Vimentin intermediate filaments undergo spatial reorganization in endothelial cells and fibroblasts in response to stimulation with platelet-derived growth factor and epidermal growth factor. In the present study, the vimentin network exhibited a curved filamentous structure in unstimulated smooth muscle cells. Vimentin filaments became straight and were arranged along the long axis of cells upon stimulation with 5-hydroxytryptamine (5-HT; serotonin). Stimulation of smooth muscle cells with 5-HT also induced phosphorylation of vimentin on Ser-56. Treatment of cells with small interfering RNA selectively down-regulated the expression of PAK1 (p21-activated kinase 1) without affecting the content of smooth muscle alpha-actin. The silencing of PAK1 inhibited the site-specific phosphorylation and spatial rearrangement of the vimentin network in response to stimulation with 5-HT. Neither the disruption of stress fibres by cytochalasin D nor the inhibition of protein tyrosine phosphorylation affects the spatial reorganization of vimentin intermediate filaments in response to stimulation with 5-HT. In addition, stimulation of smooth muscle cells with 5-HT increased the ratio of soluble to insoluble vimentin. PAK1 silencing attenuated increases in the ratio of soluble to insoluble vimentin upon stimulation with 5-HT. These results suggest that the PAK-mediated site-specific phosphorylation of vimentin may play a role in regulating the reorganization of vimentin intermediate filaments during stimulation of smooth muscle cells with 5-HT.
This review aimed to provide a general view of catalpol in protection against diabetes and diabetic complications, as well as its pharmacokinetics and safety concerns. The following databases were consulted with the retrieval of more than 100 publications through June 2019: PubMed, Chinese National Knowledge Infrastructure, WanFang Data, and web of science. Catalpol exerts an anti-diabetic effect in different animal models with an oral dosage ranging from 2.5 to 200 mg/kg in rats and 10 to 200 mg/kg in mice. Besides, catalpol may prevent the development of diabetic complications in kidney, heart, central nervous system, and bone. The underlying mechanism may be associated with an inhibition of inflammation, oxidative stress, and apoptosis through modulation of various cellular signaling, such as AMPK/PI3K/Akt, PPAR/ACC, JNK/NF-κB, and AGE/RAGE/NOX4 signaling pathways, as well as PKCγ and Cav-1 expression. The pharmacokinetic profile reveals that catalpol could pass the blood-brain barrier and has a potential to be orally administrated. Taken together, catalpol is a well-tolerated natural compound with promising pharmacological actions in protection against diabetes and diabetic complications via multi-targets, offering a novel scaffold for the development of anti-diabetic drug candidate. Further prospective and well-designed clinical trials will shed light on the potential of clinical usage of catalpol.
The human beta1-adrenergic receptor (AR) and hamster beta2-AR transcripts can be post-transcriptionally regulated at the level of mRNA stability and undergo accelerated agonist-mediated degradation via interaction of their 3' untranslated regions (UTR) with RNA binding proteins. Using RNase protection assays, we have determined that chronic isoproterenol exposure of rat C6 glioma cells results in the accelerated reduction of beta1-AR mRNAs. To determine the role of cellular environment on the agonist-independent and agonist-mediated degradation of beta1-AR mRNAs, we transfected rat beta1-AR expression recombinants into both hamster DDT1MF2 cells and rat L6 cells. The rat beta1-AR mRNAs in the two transfectant cell pools retain longer agonist-independent half-lives than in the C6 environment and undergo accelerated degradation upon chronic agonist exposure. Using UV-cross-linking/immunoblot and immunoprecipitation analyses, we have determined that the rat beta1-AR 3' UTR recognizes a predominant M(r) 39,000 component, identified as the mammalian elav-like protein HuR, and several other minor components, including the heteronuclear protein hnRNP A1. HuR levels are more highly expressed in C6 cells than in DDT1MF2 and L6 cells and are induced after chronic isoproterenol treatment. Furthermore, C6 transfectants containing an HuR expression recombinant exhibit reduced beta1-AR mRNA half-lives that were statistically comparable with half-lives identified in isoproterenol-treated C6 cells. These results imply that HuR plays a potential role in the agonist-independent and agonist-mediated down-regulation of beta1-AR mRNAs.
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