039 × age(years) + 2 38 × loge(prothrombin time [s]) + 0 859 edem

039 × age(years) + 2.38 × loge(prothrombin time [s]) + 0.859 edema (0 = no edema, no diuretic therapy; 0.5 = edema, no diuretic therapy or no edema, diuretic therapy; 1 = edema and diuretic therapy); MELD score is calculated using the following equation: = 3.8 × loge[bilirubin(mg/dL)] + 11.2 × loge(INR) + 9.6 × loge[CRE(mg/dL)] + 6.4 × (biliary

Ensartinib or alcoholic = 0; others = 1). Statistical analyses were performed using SPSS statistical software (version 13.0; SPSS Inc., Chicago, IL). The two-tailed Wilcoxon matched pairs test was used to evaluate paired biochemical values. Values with P < 0.05 were considered statistically significant. The demographic and clinical characteristics of patients at the time of enrollment are summarized in Table 1; this table also indicates when patients

begun UDCA therapy. These patients included one male and six females, Selleck CT99021 ranging from 33 to 58 years of age. All of the patients had been on UDCA therapy for at least one year and had shown an incomplete response to this treatment. All of the patients had reported fatigue, and five of them had pruritus at the beginning of UC-MSC therapy. Patient medication was not changed during the study period. The timeline of UC-MSC treatment in this group of patients is shown in Figure 1; note that clinical parameters were tested at the 0-, 24-, and 48-week time points during the study period. Because safety is a major concern regarding UC-MSC therapy for PBC patients, we examined the short-term side-effects and long-term adverse events during the 48 weeks of follow-up. All the seven patients tolerated the UC-MSC treatment well; only one patient developed a self-limiting fever (body temperature: 37–38°C) within 5 h of UC-MSC transfusion, which recovered within 12 h without any additional treatments. No short-term clinical adverse effects, such as right upper quadrant pain, skin rash, infection, coma, or shock, were reported. There were no occurrences of long-term complications,

such as hepatocellular carcinoma, upper gastrointestinal hemorrhage, hepatic encephalopathy, or primary PDK4 peritonitis within one year of follow-up. Additionally, in all the seven patients, no significant alterations were observed in renal function parameters such as urea, CRE, and UA levels during the one-year follow-up period. Routine blood tests (peripheral white blood counts, hemoglobin, platelet, etc.), serum electrolyte levels (serum Na, serum K and serum Cl, etc.), and serum AFP levels also remained stable (Table 2). The combined treatment of UC-MSC and UDCA led to a significant decrease in serum ALP levels at the endpoint of the follow-up period (474.29 ± 223.26 vs 369.86 ± 168.35 IU/L, P = 0.044). Interestingly, GGT, another biochemical marker of cholestasis, also indicated a reduction from baseline (194 ± 140.65 IU/L) compared with the endpoint of the treatment (132.71 ± 129.4 IU/L, P = 0.049).

Cell lysates were analyzed by the dual luciferase assay (Promega)

Cell lysates were analyzed by the dual luciferase assay (Promega) on a luminometer. To assess the activity of IKK, IKK was immunoprecipitated by IKKα antibody and protein G-Sepharose, and the assay was performed at 30°C for 1 hour in buffer

containing 20 mM Tris HCl, pH 7.5, 20 mM MgCl2, 2 mM dithiothreitol, 20 μM ATP, 2 μg GST-IκBα, and [γ-32P]ATP. The reaction was stopped by addition of Laemmli buffer and was resolved by 10% sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) followed by a transfer onto a membrane for imaging. Whole cell extracts were prepared as described.8 Equal amounts of VX-770 ic50 the extract (20 μg) were separated by 8%-15% SDS-PAGE and the proteins were transferred to nitrocellulose membranes (Bio-Rad, Hercules, CA). MeCP2, type I collagen, and β-actin were detected by incubating with rabbit polyclonal anti-MeCP2 (1:1,000) (Abcam), anti-type I collagen (1:4,000), and anti-β-actin (1:5,000) primary antibodies (Santa Cruz Biotechnology) in TBS (100 mM Tris-HCl,

