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Background & Aims: One major cause of hepatic sinusoidal obstruction syndrome (HSOS) is the intake of pyrrolizidine alkaloid (PA)-containing products. Over 8000 PA-induced HSOS cases have been reported worldwide and at least 51 among them were suspected to be attributed to exposure to the Chinese medicine ‘Tusanqi’. PA-induced hepatotoxicity involves cytochrome P450-mediated metabolic activation of PAs to electrophilic pyrrolic metabolites which react with macromolecules, such as proteins. However, no studies have found such protein adduction in HSOS patients. We report one HSOS case confirmed by liver biopsy, where the patient claimed taking ‘Tusanqi’ as self-medication. Methods: The herb was analyzed by HPLC–MS, and its induced hepatotoxicity in rats was assessed by monitoring the alteration of serum ALT level and liver morphology. Blood pyrrole–protein adducts were determined by UPLC–MS. Results: The herb the patient consumed was identified as Gynura segetum, an erroneous substitute of non-PA-containing Sedum aizoon, called ‘Tusanqi’. Hepatotoxic PAs senecionine and seneciphylline were detected in G. segetum. In the PA-exposed patient, serum pyrrole–protein adducts were detected by a newly developed analytical approach. The animal study showed a good correlation of liver injury with the ingestion of G. segetum. Conclusions: For the first time, serum pyrrole–protein adducts were unequivocally detected in a PA-induced HSOS patient, and such adducts show a potential to be developed as a biomarker for the assessment of PA-induced HSOS. Similar to the well-known case of aristolochic acid-poisoning, the observed HSOS was confirmed to arise from the consumption of PA-containing G. segetum, an erroneous substitute of non-PA-containing S. aizoon. [ABSTRACT FROM AUTHOR]

Abstract: Activated hepatic stellate cells (HSCs) play a crucial role in the development of liver fibrosis. Noninvasive monitoring of the activation of HSCs has been challenging due to the lack of specific receptors or motifs on the cells. The present study provides the evidence that integrin αvβ3 expressed on HSCs is a biomarker reflecting the activation of HSCs. Solid-phase synthesis of cRGDyK (Arg-Gly-Asp-DTyr-Lys) peptide and FAM-conjugated peptide were employed for binding to integrin αvβ3. The increased expression of integrin αv and β3 at mRNA and protein levels was detected during HSC activation. The affinity of cRGDyK to integrin αvβ3 was examined by both radioligand binding assay and FAM-conjugated peptide binding measurements. Quantitative RT-PCR and Western blotting showed a less dramatic, but significant increase in αv and β3 integrin mRNA and protein expression following activation of rat HSCs. Radioiodinated cRGDyK binds to both purified and membrane-bound integrin αvβ3 with high affinity in a dissociable manner. FAM-conjugated cRGDyK was coupled to activated HSCs in a time- and dose-dependent, receptor-mediated manner. Activated HSCs express sufficient number of integrin αvβ3 receptor. cRGDyK peptide binds to both purified and membrane-bound integrin αvβ3 with high affinity in a reversible fashion. Thus, the cRGDyK peptide represented a new agent potentially useful for the diagnosis of liver fibrosis. [Copyright &y& Elsevier]

Abstract: Nitric oxide synthases (NOS) and cyclooxygenase-2 (COX-2) are important enzymes involved in ulcer healing but interactions between them have not been clearly defined. The aim of this study was to investigate the effects of selective or non-selective inhibition of NOS on the expression and activity of COX-2 during healing of acetic acid-induced gastric ulcers in rats. N-[3-(aminomethyl)benzyl] acetamidine (1400W), a potent selective inhibitor of inducible nitric oxide synthase (iNOS), at a dose of 0.1 mg/kg/day, was found to reduce the ulcer sizes at day 3 and 7 post-ulcer induction. On the other hand, 15 mg/kg/day of N G-nitro-l-arginine methyl ester (l-NAME), a non-selective NOS inhibitor that suppresses both iNOS and endothelial nitric oxide synthase (eNOS), enlarged the ulcer sizes over the same time periods. The expression of COX-2 and COX activity, together with NF-κB activation in the ulcer tissues were down-regulated by l-NAME but not 1400W. It is concluded that iNOS may contribute to ulcer formation while COX-2 and eNOS promote ulcer healing. eNOS enhances COX-2 expression possibly through the activation of NF-κB. [Copyright &y& Elsevier]

