[Cirrhotic portal hypertension reversal mechanism and its therapy].

Portal hypertension is one of the most serious complications in patients with liver cirrhosis, and its prevention and treatment are essential to improve patient outcomes. The main pathophysiological basis of cirrhotic portal hypertension is increased intrahepatic vascular resistance and/or increased portal blood flow. In recent years, studies have suggested that liver sinusoid endothelial cells dysfunction, hepatic microvascular thrombosis, pathological angiogenesis, and gut-liver axis imbalance play critical roles in the development of portal hypertension. With respect to this, targeted therapy drugs have made significant advances. This article discusses the cirrhotic portal hypertension reversal mechanism and the current status of its treatment.

[Advances of TRIM superfamily proteins in chronic liver disease and hepatocellular carcinoma].

The modification of proteins with ubiquitination is closely related to the occurrence and development of chronic liver disease and hepatocellular carcinoma. The tripartite motif (TRIM) family of proteins is one of the E3 ubiquitin ligase subfamily, which participates in various biological processes such as intracellular signal transduction, apoptosis, autophagy, and immunity by regulating the ubiquitination of target proteins. A growing body of research shows that the TRIM family of proteins plays an important role in chronic liver disease. This article systematically reviews the role and molecular mechanism of TRIM protein in the process of chronic liver disease, with the aim of exploring its potential application in the clinical diagnosis and treatment.

Comparison of efficacy between uncovered and covered self-expanding metallic stents in malignant large bowel obstruction: a systematic review and meta-analysis.

AIM: Insertion of a self-expandable metallic stent (SEMS) can rapidly relieve colorectal obstruction. This study aimed to compare the efficacy between uncovered and covered SEMSs in the treatment of malignant colorectal obstruction. METHOD: A systematic search in Medline, Embase, the Cochrane controlled trials register and bibliographies of retrieved articles was performed. Randomized controlled trials and other comparative studies comparing uncovered and covered SEMSs for treatment of malignant colorectal obstruction were selected for this systematic review and meta-analysis. The main outcome measures were technical success, clinical success, tumour ingrowth, tumour overgrowth, early migration (≤ 7 days), late migration (> 7 days), overall complications and the duration of stent patency. RESULTS: Compared with covered SEMSs, uncovered SEMSs were associated with a lower late migration rate (relative risk 0.25; 95% CI 0.08, 0.80; P = 0.02), a higher tumour ingrowth rate (relative risk 5.99; 95% CI 2.23, 16.10; P = 0.0004) and a prolonged stent patency (weighted mean difference 15.34 days; 95% CI 4.31, 26.37; P = 0.006). There was no significant difference in technical success, clinical success, tumour overgrowth, early migration, perforation or overall complications between the two groups. CONCLUSION: Tumour ingrowth occurred more frequently in the uncovered SEMS group, while late migration was more common in the covered SEMS group.

Performance-based parameter tuning method of model-driven PID control systems.

In this paper, performance-based parameter tuning method of model-driven Two-Degree-of-Freedom PID (MD TDOF PID) control system has been proposed to enhance the control performances of a process. Known for its ability of stabilizing the unstable processes, fast tracking to the change of set points and rejecting disturbance, the MD TDOF PID has gained research interest recently. The tuning methods for the reported MD TDOF PID are based on internal model control (IMC) method instead of optimizing the performance indices. In this paper, an Integral of Time Absolute Error (ITAE) zero-position-error optimal tuning and noise effect minimizing method is proposed for tuning two parameters in MD TDOF PID control system to achieve the desired regulating and disturbance rejection performance. The comparison with Two-Degree-of-Freedom control scheme by modified smith predictor (TDOF CS MSP) and the designed MD TDOF PID tuned by the IMC tuning method demonstrates the effectiveness of the proposed tuning method.

Hepatocyte nuclear factor 4alpha attenuates hepatic fibrosis in rats.

