Molecular defect in human erythropoietic protoporphyria with fatal liver failure

We investigated the molecular basis of ferrochelatase in a Japanese patient with erythropoietic protoporphyria (EPP), complicated by fatal liver failure, and defined a novel point mutation in the ferrochelatase gene. cDNAs were synthesized using Epstein-Barr-virus-transformed lymphoblastoid cells from the proband. cDNA clones encoding ferrochelatase in the proband were isolated by amplification using the polymerase chain reaction. There were two sizes of ferrochelatase cDNAs; one was normal in size, the other being smaller. Sequence analysis of the abnormally sized cDNA clones revealed that they lacked exon 9 of the ferrochelatase gene. Genomic DNA analysis demonstrated that the proband had the abnormal allele and that it contained a G to A point mutation at the first position of the donor site of intron 9. An identical mutation was detected in the affected family members of the proband by allele-specific oligonucleotide hybridization analysis. EPP is inherited in an autosomal dominant manner in this family.     

The limited proteolysis of rabbit muscle aldolase by cathepsin B1

Rabbit muscle aldolase is inactivated by cathepsin B1 to approximately 10 percent of the original activity for fructose-1, 6-bisphosphate cleavage without change in the fructose-1-phosphate cleavage activity. Activity loss is related to release of one mole of the dipeptide, alanyl-tyrosine, per mole of the enzyme. The additional three moles of the peptide are released without further loss of the residual activity.     

Effects of endothelin on microcirculation of the pancreas.

Endothelin, a newly described endothelial-derived peptide, has potent vasoconstrictive properties and has been speculated to play a physiological role in the regulation of blood flow in some organs. The present study was designed to evaluate the effects of endothelin-1, endothelin-2 and endothelin-3 on the pancreatic microcirculation. Pancreatic tissue blood flow was measured by a laser Doppler flow meter in anesthetized dogs and endothelin-1, endothelin-2 or endothelin-3 was injected intravenously in graduated doses. Endothelins induced dose-dependent decreases in pancreatic tissue blood flow. Endothelin-1, endothelin-2 and endothelin-3 at a dose of 100 pmol/kg reduced pancreatic blood flow by 45.4%, 19.6% and 51.9%, respectively, whereas systemic arterial blood pressure was not significantly affected. When endothelin-3 was administered at a dose of 1000 pmol/kg, pancreatic blood flow was decreased by 73.5% with a concomitant increase of systemic arterial blood pressure by 17.6%. Endothelins potently decreased pancreatic tissue blood flow, suggesting a possible role of these agents in regulating the pancreatic microcirculation.     

CoQ10 supplementation elevates the epidermal CoQ10 level in adult hairless mice

We have already shown that prolonged supplementation of CoQ(10) in humans reduces the wrinkle area rate and wrinkle volume per unit area in the corner of the eye. CoQ(10) supplementation is known to increase the CoQ(10) level in serum and in many organs; however, the level of CoQ(10) in skin has not yet been fully investigated yet. We examined whether CoQ(10) intake elevates the CoQ(10) and CoQ(9) levels in epidermis, dermis, serum and other organs (kidney, heart, brain, muscle and crystalline lens) in 43-week-old hairless male mice. We also established a method using a high performance liquid chromatograph equipped with an electrochemical detector (HPLC-ECD) to simultaneously quantify CoQ(9) and CoQ(10) in the tissues. CoQ(10) (0, 1, 100 mg/kg p.o.) was administered daily for 2 weeks. CoQ(10) supplementation of 100 mg/kg increased the serum and epidermal CoQ(10) levels significantly, but did not increase the CoQ(10) levels in either dermis or other organs. In conclusion, we showed that CoQ(10) intake elevates the epidermal CoQ(10) level, which may be a prerequisite to the reduction of wrinkles and other benefits related to the potent antioxidant and energizing effects of CoQ(10) in skin.     

