Dae Yun Seo1, Sung Ryul Lee1,2, Jun-Won Heo3, Mi-Hyun No3, Byoung Doo Rhee1, Kyung Soo Ko1, Hyo-Bum Kwak3,*, and Jin Han1,4,*
1National Research Laboratory for Mitochondrial Signaling, Department of Physiology, BK21 Plus Team, College of Medicine, Cardiovascular and Metabolic Disease Center, Inje University, Busan 47392, 2Department of Convergence Biomedical Science, Inje University, Busan 47392, 3Department of Kinesiology, Inha University, Incheon 22212, 4Department of Health Science and Technology, Graduate School, Inje University, Busan 47392, Korea
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Ursolic acid (UA) is a natural triterpene compound found in various fruits and vegetables. There is a growing interest in UA because of its beneficial effects, which include anti-inflammatory, anti-oxidant, anti-apoptotic, and anti-carcinogenic effects. It exerts these effects in various tissues and organs: by suppressing nuclear factor-kappa B signaling in cancer cells, improving insulin signaling in adipose tissues, reducing the expression of markers of cardiac damage in the heart, decreasing inflammation and increasing the level of anti-oxidants in the brain, reducing apoptotic signaling and the level of oxidants in the liver, and reducing atrophy and increasing the expression levels of adenosine monophosphate-activated protein kinase and irisin in skeletal muscles. Moreover, UA can be used as an alternative medicine for the treatment and prevention of cancer, obesity/diabetes, cardiovascular disease, brain disease, liver disease, and muscle wasting (sarcopenia). In this review, we have summarized recent data on the beneficial effects and possible uses of UA in health and disease managements.
Plants are important regulators of ecosystems and can affect various biological functions . Various plant-derived biologically active products are effective for the treatment of a wide spectrum of diseases, including cancer , diabetes , obesity , cardiovascular diseases (CVDs) , brain disease , liver disease , and sarcopenia . Ursolic acid (UA) is a compound that has such therapeutic effects . However, the precise mechanisms of its beneficial effects are not completely known.
UA is isolated from the leaves of various plants (rosemary, marjoram, lavender, thyme, and organum), fruits (apple fruit peel), flowers, and berries . UA mediates some pharmacological processes and modulates several signaling pathways to prevent the development of chronic diseases ; it exhibits antiinflammatory , anti-oxidant , anti-carcinogenic , antiobesity , anti-diabetic , cardioprotective , neuroprotective , hepatoprotective , anti-skeletal muscle atrophy , and thermogenic effects . The mechanisms by which UA exerts these beneficial effects may involve regulation of the following: nuclear factor-kappa B (NF-kB) and apoptotic signaling in cancer cells, insulin signaling in adipose tissue, the expression of markers of cardiac damage in the heart, inflammation and the level of anti-oxidants in the brain, metabolic signaling and the level of oxidants in the liver, and atrophy signaling and metabolic signaling in skeletal muscles.
With this review, we attempt to outline the effect of therapeutic potential of UA, which includes its effects on cancer, obesity/diabetes, CVDs, brain diseases, and liver diseases. In addition, its beneficial effects in the prevention of sarcopenia and the improvement of exercise capacity are described to elaborate its possible role as an exercise mimetic.
UA (3β-3-hydroxy-urs-12-ene-28-oic-acid) is a pentacyclic triterpenoid (Fig. 1), which has the chemical formula of C30H48O3 and a molecular mass of 456.71 g/mol . UA is soluble in hot glacial acetic acid and alcoholic sodium hydroxide . It is biosynthesized mainly from the dammarenyl cation through the folding and cyclization of squalene, which forms the fifth ring of UA through ring extension and the formation of an extra ring. There are three oxygen atoms in the compound, which activate double or triple neutral ligands and the donation of electron pairs to the transition metal atom .
UA exerts a potent substance with in vitro and in vivo anticancer effects (Table 1). Numerous studies have investigated the beneficial effects of UA on cancer cell metabolism in both rodents and humans. The mechanisms underlying the anti-cancer effect of UA are reported to be inhibition of tumorigenesis  and cancer cell proliferation , modulation of apoptosis , prevention of cell cycle arrest , and promotion of autophagy .
