Corosolic Acid Research Articles

In Vitro and In Vivo Inhibitory Activities of Four Indian Medicinal Plant Extracts and their Major Components on Rat Aldose Reductase and Generation of Advanced Glycation Endproducts

The polyol enzyme aldose reductase (AR) and advanced glycation endproducts (AGEs) play an important role in diabetic complications such as cataracts. The purpose of this study was to investigate four standardized plant extracts used for the treatment of diabetes and related diseases, and their principal components for AR inhibitory activity and to find out their influence in diabetic complications. Thus, Boswellia serrata Triana & Planch. (Burseraceae), Lagerstroemia speciosa (L.) Pers. (Lythraceae), Ocimum gratissimum (L.) (Lamiaceae) and Syzygium cumin (L.) Skeels. (Myrthaceae) and their respective major constituents, boswellic acid, corosolic acid, ursolic acid and ellagic acid, were studied for their inhibitory activity against rat lens AR, rat kidney AR, human recombinant AR and generation of AGEs. In addition, in vivo inhibition of lens galactitol accumulation by the major constituents of the plants in galactose-fed rat has been studied. The results revealed that all the tested extracts and their active ingredients possess significant AR inhibitory actions in both in vitro and in vivo assays with urosolic acid showing the most potent effect. Furthermore, the study indicates the potential of the studied plants and their major constituents as possible protective agents against long-term diabetic complications.

Substrate specificity for the 2α-hydroxylation of ursolic acid by Alternaria alternata and the antitumor activities of those metabolites

Abstract Ursolic acid (UA, 1), a major bioactive constituent of apple peels, exhibits a wide spectrum of biological activities, including antioxidant, antitumor, anti-inflammatory, and hypoglycemic properties. The bioconversion of 1 by Alternaria alternata was investigated, and 8 metabolites were isolated and identified. The chemical structures of these metabolites were found to be 2α,3β-dihydroxyurs-12-en-28-oic acid (corosolic acid, 2), urs-12-en-2α,3β,28-triol (3), 3β,23-dihydroxyurs-12-en-28-oic acid (4), 2α,3β,23-trihydroxyurs-12-en-28-oic acid (5), 2α,3β,23,24-tetrahydroxyurs-12-en-28-oic acid (6), 3β,28-dihydroxy-12-ursene (7), urs-12-en-3β-ol (8), and urs-12-en-2α,3β-diol (9), as determined through chemical and spectroscopic analyses. Among these metabolites, 2 was found to be the main bioconversion product, with a yield of 77.6%. The proposed biosynthetic pathways of UA by A. alternata were drawn and are presented in this paper. Metabolites 2, 5 and 6 showed potent antiproliferative activities against human breast cancer (MCF-7, MDA-MB-231), human colon cancer (Caco-2) and human liver cancer (HepG2) cell lines.

Chemical constituents from Sambucus chinensis

Five compounds were separated from Sambucus chinensis and identified as maslinic acid(1), 12alpha, 13-dihydroxyolean-3-oxo-28-oic acid(2), 13-hydroxyolean-3-oxo-28-oic acid (3), 3-oxo oleanolic acid (4), corosolic acid (5). Of them,compound 3 was a new compound, and compounds 1, 2, 4, and 5 were seperated from this plant for the first time.

Management of Diabetes and Its Complications with Banaba (Lagerstroemia speciosaL.) and Corosolic Acid

Banaba (Lagerstroemia speciosa L.) extracts have been used for many years in folk medicine to treat diabetes, with the first published research study being reported in 1940. This paper summarizes the current literature regarding Banaba and its constituents. The hypoglycemic effects of Banaba have been attributed to both corosolic acid as well as ellagitannins. Studies have been conducted in various animal models, human subjects, and in vitro systems using water soluble Banaba leaf extracts, corosolic acid, and ellagitannins. Corosolic acid has been reported to decrease blood sugar levels within 60 min in human subjects. Corosolic acid also exhibits antihyperlipidemic and antioxidant activities. The beneficial effects of Banaba and corosolic acid with respect to various aspects of glucose and lipid metabolism appear to involve multiple mechanisms, including enhanced cellular uptake of glucose, impaired hydrolysis of sucrose and starches, decreased gluconeogenesis, and the regulation of lipid metabolism. These effects may be mediated by PPAR and other signal transduction factors. Banaba extract, corosolic acid, and other constituents may be beneficial in addressing the symptoms associated with metabolic syndrome, as well as offering other health benefits.

