Endobiliary biopsy specimens (n = 13), percutaneous liver biopsy specimens (n = 3), and surgically-resected liver specimens (n = 3) were obtained from 16 patients. Tissue sections were stained with hematoxylin–eosin (HE) and immunostained using IgG4 antibodies (The Binding Site, Birmingham, UK) with the avidin–biotin–peroxidase complex. The infiltration High Content Screening of IgG4-positive plasma cells was evaluated by counting the number of positive plasma cells in the four high-power fields (HPF; HE, original magnification ×400) and dividing the value by 4. The presence of ≥10 IgG4-positive cells per HPF was classified as significant infiltration. As disease controls, two prototypes

of benign and malignant biliary strictures, PSC and CCC, were compared with ISC to confirm the specificity of DNA Damage inhibitor IgG4-positive cells in histology. The resected liver specimens from patients with classic PSC and periductal infiltrating-type hilar CCC were immunostained for IgG4. Thirteen patients with classic PSC (males, n = 8; median age: 37years, range: 26–54 years), who were diagnosed according to the typical cholangiographic findings and showed progressive clinical course (accompanying ulcerative colitis in seven patients) resulting in liver failure and liver transplantation,6

and 13 patients with hilar CCC (males, n = 9; median age: 61 years, range: 57–70), who were histologically confirmed, were selected retrospectively. Serum IgG and IgG4 levels were measured in another 25 patients with hilar CCC (males, n = 14; median age: 68 years, range: 39–86) to evaluate the role in differential diagnosis. The clinical profiles selleck compound of 16 patients with ISC are summarized in Table 1. Of the 16 patients with ISC, 15 were male, and the mean age was 62.9 years (range: 44–80). Initial presentations included painless jaundice (n = 9, combined weight loss in two patients) and abdominal pain (n = 1). The remaining

six patients had mild abdominal discomfort without biliary pain or fever. Newly-onset diabetes mellitus was present in two patients. Neither of these patients was previously diagnosed with ulcerative colitis. The extent of bile duct involvement upon cholangiogram was as follows: both hilar and intrahepatic strictures (n = 13, including three patients with additional distal CBD strictures), hilar and distal CBD strictures (n = 1), and intrahepatic strictures alone (n = 2). The multifocal biliary tree involvement was defined when two or more different segmental branches were involved with intervening normal-looking branches. This was observed in 14 patients (Fig. 1). Marked concentric bile duct thickening with a smooth, luminal surface and preserved luminal patency was observed at the hilum in 13 patients, resembling a doughnut (Fig. 2). These thickened bile duct walls showed variable enhancement patterns.

Endobiliary biopsy specimens (n = 13), percutaneous liver biopsy specimens (n = 3), and surgically-resected liver specimens (n = 3) were obtained from 16 patients. Tissue sections were stained with hematoxylin–eosin (HE) and immunostained using IgG4 antibodies (The Binding Site, Birmingham, UK) with the avidin–biotin–peroxidase complex. The infiltration BI 6727 mouse of IgG4-positive plasma cells was evaluated by counting the number of positive plasma cells in the four high-power fields (HPF; HE, original magnification ×400) and dividing the value by 4. The presence of ≥10 IgG4-positive cells per HPF was classified as significant infiltration. As disease controls, two prototypes

of benign and malignant biliary strictures, PSC and CCC, were compared with ISC to confirm the specificity of Ipatasertib solubility dmso IgG4-positive cells in histology. The resected liver specimens from patients with classic PSC and periductal infiltrating-type hilar CCC were immunostained for IgG4. Thirteen patients with classic PSC (males, n = 8; median age: 37years, range: 26–54 years), who were diagnosed according to the typical cholangiographic findings and showed progressive clinical course (accompanying ulcerative colitis in seven patients) resulting in liver failure and liver transplantation,6

