5A) and the activation of CHOP, ATF4, and sXbp1 in both WT and LGKO mice (Fig. 5B); this was comparable to the response of WT mice injected with tunicamycin for 24 hours. In response to the combined treatment, the ALT values and ER stress responses were greater in LGKO mice versus WT mice. A pretreatment with PBA partially reduced the alcohol-induced and HIV PI–induced ER stress response and decreased the elevated ALT levels by more than 50% in both WT and LGKO mice. In addition, an accumulation of ubiquitinated proteins was detected in LGKO mice but not in WT mice treated with alcohol plus HIV PIs. Alcohol and HIV PIs reduced proteasome

activity by 15% in WT mice and by more than 50% in LGKO mice. The PBA treatment restored proteasome activity in both WT and LGKO mice (Fig. 5C). To determine the effects of the liver-specific AG 14699 Grp78 deletion on progressive learn more stages of liver injury, we examined fibrotic changes in LGKO and WT mice. Spontaneous mild fibrotic changes were observed in Sirius red–stained liver tissues of 2 of 10 LGKO mice, but this was not detected in WT mice (Fig. 6A and Supporting Fig. 5A). A chronic CCl4 treatment induced fibrotic changes in both WT and LGKO mice. However, the fibrosis was greater in LGKO mice versus WT mice. Quantitatively, the red-stained collagen was increased 15-fold in LGKO mice versus WT mice without CCl4 (Fig. 6A). The collagen deposition

was increased by 24-fold in WT mice and by 41-fold in LGKO mice after the chronic CCl4 treatment in comparison with WT mice without CCl4. The levels of type I collagen

mRNA in WT and LGKO mice were increased 7.7- and 12.5-fold, respectively, in response to CCl4 medchemexpress (Fig. 6B). There were apparent differences in the expression of select markers of fibrosis between WT and LGKO mice. Without CCl4, the levels of transforming growth factor β (TGF-β), α-smooth muscle actin (α-SMA), and matrix metalloproteinase 2 (MMP2) were increased 1.5- to 2.5-fold in LGKO mice versus WT mice (Fig. 6C). With CCl4, the levels of these markers were increased 2- to 3.5-fold in WT mice with enhanced GRP78 and 3- to 5-fold in LGKO mice. This indicates that the GRP78 deletion worsened CCl4-induced fibrosis. The PBA treatment reduced CCl4-induced fibrosis by more than 50% in LGKO mice, and this was accompanied by the decreased expression of type I collagen mRNA and decreased protein levels of CHOP, TGF-β, α-SMA, and MMP2 (Fig. 6). In reducing CCl4-induced fibrosis, the PBA treatment of WT mice appeared to be not as effective as it was in LGKO mice, and this was indicative of an ER stress contribution. In addition, the mRNA levels of sXbp1 (Fig. 6D and Supporting Fig. 5B), cysteine-rich with epidermal growth factor–like domains 2 (Creld2), Derl3, growth differentiation factor 15 (Gdf15), and Nupr1 were increased in WT mice treated with CCl4 and were increased more in LGKO mice treated with CCl4 (Fig. 6D).

However, role of CLEC-2 in regeneration after liver resection is still unclear. Therefore, the specific purpose of this study was to investigate the role of CLEC-2 in regeneration after partial liver resection in mice. Materials and methods: Irradiated chimeric mice which have CLEC-2 deleted specifically from the platelets were generated. Mice were underwent 70% partial hepatectomy (PH). They were sacrificed at the designated time points, and remnant liver tissues were harvested. Hepatic growth kinetics were analyzed as a function of the liver/body weight ratio, the proliferating cell nuclear

antigen labeling index and Ki-67 labeling index. The mRNA expression of TNF-α and selleck IL-6 were measured. Furthermore, activation of the signal transduction pathways relating to cell proliferation, including click here the IL-6 and STAT3 pathway (related with sinusoidal endothelial), and Akt and ERK1/2 pathways (related with the hepatocytes) were examined. To investigate the expression of an endogenous ligand for CLEC-2, podoplanin, immunohistochemical staining was performed. Furthermore, platelet accumulation

