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Biomedical subjects

Kazuhiko Koike

Publications and source records attributed to Kazuhiko Koike.

At least 37 records · Page 2Linked to original sources
PubMed2005

Hepatitis C as a metabolic disease: Implication for the pathogenesis of NASH.

In addition to the link with development of hepatocellular carcinoma (HCC), hepatitis C virus (HCV) infection is associated with several extrahepatic manifestations such as essential mixed cryoglobulinemia, porphyria cutanea tarda or Sjögren's syndrome. A role of hepatic steatosis in the pathogenesis of chronic hepatitis C has also been known, implying hepatitis C as a metabolic disease. In addition, recent epidemiological studies have suggested a linkage between type 2 diabetes and chronic HCV infection. However, the presence of additional factors in patients, such as obesity, aging or cirrhosis, prevents the establishment of a definite relationship between HCV infection and these two conditions, lipid metabolism disturbance and diabetes. In addition to the data indicating the presence of dyslipidemia and diabetes or insulin resistance in our cohort of chronic hepatitis C patients, we found a series of evidence showing the association between the conditions and HCV infection in mouse models that are transgenic for the HCV genes. In patients with chronic hepatitis C, a significant decrease in the serum levels of total cholesterol and apolipoproteins C2 and C3 was observed compared to those with chronic hepatitis B that were comparable in liver function. In an animal model, C18:1 mono-unsaturated fatty acids were significantly increased in the liver from HCV core gene transgenic mice, which was similarly observed in the liver from human hepatitis C patients. Thus, a disturbance in lipid metabolism was observed in both humans and an HCV mouse model, supporting that it is a specific event in HCV infection. A significant increase in the value of an indicator for homeostasis model assessment of insulin resistance (HOMA-IR), was observed in patients with chronic hepatitis C, even at the very early stage of chronic hepatitis. In the animal model, a marked insulin resistance was exhibited from a very young age in HCV core gene transgenic mice. Insulin resistance observed in the core gene transgenic mice was chiefly due to the shortage of insulin action on the suppression of glucose production in the liver. Thus, the ability of insulin to lower the plasma glucose level in the HCV transgenic mice was impaired, as observed in chronic hepatitis C patients. These results provide a direct experimental evidence for the contribution of HCV in the development of insulin resistance in human HCV infection, which finally leads to the development of type 2 diabetes. Insulin resistance may be a critical factor in the pathogenesis of chronic hepatitis C as recently suggested in non-alcoholic steatohepatitis (NASH), along with impairment in lipid metabolism. Our results would provide a clue for further understanding of pathobiology of HCV infection, and may provide an implication for the pathogenesis of NASH.

Journal Article↗
PubMed2005

Cellular and subcellular localization of kainic acid in the marine red alga Digenea simplex.

Polyclonal antibodies specific for the excitatory amino acid, kainic acid (KA), were raised in rabbits. The antibody recognized KA but did not cross-react with other structurally related amino acids, including glutamate. We used this anti-KA antibody to localize KA immunohistochemically in the KA-producing red alga Digenea simplex. KA immunoreactivity was most dense in the fine cylindrical thallus, which covers the middle to upper part of the alga. The cortical cells, but not the inner layers of the main axis, and cells of the rhizoid were also stained with this antibody. The presence of KA in cells that cover the surface of the alga might reflect its role in chemical defense. At the subcellular level, KA immunoreactivity was most intense in the nucleus, pit plugs, and the electron-dense areas denoted as "granule bodies", which were found only in the pericentral cells of the thallus.

Immunohistochemistry↗
PubMed2005

Hepatitis C virus core protein exerts an inhibitory effect on suppressor of cytokine signaling (SOCS)-1 gene expression.

