1. Anticolorectal Cancer Activity of Bilobalide in Patient-Derived Colorectal Cancer Organoids and AOM/DSS Mouse Model.
- Author
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Zhang, Heng, Fang, Shuhua, Raza, Faisal, Cao, Nengqi, Fang, Xingchao, Lu, Xu, Li, Ran, Shi, Feng, Wang, Deqiang, and Xu, Min
- Subjects
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TISSUE analysis , *GLUTATHIONE , *RESEARCH funding , *PHOSPHORYLATION , *MACROPHAGES , *ANTINEOPLASTIC agents , *ENZYME-linked immunosorbent assay , *POLYMERASE chain reaction , *COLORECTAL cancer , *TREATMENT effectiveness , *QUANTITATIVE research , *CELLULAR signal transduction , *OXIDATIVE stress , *MICE , *LIPID peroxidation (Biology) , *IMMUNOHISTOCHEMISTRY , *ANIMAL experimentation , *DEXTRAN , *CARCINOGENS , *WESTERN immunoblotting , *PHOSPHOTRANSFERASES , *STAT proteins , *CELL survival , *GINKGO , *TUMOR necrosis factors , *INTERLEUKINS , *MALONDIALDEHYDE , *PHARMACODYNAMICS - Abstract
Bilobalide has shown strong anti-inflammatory activity. Colorectal cancer (CRC) is closely associated with inflammation. However, no studies have reported on the use of bilobalide for treating CRC. This study aims to evaluate the effect of bilobalide on CRC prevention. Enzyme-linked immunosorbent assay (ELISA), quantitative real-time polymerase chain reaction (RT-qPCR), Western blotting, and immunofluorescence showed that bilobalide significantly inhibits the M2 polarization of macrophages dependent on phorbol 12-myristate 13-acetate (PMA) and interleukin-4 (IL-4). Analysis of signaling pathways showed that the phosphorylation of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and signal transducer and activator of transcription 3 (STAT3) was regulated. In particular, human CRC organoids were established. Western blotting, terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling (TUNEL), and analysis of cell viability and morphology further supported the hypothesis that the anti-CRC effects of bilobalide could be explained by its ability to suppress M2 macrophage polarization and promote M1 transformation. C57BL/6 mice treated with azoxymethane (AOM)/dextran sodium sulfate (DSS) were divided into three groups, i.e., control, AOM/DSS, low (2.5 mg/kg), and high (5 mg/kg). High-dose bilobalide markedly inhibited the progression of CRC, as evidenced by the increased body weight, decrease in disease activity index (DAI) death rate, and alleviation of colon length reduction and tumorigenesis. According to the in vivo results, reduced levels of inflammatory cytokines in the serum included tumor necrosis factor (TNF-α), IL-6, IL-1β, and IL-10. Bilobalide reduced oxidative stress indices, lipid peroxide (LPO), and malondialdehyde (MDA) and increased reduced glutathione (GSH). In addition, the expression of proliferating cell nuclear antigen (PCNA), Ki67, cellular Myc (c-Myc), and CD206 was downregulated in the drug-treated groups, as confirmed by the immunohistochemical staining. Collectively, these results indicated that bilobalide administration improve experimental CRC by inhibiting M2 macrophage polarization and oxidative stress. Thus, bilobalide may prevent CRC and serve as a potential therapeutic target for CRC. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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