A Simple Method to Avoid Bile Duct Injury during Percutaneous Radiofrequency Ablation Therapy for Hepatocellular Carcinoma.

Hepatocellular carcinoma represents a major global health burden. Its treatment is often complicated by the anatomical location of tumors, which can lead to adverse outcomes. Radiofrequency ablation has recently gained attention as a safe method for treating hepatocellular carcinoma, but only in tumors that are not adjacent to bile ducts. Here, we report a new method for cooling the bile duct during radiofrequency ablation therapy, in which the outer jacket of an elastor needle was fixed and flash-cooled with chilled saline. This method was applied in a patient with hepatocellular carcinoma tumors near the main bile duct. The patient underwent successful radiofrequency ablation with bile duct cooling. The advantages of this method include low medical cost, simpler securing of nonexpanded bile ducts, and simultaneous removal upon termination of the radiofrequency ablation therapy. Bile duct complications associated with radiofrequency ablation typically have delayed onset. Computed tomography examination 2 months after treatment showed no bile duct injury in this case.

A Case of Pathological Complete Response Following FOLFIRINOX Therapy for Pancreatic Adenocarcinoma with Synchronous Distant Lymph Node Metastases.

INTRODUCTION: We report a case of conversion surgery for pancreatic ductal adenocarcinoma (PDAC) with synchronous distant metastases showing pathological complete response (pCR) after FOLFIRINOX therapy. PRESENTATION OF CASE: A 46-year-old woman with obstructive jaundice was referred to our hospital. A CT scan revealed a hypo-vascular mass in the head of the pancreas with multiple para-aortic lymph nodes and a Virchow's node swollen. The serum CA 19-9 level was 71795.1 U/mL. The result of tumor biopsy from the biliary stenotic site was concordant with adenocarcinoma. She was diagnosed with PDAC with distant metastases. After 10 courses of FOLFIRINOX followed by 4 courses of FOLFIRI, a CT scan showed that distant lymph node swellings disappeared, and CA19-9 level became almost normal. She underwent pancreaticoduodenectomy with dissection of para-aortic lymph nodes 8 months after the initiation of chemotherapy. Pathologically, no evidence of residual adenocarcinoma was observed in neither pancreas nor lymph nodes. Adjuvant chemotherapy using S-1 was administered for 6 months, and no recurrence has been observed 4 years after surgery. BRCA1/2 mutations were not detected in patient's DNA. DISCUSSION: With the induction of intensive chemotherapies such as FOLFIRINOX, an increasing number of patients with synchronous distant metastases could become suitable candidates for surgery of the primary lesion because of the potential complete response of metastatic lesions. CONCLUSION: This case presented a rare occurrence of pCR in a patient with unresectable PDAC with distant metastases who received FOLFIRINOX. The feasibility and benefits of conversion surgery in such patients must be investigated in future trials.

Procedure of Direct Hepatic Artery Puncture for the Treatment of Hepatocellular Carcinoma: Two Case Reports.

Recently, treatment options for hepatocellular carcinoma (HCC) have expanded due to the development of the tyrosine kinase inhibitor ramucirumab and immune checkpoint inhibitors. Transcatheter arterial chemoembolization is the standard therapy for intermediate-stage HCC; however, in cases with anatomical problems, normal approaches are not possible. In such rare cases, direct hepatic puncture may be considered as an effective therapy and an indispensable treatment. We report our novel method of direct hepatic artery puncture in this case report. In 2011 and 2017, we reported 2 cases in the journal of the Japan Society of Hepatology in Japanese. This therapy is difficult and is associated with a high risk of complications; however, we succeeded in both cases in a similar way. We believe this method may provide an alternative treatment when standard treatment is not possible or when urgent therapy is required. In case 1, direct hepatic artery puncture was performed under ultrasonographic guidance, and we were able to control the disease with percutaneous lipiodol chemotherapy. Case 2 was an emergency case of ruptured HCC. Direct hepatic puncture successfully stopped tumor bleeding; furthermore, tumor necrosis also occurred, as seen on the enhanced computed tomography image. Our new method requires advanced puncture techniques and is not the treatment of choice if there are other safe alternatives available. However, it can be considered as an option if there are no other viable, effective treatments.

