Bufalin suppresses hepatocellular carcinogenesis by targeting M2 macrophage-governed Wnt1/ß-catenin signaling.

BACKGROUND: The interplay of tumor-associated macrophages (TAMs) and tumor cells plays a key role in the development of hepatocellular carcinoma (HCC) and provides an important target for HCC therapy. The communication between them is still on the investigation. Bufalin, the active component derived from the traditional Chinese medicine (TCM) Chansu, has been evidenced to possess anti-HCC activity by directly suppressing tumor cells, while its immunomodulatory effect on the tumor microenvironment (TME) is unclear. PURPOSE: To explore the mechanism of M2 TAM-governed tumor cell proliferation and the inhibitory effect of bufalin on HCC growth by targeting M2 macrophages. METHODS: Morphology and marker proteins were detected to evaluate macrophage polarization via microscopy and flow cytometry. Cellular proliferation and malignant transformation of HCC cells cultured with macrophage conditioned medium (CM) or bufalin-primed M2-CM, were assessed by cell viability, colony formation and soft agar assays. Regulations of gene transcription and protein expression and release were determined by RT-qPCR, immunoblotting, immunoprecipitation, ELISA and immunofluorescence. Tumorigenicity upon bufalin treatment was verified in orthotopic and diethylnitrosamine-induced HCC mouse model. RESULTS: In this study, we first verified that M2 macrophages secreted Wnt1, which acted as a mediator to trigger ß-catenin activation in HCC cells, leading to cellular proliferation. Bufalin suppressed HCC cell proliferation and malignant transformation by inhibiting Wnt1 release in M2 macrophages, and dose-dependently inhibited HCC progression in mice. Mechanistically, bufalin specially targeted to block Wnt1 transcription, thus inactivating ß-catenin signaling cascade in HCC cells and leading to tumor regression in HCC mouse model. CONCLUSION: These results clearly reveal a novel potential of bufalin to suppress HCC through immunomodulation, and shed light on a new M2 macrophage-based modality of HCC immunotherapy, which additively enhances direct tumor-inhibitory efficacy of bufalin.

Current Perspective of Traditional Chinese Medicines and Active Ingredients in the Therapy of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is one of the leading lethal tumors worldwide, and the treatment remains a great medical challenge. Surgery and chemotherapy are current standard curative methods for patients with HCC, but the prognosis is still dismal. Based on unique medical theories and rich practical experience, traditional Chinese medicine (TCM) has been broadly employed to effectively treat HCC for a long history. Recently, systematic clinical trials have been well designed to study the efficacy of TCMs in the treatment of HCC, and the underlying antitumor mechanisms were also deeply explored. Here, we reviewed the published clinical evaluation of some commonly used TCMs in the treatment of HCC, and the related anti-HCC mechanisms through in vitro and in vivo study, promoting the modernization of TCM study in oncology for achieving a substantial reduction of HCC burden in the future.

Rhodiola rosea L. Attenuates Cigarette Smoke and Lipopolysaccharide-Induced COPD in Rats via Inflammation Inhibition and Antioxidant and Antifibrosis Pathways.

The root cause behind the development of chronic obstructive pulmonary disease (COPD) is cigarette smoke that induces the inflammation of the lung tissue and alveolar destruction. Long-term cigarette smoking can lead to deterioration in lung parenchymal function and cause structural changes in the lung, further resulting in pulmonary fibrosis. Rhodiola rosea L., a traditional medicinal perennial herb, is well known for its numerous pharmacological benefits, including anti-inflammation, antioxidant, antifatigue, antidepressive, and antifibrotic properties. Here, we evaluated the pharmacological effects and mechanisms of the Rhodiola rosea L. (RRL) macroporous resin extract on COPD caused by lipopolysaccharide (LPS) and cigarette smoke (CS) in rats. The RRL significantly improved the pathological structure of the lung tissue. Additionally, RRL decreased the infiltration of inflammatory cells and, subsequently, oxidative stress. Furthermore, the RNAseq assay indicated that RRL attenuated the CS and LPS-induced COPD via anti-inflammatory, antifibrotic, and antiapoptotic activities. Western blot analysis substantiated that the RRL resulted in upregulated levels of Nrf2 and HO-1 as well as downregulated levels of IκBα, NF-κB p65, α-SMA, and TGF-ß1. Interestingly, the RRL could protect rats from CS and LPS-induced COPD by inhibiting the ERK1/2 and Smad3 signaling pathways and apoptosis. Thus, the RRL could attenuate CS and LPS-induced COPD through inflammation inhibition and antioxidant and antifibrosis pathways.

