The Effect of Oleanolic Acid

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This entry is adapted from the peer-reviewed paper 10.3390/molecules29040758

The natural product oleanolic acid (OA: 3b-hydroxyolean-12-en-28-oic acid) is a pentacyclic triterpenoid compound. It has been extracted from many species, including Olea europaea. Studies on biological activity have shown that OA has a liver-protective effect, and has been listed as a liver-protective drug in China. OA also has anti-inflammatory, anti-oxidant, anti-hyperglycemia, anti-hyperlipidemia, cardioprotective, anti-atherosclerotic, and some other pharmacological effects.

oleanolic acid metabolic syndrome cardiovascular diseases

1. Anti-Metabolic Syndromes’ Effects

1.1. Anti-Obesity

Obesity is associated with numerous diseases and a shortened life expectancy ^[1]. Fat production is the maturation of fat cells by which preadipocytes become adipocytes, so they play an essential part in obesity ^[2]. In the process, CCAAT/enhancer-binding protein (C/EBP) and peroxisome proliferator-activated receptor γ (PPARγ) are thought to be the vital early regulatory proteins for lipogenesis. Adiponectin, sterol regulatory element-binding protein 1 (SREBP1), and fatty acid synthetase (FAS) are in charge of the production of mature fat cells ^[3]. OA could inhibit the expression of the visceral fat-specific adipokine and downregulate PPARγ and C/EBPα to reduce the intracellular accumulation of fat in adipocytes ^[4]. Furthermore, OA may reduce obesity via the suppression of the adipogenic factors PPARα, SREBP1, and FAS ^[5]. OA has been shown to reduce the synthesis of fat and accelerate the utilization of fat through the alteration of hepatic PPARα, recombinant carnitine palmitoyltransferase 1A (CPT1A), SREBP-1, the acetyl coenzyme A carboxylase, and coupled protein 1 (UCP1) ^[6]. In addition, OA can reduce blood glucose and lipid levels by promoting carbohydrate and fat metabolism ^[7]. Another piece of research showed that OA can be effective against postmenopausal obesity by inhibiting fat synthesis acetyl-CoA carboxylase (ACC) and upregulating essential genes for estrogen production, CYP11, CYP1, and CYP17A19 ^[8].

Inflammation is crucial in obesity ^[9]; chronic inflammation in adipose tissue is primarily driven by macrophages ^[10] that are classified into two types: M1-type macrophages and M2-type macrophages ^[11]. An increase in the ratio of M1/M2-type macrophages can enhance adipocyte growth, fat storage, and adipocyte differentiation ^[12]. Recent research has discovered that OA was able to reduce inflammation via the inhibition of macrophage infiltration, the M1/M2 ratio in adipose tissues, reactive oxygen species (ROS), and decreasing NACHT, LRR, and PYD structural domain protein 3 (NLRP3) ^[13].

Resistin is an adipocyte-specific secreted factor associated with adipocyte differentiation ^[14]. OA could reduce resistin synthesis in vivo by stimulating the cellular signaling transcriptional repressor three signaling and interfering with the tyrosine kinase 2-transcriptional signaling sensor activator ^[15]. Furthermore, glucose homeostasis and adipocyte differentiation are regulated by transcription factor hepatocyte nuclear factor 1b (HNF1b) ^[16]. The research showed that OA could relieve glucose/lipid metabolic dysfunction via HNF1b ^[17].

The causes of obesity are complex, the symptoms are diverse, and multiple organs are implicated, so OA in treating obesity is far from sufficient, especially in molecular mechanisms where it is even more insufficient. Therefore, more research is needed to demonstrate the role of OA in treating obesity.

1.2. Anti-Hyperlipidemia

Hyperlipidemia is defined as elevations of the fasting total cholesterol concentration, which could directly cause some severe diseases ^[18]. Numerous studies have suggested that OA is beneficial in the treatment of hyperlipidemia. OA could attenuate the triglycerides (TG) in rats by reducing the fat synthesis factor sterol regulatory element and activating transcription factor 1 ^[19]. OA also reduces total cholesterol (TC) formation by inhibiting cholesterol acyltransferase activity ^[20]. A high-fat diet will increase the level of peroxisome proliferator-activated receptor gamma coactivator 1β (PGC-1β) leading to lipogenesis and very-low-density lipoprotein secretion ^[21]; OA could decrease serum lipids in mice via the inhibition of PGC-1β expression ^[22]. Clinical investigations also have shown that OA decreased serum lipids in hyperlipidemic patients ^[23].

Hyperlipidemia is frequently one of the risk factors for various issues. Thus, improving blood lipids is critical for human health. Recent research demonstrated that OA can decrease low-density lipoprotein-cholesterol (LDL-c), TC, and TG in mice. The process is thought to be connected to essential targets of lipid synthesis and accumulation.

1.3. Anti-Hypertension

One of the cardiovascular risk factors is hypertension ^[24]. Research revealed that OA was helpful in hypertension ^[25]^[26]. OA could diminish vascular resistance by promoting nitric oxide (NO) and inhibiting COX levels in isolated rat vessels ^[27]. OA also prevented hypertension in rats via the suppression of NO catabolism ^[28]. Another study indicated that OA can improve high blood pressure by increasing the expression of eNOS ^[29]. Meanwhile, OA increased the vasodilator endothelium-derived hyperpolarizing factor (EDHF) and NO to maintain normal blood pressure ^[30].

The renin–angiotensin system and atrial natriuretic peptide (ANP) are crucial to blood pressure homeostasis ^[31]. It was found that OA can maintain the homeostasis of blood pressure by inhibiting the renin–angiotensin system and enhancing the fluid balance ^[32]. OA also could increase the expression of atrial ANP, thus enhancing vascular homeostasis ^[33]. In addition, the diuretic and nephroprotective properties of OA could reduce hypertension ^[34]. Furthermore, OA could improve hypertension via upregulating the anti-oxidative stress capacity and enhancing diuretic and natriuretic functions in hypertensive rats ^[35].

Hypertension is one of the most prevalent systemic metabolic disorders ^[36]; hypertensive patients also have substantially elevated levels of lipid metabolites ^[37]. Numerous studies have demonstrated that reducing lipids can improve hypertension. OA was found to reduce hypertension by downregulating the expression of pro-inflammatory factor-secreting phospholipase A2 and fat synthesis factor FAS and inhibiting lipid accumulation ^[38].

In conclusion, the incidence of hypertension has been rising steadily over the past decade, and the effective treatment of hypertension has a positive impact on middle-age and old-age patients. OA, a natural compound, can protect vascular endothelial cells, enhance body fluid balance, and promote glucose and lipid metabolism to reduce hypertension.

1.4. Anti-Nonalcoholic Fatty Liver

Non-alcoholic fatty liver is caused by hepatic steatosis in the liver ^[39]. Among the pathological mechanisms, the fat overloading in the liver triggered an inflammatory cascade response and subsequently developed into steatohepatitis ^[40]. Recent research indicated that OA could delay the development of a nonalcoholic fatty liver by reducing inflammation, steatosis, and fibrosis in rats ^[41]. Furthermore, the liver could be in danger from microbial disorders and increased intestinal permeability, which may exacerbate the inflammatory responses to the nonalcoholic fatty liver ^[42]; research has shown that OA could treat nonalcoholic fatty liver by ameliorating intestinal barrier dysfunction and the Toll-like receptor 4 (TLR4)-associated inflammatory responses ^[43].

Oxidative stress induced by a hepatic lipid overload exacerbates liver injury ^[44]. It was discovered that OA could substantially mitigate a nonalcoholic fatty liver by ameliorating hepatic oxidative stress and decreasing lipid synthesis factor SREBP1 ^[45].

Liver X receptors (LXR) are highly expressed in the liver and responsible for cholesterol metabolism and homeostasis ^[46]; LXR primarily activates the hepatic fat synthesis pathway by activating the promoter region of SREBP-1 ^[47]. Research demonstrated that OA was able to improve the abnormal accumulation of fat in the liver by reducing the expression of LXR and the activity of SREBP-1, as well as increasing the expression of reverse cholesterol transport (RCT)-related genes, including ATP-binding cassette transporter protein (ABC)A1 and ABCG1 ^[48]. Furthermore, OA could directly inhibit the expression of the SREBP-1 protein and decrease fatty acid accumulation in the body, thus ameliorating the progress of nonalcoholic fatty liver ^[49].

Briefly speaking, OA inhibits fat accumulation, accelerates cholesterol transport in the liver, and suppresses hepatic inflammation and oxidative stress in the treatment of nonalcoholic fatty liver.

1.5. Anti-Diabetes Mellitus

Diabetes mellitus is a metabolic disorder characterized by elevated blood sugar, mainly caused by an absolute or relative insulin deficiency and insulin resistance, classified as type 1 and type 2, with type 2 comprising nearly 95% of cases ^[50]. Insulin sensitivity can be affected by oxidative stress, inflammation, and metabolic disorders.

Inflammation is significant in diabetes mellitus ^[51]; an inordinate increase of inflammatory factors hinders insulin receptor signaling and leads to insulin resistance ^[52]. Research has shown that the expression of TLR4, TLR9, interleukin 6 (IL-6), IL-18, tumor necrosis factor α (TNF-α), TNF-1, and C-reactive protein (CRP) was reduced by OA in diabetic rats ^[53]^[54]^[55]^[56]. Furthermore, OA also could improve insulin resistance by inhibiting the activity of nuclear factor-κB (NF-κB) ^[57].

Oxidative stress is closely associated with diabetes and causes deleterious consequences of diabetes ^[58]. OA could improve the antioxidant capacity in diabetic rats by attenuating the levels of NO and malonaldehyde (MDA), as well as enhancing the level of catalase (CAT) and superoxide dismutase (SOD) ^[59]^[60]. In addition, OA was able to enhance the antioxidant function of mitochondria by increasing the expression of glutathione peroxidase 4 (Gpx4) and SOD ^[61]. Furthermore, OA was reported to improve the mitochondrial ultrastructure and function and antioxidant capacity by inhibiting MDA and ROS levels, as well as increasing CAT, SOD, and glutathione peroxidase (GSH-px) in diabetic rats ^[62]^[63]^[64].

