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

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.