We have concluded that there is no evidence that sexual selection

We have concluded that there is no evidence that sexual selection was a factor in the evolution of giraffe morphology and that the long neck of giraffes did not evolve as a weapon in males. The more likely selective advantage of a long neck was improvement of access to high-level browse. “
“Tigers Panthera tigris continue to decline despite the best efforts of the worldwide scientific and conservation communities. Prey depletion has been linked Selinexor research buy to this decline, but a clear definition of what constitutes preferred prey and preferred prey weight range does not exist. This is critical information if we are to assess tiger reintroduction potential, monitor unforeseen poaching

of predators and prey, and successfully conserve the species. Here we reviewed the available literature on tiger diet and prey availability and calculated Jacobs’s electivity index scores from 3187 kills or scats of 32 prey species. We found that wild boar and sambar deer are significantly preferred by

tigers, with red deer and barasingha likely to be significantly preferred also with a larger sample size. Prey body mass was the only variable that related to tiger prey preference with species weighing between 60 and 250 kg preferred by tigers yielding a ratio of predator to preferred prey of 1:1, which is similar to other solitary felids. This information can be used to predict tiger diet, carrying capacity and movement patterns, as it has been for Africa’s large predator guild, and has important XAV-939 order implications for tiger conservation throughout its distribution. “
“The African wild dog Lycaon pictus is endangered, with anthropogenic impacts, pack size dynamics and competing predators explaining its decline. Relative to solar and lunar events, analysis of diel activity in two parapatric Zimbabwean populations revealed behavioural plasticity

in response to human activity. In Hwange, human presence was low; in Nyamandlovu, human presence and persecution were high. In both populations, Lycaon frequently hunted by moonlight, with 3–4 lux of light restricting nocturnal hunting to 13 days/lunar month. With diurnal hunts commencing at ‘civil twilight begin’ and ending at ‘astronomical twilight end’, light intensity was confirmed MCE as a limiting factor. Nyamandlovu dogs exhibited behavioural plasticity, demonstrated by scattered rather than clumped organization when at rest, and masked the zeitgeber by utilizing evenings and moonlight for more days under suboptimal light conditions than did Hwange dogs. Significantly, different allocation of morning, evening and moonlight hunts between Hwange (47%, 36%, 15%) and Nyamandlovu (28%, 31%, 41%), reduced the temporal potential for human encounter by 64%, but increased this potential for hyaena and lion encounters by 70% and 37%, thus highlighting the trade-off of this switch.

The operators had Hepatology experience in either nursing or scie

The operators had Hepatology experience in either nursing or science. TE was performed consecutively using the FibroScan touch FS502. Age, weight, height, BMI, diagnosis, fasting status, patient position and test location were recorded. Patients were

asked to fast for 3 hours prior to their scan and to lay in dorsal decubitus with their right arm in maximal abduction. Operators chose a test location by percussing for liver dullness. The operators were blinded to fibrosis stage obtained by clinical examination, ultrasound and hepascore. All attempted scans were included in the analysis, even if they were not reported clinically, regardless of success rates and interquartile range. No scans were excluded from the analysis. Results: The average selleck age was 52 years. 55% of patients were referred due to chronic hepatitis C (HCV) and 24% of patients had hepatitis B. Other indications included hemochromatosis, fatty liver disease and primary biliary cirrhosis,. The majority TSA HDAC supplier of scans were completed using the medium probe only (n = 73, 83%). In 38 (43.2%) patients there was a difference of <1 kPa, the discrepancy was <2 kPa in 68.2% of patients and <3 kPa in 83.0% of patients (n = 78). There were 6 cases (6.8%) where a difference of >5 kPa

was observed. In each case either two different probes had been used (n = 2), or the patient had a high liver stiffness measure and was staged as cirrhotic (n = 4). The inter-observer intraclass correlation coefficient with two operators was 0.947 (95% CI 0.907–0.970), Spearmans ρ 0.884; p < 0.001). Similar excellent inter-observer intraclass correlation

