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Dirhodium(II)‐catalyzed intramolecular insertion of aryldiazoacetates into an unactivated primary C−H bond was described in this study. The insertion reaction of aryldiazoacetates with ortho‐isopropyl or ortho‐ethyl groups in the presence of a catalytic amount of dirhodium(II) tetrakis(triphenylacetate), Rh2(tpa)4, at room temperature proceeded site‐selectively to afford 2‐unsubstituted indane‐1‐carboxylates in 75%–96% yields. In the case of o‐isopropyl‐substituted aryldiazoacetates, cis‐isomers were obtained as major products. Furthermore, a chemoselective C−H insertion reaction of aryldiazoacetate bearing 1‐oxyethyl‐substituent at the ortho position was achieved by using a bulky and electron‐deficient pivaloyl group as the protecting group of a highly active oxygen atom. The present reaction provided a direct route to 2‐unsubstituted indanes. [ABSTRACT FROM AUTHOR]

Pancreatic fistula is a complication that frequently occurs after pancreatic surgery. Although various attempts have been made to prevent pancreatic fistula after pancreatic surgery, no effective methods have been developed thus far. In this study, to prevent the pancreatic fistula, we attempted to prepare the hydrogels consisting of two types of polyvinyl alcohol (PVAs), Poval® and Exceval® by the freezing–thawing (F/T) method. As the concentration and the number of F/T cycles increased, it was revealed that the swelling degree tended to decrease, and tensile strength tended to increase. Especially, Exceval® formed more robust hydrogels than that of Poval® hydrogel prepared by the same conditions. Furthermore, the release behavior of tartrazine from 10% Exceval® hydrogels differed depending on the number of F/T cycles. It was also revealed that the diffusion pattern of the drug in the hydrogel differed along with the release, and the entire amount of tartrazine in the hydrogel was released by 120 min. As nafamostat mesylate was loaded, in vivo study, Pancreatic enzyme values were obtained after 48 h, which allowed comparison of the preventive effects against pancreatic fistula between the untreated group, the Exceval® hydrogel group, and nafamostat mesylate‐containing Exceval®‐applied group. Furthermore, there was a significant difference between the untreated group and the hydrogel‐applied group. Besides, PVA hydrogels prepared by the F/T method could probably absorb pancreatic enzymes. This study found that Exceval® hydrogel prepared by the F/T method was considered a novel hydrogel formulation to prevent pancreatic fistula. [ABSTRACT FROM AUTHOR]

Background and Aim: The incidence of non‐alcoholic steatohepatitis (NASH)‐related hepatocellular carcinoma (HCC) is progressively increasing. However, the pathophysiology and etiology of NASH progression to HCC are unknown. We hypothesized that steatosis was the key factor in NASH‐related hepatocarcinogenesis and aimed to evaluate the effects of long‐term liver X receptor (LXR) agonist stimulation on hepatic steatosis induced by a high‐fat diet and oxidative stress. Methods: We used an LXR agonist (T0901317) and CCl4 to induce hepatic steatosis and oxidative stress, respectively. C57BL/6 mice fed with a high‐fat diet were treated with either T0901317 + CCl4 (T09 + CCl4 group) or CCl4 alone (CCl4 group). T0901317 (2.5 mg/kg) and CCl4 (0.1 mL/kg) were intraperitoneally administered twice weekly for 24 weeks. Results: The liver‐to‐body weight ratio was significantly higher in the T09 + CCl4 group than in the CCl4 group. Mice in the T09 + CCl4 group exhibited abnormal lipid metabolism and NASH‐like histopathological features. Additionally, all mice in the T09 + CCl4 group developed liver tumors diagnosed as well‐differentiated HCC. The genes identified via microarray analysis were related to NASH and HCC development. Conclusions: By combining long‐term LXR agonist stimulation with oxidative stress and a high‐fat diet, we successfully reproduced liver conditions in mice similar to those in humans with NASH and progression to HCC. Our results provide new insight into NASH‐related HCC progression and therapy. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the efficacy of a novel hydrogel sheet in preventing postoperative pancreatic fistula (POPF). Background: Postoperative pancreatic fistula is a life‐threatening complication. As no study has reported the use of hydrogel sheets in preventing POPF, their effectiveness for that purpose remains unclear. Methods: A novel hydrogel sheet made of polyvinyl alcohol (PVA) was prepared by the freeze‐thaw method. The pancreatic ducts and surrounding pancreatic parenchyma of rats were transected to induce a pancreatic fistula. Next, the sheet was attached to the transection site. Ascitic fluid amylase and lipase concentrations were measured. Neoveil®, a nonwoven polyglycolic acid (PGA) felt, is already clinically used as an absorbable reinforcing material at pancreatic transection sites. Neoveil® was used for comparison, as was VIEWGEL®, which is marketed as a wound dressing. Results: The hydrogel sheet remained in place 48 hours postoperatively. The ascitic amylase concentrations in the control, VIEWGEL®‐treated, Neoveil®‐treated, and hydrogel‐treated rats, respectively, were 4992.4 ± 5355.7, 1068.4 ± 269.1, 730.2 ± 425.2, and 303.1 ± 240.1 IU/L; the ascitic lipase concentrations were 2279.8 ± 3395.2, 169.5 ± 100.6, 90.4 ± 71.0, and 86.8 ± 59.8 IU/L. The ascitic amylase and lipase levels were significantly lower in the hydrogel group than in the other groups (P <.05). Conclusions: This novel hydrogel sheet effectively prevents pancreatic fistulas and has promising clinical application potential. [ABSTRACT FROM AUTHOR]

