g., Escherichia coli urinary tract infections, pneumococcal pneumonia, gonorrhea, tuberculosis) increases and success declines to unacceptable levels, new regimens are introduced. Few would consider or recommend comparing the new highly successful regimen with a previous “locally best” or “tradition” in which resistance had undermined success (i.e., there would be no need to “prove” that the new regimen was “better” than one that was known to be no longer acceptable locally). However, this seemingly unimaginable scenario

occurs often in anti-H. pylori clinical trials. Not only are good and bad anti-H. pylori therapies compared but also the results are then subjected to meta-analyses, which only prove that what was known to a bad regimen

is reliably bad [3]. It NVP-LDE225 is unethical to enter subjects into a trial using a known inferior regimen [2]. It is also unethical to withhold full information from the subject regarding current effectiveness of a regimen even if that information would reduce the likelihood that anyone would volunteer (i.e., an inferior regimen can never be called the “standard of care” or “approved” in lieu of telling the truth about the actual expected outcome). As 100% success can be achieved, 100% success is a comparator of choice with therapies being judged in terms of how close they come to achieving that level of success. If the best local therapy PF-02341066 in vitro provides unacceptable low cure rates, it should be abandoned just as was single-drug therapy for tuberculosis or low-dose penicillin for pneumonia or Dipeptidyl peptidase syphilis. We do not suggest that comparisons between regimens should never be performed, rather comparisons should be restricted to known good therapies (i.e., to identify the best in terms of outcome, cost, convenience, side effects,

etc.). One only needs to know the success rates for a H. pylori regimen and its components, in relation to the presence of resistance and the level of resistance locally to be able to predict the range of possible outcomes. For example, with legacy triple therapy consisting of a proton pump inhibitor (PPI), clarithromycin, and amoxicillin, the data needed are as follows: the cure rate for the three-drug combination and each of the two dual therapies (i.e., PPI–clarithromycin and PPI–amoxicillin). As amoxicillin resistance is extremely rare, one only needs to know the rates for the triple therapy and the PPI–amoxicillin dual component (Table 2). In the majority of cases, the overall effect is related to the triple component. For example, with 20% clarithromycin resistance, the cure with 14-day triple would be the success with susceptible strains plus the success with clarithromycin-resistant strains.

g., Escherichia coli urinary tract infections, pneumococcal pneumonia, gonorrhea, tuberculosis) increases and success declines to unacceptable levels, new regimens are introduced. Few would consider or recommend comparing the new highly successful regimen with a previous “locally best” or “tradition” in which resistance had undermined success (i.e., there would be no need to “prove” that the new regimen was “better” than one that was known to be no longer acceptable locally). However, this seemingly unimaginable scenario

occurs often in anti-H. pylori clinical trials. Not only are good and bad anti-H. pylori therapies compared but also the results are then subjected to meta-analyses, which only prove that what was known to a bad regimen

is reliably bad [3]. It PD-1/PD-L1 inhibitor is unethical to enter subjects into a trial using a known inferior regimen [2]. It is also unethical to withhold full information from the subject regarding current effectiveness of a regimen even if that information would reduce the likelihood that anyone would volunteer (i.e., an inferior regimen can never be called the “standard of care” or “approved” in lieu of telling the truth about the actual expected outcome). As 100% success can be achieved, 100% success is a comparator of choice with therapies being judged in terms of how close they come to achieving that level of success. If the best local therapy selleck provides unacceptable low cure rates, it should be abandoned just as was single-drug therapy for tuberculosis or low-dose penicillin for pneumonia or mafosfamide syphilis. We do not suggest that comparisons between regimens should never be performed, rather comparisons should be restricted to known good therapies (i.e., to identify the best in terms of outcome, cost, convenience, side effects,

etc.). One only needs to know the success rates for a H. pylori regimen and its components, in relation to the presence of resistance and the level of resistance locally to be able to predict the range of possible outcomes. For example, with legacy triple therapy consisting of a proton pump inhibitor (PPI), clarithromycin, and amoxicillin, the data needed are as follows: the cure rate for the three-drug combination and each of the two dual therapies (i.e., PPI–clarithromycin and PPI–amoxicillin). As amoxicillin resistance is extremely rare, one only needs to know the rates for the triple therapy and the PPI–amoxicillin dual component (Table 2). In the majority of cases, the overall effect is related to the triple component. For example, with 20% clarithromycin resistance, the cure with 14-day triple would be the success with susceptible strains plus the success with clarithromycin-resistant strains.

