Vascular Hyperpermeability Response in Animals Systemically Exposed to Arsenic.

The mechanisms underlying cardiovascular diseases induced by chronic exposure to arsenic remain unclarified. The objectives of this study were to investigate whether increased vascular leakage is induced by inflammatory mustard oil in mice systemically exposed to various doses of arsenic and whether an increased vascular leakage response is still present in arsenic-fed mice after arsenic discontinuation for 2 or 6 months. ICR mice were fed water or various doses of sodium arsenite (10, 15, or 20 mg/kg/day; 5 days/week) for 8 weeks. In separate experiments, the mice were treated with sodium arsenite (20 mg/kg) for 2 or 8 weeks, followed by arsenic discontinuation for 2 or 6 months. Vascular permeability to inflammatory mustard oil was quantified using Evans blue (EB) techniques. Both arsenic-exposed and water-fed (control) mice displayed similar basal levels of EB leakage in the ears brushed with mineral oil, a vehicle of mustard oil. The levels of EB leakage induced by mustard oil in the arsenic groups fed with sodium arsenite (10 or 15 mg/kg) were similar to those of water-fed mice. However, increased levels of EB leakage in response to mustard oil stimulation were significantly higher in mice treated with sodium arsenite (20 mg/kg; high dose) than in arsenic-fed (10 or 15 mg/kg; low and middle doses) or control mice. After arsenic discontinuation for 2 or 6 months, mustard oil-induced vascular EB leakage in arsenic-fed (20 mg/kg) mice was similar to that in control mice. Dramatic increases in mustard oil-induced vascular leakage were only present in mice systemically exposed to the high arsenic dose, indicating the synergistic effects of the high arsenic dose and mustard oil.

Exercise prevents the increased anxiety-like behavior in lactational di-(2-ethylhexyl) phthalate-exposed female rats in late adolescence by improving the regulation of hypothalamus-pituitary-adrenal axis.

Both the detrimental effects of early life adversity and the beneficial effects of exercise on the hypothalamic-pituitary-adrenal (HPA) axis have been reported. Early life exposure to di-(2-ethylhexyl)-phthalate (DEHP) may impair the development of endocrine system. In this study, we investigated the effects of lactational DEHP exposure on stress responses in late adolescent female rats and examined the protective role of treadmill running. Sprague-Dawley dams were fed with DEHP (10mg/kg per day) or vehicle during lactation. After weaning, the female offspring rats were trained to exercise on a treadmill for 5 weeks and then stressed by exploring on an elevated plus maze. The activities of HPA axis were evaluated by measuring the plasma levels of ACTH and corticosterone, the expressions of adrenal enzymes cholesterol side-chain cleavage enzyme (CYP11A1) and cytochrome P-450 11ß-hydroxylase (CYP11B1), and the expression of hypothalamic glucocorticoid receptors (GR). The results demonstrate that DEHP-exposed rats exhibited enhanced anxiety-like behaviors. Increased hypothalamic GR and plasma ACTH levels, but decreased adrenal CYP11A1 and corticosterone levels, were observed in DEHP-exposed animals under stressed condition. Importantly, in DEHP-exposed animals, exercise during childhood-adolescence reduced anxiety-like behaviors by normalizing stress-induced alterations in ACTH level and adrenal CYP11A1 expression. The findings of this study suggest that treadmill running may provide beneficial effects on ameliorating the dysregulation of HPA axis in lactational DEHP-exposed adolescent female rats.

Targeted Thrombolysis with Magnetic Nanotherapeutics: A Translational Assessment.

Plasminogen activators, such as recombinant tissue-type plasminogen activators (rtPAs), while effective in treating thromboembolic diseases, often induce hemorrhagic complications due to non-specific enzyme activities in the systemic circulation. This study evaluated the targeting efficiency, efficacy, biodistribution, and potential toxicity of a rtPA covalently attached to chitosan-coated magnetic nanoparticles (chitosan-MNP-rtPA). The thrombolytic activity of a chitosan-MNP-rtPA was preserved by protection from an endogenous plasminogen activator inhibitor-1 (PAI-1) in whole blood and after circulation in vivo, as examined by thromboelastometry. Single-photon emission computed tomography (SPECT) demonstrated real-time retention of a 99mTc-MNP-rtPA induced by magnet application in a rat embolic model; an 80% reduction in rtPA dosage for a chitosan-MNP-rtPA with magnetic guidance was shown to restore blood flow. After treatment, iron deposition was observed in the reticuloendothelial systems, with portal edema and neutrophil infiltration in the liver at a ten-fold higher dose but not the regular dose. Nevertheless, no liver or renal toxicity was observed at this higher dose. In conclusion, the liver may still be the major deposit site of rtPA nanocomposites after targeted delivery; chitosan-coated MNPs are potentially amenable to target therapeutics with parenteral administration.

