Trophic discrimination factors (ΔTissue-Diet) were calculated for captive seals and then applied in ABT199 wild counterparts in each

habitat to estimate trophic position and feeding behavior. Trophic discrimination factors for δ15N of serum (+3.8‰), lipid-extracted muscle (+1.6‰), and lipid-blubber (+6.5‰) are proposed to determine trophic position. An offset between RBC and serum of +0.3‰ for δ13C and −0.6‰ for δ15N was observed, which is consistent with previous research. Specifically, weaner seals (<1 yr) had large offsets, suggesting strong trophic position shifts during this life stage. Isotopic values indicated an average trophic position of 3.6 at both San Francisco Bay and Tomales Bay and 4.2

at Channel Islands. Isotopic means were strongly dependent on age class and also suggested that mean diet composition varies considerably between all locations. Together, these Selumetinib molecular weight data indicate that isotopic composition of blood fractions can be an effective approach to estimate trophic position and dietary behavior in wild pinnipeds. “
“Distinguishing discrete population units among continuously distributed coastal small cetaceans is challenging and crucial to conservation. We evaluated the utility of stable isotopes in assessing group membership in bottlenose dolphins (Tursiops truncatus) off west-central Florida by analyzing carbon, nitrogen, and sulfur isotope values (δ13C, δ15N, Liothyronine Sodium and δ34S) of tooth

collagen from stranded dolphins. Individuals derived from three putative general population units: Sarasota Bay (SB), nearshore Gulf of Mexico (GULF), and offshore waters (OFF). Animals of known history (SB) served to ground truth the approach against animals of unknown history from the Gulf of Mexico (GULF, OFF). Dolphin groups differed significantly for each isotope. Average δ13C values from SB dolphins (−10.6‰) utilizing sea grass ecosystems differed from those of GULF (−11.9‰) and OFF (−11.9‰). Average δ15N values of GULF (12.7‰) and OFF (13.2‰) were higher than those of SB dolphins (11.9‰), consistent with differences in prey trophic levels. δ34S values showed definitive differences among SB (7.1‰), GULF (11.3‰), and OFF (16.5‰) dolphins. This is the first application of isotopes to population assignment of bottlenose dolphins in the Gulf of Mexico and results suggest that isotopes may provide a powerful tool in the conservation of small cetaceans. “
“Biopsy techniques have been developed to collect skin and blubber samples through non-lethal methods. One sample can provide data on genetics, prey preferences, foraging ecology, contaminant loads, and physiological processes. The limited data available suggest that biopsy wounds heal quickly and that there are usually no discernable adverse health effects.

We therefore performed flow-cytometric analyses for putative cancer stem cell markers in HCC cells cultured on soft (1 kPa) and stiff (12 kPa) supports, both without and following cisplatin treatment (Fig. 8A). Culture on soft versus stiff supports was associated with an enrichment for the cell surface markers CD133 (1.5-fold, P < 0.001), c-kit (1.3-fold, ATM inhibitor cancer P = 0.78), CD44 (6.4-fold, P < 0.001), and CXCR-4

(2.9-fold, P < 0.01). Following cisplatin treatment, there was statistically significant up-regulation of CD44 (1.7-fold, P < 0.01), CD133 (1.6-fold, P < 0.01) and c-kit (15.8-fold, P < 0.01) for cells maintained on soft but not stiff supports. Additionally, real-time PCR demonstrated up-regulation of selleck chemical stem cell-associated

transcription factors OCT4 and NANOG in HepG2 cells cultured on soft versus stiff supports, both in untreated controls (OCT4 2.0-fold increase, P < 0.05; NANOG 2.7-fold increase, P < 0.05) and following cisplatin treatment (OCT4 2.0-fold increase, P < 0.05; NANOG 3.4-fold increase, P < 0.05) (Fig. 8B). In this study, we demonstrated that the stiffness of the subcellular matrix profoundly alters the phenotype and behavior of HCC cells in vitro. Pathophysiological increases in matrix stiffness, as encountered in fibrotic and cirrhotic livers,19 Phloretin promote the proliferation of HCC cells. Our work defines novel mechanisms linking the physical properties of the fibrotic liver and the malignant behavior of HCC. Our data is consistent with in vivo evidence, not only of de novo HCC development and progression against a background of

