The present study aimed to assess and compare the efficacy of two separate clarithromycin including sequential regimens in Turkey which is well known with high clarithromycin and metronidazole resistance to H. pylori. Methods:  find more Consecutive H. pylori -positive patients with non-ulcer dyspepsia were randomly allocated to one of the two sequential regimens; the first group was given lansoprazole 30 mg b.i.d. plus amoxicillin 1 g b.i.d. for

the first week, followed by lansoprazole 30 mg b.i.d., clarithromycin 500 mg b.i.d., and metronidazole 500 mg t.i.d. for the second week (LA-CM). The second arm was given the same regimen but tetracycline500 g q.i.d. instead of metronidazole (LA-CT). H. pylori was detected with urea breath test (UBT) and histology before enrollment. UBT was repeated at 6th weeks after treatment. Results:  A total of 200 patients were enrolled in groups and 179 of them completed their protocols. The cumulative per protocol (“PP”) and intention-to-treat (“ITT”) eradication rates were 74.3% and 66.5% in R428 order all patients, respectively. Both “PP” (78.2% vs 70.1%) and “ITT” (72% vs 61%) eradication rates were better in LA-CT group than LA-CM group, but the differences were not statistically significant (p > .05). Both regimens were well tolerated, and the incidence of adverse effects was

comparable. Conclusion:  Two weeks clarithromycin including sequential regimens with metronidazole or tetracycline were not achieved acceptable eradication rates in Turkey. “
“Background and Aim:  Fluoroquinolone resistance of Helicobacter pylori is known to be dependent on mutations in the QRDR of gyrA. This study was performed to investigate the distribution of gyrA point mutations and to evaluate the impact of the mutations

on second-line H. pylori eradication therapy. Methods:  After H. pylori isolation from gastric mucosal specimens, fluoroquinolone resistance was examined using the agar dilution method. DNA sequencing of 上海皓元 the QRDR of gyrA was performed in 89 fluoroquinolone-resistant and 27 fluoroquinolone-susceptible isolates. Transformation experiments were performed to confirm mutations in the resistant strains. The eradication rates of moxifloxacin-containing triple therapy were evaluated depending on the resistance of fluoroquinolone. Results:  The gyrA mutations were detected in 75.3% (55 of 73 strains) of the primary resistant strains and 100% (16 strains) of the secondary resistant strains. The most common mutations were Asp-91 (36.0%) and Asn-87 (33.7%). The MIC values in the transformed strains differed depending on the gyrA mutations, N87, and D91. Six patients with fluoroquinolone-resistant strains received moxifloxacin-containing triple therapy as the second-line therapy, and two of three patients with Asn-87 mutations (66.7%) failed in the eradication. By contrast, three patients with Asp-91 mutations had successful eradication treatment. Conclusions:  Fluoroquinolone resistance of H.

pylori is a major cause of treatment failure. To find drugs for H.pylori infection treatment from traditional Chinese medicine has been a hot issue. We selected some traditional Chinese Medicine which may have antimicrobial activity on H.pylori, and evaluated the antimicrobial activity of these drugs in vitro. Methods: Eleven clinical antibiotic resistant strains and two standard strains were selected. The agar dilution method

was used to measurement the micro inhibitory concentration (MIC) of different herbal extracts on H.pylori standard strains and clinical isolates in vitro, including skullcap, dahurian Patrinia herb, Rhizoma Corydalis, Gao Fang, Tian Fang, rhubarb and Coptis chinensis. Calculate MIC50 and MIC90 of different traditional Chinese medicine extracts on H.pylori clinical Buparlisib isolates. Results: The MIC50 and MIC90 of traditional Chinese medicine extracts on H.pylori clinical isolates were as follows respectively: rhubarb 32 µg/ml and 6 µg/ml, Coptis 32 µg/ml and 64 µg/ml, Scutellaria 128 µg/ml and 256 µg/ml, Gao Fang 128 µg/ml and 256 µg/ml, Herba patriniae 512 µg/ml and 512 µg/ml, Rhizoma Corydalis 512 µg/ml and 512 µg/ml, Tian Fang 512 µg/ml

