7–12 This complicated pathway may explain why escape from this im

7–12 This complicated pathway may explain why escape from this immunodominant HIV epitope occurs only late in infection. In HCV we have previously shown that fitness constraints

limit the ability to mutate at the main HLA-B27 binding anchor of the immunodominant HLA-B27 epitope that is located within a conserved region of the RNA-dependent RNA polymerase (NS5B2841-2849). Instead, a mosaic of several mutations at the T-cell receptor contact residues within the epitope needs to evolve in order to allow significant escape from the HLA-B27-restricted CD8+ T-cell response.6, 13 Similar to HIV, these results suggest that viral escape cannot be achieved easily, giving the T-cell response sufficient time to clear the BGB324 cell line virus. These virological factors presumably contribute to the protective effect of HLA-B27. Although there is strong immunological and virological evidence that the protective effect of HLA-B27 in HIV and HCV infection,

respectively, is indeed linked to these particular immunodominant epitopes, this has not been conclusively demonstrated, as this would require a prospective analysis of a large number of B27-positive subjects with acute infection. In order to determine the contribution of the viral epitope on protection by HLA-B27, we took advantage of the fact that the immunodominant viral region targeted by HLA-B27-restricted CD8+ T cells is conserved in HCV BVD-523 supplier genotype 1 only, in which the protective effect of HLA-B27 has been described.6 In other HCV genotypes, e.g., genotype 3a (the most frequent genotype after genotype 1 in most countries) the epitope sequence differs by three out of nine amino acid residues from genotype 1. We therefore hypothesized that lack of recognition of the epitope in

patients infected with HCV genotypes other than 1 might lead to a loss DCLK1 of protection by HLA-B27. In order to test this hypothesis, in this study we analyzed the CD8+ T-cell response and autologous viral sequences in a new cohort of HLA-B27+ patients acutely or chronically infected with HCV genotype 3a and determined the frequency of HLA-B27 in a large cohort of patients chronically infected with HCV genotype 1 or 3a. Our results suggest that HLA-B27 is indeed protective in patients with HCV genotype 1 infection but not in patients infected with HCV genotype 3a. This lack of protection is most likely caused by intergenotypic sequence differences leading to the loss of the immunodominant HLA-B27 epitope in infection with HCV genotypes other than 1. Our results further support the important role of a single immunodominant NS5B epitope in mediating the protective and genotype-specific effect of HLA-B27 in HCV infection. CTL, cytotoxic T lymphocyte; HCV, hepatitis C virus; HIV, human immunodeficiency virus; HLA-B27, human leukocyte antigen B27; INF-γ interferon-γ NS5B, nonstructural protein 5B; PBMC, peripheral blood mononuclear cell.

All procedures were approved by the Human Research Ethical Commit

All procedures were approved by the Human Research Ethical Committee of the Universidade Federal de Santa Catarina. Informed consent was obtained from the patients and controls. Initially, we analysed if patients who underwent the neuropsychological evaluation were comparable with the eligible patients, who were not evaluated (dropout cases) according to their clinical, demographic, and hospitalization variables. Categorical variables were analysed using chi-square, continuous variables by

Mann–Whitney tests. The neuropsychological performance of patients and control participants was compared by the Mann–Whitney U test to identify the cognitive domains affected by TBI. Holm’s sequential rejection procedure (Holm, 1979) was applied

to counteract the problem of multiple comparisons, and p < 0.01 was considered statistically significant. selleck kinase inhibitor A univariate analysis was performed to investigate the association between the performances of patients on each neuropsychological test (dependent variables) and their clinical, demographic, and hospitalization variables (independent variables). The association Selleck PLX4032 among the neuropsychological tests and age and education (both in years) at the time point of TBI was investigated by linear regression. Normality ifenprodil of the distribution was determined by the Kolmogorov–Smirnov test. The association between the demographic clinical, laboratory, neurosurgical, and neuroradiological variables from the acute TBI phase and the neuropsychological tests was performed by Student’s t-test or analysis of variance (ANOVA). The independent variables that showed an association with the neuropsychological tests (dependent variables) in the univariate analysis with a p level of significance lower