coefficient was obtained with three operators (0.954 (95% CI 0.921–0.975)). Conclusions: (1) Excellent correlation was found across all three novice operators. TE can be performed with reproducible results in a real world clinical setting utilizing non-medical staff. (2) In accord with other studies, greater variability in results may be found in cirrhotic patients and across the two different probes. (3) A non-medical FibroScan 上海皓元 Clinic is a viable practical option for assessment of liver fibrosis using transient elastography with adequate training. (4) Accurate staging of fibrosis using FibroScan can help to prioritize patients for treatment, particularly in HCV. S PICARDO, JY KONG, N KONTORINIS, L TARQUINIO, W CHENG Department of Gastroenterology & Hepatology, Royal Perth Hospital, WA Background: The incidence of hepatocellular carcinoma (HCC), a recognized complication of chronic liver disease, has significantly increased over the last decade. Our aim was to evaluate the changing trends in risk factors for HCC at our tertiary center, in order to develop strategies for the prevention and early detection of HCC. Methods: Retrospective analysis of all patients diagnosed with HCC at Royal Perth Hospital between January 2000 and December 2013. Data was collected from clinical notes and electronic databases.

6%), secondly 6 patients (171%) complicated with shock and 5 pat

6%), secondly 6 patients (17.1%) complicated with shock and 5 patients (14.3%) with renal insufficiency. Conclusion: The clinnic manifestation was not typical with learn more severe disease condition in elderly patients with acute pancreatitis. Positive comprehensive treatment can improve the prognosis of elderly patients with acute pancreatitis. Key Word(s): 1. Pancreatitis;

2. Elderly people; 3. Clinnic analysis; Presenting Author: XIA LIANG Additional Authors: YU BANG-WEI, SU HONG-LING, LI TING-TING, CHEN JIANG, LÜ NONG-HUA Corresponding Author: XIA LIANG, LÜ NONG-HUA Affiliations: Department of Gastroenterology Objective: To discuss the correlation between the level of inflammatory mediators in serum and intestinal mucosal barrier

damage of acute necrotizing pancreatitis (ANP) in rats Methods: This study establish acute necrotizing pancreatitis rat model and observe Selleckchem Smoothened Agonist the level of TNF-α, IL-6 in serum, D-lactic acid in serum, histopathologic changes of intestinal mucosa and the water content of intestinal mucosa in the two groups at 6, 12, 24 h after establishment of model. The univariate analysis was used to compare the difference among groups. Linear correlation analysis was used to compare correlation between the level of TNF-α, IL-6 and D-lactic acid in serum, histopathologic scores of intestinal mucosa. Results: The level of TNF-α and IL-6 in serum, D-lactic acid in serum and histopathologic scores of intestinal mucosa were all significantly higher in pancreatic duct injection group at each time point after establishment of MCE model.(P < 0.05.vs sham-operated group respectively).

There was a positive relationship between inflammatory mediators (TNF-α, IL-6) and D-lactic acid in serum obviously (P < 0.01), or between inflammatory mediators (TNF-α, IL-6) and histopathologic scores of intestinal mucosa (P < 0.01). Conclusion: Intestinal mucosa barrier was injured in the early stage of acute necrotizing pancreatitis in rats, it is related to the increasing level of TNF-α, IL-6 in serum induced by SAP rats. Key Word(s): 1. Acute pancreatitis; 2. Intestinal barrier; 3. mediators; Presenting Author: HONG WEI Additional Authors: YU-XUAN WANG Corresponding Author: HONG WEI Affiliations: Department of GastroenterologyHai Nan Provincial People’s Hospital Objective: To evaluate the changes of C reactive protein (CRP) during severe acute pancreatitis (SAP) and investigate their diagnostic value to the early prediction and severity evaluation of SAP. Methods: 46 cases of SAP patients and 192 cases of mild acute pancreatitis (MAP) were diagnosed in our Hospital between January 2009 to January 2012 were enrolled in this study, and another 50 healthy volunteers were set as normal controls. 5 ml venous blood was extracted in each subject both pre and post treatment respectively, and serum was separated for CRP determination.

