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Search Results: 1 - 10 of 1466 matches for " Kenichi Harada "
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Cholangiopathy with Respect to Biliary Innate Immunity
Kenichi Harada,Yasuni Nakanuma
International Journal of Hepatology , 2012, DOI: 10.1155/2012/793569
Abstract: Biliary innate immunity is involved in the pathogenesis of cholangiopathies in cases of biliary disease. Cholangiocytes possess Toll-like receptors (TLRs) which recognize pathogen-associated molecular patterns (PAMPs) and play a pivotal role in the innate immune response. Tolerance to bacterial PAMPs such as lipopolysaccharides is also important to maintain homeostasis in the biliary tree, but tolerance to double-stranded RNA (dsRNA) is not found. Moreover, in primary biliary cirrhosis (PBC) and biliary atresia, biliary innate immunity is closely associated with the dysregulation of the periductal cytokine milieu and the induction of biliary apoptosis and epithelial-mesenchymal transition (EMT), forming in disease-specific cholangiopathy. Biliary innate immunity is associated with the pathogenesis of various cholangiopathies in biliary diseases as well as biliary defense systems.
Biliary Innate Immunity: Function and Modulation
Kenichi Harada,Yasuni Nakanuma
Mediators of Inflammation , 2010, DOI: 10.1155/2010/373878
Abstract: Biliary innate immunity is involved in the pathogenesis of cholangiopathies in patients with primary biliary cirrhosis (PBC) and biliary atresia. Biliary epithelial cells possess an innate immune system consisting of the Toll-like receptor (TLR) family and recognize pathogen-associated molecular patterns (PAMPs). Tolerance to bacterial PAMPs such as lipopolysaccharides is also important to maintain homeostasis in the biliary tree, but tolerance to double-stranded RNA (dsRNA) is not found. In PBC, CD4-positive Th17 cells characterized by the secretion of IL-17 are implicated in the chronic inflammation of bile ducts and the presence of Th17 cells around bile ducts is causally associated with the biliary innate immune responses to PAMPs. Moreover, a negative regulator of intracellular TLR signaling, peroxisome proliferator-activated receptor- (PPAR ), is involved in the pathogenesis of cholangitis. Immunosuppression using PPAR ligands may help to attenuate the bile duct damage in PBC patients. In biliary atresia characterized by a progressive, inflammatory, and sclerosing cholangiopathy, dsRNA viruses are speculated to be an etiological agent and to directly induce enhanced biliary apoptosis via the expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Moreover, the epithelial-mesenchymal transition (EMT) of biliary epithelial cells is also evoked by the biliary innate immune response to dsRNA. 1. Introduction Clarification of the molecular mechanisms of innate immunity and significance of innate immune responses to the pathogenesis of immune-mediated diseases as well as to the defense against infections has progressed steadily since the cloning of Tolls in drosophila and Toll-like receptors (TLRs) in mammals including humans [1, 2]. Innate immunity was initially thought to be limited to immunocompetent cells such as dendritic cells and macrophages, but epithelial cells also possess TLRs and proper innate immune systems. Liver and extrahepatic bile ducts consisting of hepatocytes and biliary epithelial cells (BECs) are also exposed to microorganisms and their components originating from the intestines via portal blood and duodenum. In the gastrointestinal tract, TLRs expressed in intestinal epithelial cells may be involved in innate immunity to maintain mucosal homeostasis and also the development of enterocolitis by producing inflammatory molecules [3]. Similar processes using TLRs may operate in the biliary tree. Human bile is sterile under normal conditions, but bacterial components such as lipopolysaccharide (LPS),
Cholangiopathy with Respect to Biliary Innate Immunity
Kenichi Harada,Yasuni Nakanuma
International Journal of Hepatology , 2012, DOI: 10.1155/2012/793569