1.5 M NaCl, pH 7.4) with 5% nonfat milk overnight at 4°C followed by incubation with horseradish peroxidase-conjugated goat antirabbit secondary antibodies (1:4,000) (Sigma) at room temperature for 2 hours. The antigen-antibody complexes’ chemiluminescence was detected using the ECL detection kit (Pierce). KPT-330 concentration For assessing Pparγ epigenetic regulation, carrier ChIP was performed using Raji cells as the source of carrier chromatin. For CYTH4 native ChIP, 20 μg of HSC chromatin was mixed with 80 μg of Raji cell chromatin. For crosslink ChIP, Raji cells (1.4 × 107 cells) were mixed with HSCs (0.2 × 106 cells) and fixed with 1% formaldehyde on the rotating platform for 5-10 minutes at room temperature followed by addition of glycine to a final concentration of 0.125 M. After lysis of the cells with SDS buffer (1% SDS, 10 mM EDTA, 50 mM Tris-HCl, pH 8.1) with protease inhibitors, the

lysates were sonicated and snap-frozen in aliquots. For chromatin IP, diluted samples were first precleared using protein G-agarose beads and then incubated with antibody against Ser2P RNApolyII, MeCP2, H3K27me2, H3K4me2, and H3Kacetylated (Abcam) at 1 μg/μL at 4°C overnight followed by precipitation with protein G-agarose beads. After elution of immunoprecipitated complex, crosslinking was reversed with 5 N NaCl and proteins digested with protease K. Extracted chromatin was subjected to real-time PCR using the primers flanking a segment within Pparγ promoter or exon as described.17 Ct values of the samples with nonimmune IgG were subtracted and compared to their respective input Ct values. The aqueous YGW extract (350 mg/mL in PBS) was applied to size exclusion chromatography using Super Prep Grade gel in XK 16/70 column (Amersham Pharmacia Biotech, Piscataway, NJ) and PBS as a mobile phase solvent.

We utilized the

genotype 1a/2a chimeric infectious HCV cl

We utilized the

genotype 1a/2a chimeric infectious HCV clone HJ3-5. To assess SeP promoter activity, Huh-7.5 cells were transfected with SeP-luciferase reporter plasmids, and luciferase activity was measured. For the clinical evaluations, we measured the serum levels of SeP in 63 patients with CHC who received PEG-IFN and ribavirin combination therapy. Results: In HCV-infected Huh-7.5 cells, SeP expression was increased compared with non-infected cells. We identified a C/EBPα binding site, a key regulator see more of adipocyte differentiation, in the upstream promoter region of SeP. Interestingly, the expression of C/EBPα was induced by HCV infection, and the overexpression of C/EBPα increased the expression of SeP, while the suppression of C/EBPα expression decreased the expression of SeP in Huh-7.5 cells. We performed promoter analysis using SeP promoter-luciferase reporter plasmids, and confirmed that its promoter activity was dependent on the expression of C/EBPα. These results indicated that

HCV infection induced the expression of SeP, an inducer of insulin resistance, through C/EBPα in Huh-7.5 cells. Knocking down SeP using shRNA improved glucose metabolism and insulin signaling by decreasing the expression of the gluconeogenesis genes G6PC and PCK1 and increasing the phosphorylation of insulin receptor substrate 1. Interestingly, HCS assay the suppression of SeP expression also improved IFN signaling by suppressing the Foxo3a-Socs3 signaling pathway as we reported previously (Gastroenterology, 201 1) and decreased HCV replication. Patients without a sustained viral response (SVR) (n = 33) Gemcitabine manufacturer showed significantly higher serum levels of SeP than patients with an SVR (n = 30). Conclusion: We demonstrated that HCV infection causes insulin and IFN resistance via the up-regulation of the insulin resistance inducer SeP through C/EBPα. We suggest that SeP can be a therapeutic

