Molecular mechanism of nanomaterials induced liver injury: A review

Table 1 Effects and molecular mechanisms underlying SiO₂NPs induced hepatonanotoxicity

NPs	Size	Tested model	Dose & route of administration	Effects & Mechanism	Ref.
SiO2NPs	15 nm (TEM)	HepG2 cell	1-200 ug/mL for 72hrs.	Bcl-2, GSH, Cell viability (decreased); p53, Bax, caspase-3, ROS production, LPO (increased)	[85]
				Oxidative stress & Apoptosis
SiO2NPs	15 nm (TEM)	Kupffer cells from Sprague Dawley rats; Sprague Dawley rats	50, 100, 200, 400, and 800 μg/mL for 24 h. 50 mg/kg single (i.v.)	ROS, AST, LDH, TNFα, H2O2, NO (increased); Kupffer cells (activation); Infiltration of inflammatory cells	[80]
				Activated Kupffer cells-mediated inflammation in liver toxicity
SiO2NPs	30, 50, 70, 300, 1000 nm (TEM)	BALB/c male mice	10-40 mg/kg (i.v.)	ALT, AST (increased)	[75]
				Acute liver injury
Amorphous SiO2NPs	62.26nm (DLS)	HepG2	25, 50, 75, 100 μg/mL, 24 h	ROS levels; Autophagy and autophagic cell death via PI3K/Akt/mTOR pathway	[84]
				Oxidative stress
Amorphous SiO2NPs	aSiNP-189 (20nm), aSiNP-116 (50nm), aSiNP-26 (110nm), aSiNP-8 (250nm) (EM)	HepG2	10–200 μg/mL, 24 h	Cholesterol biosynthesis (increased); May affect steroidogenesis & bile formation	[19]
Amorphous SiO2NPs	19.8 ± 2.7 nm (TEM)	HL-7702 cells; BRL-3A cells	31.4–500 μg/mL, 72 h	p53, Bax, cleaved caspase-3 (increased); GSH levels, caspase-3, Bcl-2 (decrease); Activation of p53/casp-3/Bax/Bcl-2 pathway; Human cells are more sensitive than rat cell	[86]
				Oxidative stress & apoptosis
SiO2NPs	30 nm (TEM)	Mouse hepatocytes	500 μg/mL, 24 h	ALT, AST (increased); ALR (blockage); Enlarged autolysosomes	[82]
				Inflammation
Amorphous SiO2NPs	202.3 (DLS)	HepG2; ICR mice	50 mg/kg b.w. for 24 h (oral)	GSH, NADPH oxidase depletion; ROS (increased); Altered GSH metabolism	[77]
				Oxidative stress
SiO2NPs	10 nm (BET)	Albino Wistar rats	2 mg/kg daily 20, 35 or 50 injections (i.p.)	ALP, AST, ALT, LDH, procalcitonin, iron, phosphorus, potassium (increased); Phase I and II drug metabolizing and transporting enzymes (downregulation); Hydropic degeneration, karyopicnosis, Sinusoidal dialation, Kupffer cell hyperplasia, lowered liver index, infiltration of inflammatory cells	[79]
				Oxidative stress & Inflammation
SiO2NPs	15.4 ± 1.8 nm (TEM)	Kunming mice (normal & metabolic syndrome model)	10 mg/kg b.w. daily 30 d (oral)	Liver fibrosis (collagen deposition); Hepatic ballooning; DNA damage (genotoxicity) ROS production, mitochondrial damage, infiltration of inflammatory cells	[87]
				Mitochondrial instability & inflammation
Mesoporous SiO2NPs	109.2 (DLS)	L02 cells; BALB/c mice	5–120 μg/mL, 24 and 48 h; 50 mg/kg 3 times a week for 3 wk (i.v.)	ALT, AST, ROS (increased); NLRP3 inflammasome activation; Pyroptosis via caspase-1 activation	[78]
				Oxidative stress and inflammation
SiO2NPs	58 nm (TEM)	L-02 cells	6.25, 12.5, 25, 50, and 100 μg/mL) for 12 h and 24 h	ROS production; ER stress; Activation of EIF2AK3 and ATF6 pathway; Induction of autosome formation	[83]
				Oxidative stress
SiO2NPs	58.04 ± 7.41 (TEM)	L02 cells	12.5, 25, 50, 100 μg/mL, 24 h	Affect mitochondrial quality control (MQC) process, Mitochondrial fission (increased); Induced mitophagy via activated PINK/Parkin signaling pathway; Decreased mitochondrial biogenesis via PGC1α-NRF1-TFAM signaling pathway; Mitochondrial dysfuntion	[88]
				Mitochondrial dysfunction & oxidative stress
SiO2NPs	58.11 ± 7.30 nm (TEM)	Sprague dawley rats	1.8, 5.4, 16.2 mg/kg b.w. (i.t.)	ALT, AST, TG, LDL-C (increased) HDL-C (decreased); Impact on Purine, amino acids metabolism, glucose-alanine cycle	[81]
				Metabolic disorder
SiO2NPs	15nm (XRD)	Wistar rat	25 and 100 mg/kg b.w. for 28 consecutive days (i.p.)	AST, ALT, LDH, NO, MDA, PCO, H2O2, Bax, p53, Caspase-9/3 (increased)	[89]
				CAT, SOD, GPx, Bcl2 (decreased)
				Oxidative stress & apoptosis
SiO2NPs	59.98nm (TEM)	Free Fatty Acid treated – L-02 cells; ApoE-/- mice	1.5, 3, 6 mg/kg b.w once per week for 12 times (i.t.)	LDH, AST, ALT, MDA (increased); GSH/GSSG (decreased); Fatty acid synthesis (increased); β-oxidation(decreased); Disturbed amino acid & lipid metabolism; Lipid accumulation leads to ER stress; Downregulated Nrf2 signaling	[90]
				Oxidative stress, altered lipid metabolism

Akt: Protein kinase B; ALP: Alkaline phosphatase; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; ATF6: Activating transcription factor 6; Bax: Bcl-2 associated X protein; Bcl2: B-cell lymphoma 2; CAT: catalase; DNA: Deoxy ribonucleic acid; EIF2AK3: Eukaryotic translation initiation factor 2-alpha kinase 3; ER: Endoplasmic reticulum; GPx: Glutathione peroxidase; GSH: Glutathione; GSSG: Glutathione disulfide.H₂O₂-hydrogen peroxide; HDL-C: High-density lipoprotein; LDH: Lactate dehydrogenase; LDL-C: Low-density lipoprotein; LPO: Lipid peroxidation; MDA: Malondialdehyde; mTOR: Mammalian target of rapamycin; NADPH: Reduced nicotinamide dinucleotide phosphate; NLRP3: NOD-like receptor protein 3; GSH: Glutathione; NO: Nitric oxide; NRF1/Nrf2: Nuclear factor erythroid 2-related factor1/2; p53-tumor suppressor protein p53; PGC1α: Peroxisome proliferator-activated receptor gamma coactivator 1 alpha; PI3K: Phosphatidylinositol 3-kinase; PINK: PTEN induced kinase, ROS: Reactive oxygen species, SOD: Superoxide dismutase; TFAM: Mitochondrial transcription factor A; TG: Triglyceride; TNFα: Tumor necrosis factor alpha.