and 13 patients with hilar CCC (males, n = 9; median age: 61 years, range: 57–70), who were histologically confirmed, were selected retrospectively. Serum IgG and IgG4 levels were measured in another 25 patients with hilar CCC (males, n = 14; median age: 68 years, range: 39–86) to evaluate the role in differential diagnosis. The clinical profiles selleck products of 16 patients with ISC are summarized in Table 1. Of the 16 patients with ISC, 15 were male, and the mean age was 62.9 years (range: 44–80). Initial presentations included painless jaundice (n = 9, combined weight loss in two patients) and abdominal pain (n = 1). The remaining

six patients had mild abdominal discomfort without biliary pain or fever. Newly-onset diabetes mellitus was present in two patients. Neither of these patients was previously diagnosed with ulcerative colitis. The extent of bile duct involvement upon cholangiogram was as follows: both hilar and intrahepatic strictures (n = 13, including three patients with additional distal CBD strictures), hilar and distal CBD strictures (n = 1), and intrahepatic strictures alone (n = 2). The multifocal biliary tree involvement was defined when two or more different segmental branches were involved with intervening normal-looking branches. This was observed in 14 patients (Fig. 1). Marked concentric bile duct thickening with a smooth, luminal surface and preserved luminal patency was observed at the hilum in 13 patients, resembling a doughnut (Fig. 2). These thickened bile duct walls showed variable enhancement patterns.

Endobiliary biopsy specimens (n = 13), percutaneous liver biopsy specimens (n = 3), and surgically-resected liver specimens (n = 3) were obtained from 16 patients. Tissue sections were stained with hematoxylin–eosin (HE) and immunostained using IgG4 antibodies (The Binding Site, Birmingham, UK) with the avidin–biotin–peroxidase complex. The infiltration selleck products of IgG4-positive plasma cells was evaluated by counting the number of positive plasma cells in the four high-power fields (HPF; HE, original magnification ×400) and dividing the value by 4. The presence of ≥10 IgG4-positive cells per HPF was classified as significant infiltration. As disease controls, two prototypes

of benign and malignant biliary strictures, PSC and CCC, were compared with ISC to confirm the specificity of DNA Damage inhibitor IgG4-positive cells in histology. The resected liver specimens from patients with classic PSC and periductal infiltrating-type hilar CCC were immunostained for IgG4. Thirteen patients with classic PSC (males, n = 8; median age: 37years, range: 26–54 years), who were diagnosed according to the typical cholangiographic findings and showed progressive clinical course (accompanying ulcerative colitis in seven patients) resulting in liver failure and liver transplantation,6

and 13 patients with hilar CCC (males, n = 9; median age: 61 years, range: 57–70), who were histologically confirmed, were selected retrospectively. Serum IgG and IgG4 levels were measured in another 25 patients with hilar CCC (males, n = 14; median age: 68 years, range: 39–86) to evaluate the role in differential diagnosis. The clinical profiles click here of 16 patients with ISC are summarized in Table 1. Of the 16 patients with ISC, 15 were male, and the mean age was 62.9 years (range: 44–80). Initial presentations included painless jaundice (n = 9, combined weight loss in two patients) and abdominal pain (n = 1). The remaining

six patients had mild abdominal discomfort without biliary pain or fever. Newly-onset diabetes mellitus was present in two patients. Neither of these patients was previously diagnosed with ulcerative colitis. The extent of bile duct involvement upon cholangiogram was as follows: both hilar and intrahepatic strictures (n = 13, including three patients with additional distal CBD strictures), hilar and distal CBD strictures (n = 1), and intrahepatic strictures alone (n = 2). The multifocal biliary tree involvement was defined when two or more different segmental branches were involved with intervening normal-looking branches. This was observed in 14 patients (Fig. 1). Marked concentric bile duct thickening with a smooth, luminal surface and preserved luminal patency was observed at the hilum in 13 patients, resembling a doughnut (Fig. 2). These thickened bile duct walls showed variable enhancement patterns.

