Most of the patients (77%) were successfully treated by endoscopi

Most of the patients (77%) were successfully treated by endoscopic sphincterotomy followed by clip extraction. Contributed by “
“In a recent article, Hu and Colletti suggest that acetaminophen selleck chemicals llc (N-acetyl-p-aminophenol [APAP]) hepatotoxicity in mice is caused by caspase-dependent apoptosis.1 However, we have considerable concerns regarding experimental design, data interpretation, and the conclusions. First, the authors do not show apoptotic cellular morphology in sections stained with hematoxylin and eosin, which is considered the gold standard for

apoptosis.2, 3 Instead, they rely mainly on the terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labeling (TUNEL) assay. However, this assay indicates DNA strand breaks, which are not specific for apoptosis.2 If one compares TUNEL-positive cells caused by APAP overdose with apoptotic cells induced by galactosamine/endotoxin, there is a difference in cellular staining patterns (Fig. 1). However, there is no difference in DNA ladder formation between APAP-induced necrosis and galactosamine/endotoxin-induced apoptosis, suggesting that endonucleases

are involved in both cases.4 Whereas pancaspase inhibitors eliminate DNA fragmentation after galactosamine/endotoxin-induced apoptosis,2, 3, 5 they have no effect on APAP-induced DNA fragmentation.3, 5 In contrast, scavenging of reactive oxygen and peroxynitrite in mitochondria prevents APAP hepatotoxicity.4 DNA click here damage after APAP overdose is associated with mitochondrial dysfunction and nuclear translocation of intermembrane proteins (endonuclease G, apoptosis-inducing factor).6 DNA damage during apoptosis is caused by caspase-activated deoxyribonuclease2; however, there is no relevant caspase activation after APAP overdose.3-5 A transient appearance of caspase fragments shown in overexposed gels1 is insufficient evidence for caspase activation that could be responsible for 30% of hepatocytes undergoing apoptosis.3 Second, the authors

showed that the caspase inhibitor quinolyl-valyl-O-methylaspartyl-[-2,6-difluorophenoxy]-methyl ketone (Q-VD-OPh), 上海皓元医药股份有限公司 which is only soluble in dimethyl sulfoxide (DMSO), eliminated APAP hepatotoxicity.1 Based on the dose, we estimate that 2-10 mL/kg of DMSO was injected. We have demonstrated that pretreatment with as little as 0.25 mL/kg DMSO with or without caspase inhibitor eliminates APAP toxicity because DMSO is a potent inhibitor of cytochrome P450.5 Treatment after APAP metabolism but before injury with DMSO-soluble or water-soluble caspase inhibitors is ineffective.3, 5 Thus, the results by Hu and Colletti can only be interpreted one way: First, the control group did not receive the solvent; Second, the protective effect of Q-VD-OPh was caused by the solvent DMSO, not the caspase inhibitor. Taken together, there is no credible evidence presented in this article that APAP hepatotoxicity is caused by caspase-dependent apoptosis. Hartmut Jaeschke Ph.D.*, C. David Williams B.

We agree with Kershenobich et al that

further randomized

We agree with Kershenobich et al. that

further randomized studies are needed to compare efficacy and safety of the two types of PEG-IFN in the treatment of HCV infection, especially in those individuals coinfected with HIV. Ashwani K. Singal M.D.*, Sarat C. Jampana M.D.†, Bhupinderjit S. Anand M.D., Ph.D.‡, * Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX, † Division of Gastroenterology, University click here of Texas Medical Branch, Galveston, TX, ‡ Department of Gastroenterology and Hepatology, Michael E. DeBakey Veterans Affairs Medical Center, Baylor College of Medicine, Houston, TX. “
“Background Hepatitis A illness severity increases with age. One indicator of hepatitis A illness severity is whether persons hospitalized. We describe changes in primary hepatitis A hospitalization rates in the United States from 2002-2011, including changes in demographics, secondary discharge diagnoses, and factors affecting hospitalization duration. Methods We describe