Brown, Bradley G Hammill, Laura G Qualls PURPOSE: Testosterone

Brown, Bradley G. Hammill, Laura G. Qualls PURPOSE: Testosterone replacement therapy may ameliorate symptoms of hypogonadism commonly experienced by men with cirrhosis. Anabolic steroids have been reported to be associated with tumor development including hepatic adenomas and hepatocellular carcinoma (HCC). It is unclear if hormone therapy affects HCC risk or progression. Our aim was to identify rates of symptomatic hypogonadism in male

patients listed for liver transplantation (LT), and assess the tumor burden and outcomes associated with testosterone replacement therapy. METHODS: Patients on the current LT list were surveyed to diagnose symptomatic

Romidepsin in vitro Ruxolitinib hypogonadism using the Androgen Deficiency in the Aging Male (ADAM) questionnaire. History of testosterone replacement therapy was noted. We then retrospectively reviewed records of male patients with HCC listed for LT, from 2009 to 2014. The outcomes of those who were currently or previously using testosterone therapy were compared to those never on therapy prior to LT. Measures of outcomes included tumor burden, tumor size and vascular thrombosis. Statistical analysis included Student’s t-test and Chi-square. RESULTS: On survey of the current transplant list, 20 of 32 male individuals (63%) were suspected to have symptomatic hypogonadism using the questionnaire. The primary complaints included sexual dysfunction (75%), fatigue (60%) and loss of muscle mass (60%). Only 4 individuals (20%) had been evaluated for their hypogonadism,

of which 2 were on testosterone therapy. 75% (n=15) of individuals were amenable to being on testosterone therapy. Review of 上海皓元医药股份有限公司 previously listed patients with HCC from 2009 to 2014 showed that 5 of 96 individuals were ever on testosterone therapy. Mean duration of therapy was 11 months, at a mean dose of 50mg testosterone gel daily. Of the patients who had received testosterone therapy, there was no significant difference in tumor burden (p = 0.159 for ≥3 lesions), tumor size (p = 0.44 for size ≥3cm) or vascular thrombosis (p = 0.268) prior to transplantation. CONCLUSION: Symptomatic hypogonadism is under-diagnosed in male individuals with cirrhosis and HCC. It is known that testosterone replacement therapy improves sexual function as well as bone mineral density & muscle mass, and should be offered to those who are evaluated to have symptomatic hypogonadism from low serum testosterone levels. Further studies are ongoing to correlate sex hormone levels and testosterone replacement with HCC. Disclosures: Vinay Sundaram – Advisory Committees or Review Panels: Salix, Gilead, Jansen; Speaking and Teaching: Salix Tram T.

Brown, Bradley G Hammill, Laura G Qualls PURPOSE: Testosterone

Brown, Bradley G. Hammill, Laura G. Qualls PURPOSE: Testosterone replacement therapy may ameliorate symptoms of hypogonadism commonly experienced by men with cirrhosis. Anabolic steroids have been reported to be associated with tumor development including hepatic adenomas and hepatocellular carcinoma (HCC). It is unclear if hormone therapy affects HCC risk or progression. Our aim was to identify rates of symptomatic hypogonadism in male

patients listed for liver transplantation (LT), and assess the tumor burden and outcomes associated with testosterone replacement therapy. METHODS: Patients on the current LT list were surveyed to diagnose symptomatic

