Titanium dioxide nanoparticles enhance thrombosis through triggering the phosphatidylserine exposure and procoagulant activation of red blood cells

Background Expanding biomedical application of anatase titanium dioxide (TiO2) nanoparticles (NPs) is raising the public concern on its potential health hazards. Here, we demonstrated that TiO2 NPs can increase phosphatidylserine (PS) exposure and procoagulant activity of red blood cells (RBCs), which may contribute to thrombosis. Results We conducted in vitro studies using RBCs freshly isolated from healthy male volunteers. TiO2 NPs exposure (≦ 25 μg/mL) induced PS exposure and microvesicles (MV) generation accompanied by morphological changes of RBCs. While ROS generation was not observed following the exposure to TiO2 NPs, intracellular calcium increased and caspase-3 was activated, which up-regulated scramblase activity, leading to PS exposure. RBCs exposed to TiO2 NPs could increase procoagulant activity as measured by accelerated thrombin generation, and enhancement of RBC-endothelial cells adhesion and RBC-RBC aggregation. Confirming the procoagulant activation of RBC in vitro, exposure to TiO2 NPs (2 mg/kg intravenously injection) in rats increased thrombus formation in the venous thrombosis model. Conclusion Collectively, these results suggest that anatase TiO2 NPs may harbor prothrombotic risks by promoting the procoagulant activity of RBCs, which needs attention for its biomedical application.This research was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea Government (MSIP) (2015R1A2A2A01011705), National Natural Science Foundation of China (No.82020108027 and No.82003500) as well as the Talent Introduction Program of Postdoctoral International Exchange Program (No. YJ20190263)

Inorganic Arsenite Potentiates Vasoconstriction through Calcium Sensitization in Vascular Smooth Muscle

Chronic exposure to arsenic is well known as the cause of cardiovascular diseases such as hypertension. To investigate the effect of arsenic on blood vessels, we examined whether arsenic affected the contraction of aortic rings in an isolated organ bath system. Treatment with arsenite, a trivalent inorganic species, increased vasoconstriction induced by phenylephrine or serotonin in a concentration-dependent manner. Among the arsenic species tested—arsenite, pentavalent inorganic species (arsenate), monomethylarsonic acid (MMA(V)), and dimethylarsinic acid (DMA(V))—arsenite was the most potent. Similar effects were also observed in aortic rings without endothelium, suggesting that vascular smooth muscle plays a key role in enhancing vasoconstriction induced by arsenite. This hypercontraction by arsenite was well correlated with the extent of myosin light chain (MLC) phosphorylation stimulated by phenylephrine. Direct Ca(2+) measurement using fura-2 dye in aortic strips revealed that arsenite enhanced vasoconstriction induced by high K(+) without concomitant increase in intracellular Ca(2+) elevation, suggesting that, rather than direct Ca(2+) elevation, Ca(2+) sensitization may be a major contributor to the enhanced vasoconstriction by arsenite. Consistent with these in vitro results, 2-hr pretreatment of 1.0 mg/kg intravenous arsenite augmented phenylephrine-induced blood pressure increase in conscious rats. All these results suggest that arsenite increases agonist-induced vasoconstriction mediated by MLC phosphorylation in smooth muscles and that calcium sensitization is one of the key mechanisms for the hypercontraction induced by arsenite in blood vessels

Curative Effects of Thiacremonone against Acetaminophen-Induced Acute Hepatic Failure via Inhibition of Proinflammatory Cytokines Production and Infiltration of Cytotoxic Immune Cells and Kupffer Cells

High doses of acetaminophen (APAP; N-acetyl-p-aminophenol) cause severe hepatotoxicity after metabolic activation by cytochrome P450 2E1. This study was undertaken to examine the preventive effects of thiacremonone, a compound extracted from garlic, on APAP-induced acute hepatic failure in male C57BL/6J. Mice received with 500 mg/kg APAP after a 7-day pretreatment with thiacremonone (10–50 mg/kg). Thiacremonone inhibited the APAP-induced serum ALT and AST levels in a dose-dependent manner, and markedly reduced the restricted area of necrosis and inflammation by administration of APAP. Thiacremonone also inhibited the APAP-induced depletion of intracellular GSH, induction of nitric oxide, and lipid peroxidation as well as expression of P450 2E1. After APAP injection, the numbers of Kupffer cells, natural killer cells, and cytotoxic T cells were elevated, but the elevated cell numbers in the liver were reduced in thiacremonone pretreated mice. The expression levels of I-309, M-CSF, MIG, MIP-1α, MIP-1β, IL-7, and IL-17 were increased by APAP treatment, which were inhibited in thiacremonone pretreated mice. These data indicate that thiacremonone could be a useful agent for the treatment of drug-induced hepatic failure and that the reduction of cytotoxic immune cells as well as proinflammatory cytokine production may be critical for the prevention of APAP-induced acute liver toxicity

Comparisons of obesity assessments in over-weight elementary students using anthropometry, BIA, CT and DEXA

Obesity was characterized in Korean elementary students using different obesity assessment tests on 103 overweight elementary students from three schools of Jeonbuk Province. The body mass index (BMI) and obesity index (OI) were compared, and the data using DEXA and CT were compared with the data using BIA and a tape measure. The results of this study are as follows: first, 27 students who were classified as obese by OI were classified as overweight by BMI, and 3 students who were classified as standard weight by BMI were classified as overweight by OI. Secondly, by DEXA and BIA measurements, there was 1.51% difference in body fat percentage (boys 1.66%, girls 1.17%) and the difference in body fat mass between boys and girls was 0.77 kg (boys 0.85 kg, girls 0.59 kg), but those differences in body fat percentage and mass were not statistically significant. Thirdly, the average total abdominal fat (TAF) measured by CT scans of obese children was more significantly related with subcutaneous fat (r = 0.983, P < 0.01) than visceral fat (r = 0.640, P < 0.01). Also, TAF were highest significant with waist circumference by a tape measure (r = 0.744, P < 0.01). In summary, as there are some differences of assessment results between two obesity test methods (BMI, OI), we need more definite standards to determine the degree of obesity. The BIA seems to be the most simple and effective way to measure body fat mass, whereas waist/hip ratio (WHR) using a tape measurer is considered to be the most effective method for assessing abdominal fat in elementary students

Mitochondrial Bioenergetics of Brain Mitochondria Isolated from Parkin Null Mice

Mitochondria are dynamic cellular organelles with Janus-faced functions that can be beneficial or deleterious to cells. Mounting evidences indicate the involvement of mitochondria dysfunction in an early stage of neurodegeneration. Parkinson’s disease (PD) is the debilitating neurodegenerative disorder that causes severe motor function impairment. Accumulating body of evidence suggests the mitochondrial dysfunction in the pathogenesis of PD. Genetic mutations in parkin have been reported in large numbers of families. In this study, we used parkin null mice model to examine the effect of parkin deficiency on mitochondrial function at basal state. Brain mitochondria were isolated from brain of young (8-10 weeks old) parkin null mice as well as wildtype littermate mice and mitochondrial respiration rates were measured as a biochemical marker of bioenergetics. Only a slight reduction in respiration rate was observed in parkin null mice compared with wildtype mice, suggesting that parkin deficiency-associated mitochondrial dysfunction at the basal state was not initiated at this young age. Evaluation at different time points should be carried out for further study.2