Studies

comparing treatment outcomes of

Studies

comparing treatment outcomes of DZNeP mw PEG IFN+RBV for HCV-4 with HCV-1 and 2/3 have been limited by the small sample size of the HCV-4 group. We aimed to compare SVR and predictors of SVR in HCV-4 versus HCV-1 and HCV-2/3 patients treated with PEG-IFN+RBV in a meta-analysis. Methods: We performed a comprehensive literature search in MEDLINE and EMBASE for ‘genotype 4′ in November 2013 and reviewed abstracts from 2012-2013 AASLD, APASL, DDW, and EASL. Inclusion criteria were original studies with ≥25 treatment-naïve HCV-4 patients with direct comparison arms with HCV-1, 2, and/or 3 patients, and all treated with PEG IFN+RBV. Exclusion criteria were co-infection with HIV, HBV, or other HCV genotypes. We used random-effects models to estimate effect sizes and Cochrane Q-test (p-value <0.05) and I2 statistic (>50%) to estimate level of heterogeneity. Results: We included 6 studies

(868 HCV-4, 12,033 HCV-1, and 7,194 HCV-2/3 patients) in the primary analysis. Overall SVR was 53% (CI: 43-62%) for HCV-4, 44% (CI: 40-47%) for HCV-1, and 73% (CI: 58-84%) for HCV-2/3 (Table 1). EVR rates were higher for HCV-4 [72% (CI: 64-81%)] compared to HCV-1, [59% (CI: 58-61%)]. SVR in those patients APO866 Sitaxentan with EVR were 75% (CI: 61-86%) in HCV-4 and 64% (CI: 46-79%) in HCV-1. SVR in patients who did not achieve EVR were 10% (CI: 6-17%) for HCV-4, 13% (CI: 12-15%) for HCV-1 and higher for HCV-2/3 at 23% (CI: 16-33%). Conclusions: Pooled SVR rates were lowest for HCV-1 (44%) then HCV-4 (53%) and highest for HCV-2/3 (73%). EVR was not a good stopping

rule for HCV-2/3 but excellent for HCV-1 and 4, so patients can seek alternative therapy early. However, approximately three-quarter of HCV-4 patients treated with PEG IFN+RBV achieved EVR and three-quarter of these patients also achieved SVR, making this a reasonable treatment option for HCV-4 patients. Treatment Response: HCV-4 compared to HCV-1 or HCV-2/3 Disclosures: Mindie H. Nguyen – Advisory Committees or Review Panels: Bristol-Myers Squibb, Bayer AG, Gilead, Novartis, Onyx; Consulting: Gilead Sciences, Inc.; Grant/Research Support: Gilead Sciences, Inc., Bristol-Myers Squibb, Novartis Pharmaceuticals, Roche Pharma AG, Idenix, Hologic, ISIS The following people have nothing to disclose: Brittany E. Yee, Derek Lin, Nghia H. Nguyen, Bing Zhang, Philip Vutien, Carrie R. Wong, Glen A.

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5 Fr) is used to loop around the whole right hilar plate and a me

5 Fr) is used to loop around the whole right hilar plate and a metal clip is applied just beside the catheter to mark the site of transection. A third operative cholangiography is performed to ascertain the patency of the left ductal system (Fig. 2c). The routine use of methylene blue solution to check for bile leakage at the end of operation has been advocated,[29] but its efficacy has not been confirmed.[30] Besides the operation station, find more the back table is another location where intensive attention must be exercised. Clamping

of the right hepatic duct must be avoided at all time to avoid crushing injury. The graft is flushed with University of Wisconsin solution or histidine-tryptophan-ketoglutarate solution. It has been reported that the former may be associated with a higher incidence of BAS after LDLT,[13] but a recent meta-analysis failed to conclude that there is superiority of one over the other.[31]