Abstract: Background: Schistosoma japonicum causes marked liver fibrosis, while lethal syndromes present in advanced schistosomiasis patients. Its management depends on the degree of fibrosis present. Patients and methods: Fifty-two patients were recruited to assess the diagnostic value of bio-markers in patients with advanced schistosomiasis japonica. Fibrosis was assessed in liver biopsies using METAVIR system. The correlation between conventional parameters and significant fibrosis (F2-F4) was assessed using univariate analysis and logistic regression. The method of area under receiver operating characteristic curves (AUROCs) was used as a measurement of diagnostic efficacy. Results: White blood cell counts, platelet counts and albumin (all P <0.05) were significantly lower, while prothrombin time, international normalized ratio (INR), hyaluronic acid (HA), IV collagen and ultrasound fibrosis scores (all P <0.01) were significantly elevated in F2-F4 patients compared with F0-F1 patients. HA and INR were identified as independent predictors by multivariate analysis (P =0.023 and P =0.013, respectively). Of the routine laboratory tests for the diagnosis of significant fibrosis, HA gave the best AUROC of 0.875 (95% confidence interval (CI): 0.701–0.997). We constructed a new simple index (INR×HA/100) to discriminate between F2-F4 patients and F0-F1 patients. It showed the highest AUROC of 0.921 (95% CI: 0.828-1.000), and had better diagnostic values than APRI and FIB-4. Conclusion: HA and INR were reliable markers for differentiating significant liver fibrosis in patients with advanced schistosomiasis japonica. And the new simple index can easily predict significant liver fibrosis with a high degree of accuracy. [Copyright &y& Elsevier]

Abstract: The aims of this study were to elucidate the immunomodulatory effects of glycyrrhizin (GL) on CD4+T cell responses during liver fibrogenesis. To obtain in vivo evidence about the effects of GL on CD4+T cells in livers and spleens of concanavalin A (ConA)-induced mouse model, mice were administrated with ConA together with or without GL for 8weeks. Mice treated with GL dramatically prevented liver inflammation and fibrosis. Besides, GL inhibited the infiltration of T helper (Th) cell type 1, Th2, Th17 and regulatory T cells (Treg) in livers and spleens of mouse fibrosis models, and regulated the Th1/Th2 and Treg/Th17 balances respectively to a relative dominance of Th1 and Treg lineages in livers. Moreover, GL dramatically enhanced the antifibrotic cytokine interferon (IFN)‐γ and interleukin (IL)-10. GL at a concentration of 10 or 100μg/mL was respectively incubated with ConA-stimulated splenic CD4+T cells in vitro, and JNK inhibitor (SP600125), ERK inhibitor (U0126), p38 inhibitor (SB203580) or PI3K/AKT inhibitor (LY29400225) was added during the incubation. Notably, GL not only inhibited ConA-induced proliferation of splenic CD4+T cells but also enhanced the mRNAs of IFN-γ and IL-10 in these cells. Be similar to the effects of GL, SP600125, U0126 and LY29400225, however not SB203580, also inhibited ConA-induced CD4+T cell proliferation, indicating the involvement of JNK, ERK and PI3K/AKT in this process. Moreover, GL significantly inhibited ConA-induced phosphorylation of JNK, ERK and PI3K/AKT in vitro. Collectively, GL might alleviate liver injury and fibrosis progression via regulation of CD4+T cell response in JNK, ERK and PI3K/AKT-dependent pathways. [Copyright &y& Elsevier]