Based on the observation that the growth of HCC growth critically depends on cholesterol,[5] we discuss the evidence

potentially favoring the use of statins in clinical trials aimed at primary and secondary chemoprevention Seliciclib concentration of HCC in those individuals at high risk of developing this condition and slowing the course of otherwise incurable primary or recurrent disease. A Medline search of the literature conducted on 12 June 2012, (key words: Statins; hepatocellular carcinoma) provided 119 references. Such references, which were all evaluated for potential inclusion, cross-references, and all those references deemed to be relevant by the authors represent the basis of the present review. Pure cholesterol, the molecular formula of which was established in 1888, was first extracted from gallstones and named cholesterine, namely “solid bile” in ancient Greek.[6] Medical science has progressed from an era when hypercholesterolemia was deemed to be a mere consequence of ageing—and thus atherosclerosis an unpreventable condition—to the present paradigm that atherosclerosis can be prevented through targeting hypercholesterolemia to reduce

mortality.[6, 7] This major shift in clinicians’ attitude largely results from statins having been made available. Cholesterol synthesis BMS-354825 ic50 takes place in four stages:[6] check details a  condensation of three acetate units to form a 6-carbon

intermediate, mevalonate; The discovery of statins is due to a substantial extent to the pioneer work by the Japanese researcher Akira Endo influenced by his native rural environment, by the biography of the discoverer of penicillin Alexander Fleming, and by the high rate of heart attacks observed while working in the USA.[6] In 1985, Brown and Goldstein were awarded the Nobel Prize in Physiology and Medicine for their discoveries on the regulation of cholesterol metabolism[9] and lovastatin received FDA approval to be commercialized in 1987.[6] Statins (the chemical structure of which is depicted in Fig. 2) have now been tested in many large-scale clinical trials, involving 90 000 subjects who were followed for 5 years.[6] These studies have consistently shown that treatment with statins lowers plasma low-density lipoprotein (LDL) levels by 25–35% and reduces the frequency of heart attacks to the same extent. Statins are deemed to be the largest selling class of drugs currently taken by patients throughout the world.[6] During disease development, cancer cells acquire multiple key biological capabilities conferring them a competitive survival advantage and culminating in invasion and metastasis.[10] Whether the pathogenesis of HCC is strongly etiology-dependent remains unproven.

2% vs 3.9%, P = .006).22 Stiell et al compared methotrimeprazine (not available in the USA) 37.5 mg IM to meperidine 75 mg IV plus dimenhydrinate 50 mg IM.23 There was no significant difference in pain reduction (VAS) for methotrimeprazine vs meperidine/dimenhydrinate (−40.3 vs −46.6, P = .27). There were more reports of prolonged drowsiness with methotrimeprazine (51.7% check details vs 16.7%; P = .01). Table 2 summarizes the studies involving chlorpromazine, promethazine, and methotrimeprazine. Butyrophenones, neuroleptics acting as potent dopamine receptor antagonists with some antihistamine and anti-serotonergic activity, can rapidly decrease

brainstem activity. They are used as anti-emetics, sedatives, and antipsychotic agents. As with all neuroleptics, the side effects of butyrophenones include akathisia, dystonia, hypotension, dizziness, drowsiness, and drug-induced parkinsonism. Butyrophenones can cause QTc prolongation to a degree where there is increased risk of ventricular arrhythmias and cardiac arrest. There have been 9 cases of torsade de pointes reported in 30 years, and all have been with droperidol at doses of 5 mg IV or greater.24,25 As noted previously, the likelihood of dystonia or drug-induced parkinsonism with butryophenones can be lessened by using concomitant anticholinergic medication. Orthostatic hypotension can be avoided by pretreating with a 500 mL NS bolus. Silberstein

et al compared click here 4 doses of droperidol IM (0.1, 2.75, 5.5, and 8.25 mg)