cirrhosis, but also animal studies showing that the induction of liver fibrosis is associated with accelerated tumor growth following orthotopic HCC implantation.20, 21 Furthermore, histological examination of human HCC specimens demonstrates a significant association between the presence of hepatic fibrosis and enhanced tumor cell proliferation.22 Critically, our findings suggest that a reduction in the stiffness of the cancer cell niche, as would be encountered by a disseminated tumor cell entering an unaffected secondary site, would be sufficient to promote reversible cellular quiescence and cancer cell dormancy. It has previously been demonstrated that matrix stiffness can regulate proliferation in nontransformed cells. More recently increased matrix stiffness has been shown to promote cellular proliferation in glioma cells.23 We have extended these findings to a range of epithelial malignancies, including HCC (Supporting Fig. 9). Furthermore, we have shown that β1-integrin and FAK (the canonical mediator of integrin-related signaling) regulate stiffness-dependent proliferation in HCC cells.

This is an entirely valid approach, but it leaves in doubt as to how broadly the results can be interpreted.

Are they valid for other mouse strains, other species, and other time points? This can be addressed MG-132 mouse by additional experiments that although important are typically not conducted as they are seen to lack novelty. Additional challenges are trying to determine differences between the different diseases and disease models. This is partly due to the fact that most studies focus on a single disease or disease model and compare it with controls, making comparisons between studies difficult. Finally, the recent importance of the microbiome, and the presence of both microbial PAMPs and endogenous DAMPs in the liver adds a level of complexity that will be experimentally challenging to resolve. The authors have no potential conflict of interests to declare. “
“Understanding the anatomy of the liver LY2109761 purchase may be complicated by the lack of anatomical consistency in its description. While external observation of the liver presents a clear depiction of lobar division, appreciation of its functional anatomy is often made difficult by its complex intra-hepatic architecture. In this chapter, the liver is approached through a clear delineation of its core features central to the clinical translation of its anatomy. The liver will be described in terms of its location and surface

anatomy, peritoneal relations, surfaces and lobes, segmental anatomy, blood supply and venous and lymphatic drainage. Descriptions will combine gross anatomical features and histology with a commentary of the

development and developmental anomalies of the liver. “
“Background and Aim:  Many physicians remain unaware of contemporary treatments for chronic hepatitis B (HBV) infection and do not treat their HBV-infected patients or refer them for treatment. The aim of the present study was to determine the rates of laboratory evaluation and treatment of HBV infection in a predominantly low-income Isotretinoin and immigrant population. Methods:  We identified adult patients who tested positive for hepatitis B surface antigen between 1 January 1994 and 30 April 2006. We reviewed patients’ medical records to determine two outcomes: (i) receipt of pretreatment evaluation of HBV infection; and (ii) receipt of HBV treatment. We then examined clinical and demographic factors associated with these outcomes. Results:  Twenty-eight percent of 1231 HBV surface antigen-positive patients received additional laboratory evaluation of their infection. In a multivariate analysis, receipt of a HBV evaluation was independently associated with (P < 0.05) female sex, longer duration of HBV infection, more visits to a gastroenterology clinic and less recent health-care contact. Data on treatment were available for 56% of patients; among these, 16% received HBV treatment.

