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

Table 8  In vivo miscellaneous effects and related mechanisms of action of oleanolic acid and its natural and synthetic derivatives (2014-2020)

Disease model/ physiology	Effect	Mechanism		Compound	Dose/IC50 /Ki.	Ref.
		↑↑↑	↓↓↓
Atherosclerosis	Anti-atherosclerotic	Ang1-7, ANG, NO, eNOS	IL-1β, TNF-α, and IL-6	OA	0-160 µmol/L	[29]
Immune suppression		ZFP-459, FMO-2		OA-Xs		[116]
T. cruzi, L. braziliensis, L. infantum	Anti-protozoal		-	OA, OA-X	3.3-89 µmol/L	[138]
Leishmania species	Anti-parasitic		CYP51, ergosterol synthesis	OA	30.4-68.7 µmol/L	[139]
P. berghei malaria	Anti-malaria		TNF-α, IL-6, IL-10, hepcidin	OA	34 mg/kg, 5 d	[140]
HBV	Anti-viral		HBS-Ag, HBE-Ag, HBV DNA replication	OA-Xs	8.6-38.1	[141]
Allergic conjunctivitis	Anti-allergic and anti-inflammatory	IL-10	Allergen-specific IgGs, sPLA2 -IIA, Th2, RWP-T-Cell dif, EOL-1 , IL-33, MCP-1	OA	50 mg/kg·d, 5 d after sens	[142]
Asthma	Anti-asthmatic	tBET, FOX-P3	IL-5, IL-13, IL-17, OVA-IgE, GATA-3, RORγt,	OA	2 or 20 mg/kg·2 d, 5 wk	[143]
Atherosclerosis	Anti-artherosclerotic	NRF-2, HO-1, SOX, NO, CAT, GPX, GSH, HDL	LOX, NADPH Ox, LDL, TC, TG, pGP91, pP67, pP7	OA	15-50 mg/kg·d, 3 wk; 5-20 µmol/L	[144]
Vascular injury	Prevent endothelial oxLDL effect		CASP, NO, pAKT, peNOS,	OA-Xn	5 and 100 µmol/L	[145]
Low-density lipoprotein receptor knockout (LDLR −/− ) mice	Review Atherosclerotic	AdipoR1, PPAR-γ	AdipoR2, TC, LDL-C	OA	25 mg/kg·d, 5 wk	[146]
Myocardial injury	Cardioprotection, hyperglycemia-induced myocardial injury	CASP-3/9, BAX, pERK1/2, HOMER-1α, ERK1/2, SIRT1	BCL-2, ROS	OA-Xn	12.5-50 µmol/L	[147]
Carotid artery injury	Proteccts diabetes induced artery injury	body weights, serum NO	endothelin 1, IL-1β, IL-6 , IL-18, NLRP-3, CASP-1	OA	100 mg/kg·d, 6 wk	[148]
Vascular injury	Hypotensive	physiological data	physiological data	OA, OA-Xn	0.1-100 µmol/L	[149]
Hiperlipidemia	Anti-hiperlipidemic	17 genes (microarray), CACNA-1B	TC, TG, HDLC, 4 genes	OA	3 tablets/d , 4 wk	[150]
Hiperlipidemia	Anti-hiperlipidemic likely via regulation of the miR-98-5p/PGC-1b axi		TC, TG, LDL, PGC-1b	OA	20 mg/kg, 4 wk	[151]
Fertility	Recovered fertility	increasing the permeability of the germinal epithelium		OA	30 mg/kg	[152]
Fertility	Infertility treatment	OCT-4, GDF-9, STRA-8, MVH, ZP-2, ZP-3, ITG-α6, TP-2,	SCP-3, ZP-1, ITG-β1	OA	3 µg/mL	[153]
Fertility/Reproductive function	Rejuvenates testicular function	BCL-2	pNF-κB, IL-1β , COX-2 TNF-α, H2AX, pP53, BAX, P38	OA	5-25 mg/kg·d, 24 wk	[154]
Renal fibrosis	Attenuates renal fibrosis	NRF-2, HO, NQO-1, BAX, HSP-70	BCL-2,	OA	N.R.	[155]
Nephropathy	Prevent diabetic nephropathy	sINS, SOD, adiponectin	TG, BUN, Cr, TGF-β, SMAD1/2	OA	100 mg/kg·d, 20 wk	[156]
Renal IRI	anti-Renal IRI	SOD, GPX, TT, eNOS, NRF-2, PPAR-γ, DDAHs	Cre, NGAL, TOS, NO, ADMA, NF-κB, ET-1	OA-Xs	20 mg/kg, 5 h before IR	[157]
Nephritis Lupus/SLE	Inhibition of Th17 differentiation		Th17, IL-17A, serum dsDNA, ROR-γt	OA-Xs	0-10 µmol/L, 50 mg/kg	[158]
MRSA	Anti-microbial		Microbe concentration	OA-Xs	10-30 µg/mL	[159]
