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Beneficial health effects of lupeol triterpene: A review of preclinical studies

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Since ancient times, natural products have been used as remedies to treat human diseases. Lupeol, a phytosterol and triterpene, is widely found in edible fruits, and vegetables. Extensive research over the last three decades has revealed several important pharmacological activities of lupeol. Various in vitro and preclinical animal studies suggest that lupeol has a potential to act as an anti-inflammatory, anti-microbial, anti-protozoal, anti-proliferative, anti-invasive, anti-angiogenic and cholesterol lowering agent. Employing various in vitro and in vivo models, lupeol has also been tested for its therapeutic efficiency against conditions including wound healing, diabetes, cardiovascular disease, kidney disease, and arthritis. Lupeol has been found to be pharmacologically effective in treating various diseases under preclinical settings (in animal models) irrespective of varying routes of administration viz; topical, oral, intra-peritoneal and intravenous. It is noteworthy that lupeol has been reported to selectively target diseased and unhealthy human cells, while sparing normal and healthy cells. Published studies provide evidence that lupeol modulates the expression or activity of several molecules such as cytokines IL-2, IL4, IL5, ILβ, proteases, α-glucosidase, cFLIP, Bcl-2 and NFκB. This minireview discusses in detail the preclinical studies conducted with lupeol and provides an insight into its mechanisms of action.
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Minireview
Benecial health effects of lupeol triterpene: A review of preclinical studies
Hifzur Rahman Siddique, Mohammad Saleem
Section of Molecular Chemoprevention and Therapeutics, The Hormel Institute, University of Minnesota, Austin, MN, USA
abstractarticle info
Article history:
Received 16 September 2010
Accepted 15 November 2010
Available online 28 November 2010
Keywords:
Diseases
Lupeol
Triterpene
Pharmacological
Clinical trial
Since ancient times, natural products have been used as remedies to treat human diseases. Lupeol, a phytosterol
and triterpene, is widely foundin edible fruits, and vegetables. Extensive research over thelast three decades has
revealed several important pharmacological activities of lupeol. Various in vitro and preclinical animal studies
suggest that lupeol has a potential to act as an anti-inammatory, anti-microbial, anti-protozoal, anti-
proliferative, anti-invasive, anti-angiogenic and cholesterol lowering agent. Employing various in vitro and in
vivo models,lupeol has also been tested for its therapeutic efciencyagainst conditions including wound healing,
diabetes, cardiovascular disease, kidney disease, and arthritis. Lupeol has been found to be pharmacologically
effective in treating various diseases under preclinical settings (in animal models) irrespective of varying routes
of administration viz; topical, oral, intra-peritoneal and intravenous. It is noteworthy that lupeol has been
reported to selectively target diseased and unhealthy human cells, while sparing normal and healthy cells.
Published studies provide evidence that lupeol modulates the expression or activity of several molecules such as
cytokinesIL-2, IL4, IL5, ILβ,proteases, α-glucosidase, cFLIP, Bcl-2and NFκB. This minireviewdiscusses in detail the
preclinical studies conducted with lupeol and provides an insight into its mechanisms of action.
© 2010 Elsevier Inc. All rights reserved.
Contents
Introduction ................................................................ 286
Triterpenes .............................................................. 286
Source of lupeol ............................................................ 286
Physical properties and biosynthesis of lupeol .............................................. 286
An overview of therapeutic and preventive potential of lupeol ...................................... 286
Lupeol as an anti-arthritic agent ................................................. 286
Lupeol as an anti-microbial agent ................................................ 286
Lupeol as an antiprotozoal agent ................................................. 288
Lupeol as anti-cancerous agent .................................................. 288
Lupeol as anti-diabetic agent ................................................... 288
Lupeol as cardioprotective agent ................................................. 288
Lupeol as anti-inammatory agent ................................................ 289
Lupeol as skin protective agent.................................................. 290
Lupeol as hepatoprotective agent ................................................. 290
Lupeol as nephroprotective agent ................................................ 290
Perspectives for clinical trials ........................................................ 291
Perspectives for improvement of activity ................................................... 291
Conict of interest statement ........................................................ 291
Acknowledgements ............................................................. 291
References ................................................................. 291
Life Sciences 88 (2011) 285293
Corresponding author. Section of Molecular Chemoprevention and Therapeutics, The Hormel Institute, University of Minnesota, 801, 16th Ave. NE, Austin, MN, 55912 USA.
Tel.: +1 507 437 9662; fax: +1 507 437 9606.
E-mail address: msbhat@umn.edu (M. Saleem).
0024-3205/$ see front matter © 2010 Elsevier Inc. All rights reserved.
doi:10.1016/j.lfs.2010.11.020
Contents lists available at ScienceDirect
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journal homepage: www.elsevier.com/locate/lifescie
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Introduction
Triterpenes
Triterpenes (members of phytosterol family) are natural compo-
nents of human diet (Moreau et al., 2002). Triterpenes are largely
derived from vegetable oils, cereals, and fruits. Although human
consumption of triterpenes is estimated to be approximately 250 mg
per day in the Western world, it is noteworthy that in Mediterranean
countrieswhere mostof the diets are olive oil based, the average intake
of triterpenes consumed by a person could reach 400 mg/kg/day
(Moreau et al., 2002). During the last decade, there has been an
unprecedented escalation of interest in triterpenes. Although much of
the research is focused on the cholesterol-lowering properties of
triterpenes, there are enormous amounts of published data suggesting
the utility of triterpenes for the treatment of a wide variety of disease
conditions (Ovesná et al., 2004;Liby et al., 2007; Jang et al., 2009). These
studieshave culminated intoseveral clinical studies, patents and a boom
in the marketing of triterpene-based products (ranging from supple-
mental to cosmetics) frequently found in theshelves of pharmaceutical
stores (Ovesná et al., 2004; Alander and Andersson, 2005; Liby et al.,
2007; Jang et al., 2009). A recent clinical study comprising 2500 subjects
taking different types of triterpenes with (N25 g/day) reported no
adverse effects in humans (Moreau et al., 2002, and references therein).
Lupeol is a triterpene that has gained the attention of medical
professionals, researchers and pharmaceutical marketers for its wide
ranging pharmacological activities.
Source of lupeol
Lupeol has been reported to be present in diverse species of the plant
kingdom. Lupeol is found in edible vegetables and fruits such as white
cabbage, pepper, cucumber, tomato, carrot, pea, bitter root, soy bean, ivy
gourd, black tea, gs, strawberries red grapes, mulberries, date palm and
guava. Lupeol is also found in abundance in medicinal plants such as, Shea
butter plant, licorice, Tamarindus indica,Celastrus paniculatus,Zanthoxylum
riedelianum,Allanblackia monticola,Himatanthus sucuuba,Leptadenia
hastata,Crataeva nurvala,Bombax ceiba,Sebastiania adenophora,Aegle
marmelos and Emblica ofcinalis (Erazo et al., 2008; Saleem, 2009 and
references therein). The quantication studies have shown that lupeol is
present in Olive fruit (3 μg/g), Mango fruit (1.80 μg/g pulp), Aloe leaf
(280 μg/g dry leaf), Elm plant (800 μg/g bark), Japanese Pear (175 μg/g
twig bark) and Ginseng oil (15.2 mg/100 g of oil).
Physical properties and biosynthesis of lupeol
The chemical formula of lupeol is C
30
H
50
O and its structure is
presented in Fig. 1a. The infra-red spectrum of lupeol shows the
presence of a hydroxyl function and an olenic moiety at a spectrum of
3235 and 1640 cm
1
and HPLCMS studies of lupeolconrmed a parent
ion peak at m/z 409 (M+ H-18)(+) (Saleem, 2009). The melting point
of lupeol is 215216 °C and the structural analysis shows that it
possesses the exact mass of 426.386166 (Saleem, 2009).
