Evaluation of antimicrobial activity of extracts of Tibouchina candolleana (melastomataceae), isolated compounds and semi-synthetic derivatives against endodontic bacteria

PubMed Central

dos Santos, Fernanda M.; de Souza, Maria Gorete; Crotti, Antônio E. Miller; Martins, Carlos H. G.; Ambrósio, Sérgio R.; Veneziani, Rodrigo C. S.; e Silva, Márcio L. Andrade; Cunha, Wilson R.

2012-01-01

This work describes the phytochemical study of the extracts from aerial parts of Tibouchina candolleana as well as the evaluation of the antimicrobial activity of extracts, isolated compounds, and semi-synthetic derivatives of ursolic acid against endodontic bacteria. HRGC analysis of the n-hexane extract of T. candolleana allowed identification of β-amyrin, α-amyrin, and β-sitosterol as major constituents. The triterpenes ursolic acid and oleanolic acid were isolated from the methylene chloride extract and identified. In addition, the flavonoids luteolin and genistein were isolated from the ethanol extract and identified. The antimicrobial activity was investigated via determination of the minimum inhibitory concentration (MIC) using the broth microdilution method. Amongst the isolated compounds, ursolic acid was the most effective against the selected endodontic bacteria. As for the semi-synthetic ursolic acid derivatives, only the methyl ester derivative potentiated the activity against Bacteroides fragilis. PMID:24031892

Bioassay-guided fractionation and identification of α-amylase inhibitors from Syzygium cumini leaves.

PubMed

Poongunran, Jeyakumaran; Perera, Handunge Kumudu Irani; Jayasinghe, Lalith; Fernando, Irushika Thushari; Sivakanesan, Ramaiah; Araya, Hiroshi; Fujimoto, Yoshinori

2017-12-01

Pancreatic α-amylase and α-glucosidase inhibitors serve as important strategies in the management of blood glucose. Even though Syzygium cumini (L.) Skeels (Myrtaceae) (SC) is used extensively to treat diabetes; scientific evidence on antidiabetic effects of SC leaves is scarce. SC leaf extract was investigated for α-amylase inhibitory effect and continued with isolation and identification of α-amylase inhibitors. Bioassay-guided fractionation was conducted using in vitro α-amylase inhibitory assay (with 20-1000 μg/mL test material) to isolate the inhibitory compounds from ethyl acetate extract of SC leaves. Structures of the isolated inhibitory compounds were elucidated using 1 H NMR and 13 C NMR spectroscopic analysis and direct TLC and HPLC comparison with authentic samples. Study period was from October 2013 to October 2015. An active fraction obtained with chromatographic separation of the extract inhibited porcine pancreatic α-amylase with an IC 50 of 39.9 μg/mL. Furthermore, it showed a strong inhibition on α-glucosidase with an IC 50 of 28.2 μg/mL. The active fraction was determined to be a 3:1 mixture of ursolic acid and oleanolic acid. Pure ursolic acid and oleanolic acid showed IC 50 values of 6.7 and 57.4 μg/mL, respectively, against α-amylase and 3.1 and 44.1 μg/mL respectively, against α-glucosidase. The present study revealed strong α-amylase and α-glucosidase inhibitory effects of ursolic acid and oleanolic acid isolated from SC leaves for the first time validating the use of SC leaves in antidiabetic therapy.

Steroid-like compounds in Chinese medicines promote blood circulation via inhibition of Na+/K+-ATPase

PubMed Central

Chen, Ronald JY; Chung, Tse-yu; Li, Feng-yin; Yang, Wei-hung; Jinn, Tzyy-rong; Tzen, Jason TC

2010-01-01

Aim: To examine if steroid-like compounds found in many Chinese medicinal products conventionally used for the promotion of blood circulation may act as active components via the same molecular mechanism triggered by cardiac glycosides, such as ouabain. Methods: The inhibitory potency of ouabain and the identified steroid-like compounds on Na+/K+-ATPase activity was examined and compared. Molecular modeling was exhibited for the docking of these compounds to Na+/K+-ATPase. Results: All the examined steroid-like compounds displayed more or less inhibition on Na+/K+-ATPase, with bufalin (structurally almost equivalent to ouabain) exhibiting significantly higher inhibitory potency than the others. In the pentacyclic triterpenoids examined, ursolic acid and oleanolic acid were moderate inhibitors of Na+/K+-ATPase, and their inhibitory potency was comparable to that of ginsenoside Rh2. The relatively high inhibitory potency of ursolic acid or oleanolic acid was due to the formation of a hydrogen bond between its carboxyl group and the Ile322 residue in the deep cavity close to two K+ binding sites of Na+/K+-ATPase. Moreover, the drastic difference observed in the inhibitory potency of ouabain, bufalin, ginsenoside Rh2, and pentacyclic triterpenoids is ascribed mainly to the number of hydrogen bonds and partially to the strength of hydrophobic interaction between the compounds and residues around the deep cavity of Na+/K+-ATPase. Conclusion: Steroid-like compounds seem to contribute to therapeutic effects of many cardioactive Chinese medicinal products. Chinese herbs, such as Prunella vulgaris L, rich in ursolic acid, oleanolic acid and their glycoside derivatives may be adequate sources for cardiac therapy via effective inhibition on Na+/K+-ATPase. PMID:20523340

Hawthorn ethanolic extracts with triterpenoids and flavonoids exert hepatoprotective effects and suppress the hypercholesterolemia-induced oxidative stress in rats.

