Micro RNAs in liver fibrosis: Focusing on the interaction with hedgehog signaling

Liver fibrosis is a repair process in response to damage in the liver; however, severe and chronic injury promotes the accumulation of fibrous matrix, destroying the normal functions and architecture of liver. Hepatic stellate cells(HSCs) are quiescent in normal livers, but in damaged livers, they transdifferentiate into myofibroblastic HSCs, which produce extracellular matrix proteins. Hedgehog(Hh) signaling orchestrates tissue reconstruction in damaged livers and contributes to liver fibrogenesis by regulating HSC activation. Micro RNAs(mi RNAs), endogenous small non-coding RNAs interfering with RNA post-transcriptionally, regulate various cellular processes in healthy organisms. The dysregulation of mi RNAs is closely associated with diseases, including liver diseases. Thus, mi RNAs are good targets in the diagnosis and treatment of various diseases, including liver fibrosis; however, the regulatory mechanisms of mi RNAs that interact with Hh signaling in liver fibrosis remain unclear. We review growing evidence showing the association of mi RNAs with Hh signaling. Recent studies suggest that Hh-regulating mi RNAs induce inactivation of HSCs, leading to decreased hepatic fibrosis. Although mi RNAdelivery systems and further knowledge of interacting mi RNAs with Hh signaling need to be improved for the clinical usage of mi RNAs, recent findings indicate that the mi RNAs regulating Hh signaling are promising therapeutic agents for treating liver fibrosis.

CT arterial portography and CT hepatic arteriography in detection of micro liver cancer

AIM To recognize the characteristic findings of micrQliver cancer (MLC) and to evaluate the effect of CT arterial portography (CTAP) and CT hepatic arteriography (CTHA) in diagnosis of MLC. METHODS Between April 1996 to December 1998, CTAP and CTHA were performed in 12patients with MLC, which were not detect ed byconventional CT examinations. After CTHA, 3 mL-- 5 mL mixture of lipiodol, doxorubic in andmitomycin C were injected into hepatic arterythrough the catheter, and then followed up by CTthree or four weeks later (Lipiodol CT LP-CT).RESULTS A total of 22 micro--tumors (0 .2 cm 0.6 cm in diameter ) were detected in 12patients, which manifested as small perfusiondefects in CTAP and small round enhancement inCTHA. The rate of detectability of CTAP andCTHA was 68.2% (15/ 22) and 77.3% (17/ 22)respectively, and the rate of the simultaneoususe of both procedures reached 86. 4% (19/ 22 ).All micro--tumors were demonstrated as punctatelipiodol deposit fool in LP--CT. After LP--CT, theelevated serum level of Q-fetoprotein (AFP)dropped to the normal level in all patients.CONCLUSION The CTAP and CTHA are the mostsensitive imaging methods for detecting microIiver cancer. Confirmed by the change of theelevated serum AFP level and lipiodol depositfool in LP-CT, small perfusion defects in CTAPand punctate enhancement in CTHA may suggestmicro--liver cancer.

Transient micro-elastography:A novel non-invasive approach to measure liver stiffness in mice

AIM:To develop and validate a transient micro-elastography device to measure liver stiffness(LS) in mice.METHODS:A novel transient micro-elastography(TME) device,dedicated to LS measurements in mice with a range of measurement from 1-170 kPa,was developed using an optimized vibration frequency of 300 Hz and a 2 mm piston.The novel probe was validated in a classical fibrosis model(CCl4) and in a transgenic murine model of systemic amyloidosis.RESULTS:TME could be successfully performed in control mice below the xiphoid cartilage,with a mean LS of 4.4 ± 1.3 kPa,a mean success rate of 88%,and an excellent intra-observer agreement(0.98).Treatment with CCl4 over seven weeks drastically increased LS as compared to controls(18.2 ± 3.7 kPa vs 3.6 ± 1.2 kPa).Moreover,fibrosis stage was highly correlated with LS(Spearman coefficient = 0.88,P < 0.01).In the amyloidosis model,much higher LS values were obtained,reaching maximum values of > 150 kPa.LS significantly correlated with the amyloidosis index(0.93,P < 0.0001) and the plasma concentration of mutant hapoA-□(0.62,P < 0.005).CONCLUSION:Here,we have established the first non-invasive approach to measure LS in mice,and have successfully validated it in two murine models of high LS.