BACKGROUND AND AIMS: Hepatocyte nuclear factor 4alpha (HNF4alpha) is a central transcriptional regulator of hepatocyte differentiation and function. The aim of this study was to evaluate the effect of HNF4alpha on attenuation of hepatic fibrosis. METHODS: The adenoviruses carrying HNF4alpha gene or containing siRNA targeting HNF4alpha were injected through tail vein on two distinct hepatic fibrosis models either induced by dimethylnitrosamine or by bile duct ligation in rats. Moreover, HNF4alpha, epithelial-mesenchymal transition (EMT)-related and fibrotic markers in hepatocytes, hepatic stellate cells (HSCs) and liver tissues were detected by real time PCR, immunofluorescence or immunohistochemistry. RESULTS: We demonstrated that decreased expression of HNF4alpha and epithelial markers accompanied by enhanced expression of mesenchymal markers occurred in fibrotic liver. More importantly, forced expression of HNF4alpha remarkably alleviated hepatic fibrosis and improved liver function with suppression of EMT in both fibrosis models. In contrast, downregulation of HNF4alpha by siRNA aggravated hepatic fibrosis and decreased the expression of E-cadherin in association with the enhanced expression of vimentin and fibroblast-specific protein-1. In vitro study revealed that HNF4alpha could suppress the EMT process of hepatocytes induced by transforming growth factor-beta1 and increase the expression of liver-specific genes. A similar phenomenon of the EMT process was observed during the activation of HSCs, which was abrogated by HNF4alpha. Additionally, HNF4alpha deactivated the myofibroblasts through inducing the mesenchymal-to-epithelial transition and inhibited their proliferation. CONCLUSIONS: Our study suggests that HNF4alpha is critical for hepatic fibrogenesis and upregulation of HNF4alpha might present as an ideal option for the treatment of hepatic fibrosis.

Meta-analysis: octreotide prevents post-ERCP pancreatitis, but only at sufficient doses.

BACKGROUND: Effects of octreotide on post-endoscopic retrograde cholangiopancreatography pancreatitis have been studied in many clinical trials. These trials have yielded inconclusive results. Results of more recent studies using larger doses, however, seem to be more optimistic. AIM: To examine effects of octreotide at different doses on PEP. METHODS: A comprehensive search of relevant databases, including Medline, Embase, the Cochrane Controlled Trials Register, the Cochrane Library and Science Citation Index yielded 18 randomized controlled trials (RCTs). Trials were divided into two groups according to the total dosage of octreotide: <0.5 mg (OCT1), > or =0.5 mg (OCT2). The rate of PEP was analysed using a fixed effect model. RESULTS: At doses of > or =0.5 mg, octreotide reduced the rate of PEP. In the OCT2 group, analysis revealed a statistically significant difference on PEP between the octreotide group and the controls (3.4% vs. 7.5%, pooled OR = 0.45; 95% CI: 0.28-0.73; P = 0.001, NNT = 25). In the OCT1 group, the rate of PEP was similar between patients receiving octreotide and the controls (7.2% vs. 6.0%, pooled OR = 1.23; 95% CI: 0.80-1.91; P = 0.35). CONCLUSION: Octreotide is effective in preventing PEP, but only at sufficient doses (> or =0.5 mg).

Targeted inhibition of platelet-derived growth factor receptor-beta subunit in hepatic stellate cells ameliorates hepatic fibrosis in rats.

The activation of hepatic stellate cells (HSCs) is the key event of the pathogenesis of hepatic fibrosis. Platelet-derived growth factor (PDGF) is the most potent mitogen for HSCs, and PDGF receptor-beta subunit (PDGFR-beta) is required for the proliferation of HSCs induced by PDGF. In this study, a high gene-silencing-efficacy PDGFR-beta small interference RNA (siRNA) was synthesized that could suppress the PDGFR-beta expression and inhibit the activation and proliferation but could not induce the apoptosis of HSCs in vitro. To avoid the side effect of nonspecific interference of PDGFR-beta, we constructed an HSCs-specific short hairpin RNA (shRNA) expression plasmid in which PDGFR-beta shRNA was driven by a glial fibrillary acidic protein (GFAP) promoter. The double-staining immunofluorescence examination indicated that GFAP promoter could target the transgene expression into HSCs in carbon tetrachloride induced acute injured rat's liver and bile duct ligation (BDL)-induced chronic injured rat's liver. Furthermore, HSCs-specific PDGFR-beta shRNA could relieve liver injury and hepatic fibrosis in the rat's model induced by BDL. This study demonstrates that PDGFR-beta siRNA may be presented as an antifibrogenic agent. The application of HSCs-specific RNA interference induced by the GFAP promoter might supply a new powerful tool for cell-specific gene therapy of hepatic fibrogenesis.