than .20 were included in a linear multiple regression analysis. This analysis was performed to identify the demographic, clinical, laboratory, neurosurgical, and neuroradiological variables that could be considered good predictors for each cognitive test performance later after the TBI. In this analysis, the independent continuous variables were considered covariates. Categorical variables were included in the model classified as 0 or 1 (for dichotomous) and 0, 1, or 2 for those showing three categories. Because a previous work (Senathi-Raja, Ponsford, & Schonberger, 2010) demonstrated that after maximum spontaneous recovery from TBI, poorer cognitive functioning may be independently associated with the increased time after injury, we also included in the regression analysis the time (in years) of cognitive evaluation after the occurrence of TBI.

4% (56) were receiving stable OST The majority were male (66 1%,

4% (56) were receiving stable OST. The majority were male (66.1%, 37/56) and white (94.6%, 53/56), and the mean age was 47.9 years. Nine patients (16.1%) were treatment-experienced. One patient had compensated cirrhosis. Of the 56 patients, 54 (96.4%) achieved SVR12. A majority of patients (89.3%, 50/56) experienced at least 1 adverse event (AE), most of which were mild. Two patients (3.7%) experienced a serious AE. None of the patients on OST experienced virologic failure; 1 patient (1.8%) discontinued due to an AE at day 26, and 1 patient discontinued for non-compliance. Grade 3 bilirubin elevation occurred in 1 patient (1.8%); there were no grade 3 or greater

elevations in ALT, AST, or alkaline phos-phatase. Conclusions: In agreement with previous reports, the 3D regimen

with or without RBV was well tolerated Acalabrutinib ic50 in patients on stable OST, with a high SVR12 rate of 96.4%, and a favorable toxicity profile. check details These data suggest that this interferon-free regimen may be a suitable treatment option for this patient population. Disclosures: Massimo Puoti – Advisory Committees or Review Panels: GSK, Abbott, Janssen, MSD, Roche, Gilead Sciences, Novartis, GSK, Abbott, Janssen, MSD, Roche, Gilead Sciences, Novartis, GSK, Abbott, Janssen, MSD, Roche, Gilead Sciences, Novartis, GSK, Abbott, Janssen, MSD, Roche, Gilead Sciences, Novartis; Speaking and Teaching: BMS, BMS, BMS, BMS Curtis Cooper – Advisory Committees or Review Panels: Vertex, MERCK, Roche; Grant/Research Support: MERCK, Roche; Speaking and Teaching: Roche, MERCK Mark S. Sulkowski – Advisory Committees or Review Panels: Merck, AbbVie, Idenix, Janssen, Gilead, BMS, Pfizer; Grant/Research Support: Merck, AbbVie, BIPI, Vertex, Janssen, Gilead, BMS Graham R. Foster – Advisory Committees or Review Panels: GlaxoSmithKline, Novartis, Boehringer Ingelheim, Amino acid Tibotec, Chughai, Gilead, Janssen, Idenix, GlaxoSmithKline, Novartis, Roche, Tibotec, Chughai, Gilead, Merck, Janssen, Idenix, BMS; Board Membership: Boehringer Ingelheim; Grant/Research

Support: Chughai, Roche, Chughai; Speaking and Teaching: Roche, Gilead, Tibo-tec, Merck, BMS, Boehringer Ingelheim, Gilead, Janssen Thomas Berg – Advisory Committees or Review Panels: Gilead, BMS, Roche, Tibotec, Vertex, Jannsen, Novartis, Abbott, Merck; Consulting: Gilead, BMS, Roche, Tibotec; Vertex, Janssen; Grant/Research Support: Gilead, BMS, Roche, Tibotec; Vertex, Jannssen, Merck/MSD, Boehringer Ingelheim, Novartis; Speaking and Teaching: Gilead, BMS, Roche, Tibotec; Vertex, Janssen, Merck/MSD, Novartis, Merck, Bayer Erica Villa – Advisory Committees or Review Panels: Abbvie, GSK; Grant/ Research Support: MSD, Roche Federico Rodriguez-Perez – Advisory Committees or Review Panels: Merck, Bristol, Abbive Vinod Rustgi – Advisory Committees or Review Panels: Abbvie, Gilead; Grant/ Research Support: Abbvie, Gilead, BMS; Speaking and Teaching: Gilead, Genentech David L.