and 512 µg/ml. Conclusion: The results of this study suggest that RXDX-106 chemical structure the extracts of rhubarb and Coptis had obvious antibacterial activity, and Scutellaria baicalensis and Gao Fang had lower antibacterial activity, on H.pylori clinical antibiotic resistant isolates in vitro; Patrinia, rhizoma corydalis and Tian Fang had no antibacterial activity on H.pylori clinical strains in vitro. Key Word(s): 1. H.pylori; 2. Chinese medicine; 3. Antibacterial; 4. Drug resistance; Presenting Author: PROF MOOL RAJRAJ KOTWAL Additional Authors: DR CHEWANGZANGMO RINCHEN, HSIN-LI SONY LIU Corresponding Author: PROF MOOL RAJRAJ KOTWAL Objective: M.R. Kotwal 1, 2, CZ Rinchen 2. Hsin-Li Sony Liu, RN, MSN.3. Department of Home 1 & Health 2. Shunyata, Tibet Road Sikkim India. Nursing Department College of nursing, central Taiwan University of science and Technology, Taichung, Taiwan. 3. Introduction: We live in an era of constant information and almost infinite possibilities.

上海皓元 Multitasking leaves us stressed. Daily meditation physically transforms the cerebral cortex. The most unexpected and comforting recent research confirm that the human brain retains an astonishing degree of plasticity and capacity for learning throughout life. Our mental performance, despite a few glitches with short-term memory, does not peak until mid life, when the white matter in the loftiest parts of the brain is thickest Methods: AIM & Methods: To evaluate efficacy of a self-learning de-stressing technique Swasthya Sukh Satyam Shivam Sundram in randomly assigned 60 students a meditation group from 114 students practiced meditation for 12 weeks and rest formed control group. Scientific technique is from ancient times.

VRs, p=0.02), but no significant differences were observed in IL28A and IFNβ expression among patients with different IL28B genotype or treatment response. Conclusion: Induction of IL28B expression by IFN and poly (I:C) stimulation in PBMCs is closely associated with the treatment response to IFN-based therapy. IFNλ4 expression was only detectable in PBMCs derived from patients with ss469415590-dG allele. Impaired IL28B gene induction and expression of IFNλ4 are closely associated with a non-response

to IFN-based therapy in CHC patients. Disclosures: The following people have nothing to disclose: Yasuhiro Asahina, Miyako Murakawa, Sayuri Nitta, Sorafenib in vitro Yasuhiro Itsui, Mina Nakagawa, Seishin Azuma, Sei Kakinuma, Mamoru Watanabe Background and Aim Aldo-keto reductase family 1, member B10 (AKR1 B10) is an enzyme that converts retinals into retinols, and its up-regulation reduces intracellular retinoic acid, resulting in inhibited cell differentiation. Because AKR1 B1 0 is one of the genes whose expression is increased in human hepatocellular carcinoma (HCC), its involvement in hepatocarcinogenesis is intriguing. We recently analyzed the expression profiles of approximately

41,000 genes in patients with chronic hepatitis C (CHC), and found that AKR1 B1 0 was up-regulated in the livers of patients with CHC who were at Selleck BGB324 high risk of developing HCC (Liver Int 2012). The aim of the present study was to elucidate AKR1 B1 0 expression in a large number of patients with CHC and clarify its association

