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Nippon rinsho. Japanese journal of clinical medicine 10/2011; 69 Suppl 8:355-8.
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Masanori Ikeda, Yoshinari Kawai,
Kyoko Mori,
Masahiko Yano,
Ken-ichi Abe,
Go Nishimura,
Hiromichi Dansako,
Yasuo Ariumi,
Takaji Wakita,
Kazuhide Yamamoto,
Nobuyuki Kato
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ABSTRACT: Previously we reported that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, statins, inhibited hepatitis C virus (HCV) RNA replication. Furthermore, recent reports revealed that the statins are associated with a reduced risk of hepatocellular carcinoma and lower portal pressure in patients with cirrhosis. The statins exhibited anti-HCV activity by inhibiting geranylgeranylation of host proteins essential for HCV RNA replication. Geranylgeranyl pyrophosphate (GGPP) is a substrate for geranylgeranyltransferase. Therefore, we examined the potential of geranyl compounds with chemical structures similar to those of GGPP to inhibit HCV RNA replication.
We tested geranyl compounds [geranylgeraniol, geranylgeranoic acid, vitamin K(2) and teprenone (Selbex)] for their effects on HCV RNA replication using genome-length HCV RNA-replicating cells (the OR6 assay system) and a JFH-1 infection cell culture system. Teprenone is the major component of the anti-ulcer agent, Selbex. We also examined the anti-HCV activities of the geranyl compounds in combination with interferon (IFN)-α or statins.
Among the geranyl compounds tested, only teprenone exhibited anti-HCV activity at a clinically achievable concentration. However, other anti-ulcer agents tested had no inhibitory effect on HCV RNA replication. The combination of teprenone and IFN-α exhibited a strong inhibitory effect on HCV RNA replication. Although teprenone alone did not inhibit geranylgeranylation, surprisingly, statins' inhibitory action against geranylgeranylation was enhanced by cotreatment with teprenone.
The anti-ulcer agent teprenone inhibited HCV RNA replication and enhanced statins' inhibitory action against geranylgeranylation. This newly discovered function of teprenone may improve the treatment of HCV-associated liver diseases as an adjuvant to statins.
Liver international: official journal of the International Association for the Study of the Liver 07/2011; 31(6):871-80. · 3.82 Impact Factor
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ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a multisystem disorder with impairment of frontotemporal functions such as cognition and behavior, but the behavioral changes associated with ALS are not well defined.
Twenty-one consecutive patients with sporadic ALS and 21 control subjects participated in the study. The Frontal System Behavior Scale (FrSBe) was used to assess behavioral change. Voxel-based morphometry (VBM) and voxel-based analysis of diffusion tensor images (DTI) were performed to explore the associations of brain degeneration with behavior. All patients were evaluated before the notification of ALS.
FrSBe scores of ALS patients before notification were significantly increased compared to those of control subjects. Moreover, the FrSBe Apathy score of ALS patients significantly changed from pre- to post-illness (P<0.001). The severity of apathy was significantly correlated with atrophy in the prefrontal cortex, especially in the orbitofrontal (P=0.006) and dorsolateral prefrontal (P=0.006) cortices in VBM, and in the right frontal gyrus (P<0.001) in DTI.
ALS patients exhibited apathy during the early course of the illness, the severity of which was significantly associated with frontal lobe involvement. These findings support the view that a continuum exits between ALS and frontotemporal dementia.
Journal of the neurological sciences 06/2011; 307(1-2):34-40. · 2.32 Impact Factor
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Cortex 04/2011; 48(5):641-3. · 6.08 Impact Factor
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No shinkei geka. Neurological surgery 02/2011; 39(2):181-8. · 0.13 Impact Factor
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Fusao Ikeda,
Hiromichi Dansako,
Go Nishimura,
Kyoko Mori, Yoshinari Kawai,
Yasuo Ariumi,
Yasuhiro Miyake,
Akinobu Takaki,
Kazuhiro Nouso,
Yoshiaki Iwasaki,
Masanori Ikeda,
Nobuyuki Kato,
Kazuhide Yamamoto
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ABSTRACT: Studies on patients with hepatitis C virus (HCV) of genotype 1b have suggested that amino acids (aa) 70 and/or 91 of the HCV core protein affect the outcome of interferon (IFN)-α and ribavirin (RBV) therapy, although there are no clear supporting data in vitro.