BACKGROUND/AIMS: Suppressor of cytokine signaling (SOCS)-1, a negative feedback regulator of cytokine signaling pathway, also has a tumor suppressor activity, the silencing of its gene by hypermethylation is suggested to contribute to hepatocarcinogenesis. We studied the effect of the core protein of hepatitis C virus (HCV) on the expression of SOCS-1 gene. METHODS: HCV core gene transgenic mice, which develop hepatocellular carcinoma late in life, HepG2 cells expressing the core protein, and human liver tissues were analyzed. RESULTS: The expression of SOCS-1 gene was significantly suppressed in the liver of core gene transgenic mice and HepG2 cells expressing the core protein, while that of SOCS-3 gene was conserved. SOCS-1 expression levels also decreased in HCV-positive human liver tissues. The core protein differentially down-regulated the expression of signal transducer and activator of transcription (STAT) target genes, but rather enhanced STAT1 and STAT3 activation after interleukin-6 stimulation in mouse liver tissues and cells. CONCLUSIONS: HCV core protein down-regulates the expression of SOCS-1 gene. This is a mechanism leading to SOCS-1 silencing, an alternative to the hypermethylation of the gene; this effect of the core protein may modulate the intracellular signaling pathway, contributing to the pathogenesis in HCV infection including hepatocarcinogenesis.

Animals↗
PubMed2005

Cloning and characterization of a lectin from the octocoral Sinularia lochmodes.

In the present study, the entire amino acid sequence and cDNA structure encoding the d-galactose-binding lectin, SLL-2, isolated from the octocoral Sinularia lochmodes, were determined. SLL-2 regulates the morphology of symbiotic dinoflagellates Symbiodinium spp. through unknown mechanisms. Here, three cDNAs that encode SLL-2 were cloned and characterized. All the SLL-2 cDNAs encoded 142 amino acids with high similarity to each other. The mature subunit of SLL-2 was found to be composed of 94 amino acids and to contain one putative glycosylation site common to all three SLL-2. N-Glycopeptidase F treatment of SLL-2 resulted in a protein band shift from 16.5 to 9.5kDa in SDS-PAGE, confirming that SLL-2s are glycoproteins. Two-dimensional polyacrylamide gel electrophoresis analysis of the deglycosylated SLL-2 indicated a presence of three polypeptides as encoded in SLL-2 cDNAs. The deduced sequences of SLL-2 cDNAs had a similarity to the C-terminal region of discoidin I, the slime mold Dictyostelium discoideum lectin.

Amino Acid Sequence↗
PubMed2005

Development of molecular probes for dinophysis (dinophyceae) plastid: a tool to predict blooming and explore plastid origin.

Dinophysis are species of dinoflagellates that cause diarrhetic shellfish poisoning. We have previously reported that they probably acquire plastids from cryptophytes in the environment, after which they bloom. Thus monitoring the intracellular plastid density in Dinophysis and the source cryptophytes occurring in the field should allow prediction of Dinophysis blooming. In this study the nucleotide sequences of the plastid-encoded small subunit ribosomal RNA gene and rbcL (encoding the large subunit of RuBisCO) from Dinophysis spp. were compared with those of cryptophytes, and genetic probes specific for the Dinophysis plastid were designed. Fluorescent in situ hybridization (FISH) showed that the probes bound specifically to Dinophysis plastids. Also, FISH on collected nanoplankton showed the presence of probe-hybridized eukaryotes, possibly cryptophytes with plastids identical to those of Dinophysis. These probes are useful not only as markers for plastid density and activity of Dinophysis, but also as tools for monitoring cryptophytes that may be sources of Dinophysis plastids.

Animals↗
PubMed2005

Metabolic aspects of hepatitis C viral infection: steatohepatitis resembling but distinct from NASH.