changes from 2002-2011 among U. S. residents hospitalized with a principal hepatitis A diagnosis and accompanying secondary ALK inhibitor diagnoses using ICD-9 codes from the National Inpatient Survey discharge data. We calculated rates of hospitalizations with hepatitis A as the principal discharge diagnosis and rates of secondary discharge diagnoses. Using multiple regression, we assessed the effect of secondary diagnoses on hospitalization length of stay for five time intervals: 2002-2003, 2004−2005, 2006−2007, 2008-2009 and 2010-2011. Results Rates of hospitalization for hepatitis A as a principal diagnosis decreased from 0.72/100,000 to 0.29/100,000 (p <0.0001) and mean age of those hospitalized increased from 37.6 years to 45.5 years (p <0.0001) during 2002–2011. The percentage of hepatitis A hospitalizations covered by Medicare increased from 12.4% to 22.7% (p <0.0001). Secondary comorbid discharge diagnoses increased, including liver disease, hypertension, ischemic heart disease,

disorders of lipid metabolism, and chronic kidney disease. No changes in length-of-stay or in-hospital deaths from hepatitis A overtime were found, but persons 上海皓元 with liver disease were hospitalized longer. Discussion Hospitalization rates for hepatitis A illness have declined significantly from 2002–2011, but the characteristics of the hospitalized population also changed. Persons hospitalized for hepatitis A in recent years are older and more likely to have liver diseases and other comorbid medical conditions. Hepatitis A disease and resulting hospitalizations could be prevented through adult vaccination. (Hepatology 2014;) “
“A 42-year-old man was admitted to our hospital because of elevated liver enzymes (aspartate aminotransferase, 642 IU/L [normal range: 12-37]; alanine aminotransferase, 788 IU/L [normal range: 7-45]; alkaline phosphatase, 605 IU/L [normal range: 124-367]; γ-glutamyl transpeptidase, 180 IU/L [normal range: 6-30]; and total bilirubin, 8.6 mg/dL [normal range: 0.3-1.2]).

16 Cells were incubated with BV, BR, or FeCl2 for 24 to 48 hours

16 Cells were incubated with BV, BR, or FeCl2 for 24 to 48 hours in Dulbecco’s modified essential medium containing 5% fetal bovine serum. The detailed procedure is described in Supporting Methods, available online. Cells were fixed in absolute methanol, washed in phosphate-buffered

saline, and incubated with positive HCV genotype 2A polyvalent human serum. On western blots, this antiserum specifically TAM Receptor inhibitor recognized core, NS3, and NS5A at their appropriate mobilities. Antibody binding was evaluated after labeling with anti-human secondary antibody–alkaline phosphatase conjugate and results recorded by photomicroscopy. Western blots (WB) were performed as previously described using enhanced chemiluminescence for signal detection (Amersham).17 Signal intensities were quantified by using Image J software (National Institutes of Health, Bethesda, MD). BVR small interfering RNA and control (scrambled) small interfering RNA were purchased from Santa Cruz Biotechnology (sc-44650 and sc-37007). BVR knockdown was performed as described previously.9 Efficiency of the knockdown was monitored by Pifithrin-�� ic50 semiquantitative densitometry of BVR WB. Protease activity was determined fluorometrically with the SensoLyte 620 HCV Protease Assay (AnaSpec), using a wide wavelength excitation/emission (591 nm/622 nm, respectively) fluorescence energy transfer peptide according to the manufacturer’s

instructions. Control incubations with BV or metabolite only were performed to eliminate or correct for autofluorescence or quenching. A competitive inhibitor of the NS3/4A protease, AnaSpec #25346, was used as a positive control. For assays employing endogenous NS3/4A protease, the detailed procedure is described in Supporting medchemexpress Methods, available online. The detailed procedure is described in Supporting Methods, available online. These assays were performed as described in detail in Supporting Methods, available online. Data from individual experiments as well as combined data from separate experiments were expressed as mean ± standard error of the

mean. The significance between means was determined by using Student t test and, when applicable, with analysis of variance, using pooled variances. P values less than 0.05 were considered significant. All experimental findings, whether performed singly or in parts, were repeated at least three times. We have previously shown that induction of HO-1 with hemin results in decreased HCV replication in vitro9; however, it was not known whether physiological concentrations of heme exert antiviral effects. Incubation of replicons with various amounts of hemin demonstrated a concentration-dependent antiviral effect of hemin, apparent at levels as low as 5 μM (Table 1). These concentrations are well within the physiological range of heme in human circulation (10-16 μM) and, in the presence of HO-1, would be expected to yield equimolar quantities of BV, Fe, and carbon monoxide.

