Anti-aging effects of oligomeric proanthocyanidins isolated from persimmon fruits.

Senescence-accelerated mouse prone/8 (SAMP8), a murine model of accelerated senescence, shows age-related deficits in learning and memory. The oral administration of oligomers improved spatial and object recognition impairment in SAMP8. The expression of phosphorylated neurofilament-H was significantly elevated in the hippocampal CA1. This indicates that oligomers induce an increase in the density of axons. To investigate the protective mechanisms of oligomers against brain dysfunction with aging, we carried out a receptor tyrosine kinase phosphorylation antibody array, and clarified that the administration of oligomers led to an increase in the phosphorylation of vascular endothelial growth factor receptor (VEGFR)-2, suggesting the neuroprotective role of oligomers. The phosphorylation of VEGFR-2 was more markedly increased in the hypothalamus and choroid plexus than in other brain regions of SAMP8. Memory in oligomer-treated mice was impaired by SU1498, a VEGFR-2-specific antagonist. Elucidating the relationship between memory impairment with aging and VEGFR-2 signaling may provide new suggestions for protection against memory deficit in the aging brain. In addition, we revealed that the administration of oligomers extended the life span of SAMP8. Oligomers elevated SIRT1 expression, which is recognized as an essential factor for life span extension in the brain. However, the administration of oligomers did not induce stereotypical behaviors such as rearing, jumping, or hanging from the lid of a cage, while food restriction increased these frequencies without a significant change in motor function. The present study suggests the promising role of oligomers as an anti-aging agent to extend life span.

Bioactive constituents of Corni Fructus: The therapeutic use of morroniside, loganin, and 7-O-galloyl-D-sedoheptulose as renoprotective agents in type 2 diabetes.

Corni Fructus, the fruit of Cornus officinalis Sieb. et Zucc. (Cornaceae), is an important crude herb used in Chinese medicine to exhibit several biological activities, including hypoglycemic, antineoplastic, and antimicrobial effects, and to improve liver and kidney functions. We have been investigating the mechanism and bioactive constituents of Corni Fructus using diabetic animal models. Morroniside, loganin, and 7-O-galloyl-D-sedoheptulose, the main active compounds of Corni Fructus, exhibit the same lowering effects of elevated triglyceride, oxidative stress and advanced glycation endproduct (AGE) formation in the kidney of db/db mice. The effects of morroniside and 7-O-galloyl-D-sedoheptulose were mediated through modulation by renal sterol regulatory element binding proteins and nuclear factor-kappa B expression, but the effect of loganin was presumably mediated by hypoglycemic and antioxidant effects in the kidney, and also indirectly by the amelioration of metabolic disorders in other organs such as the liver. These findings led us to conclude that morroniside, loganin, and 7-O-galloyl-D-sedoheptulose would synergistically contribute to the inhibition of metabolic disorders (hyperglycemia and dyslipidemia), oxidative stress, inflammation, as well as AGE formation in the diabetic kidney.

No effect of a traditional Chinese medicine, Hochu-ekki-to, on antibody titer after influenza vaccination in man: a randomized, placebo-controlled, double-blind trial.

BACKGROUND: It was shown that a traditional Chinese medicine, Hochu-ekki-to (HET), had adjuvant effects in influenza vaccination in an animal experiment. This, however, could not be assessed in a clinical study. METHODS: Thirty-two healthy subjects were randomly assigned to two groups (control and HET groups) in a double-blind manner. HET subjects (n=17) took 7.5 g of HET/day for two weeks; control subjects took the same amount of indistinguishable placebo. Then subjects were vaccinated against influenza (H1N1, H3N2 and B/Shandong). Hemagglutinin titers and natural killer (NK) activity were measured at weeks 0, 1, 2, 4, and 12. RESULTS: Antiinfluenza titers against the three viruses were increased continuously for the first two weeks and leveled off. However, there were no significant differences in any titers between the two groups. NK activity peaked at week 2 without any inter-group differences. CONCLUSION: We could not find any adjuvant effects of HET in this experimental condition.