Inhibitory Effects of Sodium Alginate on Hepatic Steatosis in Mice Induced by a Methionine- and Choline-deficient Diet.

Nonalcoholic steatohepatitis (NASH) progresses from nonalcoholic fatty liver disease (NAFLD); however, efficacious drugs for NASH treatment are lacking. Sodium alginate (SA), a soluble dietary fiber extracted from brown algae, could protect the small intestine from enterobacterial invasion. NASH pathogenesis has been suggested to be associated with enterobacterial invasion, so we examined the effect of SA on methionine- and choline-deficient (MCD) diet-induced steatohepatitis in mice (the most widely-used model of NASH). The mice (n = 31) were divided into three groups (mice fed with regular chow, MCD diet, and MCD diet premixed with 5% SA) for 4 and 8 weeks. The MCD diet increased lipid accumulation and inflammation in the liver, the NAFLD Activity Score and hepatic mRNA expression of tumor necrosis factor- and collagen 11, and induced macrophage infiltration. Villus shortening, disruption of zonula occludens-1 localization and depletion of mucus production were observed in the small intestine of the MCD-group mice. SA administration improved lipid accumulation and inflammation in the liver, and impaired barrier function in the small intestine. Collectively, these results suggest that SA is useful for NASH treatment because it can prevent hepatic inflammation and fatty degeneration by maintaining intestinal barrier function.

Solid pseudopapillary neoplasm of the pancreas showing marked distal atrophy: A case report.

INTRODUCTION: Solid pseudopapillary neoplasm (SPN) of the pancreas is a rare neoplasm, affecting primarily young females. Because SPNs are of low-malignancy, they rarely obstruct the main pancreatic duct (MPD) and cause atrophy of the distal pancreas even if their tumor sizes are large. PRESENTATION OF CASE: A 35-year-old female was referred to our hospital due to pancreatic tumor. Imaging findings showed the presence of well-defined round tumor in the body of the pancreas with 25-mm in diameter. The pancreas parenchyma distal to the tumor was markedly atrophic, and MPD dilatation was not observed. The lesion was diagnosed as SPN by endoscopic ultrasound-guided fine needle aspiration (EUS-FNA), and central pancreatectomy was performed. Intraoperative frozen section of the distal atrophic pancreas showed no evidence of acinar cells, indicating exocrine dysfunction. Therefore, we closed distal pancreas stump instead of reconstruction. In the distal atrophic parenchyma, scattered foci of islets of Langerhans and the vestige of dilated MPD were observed. She has shown neither endocrine nor exocrine insufficiency after surgery. DISCUSSION: SPNs are usually found without atrophic change of distal pancreas. To the best of our knowledge, this is the first report of SPN in which exocrine dysfunction of atrophic pancreas was demonstrated pathologically and central pancreatectomy without anastomosis of distal pancreas was chosen for the surgical treatment. CONCLUSION: We reported a very rare case of SPN with marked distal parenchymal atrophy. We successfully performed central pancreatectomy without reconstruction.

CD44v-dependent upregulation of xCT is involved in the acquisition of cisplatin-resistance in human lung cancer A549 cells.

Cisplatin (CDDP) is widely used as an anti-cancer platinum agent but its therapeutic efficacy is limited by acquired drug resistance. To develop a new therapeutic strategy that could overcome this resistance, it is important to characterize CDDP-resistant cancer cells. Here we established human lung cancer A549 cell-derived low- and high-grade CDDP-resistant sublines, termed ACR4 and ACR20 cells, by stepwise increasing CDDP concentrations up to 4 and 20 µM, respectively. ACR4 and ACR20 cells showed 6- and 16-fold higher resistance to CDDP than A549 cells, respectively. Cell migration, invasion, and sphere formation were significantly decreased, whereas expression of the stem cell marker CD44v was increased in order of A549, ACR4, and ACR20 cells. The expression of the cystine-glutamate transporter xCT, which is encoded by SLC7A11, was upregulated because of the increased cell surface expression of CD44v in ACR20 cells. Treatment with the xCT inhibitor salazosulfapyridine and knockdown of SLC7A11 mRNA by a specific siRNA significantly improved sensitivity to CDDP in A549, ACR4, and ACR20 cells. Thus, our results suggest that CD44v overexpression is not involved in cancer stem cell properties but increases xCT expression, which leads to the acquisition of CDDP-resistance. This mechanism may contribute to the development of a new therapeutic strategy that can overcome resistance.