This study was designed to determine the differences among the antiviral activities of HCV core proteins with various substitutions at aa70 and/or aa91.
The retroviral vectors expressing the HCV core proteins with substitutions of arginine/leucine, arginine/methionine, glutamine/leucine or glutamine/methionine at aa70/aa91 were transiently transfected or stably transducted into an immortalized hepatocyte line (PH5CH8), hepatoma cell lines and an HCV-RNA replicating cell line (sOR) to evaluate antiviral responses to IFN-α or IFN-α/RBV. Sequence analysis was performed using genome-length HCV-RNA replicating cells (OR6 and AH1) to evaluate HCV core mutations during IFN-α treatment.
The promoter activity levels of IFN-stimulated genes in the transiently transfected cells or the mRNA levels of 2'-5'-oligoadenylate synthetase in the stably transducted PH5CH8 cells were not associated with the HCV core aa70 and/or aa91 substitutions during IFN-α treatment. Antiviral responses to IFN-α or IFN-α/RBV treatment were enhanced in sOR cells stably transducted with the HCV core, although there were no differences in antiviral responses among the cells expressing different core types. Sequence analysis showed no aa mutations after IFN-α treatment.
Antiviral activities were enhanced by HCV core transduction, but they were not associated with the HCV core aa70 and/or aa91 substitutions by in vitro analysis.
Liver international: official journal of the International Association for the Study of the Liver 10/2010; 30(9):1324-31. · 3.82 Impact Factor
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ABSTRACT: Aim: The cure rate of current interferon (IFN) therapy is limited to approximately 50% and most of the relapses after therapy are caused by genotype-1. To develop a relapse model in cell culture, we attempted to obtain genome-length hepatitis C virus ribonucleic acid (HCV RNA) harboring cells possessing the IFN-alpha-resistance phenotype from previously established OR6 cells, which enabled the luciferase reporter assay for monitoring of HCV RNA replication. Methods: The IFN-alpha-resistant HCV RNA-harboring cells and control cells were obtained by the treatment of OR6 cells with and without IFN-alpha, respectively. Then, we examined the relapse of HCV in IFN-alpha-resistant HCV RNA-harboring cells. Results: Only type I IFN (alpha and beta) showed significantly different anti-HCV activity between IFN-alpha-resistant HCV RNA-harboring cells and control cells. There was no significant difference in the anti-HCV activity of IFN-gamma, fluvastatin, or cyclosporine A between the two types of cells. Furthermore, we showed that fluvastatin or cyclosporine A in combination with IFN-alpha could prevent the relapse after therapy in the IFN-alpha-resistant HCV RNA-harboring cells. Conclusion: We developed a HCV relapse model in cell culture using IFN-alpha-resistant HCV RNA-harboring cells. Thus anti-HCV reagents, which have a mechanism different from IFN-alpha, were shown to be useful for preventing a relapse of IFN-alpha-resistant HCV.
