Search

Background: Co‐occurrence of metabolic syndrome and chronic alcohol consumption is increasing worldwide. The present study investigated the effect of the chemical chaperone 4‐phenylbutyric acid (PBA)—which has been shown to alleviate dietary steatohepatitis caused by endoplasmic reticulum (ER) stress—on chronic‐plus‐binge ethanol (EtOH)–induced liver injury in a mouse model of obesity. Methods: Male KK‐Ay mice (8 weeks old) were fed a Lieber–DeCarli diet (5% EtOH) for 10 days. Some mice were given PBA intraperitoneally (120 mg/kg body weight, daily) during the experimental period. On day 11, mice were gavaged with a single dose of EtOH (4 g/kg body weight). Control mice were given a dextrin gavage after being pair‐fed a control diet. All mice were then serially euthanized before or at 9 hours after gavage. Results: Chronic‐plus‐binge EtOH intake induced massive hepatic steatosis along with hepatocyte apoptosis and inflammation, which was reversed by PBA treatment. Administration of PBA also suppressed chronic‐plus‐binge EtOH–induced up‐regulation of ER stress‐related genes including binding immunoglobulin protein (Bip), unspliced and spliced forms of X‐box‐binding protein‐1 (uXBP1 and sXBP1, respectively), inositol trisphosphate receptor (IP3R), and C/EBP homologous protein (CHOP). Further, it blocked chronic‐plus‐binge EtOH–induced expression of the oxidative stress marker heme oxygenase‐1 (HO‐1) and 4‐hydroxynonenal. Chronic EtOH alone (without binge) increased Bip and uXBP1, but it did not affect those of sXBP1, IP3R, CHOP, or HO‐1. PBA reversed the prebinge expression of these genes to control levels, but it did not affect chronic EtOH‐induced hepatic activity of cytochrome P450 2E1. Conclusions: Binge EtOH intake after chronic consumption induces massive ER stress‐related oxidative stress and liver injury in a mouse model of obesity through dysregulation of the unfolded protein response. PBA ameliorated chronic‐plus‐binge EtOH–induced liver injury by reducing ER and oxidative stress after an EtOH binge. Chronic‐plus‐binge ethanol (EtOH) feeding induced severe hepatic steatosis with hepatocyte apoptosis in obese KK‐Ay mice through dysregulation of the unfolded protein response. The treatment with 4‐phenylbutyrate (PBA) ameliorated chronic‐plus‐binge EtOH‐induced liver injury by reducing ER and oxidative stress after an EtOH binge (A: immunohistological staining for ccCK18, scale bar = 100 μm, B‐D: RT‐PCR for sXBP1, CHOP, or HO‐1). The components of ER stress pathway are potential therapeutic targets for the management and prevention of alcoholic liver disease. [ABSTRACT FROM AUTHOR]

Aim: Hepatic inclusion composed of autophagy‐specific substrate p62 is one of the histological features of non‐alcoholic fatty liver disease (NAFLD) and can be a precursor to hepatic carcinogenesis. The expression of p62 was enhanced by not only autophagic dysfunction but also oxidative stress and inflammation. M1/M2 phenotypic balance of macrophages plays a pivotal role in the progression of NAFLD. We evaluated the correlation between macrophage polarization and the formation of p62 aggregation in NAFLD. Methods: Liver biopsy specimens from NAFLD patients were analyzed by immunohistochemical staining for M1 macrophage marker CD11c, M2 macrophage marker CD163, and p62/SQSTM1 (p62). The histological severity of NAFLD is assessed by a NAFLD activity score (NAS). The number of autophagic vesicles in hepatocytes was visualized and counted by using transmission electron microscopy. Results: The aggregation of p62 was undetectable in control, whereas hepatocytes with p62 aggregation were observed in approximately 88% of NAFLD specimens. The number of hepatocytes with p62 aggregation was positively correlated with the number of autophagic vesicles, serum alanine aminotransferase, NAS, fibrosis, and the number of CD11c‐positive cells, but not CD163‐positive cells. Assembly of CD11c‐positive cells was observed around hepatocytes with p62 aggregation. The ratio of CD11c/CD163‐positive macrophages was significantly associated with the formation of p62 aggregation. Conclusions: These findings indicate that chronic inflammation by M1‐polarization of macrophages contributes to the disease progression from simple steatosis to non‐alcoholic steatohepatitis in concert with autophagic dysfunction. [ABSTRACT FROM AUTHOR]

