Molecular mechanism of nanomaterials induced liver injury: A review

Table 2 Effects and molecular mechanisms underlying NiONPs & NiNPs induced hepatonanotoxicity

NPs	Size	Tested model	Dose & route of administration	Effects & mechanism	Ref.
NiO NPs	44 nm (TEM)	HepG2 cells	2-100 μg/mL for 24 h	Cell viability (reduced); ROS (increased); Micronuclei induction, chromatin condensation and DNA damage; bax and caspase-3 (upregulated); bcl-2 (downregulated)	[95]
				Oxidative stress, apoptosis
NiO NPs	20 nm (TEM)	Wistar rat	0.015, 0.06 or 0.24 mg/kg b.w. twice a week for 6 wk (i.t.)	NO, TNOS, iNOS, ·OH, LPO, HO1 (increased); CAT, GSHPx, T-SOD and TAOC, MT1 (decreased)	[93]
				Oxidative & nitrative stress
NiO NPs	20 nm (SEM)	Wistar rat	0.015, 0.06, and 0.24 mg/kg b.w. twice a week for 6 wk (i.t.)	GRP78, CHOP (increased); Activation of PERK/eIF-2α, IRE-1α/XBP-1S, and caspase-12/-9/-3 pathways	[16]
				ER stress, apoptosis
NiO NPs	20 nm (SEM)	Wistar rat	0.015, 0.06, and 0.24 mg/kg b.w. twice a week for 6 wk (i.t.)	ALT, AST, ALP, GGT, IL-1β and IL-6, TNF-α, NIK, IKK-α, NF-κB (increased); IL-4, IL-10, IκB(α) (decreased); Activation of NF-kB signalling pathway	[94]
				Inflammation
NiO NPs	13.16 ± 2.98 nm (TEM)	Wistar rat	125, 250 and 500 mg/kg single dose (oral)	ALP, LDH, ALT, AST, LPO (upregulation); GSH, SOD (downregulation)	[92]
				Oxidative stress
NiO NPs	21.6 ± 3.6 nm (TEM)	HepG2	5, 10, 25, 50 and 100 μg/mL, 24 h	HIF-1α, miR210, p53, Caspase-3, 8 and 9, NO, MMP (increased); Phagosome formation by lysosomal pathway	[96]
				Hypoxia & oxidative stress, apoptosis
NiO NPs	44 nm (TEM)	Wistar rat; HepG2	0.015, 0.06, and 0.24 mg/kg twice a week for 9 wk (i.t.); 25-200 μg/mL	TGF-β1, Smad2, Smad3, α-SMA, MMP9, TIMP1, EMT (upregulation); E-cadherin, Smad7 (downregulation); activation of TGF-β1/Smad pathway	[97]
				Hepatic fibrosis, ECM deposition
NiNPs	55.8 ± 14.0 nm (TEM)	C57/BL6 mice	10, 20 and 40 mg/kg/d for 7 and 28 d	ALT, AST, Ire1α, Perk and Atf6, TG increased; Lipid metabolism dysfunction; Inflammation	[98]
				ER stress, apoptosis

OH: Hydroxyl radical; ALP: Alkaline phosphatase; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; Atf6: Activating transcription factor 6; CAT: Catalase; CHOP: C/EBP Homologous Protein; ECM: Extra cellular matrix; eIF2α: Eukaryotic initiation factor 2 α; EMT: Epithelial mesenchymal transition; GGT: Gamma-glutamyl transpeptidase; GRP78: Glucose regulated protein 78; GSH: Glutathione; GSHPx: Glutathione peroxidase; HIF-1α: Hypoxia inducible factor 1; HO1: Heme oxygenase 1; IKK-α: IκB kinase alpha; IL-1β: Interleukin 1 β; IL-6: Interleukin 6; iNOS: Inducible nitric oxide synthase; IRE-1α: Inositol-requiring enzyme type 1α; IκB(α): Inhibitor kappa B alpha; LDH: Lactate dehydrogenase; LPO: Lipid peroxidation; miR210: miRNA210; MMP9: Matrix metallopeptidase 9; MMP: Mitochondrial membrane potential; MT1: Metallothionein 1; NF-κB: Nuclear factor kappa beta; NIK: NF-κB-inducible kinase; NO: Nitric oxide; p53-tumor protein p53; PERK: Protein kinase RNA like ER kinase; Smad2: Suppressor of mothers against decapentaplegic2; SOD: Superoxide dismutase; TAOC: Total antioxidative capacity; TG: Triglyceride; TGF-β1: Transforming growth factor 1 beta; TIMP1: TIMP metallopeptidase inhibitor 1; TNF-α: Tumor necrosis factor α; TNOS: Total nitric oxide synthase; TSOD: Total superoxide dismutase; XBP-1S: X box binding protein-1S; α-SMA: Alpha smooth muscle actin.