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Theranostics 2020, Vol. 10, Issue 20 AgNPs might inhibit the antioxidant defense of astrocytes by increasing thioredoxin interacting protein, thus lead to the central neurotoxicity. AgNPs might induce ROS, inflammation and apoptosis through regulating the MAPK pathway, mTOR activity and Bcl-2 expression in astrocytes. AgNPs could cause severe ultrastructural changes in astrocytes, including mitochondrial contraction, endoplasmic reticulum expansion and nuclear atypia. Furthermore, AgNPs regulated the expression of multiple genes, inhibited metabolic and biosynthetic processes, thus affect astrocytes function and increase the neurotoxicity. More importantly, the impairing of learning, memory and cognition processes by AgNPs reduced the learning ability and cognition function of rats[338].AgNPsmayinduceneurologicaldiseases such as Alzheimer's disease by altering gene expression. Chin et al. [339] reported that AgNPs could induce the expression of amyloid precursor protein (APP) gene in nerve cells. APP gene promoted the deposition of amyloid-β (Aβ) protein, a key pathological feature of Alzheimer's disease. Kidney Toxicity The kidney participates in balancing body fluid volume and pH, regulating osmotic pressure and electrolyte concentration, drug metabolism, and toxic emissions. Abnormal renal function may occur in AgNPs-treated mammalian kidneys. AgNPs exhibits a dose-dependent accumulation in most examined tissues, such as the brain, lung, liver, dermis, blood and testes. However, there is a gender-related difference in silver accumulation in the kidney. Wan et al. [340] observed that female rats treated with AgNPs had a twofold higher concentration of silver in kidneys than male rats. Ag enhancement staining of the kidneys showed that AgNPs preferentially accumulated in the basement membrane of the glomerulus as well as renal tubules, while mildly accumulated in the adrenal capsule and cortex. There were two possible mechanisms of gender difference in the accumulation of AgNPs: the gender difference in the expression of organic cation transporters, and hormonal regulation. Renal metallothionein and zinc-binding protein, a kind of transporter or binding protein molecules in the kidney, might contribute to the silver accumulation. While organic anions secreted by kidneys might influence the clearance and accumulation of silver [341]. Mirta et al. [342] studied the uptake mechanism and potential cytotoxicity of AgNPs in porcine kidney (Pk15) cells in vitro. TEM results showed that there were aggregates in the lysosome and early endosomes. In addition to micropinocytosis, as an uptake pattern, clathrin- and caveolin-mediated endocytosis could also be the 9022 possible endocytotic mechanisms. AgNPs could decrease the number of viable Pk15 cells in vitro in a dose-dependent manner. Hua et al. [343] studied the distribution, accumulation and potential toxicity of AgNPs in different sizes in liver, lung and kidney of mice. They found that AgNPs could be taken up by vascular endothelial cells, then induced the generation of intracellular ROS and down-regulated the expression of vein endothelial cadherin. Therefore, AgNPs destroyed the conjunction between endothelial cells, allowing AgNPs to cross the endothelial layer and accumulate in organs. Besides, the leaking AgNPs could also result in peripheral inflammation in a size-dependent manner. Mice receiving single or multiple intravenous injections of AgNPs showed basement membrane injury in glomeruli. Immune System Toxicity Our immune system, a natural host defense barrier, is composed of immune cells, tissues and organs, can constantly interact with the internal environment and protect us from pathogens in the external environment, and provide the inherent knowledge to separate the friend and foe within our body [344]. Seung et al. [345] found that AgNPs inhibited the proliferation and the production of cytokines, including IL-5, INF-γ and TNF-α, and induced cytotoxicity in peripheral blood mononuclear cells in a concentration-dependent manner. AgNPs may deposit in the immune organs and influence the number of immune cells and the production of cytokines. Wim et al. [45] investigated the effects of AgNPs on the immune system of rats by repeated intravenous administration of AgNPs with different sizes (20 nm and 100 nm) for 28 days. They found that AgNPsadministeredatthemaximumdose(6mg/kg) were still well tolerated by the rats. The size and weight of the spleen increased significantly, possibly due to the increased cell number of T cells and B cells. However, the cytotoxic activity of NK cells in the spleen was almost completely inhibited. For multiple immune-related cytokines in serum, levels of interferon-γ, IL-10, IL-6 and TNF-α declined, while levels of IL-1β, IgM and IgE increased. The number of neutrophilic granulocytes in peripheral blood also increased. Besides, brown and black pigments were observed in histopathological sections of spleen and lymph nodes, indicating the accumulation of AgNPs in these immune organs. This study suggested that the immune system was sensitive to the potential adverse effects of AgNPs. The spleen may be one of themainorgansfortheaccumulationandelimination of AgNPs, and both processes are in a sex-dependent manner. Yuying et al. [346] observed the potential http://www.thno.orgPDF Image | Silver nanoparticles Synthesis medical applications safety
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