Recent trends in studies on UA have indicated the beneficial effects of the compound on autophagy and apoptosis in human breast cancer cell lines. Lewinska et al.  report that 20 µM UA inhibits Akt activation and promotes autophagy and apoptosis in breast cancer cells. It also decreases phospho-extracellular signal-regulated kinase 1/2 level and mitochondrial membrane depolarization potential. Interestingly, it is reported that UA induces activation of Akt, increases oxidative system, and decreases the levels of adenosine triphosphate (ATP), lactate, and glycolytic enzymes, such as hexokinase 2 and pyruvate kinase in breast cancer cells . In addition, it decreases ATP production and activates adenosine monophosphate-activated protein kinase (AMPK), which results in inhibition of proliferation in T24 bladder cancer cells  and induces autophagy in U87MG glioma cells . UA may be a potent regulator of AMPK, which inhibits of glycolysis and tumor growth in vivo . Xavier et al.  demonstrated that UA promotes autophagy in HCT15 colorectal and TC-1 cervical cancer cells . In addition, it inhibits apoptosis and cell proliferation in human pancreatic cancer cells  and ovarian cancer cells . Yan et al.  reported that UA induces pro-apoptotic signaling in human liver cancer cell lines such as HepG2, Hep3B, Huh7, and HA22T cell lines, which are widely used to assess apoptotic mechanism of action in cancer research . They demonstrated that UA exerts significantly improved pro-apoptotic effects by increasing the levels of caspase-3 and caspase-8, and DNA fragmentation in human liver cancer cells. Additionally, UA decreases Na+−K+-ATPase activity and mitochondrial membrane potential, indicating mitochondrial dysfunction in these cancer cells.
An increase in the incidence of obesity and diabetes has heightened the need for a treatment against these conditions; the effects of UA are summarized in Table 2. Key effects of UA are inhibition of pancreatic α-amylase activity and reduction of blood glucose level in vivo and vitro . Early work by Ramirez et al.  have evaluated the effects of UA on body weight and glucose tolerance in metabolic syndrome patients who received 150 mg of UA per day before breakfast for 12 weeks. Reductions in body weight, body mass index, waist circumference, and fasting blood glucose level were observed in the patients, which suggests that it significantly improves insulin sensitivity. Chu et al.  have also demonstrated that 0.5% UA-supplemented diet caused an decreases body weight, free fatty acids, and β-oxidation via uncoupling protein 3/AMPK-dependent pathways in high fat diet (HFD)-induced obese rats after six weeks of treatment. Similarly, mice treated with 0.14% UA-supplemented diet for six weeks exhibited a decrease in body weight gain and glucose intolerance . Furthermore, Li et al.  demonstrated that UA (0.125, 0.25, and 0.5%) decreased body weight gain and insulin resistance in HFD-induced obese mice by improving hepatic lipid accumulation and antioxidant enzyme levels. It is also reported that 80 µM UA reduces triglyceride (TG) and cholesterol levels by increasing fatty acid oxidation and decreasing fatty acid synthesis in hepatocytes, suggesting that the upregulation of peroxisome proliferator-activated receptor alpha (PPAR-α) expression is possibly critical for the beneficial effect of UA . Accordingly, UA treatment (50 and 200 mg/kg) decreases body weight, fat mass, TG level, plasma leptin concentration, and lipid accumulation and increases in high-density lipoprotein (HDL)-cholesterol, brown adipose tissue, insulin sensitivity, fatty acid uptake, and β-oxidation in HFD-induced obese rats, indicating that it increases energy expenditure . Similar result was obtained by Jang et al. , who showed that UA (0.05%) inhibits glucose intolerance and insulin resistance by preserving pancreatic β-cells in diabetic mice.
The mechanisms underlying these effects of UA were investigated by Kunkel et al. , who studied that the beneficial effects of 0.14% UA supplementation in HFD-induced obese rats are due to an increase in Akt phosphorylation and an improvement in glucose uptake by skeletal muscles. In a similar, diabetic models treated with UA (1 µg/ml) did not develop insulin resistance and exhibited normal glucose transporter type 4 translocation and insulin receptors via Akt activation, suggesting that UA is a key regulator of glucose levels in diabetes . Additionally, it was confirmed that 2.5-10 µM UA increases the levels of adipocyte transcription factors such as PPARγ, sterol regulatory factor-binding protein 1c transcription (SREBP-1c), fatty acid-synthase and fatty acid binding protein 4 (FABP4) in 3T3-L1 cells. These results suggest that the regulation of AMPK levels by inhibiting liver enzyme B1 is crucial for the treatment of obesity. Therefore, these findings highlight the importance of UA in the treatment of obesity and diabetes.
