Depletion of serotonin relieves concanavalin A-induced liver fibrosis in mice by inhibiting inflammation, oxidative stress, and TGF-β1/Smads signaling pathway
Autor: | Shuangchi Liu, Yong Wang, Zheng Lu, Huichun Liu, Hao Jin, Qing Pang, Yi Tan, Mengnan Dai |
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Rok vydání: | 2021 |
Předmět: |
Liver Cirrhosis
Male 0301 basic medicine Serotonin medicine.medical_specialty Smad Proteins Inflammation Tryptophan Hydroxylase Toxicology medicine.disease_cause Proinflammatory cytokine Transforming Growth Factor beta1 Superoxide dismutase Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Fibrosis Internal medicine Concanavalin A medicine Animals Humans Sirius Red Mice Knockout TPH1 biology Chemistry General Medicine medicine.disease Mice Inbred C57BL Oxidative Stress 030104 developmental biology Endocrinology biology.protein Mitogens medicine.symptom 030217 neurology & neurosurgery Oxidative stress Signal Transduction |
Zdroj: | Toxicology Letters. 340:123-132 |
ISSN: | 0378-4274 |
Popis: | Serotonin exerts important functions in several liver pathophysiological processes. In this study, we investigated the role of serotonin in concanavalin A (Con A)-induced liver fibrosis (LF) in mice and the underlying mechanisms. To establish the mouse model of LF, mice of wild-type (WT) and tryptophan hydroxylase 1 (Tph1) knockout (serotonin depletion) received Con A for 8 successive weeks. Degree of fibrosis was assessed by Sirius red staining, as well as the measurements of alpha smooth muscle actin (α- SMA), hydroxyproline (Hyp) and type I collagen in liver tissues. To elucidate the potential mechanisms, we assessed the effect of serotonin depletion on inflammatory, oxidative stress as well as TGF-β1/Smads signaling pathway. We found that serotonin depletion significantly inhibited collagen deposition as evaluated by less collagenous fiber in Sirus Red staining and reduced contents of Hyp and type I collagen. In addition, the absence of serotonin significantly inhibited the release of several inflammatory cytokines, including interleukin-6 (IL-6), interferon-gamma (IFN-γ), tumor necrosis-alpha (TNF-α), and transforming growth factor β1 (TGF-β1). Oxidative stress was also largely mitigated in LF mice with serotonin deficiency as manifested by the decreases of oxidative stress markers (malonaldehyde (MDA) and myeloperoxidase (MPO)), as well as the increases of antioxidant stress indicators (glutathione (GSH), and GSH-px, catalase (CAT), superoxide dismutase (SOD)) in liver tissues. Moreover, the lack of serotonin may provide an antifibrotic role by inhibiting the intrahepatic expressions of TGF-β1, phosphorylated-smad2 (p-smad2), and phosphorylated-smad3 (p-smad3). These results indicated that, serotonin depletion attenuates Con A-induced LF through the regulation of inflammatory response, oxidative stress injury, and TGF-β1/Smads signaling pathway. |
Databáze: | OpenAIRE |
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