Lupeol biosynthesis in plants is orchestrated by the triterpene
synthases and is considered as one of the most complex reactions
occurring in nature (Phillips et al., 2006). The biosynthesis of lupeol is
briey presented in Fig. 1b.Lupeol biosynthesis occurs in the cytosol and
occurs through the stepwise formation of the mevalonate (MVA), the
isopentenyl pyrophosphate (IPP), and dimethylallyl pyrophosphate
(DMAPP) and farnesyl pyrophosphate (FPP) from acetyl CoA. This
reaction is catalyzed by farnesyl pyrophosphate synthase (FPS). Next,
Squalene synthase (SQS) converts FPP into squalene. Squalene
epoxidase (SQE) oxidizes squalene to 2, 3-oxidosqualene, which is
then cyclized by lupeol synthases (LUS), to form the lupenyl cation.
Finally, lupenyl cation is converted into lupeol by deprotonation of the
29-methyl group (Phillips et al., 2006).
An overview of therapeutic and preventive potential of lupeol
Lupeol isreported to exhibita spectrum of pharmacological activities
against various disease conditions (Fig. 2). These include conditions
such as inammation, arthritis, diabetes, cardiovascular ailments, renal
disorder, hepatic toxicity, microbial infections and cancer (Al-Rehaily
et al., 2001; Fernández et al., 2001a,b; Chaturvedi et al., 2008; Sudhahar
et al., 2008a,b). The available literature suggests that lupeol is a non-
toxic agent and does not cause any systemic toxicity in animals at doses
ranging from 30 to 2000 mg/kg (Geetha et al., 1998; Al-Rehaily et al.,
2001; Saleem et al., 2004, 2005, 2008; Bani et al., 2006; Preetha et al.,
2006; Prasad et al., 2008; Sudhahar et al., 2008a,b; Murtaza et al., 2009).
The doses of lupeol which have been tested in animal models
(representing various human diseases) are summarized in Table 1.
Lupeol has been shown to target molecules which are known to play a
key role in the development of various human ailments. A summary of
molecular targets of lupeol is presented in Fig. 3. The summary of
preclinical studies conducted to test the pharmacological action of
lupeol for various ailments is discussed as following:
Lupeol as an anti-arthritic agent
The potential of lupeol as an anti-arthritic agent has been tested in
various in vitro and in vivo models of arthritis (Geetha et al., 1998; Geetha
and Varalakshmi, 1999a,b, 2001; Bani et al., 2006; Azebaze et al., 2009;
Blain et al., 2009). Arthritis is a systemic disease and causes alteration in
lysosomal integrity and metabolism of connective tissue (Geetha and
Varalakshmi, 1999a). Alteration of lysosomal integrity results in signi-
cantly increased destruction of connective tissue and cartilage by
lysosomal enzymes (Geetha and Varalakshmi, 1999a). A study conducted
by Geetha and Varalakshmi (1999a) established the role of lupeol in
treating the arthritic condition in a rat model. In this study, arthritis was
induced by the intradermal injection of 0.1 ml of Complete Freund's
Adjuvant (CFA; 10 mg heat killed Mycobacterium tuberculosis in 1 ml
parafn oil) in the right hind paw. Arthritic rats treated with lupeol
(50 mg/kg for 7 days) showed signicantly reduced levels of lysosomal
enzymes and increased collagen levels (Geetha and Varalakshmi, 1999a).
Chronic inammation, bone degradation and swelling at joints are the
markers of human arthritis (Blain et al., 2009). Arthritic animals exhibit
similar features as are observed in human disease (Geetha et al., 1998;
Geetha and Varalakshmi, 1999a; Azebaze et al., 2009). As evident from
several published reports, lupeol treatment decreases inammation and
paw swelling in animals suffering from arthritis (Geetha et al., 1998;
Azebaze et al., 2009; Geetha and Varalakshmi, 1999a,b, 2001)lupeol
treatment also improved the overall condition of arthritic animals by
affording protection from pain and improving their mobility (Geetha et al.,
1998; Azebaze et al., 2009; Geetha and Varalakshmi, 1999a,b, 2001).
Arthritic animals exhibit decreased collagen levels and increased
excretion of urinary hydroxyproline, hexosamine, hexuronic acid and
glycosaminoglycans (Geetha and Varalakshmi, 2001). Lupeol treatment is
reported to restore altered levels of hydroxyproline, hexosamine,
hexuronic acid and glycosaminoglycans to the normal (Geetha and
Varalakshmi, 1999a, 2001). Notably, when compared to well known
anti-inammatory agents indomethacin and aspirin (Geetha and
Varalakshmi, 2001; Bani et al., 2006), lupeol does not exhibit any
antinociceptive and ulcerogenic actions in arthritic animals, suggesting
that the mechanism of action of lupeol is different from the non-steroidal
anti-inammatory drugs (Geetha and Varalakshmi, 2001; Bani et al.,
2006; Preetha et al., 2006).
Lupeol as an anti-microbial agent
Lupeol has been found to exhibit antimicrobial activity against a wide
range of commonly encountered microbes (Hernández-Pérez et al., 1994;
Ajaiyeoba et al., 2003; Tanaka et al., 2004; Erazo et al., 2008; Shai et al.,
2008; Abd-Alla et al., 2009; Ahmed et al., 2010). Lupeol is reported to
inhibit the growth of a several types of bacteria, fungi and viral species
(Hernández-Pérez et al., 1994; Ajaiyeoba et al., 2003; Tanaka et al., 2004;
286 H.R. Siddique, M. Saleem / Life Sciences 88 (2011) 285293
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Erazo et al., 2008; Shai et al., 2008; Abd-Alla et al., 2009; Ahmed et al.,
2010). Lupeol has been found to act as an effective anti-bacterial agent
when tested against both gram positive and gram negative bacteria (Erazo
et al., 2008; Ahmed et al., 2010). These include B. cereus,B. megaterium,
B. subtilis,S. aureus,S. lutea,S. paratyphi,S. typhi,S. boydi,S. dysenteriae,
V. mimicus,V. parahemolyticus,E. coli,D. spinosa,K. pneumoniae,S. aviatum,
P. aeruginosa,andM. avus (Erazo et al., 2008; Ahmed et al., 2010). Most of
these bacteria cause diseases in humans such as pneumonia, urinary tract
infection and sepsis (K. pneumoniae), typhoid and paratyphoid fever
(S. typhi and S. paratyphi), shigellosis (S. dysenteriae), meningitis,
osteomyelitis, endocarditis and toxic shock syndrome (S. aureus).
Similarly, lupeol (12250 μg/ml) has been shown to inhibit the growth
of a variety of fungal species such as S. schenckii;M. canis;A. fumigatus;
C. albicans;C. neoformans;C. guilliermondi and C. spicata (Shai et al., 2008).
AstudybyAjaiyeoba et al. (2003) showed that lupeol-rich extract of
Buchholzia coriacea exhibits a dose-dependent antibacterial and antifungal
activity. In this study, the antimicrobial effect of lupeol was shown to be
more than well-known antibiotics such as ampicillin and tioconazole
(Ajaiyeoba et al., 2003). Hernández-Pérez et al. (1994) has reported
the antimicrobial activity of lupeol-containing Visnea mocanera leaf
extract. Further, lupeol has been reported to exhibit anti-viral activity
(Hernández-Pérez et al., 1994). Lupeol exhibited signicantly high anti-
viral activity when tested against Herpes simplex virus 1 (HSV1) virus.
Lupeol (EC
50
: 11.7 μM) caused a 100% inhibition of virus plaque formation
at 58.7 μM(Tanaka et al., 2004). Lupeol is also reported to inhibit the
growth of inuenza A virus (Hernández-Pérez et al., 1994).
HO
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
H
H
C
H2C
SCoA
O+
PPO
OPP
H
OPP
O
Squalene
2,3-Oxidosqualene
HO
Lupenyl cation
FPP
DMAPP
HO
Lupeol
2
2
LUS
SQS
SQE
OSC
FPS
O
O
OH
O
HO
Mevalonate (MVA)
3 ATP
H+
b
a
IPP
Fig. 1. (a) Chemical structure of lupeol and (b) schematic representation of the critical steps of the biosynthesis of lupeol in plants; DMAPP represents dimethylallyl pyrophosphate;
IPP represents isopentenyl pyrophosphate; FPS represents farnesyldiphosphate synthase; FPP represents farnesyl pyrophosphate; SQS represents squalene synthase; SQE represents
squalene epoxidase; OSC represents oxidosqualene cyclase; LUS represents lupeol synthase.