Corosolic Acid Ameliorates Atherosclerosis in Apolipoprotein E-Deficient Mice by Regulating the Nuclear Factor-κB Signaling Pathway and Inhibiting Monocyte Chemoattractant Protein-1 Expression

Corosolic acid (CRA) is a pentacyclic triterpene acid that has been shown to exhibit an anti-atherosclerotic effect when added to diets of low-density lipoprotein-deficient mice, but the mechanisms are unclear. The purpose of the present study was to investigate the molecular mechanisms by which CRA ameliorates atherosclerosis. The anti-atherosclerosis effect of CRA in apolipoprotein E-deficient mice fed a Western-type diet was evaluated using atherosclerosis lesion area, serum profiles, gene expression and histological lesions. In vitro, the mechanisms responsible for the anti-inflammatory effect of CRA were investigated on a lipopolysaccharide-induced inflammation model. This model was also used to investigate in detail the effects of CRA on gene expression and nuclear factor (NF)-κB activation. Compared with the control group, the CRA-treated group exhibited a significant decrease in atherosclerotic lesion area, as well as expression of monocyte chemoattractant protein-1 (MCP-1) and CCR2. In vitro studies showed that CRA treatment downregulated the mRNA levels of MCP-1, and inhibited monocyte adhesion and migration, together with suppression of NF-κB signaling pathway. CRA is capable of ameliorating atherosclerosis in apolipoprotein E-deficient mice by, partly at least, inhibition of NF-κB activity along with decreased MCP-1 expression.

Positive Relationship between Anthocyanin and Corosolic Acid Contents in Leaves of Lagerstroemia speciosa Pars.

Corosolic acid content and distribution in Lagerstroemia speciosa Pars. were investigated, indicating that the red leaves contained more corosolic acid than the green leaves and other plant parts such as petals, roots and seeds. The leaf redness was derived from cyanidin 3-O-glucoside which was first identified in this species. The contents of corosolic acid and cyanidin 3-O- glucoside were found to be well correlated, supporting the traditional perception of local people of the Philippines that red leaf banaba tea exerts more pronounced medicinal effects.

A Review of the Efficacy and Safety of Banaba (Lagerstroemia speciosa L.) and Corosolic Acid

Banaba (Lagerstroemia speciosa L.) extracts have been used for many years in folk medicine to treat diabetes, with the first published research study being reported in 1940. This review summarizes the current literature regarding banaba and its constituents. The hypoglycemic effects of banaba have been attributed to both corosolic acid as well as ellagitannins. Studies have been conducted in various animal models, human subjects and in vitro systems using water soluble banaba leaf extracts, corosolic acid-standardized extracts, and purified corosolic acid and ellagitannins. Pure corosolic acid has been reported to decrease blood sugar levels within 60 min in human subjects. Corosolic acid also exhibits antihyperlipidemic, antioxidant, antiinflammatory, antifungal, antiviral, antineoplastic and osteoblastic activities. The beneficial effects of banaba and corosolic acid with respect to various aspects of glucose and lipid metabolism appear to involve multiple mechanisms, including enhanced cellular uptake of glucose, impaired hydrolysis of sucrose and starches, decreased gluconeogenesis and the regulation of lipid metabolism. These effects may be mediated by PPAR, MAP K, NF-κB and other signal transduction factors. No adverse effects have been observed or reported in animal studies or controlled human clinical trials. Banaba extract, corosolic acid and other constituents may be beneficial in addressing the symptoms associated with metabolic syndrome, as well as offering other health benefits.