Abstract: The aim of the study was to investigate the effect of curcumin on the liver fibrosis induced by carbon tetrachloride (CCl4) in rats, and to elucidate its underlying molecular mechanisms. Rats were administered with CCl4 together with or without curcumin for 6weeks. Hepatic damage was evaluated by analysis of liver function tests in serum. Hepatic histopathology and collagen content were employed to quantify liver fibrosis; and activated hepatic stellate cells were assessed. Moreover, the mRNA and protein expression levels of interleukin (IL)-6, tumor necrosis factor (TNF)-α, monocyte chemotactic protein (MCP)-1, high-mobility group box 1 (HMGB1), Toll like receptor (TLR) 2 and TLR4 were determined by quantitative real time PCR, Western blot or immunohistochemistry. Treatment with curcumin significantly attenuated CCl4-induce liver injury, hepatic inflammation and reduced the levels of proinflammatory mediators (TNF-α, IL-6 and MCP-1). Moreover, curcumin significantly inhibited extracellular matrix deposition, reduced the number of activated stellate cells, and decreased the levels of HMGB1, TLR4 and TLR2 expression in the rat model of fibrogenesis. These results suggest that curcumin could be an effective agent for preventing liver fibrosis and its mechanism may in part be a consequence of the reduction TLR2, TLR4 and HMGB1 expression. [Copyright &y& Elsevier]

Abstract: Background: Intravascular Brachytherapy as a tool to reduce restenosis is thought to alter vascular wall biology and vessel wall protein function. Platelet accumulation is also indeed important in the genesis of restenosis. We examine the in vitro effects of beta-radiation on the certain vessel wall extra cellular matrix proteins. We hypothesized that vessel wall (proteins) had become less prone to thrombosis. Methods: We examined platelet adhesion to 20-Gy beta radiation treated extra cellular matrix proteins under flow conditions. Platelet flow adhesion was evaluated or quantified by image analysis, aggregation size analysis using the Watershed program and real-time fluorescence images of thrombus formation. The effect of beta radiation on vWF was further showing by measuring the binding of domain-specific antibodies to radiation treated vWF. Results: 20-Gy beta radiation significantly decreased platelet adhesion to extra cellular matrix protein; vWF and collagen Type III and had no effect on the adhesion upon fibrinogen and fibronectin. The beta-radiation affected mostly the AI, A2 and A3 domains of the vWF molecule on the surface, whereas the D′–D3 and B–C1 domains on the surface remain unaffected and suggesting a significant decrease in vWF binding capacity to the GPIb, heparin and collagen ligands. Conclusion: Beta radiation treatment can alter the reactivity of the certain vessel wall extra cellular matrix proteins, in particular vWF and collagen. The vessel wall may become less prone to platelet adhesion, which results in decrease thrombus formation. It might help to reduce the onset of acute coronary occlusion after the intervention. [Copyright &y& Elsevier]

Abstract: Background and aims: Few drugs have been confirmed to be effective for fulminant hepatic failure (FHF). The purpose of this study was to prepare sterically stable liposomes (SSL) encapsulating hepatic stimulator substance (HSS) and determine their therapeutic effect on FHF. Methods: HSS were encapsulated into SSL (HSS-SSL). FHF was induced in rats by thioacetamide (TAA) injection (400mg/kg, three times with a 24-h interval). The agents, including HSS-SSL, SSL, HSS, and sodium chloride (NS), were each injected intravenously 2h after the second and the third TAA injection. Results: Freshly prepared HSS-SSL had a mean size of 93.59nm and the average encapsulation efficiency was 37.20%. HSS encapsulated in SSL showed a longer half life and more potent target to injured livers than free HSS. Twenty-four hours after the third TAA-injection, the survival rate of HSS-SSL-treated rats (80%) was significantly higher than that of rats treated with NS (20%), SSL (25%), or HSS (50%). Histopathologic examination showed that there was the least necrosis and inflammation in the livers of HSS-SSL-treated rats. The incidence of stage 3 or 4 hepatic encephalopathy in HSS-SSL-treated rats was significantly lower than that in rats treated with other agents. The serum pro-inflammatory cytokine levels and hepatic lipid peroxidation levels were both markedly reduced, while hepatocyte proliferative rate was markedly increased after HSS-SSL treatment. Conclusion: Encapsulation by SSL markedly improved the therapeutic effect of HSS on FHF in rats. Encapsulation by SSL may be an effective approach to enhance the therapeutic potency of drugs for FHF. [Copyright &y& Elsevier]