PubMed

Rezaei-Golmisheh, Ali; Malekinejad, Hassan; Asri-Rezaei, Siamak; Farshid, Amir Abbas; Akbari, Peyman

2015-07-01

The current study was aimed to determine the bioactive constituents and biological effects of the Crataegus monogyna ethanolic extracts from bark, leaves and berries on hypercholesterolemia. Oleanolic acid, ursolic acid, quercetin and lupeol concentrations were quantified by HPLC. Total phenol content and radical scavenging activity of extracts were also measured. The hypocholesterolemic, antioxidant, and hepatoprotective effects of the extracts were examined in hypercholesterolemic rats and compared with orlistat. The highest phenol content, oleanolic acid, quercetin and lupeol levels and free radical scavenging potency were found in the bark extract, and the highest ursolic acid level was found in the berries extract. Orlistat and extracts significantly (P<0.05) lowered the hypercholesterolemia-increased serum level of hepatic enzymes and lipid peroxidation level. Hawthorn's extracts protected from hepatic thiol depletion and improved the lipid profile and hepatic damages. Data suggested that hawthorn's extracts are able to protect from hypercholesterolemia-induced oxidative stress and hepatic injuries. Moreover, the hypocholesterolemic effect of extracts was found comparable to orlistat.

Antiproliferative terpenoids from almond hulls (Prunus dulcis): identification and structure-activity relationships.

PubMed

Amico, Vincenzo; Barresi, Vincenza; Condorelli, Daniele; Spatafora, Carmela; Tringali, Corrado

2006-02-08

Bioassay-guided fractionation of the EtOAc crude extract from Sicilian almond hulls, a waste material from Prunus dulcis crop, allowed identification of 10 constituents, isolated as pure compounds (1-5, 7, and 10) or unseparable mixtures (5 + 6 and 8 + 9). All compounds were subjected to spectroscopic analysis and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide bioassay on MCF-7 human breast cancer cells. In addition to the main components oleanolic (1), ursolic (2), and betulinic (3) acids, the 2-hydroxy analogues alphitolic (4), corosolic (5), and maslinic (6) acids, as well as the related aldehydes, namely, betulinic (7), oleanolic (8), and ursolic (9), were identified. From a more polar fraction, the beta-sitosterol 3-O-glucoside (10) was also identified. A sample of commercially available betulin (11) was also included in bioassays as further support to a structure-activity relationship study. Betulinic acid showed antiproliferative activity toward MCF-7 cells (GI50 = 0.27 microM), higher than the anticancer drug 5-fluorouracil.

Ursolic acid enhances pentobarbital-induced sleeping behaviors via GABAergic neurotransmission in mice.

PubMed

Jeon, Se Jin; Park, Ho Jae; Gao, Qingtao; Pena, Irene Joy Dela; Park, Se Jin; Lee, Hyung Eun; Woo, Hyun; Kim, Hee Jin; Cheong, Jae Hoon; Hong, Eunyoung; Ryu, Jong Hoon

2015-09-05

Prunella vulgaris is widely used as a herbal medicine for cancers, inflammatory diseases, and other infections. Although it has long been used, few studies have examined its effects on central nervous system function. Here, we first observed that ethanolic extracts of P. vulgaris (EEPV) prolonged pentobarbital-induced sleep duration in mice. It is known that EEPV consists of many active components including triterpenoid (ursolic acid and oleanolic acid), which have many biological activities. Therefore, we evaluated which EEPV components induced sleep extension in pentobarbital-mediated sleeping model in mice. Surprisingly, despite their structural similarity and other common functions such as anti-inflammation, anti-cancer, and tissue protection, only ursolic acid enhanced sleep duration in pentobarbital-treated mice. These results were attenuated by bicuculline treatment, which is a GABAA receptor antagonist. The present results suggest that ursolic acid from P. vulgaris enhances sleep duration through GABAA receptor activation and could be a therapeutic candidate for insomnia treatment. Copyright © 2015 Elsevier B.V. All rights reserved.

Hawthorn ethanolic extracts with triterpenoids and flavonoids exert hepatoprotective effects and suppress the hypercholesterolemia-induced oxidative stress in rats

PubMed Central

Rezaei-Golmisheh, Ali; Malekinejad, Hassan; Asri-Rezaei, Siamak; Farshid, Amir Abbas; Akbari, Peyman

2015-01-01

Objective(s): The current study was aimed to determine the bioactive constituents and biological effects of the Crataegus monogyna ethanolic extracts from bark, leaves and berries on hypercholesterolemia. Materials and Methods: Oleanolic acid, ursolic acid, quercetin and lupeol concentrations were quantified by HPLC. Total phenol content and radical scavenging activity of extracts were also measured. The hypocholesterolemic, antioxidant, and hepatoprotective effects of the extracts were examined in hypercholesterolemic rats and compared with orlistat. Results: The highest phenol content, oleanolic acid, quercetin and lupeol levels and free radical scavenging potency were found in the bark extract, and the highest ursolic acid level was found in the berries extract. Orlistat and extracts significantly (P<0.05) lowered the hypercholesterolemia-increased serum level of hepatic enzymes and lipid peroxidation level. Hawthorn’s extracts protected from hepatic thiol depletion and improved the lipid profile and hepatic damages. Conclusion: Data suggested that hawthorn’s extracts are able to protect from hypercholesterolemia-induced oxidative stress and hepatic injuries. Moreover, the hypocholesterolemic effect of extracts was found comparable to orlistat. PMID:26361538

Antimicrobial Activity of Oleanolic and Ursolic Acids: An Update

PubMed Central

Jesus, Jéssica A.; Lago, João Henrique G.; Laurenti, Márcia D.; Yamamoto, Eduardo S.; Passero, Luiz Felipe D.

2015-01-01

Triterpenoids are the most representative group of phytochemicals, as they comprise more than 20,000 recognized molecules. These compounds are biosynthesized in plants via squalene cyclization, a C30 hydrocarbon that is considered to be the precursor of all steroids. Due to their low hydrophilicity, triterpenes were considered to be inactive for a long period of time; however, evidence regarding their wide range of pharmacological activities is emerging, and elegant studies have highlighted these activities. Several triterpenic skeletons have been described, including some that have presented with pentacyclic features, such as oleanolic and ursolic acids. These compounds have displayed incontestable biological activity, such as antibacterial, antiviral, and antiprotozoal effects, which were not included in a single review until now. Thus, the present review investigates the potential use of these triterpenes against human pathogens, including their mechanisms of action, via in vivo studies, and the future perspectives about the use of compounds for human or even animal health are also discussed. PMID:25793002

[Studies on the triterpenoids of Cyclocarya paliurus (Batal.) Iljinsk].