Diabetes is associated with disorders of energy metabolism ^[65]. Lipid accumulation and the dysregulation of glucose homeostasis are significant causes of insulin resistance ^[66]. It was demonstrated that OA could improve diabetes by inhibiting the level of α-glucosidase and α-amylase ^[67]. Meanwhile, OA was able to improve diabetes in rats by stimulating insulin secretion ^[68] and decreasing blood glucose and blood lipid levels ^[69], increasing hepatic glycogen and muscle glycogen ^[70]. The research indicated that OA could prevent hyperglycemia by inhibiting glucose absorption and promoting the change of glucose to glycogen ^[71]. Elevated blood glucose and glycated hemoglobin (HbA1c) levels (referred to as the prediabetic condition) occurred before the transition from normal to diabetic ^[72] and OA could improve glucose homeostasis via the reduction of blood glucose and HbA1c levels ^[73]. It was verified that OA affects diabetes, which was related to increasing glucose transporter-5 (GLUT-5) and GLUT-4 expressions and decreasing FAS and ACC-1 expressions ^[74]. In addition, OA was observed to maintain glucose homeostasis in rats by decreasing the activity of hexokinase, the expression of glycogen phosphorylase (GP), and increasing the expression of glycogen synthase (GS) ^[75]. Another study indicated that OA could accelerate glucose and lipid metabolism via increasing the level of PPARγ/α and its related regulators, as well as GLUT-4 and fatty acid transport protein-1 (FATP-1) proteins ^[76]. Furthermore, takeda G protein-coupled receptor 5 (TGR5) belongs to the g-protein-coupled receptors involved in various cellular physiological effects ^[77]. By activating the expression of TGR5, OA was able to decrease the blood glucose levels ^[78]. Based on the accumulated evidence, the imbalance of the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) signaling pathway could cause the development of diabetes mellitus ^[79]. OA was verified to inhibit gluconeogenesis by reducing the level of Akt, forkhead box O1 (FoxO1), and glucose-6-phosphatase (G6Pase) ^[80]. It also exhibited that OA was able to accelerate glucose transport by increasing p-Akt levels and GS levels, as well as decreasing GP levels ^[81]^[82]. Furthermore, OA has positive effects on diabetes via increasing PI3K/Akt and AMPK phosphorylation, phosphoenolpyruvate carboxykinase (PEPCK), and G6Pase levels, as well as decreasing the level of the mammalian target of rapamycin (mTOR) ^[83]. It was discovered that OA could improve insulin resistance through the activation of the level of the insulin receptor substrate (IRS-1) and PI3K/Akt ^[84]. Moreover, OA may normalize insulin, high-density lipoprotein (HDL), IRS1, GLUT2, GLUT4, and Akt levels, and decrease TC, TG, and low-density lipoprotein (LDL) levels ^[85]. Furthermore, OA could decrease insulin resistance by improving β-cells ^[86].

High-glucose environments have been found to cause endothelial cell dysfunction ^[87]. Research has shown that OA attenuated human umbilical vein endothelial cells (HUVECs) function damage via activating PPARδ, increasing the phosphorylation of Akt and eNOS ^[88]. Furthermore, persistent hyperglycemia will change blood composition, such as erythrocyte morphology ^[89], and increase the production of erythropoietin (EPO) ^[90]. OA could improve diabetes by reducing plasma glucose, HbA1c, and EPO levels and increasing the antioxidant capacity of erythrocytes ^[91].

Complications caused by diabetes are also a leading cause of harm to human health, such as diabetic nephropathy ^[92]. Research reported that OA could protect rats against diabetic nephropathy by restoring plasma aldosterone and renal injury molecule-1 ^[93]. In addition, advanced glycosylation end products, such as renal N-(carboxymethyl) lysine, HbA1c, and glycosylated albumin, are also related to the development of diabetic nephropathy ^[94]. OA was able to inhibit diabetic nephropathy via a reduction of the level of renal N-(carboxymethyl) lysine, HbA1c, urinary albumin, and urine glycated albumin, as well as increasing the level of plasma insulin and renal creatinine clearance ^[95]. Furthermore, OA could also restore the damaged renal structure by increasing insulin secretion, renal units, and endothelial-selective adhesion molecules, and decreasing urinary albumin/creatinine levels ^[96].

There is accumulating evidence that OA cures diabetes by decreasing inflammation, reducing oxidative stress, and protecting endothelial cell function. Furthermore, OA could enhance the glucose–lipid metabolism in diabetic rats, restore blood components damaged by high glucose levels, and alleviate diabetic nephropathy problems. To summarize, OA in the treatment of diabetes mellitus has shown tremendous potential and is supported by numerous pieces of research; however, this research may require additional clinical trials to confirm. The detailed pharmacological effects of OA on metabolic syndrome are shown in Table 1.

Table 1. Pharmacological Effects of OA in the Treatment of MetS.