to placebo/NS IM.26 The percentages of subjects pain-free at 2 hours for placebo and droperidol doses 0.1, Proteasome inhibitor 2.75, 5.5, and 8.25 mg were 16, 27, 49, 37, and 34%, respectively (P < .01). Thirty percent of those receiving 2.75 mg or more of droperidol reported serious side effects, including anxiety, akathisia, and somnolence. No patient had ECG changes showing QT prolongation. Miner et al compared droperidol 5 mg IM or 2.5 mg IV to prochlorperazine 10 mg IM or 10 mg IV.27 There was no difference in efficacy between IM and IV routes for either medication. Pain reduction (VAS) at 1 hour was greater for droperidol (−81.4% vs −66.9%; P < .001). Frequency of side effects for droperidol and prochlorperazine were similar (15.2% vs 9.6%; P = .19), with sedation being more common with droperidol (9% vs 1%). Weaver et al also compared droperidol 2.5 mg IV to prochlorperazine 10 mg IV.28 The percentage pain-free at 30 minutes favored droperidol (54.2% vs 37.5%; P < .01), but pain reduction (VAS) was not greater for droperidol (−79.1 vs −72.1; P = .23). The rate of akathisia was similar for both treatments (6% vs 8%; P = .25). Richman et al found droperidol 2.5 mg IM and meperidine 1.5 mg/kg IM produced similar pain reduction (VAS) (−47 vs −37; P = .33); akathisia was reported in 13.3% taking droperidol, with sedation in 6.7% taking droperidol, and 14.3% taking meperidine.

2% vs 3.9%, P = .006).22 Stiell et al compared methotrimeprazine (not available in the USA) 37.5 mg IM to meperidine 75 mg IV plus dimenhydrinate 50 mg IM.23 There was no significant difference in pain reduction (VAS) for methotrimeprazine vs meperidine/dimenhydrinate (−40.3 vs −46.6, P = .27). There were more reports of prolonged drowsiness with methotrimeprazine (51.7% DAPT mw vs 16.7%; P = .01). Table 2 summarizes the studies involving chlorpromazine, promethazine, and methotrimeprazine. Butyrophenones, neuroleptics acting as potent dopamine receptor antagonists with some antihistamine and anti-serotonergic activity, can rapidly decrease

brainstem activity. They are used as anti-emetics, sedatives, and antipsychotic agents. As with all neuroleptics, the side effects of butyrophenones include akathisia, dystonia, hypotension, dizziness, drowsiness, and drug-induced parkinsonism. Butyrophenones can cause QTc prolongation to a degree where there is increased risk of ventricular arrhythmias and cardiac arrest. There have been 9 cases of torsade de pointes reported in 30 years, and all have been with droperidol at doses of 5 mg IV or greater.24,25 As noted previously, the likelihood of dystonia or drug-induced parkinsonism with butryophenones can be lessened by using concomitant anticholinergic medication. Orthostatic hypotension can be avoided by pretreating with a 500 mL NS bolus. Silberstein

et al compared selleck kinase inhibitor 4 doses of droperidol IM (0.1, 2.75, 5.5, and 8.25 mg)

to placebo/NS IM.26 The percentages of subjects pain-free at 2 hours for placebo and droperidol doses 0.1, learn more 2.75, 5.5, and 8.25 mg were 16, 27, 49, 37, and 34%, respectively (P < .01). Thirty percent of those receiving 2.75 mg or more of droperidol reported serious side effects, including anxiety, akathisia, and somnolence. No patient had ECG changes showing QT prolongation. Miner et al compared droperidol 5 mg IM or 2.5 mg IV to prochlorperazine 10 mg IM or 10 mg IV.27 There was no difference in efficacy between IM and IV routes for either medication. Pain reduction (VAS) at 1 hour was greater for droperidol (−81.4% vs −66.9%; P < .001). Frequency of side effects for droperidol and prochlorperazine were similar (15.2% vs 9.6%; P = .19), with sedation being more common with droperidol (9% vs 1%). Weaver et al also compared droperidol 2.5 mg IV to prochlorperazine 10 mg IV.28 The percentage pain-free at 30 minutes favored droperidol (54.2% vs 37.5%; P < .01), but pain reduction (VAS) was not greater for droperidol (−79.1 vs −72.1; P = .23). The rate of akathisia was similar for both treatments (6% vs 8%; P = .25). Richman et al found droperidol 2.5 mg IM and meperidine 1.5 mg/kg IM produced similar pain reduction (VAS) (−47 vs −37; P = .33); akathisia was reported in 13.3% taking droperidol, with sedation in 6.7% taking droperidol, and 14.3% taking meperidine.

