Obsessive-compulsive behavior as a symptom of dementia in progressive supranuclear palsy.

AIMS: To describe obsessive-compulsive symptoms (OCS) as under-recognized behavioral and psychological symptoms of dementia of progressive supranuclear palsy (PSP) and to discuss possible mechanisms based on MRI and SPECT findings. METHODS: We studied 74 PSP patients. OCS are defined as persistent and unreasonable, but non-delusional/hallucinatory, ideas and behaviors. Demography, cognition, the widths of middle cerebellar peduncles (MCP) and the inter-caudate distances (ICD), both corrected by the intracranial size (MCP and ICD ratios), and changes on voxel-based SPECT were compared between the subgroups with and without OCS. Finally, the predicative power of various factors to OCS was investigated. RESULTS: We observed OCS in 18 patients (24%). They were obsessed with daily trifles and physical symptoms among other things. OCS was not associated with demography or cognitive levels. OCS-positive patients had significantly smaller MCP and ICD ratios and showed marked uptake decreases in the orbitofrontal cortex, caudate and thalamus. Relative uptake increases in the cerebellum, specifically the tonsils, were milder in OCS-positive than -negative patients. A smaller right MCP, a smaller ICD ratio and lower uptake increases in the right cerebellar were the significant predictors of OCS. CONCLUSIONS: OCS are frequent but under-recognized behavioral and psychological symptoms of dementia in PSP. Dysfunction of the fronto-caudate-thalamus-cerebellum circuit may be involved.

Preventive effect of FK143, a 5alpha-reductase inhibitor, on chemical hepatocarcinogenesis in rats.

The incidence of hepatocellular carcinoma (HCC) is more prevalent in males than in females. 5alpha-Dihydrotestosterone is the most potent form of androgen and is converted from testosterone by 5alpha-reductase. The antitumor effect of a 5alpha-reductase inhibitor (FK143) was evaluated in a rat chemical hepatocarcinogenesis model (Solt-Farber). Male Fischer 344 rats were used in three groups: (a) control group; (b) low-dose FK143 (FKL) group (20 ppm FK143); and (c) high-dose FK143 (FKH) group (200 ppm FK143). The numbers of both glutathione S-transferase placental form-positive foci (P < 0.05) and hyperplastic nodules (HNs; P < 0.01) in the liver were significantly lower in the FKL group than in the control group. The numbers (P < 0.05) and tumor volume (P < 0.01) of HCCs per liver were significantly lower in the FKL group when compared with the control group. All HCCs were well differentiated in the FKL group, whereas 38% and 36% of HCCs were moderate to poorly differentiated in the control group and the FKH group, respectively. The proliferating cell nuclear antigen labeling index:apoptotic index ratios of enzyme-altered foci, HNs, and HCCs were significantly lower in the FKL group than in the control group. Serum 5alpha-dihydrotestosterone was significantly lower in both the FKL and FKH groups. However, a high dose of FK143 (200 ppm) provided no protection against hepatocarcinogenesis, and the level of serum testosterone was elevated in this group when compared with that in the control group. The low dose of FK143 significantly suppressed the formation of enzyme-altered foci, HNs, and HCCs in rat hepatocarcinogenesis. This may indicate that 5alpha-dihydrotestosterone enhances hepatocarcinogenesis. We conclude that an optimal dose of FK143 may have a suppressive effect on hepatocarcinogenesis.

Anticachectic effects of Coptidis rhizoma, an anti-inflammatory herb, on esophageal cancer cells that produce interleukin 6.

Herbs as alternative cancer therapies have attracted a great deal of recent attention due to their low toxicity and costs. In this study, the antitumor activity and anticachectic effect of Coptidis rhizoma, an anti-inflammatory herb, were investigated in nude mice carrying a human esophageal cancer cell line YES-2, which constitutively secretes interleukin-6 (IL-6) and induces cachexia when injected into these mice. In this study, in vivo growth of YES-2 cells was not affected by an oral supplement containing the extract powder of C. rhizoma at a final concentration of 1% (CR supplement). However, in comparison with normal diet, CR supplement significantly attenuated weight loss of tumor-bearing mice without a change in food or water intake. Tumor IL-6 levels were significantly lower in mice treated with CR supplement than in control mice (P<0.001). Serum IL-6 was detectable in four (50%) of eight control mice; IL-6 was not detected in mice treated with CR supplement. We also confirmed that berberine (8-32 microM), a major component of C. rhizoma, dose-dependently inhibited secretion of IL-6 by YES-2 cells in vitro. Moreover, reverse transcription-PCR assay showed that treatment of YES-2 cells with berberine (8-32 microM) for 24 h reduced IL-6 mRNA expression. Our results suggest that C. rhizoma may have an anticachectic effect on esophageal cancer and an effect is associated with the ability of berberine to down-regulate tumor IL-6 production.

