SUMMARY The regenerative capacity of the human endometrium requires a population of local stem cells. However, the phenotypes, locations, and origin of these cells are still unknown. In a mouse menstruation model, uterine stromal SM22α + -derived CD34 + KLF4 + stem cells are activated and integrate into the regeneration area, where they differentiate and incorporate into the endometrial epithelium; this process is correlated with enhanced protein SUMOylation in CD34 + KLF4 + cells. Mice with a stromal SM22α-specific SENP1 deletion (SENP1smKO) exhibit accelerated endometrial repair in the regeneration model and develop spontaneous uterine hyperplasia. Mechanistic studies suggest that SENP1 deletion induces SUMOylation of ERα, which augments ERα transcriptional activity and proliferative signaling in SM22α + CD34 + KLF4 + cells. These cells then transdifferentiate to the endometrial epithelium. Our study reveals that CD34 + KLF4 + stromal-resident stem cells directly contribute to endometrial regeneration, which is regulated through SENP1-mediated ERα suppression.

Our results demonstrate the differential responses to cold-induced changes across discrete BAT and WAT depots and support the notion that the effects of short-term cold exposure are achieved by expansion, activation and increasing thermogenic capacity of iBAT, as well as browning of sWAT and, to a lesser extent, eWAT.

This study focused on the potential toxicity of silver nanoparticles (AgNPs) on cardiac electrophysiology which is rarely investigated. We found that AgNPs (10-10g/ml) concentration-dependently depolarized the resting potential, diminished the action potential, and finally led to loss of excitability in mice cardiac papillary muscle cells in vitro. In cultured neonatal mice cardiomyocytes, AgNPs (10-10g/ml) concentration-dependently decreased the Na currents (I), accelerated the activation, and delayed the inactivation and recovery of Na channels from inactivation within 5 min. AgNPs at 10g/ml also rapidly decreased the inwardly rectifying K currents (I) and delayed the activation of I channels. Intravenous injection of AgNPs at 3 mg/kg only decreased the heart rate, while at ≥4 mg/kg sequentially induced sinus bradycardia, complete atrio-ventricular conduction block, and cardiac asystole. AgNPs at 10-10g/ml did not increase reactive oxygen species (ROS) generation and only at 10g/ml mildly induced lactate dehydrogenase (LDH) release in the cardiomyocytes within 5 min. Endocytosis of AgNPs by cardiomyocytes was not observed within 5 min, but was observed 1 h after exposing to AgNPs. Comparative Ag (≤0.02% of the AgNPs) could not induce above toxicities. We conclude that AgNPs exert rapid toxic effects on myocardial electrophysiology and induce lethal bradyarrhythmias. These acute toxicities are likely due to direct effects of AgNPs on ion channels at the nano-scale level, but not caused by Ag, ROS, and membrane injury. These findings provide warning to the nanomedical practice using AgNPs.

Dietary Zn(ii)-curcumin protects against doxorubicin-induced cardiomyopathy by modulation of the gut microbiota and maintenance of zinc homeostasis.

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Background: The growing use of silica nanoparticles (SiNPs) in many fields raises human toxicity concerns. We studied the toxicity of SiNP-20 (particle diameter 20 nm) and SiNP-100 (100 nm) and the underlying mechanisms with a focus on the endothelium both in vitro and in vivo. Methods:The study was conducted in cultured human umbilical vein endothelial cells (HUVECs) and adult female Balb/c mice using several techniques.Results: In vitro, both SiNP-20 and SiNP-100 decreased the viability and damaged the plasma membrane of cultured HUVECs. The nanoparticles also inhibited HUVECs migration and tube formation in a concentrationdependent manner. Both SiNPs induced significant calcium mobilization and generation of reactive oxygen species (ROS), increased the phosphorylation of vascular endothelial (VE)-cadherin at the site of tyrosine 731 residue (pY731-VEC), decreased the expression of VE-cadherin expression, disrupted the junctional VE-cadherin continuity and induced F-actin re-assembly in HUVECs. The injuries were reversed by blocking Ca 2+ release activated Ca 2+ (CRAC) channels with YM58483 or by eliminating ROS with N-acetyl cysteine (NAC). In vivo, both SiNP-20 and SiNP-100 (i.v.) induced multiple organ injuries of Balb/c mice in a dose (range 7-35 mg/kg), particle size, and exposure time (4-72 h)-dependent manner. Heart injuries included coronary endothelial damage, erythrocyte adhesion to coronary intima and coronary coagulation. Abdominal aorta injury exhibited intimal neoplasm formation. Lung injuries were smaller pulmonary vein coagulation, bronchiolar epithelial edema and lumen oozing and narrowing. Liver injuries included multifocal necrosis and smaller hepatic vein congestion and coagulation. Kidney injuries involved glomerular congestion and swelling. Macrophage infiltration occurred in all of the observed organ tissues after SiNPs exposure. SiNPs also decreased VE-cadherin expression and altered VE-cadherin spatial distribution in multiple organ tissues in vivo. The largest SiNP (SiNP-100) and longest exposure time exerted the greatest toxicity both in vitro and in vivo.

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