Masahiro Nakamura

Apoptotic Cell Death Triggered by Nitric Oxide in Pancreatic β-Cells

Nitric oxide (NO) is believed to be an effector molecule that mediates interleuMn (IL)-1β-induced destruction and dysfunction of pancreatic β-cells. We have demonstrated that both exogenous NO and NO generated endogenously by IL-1β brought about apoptosis of isolated rat pancreatic islet cells as well as pancreatic β-cell tumorderived cell line HIT. This apoptosis was characterized by cleavage of DNA into nucleosomal fragments of 180–200 bp and morphologically by nuclear shrinkage, chromatic condensation, and apoptotic body formation. The EL-1β-induced internucleosomal DNA cleavage occurred in a time- and dose-dependent manner. Actinomycin D, cycloheximide, and nitric oxide synthase inhibitors inhibited the DNA cleavage, which was correlated with the amount of NO produced, indicating that NO produced by HIT cells themselves could mediate the apoptosis. Furthermore, in the presence of tumor necrosis factor (TNF)-α, large amounts of NO were produced by IL-1β and DNA cleavage occurred more noticeably, although TNF-β alone did not generate NO. Streptozotocin (STZ), a diabetogenic reagent containing a nitroso moiety, also released NO and induced internucleosomal DNA cleavage in HIT cells. These results suggest that NO-induced internucleosomal DNA cleavage is an important initial step in the destruction and dysfunction of pancreatic (β-cells induced by inflammatory stimulation or treatment with STZ.

A High Expression of Heme Oxygenase-1 in the Liver of LEC Rats at the Stage of Hepatoma: The Possible Implication of Induction in Uninvolved Tissue

We have examined changes in the expression of heme oxygenase-1 (HO-1), an inducible isoform and HO-2, a constitutive isoform, in the liver of Long-Evans with a Cinnamon-like color (LEC) rat, a mutant strain which spontaneously develops acute hepatitis and hepatoma. HO-1 expression was highly enhanced in the LEC rat livers with jaundice, and then decreased slightly, but overall remained at a higher level than in the Long-Evans with Agouti color (LEA) control rats, as judged by Northern blotting analysis of the whole liver extract. The high expression of HO-1 in the LEC rat liver was, however, not due to the actual cancer lesion but, rather, due to the surrounding uninvolved tissues including hepatocytes. Immunohistochemical analysis also supported this conclusion. Among normal tissues, the expression of HO-1 but not HO-2 was high in only the spleen of both LEC and LEA rats. The high expression observed in the stage of acute hepatitis and hepatoma stages in the LEC rat is probably due to the oxidative stress caused by the accumulation of free copper and free iron levels which has been reported earlier by our group (Suzuki et al., Carcinogenesis, 1993, 14, 1881-1884 and Koizumi et al., Free Radical Research, in press) as well as by free heme levels. The inflammatory cytokines produced by the surrounding tissue at the hepatoma stage would also be expected to play a role in the induction mechanism. The physiological relevance of HO-1 induction might be an adaptive response to oxidative stress and vasodilatory effect of carbon monoxide on sinusoidal circulation.

Establishment and assessment of wide area medical information network system in hokkaido

To support regional medicine in rural area of Hokkaido, we have tried to establish advanced medical information network system. At first we connected two rural town hospitals with SMU (Sapporo Medical University) and performed medical data transmission via the Internet. We used IPsec and regional Internet exchange (IX) for ensuring security and stability. As a second stage, we established a Metropolitan Area Network (MAN), a gigabit network with a 120 km radius in order to connect three medical schools (Hokkaido University, Asahikawa Medical College and SMU) with 10 hospitals. These experiments were performed with Internet technology such as VoIP (voice over IP), VPN, IPsec. As a third stage, we have coined VGN (Virtual Global Network) a concept, which includes IPv6 Topological Addressing Policy. According to the policy we established the IPv6 network to connect SMU with Obihiro area hospitals and a preschool for disabled children. Here, we described details of these experiments in terms of applications and network technologies.