PubMed

Shu, Rengeng; Liu, Yufeng; Chen, Jie; Shu, Jicheng

2005-07-01

Three triterpenes (I-II) were obtained from the leaves of Cyclocarya paliurus (Batal.) Iljinsk. By means of physicochemical and spectral methods, the structures of the three triterpenes were identified as oleanolic acid (I), ursolic acid (II) and epikatonic acid (III) respectively. All of the three triterpenes were isolated for the first time from the plant of Cyclocarya paliurus (Batal.) Iljinsk.

Podophyllotoxin and other aryltetralin lignans from Eriope latifolia and Eriope blanchetii.

PubMed

Santos, Edlene O; Lima, Luciano S; David, Jorge M; Martins, Lidiane C; Guedes, Maria Lenise S; David, Juceni P

2011-09-01

Phytochemical investigation of the aerial parts of Eriope blanchetii and E. latifolia (Lamiaceae) yielded podophyllotoxin, as well as the aryltetralin lignans α- and β-peltatin and yatein. Oleanolic, ursolic and epikatonic acids were also isolated. This is the first occurrence of podophyllotoxin in the family.

In vitro trypanocidal activity of triterpenes from miconia species.

PubMed

Cunha, Wilson Roberto; Martins, Camila; da Silva Ferreira, Daniele; Crotti, Antonio Eduardo Miller; Lopes, Norberto Peporine; Albuquerque, Sérgio

2003-05-01

The bioassay-guided fractionation of methylene chloride extracts of Miconia fallax DC. and Miconia stenostachya DC. led to the isolation of five triterpene acids. The triterpenes ursolic acid, oleanolic acid and gypsogenic acid were active against blood trypomastigote forms of Trypanosoma cruzi. In contrast, the acetyl and methyl ester derivatives were not found to potentiate the trypanocidal activity. These results suggest the importance of the polar groups for activity.

A new ethylene glycol triterpenoid from the leaves of Psidium guajava.

PubMed

Begum, Sabira; Ali, Syed Nawazish; Hassan, Syed Imran; Siddiqui, Bina S

2007-07-10

One new pentacyclic triterpenoid psidiumoic acid (5) along with four known compounds beta-sitosterol (1), obtusol (2), oleanolic acid (3), and ursolic acid (4) have been isolated from the leaves of Psidium guajava. The new constituent 5 has been characterized as 2 alpha-glycolyl-3beta-hydroxyolean-12-en-28-oic acid through 2D NMR techniques. This is the first report of isolation of compound 2 from the genus Psidium.

In vivo activity of ursolic and oleanolic acids during the acute phase of Trypanosoma cruzi infection.

PubMed

da Silva Ferreira, Daniele; Esperandim, Viviane Rodrigues; Toldo, Miriam Paula Alonso; Kuehn, Christian Collins; do Prado Júnior, José Clóvis; Cunha, Wilson Roberto; e Silva, Márcio Luís Andrade; de Albuquerque, Sérgio

2013-08-01

Reduction in the parasitemic levels of the Y strain of Trypanosoma cruzi in mice treated with oral or intraperitoneal ursolic (UA) and oleanolic (OA) acids was evaluated during the acute phase of Chagas' disease. Oral administration of UA and OA (50mg/kg/day) provided the most significant reduction in the parasitemic peak, while intraperitoneal administration of UA and OA did not significantly affect the biological activity of the Y strain of T. cruzi. Interleukin levels in mice treated by the intraperitoneal route were compared to untreated chagasic mice. Reduced γ-IFN levels and enhanced IL-10 concentrations potentially explain the exacerbated parasitemia. Our data suggests an immunosuppressive effect for UA and OA, which could interfere with host control of parasitemia. Optimal results were achieved with oral administration. This observation may be explained by the low intestinal absorption of UA and OA, could cause a reduced immune response and promote parasite control. Taken together, these data demonstrate that triterpenes could be interesting compounds to develop therapeutically for the treatment of Chagas' disease. Copyright © 2013 Elsevier Inc. All rights reserved.

Isoprene derivatives from the leaves and callus cultures of Vaccinium corymbosum var. bluecrop.

PubMed

Migas, Piotr; Cisowski, Wojciech; Dembińska-Migas, Wanda

2005-01-01

The phytochemical analysis of Vaccinium corymbosum var bluecrop leaves and callus biomass revealed ursolic acid, oleanolic acid, alpha-amyrin and beta-amyrin in both plant materials. Beta-sitosterol was determined only in callus biomass. The structure of isolated compounds was elucidated by TLC co-chromatography with standards and with spectroscopic methods (1H NMR, 13C NMR, EI-MS).

In vivo analgesic and anti-inflammatory activities of ursolic acid and oleanoic acid from Miconia albicans (Melastomataceae).

PubMed

Vasconcelos, Maria Anita L; Royo, Vanessa A; Ferreira, Daniele S; Crotti, Antonio E Miller; Andrade e Silva, Márcio L; Carvalho, José Carlos T; Bastos, Jairo Kenupp; Cunha, Wilson R

2006-01-01

The aim of this work was to use in vivo models to evaluate the analgesic and anti-inflammatory activities of ursolic acid (UA) and oleanoic acid (OA), the major compounds isolated as an isomeric mixture from the crude methylene chloride extract of Miconia albicans aerial parts in an attempt to clarify if these compounds are responsible for the analgesic properties displayed by this plant. Ursolic acid inhibited abdominal constriction in a dose-dependent manner, and the result obtained at a content of 40 mg kg(-1) was similar to that produced by administration of acetylsalicylic acid at a content of 100 mg kg(-1). Both acids reduced the number of paw licks in the second phase of the formalin test, and both of them displayed a significant anti-inflammatory effect at a content of 40 mg kg(-1). It is noteworthy that the administration of the isolated mixture, containing 65% ursolic acid/35% oleanolic acid, did not display significant analgesic and anti-inflammatory activities. On the basis of the obtained results, considering that the mixture of UA and OA was poorly active, it is suggested that other compounds, rather than UA and OA, should be responsible for the evaluated activities in the crude extract, since the crude extract samples displayed good activities.