The mechanism of hypoglycemia caused by hemodialysis.

BACKGROUND: Although it is well-known that plasma glucose concentration ((G)p) decreases during hemodialysis, the precise mechanism underlying this decrease has not yet been fully elucidated. The aim of the present study was to investigate the mechanism underlying hemodialysis-induced decrease (HID) in (G)p during the dialysis in vivo or in vitro. METHODS: Using high CO2/ HCO3- dialysate, we measured (G)p by a hexose kinase method ((G)pHK) and concentrations of electrolytes, as well as pH, PCO2 and PO2 for both plasma and dialysate samples at pre- and postdialyzer sites obtained from hemodialysis patients with nondiabetic chronic renal failure (CRF). Furthermore, we studied the effect of PCO2 and acetazolamide (ACZ) on the changes in (G)pHK during the dialysis in vitro. RESULTS: After the first dialysis of CRF patients, the (G)pHK decreased from 118.3 +/- 18.0 to 98.6 +/- 5.7 mg/dl (p < 0.05), the latter value being significantly lower than glucose concentration in dialysate samples (approximately 105 mg/dl) at predialyzer sites. In the experiments of blood samples from healthy volunteers, (G)pHK decreased significantly after elevating or lowering CO2 level in the dialysates. In contrast, when the difference in PCO2 between the blood and dialysate was reduced, the HID in (G)pHK was abolished during hemodialysis. The addition of 10(-4) M ACZ to the blood samples completely prevented the development of HID in (G)pHK caused by the perfusion of high or low CO2/HCO3- dialysates. CONCLUSIONS: During hemodialysis using high CO2/HCO3- dialysate, the HID in (G)p results from the diffusion of glucose from plasma into erythrocytes, probably due to the consumption of glucose resulting from the accelerated anaerobic metabolism induced by the changes in the cytoplasmic pH of erythrocytes.

Effects of Keishi-bukuryo-gan on vascular function and hemorheological factors in spontaneously diabetic (WBN/kob) rats.

Keishi-bukuryo-gan (Gui-zhi-fu-ling-wan) is a formula used for the improvement of blood circulation. Recently it has often also been used for arteriosclerosis. One of the mechanisms involved is thought to be the improvement of endothelial dysfunction, but the details are still unclear. In this study, the effect of Keishi-bukuryo-gan on vascular function and hemorheological factors in spontaneously diabetic (WBN/kob) rats was studied. Rats were given Keishi-bukuryo-gan in chow for 30 weeks. Body weight, blood glucose, endothelium-dependent/-independent relaxation, vasocontraction by free radical-induced and contractive prostanoids, triglyceride, advanced glycation endproduct, lipid peroxides, serum NO2-/NO3- and blood viscosity were measured. The results indicated that Keishi-bukuryo-gan caused a decrease in endothelium-dependent relaxation by acetylcholine to become significantly increased, and vasocontraction induced by free radicals and contractive prostanoids was significantly decreased. Furthermore, serum NO2-/NO3- and blood viscosity were significantly decreased. From these results, it was supposed that Keishi-bukuryo-gan exerted a protective effect on the endothelium. The WBN/kob rat is a useful study model for the complications of human diabetes, and Keishi-bukuryo-gan showed a protective effect against vascular injury in the susceptible rat.

Study on the inhibitory effects of Korean medicinal plants and their main compounds on the 1,1-diphenyl-2-picrylhydrazyl radical.