Although the target of hepatitis C virus (HCV) infection is the liver, it has become progressively more evident that HCV can induce diseases in numerous organs. Recently, much attention has been drawn to metabolic disorders in HCV infection. Initially, hepatic steatosis and disturbances in lipid metabolism were found to be characteristic of HCV infection, and, subsequently, a correlation was noted between HCV infection and diabetes. It is now evident that HCV, by itself, can induce insulin resistance by way of disturbing the intracellular signaling pathway of insulin by the function of HCV core protein. Insulin resistance, caused by HCV infection, evolves to type 2 diabetes when superimposed on a high-fat diet and obesity. The fact that HCV infection induces insulin resistance by the virus itself may influence the progression of chronic hepatitis and open up novel therapeutic approaches. When hepatitis C is compared with nonalcoholic steatohepatitis (NASH), there are a number of similarities and several differences. From the metabolic aspect, hepatitis C resembles NASH in numerous features, such as the presence of steatosis, serum dyslipidemia, and oxidative stress in the liver, suggesting that hepatitis C is a steatohepatitis. In contrast, there are noticeable differences between hepatitis C and NASH, in that HCV modulates cellular gene expression and intracellular signal transduction, including the activation of mitogen-activated protein (MAP) kinase and transcription factor activator protein (AP)-1, while such details have not been noted for NASH. This difference may explain the markedly higher incidence of HCC development in chronic hepatitis C compared with that in NASH. HCV infection needs to be viewed not only as a liver disease but also as a metabolic disease, and this viewpoint could open up a novel way to the molecular understanding of the pathogenesis of hepatitis C, as a virus-associated steatohepatitis (VASH).

Animals↗
PubMed2005

A novel type of kleptoplastidy in Dinophysis (Dinophyceae): presence of haptophyte-type plastid in Dinophysis mitra.

Red-fluorescent, non-phycobilin-containing plastids were found in the heterotrophic dinoflagellate, Dinophysis mitra. Transmission electron microscopy showed that they contained a three-layer thylakoid, the absence of girdle lamella, and an embedded pyrenoid with thylakoid intrusions. These characteristics all coincide with haptophyte plastids. Phylogenetic analysis of the plastid small-subunit ribosomal DNA (SSU rDNA) revealed that the Dinophysis mitra sequences are distantly related to those of phycobilin-containing Dinophysis species and are positioned within a lineage of haptophytes belonging to Prymnesiophyceae. Because the plastid SSU rDNA sequences of Dinophysis mitra showed significant heterogeneity, despite being derived from a single species, it is highly likely that they were not established as plastids through an evolutionary process but are "kleptoplastids" (temporally stolen plastids) from multiple sources of haptophytes in the environment. We deduced that Dinophysis mitra takes up haptophytes myzocytotically and selectively retains the plastid with surrounding plastidal membranes, whereas other haptophyte cell components are degraded. This represents another type of kleptoplastidy in the Dinophysis species, which mostly harbor cryptophyte plastids, and is the first evidence of kleptoplastidy originating from haptophytes.

Animals↗
PubMed2005

Molecular basis of hepatitis C virus-associated hepatocarcinogenesis: lessons from animal model studies.

Despite numerous lines of epidemiologic evidence connecting HCV infection and the development of hepatocellular carcinoma (HCC), it remains controversial whether HCV itself plays a direct role or an indirect role in the pathogenesis of HCC. Through the use of transgenic mice, it has become evident that the core protein of HCV has oncogenic potential. HCV is directly involved in hepatocarcinogenesis, albeit other factors such as inflammation and environmental factors might also play a role. The direct involvement of HCV in hepatocarcinogenesis would be achieved via 2 pathways. In one pathway, the core protein acts on the function of mitochondria, leading to the overproduction of oxidative stress, which yields genetic aberrations in cell growth-related genes. The other pathway involves the modulation of cellular gene expressions and intracellular signal transductions, such as mitogen-activated protein kinase pathway, which results in the activation of transcription factors and cell cycle machineries. The combination of these alterations would be hypothesized to provoke the development of HCC in HCV infection. This would be a mechanism for HCC development in HCV infection that is distinct from those for other cancers. The presence of the HCV core protein, to which an oncogenic potential is ascribed, might allow some of the multiple steps to be bypassed in hepatocarcinogenesis. Therefore, unlike in other cancers, HCV infection can elicit HCC in the absence of a complete set of genetic aberrations. Such a scenario, "non-Vogelstein type" carcinogenesis, may explain the unusually high incidence and multicentric nature of HCC development in HCV infection.

Animals↗
PubMed2005

Development and evaluation of a loop-mediated isothermal amplification assay for rapid detection of Mycoplasma pneumoniae.

