Through experiments performed in vivo, using a water-soluble, less toxic hsp90-specific inhibitor, 17-DMAG, we show that hsp90 inhibition decreases proinflammatory cytokine production and alleviates LPS-induced liver injury. Previous limitations for in vivo use of geldanamycin and its derivatives have been their dose-limiting toxicity, leading to weight loss, hematologic, hepatic, and renal toxicity, and cell death.38, 39 Pharmacodynamic studies showed that the medium tolerated dose of 17-DMAG in vivo is 75 mg/kg with minimal toxicity.40, 41 Here, we used a single dose of 17-DMAG, ranging from 2.5 mg/kg to 30

mg/kg, with less concern GPCR Compound Library concentration for nonspecific or toxic effects. Our data here suggest hsp90 as an attractive therapeutic target in liver diseases. Although

inhibitors of hsp90 were primarily identified for their therapeutic importance in cancer, their role in inflammatory diseases,42 such as rheumatoid arthritis,28 endotoxin-mediated uveitis,18 sepsis,43 and atherosclerosis,44, 45 is emerging. Because LPS-mediated LEE011 inflammatory responses are crucial to the development of liver diseases, strategies that prevent this response in the liver could have a beneficial effect. The inhibitory function of hsp90 inhibitors on liver inflammatory responses could be a dual mechanism: either loss of client proteins resulting this website from loss of chaperone function19, 21 or induction of anti-inflammatory transcription factor HSF1 and hsp70 expression.46 Here, we report that inhibition of hsp90 in the liver induces HSF1 and inhibits LPS-induced NFκB activation and proinflammatory cytokine production, thereby alleviating liver injury (Fig. 8). The chaperone function of

hsp90 on LPS-signaling intermediates explains its effect on the expression of down-stream proinflammatory cytokines. In this context, 17-DMAG could affect the transcription of cytokine genes and their production. We observed that the proinflammatory cytokines, TNFα and IL-6, were significantly inhibited, both at the mRNA and protein level, in whole livers treated with 17-DMAG and LPS. Concomitant reduction of serum TNFα and IL-6 paralleled the liver cytokine profile. We predict that hsp90 inhibition in the liver alters LPS-signaling events proximal to proinflammatory cytokine gene transcription. The transcription factor, NFκB, is a key downstream signaling intermediate of the LPS receptors, CD14 and TLR4. Earlier studies showed that 17-DMAG reduces NFκB activity in respiratory epithelial cells,47 either directly or through inhibition of upstream the LPS receptors, CD14 and TLR4.14 Hsp90 associates with the LPS receptor complex,14 and its inhibition decreases CD14 expression.48 Our results showed significant down-regulation in CD14 mRNA without changes in TLR4 mRNA in the liver.

They are particularly useful for the arterial phase. Contrast media are also highly

useful for the delayed phase of CT. (grade A) Based on studies using CTHA, it has been known for a very long time that clinically malignant hepatocellular carcinomas show greater arterial blood flow than the surrounding liver tissue (LF062091 level 3). In CO2 ultrasound angiography, the mean doubling time of tumors with increased arterial blood flow was 70 days, and the mean doubling time of nodules with a poor arterial blood flow was 370 days; thus, hypovascular tumors MEK inhibitor have been reported to grow more slowly (LJ033682 level 3). In recent studies using CTHA and CTAP, a correlation between the histological degree of differentiation (e.g. dysplastic nodule to well-differentiated hepatocellular carcinoma, moderately- or poorly-differentiated hepatocellular carcinoma) and the tumor vascularity has been demonstrated, reflecting the multistage growth of hepatocellular carcinoma (LF062043 level 2a, LF057244 level 2a). Hepatocellular carcinomas with increased arterial blood flow may be the main targets of diagnosis and treatment. Dynamic studies using iodine-enhanced CT and extracellular Gd-enhanced MRI improve the detection rate