Abstract: Biliary innate immunity is involved in the pathogenesis of cholangiopathies in cases of biliary disease. Cholangiocytes possess Toll-like receptors (TLRs) which recognize pathogen-associated molecular patterns (PAMPs) and play a pivotal role in the innate immune response. Tolerance to bacterial PAMPs such as lipopolysaccharides is also important to maintain homeostasis in the biliary tree, but tolerance to double-stranded RNA (dsRNA) is not found. Moreover, in primary biliary cirrhosis (PBC) and biliary atresia, biliary innate immunity is closely associated with the dysregulation of the periductal cytokine milieu and the induction of biliary apoptosis and epithelial-mesenchymal transition (EMT), forming in disease-specific cholangiopathy. Biliary innate immunity is associated with the pathogenesis of various cholangiopathies in biliary diseases as well as biliary defense systems. 1. Introduction Primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), and hepatolithiasis in adults and biliary atresia and choledochal cyst in infants are biliary diseases in which different anatomical levels of the biliary tree are specifically affected and characterized by cholangiopathy. The biliary tree, consisting of cholangiocytes, is a system of connecting ducts that drain the bile secreted by hepatocytes into the duodenum. Cholangiocytes provide the first line of defense in the biliary system against luminal microbes originating from the intestines via portal blood and duodenum [1]. In general, although human bile is normally sterile, it can contain bacterial components such as lipopolysaccharide (LPS), lipoteichoic acid, and bacterial DNA fragments, known as pathogen-associated molecular patterns (PAMPs) [2–5], and cultivable bacteria are detectable in bile of patients with biliary diseases [1, 6–8]. Enteric bacteria, in particular, may be responsible for the chronic proliferative cholangitis associated with hepatolithiasis [1, 6]. These findings indicate that cholangiocytes are exposed to bacterial PAMPs under physiological as well as pathological conditions. Innate immunity was initially thought to be limited to immunocompetent cells such as dendritic cells and macrophages, but epithelial cells also possess TLRs and proper innate immune systems reflecting the specific micro-environment and function of each epithelial cell type. Recent studies concerning biliary innate immunity indicate that cholangiocytes express a variety of pathogen-recognition receptors such as Toll-like receptors (TLRs) [9, 10]. Infectious agents have been implicated in the
Cholangiocarcinoma with respect to IgG4 Reaction
Kenichi Harada,Yasuni Nakanuma
International Journal of Hepatology , 2014, DOI: 10.1155/2014/803876
Abstract: IgG4 reactions marked by infiltration of IgG4-positive plasma cells in affected organs occur in cancer patients and in patients with IgG4-related diseases. Extrahepatic cholangiocarcinomas including gall bladder cancer are often accompanied by significant IgG4 reactions; these reactions show a negative correlation with CD8-positive cytotoxic T cells, suggesting that the evasion of immune surveillance is associated with cytotoxic T cells. The regulatory cytokine IL-10 may induce IgG4-positive plasma cell differentiation or promote B cell switching to IgG4 in the presence of IL-4. Cholangiocarcinoma cells may function as nonprofessional antigen presenting cells that indirectly induce IgG4 reactions via the IL-10-producing cells and/or these may act as Foxp3-positive and IL-10-producing cells that directly induce IgG4 reactions. Moreover, IgG4-related disease is a high-risk factor for cancer development; IgG4-related sclerosing cholangitis (IgG4-SC) cases associated with cholangiocarcinoma or its precursor lesion biliary intraepithelial neoplasia (BilIN) have been reported. IgG4-positive cell infiltration is an important finding of IgG4-SC but is not a histological hallmark of IgG4-SC. For the diagnosis of IgG4-SC, its differentiation from cholangiocarcinoma remains important. 1. Introduction Inflammatory biliary diseases with periductal fibrosis are categorized as sclerosing cholangitis. In addition to the prototype of sclerosing cholangitis, primary sclerosing cholangitis (PSC), IgG4-related sclerosing cholangitis (IgG4-SC) is categorized as sclerosing cholangitis. Although IgG4-SC is characterized by the infiltration of numerous IgG4-positive cells in the wall of bile ducts, this IgG4 reaction is also found in PSC, hepatolithiasis, and cholangiocarcinoma. In particular, the differentiation between IgG4-SC and cholangiocarcinoma is an important clinical issue. Moreover, carcinogenesis in IgG4-related diseases has been noted [1] and a few cholangiocarcinoma cases arising from IgG4-SC have also been reported [2, 3]. In this review, we focus on the IgG4 reaction in cholangiocarcinoma and the pathological IgG4-SC-induced carcinogenic features of cholangiocarcinoma. 2. IgG4-Related Diseases and Clinicopathological Issues IgG4 is a minor immunoglobulin subtype that does not activate complement and comprises only 3–6% of all circulating IgG in adults [4]. Elevated serum IgG4 levels and abundant IgG4-positive plasma cell infiltration in affected organs mark IgG4-related diseases [4–6]. The physiological and pathological significance of IgG4 remains unknown in