Duct-to-duct anastomosis (DDA) and hepaticojejunostomy (HJ) are the two most common methods of BR. With DDA, the simpler one among the two, the normal physiological bilioenteric integrity can be maintained and future endoscopic access to the bile duct is possible.[32, 33] However, if the bile duct available for anastomosis is diseased or not long enough, DDA will not be feasible and HJ is the option.[5] At most centers,[30-32] DDA is preferred unless the native bile duct is not suitable for it or should not be used (e.g. with primary sclerosing cholangitis). In HJ, an intestinal segment is used as a component of the anastomosis. The adoption of HJ means that an additional anastomosis

Atezolizumab datasheet has to be made. Usually a jejuno-jejunostomy is then made 40 cm from the anastomosis, but a recent report suggested that a short Y-limb (20 cm) is sufficient.[34] Besides the need for an additional anastomosis, other disadvantages of HJ include longer operation time, possible contamination during enterotomy, and the risk of ascending cholangitis due to loss of function of the sphincter. Moreover, future endoscopic access to the bile duct will be difficult,[13, 14] although the rendezvous technique can be used at expert centers.[35] There is not any randomized study in the literature documenting the superiority of Etoposide concentration DDA over HJ or vice versa. Generally, DDA is the choice in adult RLDLT if there is no contraindication. Choledochoduodenostomy, an alternative to DDA, has been proposed to cope with hostile abdomens and to preserve maximal bowel length.[36] One pitfall in recipient total hepatectomy is preserving a common hepatic duct that is “too long”, with the fear that not enough length is left for a tension-free DDA. An excessively long common hepatic duct would leave an ischemic segment, causing ischemic anastomotic stricture or even bile leakage. Caudal shifting of the hepatic vein anastomosis helps when the gap between the hilum of the graft and the hepatoduodenal ligament of the recipient is too wide (e.g.

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Between-group differences in perforation rates were not significa

Between-group differences in perforation rates were not significant. Local recurrence rates in cases with curative resection were as follows: 0% (0/56) in ESD; 0% (0/27) in hybrid ESD; 1.4% (1/69) in EMR; and 12.1% (13/107) in EPMR; that

is, significantly higher in EPMR. No metastasis was seen at follow up. The recurrence rate for EPMR yielding ≥ three pieces was significantly high (P < 0.001). All 14 local recurrent lesions were adenomas that were click here cured endoscopically. Conclusions:  As for safety, ESD/hybrid ESD is equivalent to EMR/EPMR. ESD/hybrid ESD is a feasible technique for en bloc resection and showed no local recurrence. Although local recurrences associated with EMR/EPMR were seen, which were conducted based on our indication criteria, all local recurrences could obtain complete cure by additional endoscopic treatment. “
“The aim of this study is to evaluate the effect of metformin on intestinal inflammation. COLO205 cells were pretreated with metformin and stimulated with tumor necrosis factor (TNF)-α. Expression of interleukin

(IL)-8 was determined by luciferase assay and real-time PCR. Inhibitor of kappaB (IκB) phosphorylation/degradation and adenosine monohosphate-activated protein kinase (AMPK) activity were evaluated by Western blotting. DNA-binding activity of transcription factor nuclear factor-kappaB (NF-κB) was assessed by electrophoretic RG-7388 mouse mobility shift assay. In an acute colitis model, Glycogen branching enzyme mice were given 4% dextran sulfate sodium (DSS) for 5 days. IL-10−/− mice were used to evaluate the effect of metformin on chronic colitis. In an inflamation-associated tumor model, mice were given a single intraperitoneal injection of azoxymethane followed by three cycles of 2% DSS for 5 days and 2 weeks of free water consumption. Metformin significantly inhibited IL-8 induction in COLO 205 cells stimulated with TNF-α. Metformin attenuated IκBα phosphorylation and NF-κB DNA-binding

activity. Administration of metformin significantly reduced the severity of DSS-induced colitis. In addition, DSS-induced IκB kinase (IKK) activation was significantly reduced in mice treated with metformin. Metformin significantly attenuated the severity of colitis in IL-10−/− mice, induced AMPK activity in intestinal epithelial cells, and inhibited the development of colitic cancer in mice. These results indicate that metformin suppresses NF-κB activation in intestinal epithelial cells and ameliorates murine colitis and colitis-associated tumorigenesis in mice, suggesting that metformin could be a potential therapeutic agent for the treatment of inflammatory bowel disease. “
“The pathogenesis of nonalcoholic steatohepatitis (NASH) and inflammasome activation involves sequential hits. The inflammasome, which cleaves pro–interleukin-1β (pro–IL-1β) into secreted IL-1β, is induced by endogenous and exogenous danger signals.

