Pentacyclic triterpene distribution in various plants - rich sources for a new group of multi-potent plant extracts.
TL;DR: Pentacyclic triterpenes are secondary plant metabolites widespread in fruit peel, leaves and stem bark display various pharmacological effects while being devoid of prominent toxicity and are promising leading compounds for the development of new multi-targeting bioactive agents.
Abstract: Pentacyclic triterpenes are secondary plant metabolites widespread in fruit peel, leaves and stem bark. In particular the lupane-, oleanane-, and ursane triterpenes display various pharmacological effects while being devoid of prominent toxicity. Therefore, these triterpenes are promising leading compounds for the development of new multi-targeting bioactive agents. Screening of 39 plant materials identified triterpene rich (> 0.1% dry matter) plant parts. Plant materials with high triterpene concentrations were then used to obtain dry extracts by accelerated solvent extraction resulting in a triterpene content of 50 - 90%. Depending on the plant material, betulin (birch bark), betulinic acid (plane bark), oleanolic acid (olive leaves, olive pomace, mistletoe sprouts, clove flowers), ursolic acid (apple pomace) or an equal mixture of the three triterpene acids (rosemary leaves) are the main components of these dry extracts. They are quantitatively characterised plant extracts supplying a high concentration of actives and therefore can be used for development of phytopharmaceutical formulations.
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TL;DR: This review summarizes the potential of triterpenes belonging to the lupane, oleanane or ursane group, to treat cancer by different modes of action and utilisation of different plants as their sources is of interest.
Abstract: Today cancer treatment is not only a question of eliminating cancer cells by induction of cell death. New therapeutic strategies also include targeting the tumour microenvironment, avoiding angiogenesis, modulating the immune response or the chronic inflammation that is often associated with cancer. Furthermore, the induction of redifferentiation of dedifferentiated cancer cells is an interesting aspect in developing new therapy strategies. Plants provide a broad spectrum of potential drug substances for cancer therapy with multifaceted effects and targets. Pentacyclic triterpenes are one group of promising secondary plant metabolites. This review summarizes the potential of triterpenes belonging to the lupane, oleanane or ursane group, to treat cancer by different modes of action. Since Pisha et al. reported in 1995 that betulinic acid is a highly promising anticancer drug after inducing apoptosis in melanoma cell lines in vitro and in vivo, experimental work focused on the apoptosis inducing mechanisms of betulinic acid and other triterpenes. The antitumour effects were subsequently confirmed in a series of cancer cell lines from other origins, for example breast, colon, lung and neuroblastoma. In addition, in the last decade many studies have shown further effects that justify the expectation that triterpenes are useful to treat cancer by several modes of action. Thus, triterpene acids are known mainly for their antiangiogenic effects as well as their differentiation inducing effects. In particular, lupane-type triterpenes, such as betulin, betulinic acid and lupeol, display anti-inflammatory activities which often accompany immune modulation. Triterpene acids as well as triterpene monoalcohols and diols also show an antioxidative potential. The pharmacological potential of triterpenes of the lupane, oleanane or ursane type for cancer treatment seems high; although up to now no clinical trial has been published using these triterpenes in cancer therapy. They provide a multitarget potential for coping with new cancer strategies. Whether this is an effective approach for cancer treatment has to be proven. Because various triterpenes are an increasingly promising group of plant metabolites, the utilisation of different plants as their sources is of interest. Parts of plants, for example birch bark, rosemary leaves, apple peel and mistletoe shoots are rich in triterpenes and provide different triterpene compositions.
426 citations
TL;DR: In these interactions, the addition of SOs to reactive cysteine residues in specific molecular targets triggers biological activity, Ultimately, SOs are multifunctional drugs that regulate the activity of entire networks.