A loop-mediated isothermal amplification (LAMP) assay for the rapid detection of Mycoplasma pneumoniae was developed and evaluated. The assay specifically amplified only M. pneumoniae sequences, and no cross-reactivity was observed for other Mycoplasma species or respiratory bacterial species. The detection limit for this assay was found to be 2 x 10(2) copies, corresponding to 2-20 colour changing units of M. pneumoniae in 1 h, as observed in a real-time turbidimeter and electrophoretic analysis. The accuracy of the LAMP reaction was confirmed by restriction endonuclease analysis as well as direct sequencing of the amplified product. The assay was applied to 95 nasopharyngeal swab samples collected from patients or from healthy individuals, and compared to a real-time PCR assay in-house. A concordance of 100% was observed between the two assays. The LAMP assay is easy to perform, shows a rapid reaction and is inexpensive. It may therefore be applied in the routine diagnosis of M. pneumoniae infection in the clinical laboratory.

Adolescent↗
PubMed2005

Persisting humoral antiviral immunity within the Japanese population after the discontinuation in 1976 of routine smallpox vaccinations.

Concerns have arisen recently about the possible use of smallpox for a bioterrorism attack. Routine smallpox vaccination was discontinued in Japan in 1976; however, it is uncertain exactly how long vaccination-induced immunity lasts. We sought to evaluate the seroprevalence and intensity of anti-smallpox immunity among representatives of the present Japanese population. The subjects included 876 individuals who were born between 1937 and 1982. Vaccinia virus-specific immunoglobulin G (IgG) levels were measured by enzyme-linked immunosorbent assay (ELISA), and 152 of 876 samples were also tested for the presence of neutralizing antibodies. Of the subjects who were born before 1962, between 1962 and 1968, and between 1969 and 1975, 98.6, 98.6, and 66.0%, respectively, still retained the vaccinia virus-specific IgG with ELISA values for optical density at 405 nm (OD(405)) of > or = 0.10. The corresponding figures for retained IgGs with OD405 values of > or = 0.30 were 91.0, 90.3, and 58.2%, respectively. Neutralizing antibodies were also maintained. The sera with OD(405) values of > or = 0.30 showed 89% sensitivity and a 93% positive predictive value for detection of neutralizing antibodies (> or = 4). Thus, approximately 80% of persons born before 1969 and 50% of those born between 1969 and 1975 were also found to have maintained neutralizing antibodies against smallpox. A considerable proportion of the previous vaccinated individuals still retain significant levels of antiviral immunity. This long-lasting immunity may provide some protective benefits in the case of reemergence of smallpox, and the disease may not spread as widely and fatally as generally expected.

Adult↗
PubMed2005

[Evaluation of the endoprosthesis by metallic stent and tube stent for malignant biliary stenosis].

We evaluated the effect of biliary endoprotheses for 20 malignant stenosis patients by an expandable metallic stent and hydrophilic heparinized tube (H-PSD) connected to an implantable port (IP), which reduces bacterial adherence. Group A consisted of 6 patients of cholangiocarcinoma who underwent hepatic arterial infusion chemotherapy associated with radiotherapy. Groups B and C consisted of 8 and 6 patients of stage IVa and IVb pancreatic carcinoma, respectively, who underwent hepatic and splenic arterial infusion chemotherapy following transcatheter peripancreatic arterial embolization. The 50% patent time was 12 months, 6 months and 7 months in groups A, B and C and the 50% overall survival time was 16 months, 23 months and 13 months, respectively. There were two complications, 1 case of infection around the IP in which the IP was withdrawn, and 3 cases of cholangitis in which we had easy access to the bile duct via IP. This technique appears to offer significant benefit in selecting patients with this type of biliary obstruction.

Aged↗
PubMed2005

[Intraperitoneal and intrapleural gemcitabine in patients with advanced pancreatic cancer].