target not only for type 2 diabetes but also for HCV infection. Disclosures: Shuichi Kaneko – Grant/Research Support: MDS, Co., Inc, Chugai Pharma., Co., Inc, Toray Co., Inc, Daiichi Sankyo., Co., Inc, Dainippon Sumitomo, Co., Inc, Aji-nomoto 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: Kazuhisa Murai, Masao Honda, Takayoshi Shirasaki, Tetsuro Shimakami, Takayuki Shiomoto, Hikari Okada, Riuta Takabatake, Hirofumi Misu, Toshinari Takamura, Seishi Murakami Background and Aims: Many chronic hepatitis C (CHC) patients receive interferon (IFN) therapy, because it not only prevents progression to cirrhosis but also reduces the risk of hepatocellular carcinoma (HCC).

, 2006), bite force (Huyghe et al , 2009), and are used as cues i

, 2006), bite force (Huyghe et al., 2009), and are used as cues in male and female mate choice in lizards (Bajer et al., 2010), and are often correlated to body condition (Healey & Olsson, 2009). Recent studies on signalling focused on the possibility of several traits acting together to signal an individual’s quality (e.g. Candolin, 2003), with different components often signalling different aspects of the signaller (Badyaev et al., 2001). Females consider multiple male traits

in parallel (Calsbeek & Sinervo, 2002; Lopez, Aragon & Martin, 2003; Hamilton & Sullivan, 2005), even considering their offspring’s survival while making Venetoclax price mating decisions (Lancaster, Hipsley & Sinervo, 2009). However, the fact that a trait represents an important signal in one context, for instance in intrasexual selection, does not necessarily mean that it is also important in another context, for instance in intersexual selection, as well (e.g. Lebas & Marshall, 2001; Lopez, Munoz & Martin, 2002). The European green lizard (Lacerta viridis) is a wide-spread lacertid species in Central MK-1775 molecular weight and Eastern Europe. Males develop a blue nuptial throat patch, which shows high reflectance in the ultraviolet (UV) range (see Bajer et al., 2010).

The role of this male ornament in sexual selection is particularly interesting as both UV and blue colours represent structural colours, hence their developmental costs and the environmental factors Ribose-5-phosphate isomerase influencing them are less straightforward than in the much better studied pigment-based colours (Prum, 2006). UV colour

has been demonstrated to function as an honest signal of weapon size in the collared lizard (Crotaphytus collaris) (Lappin et al., 2006), determine outcome of male contests in the Platysaurus broadleyi (Stapley & Whiting, 2006; Whiting et al., 2006) and affect male mate choice in Ctenophorus ornatus (LeBas & Marshall, 2000). In manipulative experiments, we showed that female L. viridis prefer males with high UV chroma on their throat patch (Bajer et al., 2010) and males with high UV chroma are more successful in male contests (Bajer et al., 2011), hence throat colour of male European green lizards is likely to be under sexual selection and to hold information of male quality. Here we tested the hypotheses that (1) UV colour in male European green lizard is an honest signal, and (2) different components of the throat colour signal different aspects of male quality. Namely, we investigated the relationships between (1) UV chroma, as it affects female mate choice and male competition in the species (Bajer et al.

IL-8 produce by monocyte/ macrophage, endothelial cell, fibroblas

IL-8 produce by monocyte/ macrophage, endothelial cell, fibroblast, hepatocyte and PMN, is novel cytokine that activate neutrophil in H. pylori infected patient, and as a potential mediator for inflammation. This study aim to know the correlation of IL8 gastric mucosa with density of H. pylori infection in gastritis patient. Methods: We perform a cross-sectional study on H. pylori positive