Supported by National

Natural Science Foundation of China (No. 81000162). Key Word(s): 1. Crohn’s disease; 2. fibroblasts; 3. pathogenesis; Presenting Author: JIE LIANG Additional Authors: KAICHUN WU, DAIMING FAN Corresponding Author: JIE LIANG Affiliations: Xijing Hospital of Digestive Diseases; Xijing Hospital of Digestive DIsease Objective: Inflammatory bowel disease is an important risk factor for colorectal cancer. However, the mechanism of development from IBD to colorectal cancer remains unclear. Methods: SphK2-KO mice and control littermates were used for DSS-induced colitis and AOM-DSS-induced colitis-associated cancer model. Relative index and mechanisms were further investigated. RXDX-106 order Results: Sphingosine-1-phosphate

(S1P) produced by upregulation of sphingosine kinase 1 (SphK1) links chronic intestinal inflammation to colitis-associated cancer (CAC) and both are exacerbated by deletion of SphK2. S1P is essential for production of the multifunctional NF-κB-regulated cytokine IL-6, persistent activation of the transcription factor Stat3, and consequent upregulation of the S1P receptor, S1PR1. The pro-drug FTY720 decreased SphK1 and S1PR1 and eliminated the NF-κB-IL-6-Stat3 amplification cascade and development of CAC even in SphK2-/- mice and may be useful in treating colon cancer in individuals PF-02341066 mw with ulcerative colitis. Conclusion: SphK1-S1P-S1PR1 axis is at the nexus between NF-κB and Stat3 and connects chronic inflammation and CAC. Key Word(s): 1. S1P; 2. IBD; 3. Colorectal cancer; 4. STAT3; Presenting Author: SHI HUI Additional Authors: WAN JUN, SU BINBIN Corresponding Author: SHI HUI Affiliations: Nan lou gastrointestinal department 301 hospital; 301 hospital Objective: Many patients with ulcerative colitis (UC) in clinical remission continue to have symptoms of pain and diarrhea despite learn more minimal or no ongoing inflammation. These patients may be considered to have an overlap of UC or Irritable bowel symptoms. The aims of this study were to

prospectively determine the prevalence of Irritable bowel like symptoms in ulcerative colitis patients in remission, and to determine whether IBS-like symptoms correlate with occult inflammation. Methods: We prospectively included 185 patients with UC, who had been in remission for at least 6 months according to laboratory parameters and clinical and endoscopical appearance, 107 with IBS, and 36 healthy controls. Remission was defined by physician assessment: ulcerative colitis disease activity index <3, and serum C-reactive protein <10, while off corticosteroids or biologics. Rome III criteria for IBS. Serum intestinal fatty acid binding protein (I-FABP) and fecal calprotectin (Fc) were measured by ELISA. Results: Of the 185 UC patients, there were 107(57.8%) patients with IBS[69 male, 38 female, mean age (41 ± 17.5)], and 68 patients without IBS[41 male, 27 female, mean age (44 ± 16.2)].

Supported by National

Natural Science Foundation of China (No. 81000162). Key Word(s): 1. Crohn’s disease; 2. fibroblasts; 3. pathogenesis; Presenting Author: JIE LIANG Additional Authors: KAICHUN WU, DAIMING FAN Corresponding Author: JIE LIANG Affiliations: Xijing Hospital of Digestive Diseases; Xijing Hospital of Digestive DIsease Objective: Inflammatory bowel disease is an important risk factor for colorectal cancer. However, the mechanism of development from IBD to colorectal cancer remains unclear. Methods: SphK2-KO mice and control littermates were used for DSS-induced colitis and AOM-DSS-induced colitis-associated cancer model. Relative index and mechanisms were further investigated. Cisplatin nmr Results: Sphingosine-1-phosphate