Radiofrequency Ablation Guided by Contrast-Enhanced Sonography versus B-Mode Sonography for Hepatocellular Carcinoma after Transcatheter Arterial Chemoembolization.

PURPOSE: Contrast-enhanced sonography increases negative enhancement in the Kupffer phase after transcatheter arterial chemoembolization (TACE) for hepatocellular carcinoma (HCC). We compared contrast-enhanced sonography with B-mode sonography for guidance of radiofrequency ablation (RFA) of HCC after TACE. METHODS: After TACE was performed, 18 nodules in 12 patients were treated by B-mode sonography guided RFA, while 22 nodules in 18 patients were treated by contrast-enhanced sonography-guided RFA. RESULTS: The success rate of initial RFA was 83.3% (15/18 nodules) in the B-mode sonography group. On the other hand, the success rate was 100% (22/22 nodules) in the contrast-enhanced sonography group and the difference was significant (p = 0.046). CONCLUSION: These findings suggest that RFA guided by Kupffer phase contrast-enhanced sonography after TACE is a promising therapeutic option for curing HCC.

Down-regulation of hepatic CYP3A1 expression in a rat model of indomethacin-induced small intestinal ulcers.

The liver and the small intestine are closely related in the processes of drug absorption, metabolism and excretion via the enterohepatic circulation. Small intestinal ulcers are a serious adverse effect commonly occurring in patients taking nonsteroidal anti-inflammatory drugs. However, the influence of small intestinal ulcers on drug metabolism has not been established. This study examined the expressional changes of cytochrome P450 (CYP) in the liver using an indomethacin-induced small intestinal ulcer rat model and in cultured cells. After the administration of indomethacin to rats, ulcers were observed in the small intestine and expression of CYP3A1, the major isoform of hepatic CYP, was significantly down-regulated in the liver, accompanied by increased expression of inducible nitric oxide synthase, tumor necrosis factor α, interleukin (IL)-1ß and IL-6, in the small intestine and the liver. The indomethacin-induced small intestinal ulceration, the increase in inflammatory mediators in the small intestine and the liver, and the down-regulation of CYP3A1 expression in the liver were inhibited by co-administration of ampicillin, an antibacterial agent. In the human hepatic HepG2 cell line, IL-1ß, IL-6 and NOC-18, an NO donor, caused down-regulation of CYP3A4, the major isoform of human CYP3A. Thus, this study suggests that after indomethacin treatment small intestinal ulcers cause the down-regulation of CYP3A1 in the rat liver through an increase in ulcer-derived inflammatory mediators. Copyright © 2016 John Wiley & Sons, Ltd.

Self-expanding metallic stent improves histopathologic edema compared with transanal drainage tube for malignant colorectal obstruction.

AIMS: To compare the usefulness of the self-expanding metallic stent (SEMS) with that of the transanal drainage tube (TDT) and emergency surgery after failure of decompression (ESFD) in patients with malignant colonic obstruction (MCO), and to evaluate post-decompression histopathologic changes. METHODS: From January 2010 to June 2015, 39 patients with MCO received SEMS, TDT, and ESFD. We evaluated the outcomes including success rates of placement, clinical outcomes after decompression, and histopathologic findings of the resected specimens. RESULTS: Technical success rates were 100% for SEMS and 78.9% for TDT. Clinical success rates were 100% for SEMS and 80.0% for TDT. Postoperative ileus was significantly less frequent after SEMS than after TDT (p = 0.014). Histopathologic edema grade was significantly lower for SEMS than for TDT and ESFD (p < 0.0001). There was no significant difference between edema grade and duration of decompression in the TDT group (p = 0.629), while all patients with SEMS were classified in a low edema grade (grade 0-2). The rate of stoma creation was significantly higher in patients with a high edema grade (grade 3) than in those with a low edema grade (grade 0-2) (p = 0.003). There was no microscopic perforation in any group. CONCLUSION: Significantly greater resolution of histopathologic edema was achieved after placement of SEMS than after placement of TDT. These findings provide an indication of favorable clinical outcomes of SEMS in comparison with TDT and ESFD. This article is protected by copyright. All rights reserved.