Abstract: We review the rationale for the use of synthetic oleanane triterpenoids (SOs) for prevention and treatment of disease, as well as extensive biological data on this topic resulting from both cell culture and in vivo studies. Emphasis is placed on understanding mechanisms of action. SOs are noncytotoxic drugs with an excellent safety profile. Several hundred SOs have now been synthesized and in vitro have been shown to: 1) suppress inflammation and oxidative stress and therefore be cytoprotective, especially at low nanomolar doses, 2) induce differentiation, and 3) block cell proliferation and induce apoptosis at higher micromolar doses. Animal data on the use of SOs in neurodegenerative diseases and in diseases of the eye, lung, cardiovascular system, liver, gastrointestinal tract, and kidney, as well as in cancer and in metabolic and inflammatory/autoimmune disorders, are reviewed. The importance of the cytoprotective Kelch-like erythroid cell-derived protein with CNC homology-associated protein 1/nuclear factor (erythroid-derived 2)-like 2/antioxidant response element (Keap1/Nrf2/ARE) pathway as a mechanism of action is explained, but interactions with peroxisome proliferator-activated receptor γ (PARPγ), inhibitor of nuclear factor-κB kinase complex (IKK), janus tyrosine kinase/signal transducer and activator of transcription (JAK/STAT), human epidermal growth factor receptor 2 (HER2)/ErbB2/neu, phosphatase and tensin homolog (PTEN), the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) pathway, mammalian target of rapamycin (mTOR), and the thiol proteome are also described. In these interactions, Michael addition of SOs to reactive cysteine residues in specific molecular targets triggers biological activity. Ultimately, SOs are multifunctional drugs that regulate the activity of entire networks. Recent progress in the earliest clinical trials with 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO) methyl ester (bardoxolone methyl) is also summarized.
359 citations
Cites background from "Pentacyclic triterpene distribution..."
...Thus, crystalline ursolic acid (UA) of high purity is easily obtained in 20% yield by methanol extraction of rosemary leaf; the lupane alcohol betulin accounts for up to 20% of the dry weight of the bark from many species of common birch trees; and oleanolic acid (OA) can be easily obtained in high yield from olive pulp remaining after the oil is pressed from the olive fruit, as well as from olive leaves that are usually discarded after the trees are pruned (Jäger et al., 2009)....
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...…weight of the bark from many species of common birch trees; and oleanolic acid (OA) can be easily obtained in high yield from olive pulp remaining after the oil is pressed from the olive fruit, as well as from olive leaves that are usually discarded after the trees are pruned (Jäger et al., 2009)....
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TL;DR: The current state of knowledge about the health-promoting properties of this widespread, biologically active compound, as well as information about its occurrence and biosynthesis are presented.
Abstract: Ursolic acid (UA) is a natural terpene compound exhibiting many pharmaceutical properties. In this review the current state of knowledge about the health-promoting properties of this widespread, biologically active compound, as well as information about its occurrence and biosynthesis are presented. Particular attention has been paid to the application of ursolic acid as an anti-cancer agent; it is worth noticing that clinical tests suggesting the possibility of practical use of UA have already been conducted. Amongst other pharmacological properties of UA one can mention protective effect on lungs, kidneys, liver and brain, anti-inflammatory properties, anabolic effects on skeletal muscles and the ability to suppress bone density loss leading to osteoporosis. Ursolic acid also exhibits anti-microbial features against numerous strains of bacteria, HIV and HCV viruses and Plasmodium protozoa causing malaria.
260 citations
Cites background from "Pentacyclic triterpene distribution..."
...) leaves and flowers, coffee (Coffea arabica) leaves and the wax layer of many edible fruits [8,9]....
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TL;DR: A number of small molecules that have the potential to prevent eNOS uncoupling and, at the same time, enhance eN OS expression are identified and may have therapeutic potential.