Experimental Models	Dose of OA	Signaling Pathways	Pharmacologic Action	Refs.
Obesity
3T3-L1 cells	1 to 25 μM/L OA for 6 days	↓PPARγ, ↓C/EBPα, ↓adiponectin	↓Lipid accumulation	^[4]
Female C57BL/6J mice induced by high-fat diet (HFD)	OA in water feeders at 0.005% for 16 weeks	↑↑CD36, ↑PPARα, ↑↑SREBP1, ↓↓FAS	↓↓Adipose tissue weights, ↓↓↓TG	^[5]
HFD-induced C57BL6/J male mice	300 mg/kg OA for 10 weeks	↓PPARα, ↓↓CPT1A, ↓SERBP1, ↑↑UCP1	↓↓TC, ↓↓LDL, ↑↑HDL, ↓VLDL	^[6]
HFD-induced male Swiss mice	5, 10, or 20 mg/kg OA for 7 days	↑Blood glucose tolerance	↓Plasma lipids, ↓blood glucose	^[7]
3T3-L1 cells	3 μg/mL OA for 16 days	↓ACC, ↑CYP11A1, ↑↑CYP17, ↑↑CYP19, ↓↓CYP1A1	↓↓Fat production, ↑estrogen homeostasis	^[8]
C57BL/6J mice were fed with HFD	25 and 50 mg/kg OA for 4 weeks	↓↓↓ROS, ↓NLRP3	↓↓↓Adipose tissue hypertrophy	^[13]
3T3-L1 cells	1 to 25 μM OA for 2 days	↓STAT1/3, ↓Tyk2, ↑SOCS3, ↓resistin	↓Adipogenesis	^[15]
Polychlorinated biphenyls-induced male C57B6/J mice	50 mg/kg OA for 10 weeks	↑HNF1b, ↓ROS, ↓NOX4, ↑SOD1/2, ↑GPx1	↓TG, ↓TC, ↓FFAs, ↓adipocyte size	^[17]
Hyperlipidemia
HFD-male Sprague-Dawley (SD) rats	50 mg/kg OA for 4 weeks	↓↓Levels of acetyl-CoA carboxylase, ↓↓glycerol-3-phosphate acyltransferase, ↓↓Srebf1	↓TG, ↓TC, ↓phospholipid	^[19]
Human colorectal adenocarcinoma cells and typical western-diet-induced male Lakeview Golden Syrian hamsters	50 μg OA in vitro; 0.01% OA for 4 weeks in vivo	↓Enzyme cholesterol acyltransferase activity	↓VLDL, ↓LDL, ↓TC	^[20]
Male C57BL/6 mice were fed HFD	20 mg/kg for 4 weeks	↓↓PGC-1β	↓↓TG, ↓↓TC, ↓↓LDL-c	^[22]
Patients with hyperlipidemia	OA 4 tablets once, three times a day for 4 weeks	↑↑↑CACNA1B, ↓FCN, ↑STEAP3, ↑AMPH, ↑NR6A1	↓TC, ↓TG, ↓HDL-c	^[23]
Hypertension
Male spontaneously hypertensive rats (SHR)	10⁻⁷ to 10⁻⁴ M OA	↑NO	↑↑↑Vasorelaxation	^[25]
Male Wistar and Dahl salt-sensitive rats induced by a high-salt Na diet⁺	160 μM OA	↑NO, ↓COX	↑↑↑Relaxation in aortic rings	^[27]
Dexamethasone-induced male Wistar rats	60 mg/kg for 5 days	↑Plasma nitrate/nitrite, ↑NO	↓↓Systolic pressure	^[28]
HFD-induced Wistar Kyoto rats and SHR	800 parts per million OA for 12 weeks	↑eNOS	↑↑↑Relaxation aorta	^[29]
Male Wistar Kyoto rats, and HFD-induced SHR	800 parts per million OA for 12 weeks	↑NO/EDHF	↓↓Endothelial dysfunction	^[30]
Male SD rats induced by two-kidney, one-clip hypertensive	20 and 30 mg/kg/day OA for 7 days	↓↓Renin activity, ↓↓angiotensin II type-1/2 receptor, ↓aldosterone, ↑↑↑ANP	↑↑↑Glomerular filtration rate, ↑↑↑electrolyte excretion, ↑↑↑urinary volume, ↓↓↓arterial blood pressure	^[32]
Isoproterenol-induced male SD rats	10, 20, or 30 mg/kg/day OA for 2 weeks	↑↑↑ANP	↓Atrial pressure, ↓pulse pressure	^[33]
Glucocorticoid-induced male Wistar rats	60 mg/kg/day OA for 4 weeks	↑↑Urine volume, ↑↑urine sodium, ↑potassium	↓↓↓Blood pressure	^[34]
Dahl salt-sensitive genetically hypertensive rats and normotensive Dahl salt-resistant rats	60 mg/kg OA for 6 weeks	↑GPx, ↑SOD	↑Systolic and diastolic blood pressure	^[35]
SHR and Wistar Kyoto rats	1.08 mg/kg OA for 4 weeks	↓FAS, ↓sPLA2	↓↓TG, ↓LDL-c, ↓↓systolic blood pressure and diastolic blood pressure	^[38]
Nonalcoholic fatty liver
Fructose-induced male and female SD rats	60 mg/kg for 7 days	↓Inflammation, ↓steatosis and fibrosis	↓↓Body mass, ↓liver mass, ↓hepatic lipid storage	^[41]
HFD with 60 kcal% fat-induced rats	25, 50, or 100 mg/kg for 8 weeks	↓↓IL-6, ↓↓TLR4, ↓↓IL-1β, ↓↓TNF-α	↓↓↓Body weight, ↓↓↓fatty liver score, ↓↓fasting blood glucose, ↓↓TG, ↓↓TC, ↓ALT, ↓AST	^[43]
Male SD rats induced by a high-fat high-carbohydrate diet	80 mg/kg for 12 weeks	↓SREBP1, ↓MDA, ↑GPX, ↑SOD	↓Body/liver weight ratio, ↓TG, ↓VLDL, ↑total bilirubin, ↓ALT, ↓AST	^[45]
HepG2 cells	5, 10, or 20 μM OA	↓↓↓LXR, ↓↓↓SREBP-1c, ↑↑↑ABCA1, ↑↑↑ABCG1	↓↓↓Lipogenesis	^[48]
Liquid fructose-induced male SD rats	5 or 25 mg/kg OA for 10 weeks	↓SREBP-1	↓TG, ↓lipid accumulation	^[49]
Diabetes mellitus
Male SD rats induced by Streptozotocin (STZ)	5 mg/kg OA for 21 days	↓↓↓TLR9, ↓↓↓NF-κB, ↓IL-18, ↓↓↓MDA	↓↓Glucose	^[53]
High-fructose diet in male SD rats and pups	60 mg/kg OA for 14 days	↓↓↓TNF-α, ↓↓↓IL-6, ↑↑↑MAPK, ↑↑↑adiponectin	↓Diabetes	^[54]
Male SD rats induced by STZ and a high-fat diet	25 or 100 mg/kg OA for 8 weeks	↓↓TLR4, ↓↓NF-κB	↓↓Fasting blood glucose	^[55]
Male SD rats induced by high-fat and high-carbohydrate diet	80 mg/kg OA for 12 weeks	↓TNF-α, ↓IL-1β, ↓CRP	↓Diabetes, ↓immune cell counts	^[56]
HepG2 cells induced by free fatty acids	5, 10, or 25 μM/L OA for 24 h	↓↓NF-κB, ↓↓IL-6, ↑↑IRS1, ↑GLUT4, ↓↓TNF-α	↓Insulin resistance, ↓blood glucose	^[57]
Male SD rats induced by high-fat and -fructose (HFF) diet	25 mg/kg OA for 6 weeks	↓MDA, ↓NO, ↑SOD, ↑CAT	↓Body weights, ↓serum insulin	^[59]
STZ and high sugar and fat-induced female SD rats	25 mg/kg OA for 6 weeks	↓↓↓MDA, ↓↓↓NO, ↑↑↑SOD, ↑↑↑CAT	↓↓↓Weight gain, ↓↓↓fasting blood glucose levels, ↑↑↑insulin sensitivity index	^[60]
STZ-induced male SD rats	100 mg/kg OA for 4 weeks	↑GPx, ↑SOD	↓Blood glucose, ↑body weight	^[61]
HFD-induced Wistar rats	60 or 100 mg/kg OA for 40 days	↓↓MDA, ↑SOD, ↑↑GSH-px	↓↓Blood glucose	^[63]
C57BL/KsJ-Lepdb (db/db) mice and wild mice	20 mg/kg/day OA for 2 weeks	↓ROS, ↑Nrf2	↓Fasting blood glucose	^[62]
STZ-induced male SD rats	20, 40, or 60 mg/kg/day OA for 8 weeks	↑CAT, ↑↑↑SOD, ↑GSH	↓Diabetes	^[64]
Bioactive compound(s)	Not mentioned	↓α-glycosidase, ↓α-amylase activities	↓Diabetes	^[67]
Glucose-pancreatic β-cells, rat islets	30 or 50 μM OA	↑↑Insulin secretion	↓Blood glucose	^[68]
STZ-induced male Wistar rats	100 or 200 mg/kg OA for 40 days	↑↑Insulin	↓↓Blood glucose, ↓↓blood lipids	^[69]
STZ-induced male SD rats	40, 80, or 120 mg/kg OA for 5 weeks	↑Hepatic glycogen, ↑muscle glycogen	↓Blood glucose, ↑insulin sensitivity	^[70]
STZ-induced male Wistar rats	80 mg/kg OA for 18 h	↓Glucose uptake	↓Blood glucose	^[71]
Male SD rats induced by a high-fat high-carbohydrate diet	80 mg/kg OA for 12 weeks	↓HbA1c	↓Caloric intake, ↓body weight, ↓blood glucose	^[73]
High-fructose-diet-induced SD rats	60 mg/kg OA for 7 days	↑↑Nrf-1, ↓Acc-1, ↑↑GLUT-4, ↓FAS, ↑GLUT-5	↓↓↓Body mass, ↓visceral fat	^[74]
STZ-induced male SD rats	80 mg/kg OA for 14 days	↓GP, ↓GS, ↓hexokinase activity	↑Glycogen homeostasis	^[75]
C2C12 muscle cells and 3T3-L1 cells	1 to 50 μM OA	↑PPARγ/α, ↑GLUT4, ↑FATP1	↑Lipid homeostasis	^[76]
HFD-induced male C57BL/6J mice	100 mg/kg/day OA for 7 days	↑TGR5	↓Serum glucose, ↓insulin levels	^[78]
STZ-induced male C57BL/6J mice were fed HFD	100 mg/kg/day OA for 2 weeks	↑p-Akt, ↑↑p-FoxO1, ↓G6Pase	↓↓Urine glucose, ↓↓gluconeogenesis	^[80]
STZ-induced male SD rats	100 mg/kg OA for 14 days	↑p-Akt, ↑GS, ↓GP	↓Blood glucose	^[81]
Male C57BL/KsJ-Lepdb (db/db) mice	250 mg/kg OA for 4 weeks	↑Akt, ↑PI3K, ↑AMPK, ↓↓↓G6Pase, ↓mTOR, ↓↓↓PEPCK, ↓GP	↓↓↓Blood glucose, ↑gluconeogenesis	^[83]
High-fructose-induced male SD rats	25 mg/kg/day OA for 10 weeks	↑IRS-1, ↑PI3K, ↑p-Akt	↓Plasma glucose	^[84]
STZ-induced male Institute of Cancer Research mice	25, 50, or 75 mg/kg OA for 15 days	↑↑IRS1, ↑↑GLUT2, ↑↑GLUT4, ↑↑Akt	↓TC, ↓↓TG, ↓↓LDL, ↑↑HDL, ↓↓blood glucose	^[85]
Fructose-induced male and female SD rats	60 mg/kg OA for 7 days	↓β-cell dysfunction	↓Insulin resistance	^[86]
High-glucose-induced human vascular endothelial cells	0.1 to 50 μM OA for 24 h	↑PPARβ/δ, ↑eNOS, ↑p-eNOS, ↑p-Akt	↓Endothelial dysfunction	^[88]
STZ-induced male SD rats	80 mg/kg OA for 5 weeks	↓HbA1c, ↓EPO, ↓MDA, ↑SOD, ↑GPx	↓Diabetes	^[91]
High-fat-high-carbo-hydrate-diet-induced male SD rats	80 mg/kg OA for 12 weeks	↓Aldosterone, ↓KIM-1	↓Blood and urine electrolytes, ↓estimated glomerular filtration rate, ↓albumin/creatinine ratio	^[93]
STZ-induced male Balb/cA mice	0.05, 0.1, or 0.2% OA for 10 weeks	↓HbA1c, ↓fructose,↓renal N^ε-(carboxymethyl)lysine	↓Plasma glucose, ↑plasma insulin	^[95]
Otsuka Long-Evans Tokushima fatty rats	100 mg/kg OA for 20 weeks	↓Urinary albumin/creatinine levels	↑Blood insulin secretion, ↓ER stress, ↓damaged kidney structures	^[96]

The number of arrows indicates different statistical significance: ↓/↑: p < 0.05; ↓↓/↑↑: p < 0.01; ↓↓↓/↑↑↑: p < 0.001. PPAR: peroxisome proliferator-activated receptor; C/EBPα: CCAAT/enhancer-binding protein α; CD36: cluster of differentiation 36; SREBP1: sterol regulatory element-binding protein 1; FAS: fatty acid synthetase; CPT1A: carnitine palmitoyltransferase 1A; UCP1: coupled protein 1; TC: total cholesterol; TG: triglycerides; LDL-c: low-sensitivity lipoprotein-cholesterol; HDL-c: high-density lipoprotein-cholesterol; VLDL: very-low-density lipoprotein; ACC: acetyl-CoA carboxylase; ROS: reactive oxygen species; NLRP3: NACHT, LRR, and PYD structural domain protein 3; STAT: signal transducers and activators of transcription; Tyk2: tyrosine kinase 2; SOCS3: suppressor of cytokine signaling 3; HNF1b: hepatocyte nuclear factor 1b; Nox4: nicotinamide adenine dinucleotide phosphate oxidase 4; SOD: superoxide dismutase; Gpx1: glutathioneperoxidase; FFA: free fatty acid; PGC-1β: peroxisome proliferator-activated receptor gamma coactivator 1β; NO: nitric oxide; COX: cyclooxygenase; eNOS: endothelial nitric oxide synthase; EDHF: endothelium-derived hyperpolarizing factor; ANP: atrialnatriureticpeptide; sPLA2: secretory phospholipase A2; IL-6: interleukin 6; TLR4: toll-like receptor 4; IL-1β: interleukin 1β; TNF-α: tumor necrosis factor α; MDA: malonaldehyde; LXR: Liver X receptors; ABCA/ABCG1: ATP-binding cassette transporter A1/G1; NF-κB: nuclear factor-κB; CRP: C-reactive protein; IRS1: insulin receptor substrate 1; GLUT4: glucose transporter 4; CAT: catalase; GSH-px: glutathione peroxidase; Nrf2: nuclear factor erythroid-2-related factor 2; HbA1c: glycated hemoglobin; GP: glycogen phosphorylase; GS: glycogen synthase; FATP1: fatty acid transport protein 1; TGR5: takeda G protein-coupled receptor 5; PI3K: phosphatidylinositol-3-kinase; Akt: protein kinase B; FoxO1: forkhead box O1; G6Pase: glucose-6-phosphatase; mTOR: mammalian target of rapamycin; PERCK: phosphoenolpyruvate carboxykinase; KIM-1: kidney injury molecule 1; ER: endoplasmic reticulum; ALT: alanine aminotransferase; AST: aspartate transaminase.