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01% sodium azide (fluorescence-activated cell sorting [FACS] wash

01% sodium azide (fluorescence-activated cell sorting [FACS] wash), and fixed in 200 μL of 2% paraformaldehyde (Electron Microscopy Sciences, Hatfield, PA). Isotype-matched fluorescently labeled control antibodies were used to determine background levels of staining. Lymphocytes were identified by characteristic forward and side scatter

parameters, and populations of interest were gated on patterns of CD56/CD3 staining within the lymphocyte population. Results are expressed as the percent positive of the gated population. Intracellular perforin staining was performed after permeabilization with 0.2% saponin using a δ-G9 antibody obtained from BD Biosciences. Thawed mononuclear cell suspensions were enriched for NKs using the NK Isolation Kit II from Miltenyi NSC 683864 in vivo Biotec (Gladbach, Germany) according to the manufacturer’s instructions. The median purity of NKs was >90% in all cases. After isolation, NKs were cultured with or without IL-2 (25 ng/mL, R&D Systems) for

48 hours at 37°C and 5% CO2. Following culture, carboxyfluorescein succinimidyl ester–labeled target cells (K562s) were added to NKs at effector-to-target FK506 ic50 concentrations of 0:1 (negative control) and 10:1 (test) and incubated at 37°C for 4 hours. After incubation, cytotoxicity was measured using the flow cytometry–based Total Cytotoxicity & Apoptosis Detection Kit from Immunochemistry (Bloomington, MN). Immediately before acquisition, 7-aminoactinomycin D was added to effector-to-target populations and incubated for 15 minutes on ice. Cells treated with 0.1% Triton-X below served as positive controls. Degranulation was determined by way of flow cytometric analysis of increased CD107a (Lamp, BD Bioscences) expression on bead-isolated

NKs after 4-hour stimulation with phorbol myristate acetate (PMA) (10 ng/mL) and ionomycin (1 μg/mL) in the presence of brefeldin A (Sigma-Aldrich) and CD107a. NKs cultured under the same conditions without PMA and ionomycin served as unstimulated controls. Antibodies for intracellular interferon-γ (IFN-γ) were supplied by BD Biosciences. Thawed mononuclear cells were stimulated with PMA (10 ng/mL) and ionomycin (1 μg/mL) for 4 hours at 37°C in the presence of brefeldin A. After stimulation, cells were stained for surface antigens (as above), fixed for 30 minutes at 4°C in 100 μL Fix and Perm Medium A (Caltag, Burlingame, CA), permeabilized using 100 μL Fix and Perm Medium B (Caltag), and incubated with anti-cytokine monoclonal antibody for 1 hour at 4°C in the dark. Cell suspensions were then washed in FACS wash and fixed in 200 μL 2% paraformaldehyde and acquired after 1 hour. Cells cultured under the same conditions in the absence of PMA and ionomycin served as controls. NKs were enriched using magnetic beads and were surface-stained for CD3, CD56, and NKp30 as described above.

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Peripheral nerve blocks (PNBs) have been used for the acute and p

Peripheral nerve blocks (PNBs) have been used for the acute and preventive treatment of a variety of primary headache disorders for decades.[1-3] These procedures provide prompt pain relief for many patients with various headache types. Moreover, their analgesic effect typically lasts beyond the duration of anesthesia caused by the nerve blockade, providing some patients with pain relief for several weeks or even months.[4] This prolonged analgesia after peripheral nerve blockade may be due to an effect on central pain modulation.[5] The most widely used target for

PNBs is the greater occipital nerve (GON). Other commonly targeted nerves are the lesser occipital nerve (LON) and several branches of the trigeminal nerve, including the supratrochlear (STN), supraorbital (SON), and auriculotemporal nerves (ATN). PNBs selleck are generally safe and well-tolerated procedures that may be performed in the outpatient setting.