CVDs are the major contributors to mortality and morbidity in the worldwide . It includes coronary artery disease, myocardial infraction, stroke, heart failure, atherosclerosis, hypertensive heart disease, peripheral artery disease, and cardiomyopathy . CVDs decrease quality of life and increases social and economic costs . The effects of UA in CVDs are summarized in Table 3. In the first study, Somava et al.  have demonstrated that treatment with UA (40 mg/kg) is associated with a lower the heart rate, which indicates an alleviation of CVD risk both in vitro and in vivo. In addition, Pozo et al.  reported that the intraperitoneal administration of UA (2 and 6 mg/kg) for 10 days neointimal hyperplasia (80%) by inhibiting luminal stenosis in a rat model of vascular injury. UA also potently inhibits proliferating cell nuclear antigen expression in injured artery cells. Furthermore, Senthil et al.  have reported that UA (60 mg/kg) reduces lipid peroxide level by scavenging free radicals, improves lipid profiles, and decreases the serum levels of membrane-bound proteins after 7 days of treatment. UA contributes to the restoration of cardioprotective enzyme activity to its normal level in rats, which suggests that it protects against myocardial ischemia. Similarly, previous findings have shown that UA is able to restore cardiac enzymes and blood constituents to their normal levels. It has an anti-apoptotic effects in cardiac muscle cells . The effects of UA on lipid peroxidation and antioxidant capacity in alcoholic cardiomyopathy are also reported . Saravanan and Pugalendi  have suggested that treatment with UA (20 mg/kg/day) for 30 days promotes the activities of free radical-scavenging antioxidant enzymes. It improves the activities of glutathione, ascorbic acid, and α-tocopherol levels . Furthermore, Lv et al.  demonstrated that UA administration markedly inhibits the proliferation of human umbilical vein endothelial cells induced by interleukin 6 (IL-6) and C-reactive protein (CRP), suggesting that it inhibits atherosclerosis related parameters in a dose-dependent manner.
Mild to severe defects in the nervous system typically result due to oxidative stress and excitotoxicity . An imbalance in cellular homeostasis may permanently reduce cognitive function and cause brain damage , resulting in various brain diseases . The effects of UA on brain diseases are summarized in Table 4. UA inhibits oxidative stress  and excitotoxicity , suggesting that it may play a protective role in various brain diseases induced by oxidative stress and excitotoxicity. In addition, UA suppresses apoptotic signaling  and exerts anti-inflammatory effects in the brain .
Shih et al.  reported that UA significantly reduces free radical levels in rat neuronal cultures. In addition, it attenuates reactive oxygen species (ROS) levels in the brain . For example, Zhang et al.  found that UA increases the levels of antioxidant components, such as glutathione (GSH)/oxidized glutathione (GSSH) ratio, catalase (CAT) activity, and superoxide dismutase (SOD) activity in a rat model of subarachnoid hemorrhage. Lu et al.  showed that UA increases the levels of antioxidant enzymes, such as SOD, CAT, glutathione reductase (GR), and glutathione peroxidase (GPx). A similar work by Lu et al.  revealed that UA reduces ROS levels in D-galactose-treated mice. Moreover, it reduces the neuronal expression of pro-apoptotic factors, such as caspase-3 mRNA, caspase-9 mRNA, and reduces DNA fragmentation in a rat model of subarachnoid hemorrhage . Specifically, Huang et al.  have reported that UA inhibits the activity of matrix metalloproteinase-9 (MMP-9), which is a potential cause of various cancers, in C6 glioma cells . This occurs because UA could suppress the NF-kB-dependent pathways that are activated by tumor necrosis factor-alpha (TNF-α) or interleukin 1 beta (IL-1β). Similar results were obtained by Wang et al. , who revealed the association between UA and MMP-2/-9 expression in a rat model of cerebral ischemia and reperfusion injury. In this study, the activities of MMP-2 and MMP-9 were suppressed by UA administration. In addition, the protein levels of peroxisome proliferator-activated receptors (PPARs), particularly PPARγ, which is an effective neuroprotective agents, were elevated following UA administration to rats with cerebral ischemia and reperfusion injury. This demonstrates that UA has a protective effect against various inflammatory conditions of the brain.