Comparison of regulative functions between dietary soy isoflavones aglycone and glucoside on lipid metabolism in rats fed cholesterol

The effects of dietary soy isoflavones aglycone and glucoside on lipid metabolism were compared in male Sprague-Dawley rats (4 weeks old) given purified diets containing 0.3% cholesterol. The rats were fed a diet supplemented with either isoflavone aglycone-rich powder (IF-A group) or isoflavone glucoside-rich powder (IF-G group) or isoflavone-free diet (control group) for 40 days. The additional level of isoflavone aglycone moiety in the diet was prepared to the same level (approximately 0.096 g/100 g: approximately 0.1% in diet). The activity of hepatic cholesterol 7alpha-hydroxylase tended to be slightly higher in the rats fed isoflavones than in those fed the isoflavone-free diet. On the other hand, the activity of hepatic Delta6 desaturase in the IF-A group was lower than that of the control group. Reflecting this effect, the Delta6 desaturation indices [(20:3n-6+20:4n-6)/18:2n-6] in liver phospholipids of the IF-A group were lower than those in the control group. Liver and serum total cholesterol levels and liver TG level were also reduced by consumption of isoflavone aglycone. Moreover, serum TG level was lowered by consumption of both isoflavones aglycone and glucoside. The level of serum total isoflavones in the IF-A group was significantly higher than that in the IF-G group. Therefore, we speculate that the absorption speed of isoflavone aglycones might be faster than that of isoflavone glucosides in rats. This study suggests that dietary soy isoflavones, particularly their aglycone form, may exert a beneficial effect on lipid metabolism in rats fed cholesterol.     

Improvement of accessory symptoms of hypertension by TSUMURA Orengedokuto Extract, a four herbal drugs containing Kampo-Medicine Granules for ethical use: a double-blind, placebo-controlled study.

A double-blind, placebo-controlled study was conducted to evaluate the efficacy, safety, and utility of TSUMURA Orengedokuto Extract Granules for Ethical Use (TJ-15) as a treatment for the accessory symptoms of hypertension. Two capsules of the study drug were administered orally 3 times daily (i.e., before meals) for 8 weeks. Among 265 patients enrolled in the study, 134 were assigned to the TJ-15 group and 131 were assigned to the placebo group, of whom 204 patients (103 in the TJ-15 group and 101 in the placebo group) were included in the efficacy and utility analyze and 251 patients (128 in the TJ-15 group and 123 in the placebo group) were included in the safety analysis. Efficacy was significantly higher in the TJ-15 group based on the total score for the accessory symptoms of hypertensions which was the primary efficacy endpoint (Wilcoxon's rank sum test, p=0.013). When each accessory symptom of hypertension was assessed separately, efficacy was higher for hot flushes and facial suffusion in the TJ-15 group (Wilcoxon's rank sum test, p=0.034, and 0.022, respectively). There were no significant differences between the TJ-15 and the placebo groups with respect to the decrease of blood pressure or the antihypertensive effect. There was also no significant difference between the two groups with regard to the overall safety rating. The utility rating was significantly higher in the TJ-15 group than in the placebo group (Wilcoxon's rank sum test, p=0.016). In conclusion, TJ-15 was superior to placebo with respect to efficacy, safety, and utility for the treatment of accessory symptoms of hypertension.     

Apnea during Cheyne-Stokes-like breathing detected by a piezoelectric sensor for screening of sleep disordered breathing

Sleep and Biological Rhythms - A simplified diagnostic/monitoring instrument for use in primary screening for sleep-disordered breathing (SDB) has been desired. This study was designed to assess...     

Synthesis of a Novel C-Nucleoside, 2-Amino-7-(2-deoxy-β- D-erythro-pentofuranosyl)-3H,5H-pyrrolo-[3,2-d]pyrimidin-4-one (2′-Deoxy-9-deazaguanosine)

Abstract

A synthesis of the C-nucleoside, 2-amino-7-(2-deoxy-β-D-erythro-pentofuranosyl)-3H,5H-pyrrolo[3,2-d]pyrimidin-4-one (9-deaza-2′-deoxyguanosine) was achieved starting from 2-amino-6-metnyl-3H-pyrimidin-4-one (5) and methyl 2-deoxy-3,5-di-O-(p-nitrobenzoyl)- D-erythro-pento-furanoside (11). The anomeric configuration of the C-nucleoside was established by ¹H NMR, NOEDS and ROESY. This C-nucleoside did not inhibit the growth of T-cell lymphoma cells.