Internalization of titanium dioxide nanoparticles by glial cells is given at short times and is mainly mediated by actin reorganization-dependent endocytosis

Many nanoparticles (NPs) have toxic effects on multiple cell lines. This toxicity is assumed to be related to their accumulation within cells. However, the process of internalization of NPs has not yet been fully characterized. In this study, the cellular uptake, accumulation, and localization of titanium dioxide nanoparticles (TiO₂ NPs) in rat (C6) and human (U373) glial cells were analyzed using time-lapse microscopy (TLM) and transmission electron microscopy (TEM). Cytochalasin D (Cyt-D) was used to evaluate whether the internalization process depends of actin reorganization. To determine whether the NP uptake is mediated by phagocytosis or macropinocytosis, nitroblue tetrazolium (NBT) reduction was measured and the 5-(N-ethyl-N-isopropyl)-amiloride was used. Expression of proteins involved with endocytosis and exocytosis such as caveolin-1 (Cav-1) and cysteine string proteins (CSPs) was also determined using flow cytometry.TiO₂ NPs were taken up by both cell types, were bound to cellular membranes and were internalized at very short times after exposure (C6, 30 min; U373, 2 h). During the uptake process, the formation of pseudopodia and intracellular vesicles was observed, indicating that this process was mediated by endocytosis. No specific localization of TiO₂ NPs into particular organelles was found: in contrast, they were primarily localized into large vesicles in the cytoplasm. Internalization of TiO₂ NPs was strongly inhibited by Cyt-D in both cells and by amiloride in U373 cells; besides, the observed endocytosis was not associated with NBT reduction in either cell type, indicating that macropinocytosis is the main process of internalization in U373 cells. In addition, increases in the expression of Cav-1 protein and CSPs were observed.In conclusion, glial cells are able to internalize TiO₂ NPs by a constitutive endocytic mechanism which may be associated with their strong cytotoxic effect in these cells; therefore, TiO₂ NPs internalization and their accumulation in brain cells could be dangerous to human health.     

Curcumin attenuates spatial memory impairment by anti-oxidative,anti-apoptosis,and anti-inflammatory mechanism against methamphetamine neurotoxicity in male Wistar rats: Histological and biochemical changes

ObjectiveMethamphetamine is used extensively around the world as a psychostimulant. The complications related to methamphetamine include methamphetamine-induced neurotoxicity, mainly involving intraneuronal processes, such as oxidative stress and excitotoxicity. Curcumin is effective against neuronal injury due to its antioxidant, anti-inflammatory effects. In this study, we examined the protective effects of curcumin against methamphetamine neurotoxicity.MethodsSixty male Wistar rats were divided into the following groups: control (n = 12), DMSO (n = 12), methamphetamine (n = 12), and methamphetamine + curcumin (100 and 200 mg/kg, respectively, intraperitoneal [IP]; n = 12). Neurotoxicity was induced by 40 mg/kg of methamphetamine administrated through 4 injections (4 × 10 mg/kg, q2h, IP). Curcumin (100 and 200 mg/kg) was administered at 7 days after the last methamphetamine injection. By using a Morris water maze task, the hippocampus-dependent memory and spatial learning were evaluated 1 day after the last curcumin injection. Then, the animal brains were isolated for biochemical measurements, as well as glial fibrillary acidic protein (GFAP), ionized calcium-binding adaptor protein-1(Iba-1) and caspase-3 immunohistochemical staining.ResultsThe current study demonstrated that administration of curcumin significantly attenuates spatial memory impairment (P < 0.01) following methamphetamine neurotoxicity. Curcumin caused a significant increase in the levels of superoxide dismutase and glutathione peroxidase (P < 0.05). However, it decreased tumor necrosis factor (TNF-α) (P < 0.05) and malondialdehyde (P < 0.01) levels as compared to the methamphetamine group. Also, curcumin significantly reduced Iba-1 (P < 0. 01), GFAP and caspase-3 positive cells in the hippocampus (P < 0.001).ConclusionCurcumin exerted neuroprotective effects on methamphetamine neurotoxicity because of its antioxidant and anti-inflammatory effect.     