The liver is an important organ in the body, responsible for hormone production, xenobiotics detoxification, enzymatic digestion, and the decomposition of red blood cells . It has a unique regeneration system, which can regenerate it up to 25% of its original mass; however, the liver is vulnerable to various diseases because of its various functions and strategic location . As summarized in Table 5. Many studies have demonstrated that UA protects against several liver diseases, such as fatty liver disease , liver fibrosis , carcinoma , and liver cancer .
It is well known that the liver plays a pivotal role in the regulation of systemic lipid homeostasis . HFD-induced obese models and non-alcoholic fatty liver disease cause abnormal lipid homeostasis, which can result in various complications. However, UA can attenuate HFD-induced fatty liver diseases, hepatocellular steatosis, and hepatic TG content . In this study, plasma aspartate transaminase (AST) and alanine transaminase (ALT) levels, which are biomarkers of liver diseases, were also decreased by UA treatment, indicating that UA attenuates hepatocyte injury. Sundaresan et al.  found that UA down-regulated the mRNA expression of lipogenesis-related factors, such as acetyl-CoA carboxylase, and fatty acid synthase, but up-regulated the mRNA expression of fatty acid oxidation-related factors, such as carnitine palmitoyltransferase-1 and acyl-CoA oxidase, in a mouse model of hepatic lipid metabolism. Furthermore, UA markedly attenuated hepatic steatosis in a rat model of non-alcoholic fatty liver disease by activating PPAR-α, which is a key regulator of hepatic lipid metabolism. It also activated the PPAR-α regulated signaling pathway at both protein and mRNA levels . In addition, it reduced the serum levels of inflammatory markers, such as TNF-α, chemokine ligand 2/monocyte chemotactic protein-1, IL-6, and oxidative stress markers, such as SOD, malondialdehyde, CAT, and GPx .
Excessive deposition of extracellular matrix components in the liver can cause liver fibrosis, which could be ultimately induces liver cirrhosis . Ma et al.  demonstrated that carbon-tetrachloride-induced liver fibrosis is attenuated by UA via a nuclear factor E2-related factor 2/antioxidant responsive element pathway in the rodents liver. This finding suggest that UA can be a potent protective agent against liver fibrosis. Son et al.  reported that UA may induce apoptosis of HepG2 hepatocellular carcinoma cells through AMPK and glycogen synthase kinase-3 beta (GSK-3β) pathway. The authors also indicated that UA increase apoptotic portion and the level of cleaved caspase-3 protein, p-AMPKα (Thr 172), and GSK-3β (Ser9) in HepG2 cells. Moreover, Yang et al.  reported that UA suppresses the proliferation of hepatocellular carcinoma cells via p38 the mitogen-activated protein kinases (p38-MAPK)-mediated activation of the gene expression of insulin-like growth factor (IGF) binding protein 1 (IGFBP1). In addition, it increased the expression of forkhead box O3 (FOXO3a). These suggest that IGFBP1 and FOXO3a can potentially be therapeutic interventions in the management of hepatocellular carcinoma.
The skeletal muscles accounts for approximately 40-50% of the total body mass. They are major regulator energy catabolism and postprandial glucose disposal , and are essential for whole body metabolism and locomotion . Sarcopenia, which is defined as the loss of skeletal muscle mass and skeletal muscle function, can be induced by various conditions, especially aging . Aging-induced sarcopenia hinders locomotion, which causes immobility and falls , resulting a behavior disabilities in the elderly . Effects of UA on sarcopenia and exercise capacity were outlined in Table 6. UA stimulates skeletal muscle synthesis  and increases the strength of the skeletal muscle  via various signaling pathways, which suggest that it may be useful in the prevention of sarcopenia. The direct effects of UA on sarcopenia have not been exclusively studied; however, several similar studies on the effects of UA on age-related skeletal muscle dysfunction have been carried out .