with the risk of HCC development. Methods The study included 338 consecutive patients with CHC who underwent percutaneous liver biopsy. The expression of AKR1B10 in the liver was examined using immunohistochemical analyses and quantified as a percentage of positive staining area using image analysis software. Uni-variate and multivariate Cox proportional hazard analyses were medchemexpress used to estimate the hazard ratios of AKR1 B1 0 expression for HCC development. The cumulative incidences of HCC development were evaluated using Kaplan-Meier plot analysis and the log-rank test. Results The AKR1 B10 expression level in the cohort ranged from 0.0% to 80.1%, and 158 of 338 patients (47%) showed <1.0% AKR1B10 expression. During the median follow-up time of 3.2 years, 28 of the 338 patients developed HCC after liver biopsy. Multivariate Cox proportional hazard analysis demonstrated that high AKR1B10 expression (>6.0%) was an independent risk factor for HCC development (adjusted hazard ratio 3.98, 95% confidence interval 1.43–1 1.09; P = 0.008). The 5-year cumulative incidences of HCC were 19.8% and 2.1% in patients with high and low AKR1 B10 expressions, respectively (P<0.001). In subgroup analyses, the effects of high AKR1 B1 0 expression on the risk of HCC development were significant over strata.

VRs, p=0.02), but no significant differences were observed in IL28A and IFNβ expression among patients with different IL28B genotype or treatment response. Conclusion: Induction of IL28B expression by IFN and poly (I:C) stimulation in PBMCs is closely associated with the treatment response to IFN-based therapy. IFNλ4 expression was only detectable in PBMCs derived from patients with ss469415590-dG allele. Impaired IL28B gene induction and expression of IFNλ4 are closely associated with a non-response

to IFN-based therapy in CHC patients. Disclosures: The following people have nothing to disclose: Yasuhiro Asahina, Miyako Murakawa, Sayuri Nitta, INK 128 concentration Yasuhiro Itsui, Mina Nakagawa, Seishin Azuma, Sei Kakinuma, Mamoru Watanabe Background and Aim Aldo-keto reductase family 1, member B10 (AKR1 B10) is an enzyme that converts retinals into retinols, and its up-regulation reduces intracellular retinoic acid, resulting in inhibited cell differentiation. Because AKR1 B1 0 is one of the genes whose expression is increased in human hepatocellular carcinoma (HCC), its involvement in hepatocarcinogenesis is intriguing. We recently analyzed the expression profiles of approximately

41,000 genes in patients with chronic hepatitis C (CHC), and found that AKR1 B1 0 was up-regulated in the livers of patients with CHC who were at DAPT in vivo high risk of developing HCC (Liver Int 2012). The aim of the present study was to elucidate AKR1 B1 0 expression in a large number of patients with CHC and clarify its association

with the risk of HCC development. Methods The study included 338 consecutive patients with CHC who underwent percutaneous liver biopsy. The expression of AKR1B10 in the liver was examined using immunohistochemical analyses and quantified as a percentage of positive staining area using image analysis software. Uni-variate and multivariate Cox proportional hazard analyses were MCE used to estimate the hazard ratios of AKR1 B1 0 expression for HCC development. The cumulative incidences of HCC development were evaluated using Kaplan-Meier plot analysis and the log-rank test. Results The AKR1 B10 expression level in the cohort ranged from 0.0% to 80.1%, and 158 of 338 patients (47%) showed <1.0% AKR1B10 expression. During the median follow-up time of 3.2 years, 28 of the 338 patients developed HCC after liver biopsy. Multivariate Cox proportional hazard analysis demonstrated that high AKR1B10 expression (>6.0%) was an independent risk factor for HCC development (adjusted hazard ratio 3.98, 95% confidence interval 1.43–1 1.09; P = 0.008). The 5-year cumulative incidences of HCC were 19.8% and 2.1% in patients with high and low AKR1 B10 expressions, respectively (P<0.001). In subgroup analyses, the effects of high AKR1 B1 0 expression on the risk of HCC development were significant over strata.

