Tumor Necrosis Factor-α Induces a Preeclamptic-like Phenotype in Placental Villi via Sphingosine Kinase 1 Activation.

Preeclampsia (PE) involves inadequate placental function. This can occur due to elevated pro-inflammatory tumor necrosis factor-α (TNF-α). In other tissues, TNF-α signals via sphingosine kinase 1 (SphK1). SphK1 hinders syncytial formation. Whether this occurs downstream of TNF-α signaling is unclear. We hypothesized that placental SphK1 levels are higher in PE and elevated TNF-α decreases syncytial function, increases syncytial shedding, and increases cytokine/factor release via SphK1 activity. Term placental biopsies were analyzed for SphK1 using immunofluorescence and qRT-PCR. Term placental explants were treated after 4 days of culture, at the start of syncytial regeneration, with TNF-α and/or SphK1 inhibitors, PF-543. Syncytialization was assessed by measuring fusion and chorionic gonadotropin release. Cell death and shedding were measured by lactate dehydrogenase release and placental alkaline phosphatase-positive shed particles. Forty-two cytokines were measured using multiplex assays. Placental SphK1 was increased in PE. Increased cell death, shedding, interferon-α2, IFN-γ-induced protein 10, fibroblast growth factor 2, and platelet-derived growth factor-AA release induced by TNF-α were reversed upon SphK1 inhibition. TNF-α increased the release of 26 cytokines independently of SphK1. TNF-α decreased IL-10 release and inhibiting SphK1 reversed this effect. Inhibiting SphK1 alone decreased TNF-α release. Hence, SphK1 partially mediates the TNF-α-induced PE placental phenotype, primarily through cell damage, shedding, and specific cytokine release.

The life cycle of voltage-gated Ca2+ channels in neurons: an update on the trafficking of neuronal calcium channels.

Neuronal voltage-gated Ca2+ (CaV) channels play a critical role in cellular excitability, synaptic transmission, excitation-transcription coupling and activation of intracellular signaling pathways. CaV channels are multiprotein complexes and their functional expression in the plasma membrane involves finely tuned mechanisms, including forward trafficking from the endoplasmic reticulum (ER) to the plasma membrane, endocytosis and recycling. Whether genetic or acquired, alterations and defects in the trafficking of neuronal CaV channels can have severe physiological consequences. In this review, we address the current evidence concerning the regulatory mechanisms which underlie precise control of neuronal CaV channel trafficking and we discuss their potential as therapeutic targets.

Setosphapyrone C and D accelerate macrophages cholesterol efflux by promoting LXRα/ABCA1 pathway.

LXRα agonists have attracted significant attention due to their potential biological activities on promoting cholesterol efflux. This study was designed to investigate whether setosphapyrone C and D have potential lipid-lowering capacity and the underlying mechanisms in vitro. Our data showed that setosphapyrone C and D had weak cytotoxicity compared to the liver X receptor α (LXRα) agonist T0901317. In RAW 264.7 macrophages, setosphapyrone C and D significantly enhanced [3H]-cholesterol efflux by ~ 21.3% and 32.4%, respectively; furthermore, setosphapyrone C and D enhanced the protein levels of ATP-binding cassette transporter (ABC) A1 and LXRα by 58% and 69%, and 60% and 70% (8 µM), respectively; however, they had no effect on the protein levels of ABCG1 and scavenger receptor B type 1; additionally, they had minor effect on the mRNA expression of lipogenic genes. Of note, setosphapyrone C and D significantly enhanced LXRα/ABCA1pathway in mice primary macrophages. In BRL cells, setosphapyrone C and D significantly improved the protein levels of ABCA1 and ABCG1; setosphapyrone D significantly enhanced the protein expression of low-density lipoprotein. Collectively, setosphapyrone C and D with weak cytotoxicity exhibited effective lipid-lowering effect via enhancing LXRα/ABC pathways. Setosphapyrones possess potential application for the treatment of hyperlipidemic diseases.