Primary diffuse large B cell lymphoma of the common bile duct causing obstructive jaundice.

We report a rare case of a diffuse large B-cell lymphoma (DLBCL) arising from the common bile duct (CBD). A 77-year old man presented with general fatigue and obstructive jaundice. Abdominal computed tomography revealed a well-circumscribed enhancing mass in the midportion of the CBD with proximal bile duct dilatation. Endoscopic retrograde cholangiopancreatography (ERCP) also showed a midportion of the CBD stricture. Direct peroral cholangioscopy revealed smooth mass in the midportion of the CBD, and narrow-band imaging (NBI) showed irregular tortuous microvessels. The brushing cytology of the CBD was performed, and it was diagnosed as suspicious for poorly differentiated adenocarcinoma or malignant lymphoma. We performed extrahepatic bile duct resection for accurate diagnosis. Histological and immunohistochemical examination of the resected specimen revealed DLBCL. Although systemic chemotherapy is the mainstay of treatment for DLBCL, he refused scheduled subsequent chemotherapy, and died of multiple liver metastases 6 months after surgery.

Serologically Determined Gastric Mucosal Condition Is a Predictive Factor for Osteoporosis in Japanese Men.

BACKGROUND: There are few reports about the influence of Helicobacter pylori infection and/or atrophic gastritis on bone conditions in Japan. AIMS: To assess whether the combination of serologically determined Helicobacter pylori infection and atrophic gastritis is available as a biomarker for bone conditions. METHODS: We studied 230 men in their 50s and 60s. Helicobacter pylori infection was determined using serum antibody to this bacterium. Atrophic gastritis was diagnosed on the basis of the serum pepsinogen I and II criteria. The characteristics of the participants' bone were measured at the radius using an ultrasonic bone densitometry system. The risks of low trabecular bone density, low elastic modulus of trabecular bone, and low cortical thickness among subjects who were positive for Helicobacter pylori infection and/or atrophic gastritis relative to those who were not were calculated. RESULTS: Helicobacter pylori infection significantly increased the risk of low trabecular bone density (odds ratio 1.83, 95 % confidence interval 1.04-3.21, P = 0.03). Atrophic gastritis significantly increased the risk of low trabecular bone density (2.22, 1.17-4.22, 0.01). Compared with anti-Helicobacter pylori antibody (-) and atrophic gastritis (-) subjects, anti-Helicobacter pylori antibody (+) and atrophic gastritis (+) subjects were a significant high-risk group for low trabecular bone density (2.65, 1.27-5.55, 0.01). CONCLUSIONS: A serological diagnosis of Helicobacter pylori infection and atrophic gastritis, which is utilized for risk assessment of gastric cancer, was suggested to be useful for risk assessment of osteoporosis.

Cisplatin resistance in human lung cancer cells is linked with dysregulation of cell cycle associated proteins.

AIMS: Cisplatin (CDDP) is a platinum-based drug that is widely used in cancer chemotherapy, but the development of resistance in tumor cells is a major weakness of these treatments. Several mechanisms have been proposed to explain cisplatin resistance, and disruption of certain cellular pathways could modulate drug sensitivity to cisplatin. A lower level of cross-resistance to cisplatin leads to better outcomes in clinical use. MAIN METHODS: Cross-resistance was assessed using cisplatin resistant lung cancer cell line A549/CDDP. Cell cycle analysis was used to examine the effect of cisplatin on cell signaling pathways regulating G2/M transition in cisplatin resistant cells. KEY FINDINGS: A549/CDDP cells exhibited cross-resistance to carboplatin, but not oxaliplatin, which is often found in platinum analogues. Flow cytometry showed that nocodazole treatment caused a G2/M block in both A549/CDDP cells and cisplatin susceptible cells. However, A549/CDDP cells escaped the G2/M block following exposure to cisplatin. Activation of the Cdc2/CyclinB complex is required for transition from G2 to M phase, and the inactive form of phosphorylated Cdc2 is activated by Cdc25C dephosphorylation of Tyr15. In the cisplatin-treated susceptible cells, the levels of phosphorylated Cdc2 and Cdc25C were markedly decreased, leading to a loss of Cdc2 activity and G2/M arrest. In A549/CDDP cells, however, Cdc2 activity was supported by the expression of Cdc2 and Cdc25C after the addition of cisplatin, which resulted in G2/M progression. SIGNIFICANCE: The resistance phenotype of G2/M progression has been correlated with dysregulation of Cdc2 in a human lung cancer cell line selected for cisplatin.