Oleanolic acid inhibits macrophage differentiation into the M2 phenotype and glioblastoma cell proliferation by suppressing the activation of STAT3

Tumor-associated macrophages (TAMs) polarized to the M2 phenotype promote tumor cell proliferation and are associated with a poor prognosis in patients with high grade glioma. We previously revealed that corosolic acid, a triterpenoid compound, inhibits the M2 polarization of human monocyte-derived macrophages (HMDM). In the present study, we examined whether oleanolic acid (OA), a triterpenoid compound whose structure is similar to corosolic acid, also shows inhibitory effects on M2 polarization in HMDM. OA significantly inhibited the expression of CD163, one of the phenotype markers of M2 macrophages, as well as suppressed the secretion of IL-10, one of the anti-inflammatory cytokines preferentially produced by M2 macrophages, thus suggesting that OA suppresses the M2 polarization of macrophages. Furthermore, OA inhibited the proliferation of U373 human glioblastoma cells, and the activation of signal transducer and activator of transcription-3 (STAT3) in both human macrophages and glioblastoma cells. These results indicate that OA suppresses the M2 polarization of macrophages and tumor cell proliferation by inhibiting STAT3 activation. Therefore, OA may be a potentially new agent that can be used for the prevention and treatment of various malignant tumors, including glioma.

PSidium guajava, a potential resource rich in corosolic acid revealed by high performance liquid chromatography

Corosolic acid (CA) has become one of the most popular natural compounds in recent years because of its insulin-like and anti-cancer activities. In present study, a simple, precise and accurate high performance liquid chromatography method was developed to determine CA in Psidium guajava. An Agilent SB-C18 (4.6 × 250 mm, 5 μm) column was used for separation and analysis. The separation was performed with a constant mobile phase of acetonitrile and 0.2% formic acid in water (75:25) at a flow rate of 1 min/ml. The analytes were detected at the wavelength of 210 nm. The method was validated in terms of calibration curve, sensitivity, precision, accuracy and stability, and was applied to determine CA in leaves and fruits of P. guajava from different locations. The results showed that CA was detected in leaves with the content almost 1%, but not detectable in fruits of P. guajava. After the leaves were hydrolyzed with hydrochloric acid, the content of CA in leaf samples significantly increased up to 1.54%, and the increasing rates were more than 48.6%, suggesting that the leaf of P. guajava is a potential resource rich in CA, and hydrochloric acid hydrolysis might be a cost-effective approach to produce CA from the leaf of P. guajava. Key words: Corosolic acid, Psidium guajava, high performance liquid chromatography (HPLC), acidic hydrolysis.

Ursolic acid derivatives from Bangladeshi medicinal plant, Saurauja roxburghii: Isolation and cytotoxic activity against A431 and C6 glioma cell lines

Ursene-type pentacyclic triterpenes, including the ursolic acid, corosolic acid, and a new ursene-type pentacyclic triterpene, 7,24-dihydroxy ursolic acid, were isolated from the methanolic extract of the leaves of the Bangladeshi medicinal plant, Saurauja roxburghii, a higher plant indigenous to South East Asia and some part of North America. They were tested for the cytotoxicity against C6 rat glioma and A431 human epidermoid carcinoma cell lines. Although they have the same ursene-type pentacyclic triterpene core structure, the position and numbers of hydroxyl groups on the terpene structure significantly affected the activity and the selectivity to the cell lines.

Solubility of Corosolic Acid in Supercritical Carbon Dioxide and Its Representation Using Density-Based Correlations

The solid solubilities of 2α,3β-dihydroxyurs-12-en-28-oic acid (corosolic acid) in supercritical carbon dioxide (SC-CO2) have been measured using a dynamic method at (308.15, 313.15, 323.15, and 333.15) K over a pressure range of (8 to 30) MPa. Prior to solubility measurements, the accuracy of the experimental apparatus was examined by measuring solubilities of squalene in SC-CO2 and comparing them with literature. The corosolic acid solubilities ranged from a corosolic acid mole fraction of 3.28·10−11 at 333.15 K and 8 MPa to 7.43·10−2 at 333.15 K and 30 MPa. The del Valle and Aguilera and Méndez-Santiago and Teja (density-based) models were used to correlate the experimental data. The calculated solubilities showed good agreement with the experimental data in the temperature and pressure ranges studied.

