5ml each time, twice a week) intraperitoneally for8 weeks to establish hepatic fibrosis. After the 8th week, rats of Tet-treated modelgroups were given by gavage once a day with different doses of Tet for another8 weeks. Then the liver function, serum levels of hyaluron-ic acid (HA), laminin (LM), and procollagen type III (PCIII) were tested. Collagen type I and III, pathological changes in liver tissuewere also assessed. Results Most indices of liver function including alanine minotransferase ( ALT), aspartate aminotransferase(AST), albumin (ALB), albumin /globulin ratio (A/G) and alkaline phosphatase (ALP) improved significantly in Tet-treated groupswith the exception ofγ-glutamyl transpeptidase (γ-GT) and total bilirubin (TBIL). Secondly, markedly lowered levels of HA, LMandcollagen type I, III were also detected by radioimmunology and immunohistochemistry in the 5 mg.kg-1.d-1Tet-treated model group.Moreover, pathological findings confirmed the statistically significant improvement in hepatofibrotic degree resulted from the treatment of5 mg.kg-1.d-1rather than other doses of Tet. Conclusion For experimental Wistar rats, Tet exhibited an anti-hepatofibrotic action indoses within the range of 2.5 mg.kg-1.d-1to 10 mg.kg-1.d-1, and 5 mg.kg-1.d-1may be the optimum one among all doses.

OPTIMIZATION OF TETRANDRINE TREATMENT IN RAT HEPATIC FIBROSIS MODEL

Objective To optimize the therapeutic dosage of tetrandrine （Tet） in rat hepatic fibrosis roodel. Methods 50 Wistar rats were divided into 5 groups at random including normal control, model control, Tettreated model groups of 10mg· kg^ - 1· d^ - 1, 5mg· kg^ - 1· d^ - 1 and 2.5mg· kg^ - 1· d^ - 1（ n = 10 in each group ）. All rats, except for the normal controls, were injected with axenic porcine serum （0. 5ml each time, twice a week） intraperitoneally for 8 weeks to establish hepatic fibrosis. After the 8th week, rats of Tet-treated model groups were given by gavage once a day with different doses of Tet for another 8 weeks. Then the liver function, serum levels of hyaluronic acid （ HA ）, laminin （ LM）, and procollagen type Ⅲ （PCⅢ） were tested. Collagen type 1 and Ⅲ, pathological changes in liver tissue were also assessed. Results Most indices of liver function including alanine minotransferase （ALT）, aspartate aminotransferase （AST）, albumin （ ALB）, albumin/globulin ratio （ A/G） and alkaline phosphatase （ALP） improved significantly in Tet-treated groups with the exception of γ-glutamyl transpeptidase （γ- GT） and total bilirubin （TBIL）. Secondly, markedly lowered levels of HA, LM and collagen type I, III were also detected by radioimmunology and immunohistochemistry in the 5 mg· kg^ - 1· d^ - 1 Tet-treated model group. Moreover, pathologi- cal findings confirmed the statistically significant improvement in hepatofibrotic degree resulted from the treatment of 5mg· kg^ - 1· d^ - 1 rather than other doses of Tet. Conclusion For experimental Wistar rats, Tet exhibited an anti-hepatofibrotic action in doses within the range of 2.5mg· kg^ - 1· d^ - 1 to 10mg· kg^ - 1· d^ - 1 and 5mg· kg^ - 1· d^ - 1 may be the optimum one among all doses.

