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Insulin decreases the mortality and prevents the incidence of infection and sepsis in critically ill patients. The molecular and cellular mechanisms by which insulin improves survival have not been defined. The purpose of the present study was to determine the effect of insulin on the inflammatory reaction during endotoxemia. Endotoxemic rats were randomly divided into two groups to receive either saline or insulin. The effects of insulin on hepatic signal transcription factor mRNA expression, proinflammatory and antiinflammatory cytokine mRNA and protein concentration were determined. Insulin administration did not change glucose or electrolyte levels, but significantly decreased proinflammatory signal transcription factors [CCAAT/enhancer-binding protein-beta, signal transducer and activator of transcription-3 and-5, RANTES (regulated on activation, normal T cell expressed and secreted)] and cytokine expression in the liver and serum levels of IL-1beta, IL-6, macrophage inflammatory factor, and TNFalpha. Insulin administration further decreased high mobility group 1 protein in the serum compared with controls. In addition, insulin increased antiinflammatory cytokine expression in the liver; serum levels of IL-2, IL-4, and IL-10; and hepatic suppressor of cytokine signaling-3 mRNA expression. Insulin modulates the inflammatory response by decreasing the proinflammatory and increasing the antiinflammatory cascade. Because glucose and electrolyte levels did not differ between insulin-treated patients and controls, we hypothesize that the effects are direct antiinflammatory mechanisms of insulin, rather than indirect, through modulation of glucose or electrolyte metabolism.

We have studied regulation of the multidrug resistance protein 2 (mrp2) during bile duct ligation (BDL) in the rat. In hepatocytes isolated after 16, 48, and 72 hours of BDL, mrp2-mediated dinitrophenyl-glutathione (DNP-GS) transport was decreased to 65%, 33%, and 33% of control values, respectively. The impaired mrp2-mediated transport coincided with strongly decreased mrp2 protein levels, without any significant changes in mrp2 RNA levels. Restoration of bile flow after a 48-hour BDL period resulted in a slow recovery of mrp2-mediated transport and protein levels. The multidrug resistance protein 2 (mrp2), previously called canalicular multispecific organic anion transporter, is an adenosine triphosphate (ATP)-dependent transporter that mediates the biliary excretion of a wide variety of endogenous and xenobiotic compounds. 1 The mrp2 protein has been extensively characterized in transport-mutant rats (the TR Ϫ rat, derived from the Wistar strain), 1 and the Eisai hyperbilirubinemic rat (EHBR rat, derived from the Sprague-Dawley rat strain), 2 which lack this protein owing to mutations in the mrp2 gene. [3][4][5] In humans, mutations in the orthologous MRP2 gene cause the Dubin-Johnson syndrome, 6-8 an autosomal recessive defect in the hepatobiliary excretion of a broad range of organic anions. 1,9 The human MRP2 and rat mrp2 are members of the ATP-binding cassette transporter family, and are abundantly and specifically expressed in the canalicular membrane of the hepatocyte. 3,4 Substrates transported by this protein include conjugates of glucuronide, sulphate, and glutathione, and complexes (or cotransport) of heavy metals and oxyanions with glutathione. 1 Recently, we have shown an important role for mrp2 in the transport of reduced glutathione (GSH), 10 which probably serves a physiological function in maintenance of the bile acid-independent flow.Extrahepatic or obstructive cholestasis is a pathological condition caused by biliary obstruction leading to impaired bile flow. 11-13 As a result, bile salt and non-bile salt organic anions (including taurocholate and bilirubin-glucuronides) accumulate in hepatocytes and regurgitate into the circulation. Morphological changes associated with obstructive cholestasis include dilation of the canaliculus, loss of microvilli, and rearrangement of tight-junctional structures. [11][12][13] Kawaguchi et al. 14 have recently shown that alterations in tight-junctional structures are heterogenously distributed throughout the liver lobule during bile duct ligation (BDL) in the rat.Several studies have been published that describe an association between activity and expression levels of canalicular transporters and obstructive cholestasis using the BDL model in the rat. P-glycoprotein (P-gp) expression levels and activity are increased during BDL, 15 with a concomitant increase in both mdr1a and mdr1b RNA levels. 15 In addition, P-gp (partly) redistributes to the pericanalicular vesicles of the hepatocyte. 15,16 Trauner et al. 17 have shown that BDL in the rat is associated ...