Circadian clock	Mediates circadian clock	CLOCK, ELO-VL3, TUBB-2A CLDN-1, BMA-1	AMY-2A5, USP-2, PER-3,THRSP	OA	0.01% diet	[160]
Cisplatin induced nephrotoxicity	Prevent neprotoxicity	MAP-1A/AB, LC1	CASP-3/9, PARP cleavage, ATG-5, ERK1/2, STAT3, NF-κB	OA	10-40 mg/kg	[161]
Dermatitis/TPA-treated mouse ears	Inhibit dermatitis		MPO, COX-2, iNOS, TNF-a, IL-1β, pP65	OA-Xn	2, 5 or 10 µmol/L	[162]
Diabetes induced cardiomyopathy	Prevent diabetic induced cardiomyopathy via Nrf2	HO-1, SOD, NRF-2,	Glycogen, MDA, p-GS	OA	80 mg/kg·2 d, 14 d	[163]
Diabetic mesangial cell injury	Diabetic renal fibrosis	PI3K/AKT/mTOR	Autophagy, PTEN,	OA	10 µmol/L	[164]
Gut atrophy /piglet model	Prevent gut atrophy	TGR-5, FXR		OA	50 mg/kg·d, 14 d	[165]
Immune suppression	Immune suppressive, anti-RA	IL-10	collagen specific sIgG, CD4+ INF-γ, IL-17α, IL-2-/4/6/1β, TNF-α, GM-CSF, MCP-1 , MMP-1/3	OA-Xs	1-10 mg/kg 18 times between 28 and 53 d after the initial immunisation	[166]
Immune suppression/glucocorticoid resistance	Protecting DEX induced GC impairment	Apoptosis, GR binding	GR-α	OA+I	100 mg/kd·d, 21 d	[167]
Longevity		DAF-16, SOD-3, HSP-16.2 CTL-1		OA	0-600 µmol/L·2 d	[168]
Metal (MeHg) toxicity	Mitigate low-dose MeHg toxicity.		accumulation of metals in organs	OA-Xs	40 µg/kg	[169]
Muscle Atrophy	Reduces denervation induced muscle atrophy		CNTF, JNK-2, STAT3	OA-Xs	0.2-1 µmol/L	[170]
Muscle atrophy	Anti-muscle atrophy	mTORC-1/P70, S6K, PAX-7, MYO-D, Myogenin	FOXO-1, MURF-1, Atrogi-n1	OA-Xs	1 µmol/L, 1-10 mg/kg	[171]
Myocarditis - myocardial İnjury	EA myocarditis	IL-10, IL-33	HW/BW, BPN, IK-17, IL-6, TNF-α , Galectin	OA	50 mg/kg·d, 21 d or 65 d	[172]
Obesity	Anti-obesity		octanoylated ghrelin production, PC-1/3, PC-2	OA	20-40 mg/kg, 7 d	[173]
Obesity	Improves gustatory perception of lipids and exerts protective effects in obesity	CD36	blood insulin and glucose, hepat,c TG, IL-6	OA	0.005% (w/v) for 16 wk	[174]
Renal injury	Prevent nephropathy	nNRF-2/tNRF-2, HO-1, KEAP-1, BAX	urinary 8-OHdG and 8-iso-PGF-2 α, BCL-2	OA	N.R.	[175]
Renal IRI	Anti-Renal IRI; antioxidant, anti-inflammatory, and anti-apoptotic activities	SOD, GPX, GSH, CAT, IL-10, NRF-2, GGLc	BUN, Cr, KIM-1, LDH, MDA, IL-6, INF-γ, MPO,	OA	12.5-50 mg/kg·d, 15 d	[176]
Sepsis	Lung damage, experimental sepsis	SOD, GPX, IL-6, IL-10, KC	iNOS, NRF-2,	OA	10 mg/kg	[177]
Vascular injury	Prevent oxidative stress induced cell injury by with AKT/eNOS signaling pathway	NO, SOD, CAT, CASP-3, FAS, FASL, BCL-2	MDA, BAX	OA		[178]

IL: Interleukin; TNF-α: Tumor necrosis factor-α; OA: Oleanolic acid; OA-Xn: Natural derivatives of oleanolic acid; OA-Xs: Synthetic derivatives of oleanolic acid; LDH: Lactic dehydrogenase; ERK: Extracellular-signal-regulated kinase; IRI: Ischemia-reperfusion injury; NRF-2: Nuclear factor erythroid-2-related factor 2; JNK: cJUN NH₂-terminal kinase; FXR: Farnesoid X receptor; MMP: Matrix metalloproteinase; PGC-1b: Peroxisome proliferator-activated receptor-g coactivator-1b; PPAR: Peroxisome proliferator-activated receptor; NF-κB: Nuclear factor-κB; STAT3: Signal transducer and activator of transcription 3; GSH: Glutathione.