Contrast and efficiency enhancement in organic light-emitting devices utilizing high absorption and high charge mobility organic layers.

Organic light-emitting devices utilizing copper phthalocyanine (CuPc) and C(60) as the hole- and electron-injection layers were reported. Compared with a conventional device without CuPc and C(60) layers, the improvement of the contrast is more than 100% under 140-lx ambient lighting at a brightness of 300 cd/m(2). A maximum current efficiency of 3.93 cd/A, which is higher than 3.62 cd/A for a conventional device, was obtained at 9 V. The device has a maximum luminance of 17170 cd/m(2) at 15 V. The high contrast and high efficiency of the device are attributed to the high absorption and high charge mobility of CuPc and C(60) films.

White organic light-emitting devices with Sm:Ag black cathode.

White organic light-emitting device (WOLED) with Sm:Ag black cathode was first reported. The effect of the black cathode on the performances (such as efficiency, luminance, contrast ratio at different angle and EL spectra, etc) of the WOLEDs was discussed. We found that the efficiency of the WOLED with Sm:Ag was comparable to that of the device with conventional Mg:Ag cathode. For example, the efficiency of the device with Sm:Ag cathode is just 15% lower than that of the device with Mg:Ag cathode. However, the contrast ratio (CR) of the device with black cathode is 105:1 under 140 lx ambient lighting at a high brightness of 1000 cd/m(2), which is four times better than that of the device with Mg:Ag cathode. Besides, the CR of the WOLED with Sm:Ag cathode is insensitive to the viewing angle less than 50 degrees .

A meta-analysis of case-control studies on the combined effect of hepatitis B and C virus infections in causing hepatocellular carcinoma in China.

We investigated whether concurrent infection by hepatitis B virus (HBV) and hepatitis C virus (HCV) in China, a hyperepidemic area for these infections, was associated with a higher risk of causing hepatocellular carcinoma (HCC) than each infection alone in a meta-analysis in China, 32 case-control studies involving 3201 cases and 4005 controls, identified from a computer-based literature search from 1966 to 2004. The pooled odds ratio and 95% confidence interval (CI) for HBsAg positivity was 14.1 (95% CI: 10.6-18.8); for anti-HCV/HCV RNA positivity was 4.6 (95% CI: 3.6-5.9); for HBsAg positivity and anti-HCV/HCV RNA negativity were 15.6 (95% CI: 11.5-21.3); for HBsAg negativity and anti-HCV/HCV RNA positivity were 8.1 (95% CI: 5.0-13.0); and positivity for both HBsAg and anti-HCV/HCV RNA was 35.7 (95% CI: 26.2-48.5). We conclude that HBV and HCV infections are important independent risk factors for HCC in China, and that dual infection by HBV and HCV is associated with a higher risk of causing HCC than each infection alone, suggesting a synergism between HBV and HCV.

Matrine inhibits production and actions of fibrogenic cytokines released by mouse peritoneal macrophages.

AIM: To study the effects of matrine (Mat) on production and actions of fibrogenic cytokines from mouse peritoneal macrophages. METHODS: Mouse peritoneal macrophages were primed with calcimycin 1 micromol/L for 8 h then elicited by lipopolysaccharides (LPS) 100 microg/L for 6 h to induce fibrogenic cytokines. Proliferative and collagen stimulating activity in the macrophage culture supernatants was determined by crystal violet staining assay and [3H]-proline incorporation assay using rat hepatic stellate HSC-T6 cell or mouse fibroblast NIH3T3 cell. Transforming growth factor beta (TGFbeta) activity was measured by [3H]-thymidine incorporation assay using Mv-1-Lu mink lung epithelial cell. RESULTS: Mat (0.5-2 mmol/L) was shown to significantly inhibit LPS-induced collagen stimulating activities and TGFbeta production (P < 0.01) whereas did not inhibit proliferative activities induced by macrophages. Macrophage conditioned medium (MCM)-driven proliferation and collagen synthesis of HSC-T6 cells as well as NIH3T3 cells were attenuated by Mat (0.5-2 mmol/L) in a concentration-dependent manner. CONCLUSION: Antifibrotic effects of Mat on hepatic stellate cells may be related to reduction of fibrogenic cytokine production and blockade of their actions.