A novel in vitro effect of the mucosal protective agent sofalcone--inhibition of chemotactic motility in Helicobacter pylori.

BACKGROUND: Motility of Helicobacter pylori is essential for colonization. H. pylori has been shown to exhibit chemotactic activity toward urea and sodium and bicarbonate ions, which are secreted from the gastric epithelia. The importance of urease activity for chemotactic motility of H. pylori in a viscous environment has also been shown. Consequently, application of drugs inhibiting chemotactic motility has been proposed as a strategy for H. pylori eradication. This inhibitory effect can be evaluated through assay of chemotaxis and swarming. MATERIALS AND METHODS: H. pylori CPY3401 and ATCC43504 were grown on brucella agar plates/broth supplemented with 3% horse serum under microaerobic conditions (N2, 85%; O2, 5%; CO2, 10%). For motility assay, H. pylori cells grown on brucella-serum agar were stabbed into motility agar containing 0.35% refined agar in brucella-serum broth and the swarming zone was measured. For the chemotaxis assay, cells were suspended in 10 mM potassium phosphate buffer, pH 7.0, with 3% polyvinyl-pyrrolidone and assayed as described previously. Bacterial swimming in the fluid environment was observed under dark-field microscopy. RESULTS: Numbers of bacteria attracted toward 1 microM flurofamide were reduced with increasing concentrations of sofalcone (0.2-222 microM). In addition, the size of the swarming zone was reduced in motility agar containing 22 and 222 microM sofalcone. On the other hand, 22 microM sofalcone did not inhibit bacterial growth on day 3. Bacterial swimming speed in brucella broth was slower in the presence of 22 and 222 microM sofalcone than in its absence. CONCLUSION: Sofalcone was found to inhibit chemotactic motility of H. pylori. This drug may be useful for inhibiting the bacterium's ability to colonize the human stomach.

Inhibitory effect of Coptidis Rhizoma and berberine on the proliferation of human esophageal cancer cell lines.

Our previous study demonstrated that the herbal medicine, Oren-to, had antitumor effects on esophageal cancer cells (ECCs) in vitro. The purpose of this study was to examine which of the seven constituents of Oren-to had antitumor effects on esophageal cancer cells. MTT assay showed that, of the seven constituents, only the aqueous extract of Coptidis Rhizoma had potent inhibitory effect on the proliferation of two types of ECC lines, YES-3 and YES-4. In addition, the proliferation of all six types of ECC lines (YES-1 to YES-6) was inhibited in a dose-dependent manner (P<0.001 for all), when co-cultured at each concentration of Coptidis Rhizoma for 72 h. The ID50 of Coptidis Rhizoma for YES-1 to YES-6 was 2.2 microg/ml, 3.0 microg/ml, 0.25 microg/ml, 2.8 microg/ml, 2.5 microg/ml, and 0.5 microg/ml, respectively, berberine, one of protoberberine components of Coptidis Rhizoma, showed potent antitumor effects on all six types of ECC lines as well as Coptidis Rhizoma. In addition, the ID50 of berberine showed a positive correlation with that of Coptidis Rhizoma in six types of ECC lines examined (r2 = 0.763, P = 0.023). Cell cycle analysis of Coptidis Rhizoma-treated cancer cells showed the accumulation of cells in the G0/G1 phase and relative decrease of the S phase. These results support the possibility that the use of Coptidis Rhizoma containing abundant berberine may be useful as one of alternative therapies for esophageal cancers.

Inhibitory effects of the herbal medicine Sho-saiko-to (TJ-9) on cell proliferation and procollagen gene expressions in cultured rat hepatic stellate cells.

BACKGROUND/AIMS: It is of extreme importance to prevent liver fibrosis and subsequent progression to liver cirrhosis. The aim of our study was to elucidate in vitro whether Sho-saiko-to exerted inhibitory effects on hepatic stellate cells. METHODS: Hepatic stellate cells were isolated from male Wistar rats. Water-soluble ingredients of Sho-saiko-to were obtained at concentrations of 10, 100, 250, 500 and 1000 microg/ml. Morphological transformation was observed under a phase-contrast microscope. Flow cytometric analysis was performed on day 4 after culture to evaluate the potential to proliferate of the stellate cells by analyzing cell cycles. Northern blot analysis was carried out on day 3 after culture to determine the expressions of type I and type III procollagen mRNAs. RESULTS: (i) Sho-saiko-to 500 and 1000 microg/ml inhibited morphological transformation of the stellate cells to myofibroblast-like cells. (ii) Sho-saiko-to 500 and 1000 microg/ml significantly (p<0.0001) accumulated the cells in the G0/G1 phase (118.8+/-0.7%, 119.2+/-0.5%, respectively as compared with control) and significantly (p<0.0001) decreased cell numbers subsequently in G2/M phase (47.5+/-8.1%, 48.9+/-2.0%, respectively). (iii) Sho-saiko-to 500 and 1000 microg/ml also significantly (p<0.05 or p<0.0001) suppressed procollagen mRNA expression of type I to 51.5+/-6.4%, 34.9+/-3.7%, respectively, and type III to 51.3+/-12.3%, 46.7+/-11.4%, respectively. CONCLUSIONS: We have clarified the inhibitory effects of Sho-saiko-to on hepatic stellate cells in vitro. Sho-saiko-to could be a potent inhibitor in the pathogenesis of liver fibrosis.