of hypervascular hepatocellular carcinomas. In a study selleck inhibitor using early-period angiographic findings as the standard, a diagnosis was made in 88% of the cases based on a combination of non-contrast CT and arterial phase CT (LF025385 level 1). A subsequent study revealed that addition of a delayed phase to the arterial phase increased the diagnostic rate of CT (LF057106 level 1). Dynamic MRI study has also been demonstrated to be highly useful among imaging techniques, and the arterial phase is quite important for detecting hypervascular hepatocellular carcinomas many (LF058397 level 1). In a study of the livers of liver

transplant recipients, the detection rates of hepatocellular carcinoma were 76.9% for high-resolution MRI, 53.8% for single helical CT and 46.2% for ultrasonography, showing the superiority of MRI (LF020018 level 1). For minimizing individual differences in the appropriate timing of imaging of the arterial phase, the time required for contrast injection should be fixed for all contrast media (LF120829 level 2a). Superparamagnetic iron oxide used for MRI is taken up by reticuloendothelial cells, leading to a decrease in the signal intensity of the liver parenchyma. Reticuloendothelial cells are not present in a tumor, and the signal intensity does not decrease. Diagnosis is made based on these characteristics. A good degree of correlation has been reported between the degree of differentiation of hepatocellular carcinoma and the SPIO uptake in SPIO-MRI (LF0620210 level 3). When focusing only on the detection capability of hepatocellular carcinoma, the extracellular Gd contrast agent is superior to SPIO (LF0218211 level 1, LF0573412 level 1).

They are particularly useful for the arterial phase. Contrast media are also highly

useful for the delayed phase of CT. (grade A) Based on studies using CTHA, it has been known for a very long time that clinically malignant hepatocellular carcinomas show greater arterial blood flow than the surrounding liver tissue (LF062091 level 3). In CO2 ultrasound angiography, the mean doubling time of tumors with increased arterial blood flow was 70 days, and the mean doubling time of nodules with a poor arterial blood flow was 370 days; thus, hypovascular tumors selleck chemical have been reported to grow more slowly (LJ033682 level 3). In recent studies using CTHA and CTAP, a correlation between the histological degree of differentiation (e.g. dysplastic nodule to well-differentiated hepatocellular carcinoma, moderately- or poorly-differentiated hepatocellular carcinoma) and the tumor vascularity has been demonstrated, reflecting the multistage growth of hepatocellular carcinoma (LF062043 level 2a, LF057244 level 2a). Hepatocellular carcinomas with increased arterial blood flow may be the main targets of diagnosis and treatment. Dynamic studies using iodine-enhanced CT and extracellular Gd-enhanced MRI improve the detection rate

of hypervascular hepatocellular carcinomas. In a study this website using early-period angiographic findings as the standard, a diagnosis was made in 88% of the cases based on a combination of non-contrast CT and arterial phase CT (LF025385 level 1). A subsequent study revealed that addition of a delayed phase to the arterial phase increased the diagnostic rate of CT (LF057106 level 1). Dynamic MRI study has also been demonstrated to be highly useful among imaging techniques, and the arterial phase is quite important for detecting hypervascular hepatocellular carcinomas Amrubicin (LF058397 level 1). In a study of the livers of liver

transplant recipients, the detection rates of hepatocellular carcinoma were 76.9% for high-resolution MRI, 53.8% for single helical CT and 46.2% for ultrasonography, showing the superiority of MRI (LF020018 level 1). For minimizing individual differences in the appropriate timing of imaging of the arterial phase, the time required for contrast injection should be fixed for all contrast media (LF120829 level 2a). Superparamagnetic iron oxide used for MRI is taken up by reticuloendothelial cells, leading to a decrease in the signal intensity of the liver parenchyma. Reticuloendothelial cells are not present in a tumor, and the signal intensity does not decrease. Diagnosis is made based on these characteristics. A good degree of correlation has been reported between the degree of differentiation of hepatocellular carcinoma and the SPIO uptake in SPIO-MRI (LF0620210 level 3). When focusing only on the detection capability of hepatocellular carcinoma, the extracellular Gd contrast agent is superior to SPIO (LF0218211 level 1, LF0573412 level 1).