铁死亡诱导剂RAS合成致死分子3抑制病理性瘢痕成纤维细胞的纤维化

背景:病理性瘢痕主要表现为异常的细胞外基质积累和过度的成纤维细胞增殖,成纤维细胞过度增殖就会产生大量以胶原纤维为主的细胞外基质。因此深入探讨成纤维细胞纤维化在病理性瘢痕形成中的作用,将为揭示病理性瘢痕的机制和生物学治疗提供新思路。目的:探讨铁死亡诱导剂RAS合成致死分子3(RAS-selective lethal small molecule 3,RSL3)对人病理性瘢痕成纤维细胞纤维化的影响。方法:收集10例宁夏医科大学总医院烧伤整形美容科提供的病理性瘢痕组织和同一个体正常皮肤组织,提取人病理性瘢痕成纤维细胞和人正常皮肤成纤维细胞用于后续实验;苏木精-伊红染色观察病理性瘢痕组织和正常皮肤组织的形态;倒置显微镜观察病理性瘢痕成纤维细胞和正常皮肤成纤维细胞的外观形态;免疫荧光实验验证所提取的细胞是否为成纤维细胞;用不同浓度的RSL3(1,3,5,7,9,11,13μmol/L)干预细胞,CCK-8法检测RSL3作用于成纤维细胞的半数抑制浓度(IC_(50));设置对照组(不做处理)和RSL3干预组(用7μmol/L的RSL3干预细胞24 h),qRT-PCR和Western blot检测谷胱甘肽过氧化物酶4、Ⅰ型胶原蛋白、Ⅲ型胶原蛋白和α-平滑肌肌动蛋白的mRNA和蛋白的表达;检测细胞丙二醛浓度;划痕试验检测细胞划痕后24 h剩余划痕面积,并计算剩余划痕面积百分比。结果与结论:①与正常皮肤组相比,病理性瘢痕组的谷胱甘肽过氧化物酶4高表达(mRNA:t=3.252,P<0.01;蛋白:t=5.075,P<0.01);②与正常皮肤成纤维细胞组相比,病理性瘢痕成纤维细胞组的谷胱甘肽过氧化物酶4高表达(mRNA:t=10.32,P<0.01;蛋白:t=26.22,P<0.01);③与对照组相比,RSL3干预组谷胱甘肽过氧化物酶4表达减少(mRNA:t=2.798,P<0.05;蛋白:t=4.643,P<0.01),丙二醛浓度上升(t=2.917,P<0.05),Ⅰ型胶原蛋白(mRNA:t=15.84,P<0.01;蛋白:t=4.610,P<0.01)、Ⅲ型胶原蛋白(mRNA:t=28.86,P<0.01;蛋白:t=7.713,P<0.01)和α-平滑肌肌动蛋白(mRNA:t=2.671,P<0.05;蛋白:t=7.417,P<0.01)的表达减少,迁移能力减弱(t=14.06,P<0.01);④提示RSL3通过抑制谷胱甘肽过氧化物酶4的表达,进而抑制病理性瘢痕成纤维细胞的纤维化和迁移能力。

非酒精性脂肪性肝炎病理改变对肝脏剪切波速度的影响

目的探讨影响非酒精性脂肪性肝炎(NASH)患者肝脏剪切波速度(SWV)的病理因素。方法选择上海中医药大学附属曙光医院肝病科经肝组织穿刺活检诊断的NASH患者43例,其中男性28例,女性15例;年龄38~64岁,平均年龄48.61岁;轻度脂肪肝14例(S1组),中度脂肪肝23例(S2组),重度脂肪肝6例(S3组)。所有患者超声引导下穿刺活检前,均进行肝脏常规超声检查及声触诊组织定量分析(VTQ)。根据病理结果回顾性分析纤维化、脂肪浸润程度及炎症对NASH患者肝脏SWV的影响。结果经肝组织穿刺活检诊断的NASH患者43例,其中早期NASH 26例,纤维化性NASH 13例,肝硬化4例,不同时期的NASH肝脏SWV差异有统计学意义[早期NASH组与纤维化NASH组(1.15±0.10)m/s vs(1.25±0.10)m/s。P<0.01。早期NASH组与NASH肝硬化组(1.15±0.10)m/s vs(1.44±0.21)m/s。P<0.01。纤维化性NASH组与NASH肝硬化组(1.25±0.10)m/s vs(1.44±0.21)m/s。P=0.00]。比较各组脂肪含量不同肝脏SWV,S3组与S1组、S2组SWV的差异有统计学意义[(1.34±0.06)m/s vs(1.13±0.08)m/s,(1.34±0.06)m/s vs(1.21±0.16)m/s。P均<0.05]。根据炎症程度分为小叶炎症16例(G1组)、小叶炎症合并门静脉炎症20例(G2组)和小叶炎症合并小叶间炎症(或桥接坏死)7例(G3组),不同炎症程度NASH肝脏SWV之间差异有统计学意义[G3 vs G1(1.43±0.12)m/s vs(1.15±0.09)m/s;G3 vs G2(1.43±0.12)m/s vs(1.17±0.09)m/s。P均<0.01]。结论肝脏纤维化是影响NASH患者肝脏SWV值的重要因素,其次是脂肪肝的程度,炎症对NASH患者肝脏SWV值的影响最小。以上结果可为今后临床无创性评估NASH程度提供客观依据。