Contrast-enhanced micro-computed tomography using Exi Tron nano6000 for assessment of liver injury

AIM: To explore the potential of contrast-enhanced computed tomography(CECT) using Exi Tron nano6000 for assessment of liver lesions in mouse models.METHODS: Three mouse models of liver lesions were used: bile duct ligation(BDL),lipopolysaccharide(LPS)/D-galactosamine(D-Gal N),and alcohol.After injection with the contrast agent Exi Tron nano6000,the mice were scanned with micro-CT.Liver lesions were evaluated using CECT images,hematoxylin and eosin staining,and serum aminotransferase levels.Macrophage distribution in the injury models was shown by immunohistochemical staining of CD68.The in vitro studies measured the densities of RAW264.7 under different conditions by CECT.RESULTS: In the in vitro studies,CECT provided specific and strong contrast enhancement of liver in mice.CECT could present heterogeneous images anddensities of injured livers induced by BDL,LPS/D-Gal N,and alcohol.The liver histology and immunochemistry of CD68 demonstrated that both dilated biliary tracts and necrosis in the injured livers could lead to the heterogeneous distribution of macrophages.The in vitro study showed that the RAW264.7 cell masses had higher densities after LPS activation.CONCLUSION: Micro-CT with the contrast agent Exi Tron nano6000 is feasible for detecting various liver lesions by emphasizing the heterogeneous textures and densities of CECT images.

应用Micro CT观察洛伐他汀和秋水仙碱对CCl_4致肝损伤后小鼠骨代谢的影响

目的本实验应用Micro CT研究洛伐他汀和秋水仙碱对CCl4致肝损伤后小鼠骨代谢的影响,并比较二者的效果。方法体积分数40%的CCl4花生油皮下注射,建立小鼠肝损伤模型,同时,洛伐他汀按2.6 mg·kg-1,秋水仙碱按0.065 mg·kg-1每天1次灌胃给药,连续1个月,于实验结束后观察肝损伤血清学指标以及肝匀浆相关的抗氧化指标,并用Micro CT测定小鼠胫骨骨组织结构参数。结果单用CCl4小鼠肝指数明显增加,AST和ALT活性明显升高,肝匀浆中SOD活性和GSH-Px水平明显降低,MDA水平明显升高,且胫骨上段骨组织结构参数BVF、TMD值明显降低,SMI值明显升高,出现明显的骨质疏松症状。而洛伐他汀、秋水仙碱用药后对肝损伤没有明显影响,但洛伐他汀对肝损伤导致的骨丢失有明显的保护作用,秋水仙碱组则没有明显的保护作用。结论 CCl4致肝损伤后的小鼠出现骨质疏松症状,洛伐他汀用药后对CCl4致肝损伤的骨丢失有明显的预防作用。

新型造影剂在小鼠肝脏肿瘤Micro-CT活体成像中的应用

目的利用新型纳米颗粒造影剂结合Micro-CT成像技术,建立小鼠肝脏成像方法,并用于肝脏肿瘤的活体成像。方法 6只6-8周龄雄性C57BL/6J小鼠随机分成A组和B组,分别尾静脉注射纳米颗粒造影剂Exi Tron nano 12000 50μL和100μL;在注射前、注射后3 min、24 h、7 d、14 d、28 d和56 d对所有小鼠肝脏进行Micro-CT活体扫描;分别在小鼠肝左叶和肝右叶内选取感兴趣区（ROI）进行灰度值分析,比较不同时间点肝组织对比度的变化。确定合适的造影剂剂量,尾静脉注射至3只雄性16月龄HBV转基因肝癌模型小鼠（C组）,同上进行Micro-CT活体扫描,并于第56天全部安乐死后取肝脏观察病理学改变。结果 A组和B组小鼠在注射不同浓度造影剂后,冠状位重建图像及肝脏感兴趣区的平均灰度值结果显示：肝脏实质造影后均比注射前明显增强,24 h达到峰值,注射后56 d内,小鼠肝脏感兴趣区的平均灰度值与注射前相比仍维持在较高的水平,B组显著高于A组（P〈0.01）,确定后续实验采用B组造影剂剂量（100μL）。C组注射100μL造影剂后,各时间点均能比较清楚地看到肝脏癌性结节存在,病理学观察发现肝脏出现非典型增生,肿瘤细胞核大,染色质加深和肝细胞坏死。结论利用纳米颗粒造影剂结合Micro-CT成像技术,成功建立了小鼠肝脏活体成像方法,并可应用于肝脏肿瘤的活体成像研究。