Additionally, the transformed prevalence is weighted very slightly toward 50%, and studies with prevalence of zero can thus be included in the analysis.

The pooled proportion is calculated as the back-transform of the weighted mean of the transformed proportions, using inverse arcsine variance weights for the fixed effects model and DerSimonian-Laird weights for the random effects model: Two thousand one hundred forty-one studies were identified after an initial search. After removal of duplicates and initial screening, we reviewed 227 papers in full. After exclusion of ineligible reports, our final sample was 48 studies[14-61] published between January 1987 and June 25, 2013. The flow diagram of the search process is exhibited

in Figure 1. The characteristics of studies on the prevalence Selleckchem KPT330 of NAFLD were shown in the Table 1. The population size of the reviewed studies ranged from 805 to 95 567 with a median sample size of 3205 people. The studies included a total of 356 367 people. Forty-six reports reported data on men (n = 201 481) and 45 reports reported the data on women (n = 152 124), 6 included mixed gender samples (n = 2762). One investigated women (n = 8769) and one for men (n = 1043). In the surveys with samples, more than 60% of the individuals were men. The weighted average age of men (46 reports) and women (45 reports) was 40.32 and 34.8 years old, respectively. Selleckchem PLX-4720 Twenty-three reports were from the southern part of China (n = 242 107), 25 reports were from the northern part of China (n = 114 260), 24 reports were from facility (n = 159 353), 24 were from the general population (n = 197 014), 20 were from urban (n = 185 875), 3 was from rural (n = 8752), and 25 was from the mixed (n = 161 740). Table 1 show detailed information from the 48 studies selected. The point prevalence of NAFLD with the 48 individual study populations ranged between 6.19% and 38.24%, with an overall meta-analysis

prevalence of 20.09% (95% CI: 17.95–22.31%, Fig. 2) and evidence FAD of high-level heterogeneity between studies (I2 = 99.6%, P < 0.0001). Pooled prevalence of all subgroups according to sex, mean age, age group gender ration, study year, sample size, population source, location, and area are presented in Table 2. The summarized prevalence of male (24.81%, 95% CI: 21.88–27.87%, Fig. 3) was higher than that of female (13.16%, 95% CI: 11.33–15.11%, Fig. 4). The pooled prevalence estimate increased over time. Between the years 2000 and 2006, the pooled prevalence estimate was 18.22% (95% CI: 14.32–22.48%), which increased to 20.00% (95% CI: 16.84–23.36%) between 2007 and 2009; the estimate was 20.86% (95% CI: 15.41–22.72%) in the years 2010–2013. In two age groups (< 45 and ≥ 45 years old), the prevalence estimates in studies with people older than 45 years old were higher than estimates of people younger than 45 years old group (20.44%, 95% CI: 17.70–23.32%). The pooled prevalence estimate also increased over age.

Additionally, the transformed prevalence is weighted very slightly toward 50%, and studies with prevalence of zero can thus be included in the analysis.

The pooled proportion is calculated as the back-transform of the weighted mean of the transformed proportions, using inverse arcsine variance weights for the fixed effects model and DerSimonian-Laird weights for the random effects model: Two thousand one hundred forty-one studies were identified after an initial search. After removal of duplicates and initial screening, we reviewed 227 papers in full. After exclusion of ineligible reports, our final sample was 48 studies[14-61] published between January 1987 and June 25, 2013. The flow diagram of the search process is exhibited