287H.R. Siddique, M. Saleem / Life Sciences 88 (2011) 285293
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Lupeol as an antiprotozoal agent
Lupeol is reported to be effective against several types of pathogenic
protozoa. These include those which cause malaria, leishmaniasis and
trypanosomiasis. Lupeol is reported to inhibit the proliferation of
malarial parasite (Plasmodium falciparum). Lupeol was shown to block
the invasion of Plasmodium falciparum merozoites into erythrocytes at
IC
50
1.5 μg/ml (Suksamrarn et al., 2003; Ziegler et al., 2004, 2006).
Structureactivity relationship between lupeol and Plasmodium
falciparum showed that lupeol incorporates into the erythrocyte
membrane. The anti-plasmodial effect of lupeol seems to be related to
alterations in the membraneshape of the host cell rather than a targeted
toxic effect on the parasiteorganelles or metabolic pathways(Rodrigues
and de Souza, 2008). Lupeol treatment was shown to signicantly
inhibit the growth of Trypanosoma cruzi and Leishmania with an IC
90
at
the dose of 100 μg/ml (Fournet et al., 1992).
Lupeol as anti-cancerous agent
Lupeol is reported to exhibit strong anti-mutagenic activity when
tested underin vitro and in vivo conditions (Sunitha et al., 2001; Sultana
et al., 2003; You et al., 2003; Lee et al., 2007; Lira Wde et al., 2008.
A recently published review article from our laboratory provides a
comprehensive account of the chemotherapeutic and chemopreventive
potential of lupeol against a variety of cancers (Saleem, 2009 and
references therein). Lupeol has been reported to inhibit the growth of
several tumor types by modulatingkey molecular pathways,involved in
proliferation, survival and apoptosis. The most striking observation is
that lupeoldoes not exhibitany toxic effect on normal human cellsat the
dose at which it kills cancerous cells (Saleem et al., 2004, 2005, 2008;
Murtaza et al., 2 009). A summarized account of the mechanism of action
of lupeol against tumor cells is presented in Fig. 4.
Lupeol as anti-diabetic agent
Lupeol has been reported to exhibit anti-diabetic activity in in vitro
and in vivo models(Ali et al., 2006; Narvaez-Mastacheet al., 2006;Ortiz-
Andrade et al., 2007; Na et al., 2009). Several studies showed that lupeol
exhibits antihyperglycemic activity and its administration lowers the
risk of development of diabetes in animal models (Ali et al., 2006;
Narvaez-Mastache et al., 2006Ortiz-Andrade et al., 2007; Na et al., 2009).
Protein tyrosine phosphatase 1B (PTP1B) plays a major role in the
inhibition of insulin action, development of type 2 diabetes and obesity
(Na et al., 2009). Recently, Na et al. (2009) showed that lupeol
(IC
50
=5.6μM) inhibits the activity of PTP1B. This study suggested the
therapeutic potential of lupeol to counter other insulin resistance
related diseases. Efciency of lupeol against diabetes development has
been investigated by several investigator employing animal models of
diabetes (Narvaez-Mastache et al., 2006; Ortiz-Andrade et al., 2007.
In one study, diabetes was induced by streptozotocin administration in
experimental rats (Narvaez-Mastache et al., 2006). However, lupeol-
rich plant extract treatment inhibited the development of diabetes in
streptozotocin-induced diabetic rats (Narvaez-Mastache et al., 2006).
Lupeol is reported to be a principal constituent in medicinal plants such
as Tournefortia hartwegiana, used by country doctors in treating diabetes
Ortiz-Andrade et al. (2007).Ortiz-Andrade et al. (2007) demonstrated
that lupeol-rich extract of Tournefortia hartwegiana (310 mg/kg)
inhibits the α-glucosidase activity suggesting that anti-diabetic effect
of lupeol is through the suppression of carbohydrate absorption in the
intestine. Lupeol is reported to inhibit the alpha-amylase, an enzyme,
which is known to contribute in the development of diabetes (Ali et al.,
2006). The complete mechanism of lupeol in inhibiting diabetes in
experimental animals is not fully understood. However, targeting of
PTP1B, alpha-amylase and α-glucosidase activities (which are directly
linked with sugar metabolism) could be a potential mechanism. Further
studies are warranted in this direction (Ali et al., 2006; Ortiz-Andrade
et al., 2007; Na et al., 2009).
Lupeol as cardioprotective agent
Plant sterols have been investigated as one of the safe and potential
alternative methods in lowering plasma cholesterol levels (Rong et al.,
1997; Uusitupa et al., 1997; Frye and Leonard, 1999; Moreau et al., 2002).
Several human clinical studies have shown that plant sterols signicantly
reduce total and LDL cholesterol levels (Rudkowska et al., 2008a, b;
Microbial
activities
Arthritis
Liver
Toxicity
Cardiovascula
r
diseases
Renal
Diseases
Cancer
Lupeol
Inflammation
Diabetes
Fig. 2. Diagram represents the effect of lupeol against different types of human diseases.
Lupeol has been shown to have valuable medicinal properties for the treatment of
several chronic diseases. Studies have also shown that lupeol has no effect on normal
cells and kills only diseased cells.
Table 1
Studies with lupeol in animal models.
Animal
species
Disease
model
Route of
administration
Highest dose
(mg/kg body Wt).
Time period
(days)
Mortality Systematic
toxicity
References
Albino rats Inammation Oral 100 7 No No Al-Rehaily et al. (2001)
Albino rats Inammation Gavage 40 7 No No Al-Rehaily et al. (2001)
Wister albino rats Liver Oral 100 7 No No Preetha et al. (2006)
Wister rats Arthritis Oral 50 810 No No Geetha et al. (1998) and Latha et al. (2001)
Wister rats Renal damage Oral 50 15 No No Sudhahar et al. (2008a,b)
Cd-1 mice Skin cancer Topical 80 180 No No Saleem et al. (2004)
Athymic
nude mice
Prostate, Pancreatic and
Melanoma, Head and Neck
Intraperitoneal 40. 4256 No No Murtaza et al. (2009),Saleem et al. (2005, 2008),
Lee et al. (2007)
Balb/c Mice Inammation Oral 2000 14 No No Bani et al. (2006)
Wister rats Inammation Intra-dermal 50 8 No No Geetha and Varalakshmi (2001)
Wister rats Liver Oral 150 3 No No Sunitha et al. (2001)
Swiss albino mice Liver Gavage 25 7 No No You et al. (2003)
Wister rats Heart Intra-peritoneal 200 10 No No Frye and Leonard (1999)
Swiss albino mice Skin cancer Topical 75 4 No No Saleem et al. (2001)
Wister rats Liver Oral 50 30 No No Sudhahar et al. (2006a,b)
Wister rats Kidney Oral 35 21 No No Vidya et al. (2002)
Dogs Melanoma Intra-tumoral
injection
0.751.5 mg/tumor site 1 No No Hata et al. (2010)
288 H.R. Siddique, M. Saleem / Life Sciences 88 (2011) 285293
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Jenkins et al., 2008; Weidner et al., 2008). Hypertension is known to cause
stroke, cardiac disorders and renal failure. A study by Saleem et al. (2003)
in experimental mice (exhibiting acetylcholine-induced hypertension)
showed that lupeol treatment (15 mg/kg) restores the blood pressure to
normal levels in these animals. This study implies that lupeol has a
potential to be developed as an agent for treating hypertension.
Hyperlipidemic condition is also reported to increase the incidence of
myocardial ischemia and cardiac arrest Sudhahar et al. (2007a,b).
Hyperlipidemia is a major risk factor for the premature development of
coronary heart disease. Hyperlipidemia is marked by increased levels of
total cholesterol, triglycerides and phospholipids concurrent with
aberrant activities of enzymes including lactate dehydrogenase, aspartate
aminotransferase, alanine aminotransferase and alkaline phosphatase.