g., Escherichia coli urinary tract infections, pneumococcal pneumonia, gonorrhea, tuberculosis) increases and success declines to unacceptable levels, new regimens are introduced. Few would consider or recommend comparing the new highly successful regimen with a previous “locally best” or “tradition” in which resistance had undermined success (i.e., there would be no need to “prove” that the new regimen was “better” than one that was known to be no longer acceptable locally). However, this seemingly unimaginable scenario

occurs often in anti-H. pylori clinical trials. Not only are good and bad anti-H. pylori therapies compared but also the results are then subjected to meta-analyses, which only prove that what was known to a bad regimen

is reliably bad [3]. It click here is unethical to enter subjects into a trial using a known inferior regimen [2]. It is also unethical to withhold full information from the subject regarding current effectiveness of a regimen even if that information would reduce the likelihood that anyone would volunteer (i.e., an inferior regimen can never be called the “standard of care” or “approved” in lieu of telling the truth about the actual expected outcome). As 100% success can be achieved, 100% success is a comparator of choice with therapies being judged in terms of how close they come to achieving that level of success. If the best local therapy www.selleckchem.com/products/pf-06463922.html provides unacceptable low cure rates, it should be abandoned just as was single-drug therapy for tuberculosis or low-dose penicillin for pneumonia or ID-8 syphilis. We do not suggest that comparisons between regimens should never be performed, rather comparisons should be restricted to known good therapies (i.e., to identify the best in terms of outcome, cost, convenience, side effects,

etc.). One only needs to know the success rates for a H. pylori regimen and its components, in relation to the presence of resistance and the level of resistance locally to be able to predict the range of possible outcomes. For example, with legacy triple therapy consisting of a proton pump inhibitor (PPI), clarithromycin, and amoxicillin, the data needed are as follows: the cure rate for the three-drug combination and each of the two dual therapies (i.e., PPI–clarithromycin and PPI–amoxicillin). As amoxicillin resistance is extremely rare, one only needs to know the rates for the triple therapy and the PPI–amoxicillin dual component (Table 2). In the majority of cases, the overall effect is related to the triple component. For example, with 20% clarithromycin resistance, the cure with 14-day triple would be the success with susceptible strains plus the success with clarithromycin-resistant strains.

1B). Published reports of the effects of other HDAC inhibitors on topoIIα expression indicate a cell type- and/or context-specificity. For example, treatment of D54 glioblastoma cells with trichostatin A or vorinostat had no effect on topoIIα expression.15 Although sodium butyrate was reported to sensitize leukemia cells to etoposide by increasing topoIIα gene expression,16 treatment of MCF-7 cells with valproic acid led to transcriptional repression of topoIIα.17 check details To clarify this issue, we assessed the concentration-dependent effect of sodium butyrate on topoIIα expression in PLC5 cells. Our data show that treatment with a range of concentrations

of sodium butyrate revealed a biphasic effect on topoIIα expression levels, i.e., up-regulation at low concentrations (≤0.25 mM) and down-regulation at higher concentrations (≥0.5 mM), without disturbing topoIIβ expression (Fig. 1C). These concentrations are consistent with those of sodium butyrate (0.4 mM) and valproic acid (2 mM) that up-regulated and down-regulated topoIIα expression, respectively, in the aforementioned studies. This dichotomous effect may typify the complex mode of action of short-chain fatty

acids in regulating topoIIα expression relative to other HDAC inhibitors examined. The finding that MS-275 was able to suppress topoIIα expression suggests the involvement of class I HDACs in the drug response. selleck kinase inhibitor Thus, we assessed the effect of shRNA or siRNA-mediated knockdown of class I (HDAC1 and 2) vis-à-vis class II isozymes (HDAC4-6) on topoIIα messenger RNA (mRNA) and protein expression in PLC5 cells. Silencing of HDAC1 caused a sharp decrease in the topoIIα protein level, whereas the mRNA expression was not altered (Fig. 2A). However, the knockdown of other isozymes had no effect on the mRNA or protein expression of topoIIα. Evidence indicates that this topoIIα down-regulation was