Determination of Corosolic Acid, a Natural Potential Anti-Diabetes Compound, in Rat Plasma by High-Performance Liquid Chromatography-Mass Spectrometry and its Application to Pharmacokinetic and Bioavailability Studies

A simple, robust, and sensitive high-performance liquid chromatography/mass spectrometric method was developed for the determination of corosolic acid, a potential anti-diabetes substance, in rat plasma using glycyrrhetinic acid as the internal standard (IS). This method involved a liquid-liquid extraction with acetic ether and a subsequent analysis performed on an LC-MS system which contained an electrospray ionization interface. Chromatographic separation was performed using an ODS column, and the mobile phase was composed of methanol and 5 mmol/L ammonium acetate (88 : 12, v/v). Good linearity was observed over the concentration range of 20-10 ,000 ng/mL with a correlation coefficient (r² ≥ 0.995. The method was proved to be accurate and reliable and was applied to a pharmacokinetic study in the rat following intragastric and intravenous administration of corosolic acid.

Corosolic Acid Triggers Mitochondria and Caspase‐dependent Apoptotic Cell Death in Osteosarcoma MG‐63 Cells

The response of osteosarcoma MG-63 cells to corosolic acid treatment has been investigated. The results showed that corosolic acid significantly inhibited cell viability in both a dose and a time dependent manner. It was found that corosolic acid increased the Bax/Bcl-2 ratio by up-regulating Bax expression, disrupted mitochondrial membrane potential and triggered the release of cytochrome c from mitochondria into the cytoplasm. Corosolic acid treatment triggered the activation of caspase-8, 9 and 3. The apoptosis was obviously inhibited by pretreatment with a general caspase inhibitor, z-VAD-FMK. Moreover, pretreatment of CsA, a cyclophilin D ligand that inhibits mitochondria potential uncoupling, prevented the activation of caspase-9 and caspase-3, but not caspase-8, and the apoptosis of MG-63 cells, triggered by corosolic acid. All these results indicated that corosolic acid-induced apoptosis was associated with the activation of caspases via a mitochondrial pathway.

Bioprocess and Bioreactor: Next Generation Technology for Production of Potential Plant-based Antidiabetic and Antioxidant Molecules

Globally, diabetes and obesity are two of the most common metabolic diseases of the 21(st) century. Increasingly, not only adults but children and adolescents are being affected. New approaches are needed to prevent and treat these disorders and to reduce the impact of associated disease-related complications. Industrial-scale production using plant-root cultures can produce quantities and quality of inexpensive bioactive small molecules with nutraceutical and pharmaceutical properties. Using this approach, and targeting these diseases, a next generation approach to tackling this emerging global health crisis may be developed. Adventitious roots cultured in bioreactors under controlled and reproducible conditions have been shown effective for production of natural products. The liquid-phase airlift bioreactor in particular has been used successfully for culturing roots on an industrial-scale and thus may provide an economical production platform for expressing promising plant-based antidiabetic and antioxidant molecules. This review focuses on a next-generation, scalable, bioprocessing approach for adventitious and hairy root cultures that are a pesticide-free, seasonally-independent, plant-based source of three molecules that have shown promise for the therapeutic management of diabetes and obesity: corosolic acid, resveratrol and ginsenosides.

