Biomedical subjects

Tomoichiro Asano

Publications and source records attributed to Tomoichiro Asano.

57 records · Page 4Linked to original sources

PubMed2001

Akt protein kinase inhibits non-apoptotic programmed cell death induced by ceramide.

A growing body of evidence now suggests that programmed cell death (PCD) occurs via non-apoptotic mechanisms as well as by apoptosis. In contrast to apoptosis, however, the molecular mechanisms involved in the regulation of non-apoptotic PCD remain only poorly understood. Here we show that ceramide induces a non-apoptotic PCD with a necrotic-like morphology in human glioma cells. Characteristically, the cell death was not accompanied by loss of the mitochondrial transmembrane potential, cytosolic release of cytochrome c from mitochondria, or the activation of the caspase cascade. Consistent with these characteristics, this ceramide-induced cell death was inhibited neither by the overexpression of Bcl-xL nor by the pan-caspase inhibitor zVAD-fmk. However, strikingly, the ceramide-induced non-apoptotic cell death was inhibited by the activation of the Akt/protein kinase B pathway through the expression of a constitutively active version of Akt. The results for the first time indicate that the Akt kinase, known to play an essential role in survival factor-mediated inhibition of apoptotic cell death, is also involved in the regulation of non-apoptotic PCD.

Adenoviridae↗

PubMedDate not supplied

Erythrocytic sorbitol contents in diabetic patients correlate with blood aldose reductase protein contents and plasma glucose levels, and are normalized by the potent aldose reductase inhibitor fidarestat (SNK-860).

The accumulation of sorbitol by the activated polyol pathway is considered to be a major cause of diabetic neuropathy. Because the erythrocytic sorbitol contents reportedly reflects that in nerves, erythrocytic sorbitol measurement would be useful for confirming the effect of an aldose reductase inhibitor (ARI). In this study, we examined erythrocytic sorbitol contents in healthy subjects and diabetic patients under fasting and postprandial conditions. Then, the contributions of blood aldose reductase (AR) contents and plasma glucose levels to the accumulated erythrocytic sorbitol contents were also analyzed. Erythrocytic sorbitol contents in the healthy subjects were 11.7 and 12.5-12.6 nmol/g Hb in fasting and postprandial status, respectively. In contrast, the erythrocytic sorbitol contents in diabetic patients were apparently higher (approximately 2.5-fold), but fidarestat treatment restored the elevated erythrocytic sorbitol contents to normal. In the diabetic patients, erythrocytic sorbitol contents were highly correlated with blood AR contents multiplied by the plasma glucose levels, whereas in the normal and fidarestat-treated diabetic patients no such correlation was observed. Taken together, these results suggest both the blood AR contents and the plasma glucose levels are factors determining erythrocytic sorbitol contents in diabetic patients. Notably, the potent ARI fidarestat was shown to normalize elevated erythrocytic sorbitol contents.

Aldehyde Reductase↗

PubMedDate not supplied

Fidarestat (SNK-860), a potent aldose reductase inhibitor, normalizes the elevated sorbitol accumulation in erythrocytes of diabetic patients.

Sorbitol accumulation in nerves has been regarded as one of the major causes of diabetic neuropathy. In this study, fidarestat (SNK-860; 1 mg daily), a potent new aldose reductase inhibitor (ARI), or the commercially available ARI epalrestat (150 mg daily), was administered for 4 weeks to 58 Type 2 diabetic patients. Treatment with these drugs had no effect on glycemic control, judging from plasma glucose and HbA(1c) levels. However, fidarestat treatment normalized the elevated sorbitol content of erythrocytes under fasting as well as postprandial conditions. In contrast, the effect of epalrestat was minimal. There were no major side effects with fidarestat. Thus, fidarestat is considered to be a potent and promising ARI, possibly useful for both preventing and treating diabetic neuropathy. Further studies are needed to clarify how much the occurrence and progression of diabetic neuropathy are inhibited by normalizing sorbitol elevation with fidarestat treatment.

Aldehyde Reductase↗