Material properties of carbon nanotubes differ
remarkably from those of bulk materials of the same chemical composition. Their potential
technological applications include those in
biology and medicine (He et al., 2013; Prylutska et
al., 2013; Guo et al., 2017; Harvey et al., 2017). Carbon nanotubes are viewed
as a new option for cancer treatment, gene therapy and bioengineering,
but development of such applications is restricted by
inconsistent data on cytotoxicity and limited control over functionalized
carbon nanotubes behavior (Firme and Bandaru, 2010). Carbon nanotubes are not biodegradable and have a highly hydrophobic
surface which reduces their  biocompatibility, and consequently limits
their biomedical applications, raising concerns
about their chronic toxicity (Prylutska et al., 2008; Tejral et al., 2009; Yang et
al., 2009; Minchenko et al., 2016; Kobayashi et al., 2017). The
toxicity of carbon nanotubes
depends on their physicochemical properties, such as structure, length and aspect ratio, surface
area, degree of aggregation, extent of oxidation, surface topology, bound
functional groups, concentration, and dose offered to cells or organisms. Therefore, different types
of these nanotubes vary in toxicity both in vitro and in vivo (Tejral et al., 2009; Uo et al., 2011). For instance, it was
reported that intratracheal
administration of single-walled carbon nanotubes (SWCNTs) resulted in
inflammation (Uo et
al., 2011). There are numerous mechanisms of carbon nanotubes
toxicity: membrane damage, DNA damage, oxidative stress, changes in
mitochondrial activities, altered intracellular metabolic routes, and protein
synthesis (Yuan et al., 2011, 2012; Shvedova
et al., 2012; Ahmadi et al., 2017; Guo et al., 2017). Recently, it was
shown that functionalized SWCNTs induce oxidative stress in human circulating leukocytes (Kermanizadeh et al., 2018).

Previously, we have shown that SWCNTs affect
the expression of genes related to cell cycle control and proliferation in U87 glioma
cells (Minchenko
et al., 2016).
In particular, a remarkable
time and dose-dependent suppressive effect was shown for CCND2 gene expression. A less prominent, but still
statistically significant effect was shown for PFKFB3, PFKFB4,
and PARVB genes. Thus, our
previous results demonstrated that treatment of cells with SWCNTs is far from neutral. To the
contrary, in our experimental setting the expression of
some key cell cycle regulator genes was strongly altered. In this study we
investigate the effect of SWCNTs on the expression of genes associated with immune response, cell
proliferation and apoptosis in normal human astrocytes (line NHA/TS).
Following genes were selected: HLA-DRA (major
histocompatibility complex, class II, DR alpha), HLA-DRB1, HLA-F (major histocompatibility complex, class I, F), LMNB1 (lamin B1), HTRA1 (high-temperature requirement A
serine peptidase 1), PHLDA2 (pleckstrin homology-like domain,
family A, member 2) and PLOD2 (procollagen-lysine, 2-oxoglutarate
5-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 of
HLA-DR, which create a heterodimer. Both subunits anchored in the membrane and their co-regulated expression is mediated by the MHCII RNA operon and
is controlled by FOXP1 (Pisapia et al., 2013; Brown et al., 2016). Its primary
role in immune response is presenting peptides derived from extracellular
proteins. A reduction in HLA-DR gene expression, which is observed in cancer and in sepsis, correlates
with an impaired TNF? response (Cajander et al., 2013;
Leite et al., 2014; Winkler et al., 2017). Moreover, cancer-related microRNAs miR-7 and
miR-190b recognize specific
sites in the HLA-DRA and HLA-DRB1 mRNAs (Hung
et al., 2014; Tang et al., 2014). Human leukocyte antigen HLA-F is a non-classical HLA-class I molecule with immunosuppressive properties. Its expression is
correlated with tumor cell invasion and metastasis (Xu et al.,
2013; Ishigami et al., 2015). HLA-F expression was found to be enhanced in
gastric adenocarcinoma, breast cancer, esophageal squamous cell carcinoma,
hepatocellular carcinoma, and neuroblastoma (Morandi
et al., 2013; Zhang et al., 2013; Harada et al., 2015; Martínez-Canales et al.,
2017). Moreover,
of HLA-F in islet cells
is a hallmark in the immunopathogenesis of type 1 diabetes (Richardson et al., 2016).

Nuclear lamina protein
LMNB1 is one of the major structural proteins in
the lamina mesh. It is involved
in the maintenance of nuclear stability, chromatin structure, and regulation of
gene expression as well as in a cellular senescence program
(Young et al., 2014; Camps et al., 2015, Hernandez-Segura et
al., 2017). It was also shown that fragment of the nuclear protein lamin
B1 can non-covalently attach to SWCNTs and deliver this nanostructure to the
nucleus due to its exposed nuclear localization sequence (Boyer et al., 2016).

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requirement A serine peptidase 1 (HTRA1), which is also known as serine
protease with IGF-binding domain PRSS11, is a stress responsive enzyme, that cleaves IGF-binding proteins and thus regulates
the availability of insulin-like growth factors (IGFs). HTRA1 is also
associated with malignancy (Zhu et al., 2010; Xia et al., 2013;
Minchenko et al., 2015). It was also shown that microRNA miR-30e and
miR-181d contribute to the dynamic regulation of HTRA1 expression and Radial
Glia cell proliferation (Nigro et al., 2012). Recently
it was shown that calcium phosphate nanoparticles can transfer HTRA1 protein into MG-63
cells but the uptake pathway for dissolved HTRA1 and HTRA1-loaded
nanoparticles is
different (Rotan et al., 2017).

The PHLDA2 gene is associated
with glioma and other
cancer types (Altinoz et al., 2016). Overexpression of this gene inhibits trophoblast proliferation, migration
and invasion, and induces apoptosis (Jia et al., 2016). The PLOD2 regulates
the stiffness of the extracellular matrix as it is involved in the formation of
the stabilized collagen cross-link. It was also shown to play a role in
the development of different types of cancers such as hepatocellular carcinoma,
breast cancer and sarcoma (Miyamoto et al., 2016; Du
et al., 2017). Interestingly, PLOD2 is directly regulated by microRNAs:
miR-26a-5p and miR-26b-5p (Miyamoto et al., 2016; Du
et al., 2017).

In this study we aim to investigate the effect of SWCNTs on the expression
of a subset of genes associated with immune response and some proliferation
related genes in normal human astrocytes.

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