Although several non-alcoholic steatohepatitis (NASH) models have been reported to date, few of these models fully reflect the histopathology and pathophysiology of human NASH. The aim of this study was to establish a novel NASH model by feeding a high-fat (HF) diet and administering both carbon tetrachloride (CCl4) and the Liver X receptor agonist T0901317. Male C57BL/6J mice were divided into four groups (each n = 5): HF, HF + CCl4, HF + T0901317, and the novel NASH model (HF + CCl4 + T0901317). CCl4 (0.1 mL/kg) and T0901317 (2.5 mg/kg) were intraperitoneally administered four times and five times, respectively. The livers of the novel NASH model group presented a whitish colour. The serum levels of TNF-α and IL-6 were significantly increased in the novel NASH model group, and mice in this group exhibited histopathological features and insulin resistance reflective of NASH, i.e., macrovesicular hepatic steatosis, ballooning hepatocytes, Mallory-Denk bodies, lobular inflammation and fibrosis. The novel NASH model group presented significantly upregulated expression levels of mRNAs related to lipogenesis, oxidative stress, fibrosis and steatosis and significantly downregulated expression levels of mRNAs related to triglyceride export. We successfully established a novel experimental NASH model that exhibits similar histopathology and pathophysiology to human NASH. [ABSTRACT FROM AUTHOR]

An efficient route to highly substituted indoles was developed. It included regioselective functionalization of tetrahydroindol-4(5 H)-ones, prepared by ring-opening cyclization of cyclohexane-1,3-dione-2-spirocyclopropanes with primary amines, and subsequent oxidation. The 6-substituted indoles were synthesized from a readily available 5-substituted cyclohexane-1,3-dione-2-spirocyclopropane. The synthesis of 5- and 7-substituted indoles was achieved by regioselective electrophilic alkylation of tetrahydroindol-4(5 H)-one, followed by oxidation. The 4-substituted indoles were synthesized by nucleophilic alkylation of the corresponding pyrrole derivative, which was prepared by partial oxidation of tetrahydroindol-4(5 H)-one, and sequential oxidation. The synthesis of 4-substituted indoles was also accomplished by palladium-catalyzed coupling of 4-hydroxyindole-derived triflates. Furthermore, the synthesis of 4,5,6,7-tetrasubstituted indoles was achieved by using these regioselective alkylations. [ABSTRACT FROM AUTHOR]

Aim Apoptosis is associated with various types of hepatic disorders. We have developed a novel cell-transfer drug delivery system (DDS) using a multifunctional envelope-type nano device that targets liver sinusoidal endothelial cells (LSECs). The purpose of this study was to determine the efficacy of the novel DDS containing siRNA at suppressing apoptosis in LSECs. Methods Bax siRNA was transfected into a sinusoidal endothelial cell line (M1) to suppress apoptosis induced by an anti-Fas antibody and staurosporine. C57BL/6J mice were divided into three groups: (i) a control group, only intravenous saline; (ii) a nonselective group, injections of siRNA sealed in the nonselective DDS; and (iii) an LSEC-transfer efficient group, injections of siRNA sealed in an LSEC-transfer efficient DDS. Hepatic cell apoptosis was induced by an anti-Fas antibody. Results Bax siRNA had an anti-apoptotic effect on M1 cells. Serum alanine aminotransferase was reduced in the LSEC-transfer efficient group, as were cleaved caspase-3 and the number of terminal deoxynucleotidyl transferase dUTP nick end labeling positive hepatocytes. Silver impregnation staining indicated that the sinusoidal space was maintained in the LSEC-transfer efficient group but not in the other groups. Electron microscopy showed that the LSECs were slightly impaired, although the sinusoidal structure was maintained in the LSEC-transfer efficient group. Conclusion Hepatocyte apoptosis was reduced by the efficient suppression of LSEC apoptosis with a novel DDS. Protecting the sinusoidal structure by suppressing LSEC damage will be an effective treatment for acute liver failure. [ABSTRACT FROM AUTHOR]

