Yoshinobu Kamiya

Glucagon-like peptide-1 (GLP-1) protects against methylglyoxal-induced PC12 cell apoptosis through the PI3K/Akt/mTOR/GCLc/redox signaling pathway.

Patients with long-standing diabetes commonly develop diabetic encephalopathy, which is characterized by cognitive impairment and dementia. Oxidative stress-induced neuronal cell apoptosis is a contributing factor. Glucagon-like peptide (GLP)-1 has recently become an attractive treatment modality for patients with diabetes. It also readily enters the brain, prevents neuronal cell apoptosis, and improves the cognitive impairment characteristic of Alzheimers disease. Therefore, we investigated whether GLP-1 could protect against oxidative stress-induced neuronal cell apoptosis in pheochromocytoma (PC12) cells. PC12 cells were exposed to 1 mM methylglyoxal (MG) or MG plus 3.30 microg/ml GLP-1. Cell apoptosis, expression and phosphorylation of phosphatidylinositol-3 kinase/Akt/mammalian target of rapamycin/gamma-glutamylcysteine ligase catalytic subunit (GCLc), and redox balance were then determined. The data showed that MG induced PC12 apoptosis in accordance with the redox (glutathione (GSH) and GSH/glutathione disulfide [GSSG]) imbalance. GLP-1 protected against this MG-induced apoptosis, which corresponded to the phosphorylation of PI3K, Akt, and mTOR, as well as the upregulation of GCLc and the restoration of the redox imbalance. Inhibitors of PI3K (LY294002), Akt (Akt-I), and mTOR (rapamycin) reduced the GLP-1-induced GCLc upregulation and its protection against MG-induced PC12 apoptosis. The GLP-1-induced redox restoration was also attenuated by rapamycin. In conclusion, the neuroprotective effect of GLP-1 is due to an enhancement of PI3K/Akt/mTOR/GCLc/redox signaling.

Transforming growth factor (TGF) - α in human milk

Abstract Transforming growth factor (TGF) - α and epidermal growth factor (EGF) were measured in human milk by means of homologous radioimmunoassay. As previously reported, EGF concentration in the colostrum was approximately 200 ng/ml and decreased to 50 ng/ml by day 7 postpartum. The value of immunoreactive (IR) -TGF- α was 2.2–7.2 ng/ml, much lower than that of EGF. In contrast to EGF, the concentration of IR-TGF-α was fairly stable during the 7 postpartum days. There was no relationship between the concentrations of IR-TGF-α and IR-EGF, suggesting that the regulatory mechanism in the release of the two growth factors is different. On gel-chromatography using a Sephadex G-50 column, IR-EGF appeared in the fraction corresponding to that of authentic human EGF, while 70%–80% of the IR-TGF-α was eluted as a species with a molecular weight greater than that of authentic human TGF-α. Although the physiological role of TGF-α in milk is not known, it is possible that it is involved in the development of the mammary gland and/or the growth of newborn infants.

Effects of dehydroepiandrosterone on proliferation of human aortic smooth muscle cells

Dehydroepiandrosterone (DHEA) and its sulfate ester (DHEAS) have been shown to be associated with the progression of coronary atherosclerosis in clinical and in vivo studies. However, the mechanisms responsible for the association have not been determined. In the present study, we found that DHEA influences the in vitro growth of vascular smooth muscle cells obtained from the human aorta (hASMC). The concentrations of DHEA ranging from 10(-8) M to 10(-6) M significantly stimulated the mitogenesis of hASMC in serum-free culture. On the other hand, 4 hrs of pretreatment with DHEA attenuated the fetal calf serum induced proliferative effect in a dose-dependent manner. However, the in vitro effects of DHEA on the mitogenesis observed in hASMC were not seen in rat-derived aortic smooth muscle cell lines (A10 cells). With respect to DHEAS, the hormone, at concentrations up to 10(-5) M did not affect the growth of either hASMC or A10 cells in vitro. The growth response of hASMC to DHEA in vitro was markedly affected by the culture conditions. The differential proliferative effects of DHEA on smooth muscle cells between rat and human are of interest. We conclude that the effects of DHEA on mitogenesis of hASMC may, at least in part, explain the association between DHEA and atherosclerosis.

