TJ-48 comprises 10 herbs and its own individual ingredients have already been reported to have antioxidant properties18,43,44; therefore, it really is presumable that antioxidant impact is very important to TJ-48 to lessen liver carcinogenesis. Several research have suggested that anti-tumor aftereffect of TJ-48 could be due to the activation from the disease fighting capability which facilitates the clearance of tumor cells from the liver.13,16,19Specifically, natural killer (NK)T cells are known to exert prominent anti-tumor activity in the liver45and it has been shown that TJ-48 activates NKT cells.46Conversely, our results show that Kupffer cells, an important part of the innate immune response in liver, are affected in a protective way and TJ-48 causes attenuation of the production of proinflammatory cytokines. HCC, a significantly longer intrahepatic recurrence-free survival was observed in the TJ-48 group. In mice, TJ-48 inhibited the development of liver tumors, reduced oxidative DNA damage, inflammatory cell infiltration and cytokine expression. Administration of TJ-48 improves intrahepatic recurrence-free survival after surgical treatment of hepatocellular carcinoma. On the basis of animal experiments, we reason that the protective mechanism of TJ-48 involves inhibition of Kupffer cells. This leads to lower levels of pro-inflammatory cytokines and oxidants in liver ML401 which may slow down the process of hepatocarcinogenesis and improves ML401 hepatic recurrence-free survival in patients with HCC. Keywords:TJ-48, hepatocellular carcinoma, Kupffer cell, intrahepatic recurrence-free survival Hepatocellular carcinoma (HCC) is one of the worlds most common cancers and it is commonly associated with liver cirrhosis due to alcohol and chronic viral infection (hepatitis virus B and C), aflatoxin B1 exposure, and a variety of metabolic liver diseases.1,2Chronic inflammation is thought to be tightly linked to the mechanisms of HCC through increased production of free radicals from ML401 macrophages and neutrophils at the site of Ilf3 inflammation.3,4Indeed, markers of oxidative stress, such as 8-hydroxy-deoxyguanosine (8-OHdG), 4-hydroxynonenal and malondialdehyde, are commonly elevated in the liver of patients with chronic viral hepatitis infection and correlate well with the degree of viral infection and inflammation, known risk factors for HCC.57Recently, we evaluated the relationship between inflammation, intrahepatic oxidative stress, oxidative DNA damage and the progression of carcinogenesis in HCV-infected human liver and showed that patients with greater intra-hepatic oxidative stress exhibited much faster HCC recurrence.8 Because a strong correlation exists between inflammatory cells in liver, oxidative stress and cancer, chronic inflammation is considered to be one of the prime targets for therapeutic intervention to prevent both progression of chronic liver disease into cancer, and relapse of HCC. Currently available anti-viral therapies, which are partially directed towards mitigation of intra-hepatic inflammation, are the only means of interrupting the progression from chronic hepatitis to HCC.9However, complementary and alternative medicines are becoming popular among patients with liver disease, particularly chronic hepatitis C and alcohol-induced liver disease.10Silymarin, glycyrrhizin, Chinese traditional medicine, herbal medicine 861, CH-100, TJ-9, TJ-108, andPhyllanthus amarusare the herbs or blends commonly used for hepatic disorders around the world.11,12 Juzen-taiho-to (TJ-48) is a traditional Japanese herbal medicine formula which is composed of 10 different herbs and the content of this preparation is tightly regulated.13It is used in medical practice in Japan for treatment of patients with chronic disease. Interestingly, several recent studies have shown that TJ-48 has an anti-tumor effect in animal models.1416Although the active ingredient(s) of this or other traditional herbal medicines have not been determined and the mechanisms of their protective action remains obscure, some constituents of TJ-48 have been shown to possess antioxidant activities17,18and act as immunomodulators.19,20 Although there is a growing body of evidence that herbal preparations may prove beneficial in management of chronic liver diseases, caution has been urged as only a few clinical trials have been conducted. This study, an extension of our previous observation that higher intrahepatic inflammation correlates with shorter disease-free survival after removal of the primary HCC,8tested if administration of TJ-48 will have a beneficial effect in patients who underwent liver tumor resection. Although relatively small, the current study shows considerable improvement in intrahepatic recurrence-free survival in patients on TJ-48 supplementation. Next, we tested a hypothesis that TJ-48 exerts its beneficial effects against liver carcinogenesis by impeding Kupffer cell-induced oxidative stress. In a mouse model of liver carcinogenesis induced by diethylnitrosamine (DEN), TJ-48 inhibited the development of liver tumors, as well as reduced the number of inflammatory cells, expression of proinflammatory cytokines, and oxidative DNA damage in liver. In cultured mouse Kupffer cells, TJ-48 significantly blunted DEN-induced production of proinflammatory cytokines and reactive oxygen species. Thus, we suggest that treatment with TJ-48 may be beneficial as a chronic adjuvant therapy in patients who undergo curative HCC removal and that it acts by blunting inflammation in liver. == Material and methods == == Patients and study design == This is a retrospective single-center, open-label study. From 2000 to 2005, consecutive patients in the University of Yamanashi Hospital (Yamanashi Prefecture, Japan) who (i) were diagnosed as having HCC with no vascular ML401 invasion and (ii) underwent curative surgery (resection or intra-operative microwave coagulation therapy (MCT)), were enrolled in this study. Confirmation of the complete removal of the tumor(s) in patients who.
