Estrogen-Related Hormones Induce Apoptosis by Stabilizing Schlafen-12 Protein Turnover.

The mitochondrial pathway of apoptosis is controlled by the ratio of anti- and pro-apoptotic members of the Bcl-2 family of proteins. The molecular events underlying how a given physiological stimulus changes this ratio to trigger apoptosis remains unclear. We report here that human 17-ß-estradiol (E2) and its related steroid hormones induce apoptosis by binding directly to phosphodiesterase 3A, which in turn recruits and stabilizes an otherwise fast-turnover protein Schlafen 12 (SLFN12). The elevated SLFN12 binds to ribosomes to exclude the recruitment of signal recognition particles (SRPs), thereby blocking the continuous protein translation occurring on the endoplasmic reticulum of E2-treated cells. These proteins include Bcl-2 and Mcl-1, whose ensuing decrease triggers apoptosis. The SLFN12 protein and an apoptosis activation marker were co-localized in syncytiotrophoblast of human placentas, where levels of estrogen-related hormones are high, and dynamic cell turnover by apoptosis is critical for successful implantation and placenta development.

Impact of the Post-Thrombotic Syndrome on the Arterial Wall of the Lower Limbs.

OBJECTIVE: Deep vein thrombosis of the lower limbs is a common disease in vascular surgery. Approximately 20-50% of deep vein thrombosis patients develop post-thrombotic syndrome, which can severely affect the patient's quality of life. However, the precise science of the pathophysiology of the progression of the post-thrombotic syndrome remains unclear. Studies have demonstrated that patients with post-thrombotic syndrome of the lower limbs have impaired arterial wall endothelial function. Nevertheless, there is little research on the different impacts of post-thrombotic syndrome on the arterial wall endothelial function between the affected limbs and the healthy limbs. This study aims to assess this difference. METHODS: A total of 60 patients treated for the post-thrombotic syndrome of the lower limbs were included. The flow-mediated dilation (FMD%) and nitroglycerin-mediated dilation (NMD%) were measured to assess the different endothelial function alterations of the common femoral arterial wall between the affected limb and the healthy limb. RESULTS: No significant differences in the common femoral artery diameter between the affected limbs and the healthy limbs were discovered (8.94 ± 0.92 mm vs 8.75 ± 1.0 mm, P = 0.710). The flow-mediated dilation of the common femoral artery of the affected limbs were significantly lower compared to the healthy limbs (FMD%: 3.21 ± 1.07% vs 5.19 ± 1.35%, P = 0.001). However, there was no significant difference in the nitroglycerin-mediated dilation of the common femoral artery between the affected limbs and the healthy limbs（ NMD%: 13.37 ± 1.78% versus 14.45 ± 2.14%, P = 0.083). CONCLUSIONS: Our results demonstrated the association between post-thrombotic syndrome and deteriorated endothelial functional properties of the arterial wall of the lower limbs. Endothelial dysfunction of the arteries wall was more severe in the affected lower limbs with the post-thrombotic syndrome than in the healthy limbs. The mentioned findings may partly explain the pathophysiology of the progression post-thrombotic syndrome of the lower limbs. HIGHLIGHTS: tudies have demonstrated that patients with post-thrombotic syndrome of the lower limbs have impaired arterial wall endothelial function. Our results demonstrated the endothelial dysfunction of the arteries wall was more severe in the affected lower limbs with the post-thrombotic syndrome than in the healthy limbs. Our findings may partly explain the pathophysiology of the progression post-thrombotic syndrome of the lower limbs.

Exploring Halogen Bonds in 5-Hydroxytryptamine 2B Receptor-Ligand Interactions.

Here, we predicted the potential halogen bonding interaction between compound 2 and the 5-hydroxytryptamine 2B (5-HT2B) receptor and systematically assessed this interaction via structure-activity relationship analysis and molecular dynamics simulations. A physics-based computational protocol was then developed to further explore the opportunity of "designing in" halogen bonding interactions in structure-based ligand design for the 5-HT2B receptor, which not only facilitated the identification of previously uncharacterized halogen bonds in known 5-HT2B ligands but also enabled the rational design of halogen bonding interactions for the optimization of 5-HT2B ligands. As a proof-of-concept, a series of halogen-substituted analogues of doxepin was synthesized and evaluated, which showed improved in vitro and in vivo potency.