EFFECTS OF DEHYDROEPIANDROSTERONE ON MITOGEN-ACTIVATED PROTEIN KINASE IN HUMAN AORTIC SMOOTH MUSCLE CELLS

The objective of the present study was to determine whether dehydroepiandrosterone (DHEA) modifies growth factor-induced mitogen-activated protein kinase (MAPK) activation, based on our previous study demonstrating that DHEA attenuates fetal calf serum-induced proliferation in human male aortic smooth muscle cells (human male aortic SMCs). Human male aortic SMCs were used for this study. Platelet-derived growth factor-BB (PDGF-BB), epidermal growth factor (EGF), and basic fibroblast growth factor (bFGF), but not insulin-like growth factor-1 (IGF-1), stimulated MAPK activity. Only MAPK activation induced by PDGF-BB was reduced by pretreatment with DHEA, although DHEA did not affect the MAPK activation induced by EGF or bFGF. The basal and PDGF-stimulated MAPK activity were decreased by two types of cyclic AMP (cAMP) elevating agents and increased by cAMP-dependent protein kinase (PKA) inhibitor in human male aortic SMCs, suggesting that cAMP regulates MAPK negatively. The intracellular cAMP was increased by PDGF-BB. The increase of cAMP by PDGF-BB was augmented by pretreatment with DHEA, although DHEA alone did not affect cAMP. Neither EGF nor bFGF affected cAMP with and without DHEA pretreatment. Secretion of PGE2 induced by PDGF was augmented by pretreatment with DHEA. Stimulatory effects of DHEA on the production of PGE2 and cAMP were partially canceled by aromatase inhibitor and completely canceled by indomethacin or selective inhibitor of cyclooxygenase-2. These results suggest that DHEA inhibited MAPK activation induced by PDGF-BB via PGE2 overproduction and subsequent cAMP-dependent pathway in human male aortic SMCs.

Coexisting type III hyperlipoproteinemia and familial hypercholesterolemia: A case report

A 39-year-old man presented with type III hyperlipoproteinemia in association with heterozygous familial hypercholesterolemia (FH). He had extensive tuberous xanthomas over the knees and elbows and xanthomas in the Achilles tendons. He also had palmar xanthomas. He exhibited severe hypercholesterolemia and hypertriglyceridemia. This patient was heterozygous for FH, as evidenced by low low-density lipoprotein (LDL) receptor function on lymphocytes, and had type III hyperlipoproteinemia, as determined by apolipoprotein (apo) E phenotype 2/2 in isoelectric focusing of the E isoproteins and the presence of a broad beta band on electrophoresis. Because therapy consisting of diet restrictions and lipid-lowering agents such as clinofibrate and niceritrol did not decrease serum total cholesterol ([TC] 15.26 mmol/L) and triglyceride ([TG] 10.79 mmol/L) levels effectively, the patient underwent plasmapheresis once every 2 weeks using a dextran sulfate-cellulose column. Repeated plasmapheresis markedly reduced serum TC and TG and induced complete regression of the palmar xanthoma after 6 months. The severity of tuberous xanthomas on the knees and elbows was reduced after 2.5 years. After plasmapheresis, TC decreased to 1.94 mmol/L from 10.40 mmol/L and TG decreased to 0.33 mmol/L from 7.90 mmol/L. Plasmapheresis performed with a dextran sulfate-cellulose column was highly effective in removing the lipoprotein-remnant particles in this patient, leading to generalized improvement in the lipoprotein profile.