Differential gene expression

was also examined in chronic

Differential gene expression

was also examined in chronic hepatitis C patients PLX4032 manufacturer with and without a history of alcohol drinking. Our data showed that the expression of many studied genes correlated with hepatic HCV RNA level. Our findings suggest that nuclear receptor-mediated pathways play an important role in HCV replication and pathogenesis and thus can be potential therapeutic targets to control the disease process. ACADS, acyl-CoA dehydrogenase; ACC, acyl-coA carboxylase; ACOX, acyl-CoA oxidase; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CAR, constitutive androstane receptor; CD36, CD36 molecule; CHOL, total cholesterol; CPT-1, carnitine palmitoyl transferase 1; CYP4A11, cytochrome P450, family 4, subfamily A, polypeptide 11; CYP7A1, cytochrome P450, family 7, subfamily A, polypeptide 1; CYP2E1, cytochrome P450, family 2, subfamily E, polypeptide 1; FABP, fatty acid binding protein; FAE, fatty acyl-CoA elongase; X-396 research buy FAS, fatty acid synthase; FATP, fatty acid transport protein; FGF21, fibroblast growth factor 21; FXR, farnesoid X receptor; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; GLUT, facilitated glucose transporter; G6P, glucose-6-phosphatase; HADH, hydroxyacyl-CoA dehydrogenase; HCC, hepatocellular

carcinoma; HCV, hepatitis C virus; IFN, interferon; IL, interleukin; LDLR, low-density lipoprotein receptor; LRH-1, liver receptor homolog-1; LXR, liver X receptor; MTP, microsomal 上海皓元 triglyceride transfer protein; NCOA, nuclear receptor coactivator; NCOR, nuclear receptor corepressor; NOS2, nitric oxide synthase 2; NTCP, Na+/taurocholate cotransporter; PCR, polymerase chain reaction; PEPCK, phosphoenolpyruvate carboxykinase; PGC-1α, peroxisome proliferator activated receptor-γ coactivator 1α; PPAR, peroxisome proliferator-activated receptor; RAR, retinoic acid receptor; REV-Erbβ, nuclear receptor subfamily 1, group D, member 2; RIG1, retinoid-inducible gene 1 protein; RNA, ribonucleic acid; RXR, retinoid X receptor; SCD1, stearyl-CoA dehydrogenase; SHP,

small heterodimer partner; SREBP, steroid regulatory element-binding protein; SVR, sustained virological response; TBILI, total bilirubin; TNF, tumor necrosis factor; TRIG, triglyceride; VLDL, very low-density lipoprotein. Forty-four liver specimens were obtained from the University of Kansas (KU) Liver Center Tissue Bank (http://www.kumc.edu/livercenter/liver_tissue_bank.html). Consent was obtained from all patients according to a protocol approved by the Institutional Review Board. These specimens were from patients with genotype 1 HCV infection. Inclusion criteria were as follows: patients older than 18 years and positive for both anti-HCV antibody (Abbott ARCHITECT anti-HCV test) and serum HCV RNA (Roche Cobas Ampliprep).