Group comparisons were made with the Wilcoxon-Mann-Whitney test. Categorical variables are reported as counts and percentages. Group comparisons were made with the χ2 test or Fisher’s exact test. Survival was assessed with the Kaplan-Meier

nonparametric survivorship GSK3235025 research buy function, and group comparisons were made with the log-rank test. Univariate and multivariate Cox regression analyses were performed to detect the independent predictors of survival. In all survival analyses, the follow-up period ended either on the day of the last visit for nontransplant patients or on the day of transplantation for transplant patients. The multivariate model was built with the backward elimination technique with P < 0.10 for entering the model and P < 0.05 for staying in the model. The results are presented as crude hazard ratios (HRs) with 95% confidence intervals (CIs) in univariate analyses and as adjusted HRs with 95% CIs in multivariate analyses. Crude HRs indicate the relationship between mortality and a single predictor. Adjusted HRs indicate the relationship between mortality and a predictor and take into account the other

independent predictors. A P value < 0.05 was considered significant. Analyses were performed with the PASW statistical package (SPSS version 18.0, SPSS, Chicago, IL). A total of 151 patients were enrolled. Clinical characteristics, selleck compound biochemical

values, and treatment at inclusion are summarized in Table 1. One hundred four patients (68.9%) had diuretic-intractable ascites: renal dysfunction was found at entry in 46 patients (30.5%), and hyponatremia was found in 58 patients (38.4%). None of the patients had diuretic-intractable ascites due to abnormal serum potassium levels. Forty-seven patients (31.1%) had diuretic-resistant ascites. All patients were regularly treated with large-volume paracentesis and intravenous albumin. Seventy-seven patients (51%) were treated with nonselective C-X-C chemokine receptor type 7 (CXCR-7) beta-blockers (propranolol) for the prevention of gastrointestinal hemorrhage. Among these patients, 9 (11.7%) were given 40 mg of propranolol per day, 31 (40.3%) were given 80 mg, 1 (1.3%) was given 120 mg, and 36 (46.7%) were given 160 mg. The median follow-up time was 8 months (1-47 months). The median survival time was 10 months (95% CI = 8-12 months). The probability of survival was 41% at 1 year (95% CI = 33%-49%) and 28% at 2 years (95% CI = 20%-36%; Fig. 1). Ninety-seven patients (64.2%) died. Causes of death were sepsis in 50 patients (spontaneous bacterial peritonitis in 11 cases) and progression of hepatocellular carcinoma in 13. Twenty-five patients died at home of unspecified causes. Twenty-six patients underwent liver transplantation during the study period.

0; GraphPad Software, Inc., Cary, NC). Variables that were not previously age adjusted (e.g., bimanual coordination and

visuomotor coordination) were compared between groups using univariate analysis of covariance with age included as covariate, followed by post-hoc Bonferroni. The probability level accepted for significance was P < 0.05. Bivariate correlations among variables were evaluated using the Pearson correlation test. Partial correlation coefficients, controlled by age, were also calculated for variables not previously age adjusted. Binary logistic https://www.selleckchem.com/products/epacadostat-incb024360.html regression analyses were performed to assess whether MMN area predicts MHE, attention, or coordination deficits. The cutoffs (mean of controls ± 2 standard deviations) were 28 for Stroop Incongruent: 3.12 and 2.37 minutes for visuomotor and bimanual coordination tests, respectively, and 0 for NCT-A and NCT-B tests. Receiver operating characteristic (ROC) curves were then performed to determine sensitivity and specificity. Analyses were performed using SPSS software (version

17.0; SPSS, Inc., Chicago, IL), and two-sided P values <0.05 were considered significant. Latency and amplitude of MMN waves were similar in controls and patients with or without MHE (Fig. 1A,B). Latencies were 212 ± 5, 224 ± 8, and 213 ± 10 ms in controls, patients without MHE, and patients with MHE, respectively. Amplitudes were 5.4 ± 0.5, 5.1 ± 0.6, and 5.0 ± 0.8 μV in controls, patients without ABT-199 research buy MHE, and patients with MHE, respectively. In contrast, MMN area was reduced in patients with Phospholipase D1 MHE, compared to controls (P < 0.01) and patients without MHE (P < 0.05). Areas were 167 ± 29, 120 ± 17, and 49 ± 4 μV/ms in controls, patients without MHE, and patients with MHE, respectively (Fig. 1C). Performance in the Stroop test of selective attention was also assessed. In the congruent task (Fig. 2A), controls read 108 ± 3 words in 45 seconds. Patients without MHE read fewer words (94 ± 4; P < 0.05), and patients with MHE showed a strong reduction in number of words (77 ±