Background and Aim Heme oxygenase-1 ( HO-1) acts as a protector against hepatic inflammatory injury. HO-1 catalyzes the conversion of heme protein to biliverdin, free iron, and carbon monoxide. Pro-inflammatory responses play critical roles in hepatic ischemia-reperfusion ( I/ R) injury, and carbon monoxide effectively downregulates I/ R injury. The aim of this study was to evaluate the mechanism by which HO-1 reduces warm I/ R injury. Methods Sprague- Dawley rats were divided into two groups: the 20-min ischemia group (control group; n = 6) and the 20-min ischemia with cobalt protoporphyrin ( CoPP group; n = 6). CoPP is an inducer of HO-1 in the sinusoids. Kupffer cells were labeled using the liposome entrapment method, and platelets were labeled with rhodamine-6 G. The adherent platelets were observed for up to 120 min after reperfusion by intravital microscopy. Results In the control group, the number of adherent platelets significantly increased than in the CoPP group. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive cells were observed after 120 min of reperfusion in the control group. They were not observed in the CoPP group. In the CoPP group, serum alanine transaminase and interleukin-6 levels reduced after reperfusion. Moreover, the flow velocity of platelets in the hepatic sinusoid markedly increased. Conclusions This study suggests that HO-1 inhibits platelet adhesion to sinusoids. Such inhibition leads to the prevention of hepatic I/ R injury. [ABSTRACT FROM AUTHOR]

Background and Aim: Although there are some reports of an adverse effect of low serum high-density lipoprotein cholesterol (HDL-C) levels on gastrointestinal cancers, the specific correlation between serum HDL-C levels and gastric cancer remains unknown. Methods: Preoperative serum HDL-C levels were retrospectively examined in 184 patients who had undergone gastrectomy. The patients who had undergone gastrectomy were divided into two groups: the normal-HDL-C group and the low-HDL-C group. We examined the characteristics and outcomes of these two groups. Univariate and multivariate analyses were performed to investigate the association between serum HDL-C levels and gastric cancer. Results: There was no significant difference between the groups in terms of the progression of gastric cancer. In the low-HDL-C group, lymphatic and vascular invasion was significantly increased. The prognosis of the patients in the normal-HDL-C group was significantly better than those in the low-HDL-C group. Conclusions: In this study, a positive correlation between low preoperative serum HDL-C levels and prognosis for gastric cancer was demonstrated. Serum HDL-C level may be a clinical prognostic factor for gastric cancer patients. [ABSTRACT FROM AUTHOR]

Aim: Activated hepatic stellate cells (HSC) play a critical role in liver fibrosis. Suppressing abnormal function of HSC or reversion from activated to quiescent form is a hopeful treatment for liver cirrhosis. The interaction between platelets and HSC remains unknown although platelets go through hepatic sinusoids surrounded by HSC. This study aimed at clarifying the hypothesis that platelets control activation of HSC. Methods: We used human platelets, platelet extracts, and primary or immortalized human HSC. We examined the effect of platelets on the activation, DNA synthesis, type I collagen production, and fibrosis-relating gene expressions of HSC. We investigated what suppressed activation of HSC within platelets and examined the mechanism of controlling activation in vitro. Results: Platelets and platelet extracts suppressed activation of HSC. Platelets decreased type I collagen production without affecting DNA synthesis. Platelets increased the expression of matrix metallopeptidase 1. As platelet extracts co-cultured with an enzyme of degrading adenosine 5′-triphosphate (ATP) suppressed activation, we detected adenine nucleotides within platelets or on their surfaces and confirmed the degradation of adenine nucleotides by HSC and the production of adenosine. Adenosine and platelets increased the intracellular cyclic adenosine 5′-monophosphate (cAMP), which is important in quiescent HSC. A great amount of adenosine and ATP also suppressed activation of HSC. Conclusion: Activation of human HSC is suppressed by human platelets or platelet-derived ATP via adenosine-cAMP signaling pathway in vitro. Therefore, platelets have the possibility to be used in the treatment of liver cirrhosis. [ABSTRACT FROM AUTHOR]

An efficient method for the synthesis of highly substituted indoles via tetrahydroindol ‐ 4(5H) ‐ one intermediates, prepared by ring ‐ opening cyclization of spirocyclopropanes with amines, was developed. Syntheses of 4 ‐ , 5 ‐ , 6 ‐ or 7 ‐ substituted indoles were accomplished by regioselective functionalizations of the intermediates and subsequent oxidation. Furthermore, 4,5,6,7 ‐ tetrasubstituted indoles were synthesized by using these regioselective functionalizations. More information can be found in the Full Paper by H. Nambu, T. Yakura et al. on page 16799. [ABSTRACT FROM AUTHOR]