These enzymes are associated with proper heart functioning Sudhahar et
al. (2007a,b).Sudhahar et al. (2007a,b) reported the therapeutic efcacy
of lupeol against the hyperlipidemic-induced heart malfunction in
animals. Lupeol treatment (50 mg/kg for 15 days) signicantly prevented
the hypertrophic cardiac condition, and restored the normal ultra-
structural architecture in heart tissues of hyperlipidemic animals
Sudhahar et al. (2007a,b). In this study, lupeol was shown to restore the
altered activities of key enzymes needed for proper heart function
(Sudhahar et al., 2007a,b).
Lupeol has also been investigated for its cardioprotective potential in
animal receiving cyclophosphamide, a drug used in the treatment of
cancer and autoimmune disorders Sudharsan et al. (2005a, 2005b).
Cyclophosphamide treatment (200 mg/kg for 10 days) was reported to
signicantly decrease the activity of ATPases and alter the levels of urea,
uric acid and creatinine in serum and urine of animals (Sudharsan et al.,
2005a,b). However, lupeol (50 mg/kg for 10 days) treatment was shown
to afford protection against cyclophosphamide-induced cardiotoxicity in
these mice (Sudharsan et al., 2005a). A similar report showed that lupeol
by modulating the activities of TCA cycle enzymes (succinate dehydro-
genase, malate dehydrogenase, and isocitrate dehydrogenase), and
inhibiting the swelling of mitochondria (numerous electron dense
granules and damaged cristae) affords protection against cyclophospha-
mide-induced mitochondrial-cardiomyopathy in animals (Sudharsan
et al., 2005b). Hypercholesterolemia is reported to cause severe
malfunctioning of the cardio-vascular system Sudhahar et al. (2006a,b).
Lupeol was tested for its anti-hypercholesterolemia activity in an
experimental rat model in which hypercholesterolemia was induced by
feeding animals a high cholesterol diet Sudhahar et al. (2006a,b).The
hypercholesterolemia animals exhibited severe myocardiac damages
such as increased lysosomal hydrolase activity in serum and heart,
decreased cellular thiol levels, and swollen myobres Sudhahar et al.
(2006a,b). Lupeol (50 mg/kg) treatment to hypercholesterolemia animals
(exhibiting myocardiac damages) restored the altered levels of lysosomal
hydrolases and cellular thiol to normal Sudhahar et al. (2006a,b).Lupeol
treatment was also shown to restore the altered levels of lipoproteins and
lipid fractions to normal Sudhahar et al. (2006a,b).Recently,Reddy et al.
(2009) tested lupeol for antidyslipidemic activity in a dyslipidemic
hamster model. In this study, streptozotocin (100 mg/kg) treatment
caused an increase in the levels of triglycerides, glycerol and cholesterol in
hamster. However, when dyslipidemic hamsters were treated with lupeol
(50 mg/kg), a signicant reduction in the levels of triglycerides, glycerol
and cholesterol (LDL) was observed. Further lupeol improved the
cholesterol (HDL) levels in dyslipidemic animals' hamster. Taken together,
these studies suggest that lupeol has the potential to be developed as a
therapeutic agent against cardiovascular diseases.
Lupeol as anti-inammatory agent
Theroleoflupeolasananti-inammatory agent has been discussed in
detail in a recently published review article from our laboratory (Saleem
2009). However, a brief account of lupeol as an anti-inammatory agent is
presented here. Lupeol has been extensively studied for its ant-
inammatory potential under in vitro and in vivo conditions (Geetha
and Varalakshmi 1999b, 2001; Lambertini et al., 2005; Sudhahar et al.,
NFkB cFLIP
Tumor
Initiation,
Promotion and
Progression
Lupeol
CyclinD1
Cell
Proliferation
ROS/RNS
Mutation
β
-catenin
Transcription of
TCF/LEF Genes
Lupeol
Bcl2
Anti-Apoptosis
Fig. 4. Flowchart represents the mechanism of action of lupeol in curtailing tumor
initiation, promotion and progression. ROS represents reactive oxygen species; RNS
represents reactive nitrogen species; TCF/LEF represents T-cell factor/lymphoid enhancer
factor; NFκB represents nuclear factor kappa B; cFLIP represents cellular form of FLICE
inhibitory protein and Bcl2 represents B-cell lymphoma 2.
Cancer
NFκB, PI3K/Akt , Wnt/β-
catenin, AR, Proteosome,
Kras, p53, cFLI P, Fas, DR3,
PKCα, MMP2, cMyc, Cyclin-
D1, p21, GST, GR
and CAT
Liver Toxicity
Acyl
-CoA cholesterol
acyltransferase
Diabetes
PTP1B and
α-glucosid ase
Inflammation
PGE2, Cox-2,
ILβ, IL2, IL4, I L5, IL6, IL13
Lox-15, TNFα, arachidonic acid ,
GSK3β, 15-sLO and IFN-γ-Th1
Arthritis
IL2, IFN-γ (Τh1),
ΙL4 (Th2), hyd roxy-
Proline and
glycosaminoglycans
Cardiovascular
Na+/K+/Ca2+-ATPase,
Succinate/malate/
isocit rate -
dehyd rogenase
Fig. 3. Pie diagram represents important molecular targets of lupeol for different human
diseases. NFκB represents nuclear factor kappa B; GST represents glutathione S-
transferase; GR represents Glutathione reductase; Cox-2 represent cyclooxygenase-2;
PGE2 represents prostaglandin E2; 15-sLO represents soybean 15-lipoxygenase; TNFα
represents tumor necrosis factorα,ILβrepresents Interleukin β,ILrepresentsInterleukin;
MMP2 represents matrix metalloproteinase; AR represents androgen receptor; PKCα
represents Protein Kinase C alpha; CAT represents Catalase; cFLIPrepresents cellularform
of FLICE inhibitory protein; DR3 represents death receptor 3; and PTP1B represents
tyrosine phosphatase 1B.
289H.R. Siddique, M. Saleem / Life Sciences 88 (2011) 285293
Author's personal copy
2008a,b; Ashalatha et al., 2010). Employing inammation-associated
mouse models, several studies have established the anti-inammatory
potential of lupeol (Davis et al., 1994; Akihisa et al., 1996; Geetha and
Varalakshmi 1999b; Fernández et al., 2001a,b; Ramirez Apan et al., 2004;
Lima et al., 2007). Lupeol treatment has been shown to reduce the
inammation in mouse models of arthritis and bronchial asthma (Geetha
and Varalakshmi, 2001; Vasconcelos et al., 2008). Comparative studies
conducted in rodent models of inammation have shown that the anti-
inammatory potential of lupeol is higher than indomethacin (a non-
steroidal anti-inammatory drug), dexamethasone and α-Mangosteen,
(anti-inammatory phytochemicals) (Latha et al., 2001; Vasconcelos et al.,
2008; Nguemfo et al., 2009). Published studies have provided evidence
that the efcacy of lupeol as an anti-inammatory agent is due to its
potential to act on multiple molecular targets associated with inamma-
tion (Vidya et al., 2000; Fernández et al., 2001a,b; Moreira et al., 2001; Bani
et al., 2006; Nguemfo et al., 2009). Lupeol is reported to modulate the
expression level of several inammation associated molecules such as
soybean 15-lipoxygenase (15-sLO), tumor necrosis factor α(TNFα),
Interleukin β(ILβ), prostaglandin E2 (PGE2), cytokines (IL-2, IL-4, IL-5, IL-
6, IL-13, IFN-γ-Th1), myeloperoxidase, macrophages and T-lymphocytes
(Akihisa et al., 1996; Vidya et al., 2000; Fernández et al., 2001a, 2001b;
Moreira et al., 2001; Bani et al., 2006; Ding et al., 2009; Nguemfo et al.,
2009).
Lupeol as skin protective agent
Earlier, we showed that lupeol pretreatment alleviates the toxicity
induced by benzoyl peroxide (a chemical widely used in skin care
products) in skin tissues of Swiss Albino mice (Saleem et al., 2001). The
skin protective effects of lupeol were observed to be associated with its
potential to enhance the skin anti-oxidant system (Saleem et al., 2001).