微RNA对肝癌血管内皮细胞功能影响的研究进展

血管内皮细胞是内衬在血管内壁表面的单细胞层,活化后可增强肝癌细胞的增殖性和侵袭性,通过增殖、迁移等方式形成新的血管,促使肝癌的复发和转移。微RNA(miRNA)对血管内皮细胞功能具有重要的调节作用,其转录后可抑制或促进血管内皮细胞增殖,影响肝癌患者预后。miR-126、miR-155、miR-21、miR-221/222是常见的几种调控血管内皮细胞功能的miRNA,这些不同种类miRNA可通过不同机制对肝癌患者的血管内皮细胞功能产生影响,从而调控肝癌细胞的增殖和转移。因此,阐明不同种类miRNA调控血管内皮细胞功能的具体机制,将对肝癌的诊断、治疗和预后评估具有重要意义。

肝癌中的长链非编码RNA及其微肽

长链非编码RNA(long non-coding RNA,lncRNA)之前被认为不能编码蛋白质,但目前越来越多的研究发现,lncRNA可以通过自身的小开放阅读框编码少于100个氨基酸的微肽(micro-peptide),已有研究报道这些微肽在癌症发生发展中发挥重要作用。为了更好地阐释lncRNA编码微肽在肿瘤进展过程中的功能、机制和潜在的应用,本文主要围绕肝癌中lncRNA及其翻译产生的微肽作一概述。

微小肝癌诊断中彩色多普勒超声+高频超声检测的应用研究

目的研讨彩色多普勒超声结合高频超声检测在微小肝癌诊断中的价值。方法微小肝癌患者40例均选自2022年01月至2023年06月医院收治的患者中,所有患者经病理诊断确诊为微小肝癌,对患者实施彩色多普勒超声、高频超声检测,比较两种检测方法联合使用的效果及影像特征。结果彩色多普勒超声结合高频超声诊断的准确率较两种方法单一诊断准确率高(P<0.05);两种超声联合诊断的特异度、灵敏度、阳性检出率及阴性检出率均高于单一一种方法诊断结果(P<0.05)。两种超声显示,微小肝癌病灶内血液流动丰富,中央血管呈辐射状分布,肝脏形态比较完善,形状为圆或类圆,边缘清楚,声晕范围狭窄;由于肿瘤对周边组织的压力,形成了一种假包膜,其周边的肝脏具有更强的回声。结论微小肝癌疾病采用彩色多普勒超声结合高频超声检测具有较高的价值,其诊断准确率明显升高,可尽早确定患者病情,并予以对症治疗,可为临床医生诊断疾病提供可靠数据。

Micro-26a对沙格列汀治疗糖尿病伴非酒精性脂肪肝疗效的影响

目的:探究循环miRNA-26a水平对沙格列汀治疗糖尿病伴非酒精性脂肪肝(NAFLD)疗效的影响。方法:113例2型糖尿病伴NAFLD患者,采用沙格列汀治疗6个月;以患者治疗1 d时的血清miR-26a相对表达中位数为临界值,将患者分为miR-26a高表达组(n=49)及miR-26a低表达组(n=64);比较两组患者治疗前及治疗6个月时的空腹血糖(FPG)、餐后2 h血糖(2hPPG)、糖化血红蛋白(Hb A1c)、谷丙转氨酶(ALT)、谷草转氨酶(AST)、γ-谷氨酰转肽酶(GGT)、总胆固醇(TC)及甘油三酯(TG)水平;比较沙格列汀对两组患者NAFLD的治疗效果。结果:治疗前两组患者血清FPG、2hPPG、HBA1c、ALT、AST、GGT、TC及TG水平比较,差异无统计学意义(P> 0. 05);治疗后两组患者血清FPG、2hPPG、HBA1c、ALT、AST、GGT、TC及TG水平均较治疗前显著降低(P <0. 05),但治疗后两组患者血清FPG、2hPPG、HBA1c、ALT、AST、GGT、TC及TG水平比较,差异无统计学意义(P> 0. 05); 113例患者治疗NAFLD的总有效率为73. 5%,miR-26a高表达组治疗NAFLD的总有效率显著高于miR-26a低表达组,差异有统计学意义(P <0. 05)。结论:高miR-26a表达的糖尿病伴NAFLD患者对沙格列汀治疗的敏感性更高。