Abstract: Nitric oxide (NO) produced by the endothelium is an important protective molecule in the vasculature. It is generated by the enzyme endothelial NO synthase (eNOS). Similar to all NOS isoforms, functional eNOS transfers electrons from nicotinamide adenine dinucleotide phosphate (NADPH), via the flavins flavin adenine dinucleotide and flavin mononucleotide in the carboxy-terminal reductase domain, to the heme in the amino-terminal oxygenase domain. Here, the substrate L-arginine is oxidized to L-citrulline and NO. Cardiovascular risk factors such as diabetes mellitus, hypertension, hypercholesterolaemia or cigarette smoking reduce bioactive NO. These risk factors lead to an enhanced production of reactive oxygen species (ROS) in the vessel wall. NADPH oxidases represent major sources of this ROS and have been found upregulated in the presence of cardiovascular risk factors. NADPH-oxidase-derived superoxide avidly reacts with eNOS-derived NO to form peroxynitrite (ONOO-). The essential NOS cofactor (6R-)5,6,7,8-tetrahydrobiopterin (BH4) is highly sensitive to oxidation by this ONOO-. In BH4 deficiency, oxygen reduction uncouples from NO synthesis, thereby converting NOS to a superoxide-producing enzyme. Among conventional drugs, compounds interfering with the renin-angiotensin-aldosterone system and statins can reduce vascular oxidative stress and increase bioactive NO. In recent years, we have identified a number of small molecules that have the potential to prevent eNOS uncoupling and, at the same time, enhance eNOS expression. These include the protein kinase C inhibitor midostaurin, the pentacyclic triterpenoids ursolic acid and betulinic acid, the eNOS enhancing compounds AVE9488 and AVE3085, and the polyphenolic phytoalexin trans-resveratrol. Such compounds enhance NO production from eNOS also under pathophysiological conditions and may thus have therapeutic potential.
255 citations
Cites background from "Pentacyclic triterpene distribution..."
...Both compounds are devoid of prominent in vivo toxicity (at least in rodents) (Jäger et al., 2009; Mullauer et al., 2010)....
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...They are also important components of oriental and traditional medicine herbs widely distributed all over the world (Ovesna et al., 2004; Jäger et al., 2009)....
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TL;DR: Hundreds of extracts are currently being isolated from plants, fungi, algae, or bacteria with an inhibitory effect on pancreatic lipase activity, which could be applied in the management of the obesity epidemic.
Abstract: Obesity is a multifactorial disease characterized by an excessive weight for height due to an enlarged fat deposition such as adipose tissue, which is attributed to a higher calorie intake than the energy expenditure. The key strategy to combat obesity is to prevent chronic positive impairments in the energy equation. However, it is often difficult to maintain energy balance, because many available foods are high-energy yielding, which is usually accompanied by low levels of physical activity. The pharmaceutical industry has invested many efforts in producing antiobesity drugs; but only a lipid digestion inhibitor obtained from an actinobacterium is currently approved and authorized in Europe for obesity treatment. This compound inhibits the activity of pancreatic lipase, which is one of the enzymes involved in fat digestion. In a similar way, hundreds of extracts are currently being isolated from plants, fungi, algae, or bacteria and screened for their potential inhibition of pancreatic lipase activity. Among them, extracts isolated from common foodstuffs such as tea, soybean, ginseng, yerba mate, peanut, apple, or grapevine have been reported. Some of them are polyphenols and saponins with an inhibitory effect on pancreatic lipase activity, which could be applied in the management of the obesity epidemic.
230 citations
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TL;DR: Experimental data support the notion from a previous clinical study that TE from the outer bark of birch might represent a new tool for the topical treatment of skin cancer and skin cancer precursors like actinic keratoses.