Contraction-induced cluster formation in cardiac cell culture
Takahiro Harada,Akihiro Isomura,Kenichi Yoshikawa
Physics , 2007, DOI: 10.1016/j.physd.2008.04.013
Abstract: Evolution of the spatial arrangement of cells in a primary culture of cardiac tissue derived from newborn rats was studied experimentally over extended period. It was found that cells attract each other spontaneously to form a clustered structure over the timescale of several days. These clusters exhibit spontaneous rhythmic contraction and have been confirmed to consist of cardiac muscle cells. Addition of a contraction inhibitor (2,3-butanedione-2-monoxime) to the culture medium resulted in the inhibition of both the spontaneous contractions exhibited by the cells as well as the formation of clusters. Furthermore, the formation of clusters is suppressed when high concentrations of collagen are used for coating the substratum to which the cells adhere. From these experimental observations, it was deduced that the cells are mechanically stressed by the tension associated with repeated contractions and that this results in the cells becoming compact and attracting each other, finally resulting in the formation of clusters. This process can be interpreted as modulation of a cellular network by the activity associated with contraction, which could be employed to control cellular networks by modifying the dynamics associated with the contractions in cardiac tissue culture.
Histological Characterization of Biliary Intraepithelial Neoplasia with respect to Pancreatic Intraepithelial Neoplasia
Yasunori Sato,Kenichi Harada,Motoko Sasaki,Yasuni Nakanuma
International Journal of Hepatology , 2014, DOI: 10.1155/2014/678260
Abstract: Biliary intraepithelial neoplasia (BilIN) is a precursor lesion of hilar/perihilar and extrahepatic cholangiocarcinoma. BilIN represents the process of multistep cholangiocarcinogenesis and is the biliary counterpart of pancreatic intraepithelial neoplasia (PanIN). This study was performed to clarify the histological characteristics of BilIN in relation to PanIN. Using paraffin-embedded tissue sections of surgically resected specimens of cholangiocarcinoma associated with BilIN and pancreatic ductal adenocarcinoma associated with PanIN, immunohistochemical staining was performed using primary antibodies against MUC1, MUC2, MUC5AC, cyclin D1, p21, p53, and S100P. For mucin staining, Alcian blue pH 2.5 was used. Most of the molecules examined here showed similar expression patterns in BilIN and PanIN, in which their expression tended to increase along with the increase in atypia of the epithelial lesions. Significant differences were observed in the increase in mucin production and the expression of S100P in PanIN-1 and the expression of p53 in PanIN-3, when compared with those in BilIN of a corresponding grade. These results suggest that cholangiocarcinoma and pancreatic ductal adenocarcinoma share, at least in part, a common carcinogenic process and further confirm that BilIN can be regarded as the biliary counterpart of PanIN. 1. Introduction Cholangiocarcinoma that arises under conditions of chronic biliary diseases such as hepatolithiasis often undergoes the multistep carcinogenesis process [1]. Biliary intraepithelial neoplasia (BilIN) is known as a premalignant lesion of cholangiocarcinoma that represents the multistep cholangiocarcinogenesis [2]. The classification is applicable to flat atypical epithelial lesions in the intrahepatic large bile ducts and the extrahepatic bile ducts, and it is also applied to lesions in the gallbladder according to the current World Health Organization (WHO) classification for tumors of the digestive system [3]. BilIN is a concept that is proposed based on the morphological resemblance to pancreatic intraepithelial neoplasia (PanIN). Similar to PanIN, BilIN is classified into three grades according to the degree of cytological and architectural atypia: BilIN-1 (low-grade lesions), BilIN-2 (intermediate-grade lesions), and BilIN-3 (high-grade lesions, carcinoma in situ). Using the BilIN classification, there is increasing evidence that molecular and genetic alterations accumulate during the progression of BilIN to cholangiocarcinoma [4–7]. Since the biliary tract and pancreas share a common developmental process as