Intestinal and hepatic expression of cytochrome P450s and mdr1a in rats with indomethacin-induced small intestinal ulcers.

BACKGROUND: Non-steroidal anti-inflammatory drugs induce the serious side effect of small intestinal ulcerations (SIUs), but little information is available regarding the consequences to drug metabolism and absorption. AIM: We examined the existence of secondary hepatic inflammation in rats with indomethacin (INM)-induced SIUs and assessed its relationship to the cytochrome P450 (CYP) and P-glycoprotein (mdr1a), the major drug-metabolizing factors in the small intestine and the liver. METHODS: Gene expression of the CYP family of enzymes and mdr1a was measured with quantitative real-time polymerase chain reaction (qPCR). Vancomycin (VCM), a poorly absorbed drug, was administered intraduodenally to rats with SIUs. RESULTS: INM induced SIUs predominantly in the lower region of the small intestine with high expression of inflammatory markers. Liver dysfunction was also observed, which suggested a secondary inflammatory response in rats with SIUs. In the liver of rats with SIUs, the expression of CYP2C11, CYP2E1, and CYP3A1 was significantly decreased, and loss of CYP3A protein was observed. Although previous studies have shown a direct effect of INM on CYP3A activity, we could not confirm any change in hepatic CY3A4 expression (major isoform of human CYP3A) in vitro. The plasma VCM concentration was increased in rats with SIUs due to partial absorption from the mucosal injury, but not in normal mucosa. CONCLUSIONS: INM-induced SIUs had a subtle effect on intestinal CYP expression, but had an apparent action on hepatic CYP, which was influenced, at least in part, by the secondary inflammation. Furthermore, drug absorption was increased in rats with SIUs.

Effect of 18ß-glycyrrhetinic acid and hydroxypropyl γcyclodextrin complex on indomethacin-induced small intestinal injury in mice.

Non-steroidal anti-inflammatory drugs (NSAIDs)-induced small intestinal injury is a serious clinical event with recent advances of diagnostic technologies, but a successful therapeutic method to treat such injuries is still lacking. Licorice, a traditional herbal medicine, and its derivatives have been widely used for the treatment of a variety of diseases due to their extensive biological actions. However, it is unknown whether these derivatives have an effect on NSAIDs-induced small intestinal damage. Previously, the anti-inflammatory effects of three compounds extracted from the licorice root, glycyrrhizin, 18ß-glycyrrhetinic acid, and dipotassium glycyrrhizinate, were compared in vitro cell culture. The most prominent inhibitory effect on the tumor necrosis factor-α (TNF-α) production was observed with the administration of 18ß-glycyrrhetinic acid as an active metabolite of glycyrrhizin. In this study, a complex compound of 18ß-glycyrrhetinic acid and hydroxypropyl γcyclodextrin was examined to improve the oral bioavailability. After administration of this complex to indomethacin treated mice, a significantly high plasma concentration of 18ß-glycyrrhetinic acid was detected using the tandem mass spectrometry coupled with the HPLC. Furthermore, the complex form of 18ß-glycyrrhetinic acid and hydroxypropyl γcyclodextrin reduced mRNA expressions of TNF-α, interleukin (IL)-1ß, and IL-6, which was histologically confirmed in the improvement of indomethacin-induced small intestinal damage. These results suggest that the complex of 18ß-glycyrrhetinic acid and hydroxypropyl γcyclodextrin has the potential therapeutic value for preventing the adverse effects of indomethacin-induced small intestinal injury.

Linoleoyl ethanolamide reduces lipopolysaccharide-induced inflammation in macrophages and ameliorates 2,4-dinitrofluorobenzene-induced contact dermatitis in mice.