Hepatology Research 06/2009; 39(9):898-909. · 2.20 Impact Factor
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Masahiko Yano,
Masanori Ikeda,
Ken-ichi Abe, Yoshinari Kawai,
Misao Kuroki,
Kyoko Mori,
Hiromichi Dansako,
Yasuo Ariumi,
Shougo Ohkoshi,
Yutaka Aoyagi,
Nobuyuki Kato
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ABSTRACT: Recently, we reported that beta-carotene, vitamin D(2), and linoleic acid inhibited hepatitis C virus (HCV) RNA replication in hepatoma cells. Interestingly, in the course of the study, we found that the antioxidant vitamin E negated the anti-HCV activities of these nutrients. These results suggest that the oxidative stress caused by the three nutrients is involved in their anti-HCV activities. However, the molecular mechanism by which oxidative stress induces anti-HCV status remains unknown. Oxidative stress is also known to activate extracellular signal-regulated kinase (ERK). Therefore, we hypothesized that oxidative stress induces anti-HCV status via the mitogen activated protein kinase (MAPK)/ERK kinase (MEK)-ERK1/2 signaling pathway. In this study, we found that the MEK1/2-specific inhibitor U0126 abolished the anti-HCV activities of the three nutrients in a dose-dependent manner. Moreover, U0126 significantly attenuated the anti-HCV activities of polyunsaturated fatty acids, interferon-gamma, and cyclosporine A, but not statins. We further demonstrated that, with the exception of the statins, all of these anti-HCV nutrients and reagents actually induced activation of the MEK-ERK1/2 signaling pathway, which was inhibited or reduced by treatment not only with U0126 but also with vitamin E. We also demonstrated that phosphorylation of ERK1/2 by cyclosporine A was attenuated with N-acetylcysteine treatment and led to the negation of inhibition of HCV RNA replication. We propose that a cellular process that follows ERK1/2 phosphorylation and is specific to oxidative stimulation might lead to down-regulation of HCV RNA replication. Conclusion: Our results demonstrate the involvement of the MEK-ERK1/2 signaling pathway in the anti-HCV status induced by oxidative stress in a broad range of anti-HCV reagents. This intracellular modulation is expected to be a therapeutic target for the suppression of HCV RNA replication.
Hepatology 05/2009; 50(3):678-88. · 11.66 Impact Factor
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ABSTRACT: Our aim was to evaluate the location and extent of white matter involvement in patients with amyotrophic lateral sclerosis (ALS) using diffusion-tensor magnetic resonance imaging (DTI). We obtained fractional anisotropy (FA) values from the internal capsule and various white matter regions of 46 patients with sporadic ALS and 19 control subjects. In ALS patients, FA values in the internal capsule, frontal white matter, genu and splenium of the corpus callosum (p<0.001), parietal and temporal lobe white matter, and posterior cingulum (p<0.05) were significantly lower than in controls. FA values in frontal white matter were lower than in parietal white matter (p<0.001). Decreased FA values in frontal, parietal, and temporal white matter, and the genu of the corpus callosum, correlated significantly with those in the internal capsule (r=0.66 and p<0.001, r=0.47 and p=0.001, r=0.33 and p=0.021, r=0.41 and p=0.005, respectively). No such correlations were found for FA values in other white matter areas or in controls. Patient FA values generally were not correlated with disease duration. DTI demonstrated more widespread involvement of the cerebral white matter in ALS patients than previously believed. The severity of involvement in the frontal, temporal and parietal white matter correlated with severity in the pyramidal tract.
Amyotrophic Lateral Sclerosis 01/2009; 10(5-6):288-94. · 3.40 Impact Factor
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ABSTRACT: Pathological studies have shown remarkable pyramidal tract involvement in multiple system atrophy (MSA), while clinical pyramidal signs are relatively rare. We investigated the fractional anisotropy (FA) values to assess the degree of pyramidal tract involvement in MSA, in comparison with amyotrophic lateral sclerosis (ALS) and controls. Furthermore, we compared FA values between MSA patients with or without clinical pyramidal signs and controls, and between MSA patients with or without positive conventional MRI findings and controls.
We evaluated FA values in the internal capsule, corona radiate and whole pyramidal tract using visualized tractography of 65 subjects (20 probable MSA patients, 28 age-matched ALS patients, and 17 age-matched healthy controls) using a 3.0T magnetic resonance system.
The FA values in the internal capsule, corona radiate, and whole pyramidal tract were significantly lower in MSA patients than in controls and were at a level similar to those of ALS patients. In addition, low FA values were prominent in MSA patients, even in those with short duration of illness, lacking precentral gyrus hyperintensity in FLAIR images, and without pyramidal signs.
FA values could identify pyramidal tract degeneration even in patients with early phase MSA and those without clinical pyramidal signs or abnormal MRI findings. More extensive degeneration of the pyramidal tract occurs in MSA than so far believed.
Journal of the Neurological Sciences 09/2008; 271(1-2):40-6. · 2.35 Impact Factor
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ABSTRACT: To determine whether apparent diffusion coefficient (ADC) values and fractional anisotropy (FA) values can detect early pathological involvement in multiple system atrophy (MSA), and be used to differentiate MSA-P (multiple system atrophy if parkinsonian features predominate) from Parkinson's disease (PD).