05) Traditional dietary pattern did

05). Traditional dietary pattern did Raf inhibitor not show any significant relation to anthropometric parameters at birth. Conclusion: The present study found a significant relation between maternal dietary patterns

and anthropometric parameters at birth. Further prospective research is suggested to confirm this finding. Key Word(s): 1. Dietary pattern; 2. pregnancy; 3. anthropometric; 4. factor analysis; Presenting Author: FATEMEH HAIDARI Additional Authors: MAJID MOHAMMADSHAHI, MARYAM MOHAMMADSHAHI Corresponding Author: FATEMEH HAIDARI, MAJID MOHAMMADSHAHI Affiliations: Ahvaz Jundishapur University of Medical Sciences; Ferdows Shaheed Chamran Hospital Objective: The use of anthropometric parameters such as birth weight, height selleck compound and head circumference is one of the most common methods to study nutritional and growth status in infant. The aim of this study was to investigate influencing factors on newborn anthropometric parameters in Ferdows, Iran. Methods: In this descriptive- analytical

study, 545 dossiers of Ferdows Shaheed Chamran Hospital’ dossiers within last 5 years were randomly selected. Birth weight, height and head circumference, gestational age, birth order, maternal age, weight and height, pregnancy frequency, maternal disease and abortion history, education and socio-economic status were studied. The data were investigated by Independent sample t-test, ANOVA and Pierson correlation coefficient. Results: The overall mternal age was 27.8 ± 9.7 (mean ± SD). Almost 52.1% of mothers

were in moderate socio-economic status, and 55.4% of them had low education level. Mean of gestational age and birth weight was 39.2 (wk) and 2940 ± 1310 (g), respectively. Maternal age and anthropometric characteristics was positively correlated with newborn anthropometric parameters. Gestational age was significantly related to maternal height (r = 0.54, p = 0.04). 上海皓元 Socio-economic status and educational level significantly affected birth weight (p = 0.049 and p = 0.046, respectively). Birth order was not significantly related to any newborn characteristics. Conclusion: Fetal growth was intensively related to maternal anthropometric and nutritional status. Therefore, increased maternal knowledge and regular health-nutrition care during pregnancy and even before pregnancy could improve mother-infant safety. Key Word(s): 1. Birth weight; 2. BMI; 3. Infant; 4. Pregnancy; Presenting Author: THINESHLEE KRISHNAMOORTHY Additional Authors: CHUAH SAI WEI, NGAN CHENG LAI, TAN YU MENG, LING KHOON LIN, TAN MENG YEW Corresponding Author: THINESHLEE KRISHNAMOORTHY Affiliations: Singapore General Hospital Objective: Exocrine pancreatic insufficiency (EPI) is a complication of pancreatic surgery. Locally, faecal fat globule count is used as an indirect measure for EPI but this is subject to observer bias and complicated to perform.

Specific septal changes that are associated with irreversibility

Specific septal changes that are associated with irreversibility include: matrix modification with cross-linking, elastin-rich scars, and septal neovascularization. Additionally, the loss of cells that drive matrix turnover from the septa combined with vascular extinction may both limit reversibility. Lastly, of course, the persistence and intensity

of the initiating injury will affect the progression of cirrhosis via recurrent cycles of inflammation and repair, regardless of the capacity of the liver to restore a more normal architecture. Should antifibrotic therapies emerge, the challenges of therapeutically resorbing fibrosis in a cirrhotic liver will IWR 1 be quite different from those of a noncirrhotic liver for several reasons. First, whereas evidence clearly indicates reversibility of fibrosis in precirrhotic disease, the determinants of fibrosis regression in cirrhosis are not sufficiently clear, and the point at which cirrhosis is truly irreversible is not established, either in morphologic or functional terms. Second, there is a heightened sense of urgency in attempting to regress fibrosis in

cirrhosis, because continued progression might lead to imminent decompensation, whereas noncirrhotic disease could be decades away from clinical consequences. Thus, the speed of regression in cirrhosis may need to be greater, yet, the cirrhotic liver with its thicker, more cross-linked septa and distorted vasculature may be less amenable to treatment. On the other hand, since fibrosis is part of a chronic Roscovitine in vivo wound healing reaction to encapsulate tissue damage, preventing the formation of scar tissue without removing