A 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical-generating system was used to evaluate the antioxidant properties of Korean medicinal plants that have been used widely as folk medicines for several disorders, as well as compounds isolated from them. Among the Rosaceae, Rosa rugosa and Rosa davurica showed strong DPPH radical-scavenging activity. The most effective medicinal plant from families other than Rosaceae was Cedrela sinensis, followed in order by Nelumbo nucifera, Eucommia ulmoides, Zanthoxylum piperitum, Cudrania tricuspidata and Houttuynia cordata. These results serve as a good index of the free radical-scavenging activities of Korean medicinal plants. Furthermore, the polyphenols isolated from these plants, procyanidin B-3, (+)-catechin, gallic acid, methyl gallate, quercetin, quercetin-3-O-beta-D-glucoside, quercetin-3-O-beta-galactoside, quercetin-3-O-rutinose and kaempferol, exerted strong DPPH radical-scavenging activity. These results suggest that the Korean medicinal plants and the polyphenols isolated from them that exhibited effective radical-scavenging activity may be promising agents for scavenging free radicals and treating diseases associated with excess free radicals.

Pharmacokinetics of nateglinide and its metabolites in subjects with type 2 diabetes mellitus and renal failure.

AIMS: We evaluated the benefits and safety of nateglinide, a novel oral hypoglycemic agent, in type 2 diabetes patients with renal failure. METHODS: Single-dose pharmacokinetics were studied in 8 patients with type 2 diabetes and a low creatinine clearance (range 1.8-16.5 ml/min/1.73 m2) up to 6 hours after 90 mg nateglinide administration. Next, we treated another group of 8 patients undergoing regular hemodialysis with nateglinide 90 mg/day for 1-3 months. The effect of hemodialysis on metabolite accumulation was then tested. RESULTS: After a single 90 mg dose, nateglinide significantly increased the post-prandial secretion of insulin and thereby reduced plasma glucose levels. Mean pharmacokinetic parameters (AUC(0-6) 10.45 mg/l/h; t(1/2) 1.89 h, Cl/F 10.19 l/h) were comparable with those reported in healthy subjects. A much larger AUC value than those previously reported of M1, a major metabolite in the urine of healthy subjects, was observed, and the plasma concentration of M1 did not decline up to 6 hours after. In patients treated on a regular basis, there was marked accumulation of M1, while nateglinide could not be detected 24 hours after the last dose. Plasma M1 levels were significantly reduced by the hemodialysis sessions. CONCLUSIONS: Single 90 mg dose of nateglinide was safe and effective in patients with renal failure. However, repeated administrations could cause prolonged hypoglycemia due to accumulation of M1, which is known to have a modest hypoglycemic activity. Hemodialysis may help to eliminate excessive accumulation of M1.

Measurement of plasma procyanidin B-2 and procyanidin B-3 levels after oral administration in rat.

Using a high-performance liquid chromatographic method and mass spectrometry analysis, we successfully measured the absorption of orally administered procyanidin B-2 and procyanidin B-3 isolated from Cinnamonomi cortex (the bark of Cinnamomum cassia Blume) in the rat plasma. This method used a TSK- GEL ODS-80TS column, two solvents (A: 0.01% acetic acid; B: methanol with 0.01% acetic acid) in a linear gradient at a flow-rate of 1.0 ml/min, and fluorescence detection at excitation and emission wavelengths of 220 and 327 nm.

Inhibitory effects of Choto-san (Diao-teng-san), and hooks and stems of Uncaria sinensis on free radical-induced lysis of rat red blood cells.

The present study is designed to test our hypothesis that the ingestion of Uncaria sinensis (US), the main medicinal plant of Choto-san (Diao-teng-san, CS), would protect red blood cell (RBC) membrane from free radical-induced oxidation if polyphenolics in US could be absorbed and circulated in blood. When incubated with RBC suspension, Choto-san extract (CSE) and Uncaria sinensis extract (USE) exhibited strong protection for RBC membrane against hemolysis induced by 2,2-azo-bis (2-amidinopropane) dihydrochloride (AAPH), an azo free-radical initiator. The inhibitory effect was dose-dependent at concentrations of 50 to 1000 microg/mL. Ingestion of 200 mg of USE was associated with a significant decrease in susceptibility of RBC to hemolysis in rats. Furthermore, caffeic acid, an antioxidative hydroxycinnamic acid, was identified in rat plasma after administration of URE.