VRs, p=0.02), but no significant differences were observed in IL28A and IFNβ expression among patients with different IL28B genotype or treatment response. Conclusion: Induction of IL28B expression by IFN and poly (I:C) stimulation in PBMCs is closely associated with the treatment response to IFN-based therapy. IFNλ4 expression was only detectable in PBMCs derived from patients with ss469415590-dG allele. Impaired IL28B gene induction and expression of IFNλ4 are closely associated with a non-response

to IFN-based therapy in CHC patients. Disclosures: The following people have nothing to disclose: Yasuhiro Asahina, Miyako Murakawa, Sayuri Nitta, BMN673 Yasuhiro Itsui, Mina Nakagawa, Seishin Azuma, Sei Kakinuma, Mamoru Watanabe Background and Aim Aldo-keto reductase family 1, member B10 (AKR1 B10) is an enzyme that converts retinals into retinols, and its up-regulation reduces intracellular retinoic acid, resulting in inhibited cell differentiation. Because AKR1 B1 0 is one of the genes whose expression is increased in human hepatocellular carcinoma (HCC), its involvement in hepatocarcinogenesis is intriguing. We recently analyzed the expression profiles of approximately

41,000 genes in patients with chronic hepatitis C (CHC), and found that AKR1 B1 0 was up-regulated in the livers of patients with CHC who were at click here high risk of developing HCC (Liver Int 2012). The aim of the present study was to elucidate AKR1 B1 0 expression in a large number of patients with CHC and clarify its association

with the risk of HCC development. Methods The study included 338 consecutive patients with CHC who underwent percutaneous liver biopsy. The expression of AKR1B10 in the liver was examined using immunohistochemical analyses and quantified as a percentage of positive staining area using image analysis software. Uni-variate and multivariate Cox proportional hazard analyses were MCE used to estimate the hazard ratios of AKR1 B1 0 expression for HCC development. The cumulative incidences of HCC development were evaluated using Kaplan-Meier plot analysis and the log-rank test. Results The AKR1 B10 expression level in the cohort ranged from 0.0% to 80.1%, and 158 of 338 patients (47%) showed <1.0% AKR1B10 expression. During the median follow-up time of 3.2 years, 28 of the 338 patients developed HCC after liver biopsy. Multivariate Cox proportional hazard analysis demonstrated that high AKR1B10 expression (>6.0%) was an independent risk factor for HCC development (adjusted hazard ratio 3.98, 95% confidence interval 1.43–1 1.09; P = 0.008). The 5-year cumulative incidences of HCC were 19.8% and 2.1% in patients with high and low AKR1 B10 expressions, respectively (P<0.001). In subgroup analyses, the effects of high AKR1 B1 0 expression on the risk of HCC development were significant over strata.

Recently, intestinal microbiota analysis revealed that patients with NASH had a lower percentage of Bacteroidetes compared to healthy control, consistent with previous observations made in alcoholic patients.[38] Such correlations are strongly suggestive of the notion

that gut microbiota products promote NAFLD. In accordance, mice maintained on high-fat/simple carbohydrate, i.e., “modern Western,” diets exhibit increased intestinal permeability, elevated levels of serum endotoxin, and modestly elevated levels of proinflammatory cytokines that correlate with various aspect of metabolic syndrome including NAFLD.[39, 40] Increased levels of serum endotoxin may reflect increased permeability and the fairly large shifts Selleck Enzalutamide in gut microbiota composition that occur in mice in response to diets designed to mimic Western diets. Evidence that NAFLD is actually driven by responses selleck compound library to endotoxin and other microbial products include observations that, in mice, diet-induced metabolic syndrome is absent in germfree conditions and that ablation of innate immune signaling by deleting TLR4 ameliorates disease, while the absence of MyD88, which plays a central role in TLR/NLR signaling, appears to eliminate it entirely.[41-43] Similarly, the suppressor of cytokine signaling 1 (SOCS1) protein, a negative-feedback regulator in cytokine signaling induced upon TLR stimulation,

plays a protective role in liver injury, since SOCS1-deficient mice display fulminant hepatitis, characterized by hepatic 上海皓元 inflammation, fatty degeneration, and hepatocyte necrosis.[44-46] Thus, overall, these findings suggest that the dramatically increased incidence of NAFLD may,