gastritis patient. Degree of gastric mucosa inflammation Selleckchem MAPK inhibitor examined from gastric mucosa biopsy in anthrum and corpus with Hematoxillin-Eosin & Giemsa stain by pathologist, and evaluated base on The Updated Sydney System grade. IL8 level of gastric mucosa was examined base on ELISA method. Results: We included 65 patients, 31 male and 34 female. The age of patients 20–86 years old. Endoscopic feature of the patient were normal, superficial gastritis, erosive gastritis, ulcer in 1, 34, 23, 7 patients, respectively. IL8 gastric mucosa correlated with severity of gastric mucosa inflammation (r = 0,447; p < 0,001). And IL8 have significant correlation with density of H. pylori infection CP-673451 manufacturer (r = 0,32; p < 0,001). Conclusion: IL8 gastric mucosa significantly correlated with density of H. pylori infection in gastric mucosa. Key Word(s): 1. h pylori; 2. density;

3. IL8; Presenting Author: TINGTING WANG Additional Authors: XUEZHI ZHANG, HONG CHENG, JIANG LI, YUEMIAO ZHANG, HUI YE Corresponding Author: XUEZHI ZHANG Affiliations: Department of Integrated Traditional Chinese and Western Medicine, Peking University First Hospital; Department of Gastroenterology, Peking University First Hospital Objective: Jinghuaweikang capsules is a traditional Chinese medicine used for the treatment of Chronic Atrophic Gastritis (CAG), which has the main component of Dysphania ambrosioides and Adina pilulifera.

This study is to observe the efficacy of Jinghuaweikang capsules plus triple regimen in the treatment of CAG patients with H. pylori infection. Methods: This was a randomized controlled study. 51 patients who were endoscopically confirmed CAG with H. pylori positive [13C or 14C-urea breath test (UBT) or rapid urease test positive] were selleck enrolled, 24 males, aged 56 ± 9.87. All the patients have no H. pylori eradication backgrounds. They were randomly divided into 2 groups, Group LACJ (n = 25) were given lansoprazole (30 mg b. i. d.), amoxicillin (1000 mg b. i. d.), clarithromycin (500 mg b. i. d.), jinghuaweikang capsules (240 mg b. i. d.) for 10 days plus another 14 days only with jinghuaweikang capsules; Group LACB (n = 26) received standard quadruple regimen treatment: lansoprazole (30 mg b. i. d.), amoxicillin (1000 mg b. i. d.), clarithromycin (500 mg b. i. d.), bismuth potassium citrate (220 mg b. i. d.) for 10 days. The status of H. pylori were detected by 13C-UBT at least 4 weeks after therapy.

Multiple statistical comparisons increase the chance that signifi

Multiple statistical comparisons increase the chance that significant findings are due to

chance. Readers should be aware of this limitation when interpreting the clinical significance of the findings. Although our findings are generally consistent with those of other studies, no adjustment was made to the nominal alpha level. Thus, these results are best viewed as descriptive and hypothesis-generating rather than conclusive. Interpretation of the results should emphasize the width of the CIs rather than their corresponding P values. Third, we did not correct for potential correlations stemming from the possibility that multiple members of a single household contributed data to our analyses. However, this is unlikely

to have an effect on prevalence statistics or other main findings. Fourth, although some VX-809 cell line of the results are presented as both unadjusted and adjusted for sociodemographic variables, for the sake of parsimony, ABT-888 cost only unadjusted results are presented in Tables 5-7. It is possible that some of the outcomes such as healthcare resource utilization are affected by socioeconomic variables in addition to sex. These relationships have been explored in other AMPP Study based manuscripts and are also targets for future analyses. Finally, the analysis was cross-sectional in design, which limits our ability to examine causal relationships or longitudinal trajectories. Strengths of this study include its large sample size, population-based format, and symptom items that allow for assignment of ICHD-2 headache diagnoses. In addition, several validated instruments were used including the MIDAS questionnaire. These findings extend previous research showing that migraine and PM are not only more prevalent in females, the but also more disabling and associated with more