Reduction of plasma triglyceride level and enhancement of plasma albumin concentration by Oren-gedoku-to administration.

Oren-gedoku-to (Huanglian-Jie-Du-Tang, OGT) has been used for the treatment of cerebrovascular disease, hypertension, gastritis and liver disease in Japan. The present study was to test whether ingestion of OGT extract (TJ-15) would affect the metabolism of fatty acids and the usual antioxidant molecule (such as albumin, uric acid and bilirubin) levels in human plasma. After the administration of TJ-15, plasma total cholesterol and the triglyceride level significantly decreased, and lipoprotein lipase mass increased. Significant enhancement of plasma albumin level and reduction of the total plasma protein level resulted in an increment of the albumin/globulin ratio. Plasma fibrinogen, an independent risk factor for cerebrovascular disease, declined considerably, but the reduction was not statistically significant. The findings of this study suggest that ingestion of TJ-15 improves the microcirculation through lipid and protein metabolisms, and is useful for the treatment of cerebral vascular attack in human.

Incidence and clinical features of liver injury related to Kampo (Japanese herbal) medicine in 2,496 cases between 1979 and 1999: problems of the lymphocyte transformation test as a diagnostic method.

We retrospectively examined the summaries of all admission records of patients from 1979 to 1999 in our department, and selected for further study all liver injuries suspected of being related to Kampo medicines. Among 2,496 summaries, 30 summaries described liver disorders suspected of being related to Kampo medicines. Whether there was a causal relationship between the use of Kampo medication and the occurrence of liver injury was assessed according to the criteria described by Haller and Benowitz (2000), independently of the results of the lymphocyte transformation test (LTT). Among 30 events, we concluded that 9 were definitely unrelated, and 6 were probably unrelated to the use of Kampo medicines. Nine events (0.36% of 2,496 patient admissions and 0.06% of 14,616 outpatients) were considered possibly related, and only 6 events (0.24% of 2,496 patient admissions and 0.04% of 14,616 outpatients) were judged to be definitely or probably related to Kampo medicines. Low-grade eosinophilia was observed in a few patients of these "related" groups, and no fever or rash was observed in these "related" groups. Other clinical features, including type of liver injury, duration of Kampo medicine-use, recovery period and laboratory data, were not different from liver injuries associated with western drugs. Most patients in the definitely "unrelated" group were positive in the LTT for the suspect Kampo medicine, suggesting that the LTT may be unreliable for the diagnosis of Kampo-medicine-induced liver injury. From 1979 to 1999, our use of Kampo medicines to treat patients resulted in a low rate of liver injury and no fatalities.

Effects of Choto-san on hemorheological factors and vascular function in stroke-prone spontaneously hypertensive rats.

Choto-san is a formula used for the treatment of headache and vertigo. Recently it has often also been used for hypertension and dementia. One of the mechanisms involved is thought to be the improvement of blood circulation, but the details are still unclear. In this study, the effect of Chotosan was studied on nitric oxide (NO) function, hemorheological factors and endothelial function in stroke-prone spontaneously hypertensive rats (SHR-SP). Rats were given Choto-san in drinking water for eight weeks. Body weight, blood pressure, serum NO2-/NO3-, lipid peroxides, blood viscosity, erythrocyte deformability and endothelium-dependent/-independent relaxation were measured. The results indicated that Choto-san caused a decrease in blood pressure and an increase in erythrocyte deformability and NO function. Blood viscosity was not changed. Furthermore, endothelium-dependent relaxation by acetylcholine was significantly increased as compared to control. In this study, it was supposed that Choto-san had a protective effect on the endothelium. SHR-SP is a useful model for human brain stroke, and Choto-san showed a protective effect against cerebral vascular injury in the susceptible rat.