the cause MCE of damage might be detrimental by amplifying the injury. Ideally, therefore, administration of an antifibrotic agent would be most useful when coupled with an effective treatment for the underlying liver disease (e.g., antiviral drugs in patients with HBV or HCV). In contrast, in cirrhotic liver, where the ultimate goal is the reduction of portal pressure, the use of antifibrotic agents coupled with effective treatments to reduce portal pressure and its hemodynamic consequences might be more rational. Currently, the diagnosis of cirrhosis in diffuse disease (viral hepatitis, alcohol) relies primarily on histopathological evidence of late-stage fibrosis (e.g., stage 4 fibrosis using the METAVIR system, or stages 5 or 6 in the Ishak scoring system). In this context, and particularly in chronic hepatitis C, sampling errors may lead to underdiagnosis28 or overdiagnosis of cirrhosis.19 Regardless, when using these and related staging systems, “cirrhosis” is a static diagnosis reflecting the end stage of the wound healing process, without adequately signifying the complexity of its pathogenesis, or its functional, hemodynamic and prognostic correlates.

1 The implementation of the Barcelona Clinic Liver Cancer (BCLC)

1 The implementation of the Barcelona Clinic Liver Cancer (BCLC) staging system2, 3 revolutionized the clinical management of HCC patients as it links tumor characteristics with liver function and general condition. The BCLC staging system identified five subgroups of patients (BCLC-0, A, B, C, D), of which three subgroups (BCLC-stage B, C, D) subdivide the large group of patients who are not amenable to potentially curative treatments. Even within a given BCLC-stage, HCC is biologically very

heterogeneous and it has been shown that within these subgroups patients have different outcomes.4 This assumption has already been verified in patients at BCLC stage 0 or A, mostly Cell Cycle inhibitor by highly sophisticated genomic analysis in surgical tissue specimens.5 Similar studies in nonsurgical HCC patients are lacking, because

tumor tissue is check details not so readily available in many cases. In the palliative setting, very expensive targeted therapies are standard of care but only benefit a fraction of the eligible patients. Identifying patients with very dismal prognostic features despite treatment would be helpful in the judicious use of these agents. Application of prognostic systems like CLIP can subgroup these patients into several strata4 but the discriminative power of CLIP in the palliative setting (BCLC B and C) is not strong enough to exclude patients MCE公司 from

receiving these treatments. There is an urgent need for an easily determinable, simple, widely applicable, low-tech, and inexpensive marker from blood, which is able to identify patients with rapid progression to death despite treatment. C-reactive protein (CRP) is an acute phase protein that is mainly produced in the liver. Following an acute phase stimulus, cytokines like interleukin (IL)-1 and IL-6 stimulate CRP production in hepatocytes, which is then released to the systemic circulation.6 CRP binds to several ligands, is involved in opsonization, interacts and activates the complement system, and has an fragment crystallizable (Fc)γ-receptor binding site.7 Thus, CRP plays a key role in a wide range of inflammatory processes and provides a link between the innate and adaptive immune systems. Besides acute and chronic infections, CRP values may be elevated in cancer patients. In fact, several studies have reported a prognostic value of elevated CRP levels in different types of cancer8-10 including resectable HCC.11-13 In this study we investigated the prognostic value of CRP levels in nonsurgical HCC patients with respect to the BCLC classification. BCLC, Barcelona Clinic Liver Cancer; CRP, C-reactive protein; HCC, hepatocellular carcinoma; OS, overall survival; TACE, transarterial chemoembolization.

Results: A 27-year-old male presented twice with

hematoch

Results: A 27-year-old male presented twice with

hematochezia over a 2-year period. His evaluation included a normal gastroscopy and a colonoscopy which showed blood in the terminal ileum. Capsule endoscopy confirmed distal small bowel bleeding and single balloon enteroscopy was attempted, but was unsuccessful due visualisation obscured by blood. A mesenteric CT angiogram was normal and the Technetium-99 m pertechnetate PARP inhibitor scintigraphy scan showed radiotracer uptake in the stomach and urinary bladder. He presented to our hospital one year later with the 3rd episode of hematochezia. The mesenteric CT angiogram identified an area of ileal outpouching with enhancement and no activehaemorrhage. Retrograde single balloon enteroscopy showed a diaphragm-like luminal narrowing associated with ulceration and scaring in the proximal ileum. Beyond it, was a diverticulum extruding a small amount of stale blood. The area was tattooed and clipped for localization. Biopsies confirmed