We compared ADC and FA values in the pons, cerebellum and putamen of 61 subjects (20 probable MSA patients, 21 age matched PD patients and 20 age matched healthy controls) using a 3.0 T magnetic resonance system.
ADC values in the pons, cerebellum and putamen were significantly higher, and FA values lower in MSA than in PD or controls. These differences were prominent in MSA lacking dorsolateral putaminal hyperintensity (DPH) or hot cross bun (HCB) sign. In differentiating MSA-P from PD using FA and ADC values, we obtained equal sensitivity (70%) and higher specificity (100%) in the pons than in the putamen and cerebellum. In addition, all patients that had both significant low FA and high ADC values in each of these three areas were MSA-P cases, and those that had both normal FA and ADC values in the pons were all PD cases. Our diagnostic algorithm based on these results accurately diagnosed 90% of patients with MSA-P.
FA and ADC values detected early pathological involvement prior to magnetic resonance signal changes in MSA. In particular, low FA values in the pons showed high specificity in discriminating MSA-P from PD. In addition, combined analysis of both FA and ADC values in all three areas was more useful than only one.
Journal of neurology, neurosurgery, and psychiatry 08/2007; 78(7):722-8. · 4.87 Impact Factor
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ABSTRACT: Cognitive function of Machado-Joseph disease (MJD) patients has not been clarified.
To determine the characteristics of cognitive dysfunction in MJD patients and to assess the relationship of dysfunction to age at onset, age at examination, disease duration, education, ataxia, depression, anxiety, and CAG repeat length.
Case-control study.
Research-oriented hospitals.
Sixteen genetically confirmed MJD patients able to complete neuropsychological tests and 20 control subjects matched to patients by age and education.
Neuropsychological tests, including general cognition, verbal and visual memory, working memory, visuospatial and constructional ability, language, executive function, depression, and anxiety.
Machado-Joseph disease patients scored significantly lower than controls in verbal and visual memory, in visuospatial and constructional tasks, and in phonemic and semantic fluency tasks. None of these impairments correlated with CAG repeat length, age at onset, age at examination, disease duration, or education. Verbal fluency (words named in a category) correlated with the International Cooperative Ataxia Rating Scale score.
Machado-Joseph disease patients have verbal and visual memory deficits, visuospatial and constructional dysfunction, and verbal fluency deficits, all unrelated to CAG repeat length.
Archives of Neurology 12/2004; 61(11):1757-60. · 7.58 Impact Factor
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ABSTRACT: We developed a brief scale to evaluate communication ability of the demented elderly. This scale assesses not only abilities related to overall communication such as verbal function, judgment and emotional function, but also non-verbal communication such as eye-contact, nodding and smiling. The scale places little burden on the demented elderly subject and takes only a few minutes to perform, even if the dementia is severe. We evaluated 106 demented elderly residents of nursing homes using this brief communication ability scale, and the following results were obtained. The validity of this scale was confirmed by the high correlation coefficient between this scale and the formal caregiver questionnaire scores concerning communication ability, and the high-correlation coefficient between this scale and intellectual functions (r = -0.904), emotional functions (r = -0.841) and motor functions (r = -0.679) of dementia syndromes rating scale (Gottfries, Bråne, Steen scale; GBS scale), Hasegawa's Dementia Scale-Revised (HDS-R) (r = 0.625) and the Mini-Mental State Examination (MMS) (r = 0.733). The reliability of this scale was confirmed by the high interrater reliability coefficient of 0.828, test-retest reliability coefficient of 0.940 and Cronbach alpha coefficient of 0.938. These results indicate that the new scale is useful in the assessment of communication ability among the demented elderly.
Nippon Ronen Igakkai Zasshi Japanese Journal of Geriatrics 08/2004; 41(4):402-7.
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Nippon rinsho. Japanese journal of clinical medicine 02/2004; 62 Suppl:127-31.
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Nippon rinsho. Japanese journal of clinical medicine 02/2004; 62 Suppl:167-70.