2. Anti-Cardiovascular Diseases Effects

2.1. Anti-Stroke

Stroke is one of the main causes of increased mortality ^[97], which is affected by inflammation, oxidative stress, and nerve damage ^[98].

The key mechanism in the formation of ischemic stroke is oxidative stress ^[99], which also causes neuronal apoptosis, inflammation, and nerve injury ^[100]. It was reported that OA reduced cerebral ischemic stroke damage by increasing the level of mitochondrial antioxidant α-tocopherol (α-TOC) and GSH, as well as decreasing the leakage of the damage marker lactate dehydrogenase (LDH) ^[101]. Furthermore, OA was able to improve oxidative stress in brain-injured rats; the results showed that OA treatment significantly increased the activity of SOD, GSH-Px, mitochondrial membrane potential (MMP), and succinate dehydrogenase (SDH), and decreased MDA and LDH levels ^[102]. Meanwhile, OA also could restrain the blood–brain barrier indicator occludin, matrix metalloproteinase 9 (MMP9), and Evans blue leakage, and inhibit oxidative indicator dihydroethidium fluorescence and MDA expression ^[103]. In addition, heme oxygenase-1 (HO-1) is the most effective antioxidant response element, and glycogen synthase kinase-3β (GSK-3β) is able to regulate HO-1 in controlling oxidative stress ^[104]. OA attenuated cytotoxicity and ROS via the regulation of the GSK-3β/HO-1 signal in rats ^[105].

In general, OA from natural product sources has neuroprotective functions, such as the improvement of the blood–brain barrier, reduction of nerve injury, and cerebral edema in mice; the mechanism was primarily associated with the improvement of oxidative damage. However, it remains to be determined whether OA in stroke treatment has a more promising mechanism.

2.2. Heart Protection

Heart disease has a high mortality rate, and the number of deaths is still rising ^[106]. Oxidative stress is a significant reason for heart disease; the elevated expression of ROS causes cardiomyocyte dysfunction and damage ^[107]. Research demonstrated that OA promoted the antioxidant capacity of the heart via the reduction level of the lipid peroxidation products ^[108]. Furthermore, OA was able to prevent diabetic cardiomyopathy through the regulation of HO-1/Nrf2 to increase SOD and GS, as well as decrease MDA and GP ^[109]. Meanwhile, OA was verified to prevent CVDs by improving the inflammatory reaction, MDA, SOD, GPx, as well as heart weight in rats ^[110]. In addition, OA could improve myocardial apoptosis by increasing the antioxidant capacity and decreasing apoptosis signaling caspase-3 and BAX activity, increasing Bcl-2 activity ^[111]^[112].

Endothelin 1 (ET-1) aggravates the development of CVDs ^[113], and OA could inhibit cardiomyocyte injury through the regulation of the expression of ET-1 ^[114]. Furthermore, ET-1 and NF-κB modulate the fibrotic process in the heart, as well as promote the expression of fibronectin in cardiac tissues ^[115]. OA could improve fibrotic hearts in rats by reducing the activation of NF-κB and ET-1 ^[116]. Moreover, the Akt/mTOR exacerbates the pathological process of myocardial remodeling ^[117]; OA performed cardiac protection with the inhibition of vascular remodeling by decreasing the levels of Akt and mTOR ^[118]. In addition, OA possessed the ability to suppress the platelet aggregation mediated by phospholipase C, thereby aiding in the prevention of cardiovascular thrombosis ^[119].

Therefore, current research demonstrates that OA could treat a variety of heart diseases, as well as prevent cardiac fibrosis and the cardiac remodeling process. The mechanism includes the inhibition of inflammation, oxidative stress, and the improvement of the expression of vasoconstrictive factors.

2.3. Anti-Atherosclerosis

Atherosclerosis (AS) is the underlying pathology of CVDs ^[120]. OA could prevent AS by inhibiting many pathological developments, such as oxidative stress, endothelial dysfunction, and lipid deposition. Oxidative stress was deemed the critical mechanism in AS ^[121]. Research demonstrated that OA may safeguard HUVECs damage by inhibiting the levels of lipoprotein receptor 1 (LOX-1), ROS, as well as hypoxia-inducible factor 1 α (HIF-1α) ^[122]. Moreover, OA has been confirmed to alleviate HUVECs damage via the reduction in the level of ROS and LOX-1, as well as enhancing the level of Nrf2/HO-1 ^[123].

PPARγ is considered a ligand-activated transcription factor that regulates the glycolipid metabolism, and adiponectin promotes fatty acid biosynthesis and inhibits hepatic gluconeogenesis ^[124]. OA could reduce lipids and enhance high-density lipoprotein cholesterol (HDL-c) by increasing PPARγ and adiponectin Receptor 1 (AdipoR1) Levels, decreasing AdopoR2 levels ^[125].

Farnesoid-X-receptor (FXR) is associated with the bile metabolism ^[126], and angiotensin1-7 (Ang1-7) has been implicated as an AS protector ^[127]. OA was found to decrease the levels of lipids in rats via the regulation of the expression of FXR and Ang1-7 ^[128]. In addition, OA inhibited the expression of iNOS, thereby delaying the progression of aortic stenosis ^[129].

In conclusion, OA can reduce the area of vascular lipid plaque and treat AS by protecting HUVECs, reducing inflammatory factors and the accumulation of lipids. The detailed pharmacological effects of OA on metabolic syndrome-related cardiovascular diseases are shown in Table 2.

Table 2. Pharmacological effects of OA in the treatment of CVDs.

Experimental Models	Dose of OA	Signaling Pathways	Pharmacologic Action	Refs.
Stroke
Ischemia reperfusion experiment-induced female SD rats	0.6 or 1.2 mM/kg OA for 3 days	↓LDH, ↑GSH, ↑α-TOC	↓Brain injury	^[101]
Male Institute of Cancer Research mice and male SD rats injured by bilateral common carotid artery ligation	25 or 50 mg/kg OA for 4 days	↑SOD, ↑↑GSH-Px, ↓↓MDA, ↓↓LDH, ↑MMP, ↑↑SDH	↑↑Survival time, ↓cerebral infarction area	^[102]
Male Institute of Cancer Research mice	6 mg/kg/day OA for 3 days	↓Evans blue leakage, ↓MMP9, ↓occludin, ↓dihydroethidium fluorescence, ↓MDA	↓Infarct volumes, ↑locomotor activity, ↑memory ability	^[103]
SH-SY5Y Cells and rats	10, 20, or 40 μM OA for 12 h in vitro; 10 or 20 mg/kg OA for 3 days in vivo	↑↑GSK-3β, ↑↑HO-1, ↓↓ROS	↓↓Infarct volume in the brain, ↓↓apoptosis	^[105]
Heart protection
Isoproterenol-induced adult male albino rats of the Wistar strain	20, 40, or 60 mg/kg OA for 7 days	↓ALT, ↓AST, ↓CPK, ↓LDH, ↓TBARS	↑Heart protection	^[108]
STZ-induced male SD rats	80 mg/kg OA for 14 days	↓↓↓GS, ↓↓↓GP, ↑↑↑HO-1, ↑↑↑Nrf2	↓↓↓Diabetic cardiomyopathy	^[109]
SD rats to high-fat high-carbohydrate diet	Not mentioned	↓CRP, ↓IL-6, ↓TNF-α, ↓MDA, ↑SOD, ↑GPx	↓Mean arterial pressure, ↓heart weights, ↓TG, ↓TC, ↓LDL-c, ↓HDL-c	^[110]
H9c2 cells	5 or 10 μM OA	↓ROS, ↓GSSG, ↓IL-6, ↓TNF-α, ↑GSH, ↑GPX, ↑GR, ↑CAT, ↑NF-κB, ↑caspase-3, ↓bcl-2	↑Cell viability, ↓plasma membrane damage, ↓apoptosis	^[114]
High-glucose-induced H9c2 cells	20 or 50 μM OA for 6 and 20 h	↓↓↓Caspase-3, ↑↑SOD, ↓ROS	↓↓↓Apoptosis, ↑↑↑heart protection	^[112]
High-glucose-induced injury in neonatal rat ventricular cardiomyocytes	10 μM OA for 24 h	↓↓↓BNP, ↓↓ET-1, ↓↓MMP	↓↓Cardiomyocyte damage	^[114]
Male Zucker Diabetic fatty rats and lipopolysaccharide-induced RAW264.7	Not mentioned exactly in vivo; 10 to 300 mM OA for 24 h in vitro	↓↓ET-1, ↓ETA, ↓IκBβ, ↑↑IκBα	↓↓Cardiac fibrosis	^[116]
C57BL/6J male mice and H9c2 cells	25 or 100 mg/kg/day OA for 8 weeks	↓Akt, ↓mTOR, ↓GSK-3β, ↓FoxO3a	↓Cardiac hypertrophy, ↓tissue fibrosis	^[118]
The platelets	25, 50, 100, or 200 μM OA	↑↑Phospholipase C	↓↓Platelets aggregation	^[119]
Atherosclerosis
HUVECs induced by Ox-LDL	1, 5, or 10 μM OA	↓LOX-1, ↓ROS, ↓HIF-1α	↓Apoptosis	^[122]
High-fat-diet-induced male quails and HUVECs induced by Ox-LDL	25, 50, or 100 mg/kg OA for 10 weeks in vivo; 5, 10, or 20 μM OA for 24 h in vitro	↓NADPH, ↓ROS, ↑Nrf2, ↑HO-1, ↓LOX-1	↓TG, ↓TC, ↓LDL, ↑HDL	^[123]
New Zealand rabbits and C57BL/6J mice and Apoe-/- mice fed with an atherogenic diet	25 mg/kg OA for 5 weeks	↑PPARγ, ↑↑AdipoR1, ↓↓AdipoR2	↓↓TG, ↓TC, ↓↓LDL-c,↓intimal thickening of the artery	^[125]
Atherogenic diet (1% cholesterol and 5% lard oil)-induced male New Zealand White rabbits and Ox-LDL-induced HUVECs	50 mg/kg/day OA for 28 days in vivo; 40 μM OA for 24 h in vitro	↑↑↑Ang1-7, ↑↑↑NO, ↑↑↑eNOS, ↑FXR	↓↓↓TC, ↓↓↓TG, ↓LDL-C, ↓↓HDL-C, ↓↓↓cell apoptosis, ↓intimal thickening of the artery	^[128]
ApoE-/- mice were fed a high-cholesterol Western-type diet	100 mg/kg/day OA for 8 weeks	↓iNOS	↓Plaque area, ↓↓TC, ↓↓plaque area	^[129]