We performed intraperitoneal and intrapleural dosing gemcitabine (GEM) to eight patients with advanced pancreatic cancer having peritoneal or pleural carcinomatosis and evaluated its actions and safety. GEM (500 mg/m2) was infused into the abdominal cavity or thoracic cavity after drainage of peritoneal or pleural effusion. We checked the change of serum GEM concentration and the side effects after the GEM administration. Then, we repeated the GEM administration observing their systematic symptoms and evaluated the alteration of peritoneal or pleural effusion and cytology. Plasma concentration of GEM by infusing into the abdominal cavity or thoracic cavity was lower than by intravenous injection. In three of the five cases of peritoneal carcinomatosis, intraperitoneal administration revealed a decrease of peritoneal effusion. In two of the three cases of pleural carcinomatosis, intrapleural administration revealed a decrease of pleural effusion. Four cases had leukocytopenia of grade 1/2, three cases had thrombocytopenia, and two cases had alopecia as side effects, although all of them were minor side effects. Intraperitoneal and intrapleural dosing GEM had minor side effects and could improve QOL for the patients with advanced pancreatic cancer associated with peritoneal or pleural carcinomatosis.

Adult↗
PubMed2004

Methylation status of suppressor of cytokine signaling-1 gene in hepatocellular carcinoma.

BACKGROUND: Silencing of the suppressor of cytokine signaling ( SOCS-1) by aberrant methylation at the CpG island in the coding region gene has been reported in hepatocellular carcinoma (HCC). However, principally, it is methylation in the 5'-noncoding region but not that in the coding region which determines the regulation of gene expression. METHODS: Methylation-specific PCR was performed for the analysis of methylation status both in the 5'-noncoding region and the CpG island of SOCS-1 from 22 HCC tissue samples with adjacent non-HCC tissue samples and from two cell lines. RESULTS: Using primers in the CpG island, 9 of 22 HCC samples exhibited aberrant methylation of SOCS-1, while only 1 of 22 adjacent non-HCC samples did so. The unmethylation pattern was detected in 1 of 22 HCC and in 5 of 22 non-HCC samples. Thus, aberrant methylation of SOCS-1 was significantly associated with HCC ( P = 0.0076 by Fisher's exact test). Using primers in the 5'-noncoding region, aberrant methylation was observed in 12 of 22 HCC and in 2 non-HCC samples. The unmethylated pattern was observed in 5 of 22 HCC and in 10 of 22 non-HCC samples ( P = 0.0042). There was no significant correlation between the methylation status of SOCS-1 and clinicopathological findings, such as the presence or absence of cirrhosis or the histological grade of HCC. CONCLUSIONS: Aberrant methylation of the SOCS-1 had a significant correlation with HCC. The rate of aberrant methylation was similar in the 5'-noncoding region and in the CpG island. Aberrant methylation of SOCS-1 may be associated with hepatocarcinogenesis, although further studies are necessary.

Carcinoma, Hepatocellular↗
PubMed2004

Hepatitis C virus infection and diabetes: direct involvement of the virus in the development of insulin resistance.

BACKGROUND & AIMS: Epidemiological studies have suggested a linkage between type 2 diabetes and chronic hepatitis C virus (HCV) infection. However, the presence of additional factors such as obesity, aging, or cirrhosis prevents the establishment of a definite relationship between these 2 conditions. METHODS: A mouse model transgenic for the HCV core gene was used. RESULTS: In the glucose tolerance test, plasma glucose levels were higher at all time points including in the fasting state in the core gene transgenic mice than in control mice, although the difference was not statistically significant. In contrast, the transgenic mice exhibited a marked insulin resistance as revealed by the insulin tolerance test, as well as significantly higher basal serum insulin levels. Feeding with a high-fat diet led to the development of overt diabetes in the transgenic mice but not in control mice. A high level of tumor necrosis factor-alpha, which has been also observed in human chronic hepatitis C patients, was considered to be one of the bases of insulin resistance in the transgenic mice, which acts by disturbing tyrosine phosphorylation of insulin receptor substrate-1. Moreover, administration of an anti-tumor necrosis factor-alpha antibody restored insulin sensitivity. CONCLUSIONS: The ability of insulin to lower the plasma glucose level in the HCV transgenic mice was impaired, as observed in chronic hepatitis C patients. These results provide a direct experimental evidence for the contribution of HCV in the development of insulin resistance in human HCV infection, which finally leads to the development of type 2 diabetes.

Animals↗