PI3K inhibitor ITF2357 mw hypogonadism using the Androgen Deficiency in the Aging Male (ADAM) questionnaire. History of testosterone replacement therapy was noted. We then retrospectively reviewed records of male patients with HCC listed for LT, from 2009 to 2014. The outcomes of those who were currently or previously using testosterone therapy were compared to those never on therapy prior to LT. Measures of outcomes included tumor burden, tumor size and vascular thrombosis. Statistical analysis included Student’s t-test and Chi-square. RESULTS: On survey of the current transplant list, 20 of 32 male individuals (63%) were suspected to have symptomatic hypogonadism using the questionnaire. The primary complaints included sexual dysfunction (75%), fatigue (60%) and loss of muscle mass (60%). Only 4 individuals (20%) had been evaluated for their hypogonadism,

of which 2 were on testosterone therapy. 75% (n=15) of individuals were amenable to being on testosterone therapy. Review of 上海皓元 previously listed patients with HCC from 2009 to 2014 showed that 5 of 96 individuals were ever on testosterone therapy. Mean duration of therapy was 11 months, at a mean dose of 50mg testosterone gel daily. Of the patients who had received testosterone therapy, there was no significant difference in tumor burden (p = 0.159 for ≥3 lesions), tumor size (p = 0.44 for size ≥3cm) or vascular thrombosis (p = 0.268) prior to transplantation. CONCLUSION: Symptomatic hypogonadism is under-diagnosed in male individuals with cirrhosis and HCC. It is known that testosterone replacement therapy improves sexual function as well as bone mineral density & muscle mass, and should be offered to those who are evaluated to have symptomatic hypogonadism from low serum testosterone levels. Further studies are ongoing to correlate sex hormone levels and testosterone replacement with HCC. Disclosures: Vinay Sundaram – Advisory Committees or Review Panels: Salix, Gilead, Jansen; Speaking and Teaching: Salix Tram T.

There have been increasing reports of HCC in Fontan patients with

There have been increasing reports of HCC in Fontan patients with cardiac hepatopathy and correlates with the duration of the Fontan circuit (Fig. 2).11, 25, 26 In contrast

to FNH, HCC may be associated with an elevated alpha-fetoprotein (AFP). The incidence SB203580 solubility dmso of HCC in patients with CHD is likely to increase in the future, because patients survive longer.25 In the presence of cirrhosis, serial monitoring is with AFP and imaging every 6 months, with biopsy when imaging is not diagnostic.27 The risk of needle-track seeding is 2.7%.28 An arterial hyperenhancing lesion with washout of the contrast on the portal venous phase, or a mass associated with an AFP >200 ng/mL, would warrant treatment as an HCC. The use of magnetic resonance imaging to better characterize the lesions may be limited by the presence of cardiac pacemakers. Pacemakers also limit the treatment of tumors with radiofrequency ablation. Because the risk of cirrhosis increases with duration of Fontan circulation, it may be reasonable to start HCC surveillance at 10 years after Fontan completion or earlier, if there is imaging or clinical

evidence GDC-0199 solubility dmso of cirrhosis. Nonliver transplant surgery in patients with cirrhosis can be associated with significant risk of mortality.29 The interaction between the presence of liver disease and repair of the cardiac defect is unclear. Among patients with chronic liver disease undergoing cardiac surgery (none with CHD), patients with disease of mild severity (Child-Pugh A) did well; high morbidity and mortality were observed in more advanced liver disease.30 On the other hand, in two small studies of children with cirrhosis undergoing cardiac surgery, morbidity and mortality were not inconsequential. The limited number of cases and the population characteristics preclude generalizability to adults.31, 32 Significant pulmonary hypertension and/or right heart failure may exist in patients with CHD, leading to perioperative hemodynamic instability and thus

suboptimal outcomes.32 Cirrhotic patients have decreased effective circulating arterial volume, which may be further reduced by impaired venous return resulting from tense ascites and diuretic therapy.29 Postoperatively, MCE low cardiac output may reduce hepatic perfusion, but judicious perioperative support may lead to better outcomes.29, 32 Laparoscopic procedures (e.g., cholecystectomy) may need to be avoided, given that increased intra-abdominal pressure resulting from procedural pneumoperitoneum may decrease the passive venous flow in a Fontan circulation. Whether a lower goal for insufflation (e.g., 10-12 mmHg) would be permissive for procedures is unknown.33 There are no data to predict outcomes in adult patients with CHD and liver disease undergoing cardiac surgery.