Exercise Training Improves Mitochondrial Bioenergetics of Natural Killer Cells.

INTRODUCTION: Mitochondrial bioenergetics is critical for immune function in natural killer (NK) cell. Physical exercise modulates NK cell functionality, depending on the intensity and type of exercise. This study elucidates how interval and continuous exercise regimens affect the phenotypes and mitochondrial bioenergetics of NK cells. METHODS: Sixty healthy sedentary males were randomly assigned to engage in either high-intensity interval training (HIIT, 3-min intervals at 80% and 40% maximal O2, n = 20; age, 22.2 yr; body mass index [BMI], 24.3 kg·m-2) or moderate-intensity continuous training (MICT, sustained 60% maximal O2, n = 20; age, 22.3 yr; BMI, 23.3 kg·m-2) for 30 min·d-1, 5 d·wk-1 for 6 wk or were assigned to a control group that did not receive exercise intervention (n = 20; age, 22.6 yr; BMI, 24.0 kg·m-2). Natural killer cell phenotypes, granule proteins, and mitochondrial oxidative stress/oxidative phosphorylation after graded exercise test (GXT) were measured before and after the various interventions. RESULTS: Before the intervention, the GXT increased the mobilization of CD57+NK cells into the blood and elevated mitochondrial matrix oxidant burden (MOB) in NK cells, Following the 6 wk of interventions, both HIIT and MICT (i) diminished mobilization of CD57+NK cells into the blood and depressed mitochondrial MOB level in NK cells immediately after GXT, (ii) increased mitochondrial membrane potential and cellular perforin and granzyme B levels in NK cells, and (iii) enhanced the maximal and reserve O2 consumption rates and heightened bioenergetic health index in NK cells. In addition, HIIT increased maximal work rate than those of MICT. CONCLUSIONS: Either HIIT or MICT increases the expressions of cytotoxic granule proteins and depresses mitochondrial MOB elevated by GXT, along with improving mitochondrial bioenergetic functionality in NK cells. Moreover, HIIT is superior to MICT in improving aerobic capacity.

Cycling Exercise Training Enhances Platelet Mitochondrial Bioenergetics in Patients with Peripheral Arterial Disease: A Randomized Controlled Trial.

Exercise training influences the risk of vascular thrombosis in patients with peripheral arterial disease (PAD). Mitochondrial functionalities in platelets involve the cellular bioenergetics and thrombogenesis. This study aimed to elucidate the effect of cycling exercise training (CET) on platelet mitochondrial bioenergetics in PAD patients. Forty randomly selected patients with PAD engaged in general rehabilitation (GR) with CET (i.e., cycling exercise at ventilation threshold for 30 minute/day, 3 days/week) (GR + CET, n = 20) or to a control group that only received GR course (n = 20) for 12 weeks. Systemic aerobic capacity and platelet mitochondrial bioenergetics that included oxidative phosphorylation (OXPHOS) and electron transport system (ETS) were measured using automatic gas analysis and high-resolution respirometry, respectively. The experimental results demonstrated that GR + CET for 12 weeks significantly (1) elevated VO2peak and lowered VE-VCO2 slope, (2) raised resting ankle-brachial index and enhanced cardiac output response to exercise, (3) increased the distance in 6-minute walk test and raised the Short Form-36 physical/mental component scores, and (4) enhanced capacities of mitochondrial OXPHOS and ETS in platelets by activating FADH2 (complex II)-dependent pathway. Moreover, changes in VO2peak levels were positively associated with changes in platelet OXPHOS and ETS capacities. However, no significant changes in systemic aerobic capacity, platelet mitochondrial bioenergetics, and health-related quality of life (HRQoL) occurred following GR alone. Hence, we conclude that CET effectively increases the capacities of platelet mitochondrial bioenergetics by enhancing complex II activity in patients with PAD. Moreover, the exercise regimen also enhanced functional exercise capacity, consequently improving HRQoL in PAD patients.