in the liver was quantified. Results: In KO mice, liver/body weight ratios and expression of all cell proliferation markers decreased significantly compared with WT mice. The mRNA expression of TNF-α and IL-6 was significantly blunted in the KO mice compared with the WT mice. The protein expression of both phosphorylated (p) Akt and pERK1/2 was detected in the both groups; however there were no significant differences between two groups. On the other hand, the expression of pSTAT3 was significantly greater in the WT mice compared with the KO mice. Furthermore, the expression of IL-6 receptor gp130 was not different between two groups; however the expression

of IL-6 was significantly greater in the WT mice compared with the KO mice. The expression of podoplanin was detected in the hepatic sinusoid in both two groups. On the other hand, accumulation of the platelet in the hepatic sinusoid was significantly reduced in the KO mice compared with the WT mice. Conclusion: CLEC-2 is involved in the hepatic regeneration after liver resection. MCE This phenomenon is most likely induced by interaction between the platelet and the sinusoidal endothelial cells via the podoplanin expressed on the sinusoidal endothe-lial cells. Disclosures: The following people have nothing to disclose: Hiroshi Kono, Hideki Fujii Background: Tight junctions (TJ) between adjacent intestinal epithelial cells provide a barrier that prevents leakage of toxins and pathogens into the bloodstream. Ethanol and its primary metabolite, acetaldehyde, disrupt tight junctions that allows such leakage to trigger an inflammatory cascade in the liver. We have previously demonstrated that impairments in trans-methylation reactions contribute to the pathogenesis of alcoholic liver injury and treatment with betaine can reverse these defects and prevent liver injury.

TGF-β is another major mediator of liver fibrogenesis.25 HuR silencing in the CFSC-8B cell line markedly reduced

up-regulation of col1a1, α-SMA, and TGF-β mRNA after TGF-β treatment (Fig. 8A). RIP-qPCR analysis showed that α-SMA and TGF-β, but not col1a1, were bound to HuR in TGF-β-stimulated cells (Fig. 8A). In HSCs, TGF-β also plays a major role in inhibiting proliferation in HSCs.26 TGF-β treatment decreased levels of the cell-cycle activators, cyclin D1 and B1, while increasing levels of the cell-cycle inhibitor, p21 (Supporting Fig. 7A,B). HuR knockdown abrogated the antiproliferative effects of TGF-β in primary HSCs from BDL mice (Supporting Fig. 7C) and in the CFSC-8B cell line (Fig. 8B). This

antiproliferative effect of TGF-β was likely the result of reduced p21 levels (Fig. 8C). RIP-qPCR showed that TGF-β treatment induced an Barasertib mouse increased binding of HuR to p21 while reducing the interaction of cyclin D1 and B1 mRNA with HuR (Fig. 8C). TGF-β treatment did not regulate HuR at mRNA and protein levels, unlike PDGF (Supporting Fig. 7D,E). However, TGF-β induced CAL-101 nmr increased cytoplasmic localization of HuR, both in primary HSCs (Supporting Fig. 3G) and in the CFSC-8B cell line (Fig. 8D and Supporting Fig. 7F). This translocation is unlikely to be mediated by ERK, AKT, or LKB1, because TGF-β did not activate any of these kinases (Fig. 8E). However, TGF-β activated p38 MAPK (Fig. 8E), and inhibition of this pathway prevented TGF-β-induced HuR translocation (Fig. 8F). TGF-β did not affect phosphorylation at any of the eight residues that we previously tested for PDGF-induced translocation (data not shown), suggesting that TGF-β and PDGF mediate HuR translocation by different post-translational modifications. In summary, we found that the profibrogenic