(HEPATOLOGY 2011;) Chronic alcohol consumption causes a spectrum

(HEPATOLOGY 2011;) Chronic alcohol consumption causes a spectrum of liver pathologies ranging

from steatosis to steatohepatitis, fibrosis, cirrhosis, and can ultimately progress to hepatocellular carcinoma.1-4 X-396 in vitro Early stages of the disease are associated with macrovesicular or microvesicular steatosis predominantly in the central and mid-zonal areas of the liver (zones 3 and 2). Prolonged exposure to ethanol elicits secondary pathologies such as inflammation from gut-derived endotoxins and progresses to steatohepatitis, which is characterized by hepatocellular ballooning, degeneration and necrosis, Mallory’s hyaline body formation, and tissue neutrophil infiltration.2, 5 Cirrhosis, the late stage and most severe form of alcoholic liver disease (ALD) is marked by fibrosis, altered liver architecture, and decreased function and is often progressive and may eventually lead to organ failure.5, 6 Therefore, it is important to understand the molecular mechanisms that underlie the development of ALD to develop therapies that prevent further disease progression. Augmented generation of reactive oxygen and nitrogen species (ROS/RNS) through induction of cytochrome P450 2E1 (CYP2E1), nicotinamide adenine dinucleotide phosphate, reduced form (NADPH) oxidase, and inducible nitric oxide synthase (iNOS) have been shown

to contribute to liver pathology associated with ethanol toxicity in animal models of ALD.7-13 In addition, alcohol metabolism suppresses mitochondrial protein synthesis through LY2157299 concentration its effects on mitochondrial ribosomes and possibly mitochondrial DNA.14, 15 Indeed, the mitochondrion has long been recognized as an important target for alcohol-mediated

toxicity.3, 14, 16, 17 Chronic alcohol consumption causes marked decreases in respiratory chain enzymes resulting from decreased hepatic mitochondrial DNA (mtDNA) and proteomics studies have demonstrated changes in as many as 40 proteins in response to alcohol.15 In addition to the direct impact of alcohol consumption on mtDNA, and mitochondrial protein synthesis machinery, intramitochondrial proteins are irreversibly oxidized by ROS/RNS and reactive medchemexpress lipid species such as 4-hydroxynonenal (4-HNE).7, 9, 17-20 Functionally, this increases dysregulation of fatty acid metabolism and increases activation of the mitochondrial permeability transition pore (MPTP).21, 22 Furthermore, endotoxin-mediated activation of Kupffer cells also results in nitrosative stress through induction of iNOS.7, 9 Increased generation of nitric oxide then inhibits respiration in mitochondria sensitized by ethanol toxicity and also diet-induced fatty liver, indicating commonality in the mechanisms leading to hepatosteatosis in response to metabolic stress.

PHILIPPE HALFON, PHARM, MD, PHD “
“A 71-year-old woman w

PHILIPPE HALFON, PHARM, M.D., PH.D. “
“A 71-year-old woman was referred for a second opinion before hospice with progressive abdominal pain, fullness, diarrhea, and weight loss. A workup revealed ascites and esophageal varices. Imaging Selleckchem Decitabine showed seven liver lesions that were suspicious for hepatocellular carcinoma (HCC) on a computed tomography scan (Fig. 1A), and follow-up magnetic resonance imaging revealed arterial enhancement followed by washout. A tissue sample was compatible with well-differentiated HCC (CD34 and glutamine synthetase positivity, reticulin loss, and isolated vessels); the background liver

revealed hepatoportal sclerosis without cirrhosis (Fig. 1B). A further review of the abdominal scan revealed a dilated inferior mesenteric vein (IMV) due to an arteriovenous malformation (AVM), which was confirmed by angiography (Fig. 1C). There was no evidence of trauma or prior surgery. There was no endoscopic evidence of ischemia or a superficial AVM in the terminal ileum or ascending MLN0128 clinical trial colon, and biopsies were normal. She underwent transhepatic mesenteric

