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

Table 1 The oleanolic acid contents of some fruits[2-4]

Fruit	Content
Apple skin	0.96 mg/dry skin
Apples	16-28 µg/dm
Bilberries whole fruit	1679.2-2029.6 µg/dm
Grapes peel	176.2 µg/g dw
Jujube pulp	360 ± 10.7 µg/g dw
Lemon	0.62 ± 0.01 µg/dm
Loquat skin	1.46 mg/dry skin
Mandarin	1.05 ± 0.04 µg/dm
Olives pulp	27-29 µg/g fw
Olives skin	3094-4356 µg/g fw
Peach skin	1.49 mg/dry skin
Pear skin	1,25 mg/dry skin
Pears	164.3-3066.6 µg/g fw
Pears pulp	34.0-156.0 µg/g fw
Persimmon flesh	17.2 µg/g dw
Persimmon peel	367.7 µg/g dw
Pomegranate	1.12 - 26.96 µg/dm
Quince skin	0,25 mg/dry skin
S. adenocaulon	12.7 ± 0.2 µg/dm

Table 2  In vivo anti-inflammatory effects and related mechanisms of action of oleanolic acid and its natural and synthetic derivatives (2014-2020)

Disease model/physiology	Effect	Mechanism		Compound	Dose	Ref.
		↑↑↑	↓↓↓
Ulcerative colitis (mice, DDS)	Anti-ulcerative colitis restoring the balance of Th17/Treg cells and inhibiting NF-κB signaling	FOXP-3, IL-10, ZO-1, Occludin, Claudin-1, pJNK, pP38	MPO, Th17, RORγt, IL-17, TNF-α, IL-1β, MAPK, pIKB, pTAK, pP65, iNOS, COX-2	OA	5-10 mg/kg·d, 3 d after DSS	[14]
Experimental mammary carcinogenesis	Anti-inflammatory	cP65, cIKB-α	COX-2, HSP90, NF-ĸB, npP65	OA-Xs	0.8-1.6 mg/kg·2 d, 2 wk before 16 wk after DSS	[15]
Colonic inflammation (mice, HFD)	Prevent colon inflammation	CD206, IL-10, #goblet cells	NF-қB, pNF-қB, IL-6, TNF-α, COX-2, KI67	OA-Xs (CDDO-Me)	10 mg/kg in drinking water, 21 wk	[16]
Ulcerative colitis (mice, DDS)	Anti-ulcerative colitis, anti-inflammatory via inhibiting STAT3	-	IL-17, STAT3	OA-Xs (CDDO-Im)	0.5-2 µmol/L	[17]
Anti-inflammation and antinociception (rats)	Anti-inflammatory, anti-nociceptive	Pain latency	Paw volume	OA-Xn	40 mg/kg once	[18]
Anti-inflammation (rats)	Membrane stabilization	-	Paw volume, hemolysis	OA-Xs	20-40 µg	[19]
Anti-inflammation (rats, hPMBCs)	Anti-inflammatory	-	COX-2, 5-LOX, NOS, MPO, edema, IL-6, NF-ĸB, PGE-2	OA-Xn	50 mg/kg, 100 µg	[20]
Anti-inflammation (mouse skin)	anti-inflammatory properties	-	IL-1α, IL-1β, IL-6, IL-23	OA-X	2 µmol	[21]
Allergic airway inflammation (rats)	Anti-inflammatory and immunomodulatory	IL-6, IL-8	DTH, NO, IL-4, 5, 13, 17, TLR2, NF-ĸB and TNF-α; sIgE, COX-2, and 5-LOX	Fe-OA and Zn-OA	2 mg/kg	[22]
Anti-inflammation and antinociception (mice)	Analgesic action and expressed strong anti-inflammatory activity	-	IL-6	OA-Xs, OA-ASA	0.3-300.0 mg/kg, p.o.	[23]
Lung injury (MLE-12, NDMA)	Anti-inflammatory, anti-oxidative stress and anti-apoptotic effects	SOD, GSH, SIRT-1, NRF-2, BCL-2,	TNF-α, IL-6, IL-1β, MDA, BAX, NF-ĸB, NRLP-3, LDH, Ac-P65, BAX/BCL-2	OA	10-20 mg/kg	[24]
Pulmonary inflammation and fibrosis (mice)	Anti-inflammatory response and anti- pulmonary fibrosis in the lungs	NLRP3	IL-1β, IL-6, TNF-α, TGF-β1, and fibronectin, NRLP-3, ASC, CASP-1	OA	0.001-1 mg/kg·d, 5 d (nc)	[25]
Subarachnoid haemorrhage (rats)	Alleviated SAH-induced vasogenic edema	VE-Cadherins, P120, ZO-1, Occludin-	HO-1	OA	5-20 mg/kg	[26]

