照井 慶太

Background/Aims: Liver regeneration following hepatectomy is complicated and involves a variety of interacting factors. The present study was designed to study the roles of proliferation and hypertrophy of hepatocytes in liver regeneration following hepatectomy in liver-specific STAT3-knockout (LS3-KO) mice lacking mitogenic activity. Methods: Partial hepatectomy was performed in LS3-KO and control mice. Liver regeneration was estimated by the liver weight, cell proliferation and cell size, and the related cellular signals were analyzed. Results: Proliferation of hepatocytes following PH was markedly suppressed in LS3-KO mice with reduced cyclinD1 transcript. However, liver mass recovered sufficiently following PH in LS3-KO mice almost equal to that of control mice. Analysis of hepatocellular growth revealed that cell size following hepatectomy was significantly larger in LS3-KO mice than in control mice. Hepatectomy induced immediate but transient phosphorylation of Akt, p70(S6K), mTOR and GSK-3 beta in LS3-KO mice much more than in control mice. Additionally, adenoviral transfection of dominant negative mutant of Akt to control and LS3-KO mice led to insufficient liver regeneration following hepatectomy. Conclusions: PI3-K/Akt-mediated responsive hepatocellular hypertrophy may be essential for liver regeneration following hepatectomy and sufficiently compensated liver regeneration even in STAT3-deficient liver, in which cell proliferation is impaired. (c) 2005 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Liver regeneration is a process in which the liver recovers its mass and function after injury due to various causes such as hepatectomy, virus infection and intoxication. This regeneration invokes a series of complex processes which may involve the actions of various cytokines, cell proliferation and cell growth. In response to cytokine stimuli, receptor-mediated signaling systems are activated, and many proteins are transcriptionally up-regulated to increase liver mass and improve liver function. In this review, we focus on the roles of signal transducer and activator of transcription-3 (STAT3) and its functions in mitogenic and other responses during liver regeneration following hepatectomy. We also describe newly discovered target genes of STAT3 and discuss their potential roles in liver regeneration after injury due to various causes. (C) 2005 Prous Science. All rights reserved.

The prognosis for children with malignant solid tumors has improved dramatically in Japan. During the last two decades, various groups have conducted sequential studies of the treatment of children with neuroblastoma, Wilms' tumor, and hepatoblastoma. Most institutes participated in nonrandomized trials designed to evaluate the safety and efficacy of combination chemotherapy, surgery, and radiotherapy in each group study and treated children with these tumors The results are reviewed and areas for future investigation are identified.

Background/Aims: Hypoxia/reoxygenation (H/R) causes oxidative stress to the cell and induces apoptotic cell death. Signal transducer and activator of transcription-3 (Stat3) is one of the most important molecules involved in the initiation of liver development and regeneration, and has recently been shown to protect cells against various pathogens. In order to investigate the hepatoprotective effects of Stat3, we examined whether it protects against H/R-induced injury in primary hepatocytes. Methods: Primary cultured hepatocytes were prepared from SD rats. Adenoviruses and cytokines were added 2 days and 1 h prior to the H/R insult, respectively. Hepatocytes and culture media were harvested for the assays before and after H/R insult. Results: Interleukin-6 and cardiotropin-1, which may function mainly through Stat3 activation, protected cells from H/R-induced apoptosis. Adenoviral overexpression of the constitutively activated form of Stat3 (Stat3-C) reduced H/R-induced apoptosis as well as generation of reactive oxygen species (ROS) in hepatocytes. Interestingly, Stat3-C induced Mn-SOD, but not Cu/Zn-SOD, both at the protein and mRNA levels. Overexpression of Mn-SOD significantly reduced H/R-induced ROS and apoptosis by inhibiting redox-sensitive activation of caspase-3 activity. Conclusions: Stat3 protects hepatocytes from H/R-induced cell injury at least partly by upregulating Mn-SOD and inactivating caspase-3. (C) 2004 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

STAT1 (signal transducer and activator of transcription 1) is potentially involved in cell survival, as well as cell death, in different types of cells. The present study was designed to examine the effects of STAT1 on hypoxia/re-oxygenation (H/R)-induced cell death and/or survival, and the underlying mechanisms of any such effects. H/R was shown to induce apoptotic cell death of rat hepatocytes. The addition of a STAT1-specific inhibitor, fludarabine, significantly increased the fraction of apoptotic cells after H/R. Following H/R, STAT1 was activated and sequential phosphorylation of Tyr(701) and Ser(727) was observed, which could be inhibited by the antioxidant N-acetyl-L-cysteine. Tyrosine and serine phosphorylation of STAT1 was mediated by Janus kinase 2 and phosphoinositide 3-kinase/Akt kinase respectively in a redox-dependent manner following H/R. STAT I -induced HSP70 (heat-shock protein 70) expression and the suppression of apoptosis occurred concomitantly. In conclusion, STAT1 activation, in a redox-dependent manner, following H/R may play crucial roles in cell survival, at least partly via HSP70 induction.

Signal transducer and activator of transcription-3 (Stat3) is one of the most important molecules involved in the initiation of liver development and regeneration. In order to investigate the hepatoprotective effects of Stat3, we examined whether Stat3 protects against Fas-mediated liver injury in the mouse. A constitutively activated form of Stat3 (Stat3-C) was adenovirally overexpressed in mouse liver by intravenous injection, and then a nonlethal dose of Fas agonist (Jo2) was injected intraperitoneally into the mouse (0.3 mug/g body wt). Stat3-C dramatically suppressed both apoptosis and necrosis induced by Jo2. In contrast, liver-specific Stat3-knockout mice failed to survive following Jo2 injection. Stat3-C upregulated expression of FLICE inhibitor protein (FLIP), Bcl-xL, and Bcl-2, and accordingly downregulated activities of FLICE and caspase-3 that were redox-independent. Interestingly, Stat3-C also upregulated the redox-associated protein redox factor-1 (Ref-1) and reduced apoptosis in liver following Jo2 injection by suppressing oxidative stress and redox-sensitive caspase-3 activity. These findings indicate that Stat3 activation protects against Fas-mediated liver injury by inhibiting caspase activities in redox-dependent and -independent mechanisms.

The authors report the successful use of endoscopic ultrasonography (EUS) for finding the etiology and subsequent treatment strategy for esophageal stenosis in 2 children. In case 1, EUS showed anterior wall thickening and multiple low echoic regions in the mp layer. These regions were believed to be cartilage. Esophageal resection therefore was performed. In case 2, EUS showed disruption of the sm and mp layers at the stenosis, leading us to speculate that the stenosis was caused by gastroesophageal reflux. After balloon dilatation, he underwent antireflux surgery of Nissen's fundoplication. EUS was useful for determining the etiology of esophageal stenosis and, thus, the appropriate treatment strategy.

Bronchopulmonary sequestration (PS) is characterized by non-functioning lung tissue fed from one or several aberrant systemic arteries. The condition is diagnosed by visualizing the feeding arteries using non-invasive CT,MRI, colour Doppler sonography or conventional angiography. We present a 5-year-old boy in whom intralobar sequestration was diagnosed using contrast-enhanced 3D MR angiography, which visualised fine blood vessels in the thoraco-abdominal region without arterial puncture. This technique is useful for diagnosing PS.