血浆中micro RNA-122表达量与肝癌手术前后肝损伤的相关性

目的研究血浆中micro RNA-122（miR-122）的表达量与肝癌手术前后肝损伤的相关性。方法利用荧光定量检测30名健康人与30例肝癌患者的术前miR-122及丙氨酸氨基转移酶（ALT）的表达量,并进行比较,且检测30例肝癌患者的术前,术后第1、3、7天的血浆中miR-122及ALT,探讨miR-122与ALT的相关性。结果术前肝癌患者血浆中miR-122以及ALT的表达量均显著高于健康人群（P〈0.05）。患者术前,术后第1、3、7天血浆中的miR-122均与ALT呈正相关。结论血浆miR-122与肝切除术肝功能损伤相关,有望成为肝癌肝切除术前后肝功能损伤的检测指标。

Molecular pathways of liver regeneration:A comprehensive review

The liver is a unique parenchymal organ with a regenerative capacity allowing it to restore up to 70%of its volume.Although knowledge of this phenomenon dates back to Greek mythology(the story of Prometheus),many aspects of liver regeneration are still not understood.A variety of different factors,including inflammatory cytokines,growth factors,and bile acids,promote liver regeneration and control the final size of the organ during typical regeneration,which is performed by mature hepatocytes,and during alternative regeneration,which is performed by recently identified resident stem cells called“hepatic progenitor cells”.Hepatic progenitor cells drive liver regeneration when hepatocytes are unable to restore the liver mass,such as in cases of chronic injury or excessive acute injury.In liver maintenance,the body mass ratio is essential for homeostasis because the liver has numerous functions;therefore,a greater understanding of this process will lead to better control of liver injuries,improved transplantation of small grafts and the discovery of new methods for the treatment of liver diseases.The current review sheds light on the key molecular pathways and cells involved in typical and progenitor-dependent liver mass regeneration after various acute or chronic injuries.Subsequent studies and a better understanding of liver regeneration will lead to the development of new therapeutic methods for liver diseases.

基于Micro-CT成像对肝癌原位移植瘤血管三维结构的定量研究

目的基于Micro-CT成像定量肝癌裸鼠原位移植瘤血管的三维结构特征。方法采用雄性Balb/c裸小鼠20只,随机分为肝癌组(n=10)和正常对照组(n=10),肝癌组采用MHCC97H人肝癌细胞株构建原位移植瘤模型,正常对照组肝内注射同等量0.9%氯化钠溶液。造模21 d后进行目标血管铸型和Micro-CT扫描,重建血管图像,观察肝癌和正常肝脏血管的三维形态并定量分析血管密度特征、血管形态特征上的差异。结果正常肝脏血管呈树枝状逐级分支,走行自然;肝癌血管分布杂乱,形态不规则。定量分析结果显示,相比于正常肝脏,肝癌的血管占比[(5.57±1.16)%比(14.29±2.89)%,P<0.01]、血管分支密度[(3.86±1.15)比(7.25±3.30),P=0.007]明显降低,平均半径缩小[(0.17±0.03)mm比(0.22±0.04)mm,P=0.004],平均DF[(1.20±0.01)比(1.16±0.00),P<0.01]、平均SOAM[(4.56±0.10)rad/mm比(4.33±0.20)rad/mm,P=0.004]增加,平均血管分支长度略缩短但差异无统计学意义(P>0.05)。结论基于Micro-CT的成像展示了肝癌原位移植瘤血管的三维结构,通过量化肝癌和健康肝脏的血管特征差异,可以进一步明确抑制肿瘤血液供应的潜在途径。

mi R-122 negatively correlates with liver fibrosis as detected by histology and FibroScan