and antiproliferative actions of TGF-β could be controlled by HuR-mediated regulation of critical genes. Liver fibrosis and cirrhosis result from the majority of chronic liver insults and represent a difficult clinical MCE challenge. Recent studies have shown that HuR regulates angiotensin II–induced kidney fibrosis27 and ventricular remodeling after myocardial infarction.28 However, HuR functions during liver fibrosis development are unknown. Several studies have shown that HuR regulates the expression of several mRNAs encoding proinflammatory cytokines (e.g., TNF-α, IL-6, TGF-β, and interferon-gamma), proinflammatory mediators (e.g., iNOS), and chemoattractant factors (e.g., MCP-1).29 Most of these factors are involved in the pathogenesis of liver fibrosis.4 Here, we show that HuR silencing in a cholestactic liver injury model (i.e., BDL) reduces the expression of several of these genes, leading to decreased liver damage, oxidative stress, inflammation, macrophage infiltration, and liver fibrosis development.

Design: retrospective, descriptive and observational. Results: We reviewed 1150 medical records; 24 were excluded; finally 1126 patients were included in this study. The global prevalence

of Ch D in patients with CC was 93/1126 (8,26 %; 95 CI 6,7–10), 69/93 (74%) were Pexidartinib mw female; ♀/♂ was 3/1, mean age: 55 years (range:18–77).We additionally calculated the prevalence stratifying population into three groups according to the availability of the information in our archives: a) 1994–2000: 8/316 (2,5 %); b) 2001–2006: 36/412 (8,7 %) and c) 2007–2011: 49/398 (12,3 %) (a vs. b and c p < 0.0001). a) Systemic compromise of Ch D is described in Table 1. b) With regards place of origin 23/93 (24,7 %) were foreigners and 70/93 (75,2 %) were from Argentina. c) Barium enema was performed in 73/93 patients; the findings were: 39/73 (53,4 %) had colon dilatation: 18/39 (46,1 %) megacolon, 11/39 (28,2 %) megasigma, 9/39 (23 %) mega rectosigma, 1/39 (2,56 %) mega rectum. d) RAIR were negative in 37/93 (39,8 %). Conclusion: According to our results Ch D affected 10% of CC patients. When evaluating the data in different periods, the prevalence seems to be increasing. Half of our population had total or segmentary

colon dilatation. Primary care physicians and Gastroenterologists should have in mind this disease as an alternative diagnosis in patients with chronic constipation. Key Word(s): 1. Selumetinib in vivo CHAGAS DISEASE; 2. CHRONIC CONSTIPATION; 3. PREVALENCE; 4. COLONIC MOTILITY;

Table 1 ORGANS AFFECTED n % HEART 13 14 ESOPHAGUS 5 5 HEART & ESOPHAGUS 2 2 Presenting Author: QIAN WANG Additional Authors: YULAN LIU Corresponding Author: YULAN LIU Affiliations: Department of Gastroenterology,Peking University People’s Hospital Objective: Lupus mesenteric vasculitis (LMV) is the most common cause of abdominal pain 上海皓元 in systemic lupus erythematosus (SLE) patients. The awareness of LMV is limited and prognosis is poor. Methods: From January 2008 to December 2012, a total of 948 patients were hospitalized and diagnosed as SLE. LMV was diagnosed in 11 patients by clinical investigation and abdominal computed tomographic findings. Clinical characteristics, serological findings, treatment modalities and outcomes were collected and compared with synchronous SLE patients without gastrointestinal symptoms. Results: The mean age of LMV was 20 years old, which was lower than that of SLE control group. The female to male ratio was 9: 2. Three cases had LMV as the first presentation of underlying SLE. The SLE Disease Activity Index (SLEDAI) was generally high with an average score of 14. The concomitant system number was 3 at onset which was higher than SLE control group. Ascites and ureterohydronephrosis were more common. Abdominal computed tomography revealed bowl dilation, bowl wall thickening, target sign and comb sign.

