Extracellular-superoxide dismutase (EC-SOD) is a secreted antioxidative enzyme, and its presence in vascular walls may play an important role in protecting the vascular system against oxidative stress. EC-SOD expression in cultured cell lines is regulated by various cytokines including tumor necrosis factor-α (TNF-α). TNF-α is a major mediator of pathophysiological conditions and may induce or suppress the generation of various types of mediators. Epigenetics have been defined as mitotically heritable changes in gene expression that do not affect the DNA sequence, and include DNA methylation and histone modifications. The results of the present study demonstrated that TNF-α significantly decreased EC-SOD level in fibroblasts with an accompanying increase in methylated DNA. In DNA methylation and demethylation, cytosine is methylated to 5-methylcytosine (5mC) by DNA methyltransferase (DNMT), and 5mC is then converted to 5-hydroxymethylcytosine (5hmC) and cytosine in a stepwise manner by ten-eleven translocation methylcytosine dioxygenases (TETs). However, DNMT did not participate in TNF-α-induced DNA methylation within the EC-SOD promoter region. On the other hand, TNF-α significantly suppressed TET1 expression and EC-SOD mRNA levels were decreased by the silencing of TET1 in fibroblasts. These results demonstrate that the down-regulation of EC-SOD by TNF-α is regulated by DNA methylation through reductions in TET1.

In diabetic patients, skeletal muscle atrophy occurs due to increased oxidative stress and inflammation. Skeletal muscle atrophy reduces the QOL of patients and worsens life prognosis. Therefore, development of preventive therapy for muscle atrophy in hyperglycemic state is eagerly awaited. Juzentaihoto is a medicinal herb that has a function to supplement physical strength, and it is expected to prevent muscle atrophy. To determine the preventive effect of juzentaihoto on muscle atrophy in hyperglycemic state, streptozotocin (STZ) was administered to induce diabetes in mice and the preventive effect of juzentaihoto was evaluated. Mice that received juzentaihoto extract (JTT) showed that the decrease in muscle fiber cross-sectional area in the gastrocnemius muscle was reversed. Additionally, the expression level of tumor necrosis factor α (TNF-α), an inflammatory cytokine, in serum decreased, and that of ubiquitin ligase (atrogin-1, muscle RING-finger protein-1) mRNA in skeletal muscle decreased. An anti-inflammatory cytokine interleukin-10 showed increased levels in the serum and increased levels in spleen cell culture supernatant collected from mice that received JTT. JTT had no effect on the blood glucose level. These results suggest that prophylactic administration of JTT to STZ-induced diabetic mice affects immune cells such as in spleen, causing an anti-inflammatory effect and inhibiting excessive activation of the ubiquitin-proteasome system, to reverse muscle atrophy.

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