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The size of microplastics (MPs) plays an important role in combined toxic effects including synergistic or antagonistic effects. However, the influence of the size of MPs on the combined toxicity of contaminants remains unclear. In this study, we employed a zebrafish model to investigate the effects of MP size on the combined toxicity of benz[ a ]anthracene (BaA), a representative polyaromatic hydrocarbon, using three different sizes of polystyrene MPs (PSMPs) (0.2, 1.0, and 10 μm). Treatment of all groups did not result in any mortality of the zebrafish larvae. However, small-sized PSMPs (0.2 μm) enhanced the toxic effect of BaA in larvae such as cardiac defect and disruption of vessel formation. Medium-sized PSMPs (1.0 μm) were boundary in terms of the combined toxic effect; however, large-sized PSMPs (10 μm) alleviated the cardiotoxicity of BaA, including cardiac defect, ROS levels, and cell death. The combined effects showed a correlation with the body burden of MPs and BaA in larvae according to particle size (in the order of 0.2 μm > 1.0 μm > 10 μm). The synergistic effects occurred likely because the small PSMPs facilitated the body burden of BaA, induced excessive ROS by Ahr-mediated activity, and caused cell death in the heart, resulting in increased heart defects in the larvae. In contrast, large PSMPs abated the combined toxic effect through decreased body burden, whereas medium PSMPs form a boundary in combined effects. Therefore, the combined toxic effects of MPs are dependent on their size, which plays an important role in the transport and accumulation of environmental pollutants. [Display omitted] • PSMPs' size determines the combined toxicity with BaA in zebrafish larvae. • PSMPs (0.2 μm) affected morphological defects and disrupted vessel formation by BaA. • PSMPs (0.2 μm) accelerated CYP1A activity, ROS generation, and cell death by BaA. • PSMPs (0.2 μm) accelerated the body burden of BaA compared to PSMPs (1.0 and 10 μm). [ABSTRACT FROM AUTHOR]

The toxicity of nano-graphene oxide (NGO) on development and angiogenesis was evaluated using zebrafish embryos as in vivo model system. Microinjection of NGO resulted in gross morphological defects in a dose-dependent manner partly due to the induction of apoptosis, whereas coating NGO derivatives with polyethylene glycol (PEG), a biocompatible polymer significantly attenuated its toxicity. NGO also caused abnormal branching and mispatterning of developing trunk blood vessels monitored by endothelial cell-specific fluorescent transgenic zebrafish, presumably via Vascular Endothelial Growth Factor and Notch pathways, key signaling pathways for normal angiogenic process. Interestingly, Alexa568 conjugated, PEG-coated NGO (NGO-A568) still caused angiogenic defects to the similar degree as NGO did, suggesting differential toxic effects of nanomaterials on different developmental processes. Confocal microscopy imaging of NGO- and NGO-A568-injected embryos visualized its live distribution throughout the body including the cranial vasculature. The broader utilization of embryonic zebrafish combined with in vivo , real-time, high-resolution imaging is warranted for assessing the properties of nanomaterials. [ABSTRACT FROM AUTHOR]

Nanomaterials have been widely employed from industrial to medical fields due to their small sizes and versatile characteristics. However, nanomaterials can also induce unexpected adverse effects on health. In particular, exposure of the nervous system to nanomaterials can cause serious neurological dysfunctions and neurodegenerative diseases. A number of studies have adopted various animal models to evaluate the neurotoxic effects of nanomaterials. Among them, zebrafish has become an attractive animal model for neurotoxicological studies due to several advantages, including the well-characterized nervous system, efficient genome editing, convenient generation of transgenic lines, high-resolution in vivo imaging, and an array of behavioral assays. In this review, we summarize recent studies on the neurotoxicological effects of nanomaterials, particularly engineered nanomaterials and nanoplastics, using zebrafish and discuss key findings with advantages and limitations of the zebrafish model in neurotoxicological studies. [Display omitted] • Nanomaterials including engineered nanomaterials and nanoplastics emerge as new pollutants to the ecosystem. • In particular, studies on the adverse effects of nanomaterials on the brain are limited. • Various animal models offer opportunities to evaluate neurological effects of nanomaterials. • We summarize recent studies and key findings on neurotoxicological effects of nanomaterials, focusing on zebrafish. [ABSTRACT FROM AUTHOR]

Abstract: CHARGE syndrome is an autosomal dominant congenital disorder known to be caused by the haploinsufficiency of the CHD7 gene. Heterozygous mutations in the CHD7 gene have been identified in approximately 60–70% of patients clinically diagnosed with CHARGE syndrome. Although there have been many reports on the mutational spectrum of the CHD7 gene in patients with CHARGE syndrome worldwide, little is known about this syndrome in the Korean population. In this study, three Korean patients with CHARGE syndrome including one patient with Patau syndrome were evaluated for genetic analysis of the CHD7 gene using direct sequencing of all 38 exons and the flanking intronic regions. One nonsense and two novel missense mutations were identified in the CHD7 gene. Clinical symptoms caused by the missense mutations were much milder compared to the nonsense mutation, confirming the previously determined genotype–phenotype correlation in CHARGE syndrome. Our study demonstrates the importance of mutational screening of CHD7 in patients who have been diagnosed with other syndromes but display clinical features of CHARGE syndrome. [Copyright &y& Elsevier]