gastric metaplasia. A repeat Meckel’s scan with SPECT-CT imaging showed radiotracer uptake in the diverticulum adjacent to the clip. Laparoscopic ileum resection was performed and the specimen contained a 4.5 cm diverticulum with ectopic gastric and pancreatic tissue. Conclusion: Meckel’s diverticulum is associated with small bowel peptic ulcerations. These RAD001 chemical structure may present withhaemorrhageand a diaphragm-like narrowing of the intestine. A Meckel’s scintigraphy scan although diagnostic, may be false negative at times. These patients

medchemexpress can be further evaluated with balloon enteroscopy. Surgical excision is the recommended treatment and the co-existance of ectopic pancreatic tissue is an extremely rare occurrence. Key Word(s): 1. Meckel’s diverticulum; 2. ectopic pancreas; 3. single balloon enteroscopy Presenting Author: EUNHA CHO Additional Authors: YOOMI PARK, YOO JIN LEE, HYOJIN PARK Corresponding Author: EUNHA CHO Affiliations: Gangnam Severance Hospital, Yonsei University, Gangnam Severance Hospital, Yonsei University, Gangnam Severance Hospital, Yonsei University Objective: Achalasia is one of the most common esophageal motility disorder which is characterized by dysphagia and noncardiac chest pain. Various pathogenesis of achalasia has been suggested that hereditary, degenerative, autoimmune and infectious factor. Impairment of vagal function has been reported in achalasia. Therefore, we aimed to evaulate the autonomic nerve system (ANS) dysfuction in achalasia and correlation of ANS dysfuction and clinical significance in achalasia. Methods: Nineteen patients with achalasia (6M/13F; 47.1 ± 16.3 years) and 10 healthy peoples (4M/6F; 34.8 ± 10.7 years) were prospectively enrolled at Gangnam Severance hospital from June 2013 to June 2014. All patients completed questionnaire for ANS dysfuction symptoms and heart rate valiability test (HRV).

To determine the in vivo function of IRF9 on hepatic lipid metabo

To determine the in vivo function of IRF9 on hepatic lipid metabolism and insulin sensitivity, we used adenovirus

infection, a well-established method, to overexpress IRF9 in mouse liver. The adenovirus-mediated gene-transfer approach acutely delivers genes to the liver without confounding developmental effects that commonly occur during chronic overexpression.[27, 28] After 20 weeks of HFD feeding, the mice were injected with an IRF9-expressing adenovirus through the jugular vein. Four weeks after adenovirus injection, the protein expression level of IRF9 had a more than four-fold increase in the liver, but remained unchanged in WAT and skeletal muscle (Fig. 4A). IF staining of HNF4 and IRF9 confirmed the elevation of IRF9 expression in hepatocytes, rather than in other types of cells NVP-BGJ398 mw (Fig. 4B). Four weeks after adenovirus injection, mice with IRF9 overexpression had lower liver weight than those Epigenetics inhibitor WT mice injected with an adenovirus-expressing GFP as a control (Fig. 4C). H&E and Oil Red O staining revealed lower hepatic

lipid accumulation in livers with IRF9 overexpressed (Fig. 4D). Hepatic TG, TC, and nonesterified fatty acid (NEFA) contents were also lower in IRF9-overexpressing mice than in control mice (Supporting Fig. 4A). IRF9-injected mice displayed lower ALT, AST, and ALP levels (Supporting Fig. 4B). All these factors indicate that IRF9 promotes hepatic lipid metabolism and protects liver function. IRF9-overexpressing mice displayed lower fasting serum glucose and insulin levels when on an HFD than did control animals (Fig. 4E). Both the IPGTT and IPITT showed improved