1

In this issue CH5424802 nmr of the Journal, Yamada et al. explore the impact of ultrasound-diagnosed fatty liver on the incidence of IFG or T2D in Japanese people undergoing a health checkup.11 A total of 12 375 individuals (6799 men and 5576 women) without hyperglycemia or T2D at baseline were re-assessed after 5 years. IFG and T2D were newly diagnosed in 7.6% and 1% of men, and 3.8% and 0.5% of women, respectively, within the study period. In both sexes, the prevalence of newly diagnosed IFG and T2D was significantly higher in the participants with fatty liver than among those without fatty liver, and after adjustment for the other risk factors, fatty liver remained an independent risk factor for IFG and/or T2D. The impact of fatty liver on incidence of IFG and T2D was stronger among participants with a lower BMI. Therefore, the presence of fatty liver may be a better predictor for development of T2D than obesity

itself, and it can be considered to be an early predictor of T2D. In general, this is a well written and concise manuscript with a clear message, and answers a question that is important and significant in public health. Furthermore, it has the strength of studying selleck chemicals a large number of individuals. Some limitations of this study include the lack of liver enzymes and OGTT at baseline, the use of a single result of fasting plasma glucose (FPG) for diagnosis of diabetes at follow up, and lack of rigorous exclusion of other etiologies of fatty liver, making it difficult to draw conclusions regarding 上海皓元 the metabolic risk among subjects with NAFLD. It should be noted that regional guidelines recommend an OGTT be performed at diagnosis of NAFLD when FPG is more than 5.6 mmol/L12, and several studies now report a much higher prevalence of glucose intolerance and established T2D at diagnosis of NAFLD when OGTT is routinely performed.14–16 Both T2D

and hepatogenous diabetes (complicating cirrhosis) are associated with increased liver-related morbidity and mortality in cirrhotic patients regardless of etiology.1 Unlike the hepatogenous diabetes attributed to cirrhosis, T2D in NAFLD is more frequently associated with risk factors such as age, BMI and family history of T2D.1,4–11 It constitutes a risk factor for NASH, for fibrotic progression to cirrhosis and ultimately hepatocellular carcinoma. The finding of diabetes is thus associated with an increased risk of all-cause death and liver-related mortality in patients with NAFLD, and diabetic and cardiovascular risk may compete with liver-related complications in dictating the final outcome.1,3 The biological mechanisms by which NAFLD contributes to a higher risk of developing T2D are not fully understood. However, the fatty liver could contribute in the same way as visceral adipose tissue to insulin resistance, systemic inflammation and oxidative stress, while decreased serum adiponectin concentrations might also be part of the mechanism.

This pattern persists throughout the life span of men and throughout the reproductive ages of women.11,13 Postmenopausal women have an increase in both total adipose tissue volume and VAT volume, as compared with premenopausal women. The increase in VAT in older women has been demonstrated to first occur around the ages of 40-50 years and again from 50 to

60 years of age.11,13 Given that adipose tissue distribution varies by age and reproductive status, we distinguish PD-1/PD-L1 inhibitor between 2 categories: (1) studies that specifically recruited peri- and postmenopausal women or whose mean age of participants was over 50 (predominantly peri- & post-reproductive age); and (2) studies whose mean age was under 50 years of age or whose methods did not specifically recruit peri- and postmenopausal women (predominantly reproductive age). Obesity and Migraine

in Reproductive-Age Participants.— In 2005, 2 small clinic-based studies reported an increased frequency of migraine attacks in those with TBO (Table 4).28,29 In the first, Peres et al compared 74 patients with TBO (mean age of 39 years) who presented to an obesity surgery clinic to 70 age-matched controls.28 A total of 75% of those with TBO had a life-time headache diagnosis as compared with 42% of the controls, this website P < .001. Furthermore, ICHD migraine was reported by 66% of those with TBO as compared with 18.5% of the non-obese controls, P < .0001. Similarly, in the second clinic-based study by Horev et al, 63% of 27 patients with TBO reported episodic headache and 48% fulfilled migraine criteria.29 These 2 studies were subsequently followed by 4 cross-sectional, general population-based studies evaluating obesity in those of reproductive age with varying results.14,30-32 One of these MCE公司 studies found