A study employing an in vitro model of human skin keratinocytes
(epidermal explants) cultured at an airliquid interface on a de-
epidermized human dermis was conducted to investigate the skin
repairing potential of lupeol (Nikiéma et al., 2001). Lupeol treatment
was observed to signicantly repair the damaged skin by inducing
differentiation of keratinocytes with a well-formed stratum corneum
(Nikiéma et al., 2001). Chronic inammation is known to delay healing
of worn or damaged tissues (Harish et al., 2008). Chronic inammation
renders damaged tissues to ulceration and irregular tissue growth
(Harish et al., 2008). An excision,incision and dead space wound animal
model is a well tested model to study wound healing and associated
mechanisms (Harish et al., 2008). Utilizing this wound healing model,
Harish et al. (2008) showed that topical application of lupeol (8 mg/ml
0.2% sodium alginate gel) enhances signicant wound healing activity.
The wound healing activity of lupeol was found to be higher than
nitrofurazone, a well known skin ointment used for wound healing
(Harish et al., 2008). Aleo vera herb is well known for its skin care
properties and is widely used in skin care products (Davis et al., 1994;
Majeed and Prakash, 2005). The anti-inammatory and soothing
properties of the Aloe plant have been associated with presence of
two major compounds i.e. Salicylic acid and lupeol (Davis et al., 1994).
Shea butter and its derivatives have been known to the cosmetics
industry for a long time and are excellent emollients for both skin and
hair care applications. It is to be noted that Shea butter possesses a
signicant amount (20%) of lupeol (Alander and Andersson, 2005).
Since lupeol is reported to be useful in maintaining skin texture and
integrity, several lupeol-based anti-aging skin creams have been
reported to be under development (Davis et al., 1994; Harish et al.,
2008; Alander and Andersson, 2005; Majeed and Prakash, 2005). These
reports suggest the use of lupeol in anti-aging creams, lotions, gels and
lip balms, with use levels ranging from 0.2 to 3% w/w in formulations
(Davis et al., 1994; Harish et al., 2008; Alander and Andersson, 2005;
Majeed and Prakash, 2005). Recent reports suggest that several lupeol
based anti-aging and anti-fungal skin creams are under development
(Majeed and Prakash, 2005).
Lupeol as hepatoprotective agent
Lupeol has been investigated for its hepatoprotective potential
(Al-Rehaily et al., 2001 and references therein). A recent study showed
that lupeol affords protection against aatoxin B1, a potent hepatotoxic
agent when tested under in vivo conditions (Al-Rehaily et al., 2001).
Aatoxin feeding causes peroxidative damage in liver tissue and
increases serum levels of liver function enzymes viz; lactate dehydro-
genase, alkaline phosphatase, alanine and aspartate aminotransferases
(Al-Rehaily et al., 2001). However, oral administration of lupeol
(100 mg/kg) for 7 days caused a reversal in the altered levels of
biomarker enzymes to their normal levels in aatoxin-treated mice
(Al-Rehaily et al., 2001). Interestingly, the hepato-protective effect of
lupeol was shown to be more than silymarin, a well-known natural
hepatoprotective agent (Al-Rehaily et al., 2001). Recently, Prasad et al.
(2007) showed that lupeol and lupeol-rich mango pulp extract inhibits
7, 12-dimethylbenz(a) anthracene (DMBA)-induced liver damage in a
mouse model. Lupeol supplementation (25 mg/kg/day) for 7 days
effectively inhibited oxidative stress and restored mitochondrial
transmembrane potential in liver tissues of DMBA-treated mice (Prasad
et al., 2007). Several studies have been conducted to examine the
benecial role of lupeol against other possible conditions which cause
hepatic ailments. One of the important discoveries in this direction was
astudybySudhahar et al. (2006a,b) which showed that lupeol could
ameliorate hypercholesterolemia-induced liver damage in experimen-
tal animals. Lupeol (50 mg/kg) treatment for 15 days signicantly
alleviated the liver function abnormalities and increased fecal excretion
of cholesterol in hypercholesterolemic rats (Sudhahar et al., 2006a,b).
Importantly, lupeol was reported to signicantly induce the levels of
vitamin C and E in hypercholesterolemic animals (Sudhahar et al.,
2006a,b). Increased hepatic lipid prole along with abnormalities in
lipid-metabolizing enzyme activities (marked by increased expression
of acyl-CoAcholesterol acyltransferase mRNA) and altered liver function
enzymes were observed in hypercholesterolemic rats (Sudhahar et al.,
2006a,b). Lupeol signicantly alleviated altered liver function by
restoring normal activities of lipid metabolizing enzymes (Sudhahar
et al., 2006a,b). Another report where oral administration of lupeol
(150 mg/kg/day) alleviated the metal-induced hepatotoxicity in a rat
model validated the hepatoprotective potential of lupeol (Sunitha et al.,
2001).
Lupeol as nephroprotective agent
Lupeol has been tested in several studies for its protective efcacy
against renal ailments. Multiple reports have established the protective
role of lupeol in animal models of urolithiasis (stone formation in
kidney) (Malini et al., 1995; Vidya et al., 2000, 2002; Shirwaikar et al.,
2004; Sudhahar et al., 2008). Animals treated with 2% solution of
ammonium oxalate for 15 days induced hyperoxaluric condition in rats
(Malini et al., 1995; Vidya et al., 2000, 2002; Sudhahar et al., 2008).
These animals exhibited kidney malfunction, renal tissue damage and
renal stones as validated by increased urinary excretion of oxalate;
reduced citrate and glycosaminoglycans and increased levels of lactate
dehydrogenase, inorganic pyrophosphatase, alkaline phosphatase,
gamma glutamyl transferase, β-glucuronidase and N-acetyl β-D
glucosaminidase (Malini et al., 1995; Vidya et al., 2000, 2002;Sudhahar
et al., 2008). Lupeol treatment restored the altered levels of renal
function enzymes in these animals. Lupeol treatment was observed to
decrease the deposition of stone forming constituents in the kidney of
urolithiatic animals (Malini et al., 1995; Vidya et al., 2000, 2002;
Sudhaharet al., 2008a,b). In a study, stone formation was induced in rats
(by administration of a pyridoxine decient diet containing 3% glycollic
acid for 21 days) thus leading to increased excretion of stone forming
constituents such as calcium, oxalate and uric acid (Vidya et al., 2002).
These animals exhibited increased crystal deposition and renal tubular
damage which was evident from the altered levels of renal function
enzymes (Vidya et al., 2002). Interestingly, when these animals received
lupeol (50 mg/kg) treatment, stone formation and stone deposition
290 H.R. Siddique, M. Saleem / Life Sciences 88 (2011) 285293
Author's personal copy
activity was highly decreased (Vidya et al., 2002). Oral administration of
lupeol was observed to signicantly reverse the abnormal biochemical
and histological aberrations in these animals (Vidya et al., 2002).
Humans are constantly exposed to metals and some patients are
even treatedby metal based drugs. However, metal toxicitymanifests in
the form of renal failure. A study by Nagaraj et al. (2000) showed that
lupeol has the potential to afford protection against metal-induced
nephrotoxicity in rats. Lupeol supplementation (40 mg/kg) concurrent
with cadmium administration inhibited the cadmium-induced oxida-
tive damage in renal tissues of rats (Nagaraj et al., 2000). A similar study
showed thatoral administration of lupeol (40 and 80 mg/kg) for 10 days
decreases the concentration of blood urea nitrogen, creatinine and lipid
peroxidation, and increased glutathione and catalase activities in
cisplatin (5 mg/kg)-induced nephrotoxicity in rats (Nagaraj et al.,
2000). The association between hypercholesterolemia and kidney
damage has been widely reported (Sudhahar et al., 2008a,b). The
oxidative stress and inammatory responses are involved in renal
injury, which is upregulated in hypercholesterolemic condition. Lupeol
has been shown to afford protection from the development of
hypercholesterolmic condition in animals in which hypercholesterol-
emia was induced by feeding a high cholesterol diet (HCD) to rats for
30 days (Sudhahar et al., 2008a,b). Hypercholesterolemia in HCD-fed
rats is marked by increased levels of renal total cholesterol, triglycerides
and phospholipids, along with altered serum biochemical parameters of
tissue injury indices and elevated activities of renal marker enzymes
(lactate dehydrogenase and alkaline phosphatase) (Sudhahar et al.,
2008a,b).