in part, result from increased consumption of Western diets causing increased activation of proinflammatory signaling due to increased intestinal permeability and/or changing in microbiota composition. A recent study supports the former possibility. Specifically, this study examined mice on a HFD that did and did not develop steatosis, and observed changes in microbiota composition that correlated with this phenotypic difference.[47] Transfer of the microbiota from the steatotic mice to germfree mice promoted development of HFD-induced steatosis relative to germfree mice given the microbiota of nonsteatotic mice. Such steatosis correlated with dysglycemia, suggesting that the altered microbiota was broadly promoting metabolic syndrome. The alterations in gut microbiota involved alterations in numerous bacterial species. As reviewed elsewhere, increased proinflammatory signaling can be a direct cause of liver disease and other aspects of metabolic syndrome.[48] Effects of proinflammatory signaling on metabolism include dysregulating appetite control, thus amplifying events that can drive NAFLD/metabolic syndrome. Inflammation can also alter gut microbiota composition.

Recently, intestinal microbiota analysis revealed that patients with NASH had a lower percentage of Bacteroidetes compared to healthy control, consistent with previous observations made in alcoholic patients.[38] Such correlations are strongly suggestive of the notion

that gut microbiota products promote NAFLD. In accordance, mice maintained on high-fat/simple carbohydrate, i.e., “modern Western,” diets exhibit increased intestinal permeability, elevated levels of serum endotoxin, and modestly elevated levels of proinflammatory cytokines that correlate with various aspect of metabolic syndrome including NAFLD.[39, 40] Increased levels of serum endotoxin may reflect increased permeability and the fairly large shifts XL765 in gut microbiota composition that occur in mice in response to diets designed to mimic Western diets. Evidence that NAFLD is actually driven by responses Selleck Buparlisib to endotoxin and other microbial products include observations that, in mice, diet-induced metabolic syndrome is absent in germfree conditions and that ablation of innate immune signaling by deleting TLR4 ameliorates disease, while the absence of MyD88, which plays a central role in TLR/NLR signaling, appears to eliminate it entirely.[41-43] Similarly, the suppressor of cytokine signaling 1 (SOCS1) protein, a negative-feedback regulator in cytokine signaling induced upon TLR stimulation,

plays a protective role in liver injury, since SOCS1-deficient mice display fulminant hepatitis, characterized by hepatic MCE公司 inflammation, fatty degeneration, and hepatocyte necrosis.[44-46] Thus, overall, these findings suggest that the dramatically increased incidence of NAFLD may,

in part, result from increased consumption of Western diets causing increased activation of proinflammatory signaling due to increased intestinal permeability and/or changing in microbiota composition. A recent study supports the former possibility. Specifically, this study examined mice on a HFD that did and did not develop steatosis, and observed changes in microbiota composition that correlated with this phenotypic difference.[47] Transfer of the microbiota from the steatotic mice to germfree mice promoted development of HFD-induced steatosis relative to germfree mice given the microbiota of nonsteatotic mice. Such steatosis correlated with dysglycemia, suggesting that the altered microbiota was broadly promoting metabolic syndrome. The alterations in gut microbiota involved alterations in numerous bacterial species. As reviewed elsewhere, increased proinflammatory signaling can be a direct cause of liver disease and other aspects of metabolic syndrome.[48] Effects of proinflammatory signaling on metabolism include dysregulating appetite control, thus amplifying events that can drive NAFLD/metabolic syndrome. Inflammation can also alter gut microbiota composition.

05). There was a significant association with histological differentiation and TNM stage selleck compound (P < 0.05), and was no significant association with sex, age and lymph node metastasis (P > 0.05). The positive rate of PCNA was 82.4%, and it is significantly higher than that in the chronic inflammation tissues (1/7) and normal tissues (0/5, P < 0.05), There was a significant association with histological differentiation and TNM stage (P < 0.05), and was no significant association with sex, age and lymph node metastasis (P > 0.05). 49 had simultaneous upregulation of Mina53 and