Herbal medicine Sho-saiko-to (TJ-9) prevents liver fibrosis and enzyme-altered lesions in rat liver cirrhosis induced by a choline-deficient L-amino acid-defined diet.

BACKGROUND/AIM: A herbal medicine, Sho-saiko-to (TJ-9), has recently been orally administered to patients with chronic liver disease in Japan and has been reported to inhibit the development of hepatocellular carcinoma. The aim of this study was to investigate whether TJ-9 has an inhibitory effect on the development of preneoplastic lesions and liver fibrosis in rats. METHODS: The effects of the TJ-9 were examined using the choline-deficient L-amino acid-defined (CDAA) diet-induced liver fibrosis model in 16-week-old male Wistar rats. RESULTS: TJ-9 (1% w/w) prevented fibrosis, as indicated by reduced hydroxyproline content in the liver and inhibition of the increase in a serum marker of fibrosis (hyaluronic acid), without reducing the increase in serum alanine aminotransferase and aspartate aminotransferase. TJ-9 also reduced the expression of type III procollagen alpha 1 mRNA in the liver, as well as the proliferation of myofibroblast-like cells (activated stellate cells, activated Ito cells). Furthermore, TJ-9 reduced the number of preneoplastic lesions, detected as enzyme-altered (glutathione S-transferase placental form-positive) lesions, in the liver. CONCLUSIONS: These results indicate that the herbal medicine Sho-saiko-to (TJ-9) prevents fibrosis as well as preneoplastic lesions, not by inhibiting hepatocyte cell death but by inhibiting the activation of stellate cells, which are considered to be the main collagen-producing cells, leading to a reduction in the development of preneoplastic lesions.

Cell death induced by baicalein in human hepatocellular carcinoma cell lines.

We examined the action of baicalein, a flavonoid contained in the herbal medicine sho-saiko-to (TJ-9), on three cell lines of human hepatocellular carcinoma (HCC). Treatment with baicalein strongly inhibited the activity of topoisomerase II and suppressed the proliferation of all three HCC cell lines. But the mode of cell death induced by baicalein differed according to the cell line. Baicalein induced apoptosis in a concentration-dependent manner in only one cell line, and an increased concentration of baicalein produced cell death via necrosis in the other two lines. These results suggest that the inhibition of topoisomerase II is not by itself sufficient for induction of apoptosis, and that there is a more important mechanism which can account for the difference in susceptibility of cells to apoptosis induced by baicalein.

Prevention of fibrosis reduces enzyme-altered lesions in the rat liver.

A choline-deficient L-amino acid-defined (CDAA) diet led to the development of liver cirrhosis in 100% of male Wistar rats after 16 weeks. In contrast, an ordinary (semipurified) choline-deficient (CD) diet led to the development of liver cirrhosis in only 33.3%. After 16 weeks, the liver hydroxyproline content, which reflects the amount of collagen, increased to a level more than four times higher in rats fed a CDAA diet than in rats fed a choline-supplemented L-amino acid-defined (CSAA) diet. Concurrent administration of a prolyl 4-hydroxylase inhibitor, 2,4-pyridine dicarboxylic acid bis(2-methoxyethyl amide) (HOE 077), to rats fed a CDAA diet reduced this increase in liver hydroxyproline content in a dose-dependent manner for doses up to 200 p.p.m. Microscopically, reduction in the hydroxyproline content of the liver resulted in a reduced number of pseudolobuli and thinner fibrous septa. HOE 077 showed no effect on liver hydroxyproline content in rats fed a CSAA diet. The administration of a CDAA diet for 16 weeks led to a substantial induction of GSTP-positive lesions in the liver. The concurrent administration of HOE 077 reduced the number, average diameter and percent area of GSTP-positive lesions in a dose-dependent manner, in parallel with the reduction in hydroxyproline content. These data suggest that inhibition of fibrosis may limit the development of subsequent neoplasms.

