Yoshinori Tone

Effects of Coffee Consumption on Oxidative Susceptibility of Low-Density Lipoproteins and Serum Lipid Levels in Humans

Since little is known about how coffee intake affects low-density lipoprotein (LDL) oxidative susceptibility and serum lipid levels, we conducted anin vivo study in 11 healthy male students of Wakayama Medical University aged between 20 and 31 years fed an average Japanese diet. On days 1-7 of the study, the subjects drank mineral water. On day 7, the subjects began drinking coffee, 24 g total per day, for one week. This was followed by a one week “washout period” during which mineral water was consumed. Fasting peripheral venous blood samples were taken at the end of each one-week period. LDL oxidation lag time was approximately 8% greater (p < 0.01) after the coffee drinking period than the other periods. Serum levels of total cholesterol and LDL-cholesterol (LDL-C) and malondialdehyde (MDA) as thiobarbituric acid reactive substances (TBARS) were significantly decreased after the coffee drinking period. Finally, regular coffee ingestion may favorably affect cardiovascular risk status by modestly reducing LDL oxidation susceptibility and decreasing LDL-cholesterol and MDA levels.

Abundant expression of thromboxane synthase in rat macrophages

The cloned cDNA for rat thromboxane (TX) synthase with a size of 1851 bp contained a 1599‐bp open reading frame which encoded a 533‐amino acid protein sharing 79.7% identity with human TX synthase. RNA blot analysis was carried out with rat cells and tissues. Rat peritoneal macrophages most abundantly expressed mRNA for TX synthase, and its level was not changed by in vivo stimulation of casein. Bone marrow, spleen, lung and thymus also expressed the TX synthase gene. These findings suggest the possibility that TXA2 plays a role in the immune system.

INVERSE GENE EXPRESSION OF PROSTACYCLIN AND THROMBOXANE SYNTHASES IN RESIDENT AND ACTIVATED PERITONEAL MACROPHAGES

Prostacyclin and thromboxane A2 produced from prostaglandin H2 are known to be important modulators with opposite biological activities. To examine possible roles of these prostanoids in immune responses, we have studied the gene expression of prostacyclin synthase (PGIS) and thromboxane synthase (TXS) in murine resident macrophages or in macrophages elicited with casein or bacillus Calmette‐Guérin (BCG). Northern blot analyses showed that the PGIS mRNA was expressed in a decreasing order in the resident, and casein‐ and BCG‐elicited macrophages. In contrast, the TXS mRNA was expressed in an increasing order in the resident, and casein‐ and BCG‐elicited macrophages. On the other hand, the mRNA for cyclooxygenase‐2, which produces PGH2 and participates in the production of prostanoids in inflammation, was expressed in both the resident and BCG‐elicited macrophages but barely in the casein‐elicited cells. In situ hybridization analysis showed that the expression of mRNAs for PGIS and TXS was ascribable not only to the alteration of the expression levels of both mRNAs in the each macrophage but also to the changes in subpopulations of the cells expressing these mRNAs. These observations suggested that the inverse gene expression of PGIS and TXS in macrophages contributes to immune responses by modulating the relative levels of prostacyclin and thromboxane A2.

Various dietary protein intakes and progression of renal failure in spontaneously hypercholesterolemic Imai rats.

