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Purpose To investigate vascular endothelial dysfunction based on glycocalyx impairment in massive hemorrhage and to evaluate fluid therapy. Methods In this randomized controlled animal study, we withdrew 1.5 mL blood and administered 1.5 mL resuscitation fluid. Mice were divided into six groups according to the infusion type and administration timing: NS-NS (normal saline), NS-HES ([hydroxyethyl starch]130), HES-NS, NS-ALB (albumin), ALB-NS, and C (control) groups. Results The glycocalyx index (GCXI) of a 40-[mu]m artery was significantly larger in group C than in other groups (P < 0.01). Similarly, the GCXI for a 60-[mu]m artery was significantly higher in group C than in NS-NS (P [less than or equal to] 0.05), NS-HES (P [less than or equal to] 0.01), and NS-ALB groups (P [less than or equal to] 0.05). The plasma syndecan-1 concentration, at 7.70 ± 5.71 ng/mL, was significantly lower in group C than in group NS-NS (P [less than or equal to] 0.01). The tetramethylrhodamine-labeled dextran (TMR-DEX40) fluorescence intensity in ALB-NS and HES-NS groups and the fluorescein isothiocyanate-labeled hydroxyethyl starch (FITC-HES130) fluorescence intensity in NS-HES and HES-NS groups were not significantly different from those of group C at any time point. FITC-HES130 was localized on the inner vessel wall in groups without HES130 infusion but uniformly distributed in HES130-treated groups in intravital microscopy. FITC-FITC-HES130 was localized remarkably in the inner vessel walls in group HES-NS in electron microscopy. Conclusions In an acute massive hemorrhage mouse model, initial fluid resuscitation therapy with saline administration impaired glycocalyx and increased vascular permeability. Prior colloid-fluid administration prevented the progression of glycocalyx damage and improve prognosis. Prior HES130 administration may protect endothelial cell function., Author(s): Tadao Ando [sup.1], Kohji Uzawa [sup.1], Takahiro Yoshikawa [sup.1], Shingo Mitsuda [sup.1], Yoshihiro Akimoto [sup.2], Tomoko Yorozu [sup.1], Akira Ushiyama [sup.3] Author Affiliations: (1) grid.411205.3, 0000 0000 9340 2869, [...]

Cancer risks attributable to low-dose and low-dose-rate radiation are a serious concern for public health. Radiation risk assessment is based on lifespan studies among Hiroshima–Nagasaki A-bomb survivors; however, there are statistical limitations due to a small sample size for low-dose radiation. Therefore, basic biological studies are helpful in understanding the mechanism of radiation carcinogenesis. The detrimental effects of ionising radiation (IR) are caused by reactive oxygen species (ROS)-mediated oxidative DNA damage. IR-induced delayed ROS are produced in the electron transport chain reaction of the mitochondrial complex. Thus, mitochondria are a source of ROS and a primary target for ROS attacks. Consequently, mitochondrial dysfunction is thought to be a key event in the metabolic changes of cancer cells and is important in radiation-induced carcinogenesis. In this paper, we present recent findings on radiation carcinogenesis effect assessment, focusing on mitochondrial function as stress sensors. [ABSTRACT FROM AUTHOR]

Purpose Fluid therapy focused on glycocalyx (GCX) protection in hemorrhagic shock is a current focus of research. Hydroxyethyl starch (HES) solution is commonly used for fluid resuscitation; however, its effects on the GCX remain unclear. The primary aim of this study was to explore the protective effect of HES130 in maintaining GCX thickness and reducing plasma syndecan-1 expression. Methods An acute hemorrhage murine model with the dorsal skin chambers was used to measure GCX thickness and to evaluate vascular permeability. Groups of mice were treated with normal saline (NS), albumin (NS-A), HES130 (NS-V), or no exsanguination or infusion (C). We measured syndecan-1 plasma concentrations, performed blood gas analysis, and analyzed the 7-day cumulative mortality. Results GCX thickness in NS mice was significantly reduced compared to that in group C, but no other groups showed a difference compared to group C. The plasma concentration of syndecan-1 was significantly higher in NS mice than in group C. There were no significant differences in the fluorescence intensity of dextran in the interstitial space. HES70 leakage was suppressed in NS-V mice compared to those in other groups. HES70 was localized to the inner vessel wall in C, NS, and NS-A mice, but not in group NS-V. Blood gas analysis indicated that pH and lactate showed the greatest improvements in NS-V mice. The 7-day cumulative mortality rate was the highest in group NS. Conclusion Resuscitation with HES130 protected the GCX and suppressed vascular permeability of HES70 during early stages of acute massive hemorrhage., Author(s): Kohji Uzawa [sup.1], Akira Ushiyama [sup.2], Shingo Mitsuda [sup.1], Tadao Ando [sup.1], Marie Sawa [sup.3], Hideki Miyao [sup.4], Tomoko Yorozu [sup.1] Author Affiliations: (1) grid.411205.3, 0000 0000 9340 2869, [...]