Aim Pharmacological treatment for metabolic syndrome-related non-alcoholic steatohepatitis has not been established. We investigated the effect of L-carnitine, an essential substance for β-oxidation, on metabolic steatohepatitis in mice. Methods Male KK-Ay mice were fed a high-fat diet (HFD) for 8 weeks, with supplementation of L-carnitine (1.25 mg/mL) in drinking water for the latter 4 weeks. Results Serum total carnitine levels were decreased following HFD feeding, whereas the levels were reversed almost completely by L-carnitine supplementation. In mice given L-carnitine, exacerbation of hepatic steatosis and hepatocyte apoptosis was markedly prevented even though HFD feeding was continued. Body weight gain, as well as hyperlipidemia, hyperglycemia, and hyperinsulinemia, following HFD feeding were also significantly prevented in mice given L-carnitine. High-fat diet feeding elevated hepatic expression levels of carnitine palmitoyltransferase 1A mRNA; however, production of β-hydroxybutyrate in the liver was not affected by HFD alone. In contrast, L-carnitine treatment significantly increased hepatic β-hydroxybutyrate contents in HFD-fed mice. L-carnitine also blunted HFD induction in sterol regulatory element binding protein-1c mRNA in the liver. Furthermore, L-carnitine inhibited HFD-induced serine phosphorylation of insulin receptor substrate-1 in the liver. L-carnitine decreased hepatic free fatty acid content in 1 week, with morphological improvement of swollen mitochondria in hepatocytes, and increases in hepatic adenosine 5'-triphosphate content. Conclusions L-carnitine ameliorates steatohepatitis in KK-Ay mice fed an HFD, most likely through facilitating mitochondrial β-oxidation, normalizing insulin signals, and inhibiting de novo lipogenesis in the liver. It is therefore postulated that supplementation of L-carnitine is a promising approach for prevention and treatment of metabolic syndrome-related non-alcoholic steatohepatitis. [ABSTRACT FROM AUTHOR]

