Post on 31-Mar-2023
Ursolic acid: potential as anti-obesity treatment? Felizola S.J.A. 2015
doi: 10.13140/RG.2.1.4502.4804 1
Ursolic acid in experimental
models and human subjects:
Potential as an anti-
obesity/overweight treatment?
Saulo J.A. Felizola, MD, PhD
Abbreviated title: Ursolic acid: potential as
anti-obesity treatment?
Key terms: Ursolic acid, obesity, insulin
sensitizer, IGF-I
Abstract
Recently, the world has seen the rise of an
obesity epidemic without historical precedents.
There are several risk factors associated with the
obesity/overweight condition, including insulin
resistance and type II diabetes, cardiovascular
diseases, respiratory and bone-joint
complications, and certain forms of cancer.
Ursolic acid is a pentacyclic triterpenoid
identified in the epicuticular waxes of apples as
early as 1920 and widely found in fruits, herbs
and spices. This substance has been shown to
reduce adipogenesis and body fat percentage
while increasing muscle mass in rodent models
as well as in human volunteers.
A detailed analysis of the current literature
indicates great potential benefits of ursolic acid
as a therapeutic agents in obesity/overweight,
diabetics and metabolic syndrome as a whole.
However, in spite of promising prospects, there
have been no phase-II/III studies about the oral
administration of ursolic acid to human subjects.
Nevertheless, it is hard to ignore that, with
widespread availability of ursolic acid in its
purified and non-purified form, many ursolic
acid consumers have been conducting
experiments among and on themselves. Success
or failure in ursolic acid treatment, however,
certainly depend on several factors that will
remain ignored until wider-ranged scientific
studies and clinical research are actually
conducted.
I. Introduction
In the last few decades, the developed
world has seen the rise of an obesity epidemic
without historical precedents, and this trend is
expected to worsen in the next years (1). There
are several risk factors associated with the
obesity/overweight condition, including
insulin resistance and type II diabetes,
cardiovascular diseases, respiratory and bone-
joint complications, and certain forms of
cancer (1, 2).
For those reasons, in the past years several
research groups have been looking for an
effective and reliable treatment for obesity.
There have been different approaches
proposed, including the blockade of fat
absorption in the gut, or the direct inhibition
of appetite in the central nervous system (3).
The results, however, have been modest at
best while the cost-benefit of undesired effects
is often high.
At the same time, folk medicine and
Ursolic acid: potential as anti-obesity treatment? Felizola S.J.A. 2015
doi: 10.13140/RG.2.1.4502.4804 2
supplement makers continued to offer
alternative options, readily available to the
consumer with the promise to effectively treat
or alleviate obesity or its comorbidities. In this
scenario, the crescent demand for new
pharmacological agents and molecules led to
the scientific study of many known molecules
from a variety of natural sources, yielding
sometimes intriguing results.
Ursolic acid (3β-hydroxi-urs-12-en-28-oic
acid, Figure 1) is a pentacyclic triterpenoid
identified in the epicuticular waxes of apples
as early as 1920 and widely found in the peels
of fruits, as well as in herbs and spices like
rosemary and thyme (4, 5). This substance has
been recently shown to reduce adipogenesis
and body fat percentage while increasing
muscle mass in rodent models as well as in
human volunteers (6-11). However, in
addition to the study limitations encountered
so far, the low oral biovailability of this
triterpenoid remains one major downside in its
therapeutic potential. In this review, we
ponder about the potential benefits of ursolic
acid use for the treatment of obesity and
associated diseases, while considering the
limitations of the current knowledge about the
pharmaceutical properties of this molecule.
II. Ursolic acid in experimental models
The effect of ursolic acid on cells in vitro
and non-human mammal models has been
relatively well studied in the past few years.
Some studies present evidence pointing to
anti-inflammatory, anti-oxidant effects of
ursolic acid on inflammatory cells, kidney,
liver and heart of rodents in experimental
models (5, 12-20). A pro-apoptotic or anti-
tumoral effect of ursolic acid has also been
well documented in several human cancer cell
lines, including breast, prostate, lung, bladder,
liver, colorectal, gastric carcinoma and skin
melanoma cells (21-30). Such studies
highlight the possibilities of therapeutic use of
ursolic acid as an inflammatory process
modulator and anti-cancer agent, at least in
animals and in vitro. Nevertheless, ursolic
acid does produce interesting effects on fat
and glucose metabolism, both at the cellular
and systemic levels in experimental models,
which are discussed below.