Activation of AMP-activated protein kinase on human gastric cancer cells by apoptosis induced by corosolic acid isolated from Weigela subsessilis

Corosolic acid is one of the triterpenoids present in the leaves of Weigela subsessilis. The antidiabetic activity of corosolic acid has been reported previously, but to date, the anticancer effects on gastric cancer have been poorly studied. In this study, corosolic acid showed growth inhibition on SNU-601 human gastric cancer cells, with an IC₅₀ value of 16.9 ± 2.9 μM. Corosolic acid also triggered the activation of caspase-3 and poly (ADP-ribose) polymerase, while it was recovered by Z-VAD-FMK. Moreover, the cell growth/apoptosis activities of corosolic acid were regulated by the AMP-activated protein kinase-mammalian target of rapamycin (AMPK-mTOR) signals. These results showed that corosolic acid-mediated AMPK activation leads to inhibition of mTOR, thus providing a possible mechanism of action of corosolic acid in the inhibition of cancer cell growth and the induction of apoptosis.

Corosolic acid inhibits glioblastoma cell proliferation by suppressing the activation of signal transducer and activator of transcription‐3 and nuclear factor‐kappa B in tumor cells and tumor‐associated macrophages

Tumor-associated macrophages (TAM) of M2 phenotype promote tumor proliferation and are associated with a poor prognosis in patients with glioblastoma. We screened the natural compounds possessing an inhibitory effect on M2 polarization in human monocyte-derived macrophages. Among 130 purified natural compounds examined, corosolic acid significantly inhibited the expression of CD163, one of the phenotype markers of M2 macrophages, and also suppressed the secretion of IL-10, one of the anti-inflammatory cytokines preferentially produced by M2 macrophages, thus suggesting that corosolic acid suppresses M2 polarization of macrophages. Furthermore, corosolic acid inhibited the proliferation of glioblastoma cells, U373 and T98G, and the activation of signal transducer and activator of transcription-3 (STAT3) and nuclear factor-kappa B (NF-κB) in both human macrophages and glioblastoma cells. These results indicate that corosolic acid suppresses the M2 polarization of macrophages and tumor cell proliferation by inhibiting both STAT3 and NF-κB activation. Therefore, corosolic acid might be a potential new tool for tumor prevention and therapy.

In silico access for the discovery of 11β-HSD1 inhibiting triterpenes from Eriobotrya japonica

An elevated activity of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) has been associated with metabolic disorders including obesity and type 2 diabetes, with recent findings providing evidence for beneficial effects of 11β-HSD1 inhibitors, making this enzyme a promising therapeutic target [1]. Recently we investigated different extracts of traditionally used anti-diabetic medicinal plants for potential anti-glucocorticoid effects. Among them, the extracts of E. japonica (Thunb.) Lindl. showed a dose-dependent inhibition of 11β-HSD1, with a preferential inhibition of 11β-HSD1 versus 11β-HSD2 measured in cell lysates. These results were confirmed in intact stably transfected HEK-293 cells [2]. In this study the loquat leaves were phytochemically investigated following predictions of a pharmacophore-based virtual screening. Determination of the 11β-HSD1 and 11β-HSD2 inhibitory activities in cell lysates of virtually predicted hits in combination with a bioactivity-guided approach revealed triterpenes from the ursane type as selective, low µmolar inhibitors of 11β-HSD1: corosolic acid (IC50 0.81µM), 3-epicorosolic acid methyl ester (IC50 5.2µM), 2-α hydroxy-3-oxo urs-12-en-28-oic acid (IC50 17µM), tormentic acid methyl ester (IC50 9.4µM), and ursolic acid (IC50 1.9µM). Intriguingly, a mixture of loquat constituents with moderate activities displayed a pronounced additive effect. By means of molecular modeling studies and the identification of the 11β-HSD1 inhibiting 11-keto-ursolic acid (IC50 2.1µM) and 3-acetyl-11-keto-ursolic acid (IC50 1.3µM) a structure-activity relationship was deduced for this group of pentacyclic triterpenes [3]. The mechanism elucidated in this study together with previously determined pharmacological activities provides this class of compounds from loquat with an astonishing multi-targeted anti-diabetic profile.