symptoms and greater healthcare resource utilization. For the most part, we did not find corresponding sex differences in other (nonmigraine spectrum) severe headache. Future research into sex differences in migraine and other severe headache types should continue to explore both biologic and psychosocial hypotheses. It is imperative that females are included in both basic science and clinical studies of sex differences in headache biology and expression. Greater understanding of biologic and psychosocial factors will shed light on observed sex differences in prevalence, treatment seeking, diagnosis and treatment of migraine and nonmigraine spectrum headache and will create opportunities to improve care and outcomes for both sexes. The authors would like to thank C. Mark Sollars, MS, and Jelena M. Pavlovic, MD, PhD, for editorial support, Christa A. Bruce, MS, for editorial support and project management and Michael T. Lynch for assistance with graphics. (a)  Conception and Design (a)  Drafting the Manuscript (a)  Final Approval of the Completed Manuscript “

Grace, Amir A Qamar BACKGROUND:

Grace, Amir A. Qamar BACKGROUND: PD0325901 price Liver transplant (LT) recipients face a significant burden of readmission in the post-transplant period. The impact of post-LT discharge status on clinical outcomes is not well-defined. The study objectives were to define post LT read-mission rates and to examine the relationship between post-LT discharge status and the risk

of readmission. METHODS:The University HealthSystem Consortium database was used to identify 12,596 patients during the index LT hospitalization (ICD9 code V42.7) between 2009 and 2013. Patients who died (N=571), were discharged to acute long term care or hospice (N=314) or were transferred to another hospital (N=182) post-operatively were excluded. Logistic regression models were used to examine the effect of discharge status EGFR inhibitor on readmission rates adjusting for baseline demographics, Charl-son comorbidities, LT length of stay (LOS), and ICU stay. RESULTS: The final study sample included 12,084 adult LT recipients. Mean age was 55±1 0 years, 72% of patients were Non-hispanic white, 10% were black, and 67% were male. The median transplant length of stay (LOS) was 1 1 days (IQR 8, 21); median number of ICU days was 3 (IQR 2, 6). A total of 54% of patients were discharged home, 30% were discharged home with home health, and 16% were discharged to a rehabilitation (1 1%) or skilled nursing facility (5%). The overall

rate of readmission was 50% (30-day readmission=1 7%, 90-day readmission=35%, and 365-day readmission=50%). The majority (73%) of readmissions were classified as emergency and 27% were elective. In multivariate analysis, after adjusting for significant covariates, post-LT discharge to a facility vs. home was independently associated with increased risk of 30-day readmission (OR 6.1, 95%CI 5.2–7.3, p<.0001), 90-day readmission (OR 4.0, 95%CI 3.6–4.5, p<.0001), and 365-day readmission (OR 3.1, 95%CI 2.7–3.6, p<.0001). Age greater than 65 was protective for

30-day readmissions (OR .81, 95%CI .68-.95, p=.01); similarly for 90-day, and 365-day readmissions. No interactions were noted between age, discharge status, and medical comorbidities. CONCLUSIONS: The burden Methamphetamine of readmission among LT recipients is significant (50% within 1 year). Post-LT discharge to a facility is an independent predictor of readmission after adjusting for medical comorbidities. While the finding of the protective effect of older age was surprising, it may reflect more conservative candidate selection among older LT recipients, and merits further investigation. The specific factors that lead to worse outcomes based on discharge status need exploration in future studies. Disclosures: Josh Levitsky – Grant/Research Support: Salix, Novartis; Speaking and Teaching: Gilead, Salix, Novartis The following people have nothing to disclose: Marina Serper, Lisa B.