The number of arrows indicates different statistical significance: ↓/↑: p < 0.05; ↓↓/↑↑: p < 0.01; ↓↓↓/↑↑↑: p < 0.001. LDH: lactate dehydrogenase; GSH: glutathione; α-TOC: α-tocopherol; SOD: superoxide dismutase; GSH-px: glutathione peroxidase; MDA: malonaldehyde; MMP: mitochondrial membrane potential; MMP9: matrix metalloproteinase 9; GSK-3β: glycogen synthase kinase-3β; HO-1: heme oxygenase-1; ROS: reactive oxygen species; ALT: alanine aminotransferase; AST: aspartate transaminase; CPK: creatine phosphokinase; TBARS: thiobarbituric acid reactive substances; Nrf2: nuclear factor erythroid-2-related factor 2; CRP: C-reactive protein; IL-6: interleukin 6; TNF-α: tumor necrosis factor α; Gpx: glutathione peroxidase; TG: triglycerides; TC: total cholesterol; LDL-c: low-density lipoprotein-cholesterol; HDL-c: high-density lipoprotein-cholesterol; GSSG: oxidized glutathione; GR: glutathione reductase; CAT: catalase; NF-κB: Nuclear factor-κB; Bcl-2: B-cell lymphoma-2; BNP: natriuretic peptide B; ET-1: endothelin 1; MMP: mitochondrial membrane potential; ETA: endothelin receptors; IκBβ/α: inhibitory protein β/α; Akt: protein kinase B; mTOR: mammalian target of rapamycin; GSK-3β: glycogen synthase kinase-3β; FoxO3a: forkhead box class O3a; LOX-1: lipoprotein receptor 1; HIF-1α: hypoxia-inducible factor 1 α; NADPH: nicotinamide adenine dinucleotide phosphate; PPAR: peroxisome proliferator-activated receptor; AdiPoR1/2: adiponectin Receptor 1/2; Ang1-7: angiotensin 1-7; NO: nitric oxide; eNOS: endothelial nitric oxide synthase; FXR: farnesoid-X-receptor; iNOS: inducible nitric oxide synthase.