Determination of Oleanolic and Ursolic Acids in Hedyotis diffusa Using Hyphenated Ultrasound-Assisted Supercritical Carbon Dioxide Extraction and Chromatography

PubMed Central

Hong, Show-Jen

2015-01-01

Oleanolic acid (OA) and ursolic acid (UA) were extracted from Hedyotis diffusa using a hyphenated procedure of ultrasound-assisted and supercritical carbon dioxide (HSC–CO2) extraction at different temperatures, pressures, cosolvent percentages, and SC–CO2 flow rates. The results indicated that these parameters significantly affected the extraction yield. The maximal yields of OA (0.917 mg/g of dry plant) and UA (3.540 mg/g of dry plant) were obtained at a dynamic extraction time of 110 min, a static extraction time of 15 min, 28.2 MPa, and 56°C with a 12.5% (v/v) cosolvent (ethanol/water = 82/18, v/v) and SC–CO2 flowing at 2.3 mL/min (STP). The extracted yields were then analyzed by high performance liquid chromatography (HPLC) to quantify the OA and UA. The present findings revealed that H. diffusa is a potential source of OA and UA. In addition, using the hyphenated procedure for extraction is a promising and alternative process for recovering OA and UA from H. diffusa at high concentrations. PMID:26089939

Ursolic acid and oleanolic acid suppress preneoplastic lesions induced by 1,2-dimethylhydrazine in rat colon.

PubMed

Furtado, Ricardo A; Rodrigues, Erlon P; Araújo, Felipe R R; Oliveira, Wendel L; Furtado, Michelle A; Castro, Márcio B; Cunha, Wilson R; Tavares, Denise C

2008-06-01

Ursolic acid (UA) and oleanolic acid (OA) are pentacyclic triterpenoid compounds found in plants used in the human diet and in medicinal herbs, in the form of aglycones or as the free acid. These compounds are known for their hepatoprotective, anti-inflammatory, antimicrobial, hypoglycemic, antimutagenic, antioxidant, and antifertility activities. In the present study, we evaluated the effects of UA and OA on the formation of 1,2-dimethyl-hydrazine (DMH)-induced aberrant crypt foci (ACF) in the colon of the male Wistar rat. The animals received subcutaneous (sc) injections of DMH (40 mg/kg body weight) twice a week for two weeks to induce ACF. UA, OA and a mixture of UA and OA were administered to the rats five times a week for four weeks by gavage at doses of 25 mg/kg body weight/day each, during and after DMH treatment. All animals were sacrificed in week 5 for the evaluation of ACF. The results showed a significant reduction in the frequency of ACF in the group treated with the triterpenoid compounds plus DMH when compared to those treated with DMH alone, suggesting that UA and OA suppress the formation of ACF and have a protective effect against colon carcinogenesis.

Chemical Composition and Bioactivities of Two Common Chaenomeles Fruits in China: Chaenomeles speciosa and Chaenomeles sinensis.

PubMed

Miao, Jing; Zhao, Chengcheng; Li, Xia; Chen, Xuetao; Mao, Xinhui; Huang, Hanhan; Wang, Tingting; Gao, Wenyuan

2016-08-01

Contents of total flavonoids, total phenolics, total triterpenes, total condensed tannin and total saponins in peels, flesh and endocarps of Chaenomeles speciosa (CSP) and Chaenomeles sinensis (CSS) were determined by colorimetric method, while 5 phenolics (vanillic, gallic, chlorogenic, ferulic and p-coumaric acids), 2 triterpenes (oleanolic and ursolic acids), and 3 flavonoids (rutin, catechin and epicatechin) were identified and quantified by high-performance liquid chromatography-mass spectrometry (HPLC-MS) and HPLC, and antioxidant and α-glucosidase inhibitory activities of them also were evaluated as well as their digestive characteristics. In the correlation analysis, total phenolics, vanillic acid, catechin, ursolic acid and oleanolic acid all contribute to DPPH(·) scavenge capacity, gallic acid contributes to total ferric reducing antioxidant power, while total triterpenes, total saponins, chlorogenic acid and ferullic acid contribute to α-glucosidase inhibitory activity. In the principal component analysis, endocarps of CSP and CSS both show better quality than their peels and flesh, respectively. In vitro digestion can increase contents of total flavonoids, total condensed tannin and total saponins, while contents of total phenolics and total triterpenes decreased greatly. Our study would contribute to the full use of discarded parts of the 2 Chaenomeles and be helpful to establish a good foundation for further research of CSP and CSS. © 2016 Institute of Food Technologists®

Simultaneous Analysis of Ursolic Acid and Oleanolic Acid in Guava Leaves Using QuEChERS-Based Extraction Followed by High-Performance Liquid Chromatography

PubMed Central

Xu, Chang; Liao, Yiyi; Fang, Chunyan; Zhang, Yingxia

2017-01-01

In this paper, a novel method of QuEChERS-based extraction coupled with high-performance liquid chromatography has been developed for the simultaneous determination of ursolic acid (UA) and oleanolic acid (OA) in guava leaves. The QuEChERS-based extraction parameters, including the amount of added salt, vortex-assisted extraction time, and absorbent amount, and the chromatographic conditions were investigated for the analysis of UA and OA in guava leaves. Under the optimized conditions, the method showed good linearity over a range of 1–320 μg mL−1, with correlation coefficients above 0.999. The limits of detection of UA and OA were 0.18 and 0.36 μg mL−1, respectively. The intraday and interday precision were below 1.95 and 2.55%, respectively. The accuracies of the UA and OA determinations ranged from 97.4 to 111.4%. The contents of UA and OA in the guava leaf samples were 2.50 and 0.73 mg g−1, respectively. These results demonstrate that the developed method is applicable to the simultaneous determination of UA and OA in guava leaves. PMID:28781908

Dereplication of pentacyclic triterpenoids in plants by GC-EI/MS.