5 Switching aspirin to other antiplatelet medications (e g ticlo

5 Switching aspirin to other antiplatelet medications (e.g. ticlopidine, clopidogrel, and so on) is a reasonable alternative in the treatment of patients who cannot tolerate aspirin due to dyspepsia or allergy, or who have gastrointestinal complications from aspirin, but there are significant drawbacks with all existing antiplatelet agents. For example, ticlopidine

is associated with neutropenia in 2.1% of patients.6 Clopidogrel is associated with an increased risk of upper gastrointestinal bleeding (9–13% by 1 year) in patients with prior histories of peptic ulcer diseases.7 Clinicians should therefore balance the CV benefits and GI or hematological risks when prescribing antiplatelet agents. Currently, two categories of antiplatelet agents, aspirin and the thienopyridines (ticlopidine, clopidogrel and prasugrel) are popular for the primary or secondary prevention of cardiovascular Ibrutinib molecular weight Silmitasertib chemical structure diseases. Aspirin reduces platelet activity by decreasing thromboxane synthesis through the inhibition of cyclooxygenase (COX)-1 enzymes. However, due to its inhibition

of COX-mediated prostaglandin synthesis, direct cytotoxicity and microvascular injury, aspirin is associated with upper GI side effects, which range from mild dyspepsia (31%) to life-threatening bleeding and perforation from peptic ulcers (3%) over a period of 4 years in the UK Transient Ischaemic Attack Study.8 A prospective study by Laine

et al. reported that the 12-week cumulative incidence of ulcers in low-dose aspirin users was 7%.9 The risk of serious ulcer complications are about two- to fourfold higher in patients taking low-dose (75–325 mg daily) aspirin than control.10 Clopidogrel is a thienopyridine derivative, which inhibits platelet function by selectively Metalloexopeptidase and irreversibly blocking the adenosine diphosphate (ADP) receptor on platelets, thereby affecting ADP-dependent activation of the GpIIb-IIIa complex, the major receptors for fibrinogen present on the platelet surface.11 The CAPRIE (Clopidogrel vs Aspirin in Patients at Risk of Ischemic Events) study showed that long-term administration of clopidogrel to patients with atherosclerotic vascular disease is more effective than aspirin in reducing the combined risk of ischemic events.12 Additionally, clopidogrel induced fewer episodes of GI bleeding than aspirin. However, a recent study from our center demonstrated that 11% of the patients with a peptic ulcer history who took clopidogrel for the prevention of ischemic events had recurrent peptic ulcer during a 6-month follow-up period.13 Another prospective study also showed 9% of patients with a history of peptic ulcer bleeding who took clopidogrel had recurrent ulcer bleeding within one year.7 The mechanisms leading to recurrent peptic ulcers and ulcer bleeding among patients receiving clopidogrel are unclear.