Abstract: In this paper, we extend the VIKOR method for dynamic intuitionistic fuzzy multiple attribute decision making (DIF-MADM). Two new aggregation operators called dynamic intuitionistic fuzzy weighted geometric (DIFWG) operator and uncertain dynamic intuitionistic fuzzy weighted geometric (UDIFWG) operator are presented. Based on the DIFWA and UDIFWA operators respectively, we develop two procedures to solve the DIF-MADM problems where all attribute values are expressed in intuitionistic fuzzy numbers or interval-valued intuitionistic fuzzy numbers, which are collected at different periods. Finally, a numerical example is used to illustrate the applicability of the proposed approach. [Copyright &y& Elsevier]

Objectives: The goal of this study was to investigate the effect of pre-treatment of mesenchymal stem cells (MSCs) with growth factors (GFs) on cardiomyogenic differentiation, cytoprotective action on cardiomyocytes (CMCs), and their therapeutic efficacy in myocardial infarction. Background: Mechanisms of myocardial repair with MSC transplantation have not been fully elucidated, and therapeutic efficacy needs to be enhanced. Methods: The MSCs obtained from the bone marrow of Fisher344 rats were treated with fibroblast growth factor-2, insulin-like growth factor-1, and bone morphogenetic protein-2. The expression of cardiac specific markers and the cytoprotective effect of MSCs with its mechanism were evaluated. Efficacy of MSCs transplantation was studied in rat myocardial infarction model. Results: Treatment of MSCs with cocktails of GFs enhanced expression of cardiac transcription factors and survival. Induction of cardiac specific markers by coculture with CMCs and gap junctional communication with CMCs was more active in GF-treated MSCs than untreated MSCs. The GF-treated MSCs reduced apoptosis of neighboring CMCs in a hypoxic condition and enhanced the phosphorylated Akt and phosphorylated c-AMP response element binding protein expression of CMCs, which was markedly reduced by gap junction blockade. In a rat myocardial infarction model, transplantation of GF-treated MSCs resulted in smaller infarct size and better cardiac function than transplantation of untreated MSCs. Additionally, GF treatment enhanced gap junction formation of transplanted MSCs, which did not aggravate arrhythmia. Conclusions: Pre-treatment of MSCs with GFs enhanced cytoprotective effects on neighboring CMCs through gap junction and improved the therapeutic efficacy of MSC transplantation for myocardial repair. “Priming of MSCs with GFs” before transplantation might improve the therapeutic efficacy of cell therapy. [Copyright &y& Elsevier]

Amikacin is a semi-synthetic aminoglycoside widely used to treat infections caused by gentamicin-resistant gram-negative organisms and nontuberculous mycobacteria. However, the use of this agent often results in ototoxicity due to the overproduction of reactive oxygen species (ROS). Galangin, a natural flavonoid, has been shown to play a protective role against mitochondrial dysfunction by reducing mitochondrial ROS production. In this study, the effect of galangin on amikacin-induced ototoxicity was examined using cultures of cochlear explants. Immunofluorescent staining showed that treatment of inner hair cells (IHCs) and outer hair cells (OHCs) with galangin significantly decreased damage induced by amikacin. Moreover, pretreatment with galangin resulted in decreased amikacin-provoked increase in ROS production in both types of hair cells by MitoSOX-red staining. Attenuation of apoptotic cell death was assessed immunohistochemically using active caspase-3 antibody and with terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, compared to explants exposed to amikacin alone ( P < 0.05). These results indicate that galangin protects hair cells in the organ of Corti from amikacin-induced toxicity by reducing the production of mitochondrial ROS. The results of this study suggest that galangin can potentially be used as an antioxidant and antiapoptotic agent to prevent hearing loss caused by aminoglycoside induced-oxidative stress. [ABSTRACT FROM AUTHOR]