Figure 1. Molecular structure of ursolic acid.
A. Effects of ursolic acid on
adipocytes in vitro
The differentiation of preadipocytes into
adipocytes is tightly regulated by a sequential
activation of several transcriptional factors,
including CCAAT element binding protein α
(C/EBPα), C/EBPβ, peroxisome proliferator-
activated receptor γ (PPARγ) and sterol
regulatory element binding protein 1c
(SREBP-1c) (31). The work of He et al shows
Ursolic acid: potential as anti-obesity treatment? Felizola S.J.A. 2015
doi: 10.13140/RG.2.1.4502.4804 3
that, when 3T3-L1 mouse embryo fibroblasts
are differentiated into preadipocytes and then
induced to further differentiation in the
presence of ursolic acid, there is a significant
decrease in the expression of C/EBPβ with
subsequent inhibition of PPARγ and C/EBPα,
with an anti-adipogenic effect (31). While
there is no effect of ursolic acid over the
proliferation of the 3T3-L1 adipocytes, there
is significant decrease in lipid accumulation as
well as a dose-dependent increase in lipolysis
(31). Similar results were obtained by Kim et
al using isolated rat adipocytes, in which
ursolic acid significantly enhanced lipolytic
activity (32). Ursolic acid does also increase
glucose uptake in 3T3-L1 adipocytes by
activating the PI3K pathway and glucose
transporter 4 (GLUT4) translocation in those
cells (33). A previous work by Jung et al
demonstrates ursolic acid to be an effective
insulin-mimetic agent at doses above 50 μg/ml
and as an insulin-sensitizer at doses as low as
1 μg/ml, by increasing the number of insulin
receptors activated by insulin, potentiating the
tyrosine phosphorylation of the insulin-
receptor β-subunit and the phosphorylation of
Akt and glycogen synthase kinase-3β, and
enhancing the effect of insulin on the
translocation of GLUT4 in 3T3-L1 adipocytes
(34).
B. Ursolic acid and amelioration of
diet-induced obesity, glucose intolerance/
diabetes and metabolic syndrome in vivo
In addition to the lipolytic and insulin-
sensitizing/insulin-mimetic actions in
adipocytes, ursolic acid produces consistent
systemic effects that can facilitate the
successful treatment of obesity and its
associated conditions. Rao et al demonstrate
in their work that ursolic acid has roughly the
same effect as sibutramine on mice fed a high
fat diet (HFD) for 15 weeks (7). In that study,
vehicle-treated HFD mice had an average 24%
increase in body weight, while ursolic acid
and sibutramine treated HFD mice
respectively showed 13.3% and 13.1%
increases in body weight compared to normal
diet fed controls (7). According to the results
of independent studies, ursolic acid does
significantly reduce the increase in basal
levels of blood glucose, cell surface area of
adipocytes and weight of visceral fat in mice
after HFD (7, 11). Sundaresan et al
demonstrate that ursolic acid has an effect
superior to rosiglitazone on body weight,
epididymal fat pad weight, and reserves of
liver glycogen after 5 weeks treatment in mice
on a 15 weeks HFD (11). Ursolic acid
treatment also significantly reduces systolic
and diastolic blood pressure levels in mice
(11), exerting a full spectrum effect on the
clinical signs of HFD induced metabolic
syndrome. Similarly, Kunkel et al also show
significant decreases in body weight,
epididymal and retroperitoneal fat weight, as
well as fasting and post-prandial blood
glucose levels in HFD fed mice (6).
Furthermore, these authors demonstrate a
significant increase in skeletal muscle mass,
grip strength, fast and slow skeletal muscle
fiber size, and weight of interscapular brown
Ursolic acid: potential as anti-obesity treatment? Felizola S.J.A. 2015
doi: 10.13140/RG.2.1.4502.4804 4
fat in mice treated with ursolic acid compared
to vehicle-treated controls (6). Skeletal muscle
and brown fat have somewhat high rates of
energy expenditure, and indeed the chronic (6
weeks) treatment with ursolic acid produces
an increase in food intake and energy
expenditure in mice (6, 35).