As illustrated in Fig 3F, IFN-γ treatment inhibited the

As illustrated in Fig. 3F, IFN-γ treatment inhibited the find more expression of α-SMA and TGF-β1 in 2-week CCl4 mice but not in 10- or 12-week CCl4 mice. STAT1 was phosphorylated in isolated HSCs of the IFN-γ–treated 2-week group, but not in HSCs of the IFN-γ–treated

10- or 12-week groups. Finally, expression of SOCS1 protein, a negative regulator of STAT1,16 in HSCs was up-regulated in 2-week CCl4 mice after IFN-γ treatment. HSCs isolated from 10- or 12-week CCl4 mice had higher basal levels of SOCS1 protein than those from 2-week CCl4 mice, which were not further up-regulated after IFN-γ treatment (Fig. 3F). To further understand the underlying mechanism of suppressed NK cell function observed in advanced liver fibrosis, day 4 (D4) (early activated) or day 8 (D8) (intermediately activated) cultured HSCs were cocultured with liver NK cells for 24 hours. After coculturing with HSCs, IFN-γ

production by NK cells was significantly ICG-001 manufacturer increased in coculturing with D4 HSCs or with D8 HSCs. Higher levels of IFN-γ were observed when cocultured with D4 HSCs than those with D8 HSCs (Fig. 4A). Coculture studies of IFN-γ–deficient cells suggest that the source of IFN-γ production is from NK cells (Fig. 4B). Furthermore, incubation with NKG2D neutralizing antibody diminished IFN-γ production in the coculture experiments (Fig. 4C), suggesting that activated HSCs induce IFN-γ production by NK cells through an NKG2D-dependent mechanism. Expression of TGF-β protein was significantly higher in D8 HSCs compared with D4 HSCs (Fig. 4D). Because TGF-β is a potent inhibitor for NK cells,7, 17 we hypothesized that TGF-β1 produced by cocultured HSCs may inhibit IFN-γ production and cytotoxicity of NK

cells. As illustrated in Fig. 4E, incubation with TGF-β neutralizing antibody markedly enhanced NK cell cytotoxicity against D8 HSCs as well as D4 HSCs (albeit to a lesser extent). In addition, Thiamet G TGF-β antibody treatment increased IFN-γ production by NK cells when cocultured with D8 HSCs but did not affect IFN-γ production in coculture experiment with D4 HSCs (Fig. 4F). Furthermore, the addition of TGF-β1 ligand suppressed the cytotoxicity of NK cells against D4 and D8 HSCs (Supporting Fig. 4). Although IFN-γ–mediated STAT1 activation has been well documented in HSCs,6, 11, 12, 18 the aforementioned experiments show that IFN-γ activation of STAT1 in HSCs from livers with advanced liver fibrosis appears to be disrupted (Fig. 3F). To study the underlying mechanisms responsible for the disruption, IFN-γ–mediated inhibitory cell proliferation and activation of STAT1 were compared on D4 and D8 HSCs. As shown in Fig. 5A, IFN-γ treatment suppressed cell proliferation of D4 HSCs, but not D8 HSCs. Western blotting showed that IFN-γ induced STAT1 activation (phosphorylated STAT1) in D4 HSCs, but this activation was markedly attenuated in D8 HSCs (Fig. 5B and Supporting Fig. 5A).

For biomarker discovery, the latter was chosen as a control group

For biomarker discovery, the latter was chosen as a control group because the risk of postprocedural pancreatitis or cholangitis ethically bans ERC from application in healthy subjects. However, as the control group consists of patients with choledocholithiasis, proteomic analysis may reflect the difference between a relatively normal Luminespib chemical structure biliary tree and liver, and an inflamed, cholestatic liver, which can be expected in patients with PSC and patients with a dominant stenosis due to CC. The PSC/CC model was able to distinguish CC and PSC from nonmalignant lesions with an AUC of 0.93 (P = 0.0001), a sensitivity of 93%, and a specificity of

86% as validated in an independent cohort. These findings are of clinical significance,

as in patients with suspected CC or PSC endoscopic procedures will be performed and thus bile becomes accessible. Furthermore, even in the presence of large masses suspicious of CC, a definite diagnosis often cannot be made. The surveillance of patients with PSC is of crucial importance, as those patients have an increased risk to develop CC and curative treatment such as liver transplantation or radical resection can be performed only at an early stage. Therefore, our aim was to distinguish PSC from CC in a second model. This model was established using a training learn more set consisting of 18 patients with PSC and 16 with CC. Applied to an independent validation set (18 PSC, 25 CC) it showed an AUC of 0.87, a specificity 4��8C of 78%, and a high sensitivity of 84%. Our findings indicate a possible role of proteomic analysis for surveillance in patients with PSC. Nevertheless, PSC-associated CC may be of different origin than sporadic cholangiocarcinoma. Ten patients within the CC group developed CC in addition to PSC. Eight of those patients were identified positive for CC by proteomic analysis. This proteomic model

