Material concerns about their chronic toxicity (Prylutska

Material properties of carbon nanotubes differremarkably from those of bulk materials of the same chemical composition. Their potentialtechnological applications include those inbiology and medicine (He et al., 2013; Prylutska etal., 2013; Guo et al., 2017; Harvey et al., 2017).

Carbon nanotubes are viewedas a new option for cancer treatment, gene therapy and bioengineering,but development of such applications is restricted byinconsistent data on cytotoxicity and limited control over functionalizedcarbon nanotubes behavior (Firme and Bandaru, 2010). Carbon nanotubes are not biodegradable and have a highly hydrophobicsurface which reduces their  biocompatibility, and consequently limitstheir biomedical applications, raising concernsabout their chronic toxicity (Prylutska et al., 2008; Tejral et al., 2009; Yang etal., 2009; Minchenko et al.

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, 2016; Kobayashi et al., 2017). Thetoxicity of carbon nanotubesdepends on their physicochemical properties, such as structure, length and aspect ratio, surfacearea, degree of aggregation, extent of oxidation, surface topology, boundfunctional groups, concentration, and dose offered to cells or organisms. Therefore, different typesof these nanotubes vary in toxicity both in vitro and in vivo (Tejral et al., 2009; Uo et al., 2011).

For instance, it wasreported that intratrachealadministration of single-walled carbon nanotubes (SWCNTs) resulted ininflammation (Uo etal., 2011). There are numerous mechanisms of carbon nanotubestoxicity: membrane damage, DNA damage, oxidative stress, changes inmitochondrial activities, altered intracellular metabolic routes, and proteinsynthesis (Yuan et al.

, 2011, 2012; Shvedovaet al., 2012; Ahmadi et al., 2017; Guo et al., 2017).

Recently, it wasshown that functionalized SWCNTs induce oxidative stress in human circulating leukocytes (Kermanizadeh et al., 2018). Previously, we have shown that SWCNTs affectthe expression of genes related to cell cycle control and proliferation in U87 gliomacells (Minchenkoet al., 2016).In particular, a remarkabletime and dose-dependent suppressive effect was shown for CCND2 gene expression. A less prominent, but stillstatistically significant effect was shown for PFKFB3, PFKFB4,and PARVB genes. Thus, ourprevious results demonstrated that treatment of cells with SWCNTs is far from neutral.

To thecontrary, in our experimental setting the expression ofsome key cell cycle regulator genes was strongly altered. In this study weinvestigate the effect of SWCNTs on the expression of genes associated with immune response, cellproliferation and apoptosis in normal human astrocytes (line NHA/TS).Following genes were selected: HLA-DRA (majorhistocompatibility complex, class II, DR alpha), HLA-DRB1, HLA-F (major histocompatibility complex, class I, F), LMNB1 (lamin B1), HTRA1 (high-temperature requirement Aserine peptidase 1), PHLDA2 (pleckstrin homology-like domain,family A, member 2) and PLOD2 (procollagen-lysine, 2-oxoglutarate5-dioxygenase 2) genes as well as micro RNA miR-190b and miR-7.The HLA-DRA and HLA-DRB1 genes encode the alpha and beta1 subunits ofHLA-DR, which create a heterodimer.

Both subunits anchored in the membrane and their co-regulated expression is mediated by the MHCII RNA operon andis controlled by FOXP1 (Pisapia et al., 2013; Brown et al., 2016). Its primaryrole in immune response is presenting peptides derived from extracellularproteins. A reduction in HLA-DR gene expression, which is observed in cancer and in sepsis, correlateswith an impaired TNF? response (Cajander et al.

, 2013;Leite et al., 2014; Winkler et al., 2017). Moreover, cancer-related microRNAs miR-7 andmiR-190b recognize specificsites in the HLA-DRA and HLA-DRB1 mRNAs (Hunget al., 2014; Tang et al.

, 2014). Human leukocyte antigen HLA-F is a non-classical HLA-class I molecule with immunosuppressive properties. Its expression iscorrelated with tumor cell invasion and metastasis (Xu et al.,2013; Ishigami et al.

, 2015). HLA-F expression was found to be enhanced ingastric adenocarcinoma, breast cancer, esophageal squamous cell carcinoma,hepatocellular carcinoma, and neuroblastoma (Morandiet al., 2013; Zhang et al., 2013; Harada et al., 2015; Martínez-Canales et al.,2017). Moreover,overexpressionof HLA-F in islet cellsis a hallmark in the immunopathogenesis of type 1 diabetes (Richardson et al., 2016).

Nuclear lamina proteinLMNB1 is one of the major structural proteins inthe lamina mesh. It is involvedin the maintenance of nuclear stability, chromatin structure, and regulation ofgene expression as well as in a cellular senescence program(Young et al., 2014; Camps et al.

, 2015, Hernandez-Segura etal., 2017). It was also shown that fragment of the nuclear protein laminB1 can non-covalently attach to SWCNTs and deliver this nanostructure to thenucleus due to its exposed nuclear localization sequence (Boyer et al., 2016).High-temperaturerequirement A serine peptidase 1 (HTRA1), which is also known as serineprotease with IGF-binding domain PRSS11, is a stress responsive enzyme, that cleaves IGF-binding proteins and thus regulatesthe availability of insulin-like growth factors (IGFs). HTRA1 is alsoassociated with malignancy (Zhu et al., 2010; Xia et al., 2013;Minchenko et al.

, 2015). It was also shown that microRNA miR-30e andmiR-181d contribute to the dynamic regulation of HTRA1 expression and RadialGlia cell proliferation (Nigro et al., 2012). Recentlyit was shown that calcium phosphate nanoparticles can transfer HTRA1 protein into MG-63cells but the uptake pathway for dissolved HTRA1 and HTRA1-loadednanoparticles isdifferent (Rotan et al., 2017).The PHLDA2 gene is associatedwith glioma and othercancer types (Altinoz et al., 2016). Overexpression of this gene inhibits trophoblast proliferation, migrationand invasion, and induces apoptosis (Jia et al.

, 2016). The PLOD2 regulatesthe stiffness of the extracellular matrix as it is involved in the formation ofthe stabilized collagen cross-link. It was also shown to play a role inthe development of different types of cancers such as hepatocellular carcinoma,breast cancer and sarcoma (Miyamoto et al.

, 2016; Duet al., 2017). Interestingly, PLOD2 is directly regulated by microRNAs:miR-26a-5p and miR-26b-5p (Miyamoto et al., 2016; Duet al.

, 2017). In this study we aim to investigate the effect of SWCNTs on the expressionof a subset of genes associated with immune response and some proliferationrelated genes in normal human astrocytes.


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