Discovery of novel curcumin derivatives targeting xanthine oxidase and urate transporter 1 as anti-hyperuricemic agents.

A series of curcumin derivatives as potent dual inhibitors of xanthine oxidase (XOD) and urate transporter 1 (URAT1) was discovered as anti-hyperuricemic agents. These compounds proved efficient effects on anti-hyperuricemic activity and uricosuric activity in vivo. More importantly, some of them exhibited proved efficient effects on inhibiting XOD activity and suppressing uptake of uric acid via URAT1 in vitro. Especially, the treatment of 4d was demonstrated to improve uric acid over-production and under-excretion in oxonate-induced hyperuricemic mice through regulating XOD activity and URAT1 expression. Docking study was performed to elucidate the potent XOD inhibition of 4d. Compound 4d may serve as a tool compound for further design of anti-hyperuricemic drugs targeting both XOD and URAT1.

An Investigation of the Differences and Similarities between Generated Small-World Networks for Right- and Left-Hand Motor Imageries.

In this study, small-world network analysis was performed to identify the similarities and differences between functional brain networks for right- and left-hand motor imageries (MIs). First, Pearson correlation coefficients among the nodes within the functional brain networks from healthy subjects were calculated. Then, small-world network indicators, including the clustering coefficient, the average path length, the global efficiency, the local efficiency, the average node degree, and the small-world index, were generated for the functional brain networks during both right- and left-hand MIs. We identified large differences in the small-world network indicators between the functional networks during MI and in the random networks. More importantly, the functional brain networks underlying the right- and left-hand MIs exhibited similar small-world properties in terms of the clustering coefficient, the average path length, the global efficiency, and the local efficiency. By contrast, the right- and left-hand MI brain networks showed differences in small-world characteristics, including indicators such as the average node degree and the small-world index. Interestingly, our findings also suggested that the differences in the activity intensity and range, the average node degree, and the small-world index of brain networks between the right- and left-hand MIs were associated with the asymmetry of brain functions.

Illumina-based analysis of the rhizosphere microbial communities associated with healthy and wilted Lanzhou lily (Lilium davidii var. unicolor) plants grown in the field.

Lanzhou lily (Liliumdavidii var. unicolor) is the best edible lily as well as a traditional medicinal plant in China. The microbes associated with plant roots play crucial roles in plant growth and health. However, little is known about the differences of rhizosphere microbes between healthy and wilted Lanzhou lily (Lilium davidii var. unicolor) plants. The objective of this study was to compare the rhizosphere microbial community and functional diversity of healthy and wilted plants, and to identify potential biocontrol agents with significant effect. Paired end Illumina Mi-Seq sequencing of 16S rRNA and ITS gene amplicons was employed to study the bacterial and fungal communities in the rhizosphere soil of Lanzhou lily plants. BIOLOG technology was adopted to investigate the microbial functional diversity. Our results indicated that there were major differences in the rhizosphere microbial composition and functional diversity of wilted samples compared with healthy samples. Healthy Lanzhou lily plants exhibited lower rhizosphere-associated bacterial diversity than diseased plants, whereas fungi exhibited the opposite trend. The dominant phyla in both the healthy and wilted samples were Proteobacteria and Ascomycota, i.e., 34.45 and 64.01 %, respectively. The microbial functional diversity was suppressed in wilted soil samples. Besides Fusarium, the higher relative abundances of Rhizoctonia, Verticillium, Penicillium, and Ilyonectria (Neonectria) in the wilted samples suggest they may pathogenetic root rot fungi. The high relative abundances of Bacillus in Firmicutes in healthy samples may have significant roles as biological control agents against soilborne pathogens. This is the first study to find evidence of major differences between the microbial communities in the rhizospheric soil of healthy and wilted Lanzhou lily, which may be linked to the health status of plants.