C. Effects of ursolic acid on skeletal
and cardiac muscle of rodents
Castro et al conducted a study using rats
fed glucose marked with radiocarbon (14C) in
which the amount of glucose uptake was
measured in skeletal muscle fibers (8). These
authors found that doses as low as 0.1mg/kg
of ursolic acid can significantly reduce the
glucose tolerance curve while 1mg/kg ursolic
acid elevates the post-prandial peak of insulin
in glucose fed rats (8). These rats presented
significantly higher muscle glucose uptake 60
min post glucose ingestion, and significantly
higher intramuscular glycogen content 180
min after glucose ingestion (8). The
mechanism by which ursolic acid acts in
skeletal muscle is still unclear, but has been
partially explained by Ogasawara et al, who
demonstrate that ursolic acid can lead to an
extended increase in activation of the
mammalian target of rapamycin complex 1
(mTORC1) after muscular fiber induction by
resistance exercise (36). These authors show
that ursolic acid treated rats maintain elevated
plasma levels of IGF-I as well as higher
intramuscular levels of phosphorylated
PRAS40 and p70S6K compared to vehicle-
treated controls after 6h resistance exercise
(36). In a study evaluating heat-stress
mediated alterations in cardiac myocytes,
Yang et al demonstrate that pre-treatment with
ursolic acid significantly reduces the rate of
apoptosis in heart tissue and subsequently
attenuates the rise in plasma troponin I in mice
subjected to high temperature (41oC) for 2h
(37). These authors postulate that ursolic acid
exerts its protective effect in the heart by
interfering in mitochondrial apoptotic
pathways, as they demonstrate that pre-
treatment with ursolic acid prevents an
elevation in the protein levels of cytochrome
C, cleaved caspase 3, and cleaved caspase 9
evaluated using Western Blot (37).
D. Effects of ursolic acid in the liver
Several studies concur that ursolic acid
suppresses oxidative stress and promotes liver
regeneration, improving hepatic functions in
rodents (6, 13, 38-42). The actions of ursolic
acid in the liver appear to be intrinsically
related to its activitity in other systemic tissues,
while also playing a more direct role in liver
cells. Li et al demonstrate that HFD-induced
obese rats treated with 0.125%, 0.25% and
0.5% ursolic acid in chow for 6 weeks have a
dose-dependent reversal of advanced non-
alcoholic fatty liver disease (NAFLD), with a
return of total liver weight, serum aspartate
aminotransferase (AST) and alanine
aminotransferase (ALT) to near basal levels in
the 0.5% group (39). The histological
assessment of hepatic tissues also show a dose
dependent regeneration of the liver cell
morphology and organization, with near
Ursolic acid: potential as anti-obesity treatment? Felizola S.J.A. 2015
doi: 10.13140/RG.2.1.4502.4804 5
absence of steatosis in the 0.5% ursolic acid-
treated group (39). Kunkel et al found similar
results in HFD-induced obese mice, with
significant reductions in liver weight, hepatic
tryglicerides and plasma levels of AST and
ALT after 6 weeks treatment with 0.14%
ursolic acid in chow versus vehicle-treated
controls (6). Sundaresan et al show in their
work that, when added to chow for 5 weeks,
ursolic acid (5mg/Kg) is superior to
rosiglitazone (4mg/Kg) in reducing the
plasma concentrations of AST and ALT, free
fat acids (FFA), tryglicerides (TG) and total
cholesterol (TC) in HFD-induced obese mice
(41). In a work about carbon tetrachloride
(CCl4) induced hepatic injury, Ma et al
demonstrate that ursolic acid inhibited
oxidative stress, apoptosis and fibrosis caused
by CCl4 in the mouse liver in a dose-
dependent manner (13).
III. Ursolic acid in human subjects
Because it of its ubiquity in nature and
widespread availability, the commercial-
ization and use of ursolic acid has been free of
strict regulation in many if not all countries.
However, to this date there have been few
studies on human subjects, and the data
available have been obtained from healthy,
non-obese, non-diabetic individuals (9, 43).
Nevertheless, despite a lack of solid
scientific validation, ursolic acid has been
known for its recent popularity among sport
practitioners, especially resistance training
athletes. The currently most up-to-date
information on the use of ursolic acid by
human subjects is discussed below.
A. Pharmacokinetics
Using ultra performance liquid
chromatography tandem mass spectrometry,
Xia et al have conducted a pharmacokinetic
Figure 2. Graphic representation of the mean plasma concentrations of ursolic acid adapted from the work of Xia et al
(44): Plasma concentrations of ursolic acid in 8 healthy volunteers treated with intravenous infusion of ursolic acid
nano-lipossomes at a dose of 98mg/m2. Blood samples were collected before dosing (0h) and 0.5, 1, 2, 4h during the
4h-continuous infusion and 0.083, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12h after the end of infusion.