venous coil embolization, which reduced the IMV flow and the main portal venous pressure from 46 to 26 mm Hg. Shortly after the procedure, there was significant improvement in her diarrhea and abdominal pain. Four months later, the ascites had fully resolved, and she had gained weight. Furthermore, abdominal imaging demonstrated complete resolution of the hepatic lesions (Fig. 1D). AVM arteriovenous malformation HCC hepatocellular carcinoma IMV inferior mesenteric vein. This is the first known case in which an intra-abdominal AVM produced (1) chronic intestinal ischemia and diarrhea from arteriovenous shunting of blood; (2) noncirrhotic, presinusoidal portal hypertension with varices and ascites; and (3) multiple hepatic nodules suspicious

for HCC (all of which completely resolved MCE公司 after venous embolization). Splanchnic AVMs commonly involve the hepatic or splenic artery, but IMV involvement is rare.1 Mesenteric AVMs alter vascular flow, reduce the distal arterial pressure, and increase the proximal venous pressure.2 This bypasses the capillary bed and induces a form of mesenteric steal syndrome, which results in abdominal pain, weight loss, diarrhea, and nonocclusive ischemic colitis. Several reports describe inferior mesenteric arteriovenous fistulas resulting in clinically significant arteriovenous shunting.3–5 The symptoms correlate with the amount of blood shunted and the length of time for which the malformation has been present. Hyperdynamic flow from AVMs can also result in presinusoidal portal hypertension. Ascites, varices, and splenomegaly are well-described complications of mesenteric AVMs,1, 6 and arterialization of the portal venous system can significantly increase hepatic blood inflow.

As shown in Fig 1A,B, one of the predicted binding sites (2,280–

As shown in Fig. 1A,B, one of the predicted binding sites (2,280–2,286 nt) was highly conserved in human, mouse, rat, chicken, and dog, whereas the other putative site (2,161–2,166 nt) was poorly conserved across species. No predicted miR-196 binding sites were found in the nuclear regulatory factor erythroid 2–related factor 2 and HMOX1 gene, and no putative miR-196 binding sites were found in the coding region of Bach1 gene (data not shown). To selleck products experimentally verify that the putative miR-196 binding sites are functional,

we transfected 9–13 cells with miR-196–specific mimic and measured Bach1 protein and mRNA levels by way of Western blotting and qRT-PCR, respectively. 9–13 cells transfected with miR-196 mimic showed a significant reduction in the expression of Bach1 protein levels (≈55% after 24 hours’ transfection and ≈64% LY294002 purchase after 48 hours’ transfection) compared with MMNC, whereas

no effects on Bach1 protein levels were detectable in cells transfected with miRNA mimic negative control compared with mock transfection (Fig. 2A). However, no significant effect of miR-196 on Bach1 mRNA levels was observed in 9–13 cells (Fig. 2B). These results demonstrate that the regulation of miR-196 on Bach1 occurs at a translational level in human hepatoma 9–13 cells. Bach1 is a well-established transcriptional repressor of the HMOX1 gene10, 11; therefore, we next determined whether down-regulation of Bach1 protein by miR-196 could increase HMOX1 gene expression. 9–13 cells were transfected with miR-196 mimic or miRNA mimic negative control for 48 hours, after which the levels of HMOX1 and Cullin 3 (Cul 3, nonspecific gene control) mRNA were quantified by way of qRT-PCR. As expected, miR-196 mimic significantly up-regulated HMOX1 mRNA levels by ≈2.4-fold (Fig. 2C),

