Prophylactic and therapeutic roles of oleanolic acid and its derivatives in several diseases

Table 4  In vivo hepatoprotective effects and related mechanisms of action of oleanolic acid and its natural and synthetic derivatives (2014-2020)

Disease model/ physiology	Effect	Mechanism		Compound	Dosei	Ref.
		↑↑↑	↓↓↓
Hepatic injury (mice, EtOH)	Prevents ethanol induced liver injury, hepatoxicity	nNRF-2, HO-1, SOD-1, CAT, GR, hepatic GSH, ATP	sALT, sAST, CYP2E, ADH, TNF-α, IL-6, sTG, sLDH	OA	10 mg/kg·d, 30 d	[60]
Hepatic injury (rats, CCl4)	Hepatoprotective	SOD, GPX	ALT, AST, LDH	OA, OA-Xs	15 mg/kg	[61]
Hepatic fibrosis (HSCs, HEPG2, BEL-7402, LO-2; mice, CCl4)	Hepatoprotection	Apoptosis, Ca2+	MitMP, sALT, sAST	OA-amino acids	20 mg/kg, IC50 > 50 µmol/L	[62]
Hepatic fibrosis (rast, CCl4)	Anti-hepatic fibrosis	-	sALT, sAST, Liver indices	OA-Xs	14-28 mg/kg·3 d, 9 wk	[63]
Hepatic injury (mice)	Hepatoprotective	NQO1	mKC, MIP-2, OATP-1B2, GADD-45, CHOP-10, sALT, sMDA, pJNK, HO-1.	OA	22.5 mg/kg·d, 3 d	[64]
Cholestasis (HEPG2)	Obstructive cholestasis	urinary BA, MRP-3, MRP-4, MRP-2, NRF-2	sBA, sBil, sAST, sALT, sALP, nNRF-2, BSEP,	OA	20 mg/kg, i.p, 1-50 µmol/L	[65]
Cholestasis (mice, LCA)	Cholestasis	MRP-2, MRP-3, MRP-4, NRF-2	sALT, sALP, sAST, tBA, tBIL, SULT-2A1	OA	5-20 µg/kg	[66]
Hepatic NAFLD (rats, HFD)	Anti-NAFLD via AMPK-related pathways	HGF, ICAM, IGF-1, IGFBP-3, IGFBP-5, IGFBP-6, lipocalin-2, MCP-1, M-CSF, PREF-1, RAGE, GLUT-2, LDLR, pAMPK, pAKT, pGSK-3β,	TC, TG, LDL-C	OA-Xs	60 mg/kg·d, 4 wk	[67]
Hepatic IRI (mice)	HO-1/Sesn2 signaling pathway	PI3K, HO-1, pAKT	sAST, sALT	OA	30 mg/kg·d, 7 d	[68]
Hepatic IRI (rat)	Protects agaist hepatic IRI	pPI3K, pAKT, pGSK-3β	SALT, IL-1β	OA	100 mg/kg·d, 7 d before IRI	[69]
Hepatic IRI, (mice)	Alleviate hepatic IRI	BCL-2	apoptosis and autophagy, ALT, AST, CASP-3, CAPS-9, BAX, Beclin 1, LC3, TNF-α, HMG-B1, TLR-4, pJNK	OA	30-60 mg/kg, 7 d	[70]

OA: Oleanolic acid; OA-Xs: Natural derivatives of oleanolic acid; IRI: Ischemia-reperfusion injury; NRF-2: Nuclear factor erythroid-2-related factor 2; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; IL: Interleukin; TNF-α: Tumor necrosis factor-α; NAFLD: Non-alcoholic fatty liver disease; HFD: High-fat diet; LDH: Lactic dehydrogenase; MRPs: Multidrug resistance-associated proteins; JNK: cJUN NH₂-terminal kinase.