in Figure 1. The characteristics of studies on the prevalence RO4929097 mw of NAFLD were shown in the Table 1. The population size of the reviewed studies ranged from 805 to 95 567 with a median sample size of 3205 people. The studies included a total of 356 367 people. Forty-six reports reported data on men (n = 201 481) and 45 reports reported the data on women (n = 152 124), 6 included mixed gender samples (n = 2762). One investigated women (n = 8769) and one for men (n = 1043). In the surveys with samples, more than 60% of the individuals were men. The weighted average age of men (46 reports) and women (45 reports) was 40.32 and 34.8 years old, respectively. click here Twenty-three reports were from the southern part of China (n = 242 107), 25 reports were from the northern part of China (n = 114 260), 24 reports were from facility (n = 159 353), 24 were from the general population (n = 197 014), 20 were from urban (n = 185 875), 3 was from rural (n = 8752), and 25 was from the mixed (n = 161 740). Table 1 show detailed information from the 48 studies selected. The point prevalence of NAFLD with the 48 individual study populations ranged between 6.19% and 38.24%, with an overall meta-analysis

prevalence of 20.09% (95% CI: 17.95–22.31%, Fig. 2) and evidence Mannose-binding protein-associated serine protease of high-level heterogeneity between studies (I2 = 99.6%, P < 0.0001). Pooled prevalence of all subgroups according to sex, mean age, age group gender ration, study year, sample size, population source, location, and area are presented in Table 2. The summarized prevalence of male (24.81%, 95% CI: 21.88–27.87%, Fig. 3) was higher than that of female (13.16%, 95% CI: 11.33–15.11%, Fig. 4). The pooled prevalence estimate increased over time. Between the years 2000 and 2006, the pooled prevalence estimate was 18.22% (95% CI: 14.32–22.48%), which increased to 20.00% (95% CI: 16.84–23.36%) between 2007 and 2009; the estimate was 20.86% (95% CI: 15.41–22.72%) in the years 2010–2013. In two age groups (< 45 and ≥ 45 years old), the prevalence estimates in studies with people older than 45 years old were higher than estimates of people younger than 45 years old group (20.44%, 95% CI: 17.70–23.32%). The pooled prevalence estimate also increased over age.

7% (18/19). The mean time required to reach CHIR-99021 supplier the blind end was 34.0 min. The diagnostic success rate was 89.5% (17/19). The mean procedure time was 72.6 min. The success rate of overall modified SBE-assisted ERC was 78.9% (15/19). The complication rate was 26% (hyperamylasemia in four patients). Conclusion: Diagnostic and therapeutic ERC using our novel approach of modifying SBE without the use of special or prototype instrumentation or enteroscope replacement is safe and effective. Key Word(s): 1. single-balloon enteroscopy; 2. endoscopic retrograde cholangiography (ERC); 3. roux-en-y reconstruction; 4. billroth-II gastrectomy Presenting Author: AKIRA TERAMOTO Additional Authors:

KASEN KOBASHIKAWA, KOTA TOMISATO, AKIYUKI KONDO, ATSUSHI IRAHA, SHOKO NAKAMURA, SHINOBU MATSUKAWA, AKIRA YABUTANI, MASAMOTO NAKAMURA, TOMOKUNI NAKAYOSHI, NOBUFUMI UCHIMA, FUKUNORI KINJYO, SHINICHIRO KAMEYAMA, TOMONARI ISHIMINE, TSUTOMU ISA, AKIO YANAGISAWA Corresponding Author: AKIRA TERAMOTO Affiliations: Urasoe General Hospital, Urasoe General Hospital, Urasoe General Hospital, Urasoe General Hospital, Urasoe General Hospital, Urasoe General Hospital, Urasoe General Hospital, Urasoe General Hospital, Urasoe General Hospital, Urasoe General Hospital, Urasoe General Hospital, Urasoe General Hospital, Urasoe General Hospital, Urasoe General Hospital, Kyoto Prefectural