DDS: Diaminodiphenyl sulfone; NF-κB: Nuclear factor-κB; JNK: cJUN NH₂-terminal kinase; 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; HFD: High-fat diet; CDDO: 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid; CDDO-Me: C-28 methyl ester of CDDO; CDDO-Im: COOD-imidazole; STAT3: Signal transducer and activator of transcription 3; GSH: Glutathione; LDH: Lactic dehydrogenase; NRF-2: Nuclear factor erythroid-2-related factor 2.

Table 3  In vivo neuroprotective effects and related mechanisms of action of oleanolic acid and its natural and synthetic derivatives (2014-2020)

Disease model/ physiology	Effect	Mechanism		Compound	Dose	Ref.
		↑↑↑	↓↓↓
Focal brain hypoxia (rats)	Neuroprotective, IBI, decreased neural damage suppressing glial activities	S-100b, MAP-2	GFAP, NADP-Diaphorase, iNOS	OA	6 mg/kg·d, 6 d	[30]
Parkinsonian model (rats)	Prevents AIM, anti-PD, ameliorated dyskinesis	CAT	Affected limbs, AIMs, ROS	OA	100 mg/kg·2 d, 8 d	[31]
Neuro-degeneration (rats, hydroxydopamin)	Protects against neurodegeneration	Cerabral doapamine, contralateral limb use		OA	100 mg/kg·2 d, 7 d pre or post	[32]
Brain damage (rats, fluoride)	Brain damage	GSH, SOD, CAT, GPX, GST, GR	sALT, sAST, LPO, NO	OA	5 mg/kg·d, last 14 d,	[33]
Alzheimer’s disease model (rats, Aβ25-35)	Anti-alzheimer, increased synaptic plasticity, decreased Aβ25-35 toxicity	NMDAR-2B, CREB	CaMKII, PKC, BDNF, TRK-B, Ca2+, Latency time	OA	21.6 mg/kg	[34]
Rat coronal brain slice	Neuroprotective, anti-alzheimer,	BDNF	APP (TAU) toxicity,	OA-Xn		[35]
Cognitive dysfunction (mice)	Ameliorates cognitive dysfunction	pERK-1,2; pCREB, BNDF, TRK-B	-	OA	0.625-5 mg/kg	[36]
Chronic unpredictable mild stress (mice)	Anti-deprassant	pERK-1,2; pCREB, BNDF, miR-132, PSD-95, SYN-1	-	OA	2.5-40 mg/kg·d	[37]
Cerabral IRI (mice, PC12 cells)	Cerabral protection and prevent IRI	Body weights, sTG, pAMPK, pGSK-3β, APN, Adipo-R1, Adipo-R2, pLKB-1, MAO	sGLU, sINS, Neurological scores, BAX/BCL2, MDA, TNF-α, IL-6, CASP-3,	OA-X (CHS)	pretreatment 30,60, 120 mg/kg·d	[38]
Exprerimenal stress (mice, corticoid)	Anti-depressant	AKT/mTOR, BNDF	SGK1, GR	OA	10 mg/kg	[39]
Mice	Anti-depressant	-	MAO-A	OA	0.1 mL/10g	[40]
Mice	Anti-depressant	BNDF, sleep duration	Behavioral tests, MAO	OA	5-40 mg/kg	[41]

OA: Oleanolic acid; GFAP: Glial fibrillary acidic protein; APP: Amyloid precursor protein; AIM: Abnormal involuntary movements; CREB: cAMP response element-binding; GSH: Glutathione; ERK: Extracellular-signal-regulated kinase; IRI: Ischemia-reperfusion injury; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase.

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.

Table 5  In vivo antidiabetic effects and related mechanisms of action of oleanolic acid and its natural and synthetic derivatives (2014-2020)