References

Piché, M.E.; Tchernof, A.; Després, J.P. Obesity Phenotypes, Diabetes, and Cardiovascular Diseases. Circ. Res. 2020, 126, 1477–1500.
White, U.A.; Stephens, J.M. Transcriptional factors that promote formation of white adipose tissue. Mol. Cell Endocrinol. 2010, 318, 10–14.
Ali, A.T.; Hochfeld, W.E.; Myburgh, R.; Pepper, M.S. Adipocyte and adipogenesis. Eur. J. Cell Biol. 2013, 92, 229–236.
Sung, H.Y.; Kang, S.W.; Kim, J.L.; Li, J.; Lee, E.S.; Gong, J.H.; Han, S.J.; Kang, Y.H. Oleanolic acid reduces markers of differentiation in 3T3-L1 adipocytes. Nutr. Res. 2010, 30, 831–839.
Djeziri, F.Z.; Belarbi, M.; Murtaza, B.; Hichami, A.; Benammar, C.; Khan, N.A. Oleanolic acid improves diet-induced obesity by modulating fat preference and inflammation in mice. Biochimie 2018, 152, 110–120.
Acin, S.; Munoz, D.L.; Guillen, A.; Soscue, D.; Castano, A.; Echeverri, F.; Balcazar, N. Triterpene-enriched fractions from Eucalyptus tereticornis ameliorate metabolic alterations in a mouse model of diet-induced obesity. J. Ethnopharmacol. 2021, 265, 113298.
De Melo, C.L.; Queiroz, M.G.; Fonseca, S.G.; Bizerra, A.M.; Lemos, T.L.; Melo, T.S.; Santos, F.A.; Rao, V.S. Oleanolic acid, a natural triterpenoid improves blood glucose tolerance in normal mice and ameliorates visceral obesity in mice fed a high-fat diet. Chem. Biol. Interact. 2010, 185, 59–65.
Wan, Q.; Lu, H.; Liu, X.; Yie, S.; Xiang, J.; Yao, Z. Study of oleanolic acid on the estrodiol production and the fat production of mouse preadipocyte 3T3-L1 in vitro. Hum. Cell 2015, 28, 5–13.
Kawai, T.; Autieri, M.V.; Scalia, R. Adipose tissue inflammation and metabolic dysfunction in obesity. Am. J. Physiol. Cell Physiol. 2021, 320, C375–C391.
Yan, J.; Horng, T. Lipid Metabolism in Regulation of Macrophage Functions. Trends Cell Biol. 2020, 30, 979–989.
Lin, W.; Shen, P.; Huang, Y.; Han, L.; Ba, X.; Huang, Y.; Yan, J.; Li, T.; Xu, L.; Qin, K.; et al. Wutou decoction attenuates the synovial inflammation of collagen-induced arthritis rats via regulating macrophage M1/M2 type polarization. J. Ethnopharmacol. 2023, 301, 115802.
Chylikova, J.; Dvorackova, J.; Tauber, Z.; Kamarad, V. M1/M2 macrophage polarization in human obese adipose tissue. Biomed. Pap. Med. Fac. Univ. Palacky Olomouc. Czechoslov. 2018, 162, 79–82.
Li, W.; Zeng, H.; Xu, M.; Huang, C.; Tao, L.; Li, J.; Zhang, T.; Chen, H.; Xia, J.; Li, C.; et al. Oleanolic Acid Improves Obesity-Related Inflammation and Insulin Resistance by Regulating Macrophages Activation. Front. Pharmacol. 2021, 12, 697483.
Lazar, M.A. Resistin- and Obesity-associated metabolic diseases. Horm. Metab. Res. 2007, 39, 710–716.
Kim, H.S.; Sung, H.Y.; Kim, M.S.; Kim, J.L.; Kang, M.K.; Gong, J.H.; Park, H.S.; Kang, Y.H. Oleanolic acid suppresses resistin induction in adipocytes by modulating Tyk-STAT signaling. Nutr. Res. 2013, 33, 144–153.
Wang, X.; Wu, H.; Yu, W.; Liu, J.; Peng, J.; Liao, N.; Zhang, J.; Zhang, X.; Hai, C. Hepatocyte nuclear factor 1b is a novel negative regulator of white adipocyte differentiation. Cell Death Differ. 2017, 24, 1588–1597.
Su, S.; Wu, G.; Cheng, X.; Fan, J.; Peng, J.; Su, H.; Xu, Z.; Cao, M.; Long, Z.; Hao, Y.; et al. Oleanolic acid attenuates PCBs-induced adiposity and insulin resistance via HNF1b-mediated regulation of redox and PPARgamma signaling. Free Radic. Biol. Med. 2018, 124, 122–134.
Nelson, R.H. Hyperlipidemia as a risk factor for cardiovascular disease. Prim. Care 2013, 40, 195–211.
Yunoki, K.; Sasaki, G.; Tokuji, Y.; Kinoshita, M.; Naito, A.; Aida, K.; Ohnishi, M. Effect of dietary wine pomace extract and oleanolic acid on plasma lipids in rats fed high-fat diet and its DNA microarray analysis. J. Agric. Food Chem. 2008, 56, 12052–12058.
Lin, Y.; Vermeer, M.A.; Trautwein, E.A. Triterpenic Acids Present in Hawthorn Lower Plasma Cholesterol by Inhibiting Intestinal ACAT Activity in Hamsters. Evid. Based Complement. Altern. Med. Ecam 2011, 2011, 801272.
Lin, J.; Yang, R.; Tarr, P.T.; Wu, P.H.; Handschin, C.; Li, S.; Yang, W.; Pei, L.; Uldry, M.; Tontonoz, P.; et al. Hyperlipidemic effects of dietary saturated fats mediated through PGC-1beta coactivation of SREBP. Cell 2005, 120, 261–273.
Chen, S.; Wen, X.; Zhang, W.; Wang, C.; Liu, J.; Liu, C. Hypolipidemic effect of oleanolic acid is mediated by the miR-98-5p/PGC-1beta axis in high-fat diet-induced hyperlipidemic mice. FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol. 2017, 31, 1085–1096.
Luo, H.Q.; Shen, J.; Chen, C.P.; Ma, X.; Lin, C.; Ouyang, Q.; Xuan, C.X.; Liu, J.; Sun, H.B.; Liu, J. Lipid-lowering effects of oleanolic acid in hyperlipidemic patients. Chin. J. Nat. Med. 2018, 16, 339–346.
Lu, M.; Li, D.; Hu, Y.; Zhang, L.; Li, Y.; Zhang, Z.; Li, C. Persistence of severe global inequalities in the burden of Hypertension Heart Disease from 1990 to 2019: Findings from the global burden of disease study 2019. BMC Public Health 2024, 24, 110.
Rodriguez-Rodriguez, R.; Perona, J.S.; Herrera, M.D.; Ruiz-Gutierrez, V. Triterpenic compounds from “orujo” olive oil elicit vasorelaxation in aorta from spontaneously hypertensive rats. J. Agric. Food Chem. 2006, 54, 2096–2102.
Rodriguez-Rodriguez, R.; Herrera, M.D.; Perona, J.S.; Ruiz-Gutierrez, V. Potential vasorelaxant effects of oleanolic acid and erythrodiol, two triterpenoids contained in ‘orujo’ olive oil, on rat aorta. Br. J. Nutr. 2004, 92, 635–642.
Madlala, H.P.; Metzinger, T.; van Heerden, F.R.; Musabayane, C.T.; Mubagwa, K.; Dessy, C. Vascular Endothelium-Dependent and Independent Actions of Oleanolic Acid and Its Synthetic Oleanane Derivatives as Possible Mechanisms for Hypotensive Effects. PLoS ONE 2016, 11, e0147395.
Bachhav, S.S.; Patil, S.D.; Bhutada, M.S.; Surana, S.J. Oleanolic acid prevents glucocorticoid-induced hypertension in rats. Phytother. Res. PTR 2011, 25, 1435–1439.
Rodriguez-Rodriguez, R.; Herrera, M.D.; de Sotomayor, M.A.; Ruiz-Gutierrez, V. Pomace olive oil improves endothelial function in spontaneously hypertensive rats by increasing endothelial nitric oxide synthase expression. Am. J. Hypertens. 2007, 20, 728–734.
Rodriguez-Rodriguez, R.; Herrera, M.D.; de Sotomayor, M.A.; Ruiz-Gutierrez, V. Effects of pomace olive oil-enriched diets on endothelial function of small mesenteric arteries from spontaneously hypertensive rats. Br. J. Nutr. 2009, 102, 1435–1444.
Acelajado, M.C.; Hughes, Z.H.; Oparil, S.; Calhoun, D.A. Treatment of Resistant and Refractory Hypertension. Circ. Res. 2019, 124, 1061–1070.
Ahn, Y.M.; Choi, Y.H.; Yoon, J.J.; Lee, Y.J.; Cho, K.W.; Kang, D.G.; Lee, H.S. Oleanolic acid modulates the renin-angiotensin system and cardiac natriuretic hormone concomitantly with volume and pressure balance in rats. Eur. J. Pharmacol. 2017, 809, 231–241.
Kim, H.Y.; Cho, K.W.; Kang, D.G.; Lee, H.S. Oleanolic acid increases plasma ANP levels via an accentuation of cardiac ANP synthesis and secretion in rats. Eur. J. Pharmacol. 2013, 710, 73–79.
Bachhav, S.S.; Bhutada, M.S.; Patil, S.P.; Sharma, K.S.; Patil, S.D. Oleanolic Acid Prevents Increase in Blood Pressure and Nephrotoxicity in Nitric Oxide Dependent Type of Hypertension in Rats. Pharmacogn. Res. 2014, 7, 385–392.
Somova, L.O.; Nadar, A.; Rammanan, P.; Shode, F.O. Cardiovascular, antihyperlipidemic and antioxidant effects of oleanolic and ursolic acids in experimental hypertension. Phytomedicine Int. J. Phytother. Phytopharm. 2003, 10, 115–121.
Bacon, S.L.; Sherwood, A.; Hinderliter, A.; Blumenthal, J.A. Effects of exercise, diet and weight loss on high blood pressure. Sport. Med. 2004, 34, 307–316.
Alwardat, N.; Di Renzo, L.; de Miranda, R.C.; Alwardat, S.; Sinibaldi Salimei, P.; De Lorenzo, A. Association between hypertension and metabolic disorders among elderly patients in North Jordan. Diabetes Metab. Syndr. 2018, 12, 661–666.
Zhang, S.; Liu, Y.; Wang, X.; Tian, Z.; Qi, D.; Li, Y.; Jiang, H. Antihypertensive activity of oleanolic acid is mediated via downregulation of secretory phospholipase A2 and fatty acid synthase in spontaneously hypertensive rats. Int. J. Mol. Med. 2020, 46, 2019–2034.
Ludwig, J.; Viggiano, T.R.; McGill, D.B.; Oh, B.J. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin. Proc. 1980, 55, 434–438.
Ratziu, V.; Bellentani, S.; Cortez-Pinto, H.; Day, C.; Marchesini, G. A position statement on NAFLD/NASH based on the EASL 2009 special conference. J. Hepatol. 2010, 53, 372–384.
Nyakudya, T.T.; Mukwevho, E.; Nkomozepi, P.; Erlwanger, K.H. Neonatal intake of oleanolic acid attenuates the subsequent development of high fructose diet-induced non-alcoholic fatty liver disease in rats. J. Dev. Orig. Health Dis. 2018, 9, 500–510.
Leung, C.; Rivera, L.; Furness, J.B.; Angus, P.W. The role of the gut microbiota in NAFLD. Nat. Rev. Gastroenterol. Hepatol. 2016, 13, 412–425.
Xue, C.; Li, Y.; Lv, H.; Zhang, L.; Bi, C.; Dong, N.; Shan, A.; Wang, J. Oleanolic Acid Targets the Gut-Liver Axis to Alleviate Metabolic Disorders and Hepatic Steatosis. J. Agric. Food Chem. 2021, 69, 7884–7897.
Chen, Z.; Tian, R.; She, Z.; Cai, J.; Li, H. Role of oxidative stress in the pathogenesis of nonalcoholic fatty liver disease. Free Radic. Biol. Med. 2020, 152, 116–141.
Gamede, M.; Mabuza, L.; Ngubane, P.; Khathi, A. Plant-derived oleanolic acid ameliorates markers associated with non-alcoholic fatty liver disease in a diet-induced pre-diabetes rat model. Diabetes Metab. Syndr. Obes. Targets Ther. 2019, 12, 1953–1962.