but not Cul 3 mRNA levels (Fig. 2D) compared with the same amount of miRNA mimic negative control. To further establish that miR-196 targets the 3′-UTR of Bach1 mRNA, which contains two predicted seed match sites for miR-196 (Fig. 3A), (rather than exerting a less direct and specific regulation), a reporter construct, which we called pGL3-Bach1, with Bach1 3′-UTR downstream of the firefly luciferase medchemexpress (f-luc) open reading frame (Fig. 3B), was used. 9-13 cells were cotransfected with pGL3-Bach1 (f-luc), pRL-TK (renilla, to normalize for transfection efficiencies), and miRNA-negative controls, miR-196 mimic, or miR-16 (a negative miR with no predicted binding sites in the 3′-UTR of Bach1 mRNA). Forty-eight hours after transfection, the luciferase reporter activity was assayed. miR-196 mimic transfection significantly decreased reporter activity by ≈53%, whereas miRNA mimic negative control and miR-16 mimic had no effect on reporter luciferase activity (Fig. 3C).

Methods:  Proanthocyanidin (PAC) was extracted from the leaves of

Methods:  Proanthocyanidin (PAC) was extracted from the leaves of blueberry V. virgatum (BB-PAC), grape seeds (GS-PAC) and Croton lechleri (CL-PAC). These extracts were examined for their effects on PDGF-BB-induced LI90 cell proliferation and DNA synthesis. Extracellular signal-regulated kinase (ERK) and Akt phosphorylation and PDGF receptor-β (PDGFR-β) expression were evaluated by western blot analysis. Results:  BB-PAC potently suppressed PDGF-BB-induced proliferation and DNA synthesis of LI90 cells. BB-PAC also suppressed PDGF-BB-induced DNA

synthesis in primary cultured rat HSC. Moreover, GS-PAC and CL-PAC suppressed PDGF-BB-induced DNA synthesis in LI90 cells. In contrast, the monomeric PAC catechin and epicatechin and dimeric Opaganib price PAC procyanidin B2 only slightly suppressed PDGF-BB-induced DNA synthesis. Western blot analysis showed that BB-PAC completely or partially inhibited PDGF-BB-induced ERK and Akt phosphorylation, respectively. In addition, BB-PAC partially Navitoclax order inhibited the PDGF-BB-induced degradation of PDGFR-β. Conclusion:  Our results suggest that BB-PAC suppresses activated HSC by inhibiting the PDGF signaling pathway. In addition, these results provide novel findings that may facilitate the development of

antifibrogenic agents. “
“Tumor necrosis factor (TNF) has been implicated in the progression of many chronic liver diseases leading to fibrosis; however, the role of TNF in fibrogenesis is controversial and the specific contribution of TNF receptors to hepatic stellate cell (HSC) activation remains

to be established. Using HSCs from wild-type, TNF-receptor-1 (TNFR1) knockout, TNF-receptor-2 (TNFR2) knockout, or TNFR1/R2 double-knockout (TNFR-DKO) mice, we show that loss of both TNF receptors reduced procollagen-α1(I) expression, slowed down HSC proliferation, and impaired platelet-derived growth factor (PDGF)-induced promitogenic signaling in HSCs. TNFR-DKO HSCs exhibited decreased AKT phosphorylation and in vitro proliferation in response to PDGF. These effects were reproduced in TNFR1 knockout, but not TNFR2 knockout, HSCs. In addition, matrix metalloproteinase 9 (MMP-9) expression was dependent MCE on TNF binding to TNFR1 in primary mouse HSCs. These results were validated in the human HSC cell line, LX2, using neutralizing antibodies against TNFR1 and TNFR2. Moreover, in vivo liver damage and fibrogenesis after bile-duct ligation were reduced in TNFR-DKO and TNFR1 knockout mice, compared to wild-type or TNFR2 knockout mice. Conclusion: TNF regulates HSC biology through its binding to TNFR1, which is required for HSC proliferation and MMP-9 expression. These data indicate a regulatory role for TNF in extracellular matrix remodeling and liver fibrosis, suggesting that targeting TNFR1 may be of benefit to attenuate liver fibrogenesis.