AIM: To investigate whether expression of selected mi RNAs obtained from fibrotic liver biopsies correlate with fibrosis stage.METHODS: Altogether, 52 patients were enrolled in the study representing various etiologic backgrounds of fibrosis: 24 cases with chronic hepatitis infections(types B, C), 19 with autoimmune liver diseases(autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, overlapping syndrome cases), and 9 of mixed etiology(alcoholic and nonalcoholic steatosis, cryptogenic cases). Severity of fibrosis was determined by both histologic staging using the METAVIR scoring system and noninvasive transient elastography. Following RNAisolation, expression levels of mi R-21, mi R-122, mi R-214, mi R-221, mi R-222, and mi R-224 were determined using Taq Man Micro RNA Assays applying mi R-140 as the reference. Selection of mi RNAs was based on their characteristic up- or downregulation observed in hepatocellular carcinoma. Relative expression of mi RNAs was correlated with fibrosis stage and liver stiffness(LS) value measured by transient elastography, as well as with serum alanine aminotransferase(ALT) level.RESULTS: The expression of individual mi RNAs showed deregulated patterns in stages F1-F4 as compared with stage F0, but only the reduced level of mi R-122 in stage F4 was statistically significant(P < 0.04). When analyzing mi RNA expression in relation to fibrosis, levels of mi R-122 and mi R-221 showed negative correlations with fibrosis stage, and mi R-122 was found to correlate negatively and mi R-224 positively with LS values(all P < 0.05). ALT levels displayed a positive correlation with mi R-21(P < 0.04). Negative correlations were observed in the fibrosis samples of mixed etiology between mi R-122 and fibrosis stage and LS values(P < 0.05), and in the samples of chronic viral hepatitis, between mi R-221 and fibrosis stage(P < 0.01), whereas mi R-21 showed positive correlation with ALT values in the samples of autoimmune liver diseases(P < 0.03). The results also revealed a strong correlation between fibrosis stage and LS values(P < 0.01) when etiology of fibrosis was not taken into account.CONCLUSION: Reduced expression of mi R-122 in advanced fibrosis and its correlation with fibrosis stage and LS values seem to be characteristic of hepatic fibrosis of various etiologies.

Diffusion-weighted magnetic resonance imaging and micro-RNA in the diagnosis of hepatic fibrosis in chronic hepatitis C virus

BACKGROUND Diffusion-weighted magnetic resonance imaging has shown promise in the detection and quantification of hepatic fibrosis. In addition, the liver has numerous endogenous micro-RNAs(miRs) that play important roles in the regulation of biological processes such as cell proliferation and hepatic fibrosis.AIM To assess diffusion-weighted magnetic resonance imaging and miRs in diagnosing and staging hepatic fibrosis in patients with chronic hepatitis C.METHODS This prospective study included 208 patients and 82 age-and sex-matched controls who underwent diffusion-weighted magnetic resonance imaging of the abdomen, miR profiling, and liver biopsy. Pathological scoring was classified according to the METAVIR scoring system. The apparent diffusion coefficient (ADC) and miR were calculated and correlated with pathological scoring.RESULTS The ADC value decreased significantly with the progression of fibrosis, from controls(F0) to patients with early fibrosis(F1 and F2) to those with late fibrosis(F3 and F4)(median 1.92, 1.53, and 1.25 × 10^(-3) mm^2/s, respectively)(P = 0.001).The cut-off ADC value used to differentiate patients from controls was 1.83 × 10^(-3) mm^2/s with an area under the curve(AUC) of 0.992. Combining ADC and miR-200 b revealed the highest AUC(0.995) for differentiating patients from controls with an accuracy of 96.9%. The cut-off ADC used to differentiate early fibrosis from late fibrosis was 1.54 × 10^(-3) mm^2/s with an AUC of 0.866. The combination of ADC and miR-200 b revealed the best AUC(0.925) for differentiating early fibrosis from late fibrosis with an accuracy of 80.2%. The ADC correlated with miR-200 b(r =-0.61, P = 0.001), miR-21(r =-0.62, P = 0.001), and miR-29(r = 0.52,P = 0.001).CONCLUSION Combining ADC and miRs offers an alternative surrogate non-invasive diagnostic tool for diagnosing and staging hepatic fibrosis in patients with chronic hepatitis C.