Repa, J.J.; Liang, G.; Ou, J.; Bashmakov, Y.; Lobaccaro, J.M.; Shimomura, I.; Shan, B.; Brown, M.S.; Goldstein, J.L.; Mangelsdorf, D.J. Regulation of mouse sterol regulatory element-binding protein-1c gene (SREBP-1c) by oxysterol receptors, LXRalpha and LXRbeta. Genes Dev. 2000, 14, 2819–2830.
Zhang, Y.; Gu, Y.; Chen, Y.; Huang, Z.; Li, M.; Jiang, W.; Chen, J.; Rao, W.; Luo, S.; Chen, Y.; et al. Dingxin Recipe IV attenuates atherosclerosis by regulating lipid metabolism through LXR-α/SREBP1 pathway and modulating the gut microbiota in ApoE (−/−) mice fed with HFD. J. Ethnopharmacol. 2021, 266, 113436.
Lin, Y.N.; Chang, H.Y.; Wang, C.C.N.; Chu, F.Y.; Shen, H.Y.; Chen, C.J.; Lim, Y.P. Oleanolic Acid Inhibits Liver X Receptor Alpha and Pregnane X Receptor to Attenuate Ligand-Induced Lipogenesis. J. Agric. Food Chem. 2018, 66, 10964–10976.
Liu, C.; Li, Y.; Zuo, G.; Xu, W.; Gao, H.; Yang, Y.; Yamahara, J.; Wang, J.; Li, Y. Oleanolic Acid diminishes liquid fructose-induced Fatty liver in rats: Role of modulation of hepatic sterol regulatory element-binding protein-1c-mediated expression of genes responsible for de novo Fatty Acid synthesis. Evid. Based Complement. Altern. Med. Ecam. 2013, 2013, 534084.
Thomas, C.C.; Philipson, L.H. Update on diabetes classification. Med. Clin. North Am. 2015, 99, 1–16.
Lontchi-Yimagou, E.; Sobngwi, E.; Matsha, T.E.; Kengne, A.P. Diabetes mellitus and inflammation. Curr. Diabetes Rep. 2013, 13, 435–444.
Glass, C.K.; Olefsky, J.M. Inflammation and lipid signaling in the etiology of insulin resistance. Cell Metab. 2012, 15, 635–645.
Iskender, H.; Dokumacioglu, E.; Terim Kapakin, K.A.; Yenice, G.; Mohtare, B.; Bolat, I.; Hayirli, A. Effects of oleanolic acid on inflammation and metabolism in diabetic rats. Biotech. Histochem. Off. Publ. Biol. Stain Comm. 2022, 97, 269–276.
Matumba, M.; Ayeleso, A.; Nyakudya, T.; Erlwanger, K.; Chegou, N.; Mukwevho, E. Long-Term Impact of Neonatal Intake of Oleanolic Acid on the Expression of AMP-Activated Protein Kinase, Adiponectin and Inflammatory Cytokines in Rats Fed with a High Fructose Diet. Nutrients 2019, 11, 226.
Liu, Y.; Hu, Z.; Xing, H.; Kang, L.; Chen, X.; Liu, B.; Niu, K. Renoprotective effects of oleanolic acid and its possible mechanisms in rats with diabetic kidney disease. Biochem. Biophys. Res. Commun. 2022, 636, 1–9.
Gamede, M.; Mabuza, L.; Ngubane, P.; Khathi, A. Plant-derived oleanolic acid ameliorates markers of subclinical inflammation and innate immunity activation in diet-induced pre-diabetic rats. Ther. Adv. Endocrinol. Metab. 2020, 11, 2042018820935771.
Li, M.; Han, Z.; Bei, W.; Rong, X.; Guo, J.; Hu, X. Oleanolic Acid Attenuates Insulin Resistance via NF-kappaB to Regulate the IRS1-GLUT4 Pathway in HepG2 Cells. Evid. Based Complement. Altern. Med. Ecam 2015, 2015, 643102.
Zhang, P.; Li, T.; Wu, X.; Nice, E.C.; Huang, C.; Zhang, Y. Oxidative stress and diabetes: Antioxidative strategies. Front. Med. 2020, 14, 583–600.
Wang, S.; Du, L.B.; Jin, L.; Wang, Z.; Peng, J.; Liao, N.; Zhao, Y.Y.; Zhang, J.L.; Pauluhn, J.; Hai, C.X.; et al. Nano-oleanolic acid alleviates metabolic dysfunctions in rats with high fat and fructose diet. Biomed. Pharmacother. 2018, 108, 1181–1187.
Yan, Y.; Wang, S.; Gu, J.; Min, Z.; Wang, R. Effect of Nano-Oleanolic Acid Combined With Lipid-Lowering Ketones on Insulin Resistance in Rats with Gestational Diabetes. J. Biomed. Nanotechnol. 2022, 18, 474–480.
Wang, X.; Li, Y.L.; Wu, H.; Liu, J.Z.; Hu, J.X.; Liao, N.; Peng, J.; Cao, P.P.; Liang, X.; Hai, C.X. Antidiabetic effect of oleanolic acid: A promising use of a traditional pharmacological agent. Phytother. Res. PTR 2011, 25, 1031–1040.
Wang, X.; Liu, R.; Zhang, W.; Zhang, X.; Liao, N.; Wang, Z.; Li, W.; Qin, X.; Hai, C. Oleanolic acid improves hepatic insulin resistance via antioxidant, hypolipidemic and anti-inflammatory effects. Mol. Cell Endocrinol. 2013, 376, 70–80.
Gao, D.; Li, Q.; Li, Y.; Liu, Z.; Fan, Y.; Liu, Z.; Zhao, H.; Li, J.; Han, Z. Antidiabetic and antioxidant effects of oleanolic acid from Ligustrum lucidum Ait in alloxan-induced diabetic rats. Phytother. Res. PTR 2009, 23, 1257–1262.
Dubey, V.K.; Patil, C.R.; Kamble, S.M.; Tidke, P.S.; Patil, K.R.; Maniya, P.J.; Jadhav, R.B.; Patil, S.P. Oleanolic acid prevents progression of streptozotocin induced diabetic nephropathy and protects renal microstructures in Sprague Dawley rats. J. Pharmacol. Pharmacother. 2013, 4, 47–52.
Nosadini, R.; Tonolo, G. Role of oxidized low density lipoproteins and free fatty acids in the pathogenesis of glomerulopathy and tubulointerstitial lesions in type 2 diabetes. Nutr. Metab. Cardiovasc. Dis. NMCD 2011, 21, 79–85.
He, J.; Song, C.; Yuan, S.; Bian, X.; Lin, Z.; Yang, M.; Dou, K. Triglyceride-glucose index as a suitable non-insulin-based insulin resistance marker to predict cardiovascular events in patients undergoing complex coronary artery intervention: A large-scale cohort study. Cardiovasc. Diabetol. 2024, 23, 15.
Mohammed, A.; Victoria Awolola, G.; Ibrahim, M.A.; Anthony Koorbanally, N.; Islam, M.S. Oleanolic acid as a potential antidiabetic component of Xylopia aethiopica (Dunal) A. Rich. (Annonaceae) fruit: Bioassay guided isolation and molecular docking studies. Nat. Prod. Res. 2021, 35, 788–791.
Teodoro, T.; Zhang, L.; Alexander, T.; Yue, J.; Vranic, M.; Volchuk, A. Oleanolic acid enhances insulin secretion in pancreatic beta-cells. FEBS Lett. 2008, 582, 1375–1380.
Gao, D.; Li, Q.; Li, Y.; Liu, Z.; Liu, Z.; Fan, Y.; Han, Z.; Li, J.; Li, K. Antidiabetic potential of oleanolic acid from Ligustrum lucidum Ait. Can. J. Physiol. Pharmacol. 2007, 85, 1076–1083.
Musabayane, C.T.; Tufts, M.A.; Mapanga, R.F. Synergistic antihyperglycemic effects between plant-derived oleanolic acid and insulin in streptozotocin-induced diabetic rats. Ren. Fail. 2010, 32, 832–839.
Khathi, A.; Masola, B.; Musabayane, C.T. Effects of Syzygium aromaticum-derived oleanolic acid on glucose transport and glycogen synthesis in the rat small intestine. J. Diabetes 2013, 5, 80–87.
Tuomilehto, J.; Lindström, J.; Eriksson, J.G.; Valle, T.T.; Hämäläinen, H.; Ilanne-Parikka, P.; Keinänen-Kiukaanniemi, S.; Laakso, M.; Louheranta, A.; Rastas, M.; et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. New Engl. J. Med. 2001, 344, 1343–1350.
Gamede, M.; Mabuza, L.; Ngubane, P.; Khathi, A. The Effects of Plant-Derived Oleanolic Acid on Selected Parameters of Glucose Homeostasis in a Diet-Induced Pre-Diabetic Rat Model. Molecules 2018, 23, 794.
Molepo, M.; Ayeleso, A.; Nyakudya, T.; Erlwanger, K.; Mukwevho, E. A Study on Neonatal Intake of Oleanolic Acid and Metformin in Rats (Rattus norvegicus) with Metabolic Dysfunction: Implications on Lipid Metabolism and Glucose Transport. Molecules 2018, 23, 2528.
Mukundwa, A.; Langa, S.O.; Mukaratirwa, S.; Masola, B. In vivo effects of diabetes, insulin and oleanolic acid on enzymes of glycogen metabolism in the skin of streptozotocin-induced diabetic male Sprague-Dawley rats. Biochem. Biophys. Res. Commun. 2016, 471, 315–319.
Loza-Rodriguez, H.; Estrada-Soto, S.; Alarcon-Aguilar, F.J.; Huang, F.; Aquino-Jarquin, G.; Fortis-Barrera, A.; Giacoman-Martinez, A.; Almanza-Perez, J.C. Oleanolic acid induces a dual agonist action on PPARgamma/alpha and GLUT4 translocation: A pentacyclic triterpene for dyslipidemia and type 2 diabetes. Eur. J. Pharmacol. 2020, 883, 173252.
Thomas, C.; Gioiello, A.; Noriega, L.; Strehle, A.; Oury, J.; Rizzo, G.; Macchiarulo, A.; Yamamoto, H.; Mataki, C.; Pruzanski, M.; et al. TGR5-mediated bile acid sensing controls glucose homeostasis. Cell Metab. 2009, 10, 167–177.
Sato, H.; Genet, C.; Strehle, A.; Thomas, C.; Lobstein, A.; Wagner, A.; Mioskowski, C.; Auwerx, J.; Saladin, R. Anti-hyperglycemic activity of a TGR5 agonist isolated from Olea europaea. Biochem. Biophys. Res. Commun. 2007, 362, 793–798.
Huang, X.; Liu, G.; Guo, J.; Su, Z. The PI3K/AKT pathway in obesity and type 2 diabetes. Int. J. Biol. Sci. 2018, 14, 1483–1496.
Zeng, X.Y.; Wang, Y.P.; Cantley, J.; Iseli, T.J.; Molero, J.C.; Hegarty, B.D.; Kraegen, E.W.; Ye, Y.; Ye, J.M. Oleanolic acid reduces hyperglycemia beyond treatment period with Akt/FoxO1-induced suppression of hepatic gluconeogenesis in type-2 diabetic mice. PLoS ONE 2012, 7, e42115.
Mukundwa, A.; Mukaratirwa, S.; Masola, B. Effects of oleanolic acid on the insulin signaling pathway in skeletal muscle of streptozotocin-induced diabetic male Sprague-Dawley rats. J. Diabetes 2016, 8, 98–108.
Ngubane, P.S.; Masola, B.; Musabayane, C.T. The effects of Syzygium aromaticum-derived oleanolic acid on glycogenic enzymes in streptozotocin-induced diabetic rats. Ren. Fail. 2011, 33, 434–439.
Wang, X.; Chen, Y.; Abdelkader, D.; Hassan, W.; Sun, H.; Liu, J. Combination therapy with oleanolic acid and metformin as a synergistic treatment for diabetes. J. Diabetes Res. 2015, 2015, 973287.
Li, Y.; Wang, J.; Gu, T.; Yamahara, J.; Li, Y. Oleanolic acid supplement attenuates liquid fructose-induced adipose tissue insulin resistance through the insulin receptor substrate-1/phosphatidylinositol 3-kinase/Akt signaling pathway in rats. Toxicol. Appl. Pharmacol. 2014, 277, 155–163.
