Taurine alters respiratory gas exchange and nutrient metabolism in type 2 diabetic rats

OBJECTIVE: To assess the effect of taurine supplementation on respiratory gas exchange, which might reflect the improved metabolism of glucose and/or lipid in the type 2 diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats. RESEARCH METHODS AND PROCEDURES: Male OLETF rats (16 weeks of age) were randomly divided into two groups: unsupplemented group and taurine-supplemented (3% in drinking water) group. After 9 weeks of treatment, indirect calorimetry and insulin tolerance tests were conducted. The amounts of visceral fat pads, tissue glycogen, the blood concentrations of glucose, triacylglycerol, taurine, and electrolytes, and the level of hematocrit were compared between groups. A nondiabetic rat strain (Long-Evans Tokushima Otsuka) was used as the age-matched normal control. RESULTS: The indirect calorimetry showed that the treatment of OLETF rats with taurine could reduce a part of postprandial glucose oxidation possibly responsible for the increase of triacylglycerol synthesis in the body. Taurine supplementation also improved hyperglycemia and insulin resistance and increased muscle glycogen content in the OLETF rats. Supplementation with taurine increased the blood concentration of taurine and electrolyte and fluid volume, all of which were considered to be related to the improvement of metabolic disturbance in OLETF rats. DISCUSSION: Taurine supplementation may be an effective treatment for glucose intolerance and fat/lipid accumulation observed in type 2 diabetes associated with obesity. These metabolic changes might be ascribed, in part, to the alteration of circulating blood profiles, where the improved hyperglycemia and/or the blood accumulation of taurine itself would play roles.     

Clinical characteristics relevant to myocardial cell apoptosis: analysis of pericardial fluid

We investigated the pro-apoptotic potential of pericardial fluids from patients with different clinical conditions on cultured neonatal rat cardiomyocytes. Pericardial fluids were obtained during open heart surgery from 88 patients with ischemic heart disease (n=44), valvular heart disease (n=32), or aortic disease (n=12). The terminal deoxynucleotidyl transfer-mediated end labeling fragmented nuclei assay was performed on primary cardiac myocytes from neonatal rats in the presence of 1% pericardial fluid from each patient. We evaluated relations between these patients' clinical characteristics and the extent of myocardial cell apoptosis. Induction of myocardial cell apoptosis by pericardial fluids was observed in 29 of the 88 patients (33.0%). The prevalence of myocardial cell apoptosis was significantly influenced by diabetes mellitus (DM) (53.6% with vs. 23.3% without, P<0.005), acute coronary syndrome (ACS) (64.7% with vs. 25.4% without, P<0.005), and poor left ventricular systolic function (60.0% with vs. 25.0% without, P<0.005). Multivariate stepwise logistic regression analysis revealed that the presence of DM, ACS, and poor left systolic function were significant predictors of myocardial cell apoptosis. DM, ACS and left ventricular dysfunction may play important roles in the pathogenesis of myocardial cell apoptosis in the clinical setting.     

Dopamine D4 ligands and models of receptor activation: 2-(4-pyridin-2-ylpiperazin-1-ylmethyl)-1H-benzimidazole and related heteroarylmethylarylpiperazines exhibit a substituent effect responsible for additional efficacy tuning

A series of subtype selective dopamine D(4) receptor ligands from the hetroarylmethylphenylpiperazine class have been discovered that exhibit a remarkable structure-activity relationship (SAR), revealing a substituent effect in which regiosubstitution on the terminal arylpiperazine ring can modulate functional or intrinsic activity. Other structure-dependent efficacy studies in the dopamine D(4) field have suggested a critical interaction of the heteroarylmethyl moiety with specific protein microdomains in controlling intrinsic activity. Our studies indicate that for some binding orientations, the phenylpiperazine moiety also plays a key role in determining efficacy. These data also implicate a kinetic or efficiency term, contained within measured functional affinities for agonists, which support a sequential binding and conformational stabilization model for receptor activation. The structural similarity between partial agonist and antagonist, within this subset of ligands, and lack of bioisosterism for this substituent effect are key phenomena for these hypotheses.     

Effects of the traditional Japanese medicine Unkei-to on the corticotropin-releasing factor-induced increase in locomotor activity

The effect of Unkei-to, a traditional Japanese herbal medicine and strong in vitro releaser of cytokine-induced neutrophil chemoattractant (CINC), on the increase in locomotor activity induced by intracerebroventricular (icv) injection of corticotropin-releasing factor (CRF) in male rats in a familiar environment was investigated. Oral administration of Unkei-to (100 mg/kg) for 1 week significantly attenuated the CRF-induced increase in locomotor activity. Unkei-to also reduced the CRF-induced accumulation of hypothalamic CINC, which has a functional antagonistic action on the response to CRF; the reduction may reflect an increased release of CINC. These results suggest that Unkei-to has an alleviative effect on the action induced by brain CRF and the mechanism of this effect may partly involve CINC.     