PCNA (r = 0.562, P < 0.05) Conclusion: Mina53 and PCNA expression were high in pancreatic tissues, suggested that they were important in progression and proliferation of pancreatic cancer. Their expression had a medium correlation

and were both proliferation markers. Key Word(s): 1. Pancreatic cancer; 2. Mina53;; 3. c-myc;; 4. PCNA; Presenting Author: LIANG ZHU Additional Authors: QIU ZHAO, NONG-HUA LU Corresponding Author: LIANG ZHU Affiliations: Department of Gastroenterology, the First Affiliated Hospital of Nanchang University; Department of Gastroenterology, Tongji Hospital, Huazhong University of Science and Technology; Department of Gastroenterology, the First Affiliated Hospital of Nanchang University Objective: Response gene to complement-32 (RGC-32) is comprehensively expressed in many kinds of tissues and has been reported selleck chemicals llc to be expressed abnormally in different kinds of human tumors. Previously, we demonstrated for the first time that RGC-32 was up-regulated in pancreatic cancer and was correlated with lymph node metastasis and TNM staging of the patient. Furthermore, we revealed that RGC-32 enhanced metastatic phenotype of pancreatic cancer cell line BxPC-3 by mediating transforming

growth factor-beta (TGF-β)-induced epithelial-mesenchymal transition (EMT) which was independent of Smad signaling pathway. However, the mechanism is still unknown. The present study aims at investigating upstream signaling pathways regulating RGC-32 and downstream transcription 上海皓元 factors mediating the metastasis promoting effect of RGC-32. Methods: In order to screen the signaling pathways by which RGC-32 mediated TGF-β-induced EMT, BxPC-3 cells were treated with chemical inhibitors of Smad-independent pathways for 12 h and then with TGF-β for another 72 h. The mRNA and protein expressions of corresponding signal molecules and EMT markers such as E-cadherin and vimentin were determined by quantitative reverse transcription-PCR (qRT-PCR) and western blot respectively. To find downstream transcription factors of RGC-32, BxPC-3 cells were treated with TGF-β, and RGC-32 silencing and overexpression were performed as well. The expressions of Zeb1, Snal and Slug were determined at both mRNA and protein levels. Results: RGC-32 mediates TGF-β-induced EMT via Erk-MAPK and p38-MAPK pathways in pancreatic cancer cell line BxPC-3.

05). There was a significant association with histological differentiation and TNM stage Cell Cycle inhibitor (P < 0.05), and was no significant association with sex, age and lymph node metastasis (P > 0.05). The positive rate of PCNA was 82.4%, and it is significantly higher than that in the chronic inflammation tissues (1/7) and normal tissues (0/5, P < 0.05), There was a significant association with histological differentiation and TNM stage (P < 0.05), and was no significant association with sex, age and lymph node metastasis (P > 0.05). 49 had simultaneous upregulation of Mina53 and

PCNA (r = 0.562, P < 0.05) Conclusion: Mina53 and PCNA expression were high in pancreatic tissues, suggested that they were important in progression and proliferation of pancreatic cancer. Their expression had a medium correlation

and were both proliferation markers. Key Word(s): 1. Pancreatic cancer; 2. Mina53;; 3. c-myc;; 4. PCNA; Presenting Author: LIANG ZHU Additional Authors: QIU ZHAO, NONG-HUA LU Corresponding Author: LIANG ZHU Affiliations: Department of Gastroenterology, the First Affiliated Hospital of Nanchang University; Department of Gastroenterology, Tongji Hospital, Huazhong University of Science and Technology; Department of Gastroenterology, the First Affiliated Hospital of Nanchang University Objective: Response gene to complement-32 (RGC-32) is comprehensively expressed in many kinds of tissues and has been reported phosphatase inhibitor library to be expressed abnormally in different kinds of human tumors. Previously, we demonstrated for the first time that RGC-32 was up-regulated in pancreatic cancer and was correlated with lymph node metastasis and TNM staging of the patient. Furthermore, we revealed that RGC-32 enhanced metastatic phenotype of pancreatic cancer cell line BxPC-3 by mediating transforming