A sound knowledge of the anatomy of the different nerves is critical for obtaining good results Small molecule library cost and for avoiding adverse effects (AEs) such as bleeding or inadvertent systemic injection of the drugs used for nerve blockade. Despite the common use of PNBs by clinicians involved in the care of patients with headache, there has been no standardized approach for the performance of these procedures. A recent survey conducted by the American Headache Society Special Interest Section for PNBs and other Interventional Procedures (AHS-IPS) showed that 69% of responding practitioners used PNBs; however, patterns of use, drug dosages, volumes of injections, and injection schedules varied greatly.[2] To address this issue, members of the AHS-IPS convened, aiming to reach a consensus on the recommended techniques for the performance of PNBs for headaches. In this report, we summarize the results of this effort. This endeavor 17-DMAG (Alvespimycin) HCl was initiated by a systematic literature review[2] and a survey of the AHS membership[3] by the AHS-IPS that established the need for standardized PNB methodology. Section meetings were convened during the 2010 AHS Scottsdale Headache Symposium

and the 2011 AHS annual scientific meeting in Washington, DC, with a cross-section of the AHS membership who are active with PNBs, featuring formal discussion about each methodological point, and majority rule for consensus. No formal vote was required as an agreement was reached on each point by the AHS-IPS. The manuscript was then drafted and revised by a subcommittee of the AHS-IPS (authors of this manuscript) from July to November 2011. After consultation with the AHS Guidelines Committee and the Board of Directors throughout 2012, the manuscript was determined to be best framed as a narrative review by the AHS-IPS; further edits were implemented, followed by final manuscript submission with full approval from all authors.

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The production of these cytokines was

The production of these cytokines was Gefitinib determined from the coculture of the human monocytic cell line, THP-1, with either JFH-1-infected or uninfected hepatoma cells using the transwell system. Notably, JFH-1-infected HepG2 cells stimulated a statistically significant increase in the secretion of TGF-β, IL-6, IL-21, but not IL-12, by THP-1 cells in a transwell membrane system (Fig. 4C). However, cultures of THP-1 cells alone produced low levels of TGF-β, IL-6, and

IL-21 cytokines regardless of the presence of JFH-1sup (data not shown). Importantly, the addition of anti-TSLP-neutralizing antibodies led to a decrease of Th17-specific cytokines (Fig. 4C). These results suggest that monocytes/DCs conditioned by TSLP secreted from HCV-infected hepatocytes produce Th17 differentiating cytokines which could support the induction of CD4+ Th17 responses. Based on the role of IL-1, IL-6, and IL-21 production in Th17 polarization, we evaluated the effect of hepatocyte-derived TSLP on Th17 differentiation in coculture of naïve T cells with DCs activated by IL-1/IL-6/IL-23, JFH-1sup, or JFH-1sup plus anti-TSLP antibodies. Following stimulation with PMA/ionomycin, the production of intracellular cytokines (IFN-γ, IL-17A) by CD4+ T cells was assessed this website using flow cytometry. As expected, IL-1/IL-6/IL-23-treated DCs, used as positive control, produced more IL-17 cells compared to control cells (5.09 ± 0.6% versus 0.91 ± 0.08%). Notably, the percentage of IL-17-producing

cells increased after coculture of CD4+ T cells with JFH-1sup-treated DCs (4.65 ± 0.55%), which then significantly decreased upon the addition also of anti-TSLP mAbs (1.21 ± 0.1%) (Fig. 5A,B). There was