attributable to proteasomal degradation. First, exposure of PLC5 cells to AR42 or MS-275 did not cause appreciable changes in topoIIα mRNA levels as determined by RT-PCR (Fig. 2B). Second, Edoxaban the proteasome inhibitor MG132 protected cells against the suppressive effect of AR42, MS-275, and vorinostat on topoIIα expression (Fig. 2C). Third, in the presence of cycloheximide, AR42 promoted the elimination of topoIIα relative to the DMSO control (Fig. 2D). Together, these data suggest a pivotal role of HDAC1 in the regulation of topoIIα protein stability. It is well documented that ubiquitin-dependent protein degradation is preceded by phosphorylation.18 As shown in Fig. 3A, concentration-dependent topoIIα repression by AR42 was accompanied by parallel increases in p-Ser/Thr phosphorylation and ubiquitination. However, no appreciable acetylation of topoIIα was noted in response to AR42 treatment, suggesting that topoIIα stability is not influenced by HDAC-regulated acetylation.

The number of each cell type per mm2 of portal tract and parenchyma was calculated by counting positive cells in 10 portal tracts and in every tenth field of parenchyma, respectively. Immunofluorescence assays were performed in LabTek 8-well Permanox chamber slides (Nalge Nunc International, Rochester, NY) coated with

poly-L-lysine hydrobromide. For IL-2 detection, wells were coated with IL-2 capture antibodies (7 μg/mL). HuT 78 cells were added at a concentration of 1 × 105 per mL and left at 37°C to adhere. Following treatment, cells were fixed in 3% paraformaldehyde and where necessary permeabilized with 0.5% Triton X-100 detergent (Sigma Aldrich). IL-2 (secreted BMN-673 or intracellular) was detected using an Alexafluor 488–conjugated rat anti-human antibody. Confocal microscopy was performed using a 100× oil immersion objective

on a Nikon TE2000-U inverted microscope using a PerkinElmer LSI confocal system, equipped with an Ar/Kr laser (488 nm). Ultraview image acquisition system (Perkin Elmer) and Volocity-2 processing software (Improvision Inc.) were used for image processing and three-dimensional analyses. For analysis of lipid rafts, HuT 78 cells (1 × 105 per mL) were left at 37°C to adhere and then either left resting or treated with 1 μg/mL of E2 for 24 hours. Cells were fixed in 1% paraformaldehyde and lipid rafts were stained using a Vybrant Labeling Kit. Cells were then labeled with Alexafluor Doxorubicin 568–conjugated anti-PKCβ (Molecular Probes, Inc.). Confocal microscopy was performed using a 63× oil immersion objective on a Zeiss 510 Meta Confocal Laser Scanning Microscope (laser excitation 488 nm and 561 nm). Polymerase chain reactions (PCRs) were performed with a TaqMan Master Mix kit (Applied Biosystems, UK) and a mix of primers and fluorescently

labeled TaqMan MGB probes (Applied Biosystems, Selleck Ixazomib UK) was used for the target gene; the housekeeping gene glyceraldehyde-3-phosphate dehydrogenase was used as an endogenous control. Quantitative real-time PCR data were obtained using the comparative CT method. For cell culture supernatants, a human IL-2 DuoSet enzyme-linked immunosorbent assay (ELISA) development kit (R&D Systems, Oxon, UK) was used according to the manufacturer’s instructions. For tissue samples, ELISA antibody pairs for the detection of cytokine proteins were obtained from R&D Systems. For multiplex analysis, a Biochip Array Technology system, the Evidence Investigator (Randox Laboratories Ltd., UK), was used to measure multiple cytokines in cell culture supernatants. The results are expressed as the mean ± SEM. The data were analyzed using Microsoft Excel statistical software using the Student t test. The levels of IL-2 in HCV, alcoholic liver disease (ALD), and primary biliary cirrhosis (PBC) livers are expressed as the median, and data were analyzed using the Mann-Whitney U test. P < 0.05 was considered statistically significant.

The number of each cell type per mm2 of portal tract and parenchyma was calculated by counting positive cells in 10 portal tracts and in every tenth field of parenchyma, respectively. Immunofluorescence assays were performed in LabTek 8-well Permanox chamber slides (Nalge Nunc International, Rochester, NY) coated with

poly-L-lysine hydrobromide. For IL-2 detection, wells were coated with IL-2 capture antibodies (7 μg/mL). HuT 78 cells were added at a concentration of 1 × 105 per mL and left at 37°C to adhere. Following treatment, cells were fixed in 3% paraformaldehyde and where necessary permeabilized with 0.5% Triton X-100 detergent (Sigma Aldrich). IL-2 (secreted selleck kinase inhibitor or intracellular) was detected using an Alexafluor 488–conjugated rat anti-human antibody. Confocal microscopy was performed using a 100× oil immersion objective