The mammalian target of rapamycin (mTOR) has become an interesting target for cancer therapy through its influence on oncogenic signals, which involve phosphatidylinositol-3-kinase and hypoxia-inducible factor-1a (HIF-1a). Since mTOR is an upstream regulator of HIF-1a, a key mediator of gastric cancer growth and angiogenesis, we investigated mTOR activation in human gastric adenocarcinoma specimens and determined whether rapamycin could inhibit gastric cancer growth in mice. Expression of phospho-mTOR was assessed by immunohistochemical analyses of human tissues. For in vitro studies, human gastric cancer cell lines were used to determine S6K1, 4E-BP-1 and HIF1a activation and cancer cell motility upon rapamycin treatment. Effects of rapamycin on tumor growth and angiogenesis in vivo were assessed in both a subcutaneous tumor model and in an experimental model with orthotopically grown tumors. Mice received either rapamycin (0.5 mg/kg/day or 1.5 mg/kg/day) or diluent per intra-peritoneal injections. In addition, antiangiogenic effects were monitored in vivo using a dorsal-skin-fold chamber model. Immunohistochemical analyses showed strong expression of phospho-mTOR in 60% of intestinal-and 64% of diffuse-type human gastric adenocarcinomas. In vitro, rapamycin-treatment effectively blocked S6K1, 4E-BP-1 and HIF-1a activation, and significantly impaired tumor cell migration. In vivo, rapamycintreatment led to significant inhibition of subcutaneous tumor growth, decreased CD31-positive vessel area and reduced tumor cell proliferation. Similar significant results were obtained in an orthotopic model of gastric cancer. In the dorsal-skin-fold chamber model, rapamycin-treatment significantly inhibited tumor vascularization in vivo. In conclusion, mTOR is frequently activated in human gastric cancer and represents a promising new molecular target for therapy. ' 2007 Wiley-Liss, Inc.

Oncogenic signaling through activation of epidermal growth factor receptor (EGFR), HER-2, and hypoxia inducible-factor-1A

Large wounds resulting from severe injuries are generally treated with extended reconstructive operations (e.g., free flaps), which are accompanied by long hospitalizations and risks of infection, thrombosis, and flap loss. Integra is a collagen template that can be used for reconstruction of defects. The take rate and the rate of infection are essential for the successful use of Integra (Johnson and Johnson, Hamburg, Germany). Whether the take rate and integration of Integra could be improved with the use of fibrin glue and negative-pressure therapy was assessed. Between January of 2002 and December of 2002, patients with large defects who underwent Integra grafting for reconstruction were randomly divided into groups receiving either a new treatment with fibrin glue-anchored Integra and postoperative negative-pressure therapy or conventional treatment. Demographic features, cause of the wound, location of the wound, take rate, complications of Integra coverage, time from Integra coverage to skin transplantation, and functional and aesthetic results were assessed. Twelve patients (with similar group distributions with respect to sex, age, and location and cause of the injury) were included in the study. The take rate was 78 +/- 8 percent in the conventional treatment group and 98 +/- 2 percent in the fibrin/negative-pressure therapy group (p < 0.003). The mean period from Integra coverage to skin transplantation was 24 +/- 3 days in the conventional treatment group but only 10 +/- 1 days in the fibrin/negative-pressure therapy group (p < 0.002). The decrease in the interval between coverage with Integra and skin transplantation resulted in shorter hospital stays. The use of fibrin glue and negative-pressure therapy in combination with Integra could shorten the period from coverage to integration, which would be beneficial in terms of decreased risks of infection, thrombosis, and catabolism. Therefore, it is suggested that Integra be used in combination with fibrin glue and negative-pressure therapy to improve clinical outcomes and shorten hospital stays, with decreased risks of accompanying complications.

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