no significant difference in the percentage of IFN-γ production from JFH-1sup-treated DCs in the presence or absence of anti-TSLP antibody (Fig. 5A,B). This result was further verified by the detection of IL-17 release using ELISA. The enhancement of IL-17-producing T cells by JFH-1sup-treated DCs was significantly inhibited by neutralization of TSLP (Fig. 5C). This suggests that TSLP released from infected hepatocytes activates and conditions DCs to drive the differentiation of activated CD4+ T cells into Th17 cells. To further examine the effect of TSLP on promoting Th17 differentiation during HCV infection, we assessed the capacity of Th17 cell generation by CD4+ T cells from PBMC in a chronic HCV patient. As shown in Fig. 6A, there is a significant increase of Th17 lineage-specific transcription factor (i.e., RORc) and markers (i.e., CCR6 and CD161) from chronic HCV patients as compared to those in healthy individuals. We next determined the role of HCV-specific antigen in induction of Th17 CD4+ T cells. HCV NS3/5 proteins have been reported to induce a Th17 response.22 Th1/Th17 cells differentiations were compared using intracellular staining of IFN-γ and IL-17, respectively. The results indicated that Th17 cells were significantly increased in response to NS3/NS5 compared to normal control (5.

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There were 44 patients with biopsy-proven NASH

There were 44 patients with biopsy-proven NASH Galunisertib mw in the elderly patients group and 412 patients with biopsy-proven NASH in the nonelderly patients group (Table 3). Compared to nonelderly patients with NASH, elderly patients with NASH had higher rates of advanced fibrosis (52% versus 35%, P = 0.03), as well as other features suggestive

of severe liver disease including ballooning degeneration, acidophil bodies, megamitochondria, and Mallory-Denk bodies (P ≤ 0.05 for each) (Table 3). In contrast, compared to nonelderly patients with NASH, elderly patients had lesser degrees of steatosis (48% versus 67% >33% steatosis, P = 0.01). We then investigated the characteristics of the presence of NASH in elderly patients by comparing how it differs from those without NASH in this age group (Supporting Table 1). Elderly patients with NASH had significantly higher

www.selleckchem.com/products/Y-27632.html average values for AST (70 ± 48 versus 38 ± 12 U/L, P < 0.001), ALT (75 ± 49 versus 49 ± 21 U/L, P = 0.006), and GGT (88 ± 82 versus 49 ± 44 U/L, P = 0.02). In addition, the average platelet count was lower (204 ± 59 versus 254 ± 71 ×1,000/mm3, P = 0.02) (Supporting Table 1). The mean APRI score was significantly higher in elderly patients with NASH compared to elderly patients without NASH (0.8 ± 0.7 versus 0.4 ± 0.3, P < 0.001). There was no significant difference in steatosis and degree of lobular inflammation between those with and without NASH. However, as would be expected, NASH patients were more likely to have ballooning degeneration. In addition, Mallory-Denk bodies were present in 72% of NASH patients, while these were absent in those who did not have NASH (P < 0.001) (Supporting Table 1). The NAFLD activity score (NAS) as indicated Farnesyltransferase by the percentage of patients with NAS ≥5 was higher in elderly patients with NASH compared to elderly patients without NASH (70% versus 18%, P < 0.001). Elderly patients with NASH were more likely to have advanced fibrosis compared to elderly patients who

did not have NASH (52% versus 24%, P = 0.05) (Supporting Table 1). Independent predictors of NASH among elderly patients determined from multivariable-adjusted logistic regression analyses were: younger age among this cohort with age ≥65 (OR = 0.65, 95% CI: 0.46-0.91, P = 0.01); higher AST value (OR = 1.12, 95% CI: 1.03-1.22, P = 0.007), and lower platelet count (OR = 0.98, 95% CI: 0.96-1.00, P = 0.02) (Table 4). Characteristics of elderly patients with advanced fibrosis compared to those with stage 0-2 fibrosis are shown in Supporting Table 2. Patients with advanced fibrosis were more likely to have metabolic syndrome, higher average BMI, and increased fasting serum insulin, HOMA-IR, INR, and AST/ALT ratio. In addition, patients with advanced fibrosis had lower mean platelet count, total cholesterol, and LDL cholesterol levels.