Abstract: Triterpenes are biologically active secondary plant substances that display antimicrobial, hepatoprotective and anti-inflammatory effects. However, the poor solubility of triterpenes in both polar and non-polar solvents as well as expensive purification procedures have prevented the large-scale isolation of these compounds for medicinal purposes. Here, we describe a novel quantitative extraction method of triterpenes from the outer bark of birch (Betula species) in which betulin, a lupan triterpene, predominates. The resulting highly purified triterpene extract (TE) in the form of a dry powder contains betulin as the major compound, but also betulinic acid, lupeol, erythrodiol and oleanolic acid. We have found that this TE is able to form an oleogel, thus providing an opportunity for the topical application of pharmacologically relevant amounts of triterpenes. Furthermore, we have investigated the TE in comparison to its major isolated compounds in cell culture experiments with human immortalized keratinocytes and skin cancer cells. We could demonstrate dose-dependent cytotoxic and apoptosis-inducing effects of TE and betulin. These experimental data support the notion from a previous clinical study that TE from the outer bark of birch might represent a new tool for the topical treatment of skin cancer and skin cancer precursors like actinic keratoses.
90 citations
"Pentacyclic triterpene distribution..." refers background or methods in this paper
...The chromatographic separation was performed using GC-FID and HPLC-UV respectively and the chromatograms were inspected visually for peak purity of spiked triterpenes....
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...The measured amounts, listed in Table 2, show the dominance of BE in birch bark [15]....
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...We previously reported an extraction method with heated n-heptane, were a triterpene dry extract (TE) of birch bark is formed [13,15]....
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...This extraction and quantification method was validated and described for birch bark and mistletoe sprouts [15,22]....
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...The accelerated solvent extraction (ASE) method presented here reaches complete extraction within 45 min without any further clean-up step prior to GC-FID of silylated triterpenes [15,22]....
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TL;DR: In this paper, a combination of ultrasonic extraction, solid phase extraction, size exclusion chromatography, trimethylsilylation, and GC-MS resulted in simultaneous separation, identification and quantification of the mentioned compounds.
Abstract: Phytochemical investigations of different species of Lamiaceae family (rosemary-Rosmarinus officinalis L., sage-Salvia officinalis L., winter savory-Satureja montana L., clary sage-Salvia sclarea L. and sticky sage-Salvia glutinosa L.), using gas chromatography and mass spectrometry (GC-MS) were performed. The studies were focused on oleanolic, betulinic and ursolic acid. Since oleanolic and ursolic acid are position isomers with very similar structures, the difficulties in their separation and identification have been reported by several authors. However, both compounds can be well distinguished by order of elution during gas chromatography and by intensities of the fragment ion signals in their mass spectra, where the retro-Diels-Alder reaction was primarily observed. A combination of ultrasonic extraction, solid phase extraction, size exclusion chromatography, trimethylsilylation, and GC-MS resulted in simultaneous separation, identification and quantification of the mentioned compounds. The compounds have been identified by retention time and comparison of mass spectra with those of pure standards. The mass spectral fragmentation behavior of all three derivatised acids was investigated. The obtained characteristic fragment patterns are discussed in the presented work. Good linearity over the concentration range 1–50 mg L−1 for all three compounds was confirmed. The correlation coefficients (r 2 ) were in the range of 0.9980–0.9983. Quantitative analyses of different Lamiaceae extracts showed that the oleanolic acid content ranged from 0.09 to 0.9% dry weight, content of betulinic acid ranged from traces to 0.6%, and that of ursolic acid varied from 0.09 to 1.6% dry weight.
86 citations
"Pentacyclic triterpene distribution..." refers background or methods or result in this paper
...Using hydrogen as the mobile phase and a more polar ZB-35 column, the separation of triterpenes is better than with helium on a HP-5 column [21]....
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...found more OA than UA but the same summed amount as we quantified [21]....
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...6% UA in rosemary leaves (per dry weight) [21]....
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...combines solvent extraction with solid phase and size exclusion extraction prior to GC-MS of silylated triterpenes [21]....
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TL;DR: High selective identification of triterpenes was confirmed by multiple reaction monitoring (MRM) using the most representative transitions from the precursor ion to the different product ions, while the most sensitive transitions were used for MS-MS quantitation.
79 citations
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...5) [23]...
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...mobile phase [23]....
