👤 Takashi Morioka

Depression is a major mental illness, and its underlying mechanisms remain unclear. Emerging evidence suggests that astrocytes, which play a crucial role in brain function, may be involved in the pathophysiology of depression. We previously showed that downregulation of astrocytic connexin43 (Cx43) enhances the antidepressant effect of amitriptyline. However, the precise molecular mechanisms underlying this phenomenon remain unknown. In the present study, we investigated the signaling pathways involved in the antidepressant action of amitriptyline using an in vitro model involving Cx43-knockdown astrocytes. We found that amitriptyline potentiated the expression of brain-derived neurotrophic factor (BDNF), a key neurotrophic factor, in Cx43-knockdown astrocytes. This potentiation was mediated by the activation of Gq protein-coupled lysophosphatidic acid (LPA) receptors, a pathway that was sensitized by Cx43 downregulation. We further demonstrated that this signaling cascade involved the activation of Protein Kinase C (PKC) δ and transcription factor NF-κB, but not the conventional BDNF transcription factor CREB. We propose that Cx43 downregulation enhances the antidepressant effect of amitriptyline by specifically engaging the Gq-PKCδ-NF-κB pathway. These findings suggest that Cx43 downregulation in astrocytes, which has been considered a pathological feature of depression, may paradoxically contribute to the therapeutic efficacy of antidepressants by sensitizing a specific signaling pathway. Our study provides new insights into the molecular mechanism of antidepressant action and highlights the potential role of astrocytic Cx43 in modulating therapeutic responses. Show less

Although the expression of hepatic lipogenic genes is enhanced in insulin resistance, the underlying mechanism is unclear. To reveal the details, the aim of this study was to investigate whether the expression of hepatic lipogenic genes are mediated by epigenetic regulation and specific transcription factors in an insulin resistance model of rats. Using a rat model of insulin resistance (SHR/NDmc-cp), we investigated the relationship between hepatic expression of the lipogenic gene fatty-acid synthase (Fasn), binding of the transcription factor carbohydrate-responsive element-binding protein (ChREBP) to the Fasn gene, and histone modifications in the region of the Fasn gene by real-time reverse transcriptase polymerase chain reaction, immunoblotting, and chromatin immunoprecipitation assay. Compared with control rats, Fasn mRNA expression and protein levels were higher in the livers of SHR/NDmc-cp rats, as were protein expression levels and Fasn binding of ChREBP and RNA polymerase II. Moreover, compared with the livers of control rats, levels of mono-methylated histone H3 lysine (K) 4 and acetylated histone H4 were higher in the promoter/enhancer region of the Fasn gene in the livers of SHR/NDmc-cp rats. Levels of trimethylated histone H3K4 and acetylated histone H3 were higher in the transcribed region. The results of this study indicate that expression of the Fasn gene in the livers of insulin-resistant rats is associated with increased H3K4 methylation, increased histone H3 acetylation, and increased H4 acetylation, and also, binding levels of ChREBP to promoter/enhancer region of Fasn gene is involved in the Fasn gene expression caused by hyperglycemia. Show less

The Hairy-related transcription factor family of Notch- and ALK1-downstream transcriptional repressors, called Hrt/Hey/Hesr/Chf/Herp/Gridlock, has complementary and indispensable functions for vascular development. While mouse embryos null for either Hrt1/Hey1 or Hrt2/Hey2 did not show early vascular phenotypes, Hrt1/Hey1; Hrt2/Hey2 double null mice (H1(ko) /H2(ko) ) showed embryonic lethality with severe impairment of vascular morphogenesis. It remained unclear, however, whether Hrt/Hey functions are required in endothelial cells or vascular smooth muscle cells. In this study, we demonstrate that mice with endothelial-specific deletion of Hrt2/Hey2 combined with global Hrt1/Hey1 deletion (H1(ko) /H2(eko) ) show abnormal vascular morphogenesis and embryonic lethality. Their defects were characterized by the failure of vascular network formation in the yolk sac, abnormalities of embryonic vascular structures and impaired smooth muscle cell recruitment, and were virtually identical to the H1(ko) /H2(ko) phenotypes. Among signaling molecules implicated in vascular development, Robo4 expression was significantly increased and activation of Src family kinases was suppressed in endothelial cells of H1(ko) /H2(eko) embryos. The present study indicates an important role of Hrt1/Hey1 and Hrt2/Hey2 in endothelial cells during early vascular development, and further suggests involvement of Robo4 and Src family kinases in the mechanisms of embryonic vascular defects caused by the Hrt/Hey deficiency. Show less