Saravanakumar, K.; Park, S.; Mariadoss, A.V.A.; Sathiyaseelan, A.; Veeraraghavan, V.P.; Kim, S.; Wang, M.H. Chemical composition, antioxidant, and anti-diabetic activities of ethyl acetate fraction of Stachys riederi var. japonica (Miq.) in streptozotocin-induced type 2 diabetic mice. Food Chem. Toxicol. 2021, 155, 112374.
Nyakudya, T.T.; Mukwevho, E.; Erlwanger, K.H. The protective effect of neonatal oral administration of oleanolic acid against the subsequent development of fructose-induced metabolic dysfunction in male and female rats. Nutr. Metab. 2018, 15, 82.
Mohandes, S.; Doke, T.; Hu, H.; Mukhi, D.; Dhillon, P.; Susztak, K. Molecular pathways that drive diabetic kidney disease. J. Clin. Investig. 2023, 133, jci165654.
Zhang, Z.; Jiang, M.; Xie, X.; Yang, H.; Wang, X.; Xiao, L.; Wang, N. Oleanolic acid ameliorates high glucose-induced endothelial dysfunction via PPARdelta activation. Sci. Rep. 2017, 7, 40237.
Vilahur, G. Red Blood Cells Deserve Attention in Patients with Type 2 Diabetes. J. Am. Coll. Cardiol. 2018, 72, 781–783.
Bashiru Shola, O.; Olatunde Olugbenga, F. Hyperglycaemic Environment: Contribution to the Anaemia Associated with Diabetes Mellitus in Rats Experimentally Induced with Alloxan. Anemia 2015, 2015, 848921.
Baloyi, C.M.; Khathi, A.; Sibiya, N.H.; Ngubane, P.S. The Haematological Effects of Oleanolic Acid in Streptozotocin-Induced Diabetic Rats: Effects on Selected Markers. J. Diabetes Res. 2019, 2019, 6753541.
Qi, C.; Mao, X.; Zhang, Z.; Wu, H. Classification and Differential Diagnosis of Diabetic Nephropathy. J. Diabetes Res. 2017, 2017, 8637138.
Gamede, M.; Mabuza, L.; Ngubane, P.; Khathi, A. Preventing the onset of diabetes-induced chronic kidney disease during prediabetes: The effects of oleanolic acid on selected markers of chronic kidney disease in a diet-induced prediabetic rat model. Biomed. Pharmacother. 2021, 139, 111570.
Gugliucci, A.; Bendayan, M. Renal fate of circulating advanced glycated end products (AGE): Evidence for reabsorption and catabolism of AGE-peptides by renal proximal tubular cells. Diabetologia 1996, 39, 149–160.
Wang, Z.H.; Hsu, C.C.; Huang, C.N.; Yin, M.C. Anti-glycative effects of oleanolic acid and ursolic acid in kidney of diabetic mice. Eur. J. Pharmacol. 2010, 628, 255–260.
Lee, E.S.; Kim, H.M.; Kang, J.S.; Lee, E.Y.; Yadav, D.; Kwon, M.H.; Kim, Y.M.; Kim, H.S.; Chung, C.H. Oleanolic acid and N-acetylcysteine ameliorate diabetic nephropathy through reduction of oxidative stress and endoplasmic reticulum stress in a type 2 diabetic rat model. Nephrol. Dial. Transplant. 2016, 31, 391–400.
Hankey, G.J. Stroke. Lancet 2017, 389, 641–654.
Wu, L.; Xiong, X.; Wu, X.; Ye, Y.; Jian, Z.; Zhi, Z.; Gu, L. Targeting Oxidative Stress and Inflammation to Prevent Ischemia-Reperfusion Injury. Front. Mol. Neurosci. 2020, 13, 28.
Orellana-Urzúa, S.; Rojas, I.; Líbano, L.; Rodrigo, R. Pathophysiology of Ischemic Stroke: Role of Oxidative Stress. Curr. Pharm. Des. 2020, 26, 4246–4260.
Escobar-Peso, A.; Martínez-Alonso, E.; Masjuan, J.; Alcázar, A. Development of Pharmacological Strategies with Therapeutic Potential in Ischemic Stroke. Antioxidants 2023, 12, 2102.
Du, Y.; Ko, K.M. Oleanolic acid protects against myocardial ischemia-reperfusion injury by enhancing mitochondrial antioxidant mechanism mediated by glutathione and alpha-tocopherol in rats. Planta Med. 2006, 72, 222–227.
Rong, Z.T.; Gong, X.J.; Sun, H.B.; Li, Y.M.; Ji, H. Protective effects of oleanolic acid on cerebral ischemic damage in vivo and H2O2-induced injury in vitro. Pharm. Biol. 2011, 49, 78–85.
Shi, Y.J.; Sun, L.L.; Ji, X.; Shi, R.; Xu, F.; Gu, J.H. Neuroprotective effects of oleanolic acid against cerebral ischemia-reperfusion injury in mice. Exp. Neurol. 2021, 343, 113785.
Qin, Z.; Kong, B.; Zheng, J.; Wang, X.; Li, L. Alprostadil Injection Attenuates Coronary Microembolization-Induced Myocardial Injury Through GSK-3β/Nrf2/HO-1 Signaling-Mediated Apoptosis Inhibition. Drug Des. Dev. Ther. 2020, 14, 4407–4422.
Lin, K.; Zhang, Z.; Zhang, Z.; Zhu, P.; Jiang, X.; Wang, Y.; Deng, Q.; Lam Yung, K.K.; Zhang, S. Oleanolic Acid Alleviates Cerebral Ischemia/Reperfusion Injury via Regulation of the GSK-3beta/HO-1 Signaling Pathway. Pharmaceuticals 2021, 15, 1.
Kwan, T.W.; Wong, S.S.; Hong, Y.; Kanaya, A.M.; Khan, S.S.; Hayman, L.L.; Shah, S.H.; Welty, F.K.; Deedwania, P.C.; Khaliq, A.; et al. Epidemiology of Diabetes and Atherosclerotic Cardiovascular Disease Among Asian American Adults: Implications, Management, and Future Directions: A Scientific Statement From the American Heart Association. Circulation 2023, 148, 74–94.
Siti, H.N.; Kamisah, Y.; Kamsiah, J. The role of oxidative stress, antioxidants and vascular inflammation in cardiovascular disease (a review). Vasc. Pharmacol. 2015, 71, 40–56.
Senthil, S.; Sridevi, M.; Pugalendi, K.V. Cardioprotective effect of oleanolic acid on isoproterenol-induced myocardial ischemia in rats. Toxicol. Pathol. 2007, 35, 418–423.
Li, W.F.; Wang, P.; Li, H.; Li, T.Y.; Feng, M.; Chen, S.F. Oleanolic acid protects against diabetic cardiomyopathy via modulation of the nuclear factor erythroid 2 and insulin signaling pathways. Exp. Ther. Med. 2017, 14, 848–854.
Gamede, M.; Mabuza, L.; Ngubane, P.; Khathi, A. Plant-Derived Oleanolic Acid (OA) Ameliorates Risk Factors of Cardiovascular Diseases in a Diet-Induced Pre-Diabetic Rat Model: Effects on Selected Cardiovascular Risk Factors. Molecules 2019, 24, 340.
Chan, C.Y.; Mong, M.C.; Liu, W.H.; Huang, C.Y.; Yin, M.C. Three pentacyclic triterpenes protect H9c2 cardiomyoblast cells against high-glucose-induced injury. Free Radic. Res. 2014, 48, 402–411.
Mapanga, R.F.; Rajamani, U.; Dlamini, N.; Zungu-Edmondson, M.; Kelly-Laubscher, R.; Shafiullah, M.; Wahab, A.; Hasan, M.Y.; Fahim, M.A.; Rondeau, P.; et al. Oleanolic acid: A novel cardioprotective agent that blunts hyperglycemia-induced contractile dysfunction. PLoS ONE 2012, 7, e47322.
Barton, M.; Yanagisawa, M. Endothelin: 30 Years From Discovery to Therapy. Hypertension 2019, 74, 1232–1265.
Wu, D.; Zhang, Q.; Yu, Y.; Zhang, Y.; Zhang, M.; Liu, Q.; Zhang, E.; Li, S.; Song, G. Oleanolic Acid, a Novel Endothelin A Receptor Antagonist, Alleviated High Glucose-Induced Cardiomyocytes Injury. Am. J. Chin. Med. 2018, 46, 1187–1201.
Swynghedauw, B. Molecular mechanisms of myocardial remodeling. Physiol. Rev. 1999, 79, 215–262.
Huang, T.H.; Yang, Q.; Harada, M.; Li, G.Q.; Yamahara, J.; Roufogalis, B.D.; Li, Y. Pomegranate flower extract diminishes cardiac fibrosis in Zucker diabetic fatty rats: Modulation of cardiac endothelin-1 and nuclear factor-kappaB pathways. J. Cardiovasc. Pharmacol. 2005, 46, 856–862.
Sciarretta, S.; Volpe, M.; Sadoshima, J. Mammalian target of rapamycin signaling in cardiac physiology and disease. Circ. Res. 2014, 114, 549–564.
Liao, H.H.; Zhang, N.; Feng, H.; Zhang, N.; Ma, Z.G.; Yang, Z.; Yuan, Y.; Bian, Z.Y.; Tang, Q.Z. Oleanolic acid alleviated pressure overload-induced cardiac remodeling. Mol. Cell. Biochem. 2015, 409, 145–154.
Lee, J.J.; Jin, Y.R.; Lim, Y.; Yu, J.Y.; Kim, T.J.; Yoo, H.S.; Shin, H.S.; Yun, Y.P. Oleanolic acid, a pentacyclic triterpenoid, induces rabbit platelet aggregation through a phospholipase C-calcium dependent signaling pathway. Arch. Pharmacal Res. 2007, 30, 210–214.
Libby, P. The changing landscape of atherosclerosis. Nature 2021, 592, 524–533.
Batty, M.; Bennett, M.R.; Yu, E. The Role of Oxidative Stress in Atherosclerosis. Cells 2022, 11, 3843.
Cao, J.; Li, G.; Wang, M.; Li, H.; Han, Z. Protective effect of oleanolic acid on oxidized-low density lipoprotein induced endothelial cell apoptosis. Biosci. Trends 2015, 9, 315–324.
Jiang, Q.; Wang, D.; Han, Y.; Han, Z.; Zhong, W.; Wang, C. Modulation of oxidized-LDL receptor-1 (LOX1) contributes to the antiatherosclerosis effect of oleanolic acid. Int. J. Biochem. Cell Biol. 2015, 69, 142–152.
Luan, J.; Ji, X.; Liu, L. PPARγ in Atherosclerotic Endothelial Dysfunction: Regulatory Compounds and PTMs. Int. J. Mol. Sci. 2023, 24, 4494.
Luo, H.; Liu, J.; Ouyang, Q.; Xuan, C.; Wang, L.; Li, T.; Liu, J. The effects of oleanolic acid on atherosclerosis in different animal models. Acta Biochim. Biophys. Sin. 2017, 49, 349–354.
Wu, Q.; Sun, L.; Hu, X.; Wang, X.; Xu, F.; Chen, B.; Liang, X.; Xia, J.; Wang, P.; Aibara, D.; et al. Suppressing the intestinal farnesoid X receptor/sphingomyelin phosphodiesterase 3 axis decreases atherosclerosis. J. Clin. Investig. 2021, 131, 2865.
Zhang, Y.H.; Zhang, Y.H.; Dong, X.F.; Hao, Q.Q.; Zhou, X.M.; Yu, Q.T.; Li, S.Y.; Chen, X.; Tengbeh, A.F.; Dong, B.; et al. ACE2 and Ang-(1-7) protect endothelial cell function and prevent early atherosclerosis by inhibiting inflammatory response. Inflamm. Res. 2015, 64, 253–260.
Pan, Y.; Zhou, F.; Song, Z.; Huang, H.; Chen, Y.; Shen, Y.; Jia, Y.; Chen, J. Oleanolic acid protects against pathogenesis of atherosclerosis, possibly via FXR-mediated angiotensin (Ang)-(1-7) upregulation. Biomed. Pharmacother. Biomed. Pharmacother. 2018, 97, 1694–1700.
Buus, N.H.; Hansson, N.C.; Rodriguez-Rodriguez, R.; Stankevicius, E.; Andersen, M.R.; Simonsen, U. Antiatherogenic effects of oleanolic acid in apolipoprotein E knockout mice. Eur. J. Pharmacol. 2011, 670, 519–526.

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