Hospital of Medicine Objective: Introduction: Inflammatory pseudo-tumor (IPT) is an uncommon cause of cholangitis, composed of inflammatory cell infiltration and proliferating

fibrous tissues. Even with imaging devices, click here ERCP and cytodiagnosis that we have today, it is difficult to deny malignant neoplasm and the final diagnosis is relied on pathological outcome of surgically dissected specimen in many cases. Methods: Presentation of case: A 35year-old-man has been followed at our hospital since 2009 for chronic liver dysfunction. The cause of liver dysfunction was not identified from his hepatic biopsy and serum tests. In 2013, he has presented to our hospital with complaint of epigastric pain and ultrasonography showed upper bile duct dilation up to 8 mm. Stenosis with thickened biliary wall was located at lower bile duct using enhanced CT and MRCP, 4-Aminobutyrate aminotransferase and this was seen as a hypo-echoic tumor-like lesion in EUS. ERCP was performed and there was no malformation of Vater’s papilla or malfusion of pancreaticobiliary ducts. Main findings of cholangiography were (A) biliary stenosis at mid ∼ lower part of common bile duct, (B) caliber variations at the base of right hepatic ducts. Biopsy forceps and cytodiagnosis brush were used for biopsy at (A), and eight bile specimen were collected from ENBD but malignancy was not proven pathologically. Pancreaticoduodenectomy was conducted as the patient gave his consent to the proposal of surgery. The pathological outcome was consistent with chronic cholangitis with small duct hyperplasia, showing the nature of IPT.

4 Hilgard and colleagues have incorporated TARE into their institutional treatment algorithm based on the BCLC (Barcelona Clinic Liver Cancer) staging system.5 Tanespimycin The authors demonstrated a median overall survival (OS) of 16.4 months and TTP of 10 months in this observational study, which consisted of 108 patients with advanced HCC. These results corroborate the experience of others with TARE, and in fact, encompass

the most encouraging data that have been reported to date with TARE.6, 7 Moreover, the safety of TARE is validated in the current study. A few points merit comment. First, patients were selected for TARE if they had unresectable HCC and BCLC C or BCLC A/B that were ineligible for selective TACE (generally ≤ 2 segments) which comprised 49% of the cohort. Interestingly, the proposed candidates for potential TACE for downstaging in the authors’ treatment algorithm include tumor criteria (single nodule up to 8-10 cm, 2-3 nodules maximum 3-5 cm, or 4-5 nodules ≤ 3 cm) in which the ability to perform “selective” therapy in all such cases is questionable, because tumor size, number, and location determine the extent of selectivity of intra-arterial

therapy. The assumption that lobar TARE is a “safer” alternative compared to lobar TACE given the same tumor characteristics still requires further investigation. It is recognized that the concept of “selective”

TACE is the preferred mode; however, find more the reality is that this is ill-defined from center to center (2nd, 3rd order, etc.). In addition, most tumors are large and disease is bilobar, which often does not permit “selective infusion. Of particular interest, the median OS of BCLC C patients was not reached cAMP at the time of publication. In the largest reported single-center experience with TARE, the median OS in BCLC C patients was 7.3 months and varied according to Child-Pugh (CP) classification, in which 55% were non–CP A.6 In contrast, this European cohort was composed of 22% CP B, limited to CP-7. Additionally, the results of Hilgard et al. are favorable compared to the median OS of 8.9 months in the SHARP trial (95% CP A) among patients with portal vein thrombosis (PVT) and/or metastatic disease who received sorafenib. However, direct comparisons are limited across studies but provide a compulsion for future studies for CP A patients with PVT comparing these therapeutic modalities. Among the BCLC B patients, median survival was 16.4 months, which is comparable to earlier reports with TARE in this patient population.