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[75] showed significant correlation of FVIII

half-life wi

[75] showed significant correlation of FVIII

half-life with pre-infusion VWF antigen levels during SCH727965 treatment of haemophilia A patients with recombinant FVIII; (iii) DDAVP-induced VWF increase altered high-purity FVIII kinetics in haemophilia A patients [76] and (iv) Eikenboom et al. [77] evaluated the FVIII/VWF ratios in different types of VWD showing that the ratio increased when VWF synthesis was reduced, but remained 1 when VWF clearance was increased. It has to be emphasized that FVIII half-life significantly correlated with the VWF level over a wide concentration range between 1 U mL−1 and 3 U mL−1 VWF:Ag, i.e. there was sufficient stabilization of FVIII throughout the entire range to prevent proteolytic FVIII cleavage. The molar ratio of VWF monomers and FVIII at the physiological VWF:FVIII ratio of 1:1 unit is theoretically 50:1 and has been experimentally determined as 20:1, probably due to the globular ‘ball-of-yarn’-structure of circulating VWF presenting only a fraction of FVIII binding sites on its surface. The huge excess of FVIII-binding sites theoretically allows stabilization of ABT-263 supplier up to 20-times FVIII relative to VWF, i.e. up to 20 U FVIII:Ag by 1 U VWF:Ag before saturation of VWF. Following the thesis that (i) FVIII passively follows VWF clearance, (ii) a constant clearing rate of VWF is assumed and (iii) bearing in mind the multimeric structure of VWF, it becomes immediately

apparent that the number of FVIII molecules cleared over time strongly depends on the FVIII loading of VWF, i.e. the actual VWF:Ag/FVIII:Ag ratio. Higher loading of circulating VWF multimers increases the number of cleared FVIII molecules per VWF clearing event. This is essentially what was observed during the pharmacokinetic

study by Kessler et al. [62]: almost physiological FVIII half-life for the concentrate exhibiting a 1:1 VWF:RCo/FVIII:C-ratio and a prolonged FVIII half-life for the concentrate with a roughly 2.3:1 VWF:RCo/FVIII:C-ratio. However, the most exciting consequence of VWF-dependent FVIII clearance is the fact that this mechanism intrinsically constitutes a self-regulating mechanism of the physiological VWF/FVIII ratio in plasma. At situations of high VWF/FVIII ratios 3-mercaptopyruvate sulfurtransferase (i.e. low FVIII plasma concentrations), FVIII clearance is lower, whereas at low VWF/FVIII ratios (i.e. high FVIII plasma concentrations) FVIII clearance increases. At the physiological situation of a 1:1-ratio, VWF-dependent FVIII clearance and synthesis of FVIII and VWF are in equilibrium [Fig. 11 (C. Kannicht, Unpublished data)]. Kannicht et al. are in the process of setting up a mathematical model considering intrinsic FVIII synthesis, known VWF-clearance rates and possible clearance of free FVIII to simulate FVIII clearance in VWD patients dependent on pre-infusion VWF levels and administered VWF/FVIII ratios. There has been much work on inhibitors in haemophilia, but not in VWD.

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[72] These authors speculated the increase in SVR was related to

[72] These authors speculated the increase in SVR was related to improvements in IR, which would also be relevant to NAFLD populations. An interesting potential confounder that has not been addressed in the few studies to date

is the potential association between VX-809 order VDD and inactivity, perhaps from leading a sedentary indoor lifestyle. Further appropriately powered RCTs are required to better evaluate the efficacy of vitamin D replacement and parameters of therapy in NAFLD and other chronic liver diseases. VDD is increasingly diagnosed in Western patients and is commonly found in NAFLD populations. Given the pleiotropic effects of vitamin D ranging from hormonal to immunologic to cellular differentiation, it is quite possible vitamin D replacement find more in VDD may produce significant biochemical and histologic benefit, although more data from

appropriately powered prospective randomized placebo-controlled trials are needed. The levels of 25(OH)D that constitute deficiency versus sufficiency are debatable, although 20 ng/mL (50 nmol/L) has been suggested to be a minimal acceptable level.[73] Optimal replacement regimens have not been established. Some studies suggest that cumulative dose is more important than dosing frequency.[74] Our typical practice is to replace VDD patients with 50,000 IU vitamin D3 weekly for 12 weeks. A daily supplement of