PubMed

Gu, Jian-Qiao; Wang, Yuehong; Franzblau, Scott G; Montenegro, Gloria; Timmermann, Barbara N

2006-01-01

Three common plant-derived pentacyclic triterpenoids, oleanolic acid (1), betulinic acid (2) and ursolic acid (3), have been found to exhibit moderate anti-tubercular activity in a microplate alamar blue assay. In order to facilitate the discovery of novel anti-tubercular leads with diverse chemical structures, a new and rapid GC-EI/MS method was developed simultaneously and unambiguously to dereplicate 1-3 as their methyl esters with limits of detection of 25.6, 26.9 and 26.8 ng, respectively.

The role of pentacyclic triterpenoids in the allelopathic effects of Alstonia scholaris.

PubMed

Wang, Chao-Min; Chen, Hsiao-Ting; Li, Tsai-Chi; Weng, Jen-Hsien; Jhan, Yun-Lian; Lin, Shi-Xun; Chou, Chang-Hung

2014-01-01

Alstonia scholaris is a tropical evergreen tree native to South and Southeast Asia. Alstonia forests frequently lack understory species. However, potential mechanisms-particularly the allelochemicals involved-remain unclear. In the present study, we identified allelochemicals of A. scholaris, and clarified the role of allelopathic substances from A. scholaris in interactions with neighboring plants. We showed that the leaves, litter, and soil from A. scholaris inhibited growth of Bidens pilosa-a weed found growing abundantly near A. scholaris forests. The allelochemicals were identified as pentacyclic triterpenoids, including betulinic acid, oleanolic acid, and ursolic acid by using (1)H and (13)C-NMR spectroscopy. The half-maximal inhibitory concentration (IC50) for radicle growth of B. pilosa and Lactuca sativa ranged from 78.8 μM to 735.2 μM, and ursolic acid inhibited seed germination of B. pilosa. The triterpenoid concentrations in the leaves, litter, and soil were quantified with liquid chromatography-electrospray ionization/tandem mass spectrometry. Ursolic acid was present in forest soil at a concentration of 3,095 μg/g, i.e., exceeding the IC50. In the field, ursolic acid accumulated abundantly in the soil in A. scholaris forests, and suppressed weed growth during summer and winter. Our results indicate that A. scholaris pentacyclic triterpenoids influence the growth of neighboring weeds by inhibiting seed germination, radicle growth, and functioning of photosystem II.

Rapid and Sensitive Quantification of Ursolic Acid and Oleanolic Acid in Human Plasma Using Ultra-performance Liquid Chromatography-Mass Spectrometry.

PubMed

Stebounova, Larissa; Ebert, Scott M; Murry, Logan T; Adams, Christopher M; Murry, Daryl J

2018-04-26

Ultra-performance liquid chromatography (UPLC) interfaced with atmospheric pressure chemical ionization mass-spectrometry was used to separate and quantify ursolic acid (UA) and oleanolic acid (OA) in human plasma. UA and OA were extracted from 0.5 mL human plasma using supported liquid extraction and separated utilizing an Acquity UPLC HSS column. The method has been validated for both UA and OA quantitation with a limit of detection of 0.5 ng/mL. The UPLC separations are carried out with isocratic elution with methanol and 5 mM ammonium acetate in water (85:15) as a mobile phase at a flow rate of 0.4 mL/min. The assay was linear from 1 ng/mL to 100 ng/mL for both analytes. The total analysis time was 7 min with the retention times of 3.25 (internal standard), 3.65 (UA) and 3.85 min (OA). Recovery of drug from plasma ranged from 70% to 115%. Analysis of quality control samples at 3, 30 and 80 ng/mL (n = 14) had an intra-day coefficient of variation of 9.9%, 4.3% and 5.5%, respectively. A proof-of-concept study in human patients who consumed apple peels indicates that this analytical method could be applied to clinical studies of UA and/or OA in human subjects.

Ursolic Acid and Oleanolic Acid: Pentacyclic Terpenoids with Promising Anti-Inflammatory Activities.

PubMed

Kashyap, Dharambir; Sharma, Ajay; Tuli, Hardeep S; Punia, Sandeep; Sharma, Anil K

2016-01-01

Plant derived products are not only served as dietary components but also used to treat and prevent the inflammatory associated diseases like cancer. Among the natural products pentacyclic terpenoids including ursolic acid and oleanolic acid are considered as the promising anti-inflammatory therapeutic agents. The current review extensively discusses the anti-inflammatory therapeutic potential of these pentacyclic moieties along with their proposed mechanisms of action. Furthermore, the relevant patents have also been listed to present the health benefits of these promising therapeutic agents to pin down the inflammatory diseases. Expert opinion: Pentacyclic terpenoids are known to negatively down-regulate a variety of extracellular and intracellular molecular targets associated with disease progression. The major anti-inflammatory effects of these molecules have been found to be mediated via inactivation of NFkB, STAT3/6, Akt/mTOR pathways. A number of patents on UA & OA based moieties have been reported between 2010 and 2016. Still there have been only a few compounds which meet the need of sufficient hydro solubility and bioavailability along with higher anti-inflammatory activities. Thus, it is essential to develop novel derivatives of terpenpoids which may not only overcome the solubility issues but also may improve their therapeutic effects. In addition, scientific community may utilize nanotechnology based drug delivery systems so as to increase the bio-availability, selectivity and dosages related problems.

Determination of betulinic acid, oleanolic acid and ursolic acid from Achyranthes aspera L. using RP-UFLC-DAD analysis and evaluation of various parameters for their optimum yield.