Ursolic acid: potential as anti-obesity treatment? Felizola S.J.A. 2015
doi: 10.13140/RG.2.1.4502.4804 6
study of ursolic acid in the plasma of human
subjects (44). Quantitation was performed in
the plasma of 8 healthy volunteers who were
treated with intravenous infusion of ursolic
acid nano-lipossomes at a dose of 98mg/m2,
with about 4ml blood samples being collected
before dosing (0h) and 0.5, 1, 2, 4h during the
4h-continuous infusion and 0.083, 0.25, 0.5, 1,
2, 3, 4, 6, 8, 12h after the end of infusion (44).
Stability tests conducted by those authors
showed ursolic acid is stable in human plasma
at room temperature for 6h, at 10oC for 24h,
and after storing at -20oC for 90 days and
through freeze-thaw cycles (44). The graphic
representation of the mean plasma
concentrations of ursolic acid from the work
of Xia et al has been adapted in Figure 2. The
main pharmacokinetic parameters of ursolic
acid after intravenous infusion were: Cmax
3404.6±748.8 SD (ng/ml), Tmax 4.0±0.0 SD
(h), AUC0-t 9644.1±1193.2 SD (ng h/ml),
AUC0-∞ 9918.4±1215.2 SD (ng h/ml), t1/2
3.9±2.1 SD (h), CL 10.0±1.2 SD (L/h/m2) (44).
B. Bioavailability
By the time of writing of this review,
there were no accurate or reliable data
available regarding the oral biovailability of
ursolic acid in humans. However, studies in
rodents suggest it to be relatively low. Yin et
al show that mice (n=10) on a diet containing
0.5% ursolic acid in chow for 8 weeks
presented with plasma concentrations of
0.55±0.08 SD (µg/ml) (45). Ursolic acid
concentration in organs was detected as
follows: brain 1.7±0.2 SD (µg/g), heart
4.2±0.8 SD (µg/g), liver 10.3±1.4 SD (µg/g),
kidney 5.5±0.5 SD (µg/g), colon 6.0±1.0 SD
(µg/g), and bladder 3.7±0.4 SD (µg/g) (45).
These data show an accumulation of ursolic
acid in organs and tissues, which can also be
expected in humans.
C. Reduction of body fat percentage
and increase in skeletal muscle strength
and mass
Only two studies addressing the oral use
of ursolic acid by human subjects were
available on worldwide scientific databases, to
the best of our knowledge. One of these
studies, conducted by Bang et al, evaluated the
ursolic acid-induced elevation of serum irisin
and its correlation to muscle strength during
resistance exercise in men (9). In this study, 16
Korean male volunteers with over three years
of resistance training experience performed a
resistance training program for 8 weeks using
free weights and machines under supervision,
while receiving 3 capsules daily containing
450mg of ursolic acid or placebo after meals,
and blood samples were collected before and
after the 8 week intervention (9). These
authors found that, although there were no
significant differences in body weight, after 8
weeks individuals in the ursolic acid treatment
group (n=9) showed significantly lower body
fat percentage than their control group
counterparts (n=7) (8.7%±2.51 SD vs
12.78%±3.36 SD respectively; P<0.001) (9).
There were no significant changes in blood
glucose or insulin levels in those individuals,
but ursolic acid treated subjects had
Ursolic acid: potential as anti-obesity treatment? Felizola S.J.A. 2015
doi: 10.13140/RG.2.1.4502.4804 7
significantly higher plasmatic levels of IGF-I
and irisin compared to placebo treated
volunteers (9). Maximal muscle strength of
participants was significantly higher in the
ursolic acid group when evaluated on a
Human/Norm Testing and Rehabilitation
System (Computer Sports Medicine Inc., MA,
USA) (9). In another study, Church et al
randomized 9 healthy, resistance-trained male
volunteers between 18-30yo, who performed
three separate testing sessions of lower-body
resistance exercise involving 4 sets of 8-10
repetitions angled leg press and knee
extension exercises (43). Immediately after
each resistance exercise session, participants
ingested 3 grams (0.043 g/kg equivalent) of
placebo, L-leucine, or ursolic acid, and a
blood sample was obtained before, and 0.5, 2,
and 6h post-exercise, while a vastus lateralis
muscle biopsy obtained before and 2 and 6h
post-exercise (43). These authors found no
significant differences among the three
treatment modalities in serum IGF-I, nor in
skeletal muscle phosphoproteins IGF-IR, Akt,
and p70S6K (43).