no association between migraine prevalence and TBO;30 another found no association between migraine prevalence and TBO, but did find an association between headache prevalence and obesity.31 The other 2 studies reported a positive association between the prevalence of migraine or severe headaches and obesity.14,32 In the first of the general population studies, Bigal et al evaluated 30,215 participants, of whom 3791 fulfilled ICHD migraine criteria and 25,150 were controls (Table 3).30 The age of participants ranged from 18 to 89 years with a mean of 39 years. TBO was estimated using self-reported height and weight. Several findings from this study are of note. First, the crude and adjusted prevalence of migraine was increased in women who were underweight. In addition the crude prevalence of migraine was increased in men with a BMI ≥ 35 (8.8%) as compared with men of normal weight (7.2%), P < .01; however, this finding did not remain significant after adjusting for demographics. Finally, although migraine prevalence was not found to be associated with self-reported BMI, the prevalence of high-frequency episodic migraine was associated with TBO. Specifically, while only 4.

This pattern persists throughout the life span of men and throughout the reproductive ages of women.11,13 Postmenopausal women have an increase in both total adipose tissue volume and VAT volume, as compared with premenopausal women. The increase in VAT in older women has been demonstrated to first occur around the ages of 40-50 years and again from 50 to

60 years of age.11,13 Given that adipose tissue distribution varies by age and reproductive status, we distinguish CH5424802 ic50 between 2 categories: (1) studies that specifically recruited peri- and postmenopausal women or whose mean age of participants was over 50 (predominantly peri- & post-reproductive age); and (2) studies whose mean age was under 50 years of age or whose methods did not specifically recruit peri- and postmenopausal women (predominantly reproductive age). Obesity and Migraine

in Reproductive-Age Participants.— In 2005, 2 small clinic-based studies reported an increased frequency of migraine attacks in those with TBO (Table 4).28,29 In the first, Peres et al compared 74 patients with TBO (mean age of 39 years) who presented to an obesity surgery clinic to 70 age-matched controls.28 A total of 75% of those with TBO had a life-time headache diagnosis as compared with 42% of the controls, Y-27632 cell line P < .001. Furthermore, ICHD migraine was reported by 66% of those with TBO as compared with 18.5% of the non-obese controls, P < .0001. Similarly, in the second clinic-based study by Horev et al, 63% of 27 patients with TBO reported episodic headache and 48% fulfilled migraine criteria.29 These 2 studies were subsequently followed by 4 cross-sectional, general population-based studies evaluating obesity in those of reproductive age with varying results.14,30-32 One of these MCE studies found

no association between migraine prevalence and TBO;30 another found no association between migraine prevalence and TBO, but did find an association between headache prevalence and obesity.31 The other 2 studies reported a positive association between the prevalence of migraine or severe headaches and obesity.14,32 In the first of the general population studies, Bigal et al evaluated 30,215 participants, of whom 3791 fulfilled ICHD migraine criteria and 25,150 were controls (Table 3).30 The age of participants ranged from 18 to 89 years with a mean of 39 years. TBO was estimated using self-reported height and weight. Several findings from this study are of note. First, the crude and adjusted prevalence of migraine was increased in women who were underweight. In addition the crude prevalence of migraine was increased in men with a BMI ≥ 35 (8.8%) as compared with men of normal weight (7.2%), P < .01; however, this finding did not remain significant after adjusting for demographics. Finally, although migraine prevalence was not found to be associated with self-reported BMI, the prevalence of high-frequency episodic migraine was associated with TBO. Specifically, while only 4.