New sesquiterpenes from Capsicum annuum

The ethyl acetate soluble fraction of a MeOH extract of the dried stems and roots of Capsicum annum gave 10 new sesquiterpenoids (1-10) and nine known compounds. The structures of the new compounds were elucidated on the basis of spectroscopic evidence. The isolated new compounds were evaluated for their cytotoxic activities.     

A hot water extract of Chlorella pyrenoidosa reduces body weight and serum lipids in ovariectomized rats

The effects of a hot water extract of Chlorella pyrenoidosa, which contains chlorella growth factor (CGF), on the body weight, serum lipids, and the bone mass were evaluated using an ovariectomized rat as a model for postmenopausal bone loss. Rats were divided into four groups: sham-operated (Sham), Sham given the CGF solution, ovariectomized (OVX), and OVX given the CGF solution, respectively. Administration of the extract to OVX rats suppressed the body weight gain. After 7 weeks, the administration of the extract to the OVX group reduced increases in both serum total cholesterols and high-density lipoprotein (HDL) cholesterols. It also normalized the decrease of triglyceride level in the OVX group. The ovariectomy decreased the tibial bone mineral density (BMD) by 19%, and the administration of the extract to OVX rats did not inhibit this decrease. These results suggest that a dietary supplement of CGF may be useful to control the body weight and improve lipid metabolism of menopausal women.     

Radiotherapy combined with transarterial infusion chemotherapy and concurrent infusion of a vasoconstrictor agent for nonresectable advanced hepatic hilar duct carcinoma

BACKGROUND: The treatment of patients with advanced hepatic hilar duct carcinoma is a challenging problem. The current study was performed to evaluate the outcome of patients with advanced hepatic hilar duct carcinoma who received external beam radiotherapy (EBRT) combined with transarterial chemotherapy and infusion of a vasoconstrictor. METHODS: Between April 1993 and December 2002, 23 patients with histopathologically confirmed hilar duct carcinoma entered the study. The median total dose of EBRT was 41.4 grays (Gy). Transarterial chemotherapy was performed twice during EBRT. It was comprised of an infusion of a cocktail of 20 mg of epirubicin, 10 mg of mitomycin C, and 500 mg of 5-fluorouracil and was administered 1 minute after injection of epinephrine via a catheter introduced in the hepatic arteries. After the combined treatment, the patients underwent biliary endoprosthesis after evaluation of the initial response to treatment by percutaneous transhepatic cholangiography (PTC). The initial responses based on PTC were classified into four categories: CR, no stenosis; PR, relief of stenosis/obstruction; NC, no change; and PD, progressive stenosis/obstruction. The outcome parameters were survival rates and time, as well as frequency and type of complications. RESULTS: Excluding 1 patient who discontinued the treatment, the initial responses of 22 patients were 1 CR (5%), 8 PR (36%), 11 NC (50%), and 2 PD (9%). The response rate was 41%. The overall survival rates at 1 year, 2 years, and 3 years after treatment were 59%, 36%, and 18%, respectively. CONCLUSIONS: The combination of radiotherapy, transarterial infusion chemotherapy, and concurrent infusion of a vasoconstrictor can be delivered safely with good efficacy for patients with advanced hilar duct carcinoma.     

Comparison of K-ras point mutation distributions in intraductal papillary-mucinous tumors and ductal adenocarcinoma of the pancreas

Intraductal papillary-mucinous tumors (IPMT) consist of cells with varying histologic degrees of severity and exhibit multiple tumor loci; however, whether or not these lesions exhibit the same genetic changes has not been clarified. To investigate this point, we analyzed K-ras mutations in multiple IPMT lesions from each patient enrolled in our study and compared our findings to those for patients with ductal adenocarcinoma of the pancreas (DC). Twenty IPMT specimens and 7 DC specimens were resected, microdissected and analyzed for the presence of K-ras mutations. The mutated genes were then sequenced using a genetic analyzer. K-ras mutations were observed in 80% of IPMT and 100% of DC patients. More than 2 types of K-ras mutation were observed in the main tumors of 43.8% of IPMT and 0% of DC patients. K-ras mutations in peritumoral and separated lesions were observed in 66.7% and 62.5% of IPMT patients, respectively. At least one identical mutation between the main tumor and the peritumoral or separated lesions was recognized in all of the IPMT patients with those lesions. Different mutations from those in the main tumor were observed in 40% of IPMT patients with separated lesions. The survival curve of IPMT-carcinoma patients with more than 2 types of K-ras mutation in the main tumor was better than that with one type of K-ras mutation. IPMT patients exhibit a remarkably genetic heterogeneity in main tumor and have good prognosis.