Molecular mechanism of nanomaterials induced liver injury: A review

Table 4 Effects and molecular mechanisms underlying CuONPs induced hepatonanotoxicity

NPs	Size	Tested model	Dose & route of administration	Effects & mechanism	Ref.
CuO-NPs	33 nm (XRD)	Wister rats	300 mg/kg b.w. per day for 7 d (i.g.)	ALT, AST (increased)	[18]
CuO- NPs	40 nm (TEM)	Mature rats (Rattus norvegicus var. albinos)	0.5, 5, and 50 mg/kg b.w./d for 14 d (oral)	CAT, GPx, GR (increased) GST (decreased)	[100]
CuO-NPs	BNPs 4.14-12.82 nm CNPs 4.06-26.82 nm (XRD)	Mature mice	500 mg/kg b.w. single dose (oral)	ALT, AST, P53, Caspase - 3 (increased); Hepatic necrosis	[101]
Nano-CuO	20-40 μm (TEM)	BRL-3A cells; Wister rat	5, 10, 20 μg/mL; 10 μg/g b.w. for 60 d (i.n.)	ALT, AST, T-BIL, D-BIL, I-BIL (increased) ALP (decreased); SOD (decreased); MDA, iNOS, GSH-PX (increased); MCP-1, IL-1, IL-1β, TNF-α, IL-6 (increased); JNK, PERK, CHOP, ATF4, eIF2α, IRE1, Calpain, GRP78, ATF6, Bax, Caspase-3, Caspase-12 (upregulated)	[102]
				Oxidative stress induced ER stresspathway activation
CuO-NPs	GNPs & CNPs	Sprague dawley rat	50 & 100 mg/kg b.w. twice a week starting before mating (oral)	CAT, GSH, GPx (decreased)	[103]
CuO-NPs	< 50 nm (TEM)	Wistar rat	5 mg, 10 mg, 25 mg/kg b.w. per day for 9 d (i.p.)	Mild to severe Liver tissue damage including necrosis of hepatocyte, anti-inflammatory cell infiltration	[104]

ALP: Alkaline phosphatase; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; ATF4/6: Activating transcription factor4/6; Bax: Bcl-2 associated X protein; CAT: Catalase; CHOP: C/EBP Homologous Protein; D-BIL: Direct bilirubin; eIF2α: Eukaryotic initiation factor 2 α; BNP: Biologically synthesized nanoparticle; CNP: Chemically synthesized nanoparticle; GNP: Green nanoparticle; ER: Endoplasmic reticulum; GPx: Glutathione peroxidase; GR: Glutathione reductase; grp78: Glucose regulated protein 78; GSH: Glutathione; GSH-PX: Glutathione peroxidase; GST: Glutathione-S-transferase; I-BIL: Indirect bilirubin; IL-1: Interleukin 1; IL-1β: Interleukin 1 β, IL-6: Interleukin 6; iNOS: Inducible nitric oxide synthase; IRE-1: Inositol-requiring enzyme type 1; JNK: Jun N-terminal kinase; MCP-1: Monocyte chemoattractant protein 1; MDA: Malondialdehyde; P⁵³: Tumor protein p53; PERK: Protein kinase RNA like ER kinase; SOD: Superoxide dismutase; T-BIL: Total bilirubin; TNF-α: Tumor necrosis factor α.