05). Conclusion: ①

Smad4 gene promoter hypermethylation was Participate in esophageal cancer both in Kazak esophageal cancer and Han nationality esophageal cancer and may be used as diagnostic markers. ② Smad4 gene promoter hypermethylation in CpG Unit 15 may connected with the Kazakh esophageal cancer. Hypermethylation ABT-263 cell line in CpG units 1, units 16–19, units 27–28, units 31–33 may be the early events and connected with the Kazakh esophageal cancer. Smad4 gene promoter hypermethylation in CpG Unit 6, Unit 16–19 may the reason that High incidence of Kazakh esophageal cancer than Han nationality esophageal cancer. Key Word(s): 1. Han nationality; 2. Kazak; 3. smad4 gene; 4. esophageal cancer; Presenting Author: YANXIANG LV Additional Authors: SHUHUI LIANG, QIN ZHANG, QUANXIN FENG, SHUJUN LI, KAICHUN WU, JIE DING Corresponding Author: SHUHUI LIANG, JIE DING Objective: To investigate the mechanisms of angiogenesis inhibition

of GEBP11 in gastric cancer. Methods: The cellular mechanisms of angiogenesis inhibition of GEBP11 were clarified by proliferation assay, cellular cycle and apoptosis analysis, invasion and migration assay and adherence assay. The differential expression genes in Co-HUVECs treated by GEBP11 or not were screened by microarray to explore the molecular mechanisms, and verified by RT-PCR and Western blot. Results: Proliferation assay, cellular cycle and apoptosis analysis, invasion and migration assay and adherence assay showed that GEBP11 could inhibit the proliferation of Co-HUVECs VEGFR inhibitor and HUVECs, induce the apoptosis 上海皓元 of ECs, but not alter the cell cycle

of ECs. Additionally, GEBP11 appeared to inhibit the ECM degradation, migration and adhere of ECs. Microarray revealed that there were 1202 down-regulated genes and 2104 up-regulated genes in Co-HUVECs treated by GEBP11. And there were 579 down-regulated genes and 194 up-regulated genes in Co-HUVECs vs. HUVECs. Some expression changes which induced by co-culture were reversed after peptide treatment. For example, the expression of MMP1, CDH11, TNFSF18, VCAM1 was up-regulated 5, 2.5, 2, 4 times respectively by co-culture, and then down-regulated 32, 21, 16, 4 times respectively after peptide treatment. PT-PCR showed that the expression of MMPs, CXCR4, CAMs, IL18, KDR were down-regulated in Co-HUVECs treated by GEBP11 on transcriptional level. The expression of MMPs, KDR, Bcl-2/Bax were down-regulated on protein level which was confirmed by western-blot. Conclusion: GEBP11 may come true its inhibition effects on the proliferation, invasion, migration and adherence of ECs and induce apoptosis by down-regulate the expression of MMPs, CAMs, KDR, Bcl-2/Bax, and realize its angiogenesis inhibition function finally. Key Word(s): 1. Gastric cancer; 2. Angiogenesis; 3. GEBP11; 4.

For subjects in the fibrosis stratum, progression learn more to cirrhosis (Ishak fibrosis stage 5 or 6) was determined. A rotating group of HALT-C Trial investigators, masked as to identity of subject, study site,

and randomization group, reviewed every clinical outcome to determine whether it met predefined criteria. In addition, after completion of the study, a mortality committee reviewed every death prior to December 31, 2008, again with masking of subject, site, and randomization group, and classified the death as liver-related or unrelated, based on predefined criteria.15 For deaths that occurred between January 1, 2009, and October 31, 2009, the clinical site principal investigator determined whether or not the death was liver-related. If the cause was unknown, the death was counted as non–liver-related. Three hundred twenty-nine (31%) patients had an outcome, 197 were followed for ≥7 years without an outcome, and 298 were followed for <7 years without an outcome but were seen in the last 6 months of the trial, which represented 79% of the study cohort. Analysis of liver transplantation and liver-related death was also included in the current analysis. Because laboratory data were collected at uniform intervals, we evaluated the rate of progression of

laboratory markers of liver disease progression. Prior to analyzing laboratory data, we selected the laboratory thresholds in the CTP score (albumin ≤3.5 g/dL,