Orally disintegrating olanzapine induces less weight gain in adolescents than standard oral tablets

We compared the changes in weight (kg) and body mass index (BMI) (kg/m²) in 52 hospitalized adolescents between baseline and after 12 weeks of monotherapy with either (i) olanzapine (OLZ) orally disintegrating tablets (ODT) (N = 16; 16.6 mg/day ± 4.4 [SD]), or (ii) OLZ standard oral tablets (SOT) (N = 10; 18.0 mg/day ± 4.2), or (iii) risperidone (N = 26; 2.8 mg/day ± 1.2). Significantly greater increases in mean weight and BMI were observed in the patients treated with OLZ SOT (8.9 ± 5.1 [SD] kg; 1.9 ± 0.6 kg/m², respectively) than in those with ODT (3.0 ± 2.1 kg; 1.1 ± 0.8 kg/m²). Similarly, OLZ ODT treatment was associated with significantly greater increases in weight and BMI than risperidone (1.0 ± 1.8 kg; 0.4 ± 0.7 kg/m²). These findings suggest that adolescents gain less weight with OLZ ODT than OLZ SOT, possibly because the former formulation shortens the time of interaction with digestive serotonin receptors mediating satiety.     

西北地区汉族人群HLA-A、-B、-DRB1基因座单倍型分析

目的 分析西北地区汉族群体HLA-A、-B和-DRB1基因座等位基因频率和HIA-A-B、B-DRB1和A-B-DRB1单倍型，获得单倍型频率数据。方法 采用序列特异性寡核苷酸探针反向斑点杂交技术对西北地区62个家系和101个无关个体HLA-A、-B和-DRB1基因座进行基因分型，分析HLA单倍型。结果 在西北地区汉族人群中检出15个HLA-A等位基因，28个HLA-B等位基因，13个HLA-DRB1等位基因，A02、A11、A24、B13、B15、1340、DRB1＊04、DRB1＊07、DRB1＊09和DRB1＊15基因频率较高（〉10％），A02（0．3244）、B13（0．1200）和DRB1＊15（0．1400）等位基因频率最高。分析得出HLA-A-B、B-DRB1、A-B-DRB1单倍型分别有122、147和278种，83种A-B-DRB1单倍型有至少两条以上相同的单倍型，占总单倍型数的18．44％（83／450）。A30-B13-DRB1＊07、A02-B46-DRB1＊09、A01-B37-DRB1＊10、A24-B15-DRB＊15、A02-B46-DRB1＊08、A33-B58-DRB1＊03是最常见的单倍型。结论 西北地区汉族群体HLA单倍型多态性较为丰富，等位基因频率和单倍型频率数据可用于骨髓移植供者的选择、法医学亲权鉴定以及人类学研究。     

中国10个地区成年人自评健康状况与全因死亡、心血管疾病死亡风险的关联研究

目的 分析自评健康状况（SRH）与全因死亡和心血管疾病（CVD）死亡风险的关联性。方法 研究对象来自中国慢性病前瞻性研究,剔除有逻辑错误和信息缺失的个体,最终纳入512 713名研究对象。SRH在基线问卷调查时搜集,包括整体自评健康状况（GSRH）及与同龄人相比自评健康状况（ASRH）;死亡事件及原因通过链接到疾病死亡监测系统和国家医保系统获取。采用多因素校正的Cox比例风险回归模型估计SRH与全因死亡和CVD死亡的关联性。结果 在平均9.9年的随访时间里,共观测到44 065例死亡事件,其中17 648例死于CVD。与GSRH良好的人相比,GSRH较差的研究对象未来发生全因死亡及CVD死亡的风险效应（HR）值（95%CI）分别是1.84（1.78~1.91）和1.94（1.82~2.06）。与ASRH更好的人相比,ASRH更差的研究对象未来发生全因死亡及CVD死亡的HR值（95%CI）分别是1.75（1.70~1.81）和1.83（1.73~1.92）。两种SRH指标与全因死亡和CVD死亡的关联性在各个亚组分析和敏感性分析中都保持显著,且SRH越差、死亡风险越高。结论 SRH简单易用,SRH越差、个体未来全因死亡/CVD死亡风险越高。