The clinical backgrounds, sustained virological response (SVR) rates and cumulative positivity of serum HCV RNA were compared between the two groups. Results:  Among the 74 patients, 61 (82.4%)

had hepatic steatosis 0–10% and 13 (17.6%) had hepatic steatosis >10%. Scores of homeostasis model assessment-insulin resistance and hepatic fibrosis were higher in patients with hepatic steatosis >10% than EPZ-6438 research buy hepatic steatosis 0–10% (P = 0.040 and 0.042, respectively). Non-SVR was more frequent in patients with hepatic steatosis >10% than hepatic steatosis 0–10% (P = 0.003). Cumulative positivity of serum HCV RNA was significantly higher in patients with hepatic steatosis >10% than hepatic steatosis 0–10% (P = 0.004). Conclusions:  In CH-C patients infected with

genotype 2 treated by PEG-IFNα2b and RBV combination therapy, hepatic steatosis >10% was associated with increased insulin resistance, advanced hepatic fibrosis and higher cumulative positivity of serum HCV RNA, which lead to a higher risk of non-SVR. “
“Patients with cholestatic liver diseases such as primary biliary cirrhosis, primary sclerosing cholangitis and intrahepatic cholestasis of pregnancy commonly complain of pruritus. The underlying pathogenesis remains obscure with several mediators possibly playing an important role; these include lysophosphatidic acid, bile salts, opioids, histamine and progesterone metabolites. We describe in this review Proteases inhibitor novel insights into the pathogenesis and management of pruritus in patients with cholestasis. Pruritus, or itch, is a common complaint in patients with cholestatic liver disease. Several mechanisms are generally accepted as possible explanations to the underlying basis of itch. However, the exact pathophysiology of pruritus in cholestatic liver disease remains unclear and is complicated by the dissimilarity of complaints among patients. Severe pruritus can have debilitating effects and cause immense degradation to the patient’s quality of life. Due to the subjective nature, it is a significant challenge for the clinician to aptly evaluate and manage Phenylethanolamine N-methyltransferase pruritus

in cholestatic patients. In this review we aim to discuss the pathogenesis, evaluation and interventions used in managing this complaint and ultimately improving the patient’s quality of life. Pruritus is a common symptom in many biliary and cholestatic disorders such as primary biliary cirrhosis (PBC).1 It has been reported that the prevalence of pruritus in PBC may be as high as 69%, with 75% of patients stating that pruritus preceded the diagnosis of PBC.2 This may suggest pruritus as being a potential clinical marker for PBC, aiding in early diagnosis. Primary biliary cirrhosis is not the only disease presenting with pruritus; patients with primary sclerosing cholangitis (PSC) also report pruritus during the course of their disease.

Primarily, two types of chemistries have been used to modify the antisense oligonucleotide and increase its stability and/or uptake by cells: 2′-O-methylated oligonucleotides, usually coupled to a cholesterol group9 and, more recently, oligonucleotides containing locked

nucleic acid (LNA) residues (Fig. 1). A LNA antisense oligonucleotide binding to the 5′ part of miR-122 (SPC3649; Santaris Pharma, Hoersholm, Denmark) has been shown to be efficient via mouse models in confirming that blocking miR-122 results in a decrease in cellular targets involved in cholesterol biogenesis.10 Next, the inhibition of miR-122 and its effect on cholesterol levels was confirmed in nonhuman primates.11 The stage was set for testing the Selleck GS1101 real effect of blocking miR-122 on HCV infection in a primate model. Following up on these investigations, miRNA-122 has now been shown to be a target for antiviral intervention. In a report CHIR-99021 clinical trial this month in Science, Robert Lanford and colleagues showed that the inhibition of miR-122 in chimpanzees leads

to long-lasting suppression of HCV viremia (Fig. 1).12 Using high and low doses of the SPC3649 oligonucleotide, they demonstrated that treatment of chronically HCV-infected animals with the LNA oligonucleotide results in a marked and sustained decrease of HCV RNA in both serum and liver. The sequestration of miR-122 by the LNA oligonucleotide was confirmed, as well as the strong reduction of free miR-122 levels for the high-dose animals. No rebound in viremia was observed during the treatment, and no adaptive mutations were found in the miR-122–binding sites. The analysis of the liver transcriptome revealed a marked down-regulation of IFN-regulated genes, which confirmed that the endogenous IFN pathway in the liver was Rebamipide normalized after inhibition of HCV RNA. Finally, as expected, the antagonism of miR-122 resulted in a strong decrease in serum cholesterol (Fig. 1). Besides that effect, no measurable toxic effect in the liver could be attributed to SPC3649. What are the clinical implications of this landmark study? The results of Lanford et al. clearly show that antagonism of miR-122 by the LNA oligonucleotide