Administration of isoferulic acid improved the survival rate of lethal influenza virus pneumonia in mice.

BACKGROUND: Isoferulic acid (IFA) is a main active ingredient of the rhizoma of Cimicifuga beracleifolia, which is used frequently in Japanese traditional medicine as an anti-inflammatory drug. It has been revealed that IFA inhibits the production of macrophage inflammatory protein-2 (MIP-2), which is a murine counterpart of the chemokine family that may contribute to the pathogenesis of inflammatory diseases through the chemotactic activity for inflammatory and immune effector cells. AIM OF THE STUDY: In this study, we investigated the therapeutic effect of IFA on the progression of lethal influenza virus pneumonia in mice by comparison with that of dexamethasone (DX), a potent inhibitor for various inflammatory cytokines including MIP-2. METHODS: Mice were infected by intranasal inoculation of influenza virus under ether anesthesia. The IFA or DX was given by oral administration once daily for 4 days after infection. After infection, the survival rate and the change in body weight were daily monitored. RESULTS: IFA administration markedly improved the survival rate and body weight loss of influenza virus-infected mice in a suitable dose range (0.5 mg/day). However, DX administration did not show a beneficial effect at any dose. CONCLUSION: These data suggested that IFA is a novel tool not only for the intervention therapy, but also for the studies on the pathogenesis of influenza virus-induced pneumonia.

Protective effect of phenolic compounds isolated from the hooks and stems of Uncaria sinensis on glutamate-induced neuronal death.

We isolated the phenolic compounds epicatechin, catechin, procyanidin B-1, procyanidin B-2, hyperin and caffeic acid from the hooks and stems of Uncaria sinensis (HSUS), and studied their protective effects against glutamate-induced neuronal death in cultured rat cerebellar granule cells. Cell viability evaluated by MTT assay was significantly increased by application of epicatechin (100-300 microM), catechin (300 microM), procyanidin B-1 (30-300 microM) and procyanidin B-2 (100-300 microM) compared with exposure to glutamate only. 45Ca2+ influx into cells induced by glutamate was also significantly inhibited by administration ofepicatechin (300 microM), catechin (300 microM), procyanidin B-1 (100-300 microM) and procyanidin B-2 (100-300 microM). These results suggest that epicatechin, catechin, procyanidin B-1 and procyanidin B-2 are the active components of HSUS that protect against glutamate-induced neuronal death in cultured cerebellar granule cells by inhibition of Ca2+ influx.

Metastases to the penis from carcinoma of the prostate.

A 58-year-old man presented with dysuria at the Osaka Medical College Hospital in November 1996. Laboratory examination revealed elevated serum prostate-specific antigen (PSA) to > 100 ng/mL. Adenocarcinoma of the prostate with metastasis to the bone was diagnosed after a biopsy of the prostate and bone scintigraphy; hormonal therapy was administered. Although bone metastasis was well controlled and the serum PSA level declined to within normal levels (2.0 ng/mL), several painless nodules were found on the penile glans. Biopsy of the nodules showed that the penile tumor was a metastasis from the prostate cancer. The patient underwent partial penectomy for relief from penile pain. The serum PSA level showed no elevation 3 months after the partial penectomy, suggesting that careful observation of prostate cancer patients is necessary, even when oseous metastasis is well controlled and serum PSA levels are kept within normal ranges by hormonal therapy. The case also indicates that urologists should consider the possibility of metastasis to the penis from prostate cancer.

Access to perceptual and conceptual information in the left and right hemispheres.

It is assumed that there are hemispheric differences in the type of information available for the processing of word meanings, e.g., categorical or associative information. In the present experiment, we used a semantic priming paradigm to examine whether perceptual or conceptual properties of word meanings would be associated with the left or right hemisphere. The present experiment also examined time-course activation of these properties across the hemispheres, using short and long stimulus onset asynchronies. The results indicated that perceptual information is available only in the right hemisphere at an early rather than a late stage of target processing, while conceptual information is available in both hemispheres at both early and later stages of target processing. It is suggested that the imagery system in the right hemisphere may contribute to the perceptual priming observed in this hemisphere.