PubMed

Pai, Sandeep R; Upadhya, Vinayak; Hegde, Harsha V; Joshi, Rajesh K; Kholkute, Sanjiva D

2016-03-01

Achyranthes aspera L. is a well known herb commonly used in traditional system of Indian medicine to treat various disorders, such as cough, dysentery, gonorrhea, piles, kidney stone, pneumonia, renal dropsy, skin eruptions, snake bite, etc. Here, we used RP-UFLC-DAD method for determining triterpenoids betulinic acid (BA), oleanolic acid (OA) and ursolic acid (UA) from A. aspera. Optimum yield of these compounds were studied and evaluated using parameters viz., method of extraction, time of extraction, age of plant and plant parts (leaves, stem and roots). Linear relationships in RP-UFLC-DAD analysis were obtained in the range 0.05-100 µg/mL with 0.035, 0.042 and 0.033 µg/mL LOD for BA, OA and UA, respectively. Of the variables tested, extraction method and parts used significantly affected content yield. Continuous shaking extraction (CSE) at ambient temperature gave better extraction efficiency than exposure to ultra sonic extraction (USE) or microwave assisted extraction (MAE) methods. The highest content of BA, OA and UA were determined individually in leaf, stem and root extracts with CSE. Collective yield of these triterpenoids were higher in leaf part exposed to 15 min USE method. To best of our knowledge, the study newly reports UA from A. aspera and the same was confirmed using ATR-FT-IR studies. This study explains the distribution pattern of these major triterpenoids and optimum extraction parameters in detail.

An unusual plant triterpene synthase with predominant α-amyrin-producing activity identified by characterizing oxidosqualene cyclases from Malus × domestica.

PubMed

Brendolise, Cyril; Yauk, Yar-Khing; Eberhard, Ellen D; Wang, Mindy; Chagne, David; Andre, Christelle; Greenwood, David R; Beuning, Lesley L

2011-07-01

The pentacyclic triterpenes, in particular ursolic acid and oleanolic acid and their derivatives, exist abundantly in the plant kingdom, where they are well known for their anti-inflammatory, antitumour and antimicrobial properties. α-Amyrin and β-amyrin are the precursors of ursolic and oleanolic acids, respectively, formed by concerted cyclization of squalene epoxide by a complex synthase reaction. We identified three full-length expressed sequence tag sequences in cDNA libraries constructed from apple (Malus × domestica 'Royal Gala') that were likely to encode triterpene synthases. Two of these expressed sequence tag sequences were essentially identical (> 99% amino acid similarity; MdOSC1 and MdOSC3). MdOSC1 and MdOSC2 were expressed by transient expression in Nicotiana benthamiana leaves and by expression in the yeast Pichia methanolica. The resulting products were analysed by GC and GC-MS. MdOSC1 was shown to be a mixed amyrin synthase (a 5 : 1 ratio of α-amyrin to β-amyrin). MdOSC1 is the only triterpene synthase so far identified in which the level of α-amyrin produced is > 80% of the total product and is, therefore, primarily an α-amyrin synthase. No product was evident for MdOSC2 when expressed either transiently or in yeast, suggesting that this putative triterpene synthase is either encoded by a pseudogene or does not express well in these systems. Transcript expression analysis in Royal Gala indicated that the genes are mostly expressed in apple peel, and that the MdOSC2 expression level was much lower than that of MdOSC1 and MdOSC3 in all the tissues tested. Amyrin content analysis was undertaken by LC-MS, and demonstrated that levels and ratios differ between tissues, but that the true consequence of synthase activity is reflected in the ursolic/oleanolic acid content and in further triterpenoids derived from them. Phylogenetic analysis placed the three triterpene synthase sequences with other triterpene synthases that encoded either α-amyrin and/or β-amyrin synthase. MdOSC1 and MdOSC3 clustered with the multifunctional triterpene synthases, whereas MdOSC2 was most similar to the β-amyrin synthases. © 2011 The New Zealand Institute for Plant and Food Research Limited. Journal compilation © 2011 FEBS.

Biological activity of some naturally occurring resins, gums and pigments against in vitro LDL oxidation.

PubMed

Andrikopoulos, Nikolaos K; Kaliora, Andriana C; Assimopoulou, Andreana N; Papapeorgiou, Vassilios P

2003-05-01

Naturally occurring gums and resins with beneficial pharmaceutical and nutraceutical properties were tested for their possible protective effect against copper-induced LDL oxidation in vitro. Chiosmastic gum (CMG) (Pistacia lentiscus var. Chia resin) was the most effective in protecting human LDL from oxidation. The minimum and maximum doses for the saturation phenomena of inhibition of LDL oxidation were 2.5 mg and 50 mg CMG (75.3% and 99.9%, respectively). The methanol/water extract of CMG was the most effective compared with other solvent combinations. CMG when fractionated in order to determine a structure-activity relationship showed that the total mastic essential oil, collofonium-like residue and acidic fractions of CMG exhibited a high protective activity ranging from 65.0% to 77.8%. The other natural gums and resins (CMG resin 'liquid collection', P. terebinthus var. Chia resin, dammar resin, acacia gum, tragacanth gum, storax gum) also tested as above, showed 27.0%-78.8% of the maximum LDL protection. The other naturally occurring substances, i.e. triterpenes (amyrin, oleanolic acid, ursolic acid, lupeol, 18-a-glycyrrhetinic acid) and hydroxynaphthoquinones (naphthazarin, shikonin and alkannin) showed 53.5%-78.8% and 27.0%-64.1% LDL protective activity, respectively. The combination effects (68.7%-76.2% LDL protection) of ursolic-, oleanolic- and ursodeoxycholic- acids were almost equal to the effect (75.3%) of the CMG extract in comparable doses. Copyright 2003 John Wiley & Sons, Ltd.

Multifunctional oxidosqualene cyclases and cytochrome P450 involved in the biosynthesis of apple fruit triterpenic acids.