Renal lysosomal acid hydrolase activities (ACP, β-Glu, β-Gal, NAG
and Cat-D), acute phase proteins like C-reactive protein and brinogen
were signicantly increased in HCD-fed rats, indicating the increased
inammation in the tissues (Geetha et al., 1998). Lupeol effectively
restored renal functional enzyme levels to normal in HCD-fed animals.
Lupeol treatment also decreased renal lysosomal acid hydrolase
activities in HCD-fed rats (Geetha et al., 1998). Taken together, these
studies suggest the chemoprotective potential of lupeol against various
types of renal abnormalities.
Perspectives for clinical trials
Data obtained from in vitro and in vivo studies are promising and
further evaluation of lupeol as a candidate therapeutic agent for
different human diseases (including those not mentioned in this mini-
review) appears warranted. To test the clinical utility of lupeol, detailed
investigations are warranted in animal models which develop diseases
spontaneously. Steps are being taken in this direction by our laboratory
and others. Recently, Hata et al. (2010) tested lupeol in dogs suffering
from melanoma. This study involving 7 cases, for the rst time provided
information about the clinical utility of lupeol in treating diseases. In this
study, dogs suffering from metastatic melanoma were treated with
lupeol (0.751.5 mg). Lupeol administration was reported to result in
the regression of melanomain cases I and II. In case III, lupeol treatment
induced the increase in melanosomes and caused differentiation of
melanoma cells. In cases VVII, lupeol was tested as an adjuvant to
immunotherapeutic agents to treat melanoma. It is interesting to note
that in case VVI, melanoma was completely disappeared, however, in
case VII, no benecial effect of lupeol treatment was observed. This
study concluded that lupeol was successful in 6 out of 7 cases whichis a
promising outcome of treatment, however, ne tuning of interval of
administration, concentration and doses, could enhance the potency of
lupeol under clinical settings. This study opens the window of
opportunity for more preclinical studies and clinical trials to validate
the usefulness of lupeol either alone or in combination with existing
therapies. However, caution is needed in extrapolating the information
obtained from animal studies to humans due to the inter-species
differences.
Perspectives for improvement of activity
Lupeol has high bioavailability (Siddique et al., unpublished data),
however the introduction of synthetic analogs may enhance the potency
and bioavailability of lupeol. This is based on report where synthetic
derivatives of lupeol were observed to exhibit more pharmacological
efcacy than lupeol (Hodges et al., 2003; Sudhahar et al., 2007a,b,
2008a,b). Further, to enhance its pharmacological activity, the effective
dose of lupeol could be ne-tuned after thorough pharmaco-kinetic
studies. Further, factors such as effective dose and the duration of
treatment should be taken into account when lupeol is investigated for its
therapeutic purposes for different diseases under varied conditions.
Conict of interest statement
None.
Acknowledgements
The referenced work from author'slaboratory is supported by United
States PHS grants (CA133807; CA130064) and AICR grant (09A074) to
the corresponding author.
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293H.R. Siddique, M. Saleem / Life Sciences 88 (2011) 285293
... Additionally, lupeol is abundant in medicinal plants such as Tamarindus indica, Allanblackia monticola, Crataeva nurvala, Aegle marmelos, Bombax ceiba, Zanthoxylum riedelianum, Shea butter plant, Leptadenia hastata, Celastrus paniculatus, Sebastiania adenophora, Himatanthus sucuuba, Emblica officinalis, and licorice. Studies quantifying its presence have demonstrated lupeol in the elm plant (800 μg/g bark), olive fruit (3 μg/g), aloe leaf (280 μg/g dry leaf), ginseng oil (15.2 mg/100 g of oil), mango fruit (1.80 μg/g pulp), and Japanese pear (175 μg/g twig bark) (Siddique and Saleem, 2011). ...
... These effects include antioxidant, anticancer, cardioprotective, antimicrobial, antidiabetic, anti-inflammatory, antiatherosclerotic, antimutagenic, antiproliferative, hepatoprotective, gastroprotective, renoprotective, and other effects (Gayathri et al., 2019a;Preetha et al., 2006;Tiwari et al., 2019;Cruz-Salas et al., 2023). Lupeol's pharmacological effectiveness has been proven in some in vivo tests, and it has been observed to selectively target diseased and unhealthy human cells (Siddique and Saleem, 2011). In addition to its efficacy, it is regrettable that lupeol has poor bioavailability, which affects the applications of lupeol's distribution (Malinowska et al., 2021). ...
... Although lupeol possesses a diverse array of pharmacological effects, it has not yet been developed into a medicinal medicine. There are several problems, such as the inability to dissolve in water, restricted ability to be absorbed by the body, and a short amount of time it stays in the bloodstream (Siddique and Saleem, 2011). The oral bioavailability of lupeol is limited due to its high lipophilicity and low water solubility, as stated by Wang et al. (2016). ...
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Lupeol, a naturally occurring lupane-type pentacyclic triterpenoid, is widely distributed in various edible vegetables, fruits, and medicinal plants. Notably, it is found in high concentrations in plants like Tamarindus indica, Allanblackia monticola, and Emblica officinalis, among others. Quantitative studies have highlighted its presence in Elm bark, Olive fruit, Aloe leaf, Ginseng oil, Mango pulp, and Japanese Pear bark. This compound is synthesized from squalene through the mevalonate pathway and can also be synthetically produced in the lab, addressing challenges in natural product synthesis. Over the past four decades, extensive research has demonstrated lupeol’s multifaceted pharmacological properties, including anti-inflammatory, antioxidant, anticancer, and antibacterial effects. Despite its significant therapeutic potential, clinical applications of lupeol have been limited by its poor water solubility and bioavailability. Recent advancements have focused on nano-based delivery systems to enhance its bioavailability, and the development of various lupeol derivatives has further amplified its bioactivity. This review provides a comprehensive overview of the latest advancements in understanding the pharmacological benefits of lupeol. It also discusses innovative strategies to improve its bioavailability, thereby enhancing its clinical efficacy. The aim is to consolidate current knowledge and stimulate further research into the therapeutic potential of lupeol and its derivatives.
... The cycloartenol and cycloartanol compounds, falling under the Cycloartane subclass, exhibit a wide range of effects such as anti-inflammatory, antitumor, antioxidant, antibiosis, anti-Alzheimer's disease, apoptotic, analgesic, and antifungal activities [104][105][106][107][108][109][110]. Lupeol, belonging to the Lupane subclass, displays diverse properties like anticancer, anti-inflammatory, antimicrobial, antiprotozoal, antiproliferative, antiangiogenic, and cholesterol-lowering effects [40,[111][112][113][114][115][116][117]. Oleanane-type triterpenoids, represented by α-amyrin and β-amyrin, demonstrate activities such as cytotoxicity, antifungal, anti-inflammatory, nitric oxide inhibition, reactive oxygen species activation, and anticancer effects [118][119][120][121][122][123][124][125]. ...
... Lupeol, a triterpenoid, is found in various plants including E. trigona, Tamarindus indica, Celastrus paniculatus, Zanthoxylum riedelianum, Allanblackia monticola, Himatanthus sucuuba, Leptadenia hastata, Crataeva nurvala, Bombax ceiba, Sebastiania adenophora, Aegle marmelos, and Emblica officinalis [114,[266][267][268][269]. You et al. [116] evaluated the effects of lupeol extracted from Bombax ceiba on various cell types, including HUVEC and SK-MEL-2, as well as B16-F10 melanoma cells. ...