Next, wax-up was performed on working models for porcelain crown

Next, wax-up was performed on working models for porcelain crown fabrication, and CAD/CAM porcelain crowns were fabricated. The CAD/CAM zirconia frameworks and CAD/CAM porcelain crowns were bonded using adhesive resin cement, and the PAZ was cemented. Cementation of the implant superstructure improved the esthetics and masticatory efficiency in all patients. No undesirable outcomes, such as superstructure chipping, stomatognathic dysfunction, or periimplant bone resorption, were observed in any of the patients. PAZ may be a potential solution for ceramic-related clinical problems Everolimus such as chipping and fracture and associated complicated repair procedures in implant-supported

FDPs. “
“Purpose: To investigate the effect of the selected chemical surface treatment agents on the flexural strength of heat-polymerized acrylic resin repaired with autopolymerized acrylic resin. CFTR modulator Materials and Methods: Ninety heat-polymerized acrylic resin specimens (Meliodent) were prepared according to ISO1567 and randomly divided into nine groups: positive and negative control groups (groups I and II), and seven experimental groups (groups III to IX). Specimens in groups II to IX were cut in the middle and beveled 45°. Group III was then treated with methyl methacrylate (the liquid part

of Unifast TRAD) for 180 seconds. Group IV was treated with Rebase II adhesive according to the manufacturer’s instructions. Groups V to IX were treated with methyl formate, methyl acetate, Pyruvate dehydrogenase lipoamide kinase isozyme 1 and a mixture of methyl formate–methyl acetate at various concentrations (75:25, 50:50, 25:75% v/v, respectively) for 15 seconds. They were then repaired with autopolymerized acrylic resin (Unifast TRAD). A three-point loading test was performed using a universal testing machine. One-way ANOVA and post hoc Tukey’s analysis at p < 0.05 were used for statistical comparison.

Failure analysis was then recorded for each specimen. The morphological changes in untreated and treated specimens were observed by scanning electron microscopy. Results: The flexural strengths of groups III to IX were significantly higher than that of group II (p < 0.05). The flexural strengths of groups IV to IX showed no significant difference among them (p > 0.05). All specimens in groups V to IX showed 100% cohesive failure, while groups II, III, and IV showed cohesive failure of 10%, 60%, and 60%, respectively. From scanning electron micrographs, the application of methyl formate, methyl acetate, and a mixture of methyl formate–methyl acetate solutions on heat-polymerized acrylic resin resulted in a 3D honeycomb appearance, while specimens treated with methyl methacrylate and Rebase II adhesive developed shallow pits and small crest patterns, respectively.

Aim: In this multicentre study, we aimed to compare hepatic and t

Aim: In this multicentre study, we aimed to compare hepatic and tumour related outcomes of local regional Forskolin mw therapy for HCC in patients with chronic HBV or HCV with and without the MetS. Method: Patients with viral hepatitis treated with local regional therapy (transarterial chemoembolisation +/- radiofrequency ablation) for HCC between 2007-2013 in two large Sydney hospitals were included in this retrospective study. Medical records for these patients were audited for patient demographics, hepatic and tumour characteristics at diagnosis, number and intervals of local regional therapy

as well as episodes of hepatic decompensation (jaundice, ascites, varices, encephalopathy, infections). Patients with viral hepatitis were classified into 2 groups according to the presence Kinase Inhibitor Library manufacturer of absence of the MetS, as defined by the Adult Treatment Panel III. Results: A total of 69 patients were included in the study, 32 patients with the MetS and 37 patients without. The mean age of the whole group was 60.9 ± 12.1 and the male to female ratio was 4.31. Demographics and clinical data of patients with and without the MetS are presented in table 1. With respect to tumour response outcomes, there was no statistical difference in the average number of local regional therapy sessions in both groups (2.3±1.62 vs 2.1 ±1.53, p=0.5373), and the intervals between therapies. In contrast,

with respect to hepatic decompensations; significantly more episodes of hepatic decompensation were seen in those with MetS than those without MetS (34% vs 11%, p=0.0220). Conclusion: In patients either with HCC and viral hepatitis treated with local regional therapy, presence of metabolic syndrome is associated with significantly higher rates of hepatic

