Protein kinase C (PKC) participates in signal transduction, and its overactivation is involved in various types of cell injury. PKC depends on diacylglycerol (DAG) for its activation in vivo We have previously reported that DAG peroxides (DAG-O(O)H) activate PKC in vitro more strongly than unoxidized DAG, suggesting that DAG-O(O)H, if generated in vivo under oxidative stress, would act as an aberrant signal transducer. The present study examined whether DAG-O(O)H are formed in carbon tetrachloride (CCl 4 )-induced acute rat liver injury in association with activation of the PKC/nuclear factor (NF)-kB pathway. A single subcutaneous injection of CCl 4 resulted in a marked increase in hepatic DAG-O(O)H content. At the molecular level, immunohistochemistry and subcellular fractionation combined with immunoblotting localized PKCa, bI, bII and d isoforms to cell membranes, while immunoblotting showed phosphorylation of the p65 subunit of NF-kB, and immunoprecipitation using isoform-specific anti-PKC antibodies revealed specific association of PKCa and p65. In addition, expression of tumor necrosis factor a (TNFa) and neutrophil invasion increased in the CCl 4 -treated rats. Furthermore, we demonstrated that Vitamin E, one of the most important natural antioxidants that suppresses peroxidation of membrane lipids, significantly inhibited the CCl 4 -induced increase in hepatic DAG-O(O)H content and TNFa expression as well as phosphorylation of PKCa and p65. These data demonstrate for the first time that DAG-O(O)H are generated in the process of CCl 4 -induced liver injury, resulting in activation of the PKC/NF-kB pathway and TNFa-mediated aggravation of liver injury.
Localization of each keratin isoform differs among epidermal layers. Proliferating basal cells synthesize keratin 14 (K14) and suprabasal cells express keratin 10 (K10) in normal skin. Notch signaling is essential for keratinocyte differentiation. Notch1 is expressed in all epidermal layers, Notch2 in the basal cell layer and Notch3 in basal cell and spinous cell layers in normal epidermis. It has been poorly elucidated how localization and expression levels of Notch molecules are related to epidermal molecular markers K10 and K14 in psoriatic skin with abnormal differentiation of epidermal tissue. This study aimed to investigate the relationship between abnormal differentiation of epidermal cells in psoriatic skin and expression of Notch molecules. We investigated keratins (K14 and K10) and Notches (1, 2, 3 and 4) using immunohistochemistry in psoriatic skin (n=30) and normal skin (n=10). In normal skin, K14 and K10 were discretely observed in the basal cell layer and suprabasal layer, respectively. In psoriatic skin, K14 was expressed in the pan epidermal layer while it and K10 were co-expressed in some middle suprabasal layer cells. Notch1, 2, 3, and 4 localized in all epidermal layers in normal skin. In psoriatic skin, Notch1, 2, and 4 mainly localized in suprabasilar layers and Notch3 is lacalized in pan epidermal, suprabasilar, and basilar layers. Protein and mRNA of Notch1, 2, and 3 isoforms decreased in psoriatic epidermis compared with normal epidermis. These data suggest that decrements in these Notch molecules might cause aberrant expression of K10 and K14 leading to anomalous differentiation of the epidermis in psoriatic lesions.
Polarized hepatocytes contain tight junctions (TJs), which are among the most important junctions for sealing the bile canalicular lumen from the sinusoidal space. Alterations in TJs are implicated in chronic cholestatic liver diseases, such as primary biliary cirrhosis and primary sclerosing cholangitis, which have lipid peroxidation marker elevations or antioxidant vitamin decreases. However, the effect of oxidative stress on hepatocyte polarity or liver morphology is unknown. We found that carbon tetrachloride (CCl4)-induced oxidative stress resulted in disassembly of TJs. Ultrastructural analysis revealed disruption in TJs, Golgi morphology, and expansion of the bile canalicular lumen size in CCl4-treated hepatocytes. The Par complex [Par-3-atypical protein kinase C (aPKC) and Par-6 ternary complex] regulates TJs and lumen formation, and the Par-3-aPKC complex formation was inhibited by CCl4 treatment. Moreover, the antioxidant compound vitamin E prohibited a CCl4-induced disturbance in TJs and Par-3-aPKC complex formation. aPKC phosphorylates Par-3 and down-regulates its own affinity with Par-3. Importantly, aPKC kinase activity and Par-3 phosphorylation were significantly increased in CCl4-treated rat livers. These results indicate that the Par-3-aPKC complex plays a crucial role in the maintenance of hepatocyte polarity and sealing of the bile canalicular lumen. Our findings suggest that bile canalicular lumen expansion might explain the presence of cholestasis in patients with primary biliary cirrhosis and primary sclerosing cholangitis.
A cystic lesion of the pancreas was detected in a 25-year-old asymptomatic woman during a company medical checkup. Abdominal computed tomography (CT) revealed an ossified lesion in the pancreatic body, and the patient was referred to us for further management. Abdominal ultrasound and endoscopic ultrasound showed a hypoechoic mass with a large ossific focus, measuring 25 mm in the pancreatic body. CT and magnetic resonance imaging (MRI) showed a nonenhancing tumor lesion with a large calcific focus, measuring 20 mm in the pancreatic body. Endoscopic retrograde pancreatography revealed mild stenosis of the main pancreatic duct near the ossific focus in the pancreatic body. From the above, a pancreatic solid-pseudopapillary neoplasm (SPN) was suspected, and resection of the pancreatic body was performed. Intraoperatively, a whitish tumor measuring about 20 mm was recognized. Histopathologically, moderately large-sized tumor cells containing eosinophilic cytoplasm were arranged in a pseudopapillary formation, and infiltrated the surrounding normal tissue with ossification. Immunostaining was positive for α1-antitrypsin, not inconsistent with the diagnosis of SPN. We report this case of pancreatic SPN with ossification and a review of the literature.
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