total serum bilirubin ≥2.0 mg/dL, international normalized ratio ≥1.7), as well as creatinine ≥1.2 mg/dL and platelet count <100,000/mm3. Panobinostat We also used a model of end-stage liver disease (MELD) score16 of ≥15. Statistical analyses were performed at the Data Coordinating Center (New England Research Institutes, Watertown, MA) with SAS (release 9.1) software. Time to outcome was measured as the number of months or years from randomization to the date of the initial clinical outcome. For analyses with the initial events after CTP score ≥7, we computed time from the date of the CTP elevation to the date of the initial clinical outcome event after the CTP elevation. For comparison of time to clinical and laboratory outcomes between the fibrosis and cirrhosis strata, we performed Kaplan-Meier life-table analyses and applied the log-rank test. Cox proportional hazards 上海皓元医药股份有限公司 models were used to estimate the relative risks of clinical outcomes. Because outcomes occurred at relatively linear rates, they are reported as annualized rates. Outcomes were counted if they occurred within 8.0 years of randomization and before October 20, 2009. Other than death, clinical outcomes that occurred after liver transplantation were not counted. Annualized rates of cirrhosis development were extrapolated from the 2- and 4-year biopsy results. The HALT-C Trial was approved by the institutional review boards at each participating site.

“
“p38α mitogen-activated protein kinases (MAPK) may be essential in the up-regulation of proinflammatory cytokines and can be activated by transforming growth factor β, tumor necrosis factor-α, interleukin-1β, and oxidative stress. p38 MAPK activation results in hepatocyte growth arrest, whereas increased proliferation has been considered a hallmark of p38α-deficient cells. Our aim was to assess the role of p38α in the progression of biliary cirrhosis induced by chronic cholestasis as an experimental model of chronic inflammation associated with hepatocyte proliferation, apoptosis, oxidative stress, and fibrogenesis. Cholestasis was induced

in wildtype and liver-specific p38α knockout BIBW2992 mw mice by bile duct ligation and animals were sacrificed at 12 and 28 days. p38α knockout mice exhibited a 50% decrease in mean life-span after cholestasis induction. click here MK2 phosphorylation was markedly reduced in liver of p38α-deficient mice upon chronic cholestasis. Hepatocyte

growth was reduced and hepatomegaly was absent in p38α-deficient mice during chronic cholestasis through down-regulation of both AKT and mammalian target of rapamycin. Cyclin D1 and cyclin B1 were up-regulated in liver of p38α-deficient mice upon chronic cholestasis, but unexpectedly proliferating cell nuclear antigen was down-regulated at 12 days after cholestasis induction and the mitotic index was very high upon cholestasis in p38α-deficient mice. p38α-knockout hepatocytes exhibited cytokinesis failure evidenced by an enhanced binucleation rate. As chronic cholestasis evolved the binucleation rate decreased in wildtype animals, whereas it remained high in p38α-deficient mice. Conclusion: Our results highlight a key role of p38α in hepatocyte proliferation, in the development of hepatomegaly, and in survival during chronic inflammation such as biliary cirrhosis. (HEPATOLOGY 2013) Mitogen-activated protein kinases (MAPKs) are essential for the cellular response against injury and for regulation of cell death and tissue homeostasis. p38 MAPKs are a family of serine/threonine

protein kinases activated by environmental and genotoxic stress that have key roles in the medchemexpress control of cell proliferation, differentiation, and survival, as well as in the regulation of the inflammatory response.1 p38α is the most abundant kinase within the p38 MAPK family and displays relevant biological roles in pathophysiology. Increased proliferation and impaired differentiation have been considered hallmarks of p38α-deficient cells.2 Mice with liver-specific deletion of p38α exhibited enhanced hepatocyte proliferation after partial hepatectomy2 and developed more liver tumors with increased numbers of proliferative tumor cells.3 p38α may repress cell proliferation by antagonizing the c-Jun N-terminal kinase (JNK)/c-Jun pathway.