Dihydrotestosterone induces arterial stiffening in female mice.

BACKGROUND: Androgens are important sex hormones in both men and women and are supplemented when endogenous levels are low, for gender transitioning, or to increase libido. Androgens also circulate at higher levels in women with polycystic ovarian syndrome, a condition that increases the risk for cardiovascular diseases including hypertension and arterial stiffness. Since our previous work shows an important role for the G protein-coupled estrogen receptor (GPER) in arterial stiffness, we hypothesized that other hormones including androgens may impact arterial stiffness in female mice via downregulation of GPER. METHODS: The impact of the non-aromatizable androgen dihydrotestosterone (DHT), the glucocorticoid dexamethasone, and the progestin medroxyprogesterone acetate (all 100 nM for 24 h) on GPER and ERα expression was assessed in cultured vascular smooth muscle cells using droplet digital PCR (ddPCR). To assess the in vivo impact of the DHT-induced downregulation of GPER, female ovary-intact C57Bl/6 mice at 15-16 weeks of age were treated with silastic capsules containing DHT for 4 weeks, one with a dosage expected to mimic human male DHT levels and another to double the expected human concentration (n = 8-9/group). RESULTS: In cultured vascular smooth muscle cells, GPER mRNA was decreased by DHT (P = 0.001) but was not impacted by dexamethasone or medroxyprogesterone. In contrast, ERα expression in cultured cells was significantly suppressed by all three hormones (P < 0.0001). In control mice or mice treated with a single or double dose of DHT, a dose-dependent increase in body weight was observed (control 22 ± 2 g, single dose 24 ± 2 g, double dose 26 ± 2 g; P = 0.0002). Intracarotid stiffness measured via pulse wave velocity showed a more than two-fold increase in both DHT-treated groups (control 1.9 ± 0.3 m/s, single dose 4.3 ± 0.8 m/s, double dose 4.8 ± 1.0 m/s). This increase in arterial stiffness occurred independent of changes in blood pressure (P = 0.59). Histological analysis of aortic sections using Masson's trichrome showed a significant decrease in collagen between the control group (24 ± 5%) and the double dose group (17 ± 3%, P = 0.007), despite no changes in aortic wall thickness or smooth muscle content. Lastly, ddPCR showed that in vivo DHT treatment decreased aortic expression of both GPER (control 20 ± 5, single dose 10.5 ± 5.6, double dose 10 ± 4 copies/ng; P = 0.001) and ERα (control 54 ± 2, single dose 24 ± 13, and double dose 23 ± 12 copies/ng; P = 0.003). CONCLUSIONS: These findings indicate that androgen promotes arterial stiffening and cardiovascular damage in female mice and is associated with decreased estrogen receptor expression. These data are important for transgender men, women using testosterone for fitness or reduced libido, as well as patients with polycystic ovarian syndrome.

The current study investigated the impact of other hormones on estrogen receptor expression and its impact on vascular health. In both cultured vascular cells and in vivo vascular tissue, dihydrotestosterone decreased the expression of estrogen receptors. Female mice treated with dihydrotestosterone also displayed increased body weight and arterial stiffness despite no change in blood pressure. These findings indicate that increases in testosterone may impact vascular health, which may be important clinically for transgender men, women using testosterone for fitness or reduced libido, as well as patients with polycystic ovarian syndrome.

Mechanical Performance of 3D Printed Concrete in Steam Curing Conditions.

Three-dimensional (3D) concrete printing (3DCP) technology attracts significant attention from research and industry. Moreover, adequate mechanical performance is one of the primary properties for materials, meeting the demand of structural safety using 3DCP technology. However, research on curing conditions as the significant influence factor of mechanical capacity is required to accelerate the practical application of 3DCP technology. This study aims to explore the impact of various steam curing conditions (heating rate, constant temperature time, and constant temperature) on the mechanical performance of printed concrete containing solid wastes. Moreover, the optimal steam curing conditions are obtained for compressive, tensile, and flexural properties in different directions. Subsequently, anisotropies in the mechanical properties of printed composites and interlayer bonding behaviors are investigated when various curing conditions are employed. The result shows that steam curing conditions and solid waste incorporation improves the interlayer bond for 3D printed cement-based composites.

Mitochondrial DNA instability in cells lacking aconitase correlates with iron citrate toxicity.

Aconitase, the second enzyme of the tricarboxylic acid cycle encoded by ACO1 in the budding yeast Saccharomyces cerevisiae, catalyzes the conversion of citrate to isocitrate. aco1Δ results in mitochondrial DNA (mtDNA) instability. It has been proposed that Aco1 binds to mtDNA and mediates its maintenance. Here we propose an alternative mechanism to account for mtDNA loss in aco1Δ mutant cells. We found that aco1Δ activated the RTG pathway, resulting in increased expression of genes encoding citrate synthase. By deleting RTG1, RTG3, or genes encoding citrate synthase, mtDNA instability was prevented in aco1Δ mutant cells. Increased activity of citrate synthase leads to iron accumulation in the mitochondria. Mutations in MRS3 and MRS4, encoding two mitochondrial iron transporters, also prevented mtDNA loss due to aco1Δ. Mitochondria are the main source of superoxide radicals, which are converted to H2O2 through two superoxide dismutases, Sod1 and Sod2. H2O2 in turn reacts with Fe(2+) to generate very active hydroxyl radicals. We found that loss of Sod1, but not Sod2, prevents mtDNA loss in aco1Δ mutant cells. We propose that mtDNA loss in aco1Δ mutant cells is caused by the activation of the RTG pathway and subsequent iron citrate accumulation and toxicity.

[Effects of fraction from Phyllanthus urinaria on thrombosis and coagulation system in animals].

OBJECTIVE: To investigate the effects of PUW (a fraction containing 60% corilagin from a Chinese herbal plant Phyllanthus urinaria) on thrombosis and coagulation system. METHODS: Myers's method was used to evaluate the protection of intravenously administered PUW against the male mouse sudden death caused by injection of 75 mg/kg arachidonic acid in the tail vein; Charlton's method was modified to observe antithrombotic effect of PUW in rat electrically stimulated carotid artery thrombosis model; and the model of venous thrombosis was produced to investigate the antithrombotic effect of PUW. Rosette assay was used to observe the effect of PUW on platelet-neutrophil adhesion. The effects of PUW were monitored on euglobulin lysis time (ELT), prothrombin time (PT), kaolin partial thromboplastin time (KPTT), and bleeding time (BT) in rats, according to the methods of Kowalski, HUANG Zheng-Liang, and GU Yue-Fang, et al, respectively. RESULTS: The results showed that PUW administered intravenously significantly decreased the mouse mortality, prolonged the occlusion time of rat carotid arteries, and reduced the wet and dry thrombus weight of the inferior vena cava, respectively. PUW markedly inhibited the binding of activated platelets to neutrophils, obtaining 39.7 mg/L of the medium inhibitory concentration. Intravenously administered PUW significantly shortened ELT, prolonged KPTT while had no influence on PT; PUW increased BT in rat tail tips but the BT caused by PUW was much shorter than that by aspirin or urokinase. CONCLUSION: It is suggested that PUW has the potential of antithrombosis due to its inhibition of platelet-neutrophil adhesion. PUW shows the tendency to bleeding, however, it could not cause serious bleeding side effect as compared with aspirin or urokinase.