Safflower yellow reduces DEN-induced hepatocellular carcinoma by enhancing liver immune infiltration through promotion of collagen degradation and modulation of gut microbiota.

Safflower yellow (SY) is the main active ingredient isolated from the traditional Chinese medicine Carthamus tinctorius, which is a valuable natural edible pigment that is widely used to treat cerebrovascular and cardiovascular diseases. However, the effect of SY on hepatocellular carcinoma (HCC) remains unclear. In this study, we showed that SY decreased the degree of injury and inhibited the release of inflammatory factors in the liver of a diethylnitrosamine (DEN)-induced HCC mouse model. Flow cytometry and immunoblotting showed that SY increased the infiltration of CD8+ T cells and Gr-1+ macrophages to improve the immune microenvironment by affecting the expression of collagen fibers. Further cellular experiments showed that SY degraded the collagens in the liver cells through the TGF-ß/Smad signalling pathway. SY also regulated the gut microbiota which may contribute to the immune microenvironment. In conclusion, SY exhibited a potent effect on the development of HCC by enhancing liver immune infiltration by promoting collagen degradation and modulating the gut microbiota. This study provides novel insights into the mechanism of SY as a candidate for the treatment of HCC in the future.

High-Fat Diet Promotes Macrophage-Mediated Hepatic Inflammation and Aggravates Diethylnitrosamine-Induced Hepatocarcinogenesis in Mice.

It has been reported that diet and nutrition play important roles in the occurrence and development of hepatocellular carcinoma (HCC). In this study, we investigated the potential tumor-promoting mechanisms of a high-fat diet (HFD) in mice with dietondiethylnitrosamine (DEN)-induced hepatocarcinogenesis. HFD significantly decreased the survival rate and induced severe liver dysfunction in DEN-induced mice, as indicated by increased serum glutamic-pyruvic transaminase (ALT), glutamic oxalacetic transaminase (AST), and alkaline phosphatase (ALP) levels and increased liver index, liver nodule count, and γ-glutamyltransferase (γ-GT) activity. Moreover, an increased number of fat droplets and HCCs were found in the livers of the HFD mice, who displayed little collagen in and around the liver cancer groove and the infiltration of large number of inflammatory cells, such as macrophages, compared with the control mice. HFD also significantly increased proliferating cell nuclear antigen (PCNA), nuclear factor-κB (NF-κB), cyclin D1, tumor necrosis factor (TNF), and interleukin-1 (IL-1) expression levels in the liver. In vitro, we found that the inducible nitric oxide synthase (iNOS) percentage increased in macrophages after palmitic acid treatment, as well as the secretion of inflammatory factors and cytokines such as interleukin-6(IL-6), interleukin-10(IL-10), CCL2, Interferon γ (IFN-γ), and TNF. Thus, our results demonstrate that an HFD may promote DEN-induced hepatocarcinogenesis in mice by destroying liver function and enhancing the inflammatory response by recruiting and polarizing macrophages in the liver. This study could therefore provide new insights into the tumor promoting effects of an HFD in HCC.

Gehua Jiecheng Decoction Inhibits Diethylnitrosamine-Induced Hepatocellular Carcinoma in Mice by Improving Tumor Immunosuppression Microenvironment.

Gehua Jiecheng Decoction (GHJCD), a famous traditional Chinese medicine, has been used in the prevention and treatment of precancerous lesion of liver cancer, but its active mechanism has not been reported. This study aimed to evaluate the therapeutic effect of GHJCD on diethylnitrosamine (DEN)-induced hepatocellular carcinoma (HCC) in mice and the mechanism of this effect. We found that GHJCD effectively inhibited the occurrence of liver cancer and reduced the tumor area. The ratio of regulatory cells (Tregs), tumor-associated macrophages (TAMs), and myeloid-derived suppressor cells (MDSCs) in HCC microenvironment was down-regulated, whereas that of CD8 T and effective CD8 T cells was up-regulated. In addition, the expression levels of inflammatory factors IL-6, IL-10, TNF-α, and CCL-2 in the liver were inhibited, whereas those of the angiogenesis related molecules CD31 and VEGF were decreased. Moreover, WNT1, ß-catenin, NF-kB, p-MAPK, p-AKT, and p-SRC content in the liver decreased, whereas APC content increased. These results suggested that GHJCD exerted a good inhibitory effect on liver cancer induced by DEN and thus may have a multi-target effect; GHJCD not only antagonized the immunosuppressive effect of the microenvironment of liver cancer but also exerted strong anti-inflammatory and antiangiogenesis effects.

Integration of Metabolomics and Transcriptomics Reveals the Therapeutic Mechanism Underlying Paeoniflorin for the Treatment of Allergic Asthma.

Objectives: Asthma is a chronic airway inflammatory disease, which is characterized by airway remodeling, hyperreactivity and shortness of breath. Paeoniflorin is one of the major active ingredients in Chinese peony, which exerts anti-inflammatory and immune-regulatory effects in multiple diseases. However, it remains unclear whether paeoniflorin treatment can suppress allergic asthma. Methods: In this study, we evaluated the effect of paeoniflorin on lung function and airway inflammation in asthmatic mice. These asthmatic Balb/c mice were first sensitized and constructed through ovalbumin (OVA) motivation. Subsequently, we determined the mechanism of action of paeoniflorin in treating allergic asthma through integrated transcriptomic and metabolomic data sets. Results: Our results demonstrated that many genes and metabolites were regulated in the paeoniflorin-treated mice. Moreover, the potential target proteins of paeoniflorin played important roles in fatty acid metabolism, inflammatory response, oxidative stress and local adhesion. Conclusion: Paeoniflorin has a beneficial effect on asthma, which may be achieved through regulating fatty acid metabolism, inflammatory response and the adhesion pathway at system level.