A strong fibrinolytic activity was demonstrated in the vegetable cheese Natto, which is a typical soybean food eaten in Japan. The average activity was calculated at about 40 CU (plasmin units)/g wet weight. This novel fibrinolytic enzyme, named nattokinase, was easily extracted with saline. The mol. wt and pI were about 20,000 and 8.6, respectively. Nattokinase not only digested fibrin but also the plasmin substrate H-D-Val-Leu-Lys-pNA (S-2251), which was more sensitive to the enzyme than other substrates tried. Diisopropyl fluorophosphate and 2,2,2-trichloro-1-hydroxyethyl-o,o-dimethylphosphate strongly inhibited this fibrinolytic enzyme.

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Background. Many kinds of human malignant tissue, including hepatocellular carcinoma (HCC), were reported to overexpress transforming growth factor‐β1 (TGF‐β1) gene. However, little work has been done on the circulating TGF‐β1 in patients with malignant tumors. Methods. Plasma TGF‐β1 levels in patients with HCC (n = 26) were compared with those in patients with chronic hepatitis (CH) (n = 12) and cirrhosis (n = 11) and in normal subjects (n = 20) using an enzyme‐linked immunosorbent assay system after acid/ethanol extraction. Results. The patients with HCC had significantly higher plasma TGF‐β1 levels (19.3 ± 19.5 ng/ml; mean ± standard deviation [SD]) than those in normal subjects (1.4 ± 0.8 ng/ml) and in patients with CH (3.0 ± 3.1 ng/ml) and cirrhosis (3.7 ± 2.1 ng/ml) (P < 0.01). Plasma TGF‐β1 concentrations in the patients with cirrhosis were also significantly higher than those in the normal subjects (P < 0.05). The extracted plasma TGF‐β1 from the patients with HCC had biologic activity according to a growth inhibitory assay using mink lung epithelial cells. No significant correlation was found between the plasma TGF‐β1 levels in the patients with HCC and serum alpha‐feto‐protein levels. After successful treatment for HCC, the amount of plasma TGF‐β1 significantly decreased from 22.6 plus or minus 16.7 ng/ml (mean ± SD) to 10.2 plus or minus 6.5 ng/ml (P < 0.05). Conclusions. We demonstrated higher levels of plasma TGF‐β1 in the patients with HCC than those in patients with chronic hepatitis and cirrhosis. Plasma TGF‐β1 might he a candidate for a novel tumor marker for hepatocellular carcinoma.

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We measured the plasma transforming growth factor‐β (TGF‐β) concentration in 14 patients with human hepatocellular carcinoma (HCC) and 9 age‐matched normal subjects using growth inhibition assay of mink lung epithelial cells. The calculated plasma TGF‐β concentration in the patients with HCC was 28.6 ± 27.9 ng/ml (mean± SE), showing significant elevation compared with that in 9 normal subjects (5.3 ± 3.3 ng/ml, P<0.01). In three cases, we could measure plasma TGF‐β levels before and after their treatment for HCC. The plasma TGF‐β levels decreased from 59.0 to 18.2 ng/ml after hepatic resection in one case, and from 24.0 to 10.7 ng/ml and from 12.4 to 3.4 ng/ml after transhepatic arterial embolization in the other two cases. These data indicate that plasma TGF‐β level is elevated in patients with HCC, probably due to release from HCC tissues.

Several growth factors including hepatocyte growth factor (HGF) have been implicated in the regulation of liver regeneration. Recently, we reported that heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF) has hepatotrophic effects in vitro. We investigated the role of HB-EGF as a hepatotrophic factor in regenerating rat liver after 70% partial hepatectomy. The level of HB-EGF messenger RNA (mRNA) in regenerating rat liver increased 1.5 hours after partial hepatectomy and reached a maximum (about sevenfold over normal) at 6 hours. In contrast, hepatic HGF mRNA levels increased at 12 hours and achieved maximal expression at 24 hours. HB-EGF protein expression increased about 2.8-fold over normal at 10 hours after partial hepatectomy. The number of EGF receptors, to which HB-EGF binds, decreased 6 hours after partial hepatectomy. HB-EGF mRNA levels increased in nonparenchymal cells (NPCs) at 6 hours after partial hepatectomy but not in hepatocytes. Using the reverse transcription-polymerase chain reaction (RT-PCR), HB-EGF gene expression was increased predominantly in Kupffer cells and sinusoidal endothelial cells but not in lipocytes and hepatocytes. These results indicated that HB-EGF may be an important growth factor, produced in an earlier phase rather than HGF, in the regenerating liver after partial hepatectomy by a paracrine mechanism.

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These data revealed that IL-35 might suppress T cell activation during the peripheral immune responses of RA. Therefore our data suggest that IL-35 might have multiple therapeutic targets.