glucose regulation in IRF9-overexpressing mice (Fig. 4F and 4G). Consistent with these results, the insulin-signaling pathway was up-regulated in IRF9-overexpressing livers, compared to control livers, as measured by immunoblotting (Fig. 4H). Moreover, liver-specific IRF9 overexpression ameliorated obesity-induced inflammation in the liver. Decreased proinflammatory markers (e.g., F4/80, CD11c, TNF-α, IL-1β, IL-6, and MCP-1) and increased anti-inflammatory markers (e.g., MCE公司 IL-10, arignase 1, mannose receptor, C type 1, MGL1, and MGL2) were detected by real-time PCR and indicate a shift in the balance to M2-like macrophages (Supporting Fig. 4C). To rule out any potential effect of unidentified components of the HFD on our results, we used a genetic obesity model to assess the metabolic role of IRF9. We fed NC to leptin-deficient (ob/ob) mice, which spontaneously develop obesity. As with the dietary model described above, we injected male ob/ob mice with IRF9 adenovirus through the jugular vein for liver-specific IRF9 overexpression (Fig. 5A,B). Four weeks later, hepatic lipid depots were greatly reduced in the IRF9-overexpressing mice, compared to the GFP adenovirus-injected controls (Fig. 5C,D).

To determine the in vivo function of IRF9 on hepatic lipid metabo

To determine the in vivo function of IRF9 on hepatic lipid metabolism and insulin sensitivity, we used adenovirus

infection, a well-established method, to overexpress IRF9 in mouse liver. The adenovirus-mediated gene-transfer approach acutely delivers genes to the liver without confounding developmental effects that commonly occur during chronic overexpression.[27, 28] After 20 weeks of HFD feeding, the mice were injected with an IRF9-expressing adenovirus through the jugular vein. Four weeks after adenovirus injection, the protein expression level of IRF9 had a more than four-fold increase in the liver, but remained unchanged in WAT and skeletal muscle (Fig. 4A). IF staining of HNF4 and IRF9 confirmed the elevation of IRF9 expression in hepatocytes, rather than in other types of cells selleck kinase inhibitor (Fig. 4B). Four weeks after adenovirus injection, mice with IRF9 overexpression had lower liver weight than those PD0325901 WT mice injected with an adenovirus-expressing GFP as a control (Fig. 4C). H&E and Oil Red O staining revealed lower hepatic

lipid accumulation in livers with IRF9 overexpressed (Fig. 4D). Hepatic TG, TC, and nonesterified fatty acid (NEFA) contents were also lower in IRF9-overexpressing mice than in control mice (Supporting Fig. 4A). IRF9-injected mice displayed lower ALT, AST, and ALP levels (Supporting Fig. 4B). All these factors indicate that IRF9 promotes hepatic lipid metabolism and protects liver function. IRF9-overexpressing mice displayed lower fasting serum glucose and insulin levels when on an HFD than did control animals (Fig. 4E). Both the IPGTT and IPITT showed improved

glucose regulation in IRF9-overexpressing mice (Fig. 4F and 4G). Consistent with these results, the insulin-signaling pathway was up-regulated in IRF9-overexpressing livers, compared to control livers, as measured by immunoblotting (Fig. 4H). Moreover, liver-specific IRF9 overexpression ameliorated obesity-induced inflammation in the liver. Decreased proinflammatory markers (e.g., F4/80, CD11c, TNF-α, IL-1β, IL-6, and MCP-1) and increased anti-inflammatory markers (e.g., 上海皓元医药股份有限公司 IL-10, arignase 1, mannose receptor, C type 1, MGL1, and MGL2) were detected by real-time PCR and indicate a shift in the balance to M2-like macrophages (Supporting Fig. 4C). To rule out any potential effect of unidentified components of the HFD on our results, we used a genetic obesity model to assess the metabolic role of IRF9. We fed NC to leptin-deficient (ob/ob) mice, which spontaneously develop obesity. As with the dietary model described above, we injected male ob/ob mice with IRF9 adenovirus through the jugular vein for liver-specific IRF9 overexpression (Fig. 5A,B). Four weeks later, hepatic lipid depots were greatly reduced in the IRF9-overexpressing mice, compared to the GFP adenovirus-injected controls (Fig. 5C,D).