Aim Recent evidences indicate that hepatic steatosis suppresses autophagic proteolysis. The present study evaluated the correlation between autophagic function and cathepsin expression in the liver from patients with non-alcoholic fatty liver disease ( NAFLD). Methods Liver biopsy specimens were obtained from patients with chronic liver diseases (chronic hepatitis C [ CHC; n = 20], chronic hepatitis B [ CHB; n = 16], primary biliary cirrhosis [ PBC; n = 23], NAFLD [ n = 22] and control [ n = 14]). The number of autophagic vesicles in hepatocytes was counted by using transmission electron microscopy. Expression of cathepsin B, D, L and p62 in the liver section was analyzed by immunohistochemical staining. The histological severity of NAFLD is assessed by NAFLD activity score ( NAS). Results The number of autophagic vesicles in hepatocytes was significantly increased in both CHC and NAFLD groups, but not CHB and PBC, more than control. Although hepatocytes with aggregation of p62 were observed in less than 15% of CHC, p62 aggregation was detected in approximately 65% of NAFLD. Cathepsin B, D and L expression was significantly suppressed in the liver from NAFLD patients. Suppression of cathepsin B, D and L expression was not observed in CHB, CHC and PBC. In NAFLD patients, p62 aggregation was correlated with serum alanine aminotransferase value and inflammatory activity by NAS. Conclusion These results indicate that a decrease in hepatic cathepsin expression in NAFLD is associated with autophagic dysfunction. Hepatic inflammation correlates with autophagic dysfunction in NAFLD. These findings indicate that the suppression of autophagic proteolysis by hepatic steatosis is involved in the pathogenesis of NAFLD. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the role of natural killer (NK)T cells in the pathogenesis of non-alcoholic steatohepatitis (NASH), here we investigated the expression and function of hepatic NKT cells in KK-Ay mice, an animal model of metabolic syndrome. Methods: Male, 8-week-old KK-Ay and C57Bl/6 mice were fed a high-fat (HF) diet for 4 weeks. Some mice were given daily intragastric injections of pioglitazone for 5 days prior to or after dietary treatment. Results: In untreated KK-Ay mice, the percentages of NKT cells in liver mononucleolar cells were nearly one-third of those in C57Bl/6 controls. Elevations in interleukin (IL)-4 and interferon (IFN)-γ mRNA in the liver after a single injection of α-galactosylceramide (GalCer) were blunted in KK-Ay mice largely. Percentages of NKT cells, as well as GalCer-induced increases in IL-4 mRNA, were blunted significantly in both strains after HF diet feeding for 4 weeks. Interestingly, KK-Ay mice pretreated with pioglitazone showed significant increases in NKT cell proportion, and GalCer-induced increases in IL-4 and IFN-γ mRNA were also enhanced by pioglitazone. In KK-Ay mice, the percentages of annexin V positive NKT cells were nearly 2.5-fold higher than those in C57Bl/6 controls; however, pioglitazone decreased annexin V positive cells significantly. Moreover, pioglitazone increased NKT cell fraction in KK-Ay mice even after HF diet feeding. Conclusion: KK-Ay mice exhibit proportional and functional alterations in hepatic NKT cells in close relation with the development of steatohepatitis, and it is postulated that pioglitazone improves steatohepatitis in part through restoration of hepatic NKT cells. [ABSTRACT FROM AUTHOR]

In the ubiquitous computing environment, the physical locations of persons and goods are extremely important information. In this paper, the design of a fully distributed localization system based on ultrasound, mainly for the indoor environment, is described. This system performs localization with as few positioning references as possible by an iterative technique. When such a localization method is used, deterioration of localization accuracy due to no-line-of-sight signals and to accumulated errors is a problem. In this paper, the resolution of these problems is discussed and system evaluation by implementation experiments is carried out. With 24 devices, localization with an accuracy of about 20 cm is demonstrated. © 2007 Wiley Periodicals, Inc. Electron Comm Jpn Pt 3, 90(6): 17– 26, 2007; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/ecjc.20249 [ABSTRACT FROM AUTHOR]

It has been speculated that the use of hydroxy-methyl-glutaryl coenzyme A reductase inhibitors (statins) is associated with the risk of malignant diseases. Considering their immunosuppressive activities, malignant diseases that are associated with an immunosuppressive status seem feasible to examine the association. We therefore examined the association between statin use and development of lymphoid malignancies in a case-control study. Cases were 221 consecutive incident cases with histopathologically proven lymphoid malignancies (lymphoma and myeloma), hospitalized in the Department of Hematology of Toranomon Hospital (Tokyo, Japan) between 1995 and 2001. Two independent control groups, comprising 442 and 437 inpatients without malignancies from the Departments of Orthopedics and Otorhinolaryngology of the same hospital, were selected to test for consistency of association. Controls were matched individually with cases for age, sex and year of admission. Subject information, including statin use, was abstracted from medical records at the time of hospitalization. Strength of association was evaluated as an adjusted odds ratios (aOR) using a conditional logistic regression model. A higher frequency of statin use was found among patients with lymphoid malignancies in comparison with both orthopedic (aOR 2.11, 95% CI 1.20–3.69, P = 0.009) and otorhinolaryngology patients (aOR 2.59, 95% CI 1.45–4.65, P = 0.001), the significance being maintained when the two control groups were combined (aOR 2.24, 95% CI 1.37–3.66, P = 0.001). In conclusion, we observed an elevated risk of lymphoid malignancy with statin use among Japanese patients. Further evaluations in different populations are required to draw conclusions as to the carcinogenicity of lymphoid malignancies with statin use. ( Cancer Sci 2006; 97: 133 –138) [ABSTRACT FROM AUTHOR]