decompensation. Disclosures: Jacob George – Advisory Committees or Review Panels: Roche, BMS, MSD, Gilead, Janssen The following people have nothing to disclose: Fei Wen Chen, Amany Zekry HCC is still an unsolved burden with a rising incidence worldwide. Hypoxia and HIF1-alpha expression is a known negative predictor for overall survival. HIF1-alpha is mainly expressed in highly aggressive hcc. Cut homeobox 1 (CUX1) gene is a target of loss-of-heterozygoticy in many cancers, yet elevated CUX1 expression is frequently observed and is associated with shorter disease-free survival. It plays a critical role in the RAS dependent DNA repair under oxidative stress. The role of CUX1 in hcc is still uninvestigated. In the present study the influence of HIF-1-alpha on CUX1 expression in vitro and its effect on apoptosis and proliferation were investigated. HIF-1-alpha was induced in HepG-2-cells by Cobald chloride (CoCl). CUX1 was downregulated by 3 different si RNA. Markers of apoptosis and apoptosis like bax/bcl-2 were determined by westernblotting, RT-PCR and imunohistochemistery.

Among the families enrolled in MIBS, approximately 70% were found

Among the families enrolled in MIBS, approximately 70% were found to be concordant in which either all or none of the siblings had a history of inhibitors AZD9668 cell line [6]. The con- and discordancies in each subgroup of mutation are shown in Fig. 1. The concordance in the families with inhibitors was approximately 40%. The corresponding figures for the families with intron 22 inversions were 63% and 40%, respectively. In two families with large gene deletions, none of the siblings had an inhibitor history, and although only a small proportion of the families with missense mutations, small deletions/insertions and splice site mutations experienced inhibitors,

all siblings in some of these families had high-responding inhibitors. The family data clearly indicate that additional inherited genetic determinants, other than the type of causative fVIII mutation, will be of major VX-809 manufacturer importance in predicting the immunological outcome of replacement therapy. The HLA class

I alleles A3, B7 and C7, as well as the class II alleles DQA0102, DQB0602, DR15 have all been associated with higher risk for inhibitor development in unrelated patients [relative risk (RR) of 1.9–4.0], whereas the HLA C2, DQA0103, DQB0603 and DR13 alleles seem to be protective [7,8]. The reported associations were, however, weak and not statistically consistent. In the MIBS study, these alleles were equally distributed between the two patient groups [10].

Instead, significant associations were identified for two of the other class I alleles, i.e. HLA A26 and B44, but after correction for multiple comparisons no significant differences remained. IL-10 is an important anti-inflammatory cytokine exerting a broad spectrum of activities. IL-10 also enhances the in vitro production of all types of immunoglobulins by peripheral blood mononuclear cells in patients with autoimmune diseases and the serum concentration of IL-10 has been correlated to the disease activity in these patients [12,13]. The most interesting STK38 polymorphism with a functional implication described in the IL-10 gene is a 134 bp long variant of a CA microsatellite in the promoter region (IL-10.G) [14–16]. In the MIBS study, the allele 134 bp was identified in 44 of all 164 patients with haemophilia A (26.8%) [9]. Thirty-two of these 44 patients (72.7%) developed inhibitors compared with 45 of the 120 patients (37.5%) without the allele. Among all 77 patients with a history of inhibitors, allele 134 was found in 32 patients (41.6%) compared with 12 of the 87 inhibitor negative patients (13.8%; P < 0.001). This corresponds to an odds ratio (OR) of 4.4 with a 95% confidence interval (CI) of 2.1–9.5. A significant association between the allele and the development of inhibitors was also found in a subgroup analysis of patients with severe haemophilia A, i.e.

The majority of the white individuals in this study (>90%) had ha

The majority of the white individuals in this study (>90%) had haplotype H1 while the rest carried H2. The black population in this study showed far greater diversity, with haplotypes H1 to H5 being represented in approximately 35%, 37%, 22%, 4% and 1% of the sampled individuals, respectively. Figure 2b shows the prevalence of inhibitor development in a cohort of 76 evaluable (of 78 total) black American HA patients as well as the specific background F8 haplotypes on which