黄连素与心肌纤维化相关性研究进展

近年来,心血管疾病(cardiovascular disease,CVD)的发生率正逐年上升。心肌纤维化是一种以成纤维细胞异常增殖、胶原过渡沉积及异常分布为特征的病理变化。在病理条件下(如高血压病、心肌病、冠心病),心肌功能受损,心肌细胞或细胞外部分基质、胶原纤维结缔组织均会发生一系列变化,该过程称为心肌重构,而心肌纤维化是心肌重构的基本病理过程,黄连素可改善心肌纤维化,现对心肌纤维化的致病机制及黄连素与心肌纤维化的研究进展进行系统综述。

ALT轻度异常的慢性乙型肝炎患者肝组织病理特征及血清学无创诊断模型的价值分析

目的:分析丙氨酸氨基转移酶(ALT)<2倍正常值上限(ULN)慢性乙型肝炎(CHB)患者的肝脏病理特征,并评估不同血清学诊断模型对肝纤维化的诊断价值。方法:回顾性分析2019年10月至2023年5月于江苏省淮安市第四人民医院就诊的ALT<2ULN,且进行肝穿刺检查的CHB患者62例。收集患者临床资料,根据肝穿结果将S2以下者定为无明显纤维化组(35例),S2及以上者定为明显纤维化组(27例)。对两组患者的临床指标进行分析,采用受试者操作特征曲线(ROC)分析国际标准化比值/血小板比值(INPR)、天门冬氨酸氨基转移酶和血小板比率指数(APRI)、肝纤维化4因子指数(FIB-4)、γ-谷氨酰转肽酶和血小板比值(GPR)、S指数对肝脏病理纤维化的诊断效能。采用Spersman检验分析不同的无创诊断模型与肝组织纤维化之间的关系。结果:62例ALT<2ULN且行肝穿刺的CHB患者中纤维化程度分期为S0期16例(25.8%),S1期19例(30.6%),S2期19例(30.6%),S3期8例(12.9%)。分析62例患者的相关临床指标分层与肝脏纤维化的关系,仅HBsAg水平(以3.0×10^(3)IU/ml为界限分层)差异有统计学意义(χ^(2)=4.07,P=0.044);两组患者的凝血酶原时间(PT),血小板计数(PLT)差异均有统计学意义(P<0.05)。FIB-4(r=0.432,P<0.001)、INPR(r=0.426,P=0.001)、APRI(r=0.388,P=0.02)、S指数(r=0.373,P=0.003)、GPR(r=0.307,P=0.015)均与肝组织纤维化程度正相关。INPR诊断肝脏纤维化(S2以上)的曲线下面积最高,为0.739,灵敏度也最高,为66.7%,而FIB-4特异度最高,为94.3%。结论:ALT<2 ULN的CHB患者发生肝纤维化的比例较高,其中HBsAg<3.0×10^(3)IU/ml,PT延长,PLT降低是其危险因素。5种无创诊断模型对肝纤维化的发生具有一定的预测价值,临床实践中可动态监测这几种模型的变化,为临床初步筛查提供依据。

m6A甲基化修饰非编码RNA调控病理性心脏重塑的作用

背景:m6A甲基化修饰非编码RNA是病理性心脏重塑形成机制的研究热点,在心血管疾病的发生发展中起着重要作用。目的:总结m6A甲基化修饰非编码RNA对调控病理性心肌肥大、心肌细胞死亡、心肌纤维化与血管重塑等病理性心脏重塑主要过程的可能作用机制。方法:以“m6A甲基化修饰,非编码RNA,病理性心肌肥大,心肌细胞凋亡,心肌细胞焦亡,心肌细胞铁死亡,心肌纤维化,血管重塑”为中文主题词,以“m6A、non-coding RNA,pathological cardiac hypertrophy,cardiomyocyte apoptosis,cardiomyocyte pyroptosis,cardiomyocyte ferroptosis,myocardial fibrosis,vascular remodeling”为英文主题词,检索中国知网、PubMed、Web of Science数据库1974年1月至2023年4月发表的相关文献,对符合筛选标准的86篇文献进行综述。结果与结论:①m6A甲基化修饰是一种动态可逆的表观遗传修饰方式;②病理性心脏重塑主要包括病理性心肌肥大、心肌细胞死亡、心肌纤维化、血管重塑,m6A相关酶可调控病理性心脏重塑相关进程;③m6A甲基化修饰相关酶可通过多种非编码RNA与不同信号通路参与调控病理性心脏重塑过程,可作为心血管疾病新的潜在干预方式;④在病理性心脏重塑中,m6A甲基化修饰与非编码RNA之间的调控关系仍处于起步阶段,随着表观遗传学的发展,m6A甲基化修饰非编码RNA来调控病理性心脏重塑有望有新的发展。