Disease model/ physiology	Effect	Mechanism		Compound	Dose	Ref.
		↑↑↑	↓↓↓
STZ-induced diabetic rat	STZ ind diabetes	RBC, SOT, GPX	sGLU, HBA-1c, EPO, MDA	OA	80 mg/kg, twice, 5 wk	[80]
STZ-induced T2DM rats	Antidiabetic	p-AKT	pGS, GP	OA	80 mg/kg, 14 d	[81]
T2DM mice	Glycemic control	pFOXO-1, AcFOXO-1, HAT-1, pHDAC-1, pAKT, pGSK-3β	sGLU, G6Pase, HDAC5/4, pAMPK, pSIRT-1, PEPCK, SCD-1,SREBP-1c	OA	100 mg/kg·d, 4 wk	[84]
STZ-induced T2DM rats	Antidiabetic	-	sGLU, sGhrelin,	OA-Xn	80 mg/kg·2 d, 5 wk	[87]
Aroclor 1254-treated mice	OA-stimulated HNF-1b-endogenous antioxidant activity, protects against adioposity	SOD1, SOD2, GC-LC, GC-LM, GPX-1 CAT, HNF-1b, GLUT-4	ROS, oxidant products, NOX-4, PPAR-γ, Adionopectin, AGP-AT2, αP2, CD36	OA	50 mg/kg, 1 h before Aroclor 1254 treatment every 3 d for 10 wk	[88]
STZ-induced and db/db diabetic mouse models; NCI-H716	Antidiabetic and hepatoprotective effects	GLP-1, pPKA, sINS	sGSP, sALT, sAST, sGLU, sFBG, sTG, sHDL-C	OA, OA-Xs	100 mg/kg·d	[89]
STZ-nicotinamide-induced type 2 diabetes in mice; C2C12 cells	Anti-diabetic	pAMPK, GLUT4, CPT1	sGLU, sLDL-C, sFFA, ACC, pPKB	OA-Xn (CHS)	25-200 mg/kg·d, 14 d; 0.1-10 µg/mL	[90]
STZ-nicotinamide-induced type 2 diabetes in mice	Against diabetes induced hiperlipidemia and hypergylcemis	HK, G6Pase, GK, GSH, sHDL-C, SOD, CAT, GPX	SALP, sAST, sALT, sTC, sTG, LDL, IL-6, TNF-α	OA-Xn	20 mg/kg	[91]
HF diet-induced metabolic dysfunctions (rats)	Strategic intervention for the long-term prevention of metabolic diseases such as T2D and obesity via AMP-Activated Protein Kinase patway	AMPK, GLUT-4, CPT-1, AdipoR1, AdipoR2,	TNF-α, IL-6, MCP-1, VEGF	OA	60 mg/kg, 14 d	[92]
HF diet-induced metabolic dysfunctions (rats)	Potentially protects against the development of fructose-induced metabolic dysfunction	GLUT-4, GLUT-5 NRF-1, CPT-1, ALDO-B, FFAs	ACC-1, FAS	OA	60 mg/kg, 7 d	[93]
HFF diet-induced metabolic dysfunctions (rats)	Protected against the development of health outcomes associated with fructose	terminal body mass, visceral fat mass, epididymal fat	sINS	OA	60 mg/kg, 7 d	[94]
HFF diet-induced metabolic dysfunctions	Nano-OA was able to attenuate HFF diet-induced lipid accumulation in the liver	CAT, SOD	MDA, NO	Nano-OA	25 mg/kg·2 d, wk	[95]
T2DM in prediabetic patients (Human)	Prevention of type 2 diabetes in prediabetic patients	-	sGLU, T2DM incidence	OA	30 mg/kg	[96]
α-glucosidase inhibition	α-glucosidase inhibition, decreased blood glucose	-	α-glucosidase	OA-Xs	0.330.98 µmol/L	[97]
db/dc T2DM mice	Anti-diabetic	GS, pPI3K, pAKT, pAMPK, pACC	sLDL, sTG, sTC, GP, PGC1a, PEPCK1, GLUT-2, G6Pase, pmTOR, PCREB, sGLU, sINS	OA + Metmorfin	250 mg/kg·d, 28 d	[98]
Diet-induced pre-diabetic rat model	Prevent the onset of CVDs during pre-diabetes stage	-	TGs, LDL-C, IL-6, TNF-α, CRP, MAP, hearts weights	OA	80 mg/kg·3 d, 12 wk	[99]
Diet-induced pre-diabetic rat model	Anti-diabetic	-	Body weights, sGhrelin, HBA-1c, sGLU, sINS, muscle Glycogen	OA	80 mg/kg·3 d, 12 wk	[100]
MetS	Protects against fructose-induced oxidative damage; against MetS	GPX, SOD, CAT, GSH		OA	60 mg/kg	[101]

OA: Oleanolic acid; OA-Xn: Natural derivatives of oleanolic acid; OA-Xs: Synthetic derivatives of oleanolic acid; STZ: Streptozotocin; HAT-1: Histone acetyltransferase 1; FFA: Free fatty acid; CVDs: Cardiovascular diseases; PGC-1b: Peroxisome proliferator-activated receptor-g coactivator-1b; NRF-1: Nuclear factor erythroid-2-related factor 1; HNF: Hepatocyte nuclear factor; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; IL: Interleukin; TNF-α: Tumor necrosis factor-α; PPAR: Peroxisome proliferator-activated receptor; T2DM: Type 2 diabetes; MetS: metabolic syndrome; GSH: Glutathione.