(S1P) produced by upregulation of sphingosine kinase 1 (SphK1) links chronic intestinal inflammation to colitis-associated cancer (CAC) and both are exacerbated by deletion of SphK2. S1P is essential for production of the multifunctional NF-κB-regulated cytokine IL-6, persistent activation of the transcription factor Stat3, and consequent upregulation of the S1P receptor, S1PR1. The pro-drug FTY720 decreased SphK1 and S1PR1 and eliminated the NF-κB-IL-6-Stat3 amplification cascade and development of CAC even in SphK2-/- mice and may be useful in treating colon cancer in individuals Rucaparib price with ulcerative colitis. Conclusion: SphK1-S1P-S1PR1 axis is at the nexus between NF-κB and Stat3 and connects chronic inflammation and CAC. Key Word(s): 1. S1P; 2. IBD; 3. Colorectal cancer; 4. STAT3; Presenting Author: SHI HUI Additional Authors: WAN JUN, SU BINBIN Corresponding Author: SHI HUI Affiliations: Nan lou gastrointestinal department 301 hospital; 301 hospital Objective: Many patients with ulcerative colitis (UC) in clinical remission continue to have symptoms of pain and diarrhea despite see more minimal or no ongoing inflammation. These patients may be considered to have an overlap of UC or Irritable bowel symptoms. The aims of this study were to

prospectively determine the prevalence of Irritable bowel like symptoms in ulcerative colitis patients in remission, and to determine whether IBS-like symptoms correlate with occult inflammation. Methods: We prospectively included 185 patients with UC, who had been in remission for at least 6 months according to laboratory parameters and clinical and endoscopical appearance, 107 with IBS, and 36 healthy controls. Remission was defined by physician assessment: ulcerative colitis disease activity index <3, and serum C-reactive protein <10, while off corticosteroids or biologics. Rome III criteria for IBS. Serum intestinal fatty acid binding protein (I-FABP) and fecal calprotectin (Fc) were measured by ELISA. Results: Of the 185 UC patients, there were 107(57.8%) patients with IBS[69 male, 38 female, mean age (41 ± 17.5)], and 68 patients without IBS[41 male, 27 female, mean age (44 ± 16.2)].

225 In contrast, the mean mitochondrial diameter was higher in NASH compared Selleck Fulvestrant with fatty liver.225 Actually, some ultrastructural abnormalities of liver mitochondria could appear well before NASH.225,226 At the moment, there is no definite explanation for the progressive decline of MRC activity during NASH, although some hypotheses can be put forward (Fig. 4). Several MRC complexes including COX are sensitive to ROS and RNS.227,228 In addition, COX can be inhibited by low levels of NO229

and inactivated by 4-hydroxynonenal (4-HNE), a reactive aldehyde generated during lipid peroxidation.230 ROS overproduction within mitochondria could be favored by higher CYP2E1 expression and lower levels of mitochondrial GSH (mtGSH) (Fig. 4). TNF-α is able to impair MRC activity, possibly by inducing hypoxia inducible factor-1α (HIF-1α) and mtDNA damage.5,57,231,232 In addition, Kupffer cell-derived interferons could also impair MRC activity.20 Some lipid derivatives

such as FAs can directly inhibit several enzymes involved in MRC and OXPHOS.12,233,234 Moreover, saturated FAs are able to activate c-Jun N-terminal kinase and trigger INCB024360 in vitro the mitochondrial membrane permeability transition, thus inducing mitochondrial release of cytochrome c and apoptosis.40,235 Reduced adiponectin action in liver could be involved, since this adipokine seems to control MRC activity.236 Plasma adiponectin levels are indeed decreased in NAFLD, and especially in NASH.184,202,237 Moreover, lower hepatic expression of AdipoR1 and AdipoR2 is found in NASH,52,238-240 although other studies reported increased expression.237,241 Another mechanism could be higher activity of forkhead box O1 transcription factor (FoxO1), linked to IR.27 Indeed, FoxO1 activation is able to reduce the content of different MRC polypeptides, possibly by decreasing heme synthesis and impairing PGC1α activity.172 Reduced PGC1α activity could also be secondary to oxidative stress and inflammation, as previously mentioned (Fig. 4).197,198

