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Stress, specifically chronic unpredictable stress and chronic restrained stress, induce depigmentation in C57BL/6 mice. Fluoxetine promoted melanin production and the migration of melanocytes via 5-HT1A receptor and 5-HT2A receptor, respectively.<br><br>Display Omitted<br>• Fluoxetine ameliorates CUMS and CRS induced depigmentation in C57BL/6 mouse. • Fluoxetine induces melanogenesis via activating the phosphorylation of p38 MAPK signaling pathways. • 5-HT1A and 2A receptors regulated fluoxetine increased melanocyte melanogenesis and migration.<br>Background: 5-HT1A receptor was participated in fluoxetine induced melanogenesis in melanocytes and in normal C57BL/6 mice, but we know little about whether other 5-HT receptors are involved in regulation of fluoxetine promotes pigmentation.<br>Objective: To investigate the role of 5-HT receptors in regulation of fluoxetine ameliorates chronic unpredictable mild stress (CUMS) and chronic restraint stress (CRS) induce hypopigmentation in C57BL/6 mice.<br>Methods: CUMS and CRS were used to induce depigmentation in mice and evaluate the effect of fluoxetine. Western blot, immunohistochemistry and Q-PCR assay were used to determine the levels of protein and mRNA. Masson Fontana staining was used for melanin staining and FITC-Phalloidin staining was used to detect the expression of F-actin. Zebrafish and B16F10 cells were used for the mechanism research.<br>Results: Fluoxetine (2.6 mg/kg, ig) ameliorated hypopigmentation induced by CUMS and CRS in mice, significantly increased the mRNA and protein levels of 5-HT1 A and 5-HT2 A receptors in mice and B16F10 cells. The effect of fluoxetine on melanogenesis in B16F10 cells and zebrafish were inhibited by WAY100635 (a selective 5-HT1 A receptor antagonist) and ketanserin (a 5-HT2 A receptor antagonist), respectively. Activation of p38 MAPK signaling pathways was contributed to fluoxetine induced melanogenesis and inhibited by WAY100635, but not ketanserin. However, ketanserin selectively weakened the action of fluoxetine promoted migration and up-regulated Rab27a protein expression in B16F10 cells.<br>Conclusions: 5-HT1 A and 2 A receptors contribute to melanogenesis and migration property of fluoxetine. The newly revealed mechanism indicates that fluoxetine and its analogues may be a potential drug for treatment of depigmentation disorders.
Abstract Ethnopharmacological relevance Zuotai (gTso thal) has a long history in the treatment of cardiovascular disease, liver and bile diseases, spleen and stomach diseases as a precious adjuvant in Tibetan medicine. However, Zuotai is a mercury preparation that contains 54.5% HgS. Its application has always been controversial. Aim of the study To evaluate the toxicological effects of Zuotai in hepatocytes and in zebrafish. Materials and methods MTT was used to determine the survival rate of hepatocytes; Hoechst and TUNEL staining were used to detect the apoptosis cells; Western blot and RT-qPCR assay were used to determine the expression levels of the protein and mRNA; Liver morphology observation and H&E staining were used to evaluate the hepatotoxicity of Zuotai in Zebfrafish. Results The survival rate of L-02 cells, HepG2 cells and RBL-2A cells reduced by Zuotai (10−4–0.1 mg/mL) in a dose and time-dependent manner. Zuotai (0.1 mg/mL) induced HepG2 cells shrinkage, condensation and fragmentation and increased the number of apoptosis cells. The protein expression levels of cleaved Caspase-3 and Bax were increased and the expression levels of Bcl-2 were reduced after HepG2 cells exposed to Zuotai (10−4–0.1 mg/mL) for 24 h. In addition, Zuotai (0.2 mg/mL) induced the darker liver color of the larval zebrafish and changed the liver morphologic of adult zebrafish. Zuotai (0.2 mg/mL) also increased the mRNA levels of CYP1A1, CYP1B1 and MT-1 in the liver of adult zebrafish. However, no significantly hepatotoxicity was observed after hepatocytes and zebrafish exposed to HgS at the same dose. Conclusions Results showed that Zuotai induced hepatotoxicity effectively under a certain dose but its hepatotoxicity likely occurs via other mechanisms that did not depend on HgS. Graphical abstract Zuotai, a clinical adjuvant in Tibetan medicine, contains 54.5% HgS, which can induce apoptosis of liver cells and liver injury in zebrafish. However, HgS, the principal component of Zuotai did not exhibit hepatotoxicity at the same dose. fx1 [ABSTRACT FROM AUTHOR]