their mutations arose; the distribution of patient haplotypes was comparable with that observed in a separately studied healthy black population [13]. Two previously unknown F8 ns-SNPs (A1229C encoding Gln334Pro and G4007A encoding Arg1260Lys) (Fig. 2a), which were also identified in the cohort of 76 black HA patients, defined two additional F8 haplotypes referred see more to as H7 and H8 (Fig. 2b). The recombinant FVIII products currently used for HA replacement CCI-779 chemical structure therapy correspond to

either haplotype H1 or H2, the most common haplotypes in all populations investigated so far [13]. As a result, patients with an H1 or H2 background haplotype treated with the currently available recombinant products can receive a matched (or more accurately a ‘least mismatched’) FVIII protein, i.e. one that differs from their defective endogenous FVIII protein (if any is produced) only at the sites encoded by their HA-causing F8 mutations. Patients infused with plasma-derived products may also be receiving FVIII proteins that are matched to a greater or lesser extent to their endogenous FVIII sequence, depending on their background F8 haplotypes and the Selleckchem Paclitaxel haplotypes of the donors who contributed to the plasma pool. Our earlier study [13] indicated

that approximately one in four of the 76 black American subjects with HA had a background haplotype other than H1 or H2. The currently available recombinant FVIII proteins are thus mismatched at one or more of the sites encoded by ns-SNPs, in addition to the site corresponding to the haemophilic F8 mutation (Fig. 2). Although D1241E, the ns-SNP site that differentiates haplotypes H1 and H2, is removed in B-domain deleted FVIII (Fig. 2c), an additional amino acid sequence mismatch exists between the endogenous dysfunctional FVIII proteins in patients and this recombinant product at its non-naturally occurring B-domain junction [30]. Currently available B-domain deleted products only contain FVIII amino acid sequence, yet their synthetic junctional sites are ‘foreign’ and, as such, could be immunogenic in patients with a permissive major-histocompatibility complex (MHC). These recent findings provide one plausible mechanistic explanation for reports that black HA patients are approximately twice as likely as white HA patients to produce inhibitors against therapeutic FVIII proteins [9–12].

AB, apoptotic body; AMA, antimitochondrial antibodies; ATPB, aden

AB, apoptotic body; AMA, antimitochondrial antibodies; ATPB, adenosine-5′-triphosphate synthase subunit beta;

BCOADC-E2, E2 subunit of the branched chain 2-oxo acid dehydrogenase complex; BEC, biliary epithelial cell; BrEPC, bronchial epithelial cell; COX-IV, cytochrome C oxidase IV; DECRI, 2,4-dienoyl coenzyme A reductase 1; GCDC, glycochenodeoxycholate; gp210, glycoprotein 210 kDa; GST, glutathione S-transferase; HiBEC, human intrahepatic biliary cell; HRP, horseradish peroxidase; IgG, immunoglobulin G; MaEPC, mammary epithelial cell; MHC, major histocompatibility complex; OGDC-E2, E2 subunit of the oxo-glutarate dehydrogenase complex; PAD, postapoptotic degradation; PBC, primary biliary cirrhosis; PDC-E2, AZD6738 manufacturer E2 subunit of the pyruvate dehydrogenase complex; PSC, primary sclerosing cholangitis;

SLE, systemic lupus erythematosus; Sp100, speckled 100 kDa autoantigen; UQCR2, ubiquinol cytochrome C reductase complex core protein II. Serum samples were obtained from human subjects diagnosed with PBC (n = 114), Palbociclib price systemic lupus erythematosus (SLE; n = 23), primary sclerosing cholangitis (PSC; n = 22), or unaffected controls (n = 31). The diagnosis in all cases was based on established criteria.1, 14, 15 Patients with PBC and the three control groups were matched by sex and age. The 114 patients with PBC include 108 females and 6 males. Ninety-five patients had serum AMA, whereas 19 were negative for AMA. The AMA-positive serum samples were randomly selected from a sera bank maintained at the University of California Davis. The presence or absence of serum AMA was confirmed by both immunofluorescence