PubMed

Andre, Christelle M; Legay, Sylvain; Deleruelle, Amélie; Nieuwenhuizen, Niels; Punter, Matthew; Brendolise, Cyril; Cooney, Janine M; Lateur, Marc; Hausman, Jean-François; Larondelle, Yvan; Laing, William A

2016-09-01

Apple (Malus × domestica) accumulates bioactive ursane-, oleanane-, and lupane-type triterpenes in its fruit cuticle, but their biosynthetic pathway is still poorly understood. We used a homology-based approach to identify and functionally characterize two new oxidosqualene cyclases (MdOSC4 and MdOSC5) and one cytochrome P450 (CYP716A175). The gene expression patterns of these enzymes and of previously described oxidosqualene cyclases were further studied in 20 apple cultivars with contrasting triterpene profiles. MdOSC4 encodes a multifunctional oxidosqualene cyclase producing an oleanane-type triterpene, putatively identified as germanicol, as well as β-amyrin and lupeol, in the proportion 82 : 14 : 4. MdOSC5 cyclizes 2,3-oxidosqualene into lupeol and β-amyrin at a ratio of 95 : 5. CYP716A175 catalyses the C-28 oxidation of α-amyrin, β-amyrin, lupeol and germanicol, producing ursolic acid, oleanolic acid, betulinic acid, and putatively morolic acid. The gene expression of MdOSC1 was linked to the concentrations of ursolic and oleanolic acid, whereas the expression of MdOSC5 was correlated with the concentrations of betulinic acid and its caffeate derivatives. Two new multifuntional triterpene synthases as well as a multifunctional triterpene C-28 oxidase were identified in Malus × domestica. This study also suggests that MdOSC1 and MdOSC5 are key genes in apple fruit triterpene biosynthesis. © 2016 The Authors. New Phytologist © 2016 New Phytologist Trust.

[Determination of triterpenoic acids in fruits of Ziziphus jujuba using HPLC-MS with polymeric ODS column].

PubMed

Zhang, Yong; Zhou, An; Xie, Xiao-Mei

2013-03-01

A simple and sensitive method has been developed to simultaneously determine betunilic acid, oleanolic acid and ursolic acid in the fruits of Ziziphus jujuba from different regions by HPLC-MS. This HPLC assay was performed on PAH polymeric C18 bonded stationary phase column with mobile phase contained acetonitrile-water (90: 10) and with negative ESI detection mode. The developed approach was characterized by short time consumption for chromatographic separation, high sensitivity and good reliability so as to meet the requirements for rapid analysis of large-batch fruits of Z. jujuba from different habitats.

Synergy between Ursolic and Oleanolic Acids from Vitellaria paradoxa Leaf Extract and β-Lactams against Methicillin-Resistant Staphylococcus aureus: In Vitro and In Vivo Activity and Underlying Mechanisms.

PubMed

Catteau, Lucy; Reichmann, Nathalie T; Olson, Joshua; Pinho, Mariana G; Nizet, Victor; Van Bambeke, Françoise; Quetin-Leclercq, Joëlle

2017-12-16

Combining antibiotics with resistance reversing agents is a key strategy to overcome bacterial resistance. Upon screening antimicrobial activities of plants used in traditional medicine, we found that a leaf dichloromethane extract from the shea butter tree ( Vitellaria paradoxa ) had antimicrobial activity against methicillin-resistant Staphylococcus aureus (MRSA) with further evidence of synergy when combined with β-lactams. Using HPLC-MS, we identified ursolic (UA) and oleanolic acids (OA) in leaves and twigs of this species, and quantified them by HPLC-UV as the major constituents in leaf extracts (21% and 6% respectively). Both pure triterpenic acids showed antimicrobial activity against reference and clinical strains of MRSA, with MICs ranging from 8-16 mg/L for UA to 32-128 mg/L for OA. They were highly synergistic with β-lactams (ampicillin and oxacillin) at subMIC concentrations. Reversion of MRSA phenotype was attributed to their capacity to delocalize PBP2 from the septal division site, as observed by fluorescence microscopy, and to disturb thereby peptidoglycan synthesis. Moreover, both compounds also inhibited β-lactamases activity of living bacteria (as assessed by inhibition of nitrocefin hydrolysis), but not in bacterial lysates, suggesting an indirect mechanism for this inhibition. In a murine model of subcutaneous MRSA infection, local administration of UA was synergistic with nafcillin to reduce lesion size and inflammatory cytokine (IL-1β) production. Thus, these data highlight the potential interest of triterpenic acids as resistance reversing agents in combination with β-lactams against MRSA.

Antitrypanosomal compounds from the essential oil and extracts of Keetia leucantha leaves with inhibitor activity on Trypanosoma brucei glyceraldehyde-3-phosphate dehydrogenase.

PubMed

Bero, J; Beaufay, C; Hannaert, V; Hérent, M-F; Michels, P A; Quetin-Leclercq, J

2013-02-15

Keetia leucantha is a West African tree used in traditional medicine to treat several diseases among which parasitic infections. The dichloromethane extract of leaves was previously shown to possess growth-inhibitory activities on Plasmodium falciparum, Trypanosoma brucei brucei and Leishmania mexicana mexicana with low or no cytotoxicity (>100 μg/ml on human normal fibroblasts) (Bero et al. 2009, 2011). In continuation of our investigations on the antitrypanosomal compounds from this dichloromethane extract, we analyzed by GC-FID and GC-MS the essential oil of its leaves obtained by hydrodistillation and the major triterpenic acids in this extract by LC-MS. Twenty-seven compounds were identified in the oil whose percentages were calculated using the normalization method. The essential oil, seven of its constituents and the three triterpenic acids were evaluated for their antitrypanosomal activity on Trypanosoma brucei brucei bloodstream forms (Tbb BSF) and procyclic forms (Tbb PF) to identify an activity on the glycolytic process of trypanosomes. The oil showed an IC(50) of 20.9 μg/ml on Tbb BSF and no activity was observed on Tbb PF. The best antitrypanosomal activity was observed for ursolic acid with IC(50) of 2.5 and 6.5 μg/ml respectively on Tbb BSF and Tbb PF. The inhibitory activity on a glycolytic enzyme of T. brucei, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), was also evaluated for betulinic acid, olenaolic acid, ursolic acid, phytol, α-ionone and β-ionone. The three triterpenic acids and β-ionone showed inhibitory activities on GAPDH with oleanolic acid being the most active with an inhibition of 72.63% at 20 μg/ml. This paper reports for the first time the composition and antitrypanosomal activity of the essential oil of Keetia leucantha. Several of its constituents and three triterpenic acids present in the dichloromethane leaves extract showed a higher antitrypanosomal activity on bloodstream forms of Tbb as compared to procyclic forms, namely geranyl acetone, phytol, α-ionone, β-ionone, ursolic acid, oleanolic acid and betulinic acid. The four last compounds were proven to be inhibitors of trypanosomal GAPDH, which may in part explain these antitrypanosomal activities. Copyright © 2012 Elsevier GmbH. All rights reserved.