800-2,000 IU is then recommended, Pomalidomide typically in conjunction with calcium. Vitamin D levels are then checked in 3-6 months to confirm adequate replacement and rule out toxicity. In conclusion, the relationship of vitamin D and NAFLD requires further study but evidence to date confirms an intimate and potentially therapeutic association. “
“Acetaminophen (APAP) overdose is the leading cause of acute liver failure in Western countries. In the last four decades much progress has been made in our understanding of APAP-induced liver injury through rodent studies. However, some differences exist in the time course of injury between rodents and humans. To study the mechanism of APAP hepatotoxicity in humans, a human-relevant in vitro system is needed. Here we present evidence that the cell line HepaRG is a useful human model for the study of APAP-induced liver injury. Exposure of HepaRG cells to APAP at several concentrations resulted in glutathione depletion, APAP-protein adduct formation, mitochondrial oxidant stress and peroxynitrite formation, mitochondrial dysfunction (assessed by JC-1 fluorescence), and lactate dehydrogenase (LDH) release. Importantly, the time course of LDH release resembled the increase in plasma aminotransferase activity seen in humans following APAP overdose.

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6A These results suggest that S1P and S1P2 contribute, at least

6A. These results suggest that S1P and S1P2 contribute, at least in part, to the enhancement of Rho kinase activity in the livers of bile duct-ligated mice. Then liver fibrosis was evaluated in wildtype and S1P mice at 3 weeks following bile duct ligation. BYL719 Sirius Red staining of the livers showed that fibrosis developed around bile duct and ductal structures and in lobular septa in wildtype mice, whereas less fibrosis was observed predominantly around ductal structures in S1P mice (Fig. 6B). Smooth-muscle α-actin mRNA expression in the liver was significantly higher in wildtype mice than in S1P mice (Fig. 6C).

Collectively, liver fibrosis induced by bile duct ligation was less prominent in S1P mice than in wildtype mice. Next, an intravenous infusion of S1P2 antagonist at 1 mg/kg body weight was performed in wildtype and S1P mice at 3 weeks following bile duct ligation. The S1P2 antagonist reduced portal vein pressure in wildtype mice, but not in S1P mice

(Fig. 6D). Because previous studies indicate that S1P2 antagonist exerts its effect also on hepatocytes,14, 27 liver enzymes in serum and liver histology were examined at 24 hours after intravenous injection of the S1P2 antagonist (1 mg/kg body weight) in normal rats to examine beta-catenin activation whether its intravenous administration might affect hepatocytes. As demonstrated in Fig. 7A-E, serum levels of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and gamma-glutamyltransferase and liver histology were not altered with intravenous injection of the S1P2 antagonist. In the current study, intravenously administered S1P2 antagonist reduced portal vein pressure without affecting mean arterial pressure in cirrhotic rats caused by bile duct ligation. This effect of the S1P2 antagonist involved the reduction of Rho kinase activity in the liver. On the other hand, the same amount of S1P2 antagonist did not alter portal vein pressure and mean

arterial pressure in control sham rats. Up-regulation of S1P2 expression was observed in the bile duct-ligated livers of rats and mice, predominantly in hepatic stellate cells as smooth-muscle α-actin-expressing cells. Finally, the contribution new of S1P and S1P2 to the enhancement of Rho kinase activity in the liver as well as the formation of liver fibrosis following bile duct ligation was determined in mice. It is now well known that the intrahepatic up-regulation of Rho kinase signaling plays an important role in the pathophysiology of portal hypertension with increasing hepatic vascular resistance.22 Thus, Rho kinase has become one of the main targets when establishing the treatment strategy for portal hypertension.13, 17, 25, 28 On the other hand, among the S1P receptors it has been shown that S1P2 is specifically coupled to Rho and Rho kinase signaling.

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