| Summary: | 博士 === 國立中興大學 === 生物醫學研究所 === 107 === There is increasing global incidence of highly metastatic melanoma and therapeutic strategies like those focusing on the downstream beta-catenin/MITF axis of invading melanoma cells are urgently needed. Targeting endoplasmic reticulum (ER) stress can promote cancer cell death and inhibit epithelial mesenchymal transition (EMT) in metastatic tumors. However, whether Honokiol could promote ER stress-dependent apoptosis and regulate metastatic melanoma is still unkown. We therefore used the highly metastatic melanoma xenograft mouse model and computed tomography imaging to assess the therapeutic efficacy of Honokiol for peritoneal metastasis. The ER stress marker, Calpain-10, delineated a novel proteolytic cleavage enzyme, while CHOP/GADD153-regulated apoptosis was used for gene silencing to determine the role of the β-catenin/MITF axis in melanoma cells. Our results showed that Honokiol effectively decreased peritoneal dissemination and organ metastasis via ER stress activation and EMT marker inhibition. Knockdown Calpain-10 or CHOP/GADD153 blocked all of the biological effects in Honokiol-induced β-catenin/MITF cleavage, ERSE or TCF/LEF luciferase activity, and β-catenin kinase activity. These experimental outcomes suggest that Honokiol can significantly thwart the progression of highly metastatic melanoma using the β-catenin/MITF axis via prompt Calpain-10 and CHOP/GADD153 regulated cascades.
We also explored the molecular mechanisms and therapeutic effects of potential agents in psoriasis. Psoriasis is a chronic inflammatory skin disease characterized by abnormal keratinocyte proliferation and differentiation and by and influx of inflammatory cell that is associated with multiple coexisting conditions. The aryl hydrocarbon receptor (AhR) has become increasingly recognized for its role in the differentiation and activity of immune cell subsets; however, its role in regulating the activity of immune cells by pharmacological effect of a receptor agonist has not been described. Here we first establish and present of short-wave infrared (SWIR, defined here as ∼1000 to 2000 nm) spectroscopy and imaging techniques for biological tissue optical property characterization. We conducted and identify a novel spectroscopic instrument (GAIA) application of AhR-mediated signaling in imiquimod (IMQ)-induced psoriatic inflammation, a mouse model that shares feature with the human disease. We found that GAIA precisely evaluated psoriatic inflammation and consistent with pathological histology, which specially survey the water and collagen signals of tissue constituents but not lipids. Simultaneously, we also show that deficiency of AhR expression by knockout (AhRKO) mice is induced and aggravated in spectroscopic image, immune cells and cytokine IL-17. In contrast, activation of AhR with an AhR agonists, Leflunomide (LEU) and Omeprazole (OMP) efficiently attenuates immune activity and IL-17 of production. In vitro study, primary goldfish keratocytes (PFK) demonstrated that AhR is essential for keratinocyte barrier function by trans epithelial electrical resistance (TEER) measurement. Our studies introduce AhR as another regulator of immune cell activity in vivo, regulation of inflammatory responses and skin barrier function. We open the possibility for novel therapeutic strategies in chronic inflammatory disorders and identify AhR agonist may be a potential therapeutic target for psoriasis.
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