In living organisms, sensitivity to radiation increases in the presence of oxygen (O2) compared with that under anoxic or hypoxic conditions. Here, we investigated whether O2 concentration affected the response of mitochondria to X-rays radiation, which is associated with tumor microenvironment formation via fibroblast activation in radiation-related tumors. O2 concentrations were controlled at <5% (internal environmental oxygen condition) or anoxic levels during culture of normal human diploid lung fibroblasts TIG-3 and MRC-5. Protein expression associated with the response of mitochondria to radiation was assessed using immunostaining or western blotting. Induction of DNA damage (marker: γ-H2A histone family member X) and mitochondrial signaling (AMP-activated protein kinase), suppression of mitochondrial metabolic activity, and generation of reactive oxygen species occurred with radiation in cells cultured under 5% and 20% O2 conditions. However, reducing O2 concentration mitigated the effects of radiation on cell growth, mitochondrial damage (parkin), induction of antioxidant responses (nuclear factor E2-related factor 2), and fibroblast activation (α-smooth muscle actin). Radiation did not affect the markers used in this study in the absence of O2. O2 concentration affected the response of mitochondria to radiation and reactive oxygen species-mediated fibroblast activation. Higher O2 concentrations enhanced the effects of radiation on mitochondria in human fibroblasts. In vitro studies may overestimate in vivo radiation effects due to high O2 concentrations. [ABSTRACT FROM AUTHOR]

Intermediate frequency magnetic fields (IF-MFs) at ~85 kHz are one of the components of wireless power transfer (WPT) systems. However, the available data needed for the assessment of the safety of organisms from IF-MF exposure are scarce. Thus, there is an imminent need to accumulate evidence-based assessment data. In particular, if humans are exposed to IF-MF due to an accident or trouble, they are at increased risk of being exposed to high-intensity IF-MF within a short period. The already existing exposure system was improved to a system that could intermittently expose animals at 3 s intervals. This system allows the exposure of a mouse to high-intensity IF-MF (frequency: 82.3 kHz; induced electric field: 87 V/m, which was 3.8 times the basic restriction level for occupational exposure in the ICNIRP guideline), while regulating the heat generated by the coil. In vivo genotoxicity after IF-MF exposure was assessed using micronucleus (MN) test, Pig-a assay, and gpt assay. The results of MN test and Pig-a assay in hematopoietic cells revealed that neither the reticulocytes nor the mature erythrocytes exhibited significant increases in the IF-MF-exposed group compared with that in the sham-exposed group. In germ cells, MN test and gpt assay outcomes showed that IF-MF exposure did not cause any genetic or chromosomal abnormality. Based on these data, there was no genotoxic effect of our set IF-MF exposure on somatic and germ cells. These findings can contribute to the widespread use of WPT systems as effective data of IF-MF safety assessment. [ABSTRACT FROM AUTHOR]

Mitochondria are responsible for controlling cell death during the early stages of radiation exposure, but their perturbations are associated with late effects of radiation-related carcinogenesis. Therefore, it is important to protect mitochondria to mitigate the harmful effects of radiation throughout life. The glutathione peroxidase (GPx) enzyme is essential for the maintenance of mitochondrial-derived reactive oxygen species (ROS) levels. However, radiation inactivates the GPx, resulting in metabolic oxidative stress and prolonged cell injury in irradiated normal human fibroblasts. Here, we used the GPx activator N-acetyl-5-methoxy-tryptamine (melatonin) and a mitochondria-targeted mimic of GPx MitoEbselen-2 to stimulate the GPx. A commercial GPx activity assay kit was used to measure the GPx activity. ROS levels were determined by using some ROS indicators. Protein expression associated with the response of mitochondria to radiation was assessed using immunostaining. Concurrent pre-administration or post-administration of melatonin or MitoEbselen-2 with radiation maintained GPx activity and ROS levels and suppressed mitochondrial radiation responses associated with cellular damage and radiation-related carcinogenesis. In conclusion, melatonin and MitoEbselen-2 prevented radiation-induced mitochondrial injury and metabolic oxidative stress by targeting mitochondria. These drugs have the potential to protect against acute radiation injury and late effects of carcinogenesis in a variety of radiation scenarios assuming pre-administration or post-administration. [ABSTRACT FROM AUTHOR]

The glutathione (GSH) redox control is critical to maintain redox balance in the body's internal environment, and its perturbation leads to a dramatic increase in reactive oxygen species (ROS) levels and oxidative stress which have negative impacts on human health. Although ionizing radiation increases mitochondrial ROS generation, the mechanisms underlying radiation-induced late ROS accumulation are not fully understood. Here we investigated the radiation effect on GSH redox reactions in normal human diploid lung fibroblasts TIG-3 and MRC-5. Superoxide anion probe MitoSOX-red staining and measurement of GSH peroxidase (GPx) activity revealed that high dose single-radiation (SR) exposure (10 Gy) increased mitochondrial ROS generation and overall oxidative stress in parallel with decrease in GSH peroxidase (GPx) activity, while GSH redox control was effective after exposure to moderate doses under standard serum conditions. We used different serum conditions to elucidate the role of serum on GSH redox reaction. Serum starvation, serum deprivation and DNA damage response (DDR) inhibitors-treatment reduced the GPx activity and increased mitochondrial ROS generation regardless of radiation exposure. Fractionated-radiation was used to evaluate the radiation effect on GSH reactions. Repeated fractionated-radiation induced prolonged oxidative stress by down-regulation of GPx activity. In conclusion, radiation affects GSH usage according to radiation dose, irradiation methods and serum concentration. Radiation affected the GPx activity to disrupt fibroblast redox homeostasis. [ABSTRACT FROM AUTHOR]