microscopy and immunoblotting against recombinant antigens (see below). The clinical and pathological features of patients with PBC are summarized in Table 1. The protocol was approved by the Institutional Review Board of the University of California Davis. Recombinant human PDC-E2, OGDC-E2, and BCOADC-E2 were prepared in our laboratory as described.9, 16 Partial recombinant human DECR1 fused to glutathione S-transferase (GST) was purchased from Abnova (Taipei, Taiwan). Recombinant ubiquinol cytochrome c reductase complex core protein II (UQCRC2), cytochrome C oxidase IV C59 research buy (COX-IV), and adenosine-5′-triphosphate synthase subunit beta (ATPB) were purchased from Abcam, Inc. (Cambridge, MA). The antigens studied herein were selected based on their ubiquitous mitochondrial nature and conserved sequence across species. Mouse monoclonal antibodies against PDC-E2, OGDC-E2, and BCOADC-E2 (clones 2H-4C8, 2H-5A12, and 2H-2D3, respectively) have been described previously.17 Mouse monoclonal antibodies against ATPB (clone 3D5), DECR1, UQCRC2 (clone 13G12), COX-IV (clone 20E8), and SSA/Ro (Sjögren’s syndrome antigen A) were purchased from Abcam.

53 The suppression of cardiac contractility by CB1

53 The suppression of cardiac contractility by CB1 SCH 900776 nmr receptor activation may involve inhibition of L-type calcium channels54 and/or reductions in the myocardial cyclic adenosine

monophosphate content.55 Of the 2 major endocannabinoids, AEA is more likely to be involved, as suggested by a cirrhosis-related increase in myocardial AEA levels but not 2-AG levels.53 These findings raise the therapeutic potential of CB1 blockade in treating the hemodynamic abnormalities of patients with advanced liver cirrhosis. Because the increase in mesenteric blood flow may precipitate the rupture of varicosities and also contributes to ascites formation, CB1 blockade may avert these potentially fatal complications and thus keep patients alive until a liver transplant becomes available. CB2 receptors, which are normally undetectable in the liver, are prominently expressed in the cirrhotic human liver and are also detectable in nonparenchymal liver cells in the fibrotic mouse liver.9 THC suppresses the proliferation and induces the apoptosis of human hepatic myofibroblasts and stellate cells via CB2 receptors9 and thus may be antifibrotic and hepatoprotective.56

Accordingly, CB2−/− mice had an enhanced response to fibrogenic stimuli.9 CB2 receptor activation Cilomilast supplier by AEA also inhibits the hyperplastic proliferation of cholangiocytes, which is a frequent result of extrahepatic biliary obstruction, cholestasis, and toxic liver injury. This has been associated with the increased production of reactive oxygen species and cell death via the induction of the activator protein 4-Aminobutyrate aminotransferase 1 complex and thioredoxin 1.3 In cirrhotic rats, chronic treatment with the CB2-selective agonist JWH-133 attenuated cellular markers of fibrosis57 and enhanced the regenerative response to acute liver injury. Accordingly, CB2−/− mice had delayed liver regeneration in response to CCl4-induced injury, whereas JWH-133 treatment reduced the injury and accelerated liver regeneration.33 These

findings signal the therapeutic potential of nonpsychoactive CB2 agonists in the treatment of liver fibrosis. Paradoxically, in patients with hepatitis C virus infection, daily cannabis use increased fibrosis progression instead of protecting patients against it.58 Thus, endocannabinoids also exert a profibrotic effect that is possibly mediated by CB1 receptors. This is compatible with the finding of increased CB1 expression in stellate cells and hepatic myofibroblasts in the cirrhotic human liver and in the livers of mice with three different models of fibrosis.5 Genetic or pharmacological ablation of CB1 receptors protected mice against liver injury; this was reflected by the reduced expression of smooth muscle α-actin and transforming growth factor β.5 2-AG is the likely fibrogenic mediator because its hepatic level is preferentially increased by the CCl4 treatment of mice26 and rats.