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This study documents the Euphorbiaceae family of plants in Southern Africa, with a focus on their traditional medicinal applications, pharmacological properties, toxicity, and active secondary metabolites. A review of the literature from scientific journals, books, dissertations, and conference papers spanning from 1962 to 2023 was conducted for 15 Euphorbia species. Recent findings indicate that specific compounds found in Euphorbia plants exhibit significant biological and pharmacological properties. However, the white sticky latex sap they contain is highly toxic, although it may also have medicinal applications. Phytochemical analyses have demonstrated that these plants exhibit beneficial effects, including antibacterial, antioxidant, antiproliferative, anticancer, anti-inflammatory, antiviral, antifungal, and anti-HIV activities. Key phytochemicals such as euphol, cycloartenol, tirucallol, and triterpenoids contribute to their therapeutic efficacy, along with various proteins like lectin and lysozyme. Despite some Euphorbiaceae species undergoing screening for medicinal compounds, many remain insufficiently examined, highlighting a critical gap in the research literature. Given their historical usage, further investigations are essential to evaluate the medicinal significance of Euphorbia species through detailed studies of isolated compounds and their pharmacokinetics and pharmacodynamics. This research will serve as a valuable resource for future inquiries into the benefits of lesser-studied Euphorbia species.
... Lupeol is rapidly absorbed in animals and was determined not to cause systemic toxicity in vivo at 200 mg/kg intraperitoneal and 2000 mg/kg oral doses. 19,20 Additionally, Lupeol has been proven to inhibit the progression of osteosarcoma by regulating miR-212-3p, thereby affecting miRs. 21 It is available in the literature that miR-29b-3p, miR-34a-5p, miR-495-3p expression levels also change in studies conducted with intestinal ischemia-reperfusion models. ...
... Therefore, we chose the 100 mg/kg dose and intraperitoneal route in our study. 20,23,24 Experimental study was performed with 36 healthy Wistar-Albino female rats with an average weight of 220.00 ±14.63 g (200-240). In this study, only female rats were used to ensure independence and homogeneity in sex hormone levels. ...
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... The cycloartenol and cycloartanol compounds, falling under the Cycloartane subclass, exhibit a wide range of effects such as anti-inflammatory, antitumor, antioxidant, antibiosis, anti-Alzheimer's disease, apoptotic, analgesic, and antifungal activities [104][105][106][107][108][109][110]. Lupeol, belonging to the Lupane subclass, displays diverse properties like anticancer, anti-inflammatory, antimicrobial, antiprotozoal, antiproliferative, antiangiogenic, and cholesterol-lowering effects [40,[111][112][113][114][115][116][117]. Oleanane-type triterpenoids, represented by α-amyrin and β-amyrin, demonstrate activities such as cytotoxicity, antifungal, anti-inflammatory, nitric oxide inhibition, reactive oxygen species activation, and anticancer effects [118][119][120][121][122][123][124][125]. ...
... Lupeol, a triterpenoid, is found in various plants including E. trigona, Tamarindus indica, Celastrus paniculatus, Zanthoxylum riedelianum, Allanblackia monticola, Himatanthus sucuuba, Leptadenia hastata, Crataeva nurvala, Bombax ceiba, Sebastiania adenophora, Aegle marmelos, and Emblica officinalis [114,[266][267][268][269]. You et al. [116] evaluated the effects of lupeol extracted from Bombax ceiba on various cell types, including HUVEC and SK-MEL-2, as well as B16-F10 melanoma cells. ...
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This study documents Euphorbiaceae plants in Southern Africa, focusing on their traditional medicinal uses, pharmacological properties, toxicity, and active secondary metabolites. Literature from scientific journals, books, dis-sertations, and conference papers from 1962 to 2023 was reviewed for 15 Euphorbia species. Recent findings indicate that certain compounds in Eu-phorbia plants have significant biological and pharmacological properties. However, the white sticky latex sap they contain is highly toxic yet can also have medicinal applications. Phytochemical analysis has shown these plants exhibit beneficial effects, including antibacterial, antioxidant, antiprolifera-tive, anticancer, anti-inflammatory, antiviral, antifungal, and anti-HIV activ-ities. Key phytochemicals such as euphol, cycloartenol, tirucallol, and triterpenoids contribute to their therapeutic efficacy, along with various proteins like lectin and lysozyme. Despite some Euphorbiaceae species being screened for medicinal compounds, many have not been thoroughly exam-ined, highlighting a critical gap. Given their historical usage, further research is essential to evaluate the medicinal significance of Euphorbia species through detailed studies of isolated compounds and their pharmacokinetics and pharmacodynamics. This research will serve as a valuable resource for future inquiries into the benefits of lesser-studied Euphorbia species.
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Introduction: Renal ischemia-reperfusion (IR) is responsible for injuries such as destruction or dysfunction of tubular epithelial cells with inflammatory reaction and oxidative stress. Several therapeutic methods have been tested to alleviate ischemia-perfusion injury, ranging from using anti-inflammatory drugs, antioxidants, and plants from traditional pharmacopeia to administering RNA interference. However, there is currently no effective therapeutic option available for the treatment of renal IR injury, other than supportive therapies such as renal replacement therapy or hydration. Objective: This present study aimed to evaluate the effect of Guiera senegalensis on renal ischemia reperfusion, a recognized plant for its antioxidant and anti-inflammatory properties. Materials and Methods: Twenty-four (24) adult male Wistar rats were divided into four following groups: SLAM (subjected to a median laparotomy with simulated ischemia); GUIERRA (animals that received 250 mg/kg of guierra senegalensis orally, once a day, for 5 days, with simulated renal ischemia); IR (animals that underwent laparotomy followed by clamping of bilateral renal pedicles for 45 min and followed by reperfusion); GUIERRA + IR (animals given GUIERRA at the dosage of 250 mg/kg per day, for 5 days and then subjected to renal ischemia-reperfusion). Data analysis was performed by ANOVA, and a significance level of p < 0.05 was chosen. Blood and renal tissue samples from all rats were collected after 24 h. Histopathological analysis of the kidneys was performed by evaluating the degree of tubular degeneration, the presence of interstitial lymphocytic infiltrate, proteinaceous casts, necrosis, and loss of the brush border appearance of the tubules using a dedicated score. In the blood samples, creatinine levels were evaluated. Results: Compared with the I/R group, rats in the GUIERRA + IR group showed reduced histopathological damage scores (p < 0.05). Although the differences in creatinine levels were not statistically significant, these were significantly decreased in the treatment group. Conclusion: The results of this preliminary work suggest that Guiera senegalensis decreases the degree of tissue damage in renal ischemia-reperfusion cases. This plant seems to be a promising therapeutic; further studies could help to precise the targets of its compounds on ischemia-reperfusion pathways.
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Lupeol, a pentacyclic triterpenoid found in a variety of fruits, vegetables, and medicinal plants, has received a lot of attention due to its diverse pharmacological properties and possible therapeutic applications. A thorough literature search was carried out to acquire important information on lupeol's pharmacological actions and mechanisms of lupeol. Key databases, such as Google scholar, Science Direct, Springer Link, PubMed and Scopus, were used to ensure an extensive review of available literature. The studies included were selected based on criteria requiring peer-reviewed articles, clinical studies, and experimental research published mainly, focusing on the pharmacological properties, bioactivity, and mechanisms of action of lupeol. Lupeol's diverse beneficial effects, which include anti-inflammatory, antioxidant, antimicrobial, anticancer, and hepatoprotective properties, are attributed to its ability to modulate key molecular pathways involved in inflammation, oxidative stress, cellular proliferation, and programmed cell death. Lupeol inhibits the production of pro-inflammatory cytokines such as TNF-, IL-1, and IL-6 by downregulating the NF-B signaling pathway, leading to reduced inflammation and tissue damage. Its antioxidant properties, which include scavenging reactive oxygen species and increasing the activity of endogenous antioxidant enzymes, help it defend against diseases associated with oxidative stress, such as neurological and cardiovascular problems. Furthermore, lupeol's anticancer capabilities have been extensively studied, with results demonstrating its capacity to inhibit tumor growth, induce apoptosis, and prevent metastasis in a variety of cancer models. This review offers an in-depth analysis of current research on lupeol, highlighting its chemical structure, pharmacological properties, and the molecular mechanisms underlying its functions. By examining lupeol's multifaceted medicinal potential, this study explores its promise in developing innovative treatments for various chronic diseases. Additionally, the review identifies key areas for future investigation, outlining research opportunities to deepen the understanding of lupeol's clinical viability, optimize its therapeutic efficacy, and assess its safety across a broader spectrum of applications.