Isolation and Identification of Intestinal CYP3A Inhibitors from Cranberry (Vaccinium macrocarpon) Using Human Intestinal Microsomes

Cranberry juice is used routinely, especially among women and the elderly, to prevent and treat urinary tract infections. These individuals are likely to be taking medications concomitantly with cranberry juice, leading to concern about potential drug-dietary substance interactions, particularly in the intestine, which, along with the liver, is rich in expression of the prominent drug metabolizing enzyme, cytochrome P450 3A (CYP3A). Using a systematic in vitro-in vivo approach, a cranberry juice product was identified recently that elicited a pharmacokinetic interaction with the CYP3A probe substrate midazolam in 16 healthy volunteers. Relative to water, cranberry juice inhibited intestinal first-pass midazolam metabolism. In vitro studies were initiated to identify potential enteric CYP3A inhibitors from cranberry via a bioactivity-directed fractionation approach involving dried whole cranberry [Vaccinium macrocarpon Ait. (Ericaceae)], midazolam, and human intestinal microsomes (HIM). Three triterpenes (maslinic acid, corosolic acid, and ursolic acid) were isolated. The inhibitory potency (IC(50)) of maslinic acid, corosolic acid, and ursolic acid was 7.4, 8.8, and < 10 µM, respectively, using HIM as the enzyme source and 2.8, 4.3, and < 10 µM, respectively, using recombinant CYP3A4 as the enzyme source. These in vitro inhibitory potencies, which are within the range of those reported for two CYP3A inhibitory components in grapefruit juice, suggest that these triterpenes may have contributed to the midazolam-cranberry juice interaction observed in the clinical study.

Regulation and improvement of triterpene formation in plant cultured cells of Eriobotrya japonica Lindl

Loquat (Eriobotrya japonica Lindl) is a traditional Chinese medicinal plant that contains triterpenes, which have been shown to exhibit pharmaceutical activities. In this study, we investigated various different culture conditions for cultured cells of loquat to produce triterpenes, including illumination, carbon source, nutrient composition and culture system. When cultured on 2.5mg/l of 6-benzyladenine, 1mg/l of naphthalene acetic acid and 30 g/l of sucrose at 25 ± 2 °C in the dark for 30 days, the nutrient composition significantly regulated the cell growth and triterpene production. Supplied with the Murashige and Skoog medium reached higher level of dry weight (1.27 ± 0.09 g per flask) and total triterpene production (151.54 ± 12.58 mg/g of cultured cells), and the N6 medium produced tormentic acid but inhibited other triterpene products, while the B5 medium produced relatively high corosolic acid. Also found, suspension cultures of loquat cell could achieve high productivity as callus culture.

Antidiabetic Medicinal Plants as a Source of Alpha Glucosidase Inhibitors

The aim of this study is to collate all available data on antidiabetic plants that inhibit alpha glucosidase, reported mainly by Medline (PubMed) these last years. In the present study, interest is focused on experimental researches conducted on hypoglycemic plants particularly those which show alpha glucosidase inhibitor activity alongside bioactive components. This study describes 47 species that belong to 29 families. The plant families, which enclose the species, studied most as inhibitors of alphaglucosidase, are Fabaceae (6 species.), Crassulaceae (3 species), Hippocrateacaea (3 species), Lamiaceae (3 species), and Myrtaceae (3 species), with most studied species being Salacia reticulata (Hippocrateaceae) and Morus alba (Moraceae). The study also covers natural products (active natural components and crude extracts) isolated from the medicinal plants which inhibit alpha glucosidase as reported this last decade. Many kinds of these isolated natural products show strong activity such as, Alkaloids, stilbenoids (polyphenol), triterpene, acids (chlorogenic acid, betulinic acid, syringic acid, vanillic acid, bartogenic acid, oleanolic acid, dehydrotrametenolic acid, corosolic acid, ellagic acid, ursolic acid, gallic acid), phytosterol, myoinositol, flavonoids, Flavonolignans, anthraquinones, anthrones, and xanthones, Feruloylglucosides, flavanone glucosides, acetophenone glucosides, glucopyranoside derivatives, genine derivatives, flavonol, anthocyanin and others.