5), which was lower than for controls (P < 0.001) and patients without MHE (P < 0.05). In the neutral task (Fig. 2B), control subjects named 80 ± 3 colors. Patients without MHE named fewer colors (67 ± 3; P < 0.01) and patients with MHE named 53 ± 5, which was lower than for controls (P < 0.001) and patients without MHE (P < 0.05). In the incongruent task (Fig. 2C), controls named 45 ± 2 colors. Patients without MHE named fewer colors (37 ± 2; P < 0.01) and patients with MHE named 30 ± 2, which was lower than for controls (P < 0.001) and patients without MHE (P < 0.05). Visual selective attention was evaluated by performing the Map Search. In the 2-minute Map Search test (Fig. 2D), control subjects obtained a scaled score of 9.7 ± 0.8. The score was not affected in patients without MHE (7.9 ± 0.5). Patients with MHE showed a reduction in score (5.7 ± 0.8), which was lower than for controls (P < 0.

Plasma levels of inflammatory cytokines and alanine aminotransferase were increased in FGF21 KO mice. FGF21 depletion exacerbated alcohol-induced hepatic steatosis and liver injury, which was associated with increased

activation of genes involved in lipogenesis mediated by SREBP-1c and decreased expression of genes involved in fatty acid p-oxidation mediated by PGC-1α. Hepatic inflammation was higher in alcohol-exposed FGF21 KO mice than controls. Recombinant FGF21 administration reduced alcohol-induced hepatic steatosis and inflammation in WT mice. Conclusion: Alcohol-induced FGF21 expression is a hepatic adaptive response to lipid dysregulation. FGF21 deficiency exacerbates chronic alcohol-induced liver injury in mice via SREBP-1c-mediated regulation in hepatic lipogenesis, PGC-1 α-mediated fatty acid p-oxidation, and TNF-α-mediated inflammation. Developing Selumetinib in vivo strategies targeting FGF21 signaling is KU-57788 solubility dmso a novel treatment approach for alcoholic steatohepatitis. Disclosures: Craig J. McClain – Consulting: Vertex, Gilead, Baxter, Celgene, Nestle, Danisco, Abbott, Genentech; Grant/Research Support: Ocera, Merck, Glaxo SmithKline; Speaking and Teaching: Roche The following people have nothing to disclose: Cuiqing Zhao, Liming Liu, Fengyuan Li, Wenke Feng BACKGROUND:

decreased muscle mass or sarcopenia has been recently recognized as a risk factor for nonalcoholic fatty liver disease (NAFLD) but its mechanisms and consequences has not been tested. AIM: to explore if experimental NAFLD is associated to sarcopenia in mice and assess its association to functional changes and serum insulin growth factor-1 (IGF-1), a liver derived anabolic hormone. METHODS: C57/Bl6 mice were fed with a westernized diet (ALIOS-diet, Am J Physio Gastrointest Liver Physiol 295: G987-G995,

2008.) and fruc tose in drinking water during 16 weeks. Weight gain, viscera fat, serum biochemical parameters, liver histology, hepatic tri glyceride content and morphological and functional evaluation of skeletal muscle Dapagliflozin (gastrocnemius) were carried out. Muscle fiber cross-sectional area (CSA) was determined estimating the minimal Feret’s diameter. In addition, we evaluated myosin protein levels by western blot as marker of muscle atrophy. Muscle strength was estimated by electro stimulation. IGF-1 serum levels were measured using a commercially available ELISA. RESULTS: The ALIOS diet induced significant weigh gain and NAFLD with a significant increase in hepatic triglycer ide content (23,97±7.9 mg/g liver vs. 2,47±1,5 mg/g liver in chow-fed mice, p<0.05), hepatic steatosis and inflammation as well as increased visceral fat (size of epydidimal pad: 0,76 g±0.33 vs. 0.33±0.07 g in chow-fed mice).