IV. Discussion
When looking at the data from cell lines
and animal models, the potential benefits of
ursolic acid as a therapeutic agents in
obesity/overweight, diabetics and metabolic
syndrome as a whole appear obvious. In spite
of promising prospects, however, it was not
possible to find any phase-II/III studies
involving the oral administration of ursolic
acid in human subjects. As ursolic acid is
expected to yield low oral bioavailability
based on rodent model studies and theoretical
predictions, one might wonder whether low
levels can be enough to shift a few
physiopathological parameters, as the pauper
present literature on human subjects indicates
(9). Apparent contradictions (9, 43) in the
currently available information from human
studies and the low number of
patients/volunteers enlisted are also reason for
skepticism about any possible benefits of the
oral administration of ursolic acid in humans.
Despite the widespread availability of
ursolic acid in its purified and non-purified
form in the market, the lack of information
about its use in humans is blatant in the
scientific literature. It is, however, true and
difficult to ignore that, as easy as it is to
exchange and publish information nowadays,
many ursolic acid consumers have been
conducting experiments among and on
themselves, sometimes confirming the
findings in experimental model studies,
sometimes generating no more than self-
frustration. The reason for success and failure
in ursolic acid treatment does certainly depend
on several currently ignored factors that will
remain unknown until further and wider-
ranged scientific studies and clinical research
are in fact conducted.
Acknowledgements
The present scientific review is an
independent work and the author has no
conflicts of interest to declare.
Ursolic acid: potential as anti-obesity treatment? Felizola S.J.A. 2015
doi: 10.13140/RG.2.1.4502.4804 8
References
1- Kopelman PG. Obesity as a medical problem.
Nature. 2000; 404: 635-643.
2- Despres JP, Lemieux I. Abdominal obesity
and metabolic syndrome. Nature. 2006; 444: 881-887.
3- Halford JCG. Obesity drugs in clinical
development. Current Opinion in Investigational Drugs.
2006; 7: 312-318.
4- Szakiel A, Paczkwski C, Pensec F, Bertsch C.
Fruit cuticular waxes as a source of biologically active
triterpenoids. Phytochem Rev. 2011 ;11: 263-284.
5- Ullevig SL, Zhao Q, Zamora D, Asmis R.
Ursolic acid protects diabetic mice against monocyte
dysfunction and accelerated atherosclerosis.
Atherosclerosis. 2011; 219: 409-416.
6- Kunkel SD, Elmore CJ, Bongers KS et al.
Ursolic acid increases skeletal muscle and brown fat and
decreases diet-induced obesity, glucose intolerance and
fatty liver disease. PLoS ONE. 2012; 7: e39332.
7- Rao VS, de Melo CL, Queiroz MGR et al.
Ursolic acid, a pentacyclic triterpene from Sambucus
australis, prevents abdominal adiposity in mice fed a
high-fat diet. Journal of Medicinal Food. 2011; 14: 1375-
1382.
8- Castro AJG, Frederico MJS, Cazarolli LH et
al. The mechanism of action of ursolic acid as insulin
secretagogue and insulinomimetic is mediated by cross-
talk between calcium and kinases to regulate glucose
balance. Biochimica et Biophysica Acta. 2015 ;1850:
51-61.
9- Bang HS, Seo DY, Chung YM et al. Ursolic
acid-induced elevation of serum irisin augments muscle
strength during resistance training in men. Korean J
Physiol Pharmacol. 2014; 18: 441-446.
10- Jia Y, Kim S, Kim J et al. Ursolic acid
improves lipid and glucose metabolism in high-fat-fed
C57BL/6J mice by activating peroxisome proliferator-
activated receptor alpha and hepatic autophagy. Mol
Nutr Food Res. 2015; 59: 344-54.
11- Sundaresan A, Harini R, Pugalendi KV.
Ursolic acid and rosiglitazone combination alleviates
metabolic syndrome in high fat diet fed C57BL/6J mice.
Gen Physiol Biophys. 2012; 31: 323-33.
12- Liobikas J, Majiene D, Trumbeckaite S et al.
