• N-nitrosamines
• androgen receptor
• exposure
• hepatic carcinoma
• testosterone

• the National Natural Science Foundation of China
• the Health Research Foundation of Wuhan Municipal Health Commission, China

• fatty liver
• high-fat diet
• liver cancer
• nano-diethylnitrosamine
• transcriptomics

• 82174110 National Natural Science Foundation of China
• 81673711 National Natural Science Foundation of China
• 81573887 National Natural Science Foundation of China
• CZZ23009 Fundamental Research Funds for the Central Universities, South-Central MinZu University

• Althaea officinalis L.
• N‐diethylnitrosamine
• antioxidant
• hepatocellular carcinoma
• liver

• AMPK
• aging
• fatty Liver
• hypoxia
• inflammation
• liver cancer
• tumor microenvironment

• National Natural Science Foundation of China

• Caffeoylquinic acid
• Ethanol extract of Gynura procumbens stems
• Liver cancer
• Nanodiethylnitrosamine
• Non-caffeoylquinic acid
• Tumor microenvironment

• Animals
• Antineoplastic Agents, Phytogenic/chemistry
• Antineoplastic Agents, Phytogenic/pharmacology
• Asteraceae/chemistry
• Diethylnitrosamine/toxicity
• Drugs, Chinese Herbal/therapeutic use
• Ethanol
• Inflammation/drug therapy
• Inflammation/metabolism
• Liver Neoplasms/chemically induced
• Liver Neoplasms/drug therapy
• Male
• Mice
• Nanostructures
• Plant Extracts/chemistry
• Plant Extracts/pharmacology
• Random Allocation
• Tumor Microenvironment/drug effects

BIR repeat-containing ubiquitin conjugating enzyme (BRUCE) is a liver tumor suppressor, which is downregulated in a large number of patients with liver diseases. BRUCE facilitates DNA damage repair to protect the mouse liver against the hepatocarcinogen diethylnitrosamine (DEN)-dependent acute liver injury and carcinogenesis. While there exists an established pathologic connection between fibrosis and hepatocellular carcinoma (HCC), DEN exposure alone does not induce robust hepatic fibrosis. Further studies are warranted to identify new suppressive mechanisms contributing to DEN-induced fibrosis and HCC.

To investigate the suppressive mechanisms of BRUCE in hepatic fibrosis and HCC development.

Male C57/BL6/J control mice [loxp/Loxp; albumin-cre (Alb-cre)^-] and BRUCE Alb-Cre KO mice (loxp/Loxp; Alb-Cre⁺) were injected with a single dose of DEN at postnatal day 15 and sacrificed at different time points to examine liver disease progression.

By using a liver-specific BRUCE knockout (LKO) mouse model, we found that BRUCE deficiency, in conjunction with DEN exposure, induced hepatic fibrosis in both premalignant as well as malignant stages, thus recapitulating the chronic fibrosis background often observed in HCC patients. Activated in fibrosis and HCC, β-catenin activity depends on its stabilization and subsequent translocation to the nucleus. Interestingly, we observed that livers from BRUCE KO mice demonstrated an increased nuclear accumulation and elevated activity of β-catenin in the three stages of carcinogenesis: Pre-malignancy, tumor initiation, and HCC. This suggests that BRUCE negatively regulates β-catenin activity during liver disease progression. β-catenin can be activated by phosphorylation by protein kinases, such as protein kinase A (PKA), which phosphorylates it at Ser-675 (pSer-675-β-catenin). Mechanistically, BRUCE and PKA were colocalized in the cytoplasm of hepatocytes where PKA activity is maintained at the basal level. However, in BRUCE deficient mouse livers or a human liver cancer cell line, both PKA activity and pSer-675-β-catenin levels were observed to be elevated.

Our data support a “BRUCE-PKA-β-catenin” signaling axis in the mouse liver. The BRUCE interaction with PKA in hepatocytes suppresses PKA-dependent phosphorylation and activation of β-catenin. This study implicates BRUCE as a novel negative regulator of both PKA and β-catenin in chronic liver disease progression. Furthermore, BRUCE-liver specific KO mice serve as a promising model for understanding hepatic fibrosis and HCC in patients with aberrant activation of PKA and β-catenin.