Porcine acute liver failure model established by two-phase surgery and treated with hollow fiber bioartificial liver support system

AIM: To establish a highly reproducible animal model of acute liver failure (ALF), for assessing theeffect of bioartificial liver support system (BALSS).METHODS: A two-phase complete liver devascularization procedure was performed in eight loco-hybrid pigs. Blood biochemical index and liver biopsy were studied every 2 h after surgery, and survival time was recorded. The BALSS constructed with high volume recirculating technique was a hollow fiber circulating system consisting of a hepatocyte reactor-hollow fiber module inoculated with microcarrieradhering hepatocytes, and a double pump, heparinized,thermostabilized, micro-capsulized activated carbonadsorbing plasmapheresis system. Twelve pigs undergoing two-phase surgery were randomized into: control group (perfused without hepatocytes, n = 6) and treatment group (perfused with hepatocytes, n = 6). Intergroup liver biochemical indexes, survival time, and liver pathological changes were analyzed at regular intervals.RESULTS: Two-phase surgery was performed in all the experimental pigs, and there was no obvious difference between their biochemical indexes. After 3 h of phase Ⅱ surgery, ammonia (Amm) increased to (269±37) μmol/L.After 5 h of the surgery, fibrinogen (Fib) decreased to (1.5±0.2) g/L. After 7 h of the surgery, ALT, AST, Tbil and PT were (7.6±1.8) nka/L, (40±5) nka/L, (55±8) μmol/L and (17.5±1.7) nka/L respectively. After 9 h of surgery, ALB and Cr were (27±4) g/L and (87±9) μmol/L. After 13 h of surgery, BUN was (3.5±0.9) μmol/L. All the above values were different from those determined before surgery.Survival time of pigs averaged 13.5±1.4 h. ALF pigs in the other group were treated with BALSS. The comparison analysis between the treated and control animals showed the changes of Tbil, PT, Alb, BUN, Cr, Fib, and Amm (P＜0.01), but there was no change of ALT and AST. The survival time was statistically different (P＜0.01), and there was no significant difference in histological changes.CONCLUSION: The porcine ALF model established bytwo-phase devascularized surgery is valid and reproducible.The hollow fiber BALSS can meet the needs of life support and is effective in treating ALF.

MicroRNA signature in patients with hepatocellular carcinoma associated with type 2 diabetes

BACKGROUND Nonalcoholic steatohepatitis-related cirrhosis is one of the liver complications in type 2 diabetes mellitus(T2DM)and reported to be a risk factor for developing hepatocellular carcinoma(HCC).A reliable screening biomarker of liver cirrhosis(LC)and HCC among T2DM patients is important to reduce the morbidity and mortality of this disease.MicroRNA(miRNA)is considered a key player in HCC and T2DM,and it might be a hidden culprit in diabetes-associated HCC,making it a promising reliable prognostic tool.AIM To investigate the signature of serum miRNAs as early biomarkers for the screening of HCC among diabetic patients.METHODS Expression profiles of miRNAs in serum samples of diabetic LC and diabetic HCC patients were assessed using Illumina sequencing;then,RT-qPCR was used to validate significantly altered miRNAs between the two groups.Candidate miRNAs were tested in serum samples of 200 T2DM patients,270 LC patients,200 HCC patients,and 225 healthy control subjects.Additionally,receiver operating characteristic(ROC)analysis,with area under the curve(AUC),was performed to assess the diagnostic performance of the screened miRNAs for discriminating HCC from LC and nonmalignant patients(LC+T2DM).RESULTS Expression of the sequenced miRNAs in serum was different in HCC vs LCpositive T2DM patients.Two miRNAs(miR-34a,miR-221)were significantly upregulated and five miRNAs(miR-16,miR-23-3p,miR-122-5p,miR-198,miR-199a-3p)were significantly down-regulated in HCC compared to LC patients.Analysis of ROC curve demonstrated that the combination of these seven miRNAs can be used as a reliable biomarker for detection of HCC in diabetic patients,as it could identify HCC with high diagnostic accuracy in diabetic LC patients(AUC=0.993)and in diabetic nonmalignant patients(AUC=0.961).CONCLUSION This study validates a panel of serum miRNAs that can be used as a reliable noninvasive screening biomarker of HCC among T2DM cirrhotic and noncirrhotic patients.The study recommends further research to shed light on a possible role of c-Met in T2DM-associated HCC via the miRNA regulatory pathway.