on a Nikon TE2000-U inverted microscope using a PerkinElmer LSI confocal system, equipped with an Ar/Kr laser (488 nm). Ultraview image acquisition system (Perkin Elmer) and Volocity-2 processing software (Improvision Inc.) were used for image processing and three-dimensional analyses. For analysis of lipid rafts, HuT 78 cells (1 × 105 per mL) were left at 37°C to adhere and then either left resting or treated with 1 μg/mL of E2 for 24 hours. Cells were fixed in 1% paraformaldehyde and lipid rafts were stained using a Vybrant Labeling Kit. Cells were then labeled with Alexafluor Epigenetics Compound Library 568–conjugated anti-PKCβ (Molecular Probes, Inc.). Confocal microscopy was performed using a 63× oil immersion objective on a Zeiss 510 Meta Confocal Laser Scanning Microscope (laser excitation 488 nm and 561 nm). Polymerase chain reactions (PCRs) were performed with a TaqMan Master Mix kit (Applied Biosystems, UK) and a mix of primers and fluorescently

labeled TaqMan MGB probes (Applied Biosystems, O-methylated flavonoid UK) was used for the target gene; the housekeeping gene glyceraldehyde-3-phosphate dehydrogenase was used as an endogenous control. Quantitative real-time PCR data were obtained using the comparative CT method. For cell culture supernatants, a human IL-2 DuoSet enzyme-linked immunosorbent assay (ELISA) development kit (R&D Systems, Oxon, UK) was used according to the manufacturer’s instructions. For tissue samples, ELISA antibody pairs for the detection of cytokine proteins were obtained from R&D Systems. For multiplex analysis, a Biochip Array Technology system, the Evidence Investigator (Randox Laboratories Ltd., UK), was used to measure multiple cytokines in cell culture supernatants. The results are expressed as the mean ± SEM. The data were analyzed using Microsoft Excel statistical software using the Student t test. The levels of IL-2 in HCV, alcoholic liver disease (ALD), and primary biliary cirrhosis (PBC) livers are expressed as the median, and data were analyzed using the Mann-Whitney U test. P < 0.05 was considered statistically significant.

The number of each cell type per mm2 of portal tract and parenchyma was calculated by counting positive cells in 10 portal tracts and in every tenth field of parenchyma, respectively. Immunofluorescence assays were performed in LabTek 8-well Permanox chamber slides (Nalge Nunc International, Rochester, NY) coated with

poly-L-lysine hydrobromide. For IL-2 detection, wells were coated with IL-2 capture antibodies (7 μg/mL). HuT 78 cells were added at a concentration of 1 × 105 per mL and left at 37°C to adhere. Following treatment, cells were fixed in 3% paraformaldehyde and where necessary permeabilized with 0.5% Triton X-100 detergent (Sigma Aldrich). IL-2 (secreted Natural Product Library manufacturer or intracellular) was detected using an Alexafluor 488–conjugated rat anti-human antibody. Confocal microscopy was performed using a 100× oil immersion objective

on a Nikon TE2000-U inverted microscope using a PerkinElmer LSI confocal system, equipped with an Ar/Kr laser (488 nm). Ultraview image acquisition system (Perkin Elmer) and Volocity-2 processing software (Improvision Inc.) were used for image processing and three-dimensional analyses. For analysis of lipid rafts, HuT 78 cells (1 × 105 per mL) were left at 37°C to adhere and then either left resting or treated with 1 μg/mL of E2 for 24 hours. Cells were fixed in 1% paraformaldehyde and lipid rafts were stained using a Vybrant Labeling Kit. Cells were then labeled with Alexafluor Omipalisib 568–conjugated anti-PKCβ (Molecular Probes, Inc.). Confocal microscopy was performed using a 63× oil immersion objective on a Zeiss 510 Meta Confocal Laser Scanning Microscope (laser excitation 488 nm and 561 nm). Polymerase chain reactions (PCRs) were performed with a TaqMan Master Mix kit (Applied Biosystems, UK) and a mix of primers and fluorescently