• BIR repeat-containing ubiquitin conjugating enzyme
• Diethylnitrosamine
• Mouse model
• Liver fibrosis
• Liver cancer
• Hepatocellular carcinoma

• T32 CA117846 NCI NIH HHS

We previously isolated an ethanol fraction of LSW (Liushenwan pill, a traditional Chinese medicine) which has been shown to prevent and treat liver cancer induced by nanodiethylnitrosamine (nanoDEN) in mice. In the present study, we utilized a high-pressure microfluidics technique to generate LSW lipid nanoparticles (nano-LSW) to reduce its toxicity, and enhance its inhibitory effect on tumor growth, and further evaluate its therapeutic effect using a nanoDEN-induced mouse model of liver cancer. Our in vitro results indicated that nano-LSW-low could induce apoptosis in HepG2 cells, but exhibited low toxicity in L02 cells. Furthermore, the in vivo results indicated that nano-LSW-low exerted minimal or no damage to normal hepatocytes, kidney, and small intestine tissues. In addition, our results showed that at the 20^th week, the inflammatory infiltration in the mice in the model group increased severely, and partial pimelosis and fibrosis occurred. In contrast, the liver tissues in the mice treated with nano-LSW exhibited only slight inflammatory infiltration, without pimelosis and fibrosis. At the 30^th week, 4 out of 5 liver tissues in the model group showed hyperplastic nodules by hematoxylin and eosin (H&E) staining. However, the liver tissues in the nano-LSW treatment group did not showed hyperplastic nodules. Immunohistochemical staining showed that, in contrast to the model group, the levels of COX-2, PCNA, β-catenin, and HMGB1 protein expressions were significantly lower in the nano-LSW-low group at the 20^th and 30^th week. Compared to model group, the COX-2, TNF-α, Smad-2, and TGF-β1 mRNA levels obviously decreased in the liver tissue after the nano-LSW-low treatment. Taken together, nano-LSW-low may serve as a potent therapeutic agent for preventing liver cancer by interfering with multiple critical factors for the tumor microenvironment during oncogenesis.

• liver cancer
• low toxicity
• nano-LSW-low
• nanodiethylnitrosamine
• tumor microenvironment

• 2-acetaminofluorene/partial hepatectomy (2-AAF/PH)
• Diwu Yanggan
• Wnt/β-catenin pathway
• hepatocarcinogenesis
• liver regeneration

• angiogenesis
• breast cancer
• immunostimulation
• metastasis
• neoplasm
• umbelliprenin

Shengfu oil is a traditional Chinese medicine formula containing 16 ingredients, including Scutellariae radix, Olibanum, and Rehmanniae radix. In this study, we aimed to enhance the wound healing of rabbit full-thickness scalded skin by Shengfu oil and to elucidate its regulatory effects on β-catenin, Dlk1, and COX-2. We found that Shengfu oil exhibited significant anti-inflammatory, analgesic, and antimicrobial activities. The structure of wound tissues in Shengfu oil group was intact, including regenerated cutaneous appendages, indicating better healing capability of Shengfu oil compared to the controls. The protein expression of β-catenin, Dlk1, and COX-2 in wound tissues were investigated by immunohistochemistry staining and were further quantitated with the use of multispectral imaging analysis. The protein expression of β-catenin and Dlk1 in the Shengfu oil group was higher than that in the sesame oil group in early wound repair, accompanied by the lower expression of COX-2; the protein expression of β-catenin decreased in the middle of wound healing; the protein expression of β-catenin and Dlk1 increased at the end of wound healing. These results strongly suggest that Shengfu oil can enhance wound healing by regulating the expression of β-catenin, Dlk1, and COX-2 due to its excellent anti-inflammatory, analgesic, and antimicrobial activities.

• COX-2
• Dlk1
• Shengfu oil
• traditional Chinese medicine
• wound healing
• β-catenin

• Animal model
• Apoptosis
• Diethylnitrosamine
• Lipid nanoparticles
• Liver cancer