3 pg/ml (range, 43.0-5556.3 pg/ ml). Serum

DKK-1 levels did not correlate with those of AFP or des-γ-carboxy prothrombin (DCP). When cut off value of 450 pg/ml was used, sensitivity Selleck AZD1208 and specificity of DKK-1 for HCC were 26.8% and 88.9%, respectively. HpSC-HCCs showed poor prognosis with high serum DKK-1 levels compared with MH-HCCs who received surgery, and HCC patients showed elevation of DKK-1 (DKK-1 high HCC) showed a significantly high frequency of portal vein invasion (p < 0.001). Among Barcelona Clinic Liver Cancer (BCLC) stage C patients treated with sorafenib or hepatic arterial infusion chemotherapy using interferon-α/5-FU/cisplatin, DKK-1high HCCs showed a significantly poor prognosis compared with DKK-1 low HCCs (median overall survival 10.6 vs. 13.2 months: p=0.03, and 4.1 vs. 26.7 months: p=0.01, respectively). The expression of DKK1 was correlated to the EpCAM expression, in vitro. Furthermore, anti-DKK1 antibody administration suppressed tumor formation ability of EpCAM-positive HCC cells,

in vivo(p=0.044). Conclusions Serum DKK-1 is elevated in HCC with stem cell features. The poor response of DKK-1 high HCCs to sorafenib or cytotoxic reagents warrants the needs for the development of a novel treatment strategy against this deadly HCC subtype. Disclosures: Lapatinib in vivo Shuichi Kaneko – Grant/Research Support: MDS, Co., Inc, Chugai Pharma., Co., Inc, Toray Co., Inc, Daiichi Sankyo., Co., Inc, Dainippon Sumitomo, Co., Inc, Ajinomoto Co., Inc, MDS, Co., Inc, Chugai Pharma., Co., Inc, Toray Co., Inc, Daiichi Sankyo., Co., Inc, Dainippon Sumitomo, Co., Inc, Ajinomoto Co., Inc, Bayer Japan The following people have nothing to disclose: Hajime Sunagozaka, Taro Yamashita, Naoki Oishi, Takehiro Hayashi, Hajime Takatori, Tetsuro Shimakami, Kazuya Kitamura,

Kuniaki Arai, Takashi Kagaya, Yoshio Sakai, Tatsuya Yamashita, Eishiro Mizukoshi, Masao Honda Background: Hepatocellular carcinoma (HCC) is one of the cancer types with poor prognosis. At present, serum tumor markers of HCC such as alpha-fetoprotein (AFP), prothrombin induced by vitamin K absence II (PIVKA II) or alpha-fetoprotein Lens culinaris agglutinin 3 (AFP-L3%) are not adequate to predict survival or recurrence after curative hepatectomy. We reported Fatty Acid Binding Protein 5 (FABP5) was a significant prognostic and recurrence factor Adenosine for HCC patients by immunohistochemical analysis and showed positive correlation of tumor size, intrahepatic metastasis, and micro/macro vascular invasion (Ohata T, et al. AASLD Liver Meeting 2013). Purposes: To examine a correlation between the expression of FABP5 and malignant behavior of HCC using human HCC cell lines. Methods: Protein expression of FABP5 in HCC cell lines (HLE, HLF, Li7, HepG2 and Hep3B) was assessed by western blot analysis. Lentiviral short-hairpin RNA (shRNA) vectors were used to suppress FABP5 expression in higher expression cells or lentiviral overexpression vectors to express FABP5 in lower expression cells.