labeled TaqMan MGB probes (Applied Biosystems, Cyclin-dependent kinase 3 UK) was used for the target gene; the housekeeping gene glyceraldehyde-3-phosphate dehydrogenase was used as an endogenous control. Quantitative real-time PCR data were obtained using the comparative CT method. For cell culture supernatants, a human IL-2 DuoSet enzyme-linked immunosorbent assay (ELISA) development kit (R&D Systems, Oxon, UK) was used according to the manufacturer’s instructions. For tissue samples, ELISA antibody pairs for the detection of cytokine proteins were obtained from R&D Systems. For multiplex analysis, a Biochip Array Technology system, the Evidence Investigator (Randox Laboratories Ltd., UK), was used to measure multiple cytokines in cell culture supernatants. The results are expressed as the mean ± SEM. The data were analyzed using Microsoft Excel statistical software using the Student t test. The levels of IL-2 in HCV, alcoholic liver disease (ALD), and primary biliary cirrhosis (PBC) livers are expressed as the median, and data were analyzed using the Mann-Whitney U test. P < 0.05 was considered statistically significant.

To this end, we incubated T cells with a KPT 330 conditioned medium from activated HSCs and then determined αCD3/CD28-induced T cell proliferation. Under these conditions, we did not observe any veto effect (Fig. 5A). Using a Transwell system, we found that HSCs required physical contact with T cells to exert their inhibitory effect (Fig. 5B). Also, antibody-mediated neutralization experiments showed no contribution of IL-6, IL-10, or transforming

growth factor β (TGF-β) to the HSC veto effect (Supporting Fig. 4). Furthermore, HSCs needed to be viable to have veto function, and glutaraldehyde-fixed HSCs failed to have any effect on T cell proliferation (Fig. 5C). This suggests that a reciprocal interaction between HSCs and T cells is required for the veto function. The requirement for physical interactions led us to investigate the involvement of the adhesion molecule CD54 in the inhibitory function of HSCs. CD54 is critical for mediating interactions with T cells and is dynamically regulated during these interactions.24 We observed that CD54 was up-regulated on HSCs upon contact with αCD3/CD28-stimulated T cells (Fig. 6A). To demonstrate that CD54 was involved in the veto effect, we employed HSCs from CD54 knockout animals or blocked CD54 with specific antibodies. In both situations, we observed an abrogation of the third-party inhibitory effect of HSCs on T cell proliferation

(Fig. 6B) and cytokine expression (Fig. 6C). There selleck screening library was no difference between CD54+/+ and CD54−/− HSCs with respect to

the acquisition of an activated phenotype (Fig. 6D); this confirms that CD54 expression is the critical parameter for the HSC-mediated veto function. Another adhesion molecule, CD106, which is constitutively expressed on HSCs,13 contributed in a minor way to the HSC veto effect (Supporting Fig. 5). These results raised the question whether the CD54 expression levels directly correlated with the veto function. Quantifying the absolute numbers of CD54 learn more molecules per cell by flow cytometry with a well-established bead-based calibration method, we observed that activated HSCs on day 7 after isolation expressed twice as many CD54 molecules in comparison with freshly isolated HSCs (Fig. 6E), and this directly correlated with their veto function (Fig. 4A). As expected, primary murine hepatocytes as well as the hepatocyte cell line αML had lower CD54 expression levels on a per cell basis in comparison with primary murine HSCs (Fig. 6E), and they consequently lacked the veto function (Fig. 3A,B). To demonstrate that the CD54 expression levels were critical for third-party inhibition, we increased CD54 expression in αML by transfection. Figure 6F shows that CD54-transfected αML gained some inhibitory ability with respect to αCD3/CD28-driven T cell proliferation. This small increase in the inhibitory capacity may have been due to the relatively small increase in CD54 expression levels after transfection (Supporting Fig. 6).

2% after five years among treatment-naïve subjects).47 The low resistance rate is related to both the profound viral suppression Opaganib in vivo as well as the requirement of at least three sites of genetic mutations in order to confer entecavir resistance. (Two of these three sites overlap with lamivudine resistance, both lamivudine and entecavir being nucleoside analogues.) This characteristic is referred to as “high genetic barrier”. Because of these merits, entecavir is now the first line agent for treatment-naïve CHB patients. However, it is not a drug of choice for patients with lamivudine-resistant

disease because of the common sharing of two out of the three required mutations between entecavir and lamivudine resulting in a high rate of development of entecavir resistant mutations.48,49 The chance of emergence