In our previous study, it was found that linoleoyl ethanolamide (LE) is present in sake lees, which are produced as a byproduct during the making of Japanese sake. LE is a fatty acid ethanolamide, which have been demonstrated to exert a variety of biological functions, and in this study, the anti-inflammatory effects of LE were examined using in vitro cell culture and in vivo animal experiments. In mouse RAW264.7 macrophages, LE suppressed the lipopolysaccharide (LPS)-induced expression of pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interleukin (IL)-1ß, and IL-6. In addition, LE inhibited LPS-induced increases in the levels of cyclooxygenase enzyme-2 and prostaglandin E(2), which are indicators of inflammation. The inhibitory effect of LE on the release of TNF-α was stronger than that of dipotassium glycyrrhizinate, which is widely used in external human skin care treatments. LE also suppressed the LPS-induced activation of Toll-like receptor 4 signaling and nuclear translocation of nuclear factor-κB (NF-κB) p65. In a contact dermatitis animal model, applying LE to affected ear skin ameliorated 2,4-dinitrofluorobenzene-induced contact dermatitis and pro-inflammatory cytokine expression at inflamed sites. These results indicate that LE exerts anti-inflammatory effects by inhibiting NF-κB signaling, and LE is proposed to be a useful therapeutic agent against contact dermatitis.

THRB genetic polymorphisms can predict severe myelotoxicity after definitive chemoradiotherapy in patients with esophageal squamous cell carcinoma.

OBJECTIVE: Chemotherapy-related toxicities are difficult to predict before treatment. In this study, we investigated whether thyroid hormone receptor beta (THRB) genetic polymorphisms can serve as a potential biomarker in patients with esophageal squamous cell carcinoma (ESCC). METHODS: Forty-nine Japanese patients with ESCC who received a definitive chemoradiotherapy (CRT) with 5-fluorouracil and cisplatin in conjunction with concurrent irradiation were retrospectively analyzed. Severe acute toxicities, including leukopenia, stomatitis, and cheilitis, were evaluated according to 6 single nucleotide polymorphisms (SNPs) in the gene; the intronic SNPs of rs7635707 G/T, rs6787255 A/C, rs9812034 G/T, and rs9310738 C/T and the SNPs in the 3'-untranslated region (3'-UTR) of rs844107 C/T and rs1349265 G/A. RESULTS: Distribution of the 4 intronic SNPs, but not the 2 SNPs in the 3'-UTR, showed a significant difference between patients with and without severe acute leukopenia. Stomatitis and cheilitis were not associated with any of the 6 analyzed SNPs. Frequency of haplotype of the 4 intronic SNPs reached approximately 97% with the 2 major haplotypes G-A-G-C (73.4%) and T-C-T-T (23.5%). CONCLUSIONS: THRB intronic SNPs can provide useful information on CRT-related severe myelotoxicity in patients with ESCC. Future studies will be needed to confirm these findings.

Inhibitory effects of glycyrrhetinic Acid on DNA polymerase and inflammatory activities.

We investigated the inhibitory effect of three glycyrrhizin derivatives, such as Glycyrrhizin (compound 1), dipotassium glycyrrhizate (compound 2) and glycyrrhetinic acid (compound 3), on the activity of mammalian pols. Among these derivatives, compound 3 was the strongest inhibitor of mammalian pols α, ß, κ, and λ, which belong to the B, A, Y, and X families of pols, respectively, whereas compounds 1 and 2 showed moderate inhibition. Among the these derivatives tested, compound 3 displayed strongest suppression of the production of tumor necrosis factor-α (TNF-α) induced by lipopolysaccharide (LPS) in a cell-culture system using mouse macrophages RAW264.7 and peritoneal macrophages derived from mice. Moreover, compound 3 was found to inhibit the action of nuclear factor-κB (NF-κB) in engineered human embryonic kidney (HEK) 293 cells. In addition, compound 3 caused greater reduction of 12-O-tetradecanoylphorbol-13-acetate-(TPA-) induced acute inflammation in mouse ear than compounds 1 and 2. In conclusion, this study has identified compound 3, which is the aglycone of compounds 1 and 2, as a promising anti-inflammatory candidate based on mammalian pol inhibition.

AP1B plays an important role in intestinal tumorigenesis with the truncating mutation of an APC gene.