Multistep carcinogenesis of perihilar cholangiocarcinoma arising in the intrahepatic large bile ducts
Yasuni Nakanuma, Motoko Sasaki, Yasunori Sato, Xiangshan Ren, Hiroko Ikeda, Kenichi Harada
World Journal of Hepatology , 2009,
Abstract: Flat-type “ biliary intraepithelial neoplasia (BilIN)” and papillary-type “ intraductal papillary neoplasm of the bile duct (IPN-B)” are proposed as precursors of invasive, perihilar intrahepatic cholangiocarcinoma (ICC). Three carcinogenetic pathways are proposed: BilIN progressing to tubular adenocarcinoma, and IPN-B progressing to tubular adenocarcinoma or to colloid carcinoma. Carcinogenesis via BilIN was characterized by mucin core protein 2-/cytokeratin 20-(MUC2-/CK20-) with MUC1 expression, while carcinogenesis via IPN-B leading to tubular adenocarcinoma was associated with MUC1 expression or that to colloid carcinoma with MUC1-negativity. In both the BilIN and IPNB series, the expression of p21, p53, and cyclin D1 was upregulated with histological progression. Interestingly, p53 expression was upregulated at the invasive stage of BilIN, but was low in noninvasive BilIN, while p53 expression was upregulated in IPN-B1 and reached a plateau in IPN-B2 and invasive ICC. Expression of p16 INK4a, which was frequent in BilIN1, was decreased in BilIN-2/3 and invasive carcinoma. EZH2 expression showed a stepwise increase from BilIN to invasive carcinoma. Membranous expression of β -catenin and E-cadherin was more markedly decreased in ICC with BilIN than in ICC with IPNB. Interestingly, disruption of the membranous distribution of β -catenin and E-cadherin seems to result in the invasion and metastasis of carcinoma cells of BilIN and IPN-B expressing MMP-7 and MT1-MMP. Increased expression of cyclin D1 and c-myc was more frequent in the IPNB lineage than BilIN lineage, possibly related to the Wnt signaling pathway associated with the nuclear accumulation of β -catenin. In conclusion, BilIN and IPN-B progress to invasive ICC through characteristic multistep processes.
Pathological classification of intrahepatic cholangiocarcinoma based on a new concept
Yasuni Nakanuma, Yasunori Sato, Kenichi Harada, Motoko Sasaki, Jing Xu, Hiroko Ikeda
World Journal of Hepatology , 2010,
Abstract: Intrahepatic cholangiocarcinoma (ICC) arises from the lining epithelium and peribiliary glands of the intrahepatic biliary tree and shows variable cholangiocytic differentiation. To date, ICC was largely classified into adenocarcinoma and rare variants. Herein, we propose to subclassify the former, based on recent progress in the study of ICC including the gross classification and hepatic progenitor/stem cells and on the pathological similarities between biliary and pancreatic neoplasms. That is, ICC is classifiable into the conventional (bile duct) type, the bile ductular type, the intraductal neoplasm type and rare variants. The conventional type is further divided into the small duct type (peripheral type) and large bile duct type (perihilar type). The former is a tubular or micropapillary adenocarcinoma while the latter involves the intrahepatic large bile duct. Bile ductular type resembles proliferated bile ductules and shows a replacing growth of the hepatic parenchyma. Hepatic progenitor cell or stem cell phenotypes such as neural cell adhesion molecule expression are frequently expressed in the bile ductular type. Intraductal type includes papillary and tubular neoplasms of the bile duct (IPNBs and ITNBs) and a superficial spreading type. IPNB and ITNB show a spectrum from a preneoplastic borderline lesion to carcinoma and may have pancreatic counterparts. At invasive sites, IPNB is associated with the conventional bile duct ICC and mucinous carcinoma. Biliary mucinous cystic neoplasm with ovarian-like stroma in its wall is different from IPNB, particularly IPNB showing cystic dilatation of the affected ducts. Rare variants of ICC include squamous/adenosquamous cell carcinoma, mucinous/signet ring cell carcinoma, clear cell type, undifferentiated type, neuroendocrine carcinoma and so on. This classification of ICC may open up a new field of research of ICC and contribute to the clinical approach to ICC.