Uncoupling and antioxidant effects of ursolic acid in
isolated rat heart mitochondria. J Nat Prod. 2011; 74:
1640-1644.
13- Ma JQ, Ding J, Zhang L, Liu CM. Ursolic
acid protects mouse liver against CCl4-induced
oxidative stress and inflammation by the MAPK/NF-κB
pathway. Environ Toxicol Pharmacol. 2014; 37: 975-983.
14- Ma JQ, Ding J, Xiao ZH, Liu CM. Ursolic
acid ameliorates carbon tetrachloride-induced oxidative
DNA damage and inflammation in mouse kidney by
inhibiting the STAT3 and NF-κB activities. Int
Immunopharmacol. 2014; 21: 389-395.
15- Baek SY, Lee J, Lee DG et al. Ursolic acid
ameliorates autoimmune arthritis via suppression of
Th17 and B cell differentiation. Acta Pharmacol Sin.
2014; 35: 1177-1187.
16- Chun J, Lee C, Hwang SW, Im JP, Kim JS.
Ursolic acid inhibits nuclear factor-κB signaling in
intestinal epithelial cells and macrophages, and
attenuates experimental colitis in mice. Life Sci. 2014;
110: 23-34.
17- Ullevig SL, Kim HS, Nguyen HN et al.
Ursolic acid protects monocytes against metabolic
stress-induced priming and dysfunction by preventing
the induction of Nox4. Redox Biol. 2014; 2: 259-266.
18- Ling C, Jinping L, Xia L, Renyong Y.
Ursolic Acid provides kidney protection in diabetic rats.
Curr Ther Res Clin Exp. 2013; 75: 59-63.
Ursolic acid: potential as anti-obesity treatment? Felizola S.J.A. 2015
doi: 10.13140/RG.2.1.4502.4804 9
19- Checker R, Sandur SK, Sharma D et al.
Potent anti-inflammatory activity of ursolic acid, a
triterpenoid antioxidant, is mediated through
suppression of NF-κB, AP-1 and NF-AT. PLoS One.
2012; 7: e31318.
20- Ramachandran S, Prasad NR. Effect of
ursolic acid, a triterpenoid antioxidant, on ultraviolet-B
radiation-induced cytotoxicity, lipid peroxidation and
DNA damage in human lymphocytes. Chem Biol
Interact. 2008; 176: 99-107.
21- Kim ES, Moon A. Ursolic acid inhibits the
invasive phenotype of SNU-484 human gastric cancer
cells. Oncol Lett. 2015; 9: 897-902.
22- Mahmoudi M, Rabe SZ, Balali-Mood M,
Karimi G, Tabasi N, Riahi-Zanjani B. Ursolic acid
induced apoptotic cell death following activation of
caspases in isolated human melanoma cells. Cell Biol Int.
2015; 39: 230-236.
23- Gai L, Cai N, Wang L, Xu X, Kong X.
Ursolic acid induces apoptosis via Akt/NF-κB signaling
suppression in T24 human bladder cancer cells. Mol
Med Rep. 2013; 7: 1673-1677.
24- Park JH, Kwon HY, Sohn EJ et al. Inhibition
of Wnt/β-catenin signaling mediates ursolic acid-
induced apoptosis in PC-3 prostate cancer cells.
Pharmacol Rep. 2013; 65: 1366-74.
25- Wang W, Zhao C, Jou D et al. Ursolic acid
inhibits the growth of colon cancer-initiating cells by
targeting STAT3. Anticancer Res. 2013; 33: 4279-4284.
26- Achiwa Y, Hasegawa K, Udagawa Y. Effect
of ursolic acid on MAPK in cyclin D1 signaling and
RING-type E3 ligase (SCF E3s) in two endometrial
cancer cell lines. Nutr Cancer. 2013; 65: 1026-1033.
27- Lin J, Chen Y, Wei L, Hong Z, Sferra TJ,
Peng J. Ursolic acid inhibits colorectal cancer
angiogenesis through suppression of multiple signaling
pathways. Int J Oncol. 2013; 43: 1666-74.
28- Huang CY, Lin CY, Tsai CW, Yin MC.
Inhibition of cell proliferation, invasion and migration
by ursolic acid in human lung cancer cell lines. Toxicol
In Vitro. 2011; 25: 1274-1280.