Non-Invasive Vibration-Stress of the Cirrhotic Liver of Patients Waiting for Transplantation Induces of Circulating CD133+ Stem Lymphocytes Committed Phenotypically toward the Liver

Background: Numerous studies of tissues’ regeneration have confessed the recovery of damaged liver by hematopoietic stem cells. The cells act not only by cell replacement in the target organ but also by delivering trophic factors that support endogenous liver regeneration. A little is known of how organ-derived signals recruit such committed cells into circulation. Objective: We investigated the roles of noninvasive mechanical percutaneous stress of cirrhotic human liver in numbers fluctuation of trophic, liver-specific alpha-fetoprotein-positive fraction of CD133-positive hematopoietic stem cells in lymphocytes of patients waiting for liver transplantation. Methods: To promote in blood the number of the alpha-fetoprotein-positive fraction of CD133-positive hematopoietic stem cells, committed to liver’ tissue, we activated mechanically the cirrhotic liver of patient by transcutaneous micro vibration received from skin-contacted electro-magnetic vibraphones generated mechanical pulses with amplitude 10 μm and smoothly changing frequency from 0.03 kHz to 18 kHz and back forth during one cycle duration 1 minute. The number of the alpha-fetoprotein-positive fraction of CD133-positive hematopoietic stem cells in lymphocytes of potential recipients was controlled by flow cytometry before and during daily sonication of skin area, which corresponds to liver projection on it. The 15 minutes cyclic sonication of the liver area performed daily for three weeks. Results: The sonication increased significantly averaged number of liver-specific alpha-fetoprotein-positive CD133-positive blood lymphocytes in 2 - 3 times compared to a base lane. The second similar sonication, the same zone after three weeks break showed differences with baseline, but it was statistically insignificant. The result was specifically related to the liver as it showed the control sonication of the backbone’s projection on the skin of a separate group of patients with cirrhotic liver from the waiting list. Conclusion: The stem cells committed to the liver recruit from the bone marrow into circulation, when organ mechanically stresses and secretes specific humoral signals to provoke of lymphopoiesis on host liver repair.

Small RNA- and DNA-based gene therapy for the treatment of liver cirrhosis, where we are?

Chronic liver diseases with different aetiologies rely on the chronic activation of liver injuries which result in a fibrogenesis progression to the end stage of cirrhosis and liver failure.Based on the underlying cellular and molecular mechanisms of a liver fibrosis,there has been proposed several kinds of approaches for the treatment of liver fibrosis.Recently,liver gene therapy has been developed as an alternative way to liver transplantation,which is the only effective therapy for chronic liver diseases.The activation of hepatic stellate cells,a subsequent release of inflammatory cytokines and an accumulation of extracellular matrix during the liver fibrogenesis are the major obstacles to the treatment of liver fibrosis.Several targeted strategies have been developed,such as antisense oligodeoxynucleotides,RNA interference and decoy oligodeoxynucleotides to overcome this barriers.With this report an overview will be provided of targeted strategies for the treatment of liver cirrhosis,and particularly,of the targeted gene therapy using short RNA and DNA segments.

Computer-aided diagnosis for contrast-enhanced ultrasound in the liver

Computer-aided diagnosis(CAD) has become one of the major research subjects in medical imaging and diagnostic radiology.The basic concept of CAD is to provide computer output as a second opinion to assist radiologists' image interpretations by improving the accuracy and consistency of radiologic diagnosis and also by reducing the image-reading time.To date,research on CAD in ultrasound(US)-based diagnosis has been carried out mostly for breast lesions and has been limited in the fields of gastroenterology and hepatology,with most studies being conducted using B-mode US images.Two CAD schemes with contrast-enhanced US(CEUS) that are used in classifying focal liver lesions(FLLs) as liver metastasis,hemangioma,or three histologically differentiated types of hepatocellular carcinoma(HCC) are introduced in this article:one is based on physicians' subjective pattern classifications(subjective analysis) and the other is a computerized scheme for classification of FLLs(quantitative analysis).Classification accuracies for FLLs for each CAD scheme were 84.8% and 88.5% for metastasis,93.3% and 93.8% for hemangioma,and 98.6% and 86.9% for all HCCs,respectively.In addition,the classification accuracies for histologic differentiation of HCCs were 65.2% and 79.2% for well-differentiated HCCs,41.7% and 50.0% for moderately differentiated HCCs,and 80.0% and 77.8% for poorly differentiated HCCs,respectively.There are a number of issues concerning the clinical application of CAD for CEUS,however,it is likely that CAD for CEUS of the liver will make great progress in the future.