of entecavir-resistant HBV is as high as 51% in patients with pre-existing lamivudine resistant mutations after five years of entecavir treatment.47 Napabucasin manufacturer Because of this limitation, patients with lamivudine resistant HBV should be preferably treated by tenofovir which will be mentioned below, or adefovir if tenofovir is not widely available. HBsAg seroconversion occurs in 5.1% of patients after 96 weeks of entecavir.50 In patients who continue to receive entecavir, a further 1.4% have HBsAg seroconversion by year 5.45 While better treatment for lamivudine-resistant disease was still under investigation, telbivudine, another NA belonging to the L-nucleoside subgroup was approved for treatment for CHB in 2006. Telbivudine is more potent than lamivudine in reducing the HBV DNA levels by an addition of l log copies/mL after one year of therapy.51 The HBV DNA undetectable rates are 60% vs 40% for HBeAg-positive and 88% vs 71% for HBeAg-negative patients, respectively. Therefore the chance of drug resistance compared

to lamivudine-treated patients is lower in telbivudine-treated patients, although they share the same genetic mutation sites, and like lamivudine, a single mutation can cause resistance. However, the emergence of viral resistance to telbivudine (25% for HBeAg-positive patients and 11% for HBeAg-negative patients after two years)52 is still higher than adefovir and entecavir. The use of lamivudine and telbivudine has shown the Pyruvate dehydrogenase importance of selecting patients who achieve early potent HBV DNA suppression as a criterion for continuing therapy with these agents. Yuen et al. first demonstrate that HBV DNA levels after 24 weeks of lamivudine therapy is a reliable marker for predicting the chance of lamivudine resistance on continuous treatment.53 This concept of CHB treatment has also been proven in the GLOBE trial of telbivudine vs lamivudine.51,52 In addition to the measurement of HBV DNA treatment response at week 24, baseline HBV DNA levels and ALT levels are also important in selecting patients to be treated with these two agents. According to Zeuzem et al.

The

aim is to investigate the therapeutic potential of a PAR2-based liver-homing pepducin PZ-235 in fatty liver models and evaluate efficacy against liver fibrosis in severe NASH models using histologic, systemic and liver specific reporters as markers of disease progression. Given its lipidic nature, we hypothesized that PZ-235 may efficiently partition to liver and thereby suppress liver fibrosis in animals. Methods: We used mouse models of NASH including an click here acute 2-week methionine/choline-defi-cient (MCD) diet and chronic 16-week high fat diet (HFD), and chronic liver injury model with carbon tetrachloride (CCl4) for 8-weeks to evaluate the efficacy

of PZ-235. Mechanistic studies to interrogate the role of PAR2 in liver stellate cell activation and hepatocellular cell death using LX2 and HepG2 cells were performed. Results: Biodistribution and pharmacokinetic analysis showed that PZ-235 preferentially homed to liver with 27-48% of PZ-235 present in liver at 4-48 h after injection. In NASH models in mice, there was a striking reduction in vesicular fat and triglycerides in PZ-235 treatment groups that was confirmed by liver histology. Significantly decreased plasma ALT was observed in the PZ-235 cohorts. NAS scores were lower in the PZ-235 treated animals with the largest reductions in both steatosis and lobular inflammation. These data suggest that PAR2 antagonism with PZ-235 protects against liver steatosis, inflammatory Dactolisib manufacturer infiltrates, and hepatocyte injury in diet-induced models of NASH. Concurrent treatment of mice with PZ-235 undergoing CCl4-induced liver fibrosis/necrosis gave 66% suppression of hepatocellular necrosis compared to vehicle treatment (P=0.006) and 36% protection against fibrosis as

assessed by Sirius-red staining (P=0.031) at the 8 week endpoint. Importantly, delayed PZ-235 treatment at 4 weeks after initiation of CCl4-induced liver fibrosis retained the ability to suppress the further development of liver fibrosis by 70% (P=0.0006). PZ-235 conferred Amisulpride resistance to oxidative stress-damage in hepatocytes and suppressed PAR2-induced stellate cell calcium mobilization, ERK1/2 phosphorylation and inflammatory cytokine secretion. Conclusion: These findings reveal that inhibiting PAR2 with PZ-235 affords significant protection against liver fibrosis, necrosis, inflammation and steato-sis, pointing to PAR2 pepducins as an effective broad-based strategy of therapeutic intervention in NASH. Disclosures: Lidija Covic – Grant/Research Support: Oasis Pharmaceuticals Athan Kuliopulos – Management Position: Oasis Pharmaceuticals The following people have nothing to disclose: Andrew M.