Background/Aim: Dietary protein restriction is known to be beneficial in the preservation of the renal function in patients with chronic renal failure. Recently, the effect of varying quantity and quality of dietary protein intakes was also studied. This study investigates the effects of different dietary animal proteins on renal function in spontaneously hypercholesterolemic Imai rats that exhibit renal lesions similar to human focal and segmental glomerulosclerosis. The sources of proteins were from casein, pork, and fish. Primary concern was the effect of fish meat protein, because the effects of fish oil are well reported. To examine whether remnants of fish oil affect the experimental results, semi-defatted fish meat and fully defatted fish meat were prepared for these experiments. Methods: Forty-two Imai rats were placed on diets containing casein, defatted pork meat, semi-defatted fish meat, or defatted fish meat as a protein sources from 10 to 22 weeks of age. Twenty-four hour urine collections were obtained along with measurements of systolic blood pressure and drawing blood from the tail artery every 4 weeks. Finally, the kidneys were removed and prepared for histological study. Results: The semi-defatted fish meat diet retarded the rise of plasma cholesterol, virtually completely prevented the development of hypertriglyceridemia, and slowed the progression of proteinuria, renal function failure, and glomerular injury as compared with the control casein diet. However, the fully defatted fish meat diet led to renal failure at the same rate as the casein diet. The defatted pork diet group exhibited a higher creatinine clearance at the end of the experiments as compared with the casein and the fully defatted fish meat diet groups. Conclusions: These data suggest that an important determinant of the protective effects of the semi-defatted fish meat diet was related to the prevention of hypercholesterolemia and hypertriglyceridemia by the remaining fish oil. Fish meat protein itself did not indicate superior beneficial effects in the regression of the renal function in Imai rats as compared with casein protein, and defatted pork showed better results than casein and fully defatted fish meat.

Intravenous Maxacalcitol Therapy Correlates with Serum Fibroblast Growth Factor 23 Levels in Hemodialysis Patients Independent of Serum Phosphate or Calcium Levels

Fibroblast growth factor 23 (FGF23) is a regulator of phosphate and vitamin D homeostasis that carries out primary bone- and mineral-related physiological functions to increase renal phosphate excretion and reduce 1α-hydroxylation of 25-hydroxyvitamin D. In a negative endocrine feedback loop, 1,25-dihydroxyvitamin D also stimulates FGF23 secretion. Previous studies have assessed the correlation between vitamin D receptor activator therapy and FGF23 concentrations, and to our knowledge, none has assessed the correlation between intravenous (i.v.) maxacalcitol therapy and FGF23 concentration in hemodialysis patients. Subjects included 148 patients on maintenance hemodialysis. Serum FGF23 concentrations were measured. The correlations among serum FGF23 concentrations with i.v. maxacalcitol therapy and other clinical parameters and medications were analyzed. Mean serum log FGF23 was 3.7 ± 0.8 pg/mL. After division into two equal groups based on median serum log FGF23 level, the percentages of patients administered i.v. maxacalcitol (60/74 [81.1%] vs. 45/74 [60.8%], p < 0.01) were significantly higher in the high log FGF23 group. The amounts of serum FGF23 concentrations had been significantly higher to the amounts of i.v. maxacalcitol per week dependency. Multivariate regression analysis showed that treatment with i.v. maxacalcitol was an independent predictor of serum FGF23 levels, regardless of phosphate or calcium concentrations. i.v. maxacalcitol correlates with serum FGF23 concentration in hemodialysis patients, independent of serum phosphate or calcium concentrations.

Studies on the inhibitory effect of uremic toxins on proliferation of cultured tumor cells. Comparison between serum and urine from normal subjects and uremic patients.

Uremic toxinは正常の細胞機能を種々に障害することはよく知られているが, 腫瘍細胞のような増殖能の高い細胞にも抑制的に働くのかどうかは現在のところよく知られていない. そこで今回uremic toxinの培養腫瘍細胞におよぼす影響について, hexosaminidase assayを用いて検討した. すべての細胞株で濃度依存的な抑制が認められた. 個々の細胞株ではヒト肝癌細胞 (HCC) は正常血清添加に比べ透析患者血清添加で著明な抑制がみられ, 透析前血清では30%添加にて増殖が完全に抑制された. 透析後血清添加ではこの濃度で, 抑制率は50%まで回復した. 一方尿添加による影響は血清添加による場合とは全く逆で, 腎不全尿を3%添加しても増殖に影響がなかったが, 健常人尿は1%添加でも50%の増殖抑制を示した. 他のP3U1細胞およびNUGC-4細胞でも程度の差はあるがほぼ同様の結果を示した. さらに正常人尿をSephadex G-15カラムにて細分画に分けて検討すると, 溶出の早い方から2番目の分画で最も強い抑制作用がみられた. 以上により透析患者の悪性腫瘍ではこの蓄積された因子が, 直接的には腫瘍の増殖を抑制する方向に働いて担癌状態を修飾していると考えられる.