Evaluation of new therapy for eradication of H. pylori infection in nude mouse model.

OBJECTIVES: developing a new therapy for eradication of H. pylori by using the nude mouse model. METHODS: By quantifying the number of colonies of Helicobacter pylori and the score of H. pylori-associated gastritis from the gastric tissue following different drug regimens in inoculated nude mice, we evaluated the effectiveness of each regimen, including a new drug, plaunotol. Drugs were administered daily for a 1-wk period, beginning 4 wk after inoculation. RESULTS: In the examination after therapy, the number of colonies of H. pylori and the score of gastritis in the triple-therapy group were significantly lower than in any of the singly- and dual-drug groups or control group from 5 wk to the end of the study after inoculation. Inflammation of the stomach was less apparent in the treatment groups than in the control group. CONCLUSION: With the nude mouse model, we quantitatively demonstrated that the new triple therapy is the most effective therapy for eradication of H. pylori.

Anti-growth effects with components of Sho-saiko-to (TJ-9) on cultured human hepatoma cells.

The present study was undertaken to investigate the effects and the mechanism of the components of Sho-saiko-to (baicalein, baicalin, saikosaponin-a, saikosaponin-c, ginsenoside Rb1, ginsenoside Rg1) on cultured human hepatoma cells (HuH-7). Cell cycle analysis was carried out with flow cytometry and the bromodeoxyuridine (BrdU)-labelling method. The results showed that baicalein, baicalin and saikosaponin-a inhibited cell proliferation dose-dependently but independently of the cell cycle. Furthermore, it was found that saikosaponin-a possesses a strong cell-killing effect. On the other hand, saikosaponin-c, ginsenoside Rb1 and ginsenoside Rg1 had no effect on cell proliferation.

[Nutritional treatment of hepatocellular carcinoma].

We investigated the relationship between the growth of HCC and nutrition, especially amino acids, and reconsidered the clinical application of amino acid imbalance. At first, rat chemical hepato-carcinogenesis was performed to investigate whether Aminoleban EN stimulates or restrains the occurrence of HCC. 2-Acetyl-amino-fluorene containing diet was administered intermittently according to Epstein's method. Rats were divided into two groups; group 1 was fed on Aminoleban EN containing diet and group 2 on a basal diet. There was no significant difference between the survival rate in the two groups. The average body weight of group 1 was significantly higher than that of group 2. The rats were sacrificed at the 25th week. All 11 rats of group 1 had no liver tumor, but 2 of 17 rats of group 2 had liver tumors, including a HCC and cholangiocellular carcinoma. The incidence of the liver tumor was significantly different between the two groups. Aminoleban EN could inhibit rat liver carcinogenesis, so it is considered to be a desirable nutritional product for LC patients from the stand point of cancer prevention. Secondly, the composition of amino acid was studied on HCC and surrounding tissue. There was no significant difference of Val, Leu, Leu, Phe, Tyr, Met and Fischer ratio between HCC and surrounding tissue.

Phosphorus-31 magnetic resonance spectroscopy of forearm flexor muscles in student rowers using an exercise protocol adjusted for differences in cross-sectional muscle area.

To assess exercise energy metabolism of forearm flexor muscles in rowers, six male student rowers and six control subjects matched for age and sex were studied using phosphorus-31 magnetic resonance spectroscopy (31P-MRS). Firstly, to adjust for the effect of differences in cross-sectional muscle area, the maximal cross-sectional area (CSAmax) of the forearm flexor muscles was estimated in each individual using magnetic resonance imaging. Multistage exercise was then carried out with an initial energy production of 1 J.cm-2 CSAmax for 1 min and an increment of 1 J.cm-2 CSAmax every minute to the point of muscle exhaustion. A series of measurements of 31P-MRS were performed every minute. The CSAmax was significantly greater in the student rowers than in the control subjects [19.8 (SD 2.2) vs 17.1 (SD 1.2) cm2, P less than 0.05]. The absolute maximal exercise intensity (J.min-1) was greater in the rowers than in the control subjects. However, the maximal exercise intensity per unit of muscle cross sectional area (J.min-1.cm-2) was not significantly different between the two groups. During mild to moderate exercise intensities, a decrease in phosphocreatine and an increase in inorganic phosphate before the onset of acidosis were significantly less in the rowers, indicating a requirement of less adenosine 5'-diphosphate to drive adenosine 5'-triphosphate production. The onset of acidosis was also significantly delayed in the rowers. No difference was observed in forearm blood flow between the two groups at the same exercise intensity (J.min-1.cm-2).(ABSTRACT TRUNCATED AT 250 WORDS)