SPC3649 leads to marked suppression of viremia in chronically HCV-infected chimpanzees and improvement of HCV-induced liver pathology. The prolonged virological response to SPC3649 treatment without HCV rebound suggests that targeting miRNA-122 by antagonists holds promise as a novel antiviral therapy. A potential advantage compared to therapeutic strategies that target viral factors may be the high barrier to resistance, as demonstrated by the lack of rebound in viremia during the treatment and the lack of adaptive mutations in the two miR-122 seed sites of the HCV 5′ noncoding region. Furthermore, conservation of both miR-122 seed sites in all HCV genotypes and subtypes suggests that such therapy will most likely be genotype-independent.

pylori within 30 minutes after adherence as compared to the unadhered control (Fig. 1). In AGS-adhered H. pylori, cagA expression increased progressively up to 24 hours examined; however, vacA expression increased immediately after adherence and thereafter remained almost constant. No difference in ureA expression was observed between unadhered and adhered H. pylori cells (data not

shown). To examine whether any component(s) secreted by AGS cells into the medium was responsible for the induction of virulence genes in H. pylori, expression of cagA and vacA was examined in unadhered bacteria isolated from the supernatant of an H. pylori-infected AGS monolayer. Expression of the virulence genes in these bacteria was comparable to that in H. pylori grown without cell line (data not shown), suggesting that the induction of virulence genes in AGS cell-associated buy CH5424802 H. pylori was not due to any component secreted by AGS cells and the induction required direct contact of the bacteria with the AGS cells. Because the iron-sensing transcription factor Fur acts as a global regulator in H. pylori, we next examined whether Fur has a role in the contact-dependent upregulation of virulence genes in AGS-adhered H. pylori. For this purpose, two Δfur mutants were independently constructed and analyzed. Two independent mutants were used to decrease selleck chemicals llc the possibility of erroneous results due to unidentified spontaneous

mutations in one. The growth rates of the Δfur mutant strains were similar to the wild-type strain as has been reported previously [34]. The wild-type parental strain and the Δfur mutant strains were allowed to adhere to AGS cells for 2 hours, and CFU of the adhered bacteria was determined. Adherence of the two independently isolated H. pylori Δfur mutants to AGS cell line was comparable to that of the wild-type strain (Table S2). Next, expression of cagA and vacA in the adhered wild-type strain and two Δfur mutants was examined and compared with that in the corresponding unadhered strains isolated from the supernatant of infected AGS monolayers. Expression of cagA and vacA in unadhered bacteria was comparable between the wild-type and the Δfur mutant strains (Fig. 2).

PLEKHB2 Interestingly, however, although cagA and vacA expression increased about 5.5- and 3.5-fold, respectively, after adherence of the wild-type H. pylori to the AGS cells, much lower upregulation of cagA (about 2.5-fold) and practically no upregulation of vacA were observed in AGS-adhered Δfur mutant strains (Fig. 2). These results suggest that the upregulation of cagA and vacA upon contact with AGS cells was dependent on Fur, and the effect of Fur was significantly higher in adhered H. pylori than in the unadhered bacteria. Helicobacter pylori Fur can activate or repress gene expression in both the iron-bound (Fe-Fur) and apo (apo-Fur) forms. In view of the fact that expression of cagA and vacA is upregulated in a Fur-dependent manner in AGS cell-associated H.