Assessing oxidative stress induction ability and oxidative potential of PM2.5 in cities in eastern and western Japan.

Oxidative stress is an important cause of respiratory diseases associated with exposure to PM2.5. Accordingly, acellular methods for assessing the oxidative potential (OP) of PM2.5 have been evaluated extensively for use as indicators of oxidative stress in living organisms. However, OP-based assessments only reflect the physicochemical properties of particles and do not consider particle-cell interactions. Therefore, to determine the potency of OP under various PM2.5 scenarios, oxidative stress induction ability (OSIA) assessments were performed using a cell-based method, the heme oxygenase-1 (HO-1) assay, and the findings were compared with OP measurements obtained using an acellular method, the dithiothreitol assay. For these assays, PM2.5 filter samples were collected in two cities in Japan. To quantitatively determine the relative contribution of the quantity of metals and subtypes of organic aerosols (OA) in PM2.5 to the OSIA and the OP, online measurements and offline chemical analysis were also performed. The findings showed a positive relationship between the OSIA and OP for water-extracted samples, confirming that the OP is generally well suited for use as an indicator of the OSIA. However, the correspondence between the two assays differed for samples with a high water-soluble (WS)-Pb content, which had a higher OSIA than would be expected from the OP of other samples. The results of reagent-solution experiments showed that the WS-Pb induced the OSIA, but not the OP, in 15-min reactions, suggesting a reason for the inconsistent relationship between the two assays across samples. Multiple linear regression analyses and reagent-solution experiments showed that WS transition metals and biomass burning OA accounted for approximately 30-40% and 50% of the total OSIA or the total OP of water-extracted PM2.5 samples, respectively. This is the first study to evaluate the association between cellular oxidative stress assessed by the HO-1 assay and the different subtypes of OA.

Dietary intake of microplastics impairs digestive performance, induces hepatic dysfunction, and shortens lifespan in the annual fish Nothobranchius guentheri.

Microplastics (MPs) are ubiquitous in aquatic and terrestrial ecosystem, increasingly becoming a serious concern of human health. Many studies have explored the biological effects of MPs on animal and plant life in recent years. However, information regarding the effects of MPs on aging and lifespan is completely lacking in vertebrate species to date. Here we first confirm the bioavailability of MPs by oral delivery in the annual fish N. guentheri. We then show for the first time that administration of MPs not only shortens the lifespan but also accelerates the development of age-related biomarkers in N. guentheri. We also demonstrate that administration of MPs induces oxidative stress, suppresses antioxidant enzymes, reduces digestive enzymes, and causes hepatic dysfunction. Therefore, we propose that administration of MPs reduces lifespan of N. guentheri via induction of both suppressed antioxidant system and digestive disturbance as well as hepatic damage. Our results also suggest that smaller MPs appear more toxic to digestion, metabolism and growth of animals.

Combined Targeting of Mutant p53 and Jumonji Family Histone Demethylase Augments Therapeutic Efficacy of Radiation in H3K27M DIPG.

Diffuse intrinsic pontine glioma (DIPG) is an aggressive pediatric brainstem tumor with a 5-year survival of <1%. Up to 80% of the DIPG tumors contain a specific K27M mutation in one of the two genes encoding histone H3 (H3K27M). Furthermore, p53 mutations found in >70-80% of H3K27M DIPG, and mutant p53 status is associated with a decreased response to radiation treatment and worse overall prognosis. Recent evidence indicates that H3K27M mutation disrupts tri-methylation at H3K27 leading to aberrant gene expression. Jumonji family histone demethylases collaborates with H3K27 mutation in DIPG by erasing H3K27 trimethylation and thus contributing to derepression of genes involved in tumorigenesis. Since the first line of treatment for pediatric DIPG is fractionated radiation, we investigated the effects of Jumonji demethylase inhibition with GSK-J4, and mutant p53 targeting/oxidative stress induction with APR-246, on radio-sensitization of human H3K27M DIPG cells. Both APR-246 and GSK-J4 displayed growth inhibitory effects as single agents in H3K27M DIPG cells. Furthermore, both of these agents elicited mild radiosensitizing effects in human DIPG cells (sensitizer enhancement ratios (SERs) of 1.12 and 1.35, respectively; p < 0.05). Strikingly, a combination of APR-246 and GSK-J4 displayed a significant enhancement of radiosensitization, with SER of 1.50 (p < 0.05) at sub-micro-molar concentrations of the drugs (0.5 µM). The molecular mechanism of the observed radiosensitization appears to involve DNA damage repair deficiency triggered by APR-246/GSK-J4, leading to the induction of apoptotic cell death. Thus, a therapeutic approach of combined targeting of mutant p53, oxidative stress induction, and Jumonji demethylase inhibition with radiation in DIPG warrants further investigation.