In multicast delivery in a network environment with various bandwidth limitations, it is effective to apply the layered multicast technique, which realizes delivery at a reception rate matched to each receiver, although the rate is set discretely. This paper assumes a multimedia session such as a multichannel broadcast or a video conference, composed of multiple streams. In such an application, it is desirable from the viewpoint of efficient use of bandwidth that not only should the streams be transmitted with stable quality, but that the rate should be assigned according to requests, such as attention to the speaker. However, it is difficult to achieve the above goal by directly applying the conventional layered multicast rate control technique, since each stream controls the rate independently. From such a viewpoint, this paper presents a session level mechanism covering multiple layered streams. A multiple streams controller (MSC) is introduced into each receiver, and each MSC autonomously controls the reception rate with interstream coordination in the session. The MSC monitors the reception state of the multiple streams simultaneously and estimates the bandwidth information on the bottleneck link and the set of transiting streams, based on the detected congestion data. Based on the estimation, the learning efficiency of the reception rate is improved and rate assignment control over the streams is applied. An evaluation is performed by computer simulation, and it is shown that the reception quality of the stream is improved by applying the proposed method, and that the reception rate can be coordinated among the streams. © 2005 Wiley Periodicals, Inc. Electron Comm Jpn Pt 1, 88(8): 18–31, 2005; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/ecja.20142 [ABSTRACT FROM AUTHOR]

This paper considers the ubiquitous environment, in which a tremendous number of objects, such as physical devices, multimedia contents, and software components, exist everywhere. In order to provide and utilize various services transparently in such an environment, there must be a service synthesis technique that can dynamically construct services by mutually connecting objects. The realization of service synthesis requires a position-independent naming service which can securely and transparently call from the network the functions (functional objects) that act as the service component. The authors designed an interface-based naming service which can perform transparent calling of functional objects on the basis of interface information on the objects. The interface-based naming service not only can call functional objects efficiently from the network, but also can provide several useful features of service synthesis support: when two functional objects are interconnected, the required supplementary functional object is automatically determined, and when a function cannot be found, that function is realized equivalently by using multiple functional objects. This paper describes the architecture of the interface-based naming service, together with its algorithm. The approach is evaluated by simulation and it is shown that the interface-based naming service is a useful system in a ubiquitous environment with an increased number of objects and an enlarged network scale. © 2004 Wiley Periodicals, Inc. Electron Comm Jpn Pt 1, 88(3): 63–75, 2005; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/ecja.10177 [ABSTRACT FROM AUTHOR]

In this paper, we present a detailed description of the Reliable Multicast using Adaptive Caching (RMAC) system and protocol, and describe its performance evaluation. From the idea that support based on functional processing in the network is essential to efficiently perform reliable multicast, routers that process the RMAC protocol are introduced by RMAC. RMAC can improve retransmission efficiency by packet caching and retransmission at the routers. The required cache size can be decreased by distributing the caching among the routers to adapt to the congestion. The performance evaluation by a simulation showed that RMAC has lower recovery latency compared to conventional techniques and improved scalability with respect to the number of receivers. © 2003 Wiley Periodicals, Inc. Electron Comm Jpn Pt 1, 86(10): 89–99, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/ecja.1179 [ABSTRACT FROM AUTHOR]

Recently, with advances in differential GPS (DGPS) technology, the measurement performance of GPS has improved significantly. In this environment, degradation of the measurement performance of GPS due to multipath error that cannot be eliminated by the DGPS technique is a serious problem. In this paper, as a multipath solution in GPS, multipath estimation is carried out with an adaptive filter based on the least squares method. A method is presented to reduce the locking error in code phase locking and carrier phase locking by eliminating the multipath effect from the received signal correlation. Also, by means of computer simulation, the effectiveness of the present method is confirmed. © 2002 Wiley Periodicals, Inc. Electron Comm Jpn Pt 1, 86(1): 74–82, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/ecja.1148 [ABSTRACT FROM AUTHOR]

The article discusses the case of a 72 year old woman with JAK2V617F mutation-positive essential thrombocythemia (ET) presented at the Juntendo University Hospital, Tokyo, Japan. She was hospitalized for acute hepatitis due to HBV reactivation and entecavir was administered at a dose of 0.5mg/day . It recommends close monitoring of HBV-DNA levels in patients with positive HBsAG, HBsAB or HBcAb status as hydroxyurea could induce reactivation of HBV.