Table 6  In vivo anti-osteoporotic and related mechanisms of action of oleanolic acid and its natural and synthetic derivatives (2014-2020)

Disease model/ physiology	Effect	Mechanism		Compound	Dose	Ref.
		↑↑↑	↓↓↓
OVX-mice	Increased bone mineral density	1,25(OH)2D3, renal CYP27B1	Urinary Ca excretion, CYP24A1	OA	50 or 100 mg/kg·d, 6 wk	[107]
OVX-mice	Better bone density	1,25(OH)2D3	Decreased urinary excreation of Ca	OA	0.67 g/kg in diet, 6 wk	[108]
Glucocorticoid-induced osteoporosis (rats)	Bone protection	Bone density of lumbar and femur were reversed, osteocalcin, sCa2+	-	OA	9 mg/kg, 14 d	[110]
Bone marrow macrophage (mice)	Inhibit osteoclastogen-esis	-	c-FOS, NFAT-c1, TRAP, CTSK,MMP-9	OA	10 mg/kg·2 d, 12wk	[111]
OVX- mice	Inhibit osteoclastogen-esis	-	NFAT-c1, c-FOS, MMP-9, CTSK, TRAP, CAR-2	OA	10 mg/kg·2 d,3 mo	[113]
Cartilage degeneration in osteoarthritis (rats)	Anti-cartilage damage	Collagen II	MMP-3, MMP-1, MMP-13, ADAMTS-4, -5,	OA	1-100 µmol/L, 50-100 µmol/L/rat single	[115]
Experimental periodontitis (mice)	Bone formation and remodeling through proper modulation of osteoblast and osteoclast	BMP-2,6,7; AXIN-2, β-CAT, LEFT, TWIST	IL-6,	OA-Xs	2µL (50 ng/µL)/d, 1-3 wk	[116]

OVX: Ovariectomised; OA: Oleanolic acid; TRAP: Tartrate-resistant acid phosphatase; CTSK: Cathepsin K; MMP: Matrix metalloproteinase; CAR: Constitutive androstane receptor; IL: Interleukin.

Table 7  In vivo anticancer 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.
		↑↑↑	↓↓↓
Liver, lung and prostate cancer	Inhibits proliferation and induces apoptosis	cPARP-1,	pAKT, NF-κB, pmTOR	OA-Xs	7.5 mg/kg·d; d	[118]
PC3 prostate	Inhibits proliferation and induces apoptosis	HIF-1a, NAC-1	SENP-1	OA-Xn	10 mg/kg·d; 20d	[119]
Colorectal cancer mouse xenograft model	Induce apoptosis	BAX, P21, P53	BCL-2, CYC-D1, CDK-4, AKT p70S6K and MAPK	OA	16 mg/kg·d, 16d	[120]
Gastric cancer	Induce autophagy	pAMPK	pmTOR, pPI3K, AKT, pERK1/2, P38, pmTOR	OA	100 mg/kg·d; 7d	[121]
Kras G12D/+ ;Pdx-1-Cre (KC) pancreactic cancer	Inhibits infiltration		IL-6, CCL-2, VEGF, G-CSF	CDDO-imidazolide	25 or 100 mg/kg diet, 4 or 8 wk	[122]
Lung carcinoma	Inhibits proliferation	miR122, HNF-1a, HNF-3b, HNF-4a, HNF-6	CCNG-1, MEF-2D	OA	40, 120 mg/kg·d; 4 wk	[123]
Ovarian and endometrial cancer	Inhibition of profiferation	PARP, BCL-2, CASP-8,-3, -7.		OA-Xs	10-40 mg/kg·d; 21 d	[124]
Prostate cancer	Cell cycle arrest		AKT/mTOR, pAKT, pmTOR	OA-Xs	8.5-17 mg/kg·d; 21 d	[125]

NF-κB: Nuclear factor-κB; OA: Oleanolic acid; OA-Xn: Natural derivatives of oleanolic acid; OA-Xs: Synthetic derivatives of oleanolic acid; CDDO: 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid; HNF: Hepatocyte nuclear factor; ERK: Extracellular-signal-regulated kinase.

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.