Numerous drugs are currently tested in order selleck compound to alleviate fatty liver and NASH. These treatments can have different pharmacological effects including improvement of insulin sensitivity, stimulation of lipid oxidation, as well as reduction of DNL, oxidative stress, and inflammation.63,242,243 Regarding mtFAO, some investigations showed that fatty liver could be alleviated by further stimulating the already enhanced capacity for lipid oxidation.75,77 Drug-induced stimulation of mtFAO could have, however, deleterious consequence over the long term if this is not associated with concomitant improvement of MRC. Indeed, an imbalance between mtFAO and MRC activity induces ROS overproduction,5,7,17,63,171 as previously mentioned. Hence, it will be important in the future to find therapeutic strategies able to restore both mtFAO and MRC activity in a coordinated manner.

After filtering against existing SNP databases and picking out variants on exonic and splicing, 44 variants were reserved. The largest overlapping autozygous regions were at chromosome 16. We focused on two non-synonymous variants from HSD3B7 gene. Follow-up Sanger sequencing

identified Bortezomib HSD3B7 mutations in the proband and his families. Conclusion: We make a genetic diagnosis of HSD3B7 deficiency using exome sequencing and homozygosity mapping. HSD3B7 deficiency is an automatic recessive disease and early diagnosis and primary bile acid treatment lead to progressive normalization of liver function and avoidance of liver transplantation. Key Word(s): 1. Exome sequencing; 2. Cholestasis; 3. HSD3B7 deficiency; Presenting Author: QINGHUA HU Additional Authors: ZHONGWEI LIU, HAITAO ZHU, KUNLUN CHEN, CHUAN QIU, KAIFA TANG Corresponding Author: QINGHUA HU Affiliations: Department of Medicine, 323 Hospital of PLA; School of Medicine, Xi’an Jiaotong University; School

of Public Health & Tropical Medicine, Tulane University; Affiliated Hospital of Guiyang Medical College Objective: Excessive endoplasmic reticulum (ER) stress plays an important role in inducing hepatocytes apoptosis in alcoholic liver disease (ALD). Curcumin has been proved to have a broad spectrum of biological activities including anti-inflammation, anti- neoplasm, antioxidation and anti- apoptosis. Previous studies have demonstrated the protective effect of curcumin selleck chemical against ethanol- induced hepatocyte apoptosis, but the mechanism is not completely clarified. In this study, we investigated whether curcumin’s hepatoprotecive effect acts via attenuating GDC-0449 mw ER stress. Methods: Liver slice culture was used in this study. Isolated hepatocyte cultures were incubated whether by ethanol or curcumin or both of them. Ethanol cytotoxicity was evaluated by trypan blue exclusion test and released lactate dehydrogenase (LDH) activity. Hepatocyte apoptosis was assessed by flow cytometry. Real- time PCR and western blotting were utilized to qualify the expression

levels of GRP78 which is the hall marker of ER stress and Casepase 12 which reflexes ER stress- induced apoptosis specifically at transcriptional and translational levels. Results: Ethanol’s cytotoxicity to hepatocytes was evidenced by trypan blue exclusion test and released LDH activity. The apoptosis rate increases significantly after ethanol incubation but attenuated by co- administration of curcumin. Expectedly, expressions of GRP78 and cleaved Caspase12 increased significantly after ethanol incubation, indicating that ethanol evoked ER stress. However, after co- administration of curcumin, expression levels of GRP78 and cleaved Caspase12 were impaired dramatically. Conclusion: These results indicated that curcumin exerts its hepatoprotective effects by attenuating ER stress- induced apoptosis in hypatocytes incubated by ethanol. Key Word(s): 1. Curcumin; 2. Apoptosis; 3. Ethanol; 4.