133例口腔黏膜下纤维性变癌变的病理及临床生物学行为研究

目的分析嚼食槟榔鲜果习惯的口腔黏膜下纤维性变(OSF)癌变的临床特点、病理及临床生物学行为。方法回顾性分析经手术治疗的247例口腔鳞状细胞癌(OSCC)患者,其中嚼食槟榔鲜果习惯的OSF癌变组133例,非OSF癌变组114例,收集患者临床资料和病理结果,对患者的年龄、性别、病变部位、临床分期、病理分级、淋巴结转移率、肿瘤复发率及5年生存率进行分析;使用SPSS 26.0统计软件进行数据分析,P<0.05记为差异有统计学意义。结果OSF癌变组的平均年龄(50.68±11.54)岁低于非OSF癌变组(57.90±12.85)岁,OSF癌变组的男女比例高于非OSF癌变组(6.82∶1 vs 2.16∶1),差异具有统计学意义(P<0.05)。OSF癌变组和非OSF癌变组的OSCC病理分化结果差异具有统计学意义(P<0.05),经比较,OSF癌变组的肿瘤分化较好,非OSF癌变患者肿瘤分化较差。OSF癌变组复发率(19.1%)低于非OSF癌变组(31.5%),OSF癌变组5年生存率(85.5%)高于非OSF癌变组(74.8%),差异具有统计学意义(P<0.05)。是否OSF癌变对OSCC淋巴结转移及临床分期的差异无统计学意义(P>0.05)。结论具有嚼食槟榔鲜果习惯的OSF癌变患者以男性为主,肿瘤好发于舌及唇颊部,病理分化程度较高,预后较好。

瞬时弹性成像技术对乙肝及自身免疫性肝病诊断效能对比分析

目的 探讨瞬时弹性成像技术(fibrotouch,FT)对乙型肝炎及自身免疫性肝病诊断效能对比价值。方法 选取我院收治的乙型肝炎患者59例(A组)、原发性胆汁性胆管炎患者31例(B组),两组均接受肝组织穿刺病理检查,获取患者病理纤维化程度分期;分别对两组进行FT检查,获得两组患者的肝硬度值(LSM),尝试分析患者LSM与病理纤维化分期的关联及差异。结果 两组患者的肝细胞炎症程度、肝组织纤维化变化基本趋于一致,Pearson分析结果显示,炎症、纤维化程度呈正相关(P<0.05);两组无纤维化、轻中度、重度纤维化患者的肝硬度值呈上升趋势,病理分期越严重,LSM越大,且不同病理分期LSM差异有统计学意义(t=234.599,321.819;均P<0.001);两组患者LSM:A组无纤维化、中轻度及重度纤维化患者LSM均低于B组,其中S0分期差异无统计学意义(t=1.780;P=0.079);S1~S2、S3~S4分期差异具有统计学意义(t=8.352,6.392;P<0.001)。结论 FT为无创、定量评估肝病患者肝脏纤维化程度的有效方式,为临床诊治提供科学依据;肝纤维化程度越高则FT检查提示LSM越高;同一病理分期下,乙型肝炎、原发性胆汁性胆管炎患者LSM存在差异;后续可尝试构建不同类型肝炎患者FT检查肝脏损伤程度参考标准。

病理性瘢痕形成的细胞分子机制的研究进展

皮肤损伤在愈合后会形成纤维化组织,即瘢痕。其中的病理性瘢痕因其外观不佳及痛痒不适感,严重影响患者的生活质量。然而,目前病理性瘢痕的发病机制尚不完全明确,缺乏有效的动物模型及临床根治手段。本文回顾总结了病理性瘢痕免疫微环境中的细胞分子学机制与相互作用,旨在为病理性瘢痕诊断标志物与治疗靶点的研发以及组织工程构建的优化提供参考。