Acetaminophen overdose causes liver injury by mechanisms involving glutathione depletion, oxidative stress and mitochondrial dysfunction. The role of apoptosis in acetaminophen-induced cell killing is still controversial. Here, our aim was to evaluate the mitochondrial permeability transition (MPT) as a key factor in acetaminophen-induced necrotic and apoptotic killing of primary cultured mouse hepatocytes. Acetaminophen (10 μmol/L) induced necrotic killing in approximately 50% of hepatocytes after 6 h and cyclosporin A (CsA), MPT inhibitor, temporarily decreased necrotic killing after 6 h, but cytoprotection was lost after 16 h. Confocal microscopy revealed mitochondrial depolarization and inner membrane permeabilization at approximately 4.5 h after acetaminophen. CsA delayed these changes indicative of the MPT to about 11 h after acetaminophen. TUNEL labeling and caspase 3 activation also increased after acetaminophen. Fructose (20 mmol/L, an ATP-generating glycolytic substrate) plus glycine (5 mmol/L, a membrane stabilizing amino acid) prevented nearly all necrotic cell killing but paradoxically increased apoptosis. In conclusion, acetaminophen induces the MPT and ATP-depletion-dependent necrosis or caspase-dependent apoptosis as determined, in part, by ATP availability from glycolysis. [ABSTRACT FROM AUTHOR]

Background: Co-occurrence of metabolic syndrome and chronic alcohol consumption is increasing worldwide. The present study investigated the effect of the chemical chaperone 4-phenylbutyric acid (PBA)-which has been shown to alleviate dietary steatohepatitis caused by endoplasmic reticulum (ER) stress-on chronic-plus-binge ethanol (EtOH)-induced liver injury in a mouse model of obesity., Methods: Male KK-A y mice (8 weeks old) were fed a Lieber-DeCarli diet (5% EtOH) for 10 days. Some mice were given PBA intraperitoneally (120 mg/kg body weight, daily) during the experimental period. On day 11, mice were gavaged with a single dose of EtOH (4 g/kg body weight). Control mice were given a dextrin gavage after being pair-fed a control diet. All mice were then serially euthanized before or at 9 hours after gavage., Results: Chronic-plus-binge EtOH intake induced massive hepatic steatosis along with hepatocyte apoptosis and inflammation, which was reversed by PBA treatment. Administration of PBA also suppressed chronic-plus-binge EtOH-induced up-regulation of ER stress-related genes including binding immunoglobulin protein (Bip), unspliced and spliced forms of X-box-binding protein-1 (uXBP1 and sXBP1, respectively), inositol trisphosphate receptor (IP3R), and C/EBP homologous protein (CHOP). Further, it blocked chronic-plus-binge EtOH-induced expression of the oxidative stress marker heme oxygenase-1 (HO-1) and 4-hydroxynonenal. Chronic EtOH alone (without binge) increased Bip and uXBP1, but it did not affect those of sXBP1, IP3R, CHOP, or HO-1. PBA reversed the prebinge expression of these genes to control levels, but it did not affect chronic EtOH-induced hepatic activity of cytochrome P450 2E1., Conclusions: Binge EtOH intake after chronic consumption induces massive ER stress-related oxidative stress and liver injury in a mouse model of obesity through dysregulation of the unfolded protein response. PBA ameliorated chronic-plus-binge EtOH-induced liver injury by reducing ER and oxidative stress after an EtOH binge., (© 2019 by the Research Society on Alcoholism.)