29- Wang JS, Ren TN, Xi T. Ursolic acid induces
apoptosis by suppressing the expression of FoxM1 in
MCF-7 human breast cancer cells. Med Oncol. 2012; 29:
10-15.
30- Yeh CT, Wu CH, Yen GC. Ursolic acid, a
naturally occurring triterpenoid, suppresses migration
and invasion of human breast cancer cells by modulating
c-Jun N-terminal kinase, Akt and mammalian target of
rapamycin signaling. Mol Nutr Food Res. 2010;
54:1285-1295.
31- He Y, Li Y, Zhao T, Wang Y, Sun C. Ursolic
acid inhibits adipogenesis in 3T3-L1 adipocytes through
LKB1/AMPK pathway. PLoS One. 2013; 8: e70135.
32- Kim J, Jang DS, Kim H, Kim JS. Anti-lipase
and lipolytic activities of ursolic acid isolated from the
roots of Actinidia arguta. Arch Pharm Res. 2009;
32:983-987.
33- He Y, Li W, Li Y, Zhang S, Wang Y, Sun C.
Ursolic acid increases glucose uptake through the PI3K
signaling pathway in adipocytes. PLoS One. 2014; 9:
e110711.
34- Jung SH, Ha YJ, Shim EK et al. Insulin-
mimetic and insulin-sensitizing activities of a
pentacyclic triterpenoid insulin receptor activator.
Biochem J. 2007; 403: 243-250.
35- Tschöp MH, Speakman JR, Arch JR et al. A
guide to analysis of mouse energy metabolism. Nat
Methods. 2011; 9: 57-63.
36- Ogasawara R, Sato K, Higashida K,
Nakazato K, Fujita S. Ursolic acid stimulates mTORC1
signaling after resistance exercise in rat skeletal muscle.
Ursolic acid: potential as anti-obesity treatment? Felizola S.J.A. 2015
doi: 10.13140/RG.2.1.4502.4804 10
Am J Physiol Endocrinol Metab. 2013; 305: E760-5.
37- Yang Y, Li C, Xiang X et al. Ursolic acid
prevents endoplasmic reticulum stress-mediated
apoptosis induced by heat stress in mouse cardiac
myocytes. J Mol Cell Cardiol. 2014; 67: 103-111.
38- Yang Y, Zhao Z, Liu Y, Kang X, Zhang H,
Meng M. Ursolic acid via LKB1-AMPK signaling
suppresses oxidative stress and improves liver functions
in mice. J Gastroenterol Hepatol. 2014; doi:
10.1111/jgh.12723. [Epub ahead of print]
39- Li S, Liao X, Meng F et al. Therapeutic role
of ursolic acid on ameliorating hepatic steatosis and
improving metabolic disorders in high-fat diet-induced
non-alcoholic fatty liver disease rats. PLoS One. 2014;
9: e86724.
40- Jin YR, Jin JL, Li CH, Piao XX, Jin NG.
Ursolic acid enhances mouse liver regeneration after
partial hepatectomy. Pharm Biol. 2012; 50: 523-528.
41- Sundaresan A, Radhiga T, Pugalendi KV.
Effect of ursolic acid and Rosiglitazone combination on
hepatic lipid accumulation in high fat diet-fed C57BL/6J
mice. Eur J Pharmacol. 2014; 741: 297-303.
42- Jia Y, Bhuiyan MJ, Jun HJ et al. Ursolic acid
is a PPAR-α agonist that regulates hepatic lipid
metabolism. Bioorg Med Chem Lett. 2011; 21: 5876-
5880.
43- Church D, Schwarz N, Spillane M,
McKinley S, Andre T, Willoughby DS. A comparison of
the effects of ursolic acid and l-leucine supplementation
on IGF-1 receptor and AKT-mTOR signaling in
response to resistance exercise in trained men. Journal of
the International Society of Sports Nutrition. 2014;
11(Suppl 1):P19. doi:10.1186/1550-2783-11-S1-P19.
44- Xia Y, Wei G, Si D, Liu C. Quantitation of
ursolic acid in human plasma by ultra performance liquid
chromatography tandem mass spectrometry and its
pharmacokinetic study. J Chromatogr B Analyt Technol
Biomed Life Sci. 2011; 879: 219-224.
45- Yin MC, Lin MC, Mong MC, Lin CY.
Bioavailability, distribution, and antioxidative effects of
selected triterpenes in mice. J Agric Food Chem. 2012;
60: 7697-7701.