Intraductal papillary neoplasm of the bile duct in liver cirrhosis with hepatocellular carcinoma
Jing Xu, Yasunori Sato, Kenichi Harada, NorihideYoneda, Teruyuki Ueda, Atsushi Kawashima, AkishiOoi, YasuniNakanuma
World Journal of Gastroenterology , 2011,
Abstract: A case of intraductal papillary neoplasm of the bile duct (IPNB) arising in a patient with hepatitis B-related liver cirrhosis with hepatocellular carcinoma (HCC) is reported. A 76-year-old man was admitted to our hospital with recurrent HCC. Laboratory data showed that levels of carcinoembryonic antigen and carbohydrate antigen 19-9 were elevated. He died of progressive hepatic failure. At autopsy, in addition to HCCs, an intraductal papillary proliferation of malignant cholangiocytes with fibrovascular cores was found in the dilated large bile ducts in the left lobe, and this papillary carcinoma was associated with an invasive mucinous carcinoma (invasive IPNB). Interestingly, extensive intraductal spread of the cholangiocarcinoma was found from the reactive bile ductular level to the interlobular bile ducts and septal bile ducts and to the large bile ducts in the left lobe. Neural cell adhesion molecule, a hepatic progenitor cell marker, was detected in IPNB cells. It seems possible in this case that hepatic progenitor cells located in reactive bile ductules in liver cirrhosis may have been responsible for the development of the cholangiocarcinoma and HCC, and that the former could have spread in the intrahepatic bile ducts and eventually formed grossly visible IPNB.
Activation of the PI3K/mTOR Pathway Is Involved in Cystic Proliferation of Cholangiocytes of the PCK Rat
Xiang Shan Ren, Yasunori Sato, Kenichi Harada, Motoko Sasaki, Shinichi Furubo, Jing Yu Song, Yasuni Nakanuma
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0087660
Abstract: The polycystic kidney (PCK) rat is an animal model of Caroli’s disease as well as autosomal recessive polycystic kidney disease (ARPKD). The signaling pathways involving the mammalian target of rapamycin (mTOR) are aberrantly activated in ARPKD. This study investigated the effects of inhibitors for the cell signaling pathways including mTOR on cholangiocyte proliferation of the PCK rat. Cultured PCK cholangiocytes were treated with rapamycin and everolimus [inhibitors of mTOR complex 1 (mTOC1)], LY294002 [an inhibitor of phosphatidylinositol 3-kinase (PI3K)] and NVP-BEZ235 (an inhibitor of PI3K and mTORC1/2), and the cell proliferative activity was determined in relation to autophagy and apoptosis. The expression of phosphorylated (p)-mTOR, p-Akt, and PI3K was increased in PCK cholangiocytes compared to normal cholangiocytes. All inhibitors significantly inhibited the cell proliferative activity of PCK cholangiocytes, where NVP-BEZ235 had the most prominent effect. NVP-BEZ235, but not rapamycin and everolimus, further inhibited biliary cyst formation in the three-dimensional cell culture system. Rapamycin and everolimus induced apoptosis in PCK cholangiocytes, whereas NVP-BEZ235 inhibited cholangiocyte apoptosis. Notably, the autophagic response was significantly induced following the treatment with NVP-BEZ235, but not rapamycin and everolimus. Inhibition of autophagy using siRNA against protein-light chain3 and 3-methyladenine significantly increased the cell proliferative activity of PCK cholangiocytes treated with NVP-BEZ235. In vivo, treatment of the PCK rat with NVP-BEZ235 attenuated cystic dilatation of the intrahepatic bile ducts, whereas renal cyst development was unaffected. These results suggest that the aberrant activation of the PI3K/mTOR pathway is involved in cystic proliferation of cholangiocytes of the PCK rat, and inhibition of the pathway can reduce cholangiocyte proliferation via the mechanism involving apoptosis and/or autophagy.
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