Recent evidence has suggested that carcinoma is accompanied by the loss of cell polarity. An epithelial cell-specific form of the AP-1 clathrin adaptor complex, AP1B, is involved in the polarized transport of membrane proteins to the basolateral surface of epithelial cells. In our study, we investigated whether AP1B is involved in intestinal tumorigenesis. The cellular polarity of intestinal tumor cells was examined using APC(Min/+) mice as an in vivo model and SW480 cells with a truncating mutation in the adenomatous polyposis coli (APC) gene as an in vitro model by confocal microscopy. Next, the expression of AP1B in intestinal tumor cells was examined by real-time polymerase chain reaction (PCR) and Western blotting. The localization of ß-catenin and the expression of AP1B in the tumor tissue of patients with colorectal cancer were evaluated by confocal microscopy and real-time PCR, respectively, and the relationships among cell polarity, AP1B expression and intestinal tumorigenesis were examined. Cellular polarity was lost in intestinal tumor cells, and the expression of AP1B was downregulated. In addition, the reduction in the expression level of AP1B correlated with the nuclear localization of ß-catenin in human colorectal cancer. Our study indicates the close associations between AP1B, intestinal tumorigenesis and mutations in the APC gene. This is the first report to reveal the relationships among AP1B, cellular polarity and intestinal tumorigenesis, and achieving a detailed understanding of AP1B will hopefully lead to discovery of therapeutic targets and novel biomarkers for intestinal cancer.

Soluble ß-glucan from Grifola frondosa induces proliferation and Dectin-1/Syk signaling in resident macrophages via the GM-CSF autocrine pathway.

MD-Fraction, a highly purified, soluble ß-(1,3) (1,6)-glucan obtained from Grifola frondosa (an oriental edible mushroom), has been reported to inhibit tumor growth by modulating host immunity. ß-Glucan, a major component of the fungal cell wall, is generally recognized by PRRs expressed on macrophages and DCs, such as Dectin-1, and the ability of ß-glucans to modulate host immunity is influenced by their structure and purity. Most cellular studies have used particulate ß-glucans, such as yeast zymosan (crude ß-glucan) and curdlan (purified ß-glucan). However, little is known about the cellular mechanism of soluble ß-glucans, including MD-Fraction, despite significant therapeutic implications. In this study, we investigated the cellular mechanism of MD-Fraction in murine resident macrophages and compared it with two well-known ß-glucan particles. MD-Fraction induced GM-CSF production rapidly through Dectin-1-independent ERK and p38 MAPK activation. Subsequently, MD-Fraction-induced GM-CSF enhanced proliferation and Dectin-1 expression, which permitted Dectin-1-mediated TNF-α induction through the Syk pathway. Curdlan induced not only the proliferation and activation of Dectin-1/Syk signaling in a manner similar to MD-Fraction but also the uncontrolled, proinflammatory cytokine response. Contrastingly, zymosan reduced proliferation and Dectin-1 expression significantly, indicating that the mechanism of macrophage activation by MD-Fraction differs from that of zymosan. This is the first study to demonstrate that purified ß-glucans, such as MD-Fraction and curdlan, induce GM-CSF production directly, resulting in Dectin-1/Syk activation in resident macrophages. In conclusion, we demonstrated that MD-Fraction induces cell proliferation and cytokine production without excessive inflammation in resident macrophages, supporting its immunotherapeutic potential.

Monoacetylcurcumin strongly regulates inflammatory responses through inhibition of NF-kappaB activation.

Curcumin, a component of turmeric (Curcuma longa), is known to exert a variety of biological functions including anti-inflammatory activity. We examined the inhibitory effects of chemically synthesized derivatives of curcumin against inflammatory responses and compared them with those of curcumin, in order to find derivatives with stronger effects than curcumin. In a cell culture system using the mouse macrophage cell line RAW264.7, monoacetylcurcumin strongly inhibited IkappaB phosphorylation, nuclear factor (NF)-kappaB activation and tumor necrosis factor (TNF)-alpha production induced by lipopolysaccharide (LPS). In addition, oral administration of monoacetylcurcumin to mice led to greater suppression of TNF-alpha production after LPS stimulation than the administration of curcumin or tetrahydrocurcumin in vivo. Monoacetylcurcumin also inhibited the LPS-induced NF-kappaB activation in the liver. Collectively, monoacetylcurcumin is a potential chemopreventive agent for treating inflammatory responses more effectively than curcumin.