Abstract: Aim of the study: Rehmannia glutinosa, the steamed root of the Scrophulariaceae family, has been widely used in Asian countries for the treatment of renal diseases. In this study, we evaluated the renoprotective effect of aqueous extract of Rehmannia glutinosa in progressive renal failure. Materials and methods: The effects of Rehmannia glutinosa on renal function, 24-h proteinuria, and the expression of angiotensin II, angiotensin II type 1 (AT1) receptor, TGF-β1, and type IV collagen in renal cortex were analyzed in progressive renal failure rats induced by 5/6 nephrectomy. Results: Rehmannia glutinosa reduced the serum creatinine level, 24-h urinary protein excretion, and glomerulosclerosis, and it also inhibited the expression of angiotensin II, AT1 receptor, TGF-β1 and type IV collagen in the renal cortex. Conclusions: These results suggest that the renoprotective effect of Rehmannia glutinosa might be mediated by suppressing the expression of angiotensin II and AT1 receptor and by regulating TGF-β1 and type IV collagen expression. [Copyright &y& Elsevier]

Objectives: The goal of this study was to investigate the effect of mobilized stem cells by granulocyte-colony stimulating factor (G-CSF) on neointimal growth, the biologic impact on vascular healing process, and the utility of paclitaxel-eluting stent (PES) in this circumstance. Background: Questions have been raised on the safety of stem cell mobilization because of the tendency of neointimal overgrowth in a recent clinical trial, despite improvement of cardiac function. Methods: Rabbits underwent iliac artery injury with bare-metal stent (BMS) or PES and then received rhG-CSF or placebo for 6 days. Morphometric analysis and scanning electron microscopy for re-endothelialization were performed. The characteristics of mobilized peripheral blood mononuclear cells were determined in vitro, and the fate of these cells was evaluated by re-infusion with tagging in vivo. Results: At day 60 after stenting, neointimal overgrowth was observed at BMS with G-CSF. The tendency of neointimal overgrowth was substantially reduced on PES. Intriguingly, the delayed endothelial recovery on PES was restored to normal after G-CSF treatment. The G-CSF increased not only the endothelial progenitor cells, but also putative smooth muscle progenitor cells. Paclitaxel, at working concentration, preferentially inhibited proliferation of smooth muscle lineage cells rather than endothelial lineage cells. Conclusions: Our findings demonstrate that G-CSF mobilizes putative vascular progenitor cells in peripheral blood, which induces neointimal overgrowth at stented vasculature. Unique differential action of paclitaxel results in the enhanced endothelial healing with reduced neointimal growth after G-CSF treatment, suggesting that drug-eluting stents might be the optimal modality for revascularization in cytokine-based stem cell therapy. [Copyright &y& Elsevier]

A number of genome-wide association studies have reported several variants that influence the risk of lung cancer in never-smoking females. We evaluated the impact of these variants on survival outcome in never-smoking females with non-small cell lung cancer (NSCLC). In total, 510 never-smoking females with NSCLC who underwent curative surgery were enrolled. Eleven variants associated with lung cancer susceptibility in never-smoking females were genotyped and their associations with survival outcome were analyzed. Among these 11 variants, TP63 rs7631358 and CSF1R rs10079250 affected survival outcomes. TP63 rs7631358 G > A was associated with a relatively worse overall survival (under a dominant model; hazard ratio = 2.31, 95% confidence interval = 1.18–4.52, P  = 0.01). CSF1R rs10079250 A > G was associated with a relatively better disease-free survival (under a codominant model; hazard ratio = 0.70, 95% confidence interval = 0.53–0.93, P  = 0.01). These results suggest that TP63 rs7631358 G > A and CSF1R rs10079250 A > G may affect the prognosis of NSCLC in never-smoking females, as well as the risk of lung cancer. [ABSTRACT FROM AUTHOR]

Abstract: Cell therapy is a promising approach for repairing damaged heart. However, there are large rooms to be improved in therapeutic efficacy. We cultured a small quantity (5–10 mg) of heart biopsy tissues from 16 patients who received heart transplantation. We produced primary and secondary cardiospheres (CSs) using repeated three-dimensional culture strategy and characterized the cells. Approximately 5000 secondary CSs were acquired after 45 days. Genetic analysis confirmed that the progenitor cells in the secondary CSs originated from the innate heart, but not from extra-cardiac organs. The expressions of Oct4 and Nanog were significantly induced in secondary CSs compared with adherent cells derived from primary CSs. Those expressions in secondary CSs were higher in a cytokine-deprived medium than in a cytokine-supplemented one, suggesting that formation of the three-dimensional structure was important to enhance stemness whereas supplementation with various cytokines was not essential. Signal blocking experiments showed that the ERK and VEGF pathways are indispensable for sphere formation. To optimize cell processing, we compared four different methods of generating spheres. Method based on the hanging-drop or AggreWell™ was superior to that based on the poly-d-lysine-coated dish or Petri dish with respect to homogeneity of the product, cellular potency and overall simplicity of the process. When transplanted into the ischemic myocardium of immunocompromised mice, human secondary CSs differentiated into cardiomyocytes and endothelial cells. These results demonstrate that generation of secondary CSs from a small quantity of adult human cardiac tissue is a feasible and effective cell processing strategy to improve the therapeutic efficacy of cell therapy. [Copyright &y& Elsevier]