Antifibrotic effects of matrine on in vitro and in vivo models of liver fibrosis in rats.

AIM: To study the antifibrotic effects of matrine in vitro a nd in vivo. METHODS: Rat hepatic stellate cell HSC-T6 and mouse fibroblast cell NIH3T3 proliferation stimulated with serum and platelet-derived growth factor (PDGF) was measured b y crystal violet staining assay. Collagen synthesis stimulated with serum and transforming growth factor beta1 (TGF-beta1) was determined by [3H]proline incorporation. Liver fibrosis was induced by carbon tetrachloride (CCl4) in rats an d evaluated with plasma hyaluranic acid level and hepatic hydroxyproline content. RESULTS: Matrine (1-2 mmol/L) markedly reduced serum-driven proliferation and collagen synthesis of HSC-T6 cells as well as NIH3T3 cells. PDGF-driven proliferative activity and TGF-beta1-driven collagen synthesis in HSC-T6 cel ls were attenuated by matrine (0.25-2 mmol/L) in a concentration-dependent manner. In vivo matrine (50 mg/kg and 100 mg/kg) significantly decreased serum hyaluranic acid levels and hepatic hydroxyproline contents in rats treated with CCl4. CONCLUSION: Inhibition of PDGF and TGF-beta1 actions on hepatic stellate cell by matrine might provide a possible mechanism of its antifibrotic activities.

Cytokine regulation of cartilage-derived retinoic acid-sensitive protein (CD-RAP) in primary articular chondrocytes: suppression by IL-1, bfGF, TGFbeta and stimulation by IGF-1.

Cartilage-derived retinoic acid-sensitive protein (CD-RAP) is a secreted protein identified in our laboratory by RT-PCR and differential display [U.H. Dietz, L.J. Sandell. Cloning of a retinoic acid-sensitive mDNA expressed in cartilage and during chondrogenesis. J. Biol. Chem. 271 (1996) 3311-3316]. It is synthesized by chondrocytes throughout development and down-regulated by retinoic acid in coordination with type II collagen gene expression. To further explore the regulation CD-RAP in primary articular chondrocytes, we examined effects of selected cytokines on CD-RAP gene expression compared to their effects on type II collagen expression. Northern blot analysis showed that expression of CD-RAP mRNA was suppressed by bFGF, IL-1beta and retinoic acid in coordination with type II collagen mRNA. TGF-beta decreased CD-RAP expression while increasing type II collagen mRNA whereas both mRNAs were up-regulated by IGF-1. In chondrocytes dedifferentiated with retinoic acid, IGF-1 induced re-expression of both CD-RAP and type II collagen mRNAs. The mechanism of stimulation of CD-RAP by IGF-1 was further investigated. An mRNA stability assay revealed that IGF-1 had no effect on CD-RAP or type II collagen mRNA half life, suggesting that the enhancement by IGF-1 is due to increased gene transcription. To study the transcriptional mechanism, we used the 5'-flanking region of the CD-RAP gene fused to a promoter-less reporter plasmid encoding luciferase. Deletion analysis of the CD-RAP promoter indicated that an IGF-1-responsive element is present between nucleotides -475 and -458. These data indicate that CD-RAP expression can be regulated by cytokines known to influence chondrocyte metabolism and that IGF-1 up-regulates CD-RAP gene expression through a transcriptional mechanism.

The 2.2-kb promoter of cartilage-derived retinoic acid-sensitive protein controls gene expression in cartilage and embryonic mammary buds of transgenic mice.

Cartilage-derived retinoic acid-sensitive protein (CD-RAP) is a secreted protein primarily expressed in chondrocytes. Pathologically, CD-RAP is detected in melanoma, chondrosarcoma and breast cancer. As an approach to define the transcriptional regulatory domains responsible for induction of chondrocyte activity in vivo, we generated transgenic mice harboring various fragments of the mouse CD-RAP promoter linked to the Escherichia coli beta-galactosidase gene. Analysis of the transgene expression pattern by X-gal staining indicates that 2251 bp of the CD-RAP 5'-flanking sequence generates beta-galactosidase activity in all cartilage in embryos and adult animals. In addition, we also detected transient X-gal staining in mammary gland primordium from day 11.5 to 15.5 of gestation. Histological examination revealed that the transgene is located in the chondrocytes of cartilage and the epithelial cells of mammary buds. The cartilage transgene expression pattern is consistent with that of endogenous CD-RAP gene expression. The presence of beta-galactosidase in the mammary buds led us to the demonstration of a unique pattern of transient endogenous expression of CD-RAP in the mammary bud. The finding of transient CD-RAP expression in mammary buds suggests that it may play a role in the organogenesis of mammary glands.