reaches a high sensitivity compared to single biochemical markers. Direct comparison with the widely used CA 19-9 tumor marker is impossible, because previous studies used different cutoff values in various study populations, leading to enormous range of sensitivity (53%-92%) and specificity (50%-98%).44 Our proposed model may be of clinical relevance in diagnosing CC in patients with PSC especially if supplementary to other diagnostic methods, as a higher accuracy can be reached by a combination of different diagnostic tools.45 All in all, proteomic analysis of bile as a diagnostic tool for surveillance of patients with PSC alone or in combination with other methods may provide an early and reliable diagnosis of CC. In summary, our data indicate a possible role of proteomic analysis of bile to differentiate CC from PSC and benign lesions.

Ucp2-null mice, however, were sensitive to APAP-induced hepatotox

Ucp2-null mice, however, were sensitive to APAP-induced hepatotoxicity despite activation of PPARα with Wy-14,643. Protection against hepatotoxicity by UCP2-induction through activation of PPARα is associated with decreased APAP-induced c-jun and c-fos expression, Palbociclib cost decreased phosphorylation of JNK and c-jun, lower mitochondrial H2O2 levels, increased mitochondrial glutathione in liver, and decreased levels of circulating fatty acyl-carnitines. These studies indicate that the PPARα target gene UCP2 protects against elevated reactive oxygen species generated during drug-induced hepatotoxicity and suggest that induction

of UCP2 may also be a general mechanism for protection of mitochondria during fatty acid β-oxidation. (HEPATOLOGY 2012;56:281–290) Peroxisome proliferator-activated receptor alpha (PPARα), a member of the nuclear receptor superfamily, controls the expression of a battery of genes involved in lipid homeostasis including those encoding peroxisomal and mitochondrial enzymes that carry out fatty acid catabolism. PPARα is mainly expressed in organs that are critical in fatty acid catabolism, such as liver, heart, and kidney.1-3 Perhaps the most critical role of PPARα is to modulate hepatic fatty acid catabolism. In untreated mice, PPARα controls constitutive expression of NVP-AUY922 cost mitochondrial

fatty acid β-oxidation enzymes.4 During periods of starvation in mice Montelukast Sodium PPARα is activated, resulting in induction of both mitochondrial and peroxisomal fatty acid catabolism.5 Notably, in the course of spontaneous and ligand-induced activation of fatty acid catabolism excess H2O2 is produced as a byproduct of induction of peroxisomal acyl-CoA oxidase. Reactive oxygen species (ROS) are also produced during mitochondrial fatty acid β-oxidation. Although this increase in H2O2 is dealt with in part by catalase, glutathione peroxidase, and manganese superoxide dismutase, the cellular responses to ROS are saturated upon the massive activation of fatty

acid catabolism that occurs after ligand activation of PPARα. Consequently, increased PPARα activity during accelerated fatty acid catabolism is associated with increased expression of free-radical scavengers such as catalase and Cu/Zn dismutase6 and mitochondrial uncoupling proteins (UCPs) that may serve to reduce mitochondrial ROS levels.7, 8 Both direct and indirect effects suggest that PPARα may serve a protective role to combat the deleterious side effects of fatty acid catabolism, thus preserving, in particular, mitochondrial function. Increased ROS levels are frequently associated with hepatotoxicity produced by overdose of drugs such as acetaminophen (APAP). APAP, the most common nonprescription analgesic used for pain relief and antipyresis, is a representative compound that causes liver toxicity upon overdose and is a significant public health concern due to occasional overdose in children and adults.