超声E成像无创定量评价慢性肝病肝纤维化临床研究

目的应用超声E成像(即剪切波弹性成像,SWE)技术对慢性肝病患者进行检测和分析,探讨该技术在无创定量评价慢性肝病肝纤维化程度中临床应用价值。方法选择2019年8月至2021年7月在南京中医药大学附属医院就诊的慢性肝病患者148例,其中男性56例,女性92例;年龄17~75岁,平均年龄48.9岁;身高1.47~1.87 m,平均身高1.65 m;体质量44~106 kg,平均体质量65.50 kg;身体质量指数(BMI)17.51~35.85 kg/m^(2),平均BMI 24.00 kg/m^(2);疾病类型,病毒性肝炎44例,代谢相关脂肪性肝病36例,自身免疫性肝炎22例,药物性肝炎20例,原发性胆汁性胆管炎26例。对所有患者肝脏均应用SWE技术进行检测并行超声引导下肝脏组织穿刺活检,以病理诊断为金标准,对肝脏SWE弹性测值与肝脏纤维化分期关系进行统计学分析。结果经病理诊断,慢性肝病有肝纤维化患者130例,无纤维化患者18例。两者SWE弹性测值、天冬氨酸氨基转移酶(AST)、丙氨酸氨基转移酶(ALT)、总胆红素(TBiL)、直接胆红素(DBiL)及高密度脂蛋白胆固醇(HDL-C)比较,差异均有统计学意义[(9.34±4.73)kPa vs(6.24±1.46)kPa,(147.89±62.79)U/L vs(73.32±34.78)U/L,(270.56±60.95)U/L vs(105.94±52.97)U/L,(57.12±10.82)μmol/L vs(20.57±5.01)μmol/L,(38.41±7.95)μmol/L vs(9.35±4.88)μmol/L,(1.35±0.36)mmol/L vs(1.39±0.84)mmol/L。t=2.755、1.972、2.615、3.898、3.957、0.359,P<0.05]。对慢性肝病肝纤维化组患者SWE弹性测值与各项指标间进行相关分析显示,SWE弹性测值与年龄(r=0.338)、纤维化分期(r=0.736)、血糖(GLU)(r=0.174)及凝血酶原时间(PT)(r=0.424)呈正相关(P<0.05)。SWE技术对慢性肝病肝纤维化诊断效能分析,受试者工作特性(ROC)曲线分析结果显示,应用SWE技术诊断慢性肝病肝纤维化S0/S1期、S1/S2期、S2/S3期及S3/S4期SWE弹性测值截断值分别为6.35 kPa、7.65 kPa、8.35 kPa、17.30 kPa,其曲线下面积(AUC)分别为0.736[95%可信区间(CI)0.628~0.844]、0.751(95%CI 0.657~0.845)、0.803(95%CI 0.680~0.927)及0.752(95%CI 0.566~0.939)。结论SWE技术作为一种实时超声弹性成像技术,操作简便、无创,患者接受度高,其弹性测值可用来无创定量评价慢性肝病肝纤维化及其分期,具有良好的临床应用前景。

Inhibition of Pathological Angiogenesis of Chinese Medicine against Liver Fibrosis

Pathological angiogenesis of liver which includes liver sinusoidal capillarization due to lose of fenestraes of liver sinusoidal endothelial cells（LSECs） and formation of new vascular, is a crucial mechanism responsible for origination and development of liver fibrosis and closely involves in the development of cirrhosis and hepatic cancer. Anti-neovascularization medicine such as sorafenib can decrease portosystemic shunts, improve splanchnic hyperdynamic circulation, lower portal hypertension, while it can not be applied in clinic due to its serious toxic and side reactions. Chinese herbal formula can effectively inhibit pathological angiogenesis of liver, improve microcirculation of liver, and decrease the probability of gastrointestinal hemorrhage in cirrhotic patients. Different Chinese herbal formula are of different characteristics on inhibiting pathological angiogenesis in liver fibrosis, which partly explains synergistic effect of different compatibility of Chinese materia medica and opens up good vista for Chinese medicine against liver fibrosis through inhibiting angiogenesis.