Increased content of epidermal growth factor in platelet lysates in non-insulin-dependent diabetes mellitus

We evaluated the content of EGF in platelet lysates obtained from 49 patients with non-insulin-dependent diabetes mellitus (NIDDM)(18 males, 31 females, age 58 +/- 13 years) and from 23 clinically healthy control subjects (11 males, 12 females, age 53 +/- 18 years). Platelets were collected from platelet-rich plasma and lysed. EGF was determined by radioimmunoassay. The immunoreactive EGF content in the platelet lysates in diabetic patients significantly exceeded that of control subjects (44.9 +/- 18.5 pg/mm3platelet vs. 34.2 +/- 7.8 pg/mm3platelet, mean +/- SD p < 0.008). In performing multiple regression analysis with ten clinical parameters, urinary albumin excretion (F = 16.1, r = 0.551, p < 0.001), duration of diabetes (F = 13.0, r = 0.511, p < 0.001) and the presence of diabetic proliferative retinopathy (F = 8.8, p < 0.01) were significantly associated with irEGF content in platelet lysates. These observations suggest that the amount of EGF in platelets may increase with the progression of diabetic complications. The mechanism for the increase of EGF in platelets remains to be clarified.

Different regional dynamics of end-stage renal disease in Japan by different causes

Background:  We recently showed that there were clear regional differences in the dynamics of end‐stage renal disease (ESRD) within Japan, which has an ethnically homogenous population. We speculate on the reason for these regional differences by correlating the regional distributions in the incidence of ESRD due to each of the following individual causes of ESRD: chronic glomerulonephritis (CGN), diabetic nephropathy (DMN) and polycystic kidney disease (PKD).

Effects of vitamin C and vitamin E on plasma levels of lipid hydroperoxides and thiobarbituric acid reactive substance in humans

Abstract A study was conducted to investigate the effects of vitamin C and vitamin E on plasma levels of lipid hydroperoxides (LPO) and thio-barbituric acid reactive substance (TBARS) in human volunteers to identify the step in the lipid peroxidation cascade at which these vitamins act. Forty subjects (20 men and 20 women) were randomly assigned to receive either vitamin C or vitamin E. Twenty subjects received 500 mg of vitamin C daily for 4 weeks, and 20 subjects received 300 mg of vitamin E daily for 4 weeks. Blood samples were collected before and 4 weeks after vitamin treatment, in the morning, after the subjects had fasted for 12 hours. Plasma levels of LPO and TBARS were determined. Plasma levels of lipids, apolipoproteins, vitamin C, and vitamin E were also measured. Vitamin C significantly reduced plasma levels of LPO and TBARS. Vitamin E significantly increased plasma levels of LPO and significantly reduced plasma levels of TBARS. Plasma concentrations of vitamin C and vitamin E significantly increased after 4 weeks of vitamin treatment. There were no significant changes in the plasma levels of lipids except LPO, TBARS, and apolipoproteins. From these results, it was concluded that vitamin C reduced LPO and TBARS levels, and vitamin E increased LPO levels and reduced TBARS levels.

Prevalence of Alzheimer's disease with diabetes in the Japanese population

Background:  The aim of the present study was to estimate the prevalence of impaired cognitive function and Alzheimers disease (AD) in diabetic subjects from Japan.

Excretion of urinary epidermal growth factor in non-insulin dependent diabetes mellitus

Morning urine samples were assayed for human EGF (hEGF) in 137 non-insulin dependent diabetic patients with normal serum creatinine and beta 2-microglobulin levels. Serving as controls, 80 age- and sex-matched healthy subjects were also examined. A significant positive correlation between hEGF excretion and the level of hemoglobin A1C (HbA1c) was present in those patients with a HbA1c value exceeding 8% (r = 0.37; p = 0.003) but not in the overall patients. The urinary hEGF level did not correlate with the concentration of glucose in urine or plasma. The mean urinary hEGF level of diabetic patients was significantly lower than that of healthy subjects. The mean urinary hEGF level was significantly lower in the patients with a diabetic history that exceeded five years as compared with those with a history below five years. The mean urinary hEGF level was significantly lower in the patients with retinopathy vs. those without retinopathy. In the patients with HbA1c value below 8%, the mean urinary hEGF level was lower in the patients whose urinary albumin level exceeded 1.7 mg/mmol.creatinine as compared with those whose urinary albumin excretion was below 1.7 mg/mmol.creatinine. These findings suggest that urinary hEGF excretion may decrease with the progression of diabetic complications in the patients with well-controlled glycemia, and that inadequate glycemic control may lead to an increased excretion of urinary hEGF in the early disease stage.