Ebert et al.  reported that UA may be a therapeutic intervention against aging-induced muscle atrophy and dysfunction, and demonstrated that UA significantly improves skeletal muscle mass and grip strength in a rodents. A similar study conducted by Bakhtiari et al.  revealed that UA increases the number of satellite cells and activates myoglobin expression in aged mice, suggesting that it positively modulates skeletal muscle turnover by stimulating protein synthesis and suppressing atrophy factors. Kunkel et al.  have reported that UA ameliorates skeletal muscle atrophy by inhibiting of muscle-atrophy-related pathways. These include the muscle ring-finger protein-1 (MuRF-1) and atrogin-1 pathways, which are pivotal mediators of protein degradation in skeletal muscles. It was also demonstrated that UA increases skeletal muscle hypertrophy by increasing of insulin-like growth factor-1 (IGF-1) secretion. A similar investigations showed that UA increases skeletal muscle mass and strength . Jeong et al.  also demonstrated that treatment with UA for 12 weeks improves skeletal muscle strength and skeletal muscle mass in a dose-dependent manner through the upregulation of Akt/mammalian target of rapamycin (mTOR) signaling and the downregulation of skeletal muscle atrophy parameters such as atrogin-1 and MuRF-1.
Recently, it has been reported that UA improves exercise capacity via various molecular pathways in vitro and in vivo (Table 6). UA supplementation improves exercise capacity and decreases resting heart rate . It has been found that intraperitoneal treatment with UA for seven days increases expression of sirtuin-1 and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) in the skeletal muscles of aged rodents , revealing that UA may enhance physical performance.
In the above mentioned reports, UA treatment improves exercise capacity under various disease and non-disease conditions in rodents and humans . Ogasawara et al.  found that UA supplementation stimulates the expression of ribosomal protein S6 kinase beta-1, and mammalian target of rapamycin complex 1 in rats after treatment with UA, which led to skeletal muscle synthesis and hypertrophy. Moreover, Jeong et al.  showed that UA treatment for 12 weeks improves physical performance in a dose-dependent manner (75, 150, and 300 mg/kg), as indicated by an enhancement in exercise time and distance in mice. In this study, increased skeletal muscle strength and decreased fatigue-related parameters, such as lactate, lactate dehydrogenase (LDH), aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), and creatinine. Recently, Chen et al.  also revealed that UA stimulates mitochondrial biogenesis by activating of AMPK and PGC-1α signaling in C2C12 myotubes, leading to improved exercise endurance. Bang et al.  reported that UA supplementation increases resistance exercise capacity in men by significantly increasing the levels of IGF-1, irisin, and maximal muscle strength (peak torque) measured by a dynamometer, suggesting that UA mediated increase in irisin level may be useful to enhance the maximal skeletal muscle strength during resistance exercise . They also reported that UA inhibits skeletal muscle damage markers, such as B-type natriuretic peptide (BNP), creatine kinase (CK), CK−myocardial band (CK-MB), LDH, cortisol, and myoglobin levels .
However, two recent studies  have been argued indicated that UA has no effect on exercise capacity. Cho et al.  showed that the supplementation with loquat leaf extract containing UA for 12 weeks does not enhance skeletal muscle strength, mass, and function in healthy subjects; only right-handgrip strength in female subjects treated with loquat leaf extract was significantly increased compared with that in placebo-treated female subjects. In addition, Church et al.  demonstrated that UA supplementation does not affect Akt/mTOR1 signaling and IGF-1 level following resistance exercise in resistance-trained men.
Taken together, there are several reports on dealing with the positive effects of UA in rodents and humans, which suggest that UA may be an important therapeutic agent for improving exercise capacity. However, more studies should be conducted to verify the effects of UA on exercise capacity.
UA is a preventive and therapeutic intervention against various chronic diseases including cancer, metabolic syndrome, CVDs, brain disease, liver disease, and sarcopenia (Fig. 2). Although numerous findings suggest that UA improves exercise capacity and has beneficial effects on cardiopulmonary endurance and muscle strength, which indicates that it might be useful as an exercise mimetic, more investigations are needed to further elucidate how UA improves exercise capacity. Additionally, the cellular and molecular mechanisms underlying the effects of UA in various diseases must be further studied to implement UA as an exercise mimetics.
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