growth factor-beta (TGF-β)-induced epithelial-mesenchymal transition (EMT) which was independent of Smad signaling pathway. However, the mechanism is still unknown. The present study aims at investigating upstream signaling pathways regulating RGC-32 and downstream transcription medchemexpress factors mediating the metastasis promoting effect of RGC-32. Methods: In order to screen the signaling pathways by which RGC-32 mediated TGF-β-induced EMT, BxPC-3 cells were treated with chemical inhibitors of Smad-independent pathways for 12 h and then with TGF-β for another 72 h. The mRNA and protein expressions of corresponding signal molecules and EMT markers such as E-cadherin and vimentin were determined by quantitative reverse transcription-PCR (qRT-PCR) and western blot respectively. To find downstream transcription factors of RGC-32, BxPC-3 cells were treated with TGF-β, and RGC-32 silencing and overexpression were performed as well. The expressions of Zeb1, Snal and Slug were determined at both mRNA and protein levels. Results: RGC-32 mediates TGF-β-induced EMT via Erk-MAPK and p38-MAPK pathways in pancreatic cancer cell line BxPC-3.

4A). It is yet to be determined whether the reduced inflammatory response in TLR4−/− mice was responsible for retardation of compensatory proliferation. Therefore, we generated TLR4-chimeric mice using irradiation and bone-marrow transplantation (BMT). Successful BMT in all mice was confirmed

GDC 0199 by assessing expression of TLR4 using genomic DNA from tail, blood, bone marrow (Fig. 4B). Expression of TLR4 on Kupffer cells (CD11b+) isolated from the chimeric mice was demonstrated by flow cytometry (Supporting Information Fig. 5). As expected, chimeric mice containing TLR4−/− bone marrow showed a significant reduction in TNFα and IL-6 production in the livers in response to DEN compared to mice transplanted with wt bone marrow (Fig. 4C), and the

levels of circulating TNFα and IL-6 were also lower in chimeric mice containing TLR4−/− bone marrow (Fig. 4D). In contrast, chimeric mice containing Raf inhibitor TLR4-wt bone marrow, but TLR4−/− resident liver cells (wt/TLR4−/−), had markedly elevated inflammatory responses relative to TLR4−/−/TLR4−/− mice. The restoration of inflammatory activation in TLR4−/− mice coincided with the presence of extended areas of epithelial proliferation, as visualized by immunohistochemical staining for Ki-67 (Fig. 4E). Kupffer cells are the main targets of LPS in the liver, and they have a pivotal role in the induction of TNFα and IL-6. As inactivation of Kupffer cells has been shown to MCE公司 cause a significant reduction in cytokine production and complementary proliferation in response to DEN,14 these data clearly indicate that TLR4 in Kupffer cells was generally required for inflammatory cytokine production and compensatory proliferation in

response to DEN exposure. NF-κB is involved in signal transduction of various extracellular stress stimuli including DEN treatment14 and regulates both proinflammatory and protective responses in the liver.19,20 We detected a marked decrease in nuclear staining of NF-κB, which is predominantly adjacent to the centrilobular area, in livers of DEN-treated-TLR4−/− mice compared to DEN-treated wt mice (Fig. 5A). ChIP assay revealed reduced binding of NF-κB to the promoter regions of its downstream genes including Bcl-xl, A20 and MnSOD(Supporting Information Fig. 6A) in TLR4−/− mice than wt mice. Consistently, quantitative PCR analysis revealed evidently decreased expression of A20 and Bcl-xl(Fig. 5B). Previous results suggest that ROS production contributes to DEN-induced cell apoptosis, whereas NF-κB inhibits oxidative stress through controlling expression of Mn-superoxide dismutase (MnSOD), a mitochondrial enzyme that detoxifies superoxide anions.21 Indeed, TLR4−/− mice exhibited decreased expression MnSOD but not CuZnSOD(Fig. 5C). The levels of reduced glutathione (GSH), a major cellular antioxidant, were much lower in the livers of DEN-treated TLR4−/− mice than in similarly treated wt mice (Fig. 5D).