[27] The use of RGT

in a telaprevir-containing regimen was studied explicitly in the PS-341 purchase ILLUMINATE trial,[28] which enrolled treatment-naïve (TN) patients with chronic HCV genotype 1 infection. All patients received telaprevir-based triple therapy for 12 weeks. Those who experienced eRVR were then randomized to receive PegIFN/RBV for either 12 or 36 more weeks (those not experiencing eRVR received PegIFN/RBV for 36 more weeks.) Sixty-five percent of participants experienced eRVR. Among those participants who had eRVR, those randomized to receive an additional 12 weeks of PegIFN/RBV achieved SVR rates of 92% and those https://www.selleckchem.com/products/PD-0332991.html randomized to receive an additional 36 weeks of PegIFN/RBV achieved SVR rates of 88%. The results satisfied the criteria for non-inferiority, allowing the investigators to conclude

that the shorter duration of therapy for patients who achieved eRVR was non-inferior to the longer duration. Notably, significantly more participants randomized to the longer duration of therapy discontinued treatment because of adverse events compared with those randomized to the shorter duration (12% vs 1%; P < 0.001).[28] Telaprevir was also studied in previously treated patients in the REALIZE trial.[31] However, the treatment protocol for that trial did not employ RGT. Current guidelines note that the use of boceprevir- or telaprevir-containing therapy, in combination with PegIFN/RBV, is optimal for treatment-naïve patients with genotype 1 HCV.[2] Treatment regimens employing boceprevir should use a 4-week PegIFN/RBV lead-in period prior to initiation of triple therapy.[32] Triple therapy should then be administered for 24 weeks in patients eligible for RGT (i.e. those without cirrhosis and who have undetectable HCV Etofibrate RNA levels at weeks 8 and 24). Patients with cirrhosis should receive triple therapy for 44 weeks. Triple therapy

should be stopped if the HCV RNA level is > 100 IU/mL at treatment week 12 or detectable at treatment week 24.[32] Telaprevir-containing regimens do not require a lead-in period. Triple therapy with telaprevir should be administered for 12 weeks, followed by 12 weeks of PegIFN/RBV in patients eligible for RGT (i.e. those without cirrhosis and who have undetectable HCV RNA levels at weeks 4 and 12). Patients with cirrhosis should continue PegIFN/RBV therapy for a total of 48 weeks. Triple therapy should be stopped at week 12 if HCV RNA levels are > 1000 IU/mL at weeks 4 and 12 of the triple-therapy phase, or at week 24 if HCV RNA is detectable at that time.

for their continuing support of the Southern Right Whale Project/Chile and the Global Greengrants Fund for funding the project. We would also like to thank Carole Carlson, Katherine Ralls, Vicky Rowntree, Mariano

Sironi, and two anonymous reviewers for their improvements to the note. Note added in proof: After the paper was accepted we learned of another sighting in central Chile. On 9 September 2011, a mother with calf was sighted and photographed off Viña del Mar (33°01′S ; 71°35′W; Pers. Comm. Sarah Allen, Ocean and Coastal Resources VX-809 purchase Program, Pacific West Region, National Park Service, 495 Jefferson Street, San Francisco, CA 94123, March 2013). “
“Fission-fusion dynamics seem to reflect individual decisions as well as temporal and spatial variations in the organization of groups of the same species. To understand the group dynamics of the Guiana dolphin, Sotalia guianensis, at Pipa Bay, Brazil, we investigated the three dimensions of a fission-fusion social system: (1) variation in spatial cohesion, (2) variation in party size, and (3) variation in party composition. Sampling took

