Current molecular pharmacology · 2024
Fenofibrate Inhibits LPS and Zymosan-induced Inflammatory Responses through Sonic Hedgehog in IMG Cells.
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Wang Yu-Wen, Huang Bor-Ren, Lu Dah-Yuu, Chen Jin-Wun, Charoensaensuk Vichuda, Yang Liang-Yo, Lai Sheng-Wei, Tsai Cheng-Fang, Yeh Wei-Lan
Аннотация
BACKGROUND: Neuroinflammatory responses are strongly associated with the pathogenesis of progressive neurodegenerative conditions and mood disorders. Modulating microglial activation is a potential strategy for developing protective treatments for central nervous system (CNS)-related diseases. Fibrates, widely used in clinical practice as cholesterol-lowering medications, exhibit numerous biological activities, such as anticancer and antiinflammatory activities. However, the mechanisms underlying their beneficial effects on the CNS remain unclear.
OBJECTIVE: This study investigated the mechanisms through which fibrates influence inflammatory and anti-inflammatory homeostasis in microglial cells.
METHODS: Cell viability assay, nitric oxide measurement, Western blot analysis,, real-time PCR, and cell transfection were used in this study.
RESULTS: Fenofibrate, a well-known fibrate, reduced the production of nitric oxide and interleukin-6 and the expression of inducible nitric oxide synthase and cyclooxygenase-2 in microglial cells. It also inhibited the expression of various proinflammatory cytokines and chemokines, including tumor necrosis factor-ɑ and interleukin-1β, and chemokine (C-C) motif ligand 2 and chemokine (C-X-C motif) ligand 10. Notably, treatment of fenofibrate dramatically activated the sonic hedgehog (SHH) and sirtuin-1 (SIRT1). Furthermore, the inhibition of SHH or SIRT1 mitigated the anti-inflammatory effects of fenofibrate in IMG microglial cells.
CONCLUSION: Our findings suggest that fenofibrate may inhibit inflammatory responses by activating SIRT1 and SHH in IMG microglial cells. Our study suggests that fenofibrate or targeting SHH molecule is a promising therapeutic strategy for neuroinflammation-associated conditions. Further research with additional cell lines and in vivo models is needed to understand its therapeutic potential.
OBJECTIVE: This study investigated the mechanisms through which fibrates influence inflammatory and anti-inflammatory homeostasis in microglial cells.
METHODS: Cell viability assay, nitric oxide measurement, Western blot analysis,, real-time PCR, and cell transfection were used in this study.
RESULTS: Fenofibrate, a well-known fibrate, reduced the production of nitric oxide and interleukin-6 and the expression of inducible nitric oxide synthase and cyclooxygenase-2 in microglial cells. It also inhibited the expression of various proinflammatory cytokines and chemokines, including tumor necrosis factor-ɑ and interleukin-1β, and chemokine (C-C) motif ligand 2 and chemokine (C-X-C motif) ligand 10. Notably, treatment of fenofibrate dramatically activated the sonic hedgehog (SHH) and sirtuin-1 (SIRT1). Furthermore, the inhibition of SHH or SIRT1 mitigated the anti-inflammatory effects of fenofibrate in IMG microglial cells.
CONCLUSION: Our findings suggest that fenofibrate may inhibit inflammatory responses by activating SIRT1 and SHH in IMG microglial cells. Our study suggests that fenofibrate or targeting SHH molecule is a promising therapeutic strategy for neuroinflammation-associated conditions. Further research with additional cell lines and in vivo models is needed to understand its therapeutic potential.