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...3% MA in fresh olive leaves [23]....
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TL;DR: OA and UA are responsible for the cholesterol lowering effect of hawthorn by inhibiting intestinal ACAT activity, and particularly its bioactive compounds (OA and UA) enhanced the cholesterol lowered effect of plant sterols.
Abstract: Hawthorn (Crataegus pinnatifida) is an edible fruit used in traditional Chinese medicine to lower plasma lipids. This study explored lipid-lowering compounds and underlying mechanisms of action of hawthorn. Hawthorn powder extracts inhibited acylCoA:cholesterol acyltransferase (ACAT) activity in Caco-2 cells. The inhibitory activity was positively associated with triterpenic acid (i.e., oleanolic acid (OA) and ursolic acid (UA)) contents in the extracts. Cholesterol lowering effects of hawthorn and its potential additive effect in combination with plant sterol esters (PSE) were further studied in hamsters. Animals were fed a semi-synthetic diet containing 0.08% (w/w) cholesterol (control) or the same diet supplemented with (i) 0.37% hawthorn dichloromethane extract, (ii) 0.24% PSE, (iii) hawthorn dichloromethane extract (0.37%) plus PSE (0.24%) or (iv) OA/UA mixture (0.01%) for 4 weeks. Compared to the control diet, hawthorn, PSE, hawthorn plus PSE and OA/UA significantly lowered plasma non-HDL (VLDL + LDL) cholesterol concentrations by 8%, 9%, 21% and 6% and decreased hepatic cholesterol ester content by 9%, 23%, 46% and 22%, respectively. The cholesterol lowering effects of these ingredients were conversely associated with their capacities in increasing fecal neutral sterol excretion. In conclusion, OA and UA are responsible for the cholesterol lowering effect of hawthorn by inhibiting intestinal ACAT activity. In addition, hawthorn and particularly its bioactive compounds (OA and UA) enhanced the cholesterol lowering effect of plant sterols.
75 citations
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...52 [32]...
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TL;DR: Interestingly, the developing olive fruit was found to accumulate significant amounts of parkeol as an ester conjugate, indicating a redirection of the carbon flux from the triterpenoid pathway towards the sterol pathway.
Abstract: Drupes were handpicked from olive (Olea europaea L.) trees, cv chemlali, at 13 distinct stages of fruit development, referred to as weeks after flowering (WAF), and analyzed for their free and esterified sterols and triterpenoids content. These two classes of compounds are synthesized via the acetate/mevalonate pathway and share common precursors up to oxidosqualene (OS). Cyclization of OS in either cycloartenol or β-amyrin constitutes a branch point between primary (sterol pathway) and secondary (triterpenoid pathway) metabolisms. At the onset of fruit development, i.e., between 12 and 18 WAF, drupes were found to contain high amounts of α- and β-amyrins as well as more-oxygenated compounds such as triterpenic diols (erythrodiol and uvaol) and acids (oleanolic, ursolic and maslinic acids). Concomitantly, sterol precursors were barely detectable. From 21 WAF, when the olive fruit reached its final size and began to turn from green to purple, α- and β-amyrins were no longer present, while 4,4-dimethyl- and 4α-methylsterols started to be formed, indicating a redirection of the carbon flux from the triterpenoid pathway towards the sterol pathway. Between 21 and 30 WAF, sterol end products, mainly represented by sitosterol, progressively accumulated and triterpenic diols were replaced by triterpenic acids, essentially maslinic acid. Interestingly, the developing olive fruit was found to accumulate significant amounts of parkeol as an ester conjugate. Whatever the stage of development, triterpenoids represent the major triterpenic compounds of the olive fruit.
74 citations
"Pentacyclic triterpene distribution..." refers background in this paper
...Olives contain low amounts of bAM, aAM, ER, UV, 3epi-betulin and higher amounts of OA and MA [37]....
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...23% respectively within the dry matter) during weeks 12 and 30 after flowering [37]....
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