place from December 2007 to February 2009 over 176 d and we analyzed the behavioral patterns of 658 groups. Within subgroups, animals remained cohesive, particularly in groups of adults and calves. Greater cohesion was also observed during resting and fission-fusion rates were higher during milling and feeding. Groups composed of adults and juveniles showed a higher dynamics index (group size variation as a function of time) than groups composed only of adults and the fission-fusion buy LY2109761 rate was higher during dry periods. Guiana dolphin groups frequently changed their group size and composition every 20 min on Tau-protein kinase average. Taking these factors into consideration, we suggest that the Guiana dolphin demonstrates fission-fusion dynamics, a pattern of behavior similar to what has been observed in other coastal odontocete species, such as Tursiops spp. and Lagenorhynchus obscurus. “
“Killer whales produce

repertoires of stereotyped call types that are primarily transmitted vertically through social learning, leading to dialects between sympatric pods. The potential function of these call repertoires remains untested. In this study, we compared the reaction of Kamchatkan fish-eating killer whales to the playbacks of calls from the same and different pods. After the playback of recordings from a different pod, in three cases whales changed the direction of their movement toward the boat, and in three cases no changes in direction were observed. After the playback of recordings from the same pod (either from the same or a different unit within the pod), in seven cases whales changed the direction of their movement toward the boat, and in only one case no change in direction was observed. Whales remained silent after all six playbacks of recordings from a different pod, even when they changed direction toward the boat.

31 Our results identify CB2 receptors as a novel regulator of Kupffer-cell polarization. Indeed, in vivo and in vitro experiments demonstrate GSK3235025 cell line that genetic deletion of CB2 receptors is associated with a marked hepatic induction of the M1 signature in response to chronic alcohol feeding and a parallel loss of the M2 alternative response. These findings, therefore, suggest that endogenous

CB2 receptors are responsible for M2 response to alcohol feeding. Interestingly, the CB2 agonist, JWH-133, blunts the induction of the M1 classical signature without affecting M2 response to alcohol. Whether the lack of enhancement of M2 markers in animals treated with the CB2 agonist may be the result of partial agonist properties of the compound or to constitutive activity of CB2 receptors remains to be determined.36, 37 Nevertheless, these data demonstrate that, during chronic alcohol exposure, CB2 receptors shift the M1/M2 balance toward a predominant alternative M2 response. Besides their anti-inflammatory properties click here on Kupffer cells, CB2 receptors also prevent the development of

alcohol-induced fatty liver. Recent studies have demonstrated that cross-talk between Kupffer cells and hepatocytes is determinant in the control of hepatic steatosis. In rodents exposed to an alcohol diet or a high-fat diet, depletion of Kupffer cells blunts the development of fatty liver.9, 38-40 Furthermore, cocultures of M1-polarized Kupffer cells with hepatocytes promote lipid accumulation into parenchymal cells.5, 6, 38, 39 In keeping with these data, we show that CM obtained

from JWH-133- and LPS-stimulated macrophages reduces lipid accumulation in hepatocytes, compared to CM prepared from macrophages exposed to LPS alone. These data indicate that Kupffer-cell CB2 receptors decrease hepatocyte steatosis after inhibition of M1 polarization. Of note, recent studies have shown that IL-1β and TNF-α, two proinflammatory Kupffer-cell–derived cytokines, promote steatosis.38-40 We show that liver Sclareol expression of IL-1β and TNF-α decreases in alcohol-fed mice concurrently treated with JWH-133 and increases in CB2-deficient counterparts. A similar pattern of regulation was also found in our in vitro experiments, therefore suggesting that the reduction in Kupffer-cell production of IL-1β and TNF-α may contribute to the protective effects of CB2 receptors on hepatocyte lipid accumulation. HO-1 is the rate-limiting enzyme in the catabolism of heme into biliverdin, free iron, and carbon monoxide. HO-1 is a stress-inducible protein with potent-protective effects against hepatocyte damage,41 liver inflammation,31, 33 and fibrogenesis.42, 43 Recent studies have shown that up-regulating HO-1 in Kupffer cells by means of overexpression or by pharmacological activators prevents alcohol-induced release of inflammatory mediators by Kupffer cells.31, 41 However, characterization of HO-1 inducers in Kupffer cells remains poorly documented.