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Novel natural approaches to anti-aging skin care, targeting the root causes of skin damage and texture loss, are presented. Four proprietary extracts, Boswellin® (a natural extract derived from Indian frankincense), Umbelliferin® (a composition derived from coriander seeds), Lupeol 80% (a multifunctional natural extract from Crataeva nurvula (Varuna) and CococinTM (a patent-pending composition derived from green coconut water) are highlighted. The use of these extracts in anti-aging skin care compositions is described.
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A novel constituent, shamimicin, 1"', 1"'-bis-2-(3,4-dihydroxyphenyl)-3,4-dihydro-3,7-dihydroxy-5-O-xylopyranosyloxy-2H-1-benzopyran along with lupeol, which possesses potent hypotensive activity, has been isolated from Bombax ceiba stem bark. BCBMM--one of the most active hypotensive fractions has revealed its adverse effects on heart, liver and kidneys of mice at the dose of 1000 mg/kg/d.
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Plant sterol (PS) consumption decreases low-density lipoprotein cholesterol (LDL-C) levels however, high variability of responsiveness of lipid levels to PS intervention has been observed. We hypothesized that common single-nucleotide polymorphisms (SNPs) in the genes for the ATP binding cassette proteins G5 (ABCG5) and G8 (ABCG8), Niemann-Pick C1-like 1 (NPC1L1), or other proteins of the cholesterol pathway, would underline inter-individual variations in response to PS. Twenty-six hyperlipidemic subjects completed a randomized trial of 3 PS phases and a control phase. Three non-responders were identified who failed on 3 consecutive occasions to decrease either total cholesterol or LDL-C level vs. control. It was observed that after 3 PS phases compared with a control phase, cholesterol absorption changed to a lesser degree (7.7% 10.8%) in the non-responders than in the top 3 responders (22.1% 8.8%) however, cholesterol synthesis rates did not differ between sub-groups. No common polymorphisms in ABCG8, ABCG5, or NPC1L1 were demonstrated between the 3 top responders and the non-responders. Yet, 1 non-responsive subject did demonstrate a rare SNP in NPC1L1. Results indicate PS intake did not decrease cholesterol absorption rates to the same degree in certain subjects, possibly clarifying the inter-individual variability in the cholesterol-lowering effect hence, this work should be expanded.
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Ursolic acid and oleanolic acid are pentacyclic triterpenoic acids having a similar chemical structure and are the major components of some oriental and traditional medicine herbs wildly distributed all over the world. There is a growing interest in the elucidation of the biological roles of both these triterpenoid compounds. This review summarizes the biological activities of presented triterpenoid acids (anti-inflammatory, hepatoprotective, gastroprotective, anti-ulcer, anti-HIV, cardiovascular, hypolipidemic, antiatherosclerotic and immunoregulatory effects). Our interest has been focussed especially on their anti-tumor and chemopreventive activity. Both compounds have been shown to act at various stages of tumor development, including inhibition of tumorigenesis, inhibition of tumor promotion, and induction of tumor cell differentiation. They effectively inhibit angiogenesis, invasion of tumor cells and metastasis. However, the mechanisms by which they act are poorly understood. Ursolic acid and oleanolic acid are relatively non-toxic and could be use as chemopreventive/chemoprotective agens in clinical praxis.
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The pharmacological activities of the acetonitrile (MeCN), hexane extracts and isolated pure terpenoidal compound Lupeol from the leaves of Teclea nobilis, Delile (TN), on inflammation induced by carrageenan and implantation of cotton pellets in rats; the nociceptive response using writhing and tail flick tests and the antipyretic activity in yeast-induced fever were examined in mice. Oral administration of TN extracts at doses of 150 and 300 mg/kg and lupeol 5 and 10 mg/kg showed a significant anti-inflammatory activity in rats. The extracts of TN and lupeol significantly decreased the number of contractions and stretchings induced by acetic acid and heat-induced pain in mice. The antipyretic effect of extracts and lupeol was also found to be significant. The behavioral observation of animals showed that the hexane extract and lupeol caused CNS depressant activity and did not produce any toxic or lethal effects in animals at various dose levels. The results suggest that the Teclea nobilis extracts and lupeol possesses anti-inflammatory, analgesic and antipyretic activities.
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The triterpenoid, lupeol (1) has been isolated from the leaves extract of Aegle marmelos. Few novel derivatives (2-13) were synthesized from the naturally occurring lupeol (1) and screened for their antihyperglycemic activity (2-11) and antidyslipidemic activity (2-4 and 12-13). The derivative 4 lowered the blood glucose levels by 18.2% and 25.0% at 5h and 24h, respectively, in sucrose challenged streptozotocin induced diabetic rats (STZ-S) model at the dose of 100mg/kg body weight. The compound 4 also significantly lowered 40% (P <0.001) in triglycerides, 30% (P <0.05) in glycerol, 24% (P <0.05) in cholesterol quantity and also improved the HDL-cholesterol by 5% in dyslipidemic hamster model at the dose of 50mg/kg b.wt.
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In the hypercholesterolemic condition, the net result of combined lipemic-oxidative and inflammatory aberrations is manifested as an increase in adhesion molecule expression, increased vascular permeability, and the progress of atherogenesis. The aim of the present work is to evaluate the role of lupeol and its ester derivative on oxidative and inflammatory abnormalities in hypercholesterolemic condition. Hypercholesterolemia was induced in male albino rats of Wistar strain by feeding them a high-cholesterol diet (HCD) containing normal rat chow supplemented with 4% cholesterol and 1% cholic acid for 30 days. The pentacyclic triterpene, lupeol, and the ester derivative of lupeol, lupeol linoleate, were supplemented (50 mg/kg body weight per day, PO) during the last 15 days. Oxidative stress in HCD-fed animals was characterized by a significant increase in reactive oxygen species with concomitant decrease in the thiol levels in heart. Cardiac nuclear factor-κB nuclear translocation was confirmed by immunohistochemisty in HCD-fed rats. The tumor necrosis factor-α levels showed an increase in hypercholesterolemic condition, whereas a departure toward control values and decreased nuclear translocation of nuclear factor-κB and oxidative stress were notable in supplementation with triterpenes. The nitric oxide levels and mRNA expression for inducible nitric oxide synthase was also significantly increased in HCD-fed animals. Treatment with lupeol and lupeol linoleate reversed the nitrosative stress to near normalcy. These observations highlight the beneficial effects of the triterpene, lupeol, and linoleate ester in ameliorating the oxidative and inflammatory abnormalities in the hypercholesterolemic conditions.
Article
Lupeol-3-palmitate (LP) and lupeol-3-linoleate (LL), two synthetic long chain fatty acid ester analogues of the plant-derived anti-inflammatory pentacyclic triterpenoid lupeol (L), were studied in vitro as potential inhibitors of serine protease activity. With respect to the natural protein substrate bovine serum albumin (BSA), lupeol palmitate and lupeol linoleate inhibited trypsin activity in a manner consistent with mixed inhibition (K(IC) values of 103 and 52 microM respectively; K(IU) values of 30 and 14 microM respectively). However, the lupeol esters showed no inhibitory effect on the catalytic activity of porcine pancreatic elastase (PPE) with respect to the synthetic tetrapeptide substrate succinyl-(alanyl)3-p-nitroanilide (SAAANA). The present paper shows the lupeol triterpenes to be selective protease inhibitors.
Chapter
Lupeol induced the hallmarks of B16 2F2 mouse melanoma cell differentiation such as tyrosinase, MITF, Rab27a and myosin-Va, and dendritic formation. We studied the effects of lupeol on some cancer cell migrations. As the results, lupeol markedly inhibited the migration of human melanoma and neuroblastoma cells. Furthermore, the clinical tests revealed that lupeol took some actions on 6 cases of 7 dogs with malignant melanomas. KeywordsLupeol-Melanoma cell differentiation-Cell motility-Spontaneous melanoma