Intracranial aneurysms and autosomal dominant polycystic kidney disease: followup study by magnetic resonance angiography.

PURPOSE: Intracranial aneurysms are known to complicate autosomal dominant polycystic kidney disease. We assess the value of magnetic resonance angiography to detect intracranial aneurysms early in patients with autosomal dominant polycystic kidney disease. MATERIALS AND METHODS: We evaluated 15 patients with asymptomatic autosomal dominant polycystic kidney disease treated at our hospital between 1992 and 1998. Magnetic resonance angiography was performed at presentation and was repeated 18 to 72 months after treatment. RESULTS: On the initial magnetic resonance angiogram 3 intracranial aneurysms were detected in 3 patients. The intracranial aneurysms ranged from 4 to 8 mm. in diameter, and were in the anterior communicating artery in 1, in the vertebral artery in 1, and at the bifurcation of the internal carotid artery and ophthalmic artery in 1 case. Repeat magnetic resonance angiography 18 to 72 months after treatment revealed new intracranial aneurysms in 2 patients. In 1 case the lesion was 7 mm. in diameter, in the internal carotid artery and posterior communicating artery, and detected 69 months after the initial angiogram. In the other patient the lesion was 4 mm. in diameter, in the anterior communicating artery and detected 71 months after treatment. CONCLUSIONS: Since new intracranial aneurysms were demonstrated in patients followed for a long time periodic repeat magnetic resonance angiography is important.

Ruptured cerebral aneurysm not detected by magnetic resonance angiography in juvenile autosomal dominant polycystic kidney.

Recently, it has been reported that magnetic resonance angiography (MRA) is useful for screening and following up cerebral aneurysms in patients with autosomal dominant polycystic kidney disease (ADPKD). However, a patient was encountered with a ruptured cerebral aneurysm that was not detected by routine MRA. The patient, a 29-year-old man with ADPKD, was followed up at our hospital for more than 5 years. Ten months after an MRA examination, he suddenly developed severe headache. Brain computed tomography revealed subarachnoid hemorrhage. Digital subtraction angiography detected an aneurysm with a diameter of approximately 2 mm in the anterior communicating artery. Clipping of the aneurysm was immediately performed and he recovered without sequela after operation. Magnetic resonance angiography is useful to detect cerebral aneurysms, but it can not detect aneurysms measuring less than 4 mm.

Biochemical and virological response to interferon therapy in patients with chronic hepatitis C, co-infected with hepatitis G virus.

It is still unclear whether hepatitis G virus (HGV) and hepatitis C virus (HCV) co-infection influences the natural course of chronic HCV infection and the response to interferon (IFN) therapy. In this study, we investigated the HGV RNA changes and responses to IFN therapy of HGV RNA-positive hepatitis C patients. The presence of HGV RNA in 264 patients who received IFN therapy at our institute was examined using the nested reverse transcription-polymerase chain reaction with primers deduced from the 5' non-coding region (5'-NCR) of the HGV. We also analysed the nucleotide sequences of the 5'-NCR and HGV before and after IFN therapy. Twelve (4.5%) of the 264 patients with chronic hepatitis C were HGV RNA positive. Of these 12 patients, full information was available in nine. Of those nine, seven became HGV RNA negative during IFN therapy but in six of the seven a relapse occurred. HCV RNA was not detected 1 year after IFN therapy in six patients. The serum alanine aminotransferase (ALT) levels of all the HCV RNA-negative patients post-treatment was within the normal range, irrespective of their HGV RNA status. Nucleotide sequences did not change after IFN therapy in any patient. Hence, we confirm that HGV is sensitive to IFN therapy but the liver damage caused by HGV infection is very mild or does not modify the liver function tests.