Trans-activation of the mouse cartilage-derived retinoic acid-sensitive protein gene by Sox9.

The transcription factor Sox9 is capable of enhancing type II collagen gene expression and may play a crucial role in chondrogenesis. To determine whether Sox9 is an inducer of the chondrocyte phenotype, we investigated the role of Sox9 in transcription of another cartilage gene encoding the cartilage-derived retinoic acid-sensitive protein (CD-RAP). CD-RAP is specifically expressed during chondrogenesis. We show here that Sox9 protein is able to bind to a SOX consensus sequence in the CD-RAP promoter. Mutation of the SOX motif led to decreased transcription of a CD-RAP promoter construct in chondrocytes. Overexpression of SOX9 resulted in a dose-dependent increased activity of CD-RAP promoter-driven reporter gene in both chondrocytes and nonchondrogenic cells. A truncated SOX9, which contains a binding domain but no trans-activation function, inhibited CD-RAP promoter activity. Overexpression of SOX9 increased the level of endogenous CD-RAP mRNA in chondrocytes, but was unable to induce endogenous gene expression in 10T1/2 mesenchymal cells or BALB/c-3T3 fibroblasts. These results suggest that Sox9 is a general transcriptional regulator of cartilage-specific genes. However, Sox9 does not appear to be able to induce the chondrocyte phenotype in nonchondrogenic cells, implying that other factors are involved in chondrogenesis.

Regulation of the mouse cartilage-derived retinoic acid-sensitive protein gene by the transcription factor AP-2.

The expression of cartilage-derived retinoic acid-sensitive protein (CD-RAP) is initiated at the beginning of chondrogenesis and continues throughout the cartilage development. In chondrocytes, CD-RAP is down-regulated by retinoic acid. To understand the molecular mechanism underlying this regulation and the cell-specific expression, the deletion constructs of the mouse CD-RAP promoter were transfected into chondrocytes and a melanoma cell line. The results revealed a domain that demonstrated high levels of expression specifically in chondrocytes. In this functional domain, we show that a cis-acting element, 5'-GCCTGAGGC-3', binds to the trans-acting factor protein AP-2. Mutation of the AP-2 site on the CD-RAP promoter led to decreased transcription in C5.18 chondrocytes, indicating that this site may act as an activator of transcription. In contrast, increased concentration of AP-2, stimulated by retinoic acid, led to decreased transcription of the CD-RAP promoter, an effect that was abolished by mutation of the AP-2 binding site. The effect of AP-2 was further examined by co-transfection of C5.18 and HepG2 cells with the CD-RAP promoter constructs and an AP-2 expression plasmid. In a dose-dependent manner, cotransfection with AP-2 elevated and then decreased CD-RAP promoter activity. Taken together, these results suggest that AP-2 is involved in the biphasic regulation of CD-RAP transcription.

Effects of matrine on mouse splenocyte proliferation and release of interleukin-1 and -6 from peritoneal macrophages in vitro.

AIM: To investigate the mechanisms of anti-inflammatory effect of matrine (Mat), its effects on mouse splenocyte proliferation, and release of interleukin-1 (IL-1) and interleukin-6 (IL-6) from mouse peritoneal macrophages. METHODS: Splenocyte proliferation was assayed by [3H] TdR incorporation. IL-1 and IL-6 activities were measured by thymocyte proliferation assay and B9 cell proliferation MTT colorimetric method, respectively. RESULTS: Mat (125-500 mg.L-1) obviously inhibited concanavalin A (Con A, 5 mg.L-1)- and lipopolysaccarides (LPS, 10 mg.L-1)-induced splenocyte proliferation and LPS-induced release of IL-1 and IL-6 from mouse peritoneal macrophages. CONCLUSION: Mat inhibited splenocyte proliferation and release of IL-1 and IL-6 in vitro.