Anti-inflammatory activity of standardized dichloromethane extract of Salvia connivens on macrophages stimulated by LPS.

PubMed

González-Chávez, Marco Martín; Ramos-Velázquez, Cinthia Saraí; Serrano-Vega, Roberto; Pérez-González, Cuauhtemoc; Sánchez-Mendoza, Ernesto; Pérez-Gutiérrez, Salud

2017-12-01

A previous study demonstrated that the chloroform extract of Salvia connivens Epling (Lamiaceae) has anti-inflammatory activity. Identification of the active components in the dicholorometane extract (DESC), and, standardization of the extract based in ursolic acid. DESC was prepared by percolation with dichlromethane and after washed with hot hexane, its composition was determined by CG-MS and NMR, and standardized by HPLC. The anti-inflammatory activity was tested on acute TPA-induced mouse ear oedema at doses of 2.0 mg/ear. The cell viability of macrophages was evaluated by MTT method, and pro- and anti-inflammatory interleukin levels were measured using an ELISA kit. Ursolic acid, oleanolic acid, dihydroursolic acid and eupatorin were identified in DESC, which was standardized based on the ursolic acid concentration (126 mg/g). The anti-inflammatory activities of DESC, the acid mixture, and eupatorin (2 mg/ear) were 60.55, 57.20 and 56.40% inhibition, respectively, on TPA-induced ear oedema. The IC 50 of DESC on macrophages was 149.4 μg/mL. DESC (25 μg/mL) significantly reduced TNF-α (2.0-fold), IL-1β (2.2-fold) and IL-6 (2.0-fold) in macrophages stimulated with LPS and increased the production of IL-10 (1.9-fold). Inflammation is a basic response to injuries, and macrophages are involved in triggering inflammation. Macrophage cells exhibit a response to LPS, inducing inflammatory mediators, and DESC inhibits the biosynthesis of the pro-inflammatory and promote anti-inflammatory cytokines. DESC has an anti-inflammatory effect; reduced the levels of IL-1β, Il-6 and TNF-α; and increases IL-10 in macrophages stimulated with LPS. Ursolic acid is a good phytochemical marker.

Ultrasound-assisted Extraction of Ursolic Acid from the Flowers of Ixora coccinia Linn (Rubiaceae) and Antiproliferative Activity of Ursolic Acid and Synthesized Derivatives

PubMed Central

Alves Monteath, Silvana Amadeu Ferreira; Maciel, Maria Aparecida M.; Vega, Raquel Garcia; de Mello, Heloisa; de Araújo Martins, Carollina; Esteves-Souza, Andressa; Gattass, Cerli Rocha; Echevarria, Aurea

2017-01-01

Background: Ixora coccinea Linn (Rubiaceae) is an evergreen shrub with bright scarlet colored flowers found in several tropical and subtropical countries. It is used as an ornamental and medicinal plant. Phytochemical studies revealed that its major special metabolites are triterpene acids, such as ursolic and oleanolic acid. Objective: To evaluate the isolation of ursolic acid (UA) (1) from methanol extracts of I. coccinea flowers through two methodologies, to prepare four derivatives, and to evaluate the cytotoxic effect against six cancer cell lines. Materials and Methods: The UA was isolated from vegetal material by percolation at room temperature and by ultrasound-assisted extraction. The preparation of derivatives was performed according to literature methods, and the cytotoxic effects were evaluated using the MTT (3,4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide) assay. Results: The most efficient extraction was achieved through ultrasound irradiation with a yield of 35% after KOH-impregnated silica in chromatography column. Furthermore, four derivatives (3, 5, 6, 7) of UA were prepared and evaluated, including 1, against two lung cancer (A549 and H460) and four leukemia (K562, Lucena, HL60, and Jurkat) cell lines. Generally, results showed that 1 and 7 were the most active compounds against the assayed cell lines. Also, the cytotoxic effects observed on terpenes 1 and 7 were higher when compared with cisplatin, used as positive control, with the exception of Jurkat cell line. Conclusion: The efficiency of such an alternative extraction method led to the principal and abundant active component, 1, of I. coccinea, thus representing a considerable contribution for promising triterpenoid in cancer chemotherapy. SUMMARY The ultrasound-assisted extraction of Ixora coccinea flowers improved of the ursolic acid isolationMethanolic extract from flowers of I. coccinea provided, by ultrasound irradiation, after KOH-impregnated silica in chromatography column, the ursolic acid in 35% yieldThe ursolic acid and four derivatives were prepared and assayed against two lung cancer and four leukaemia cell linesThe ursolic acid and their 3-oxo-derivative, in general, were more cytotoxic when compared to cisplatin, used as positive control Abbreviations used: MTT: 3,4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide, RP: reverse phase, TLC: thin layer chromatography, KOH: potassium hydroxide, IR: infrared, DMF: dimethylformamide, DMSO: dimethyl sulfoxide, TEA: triethylamine, RT: room temperature, EtOAc: ethyl acetate, MeOH: methanol, i-PrOH: iso-propanol, NMR: nuclear magnetic resonance, MDR: multiple drug resistance, RPMI: Roswell Park Memorial Institute PMID:28539719

[Chemical Constituents from Melissa officinalis Leaves].

PubMed

Ji, Zi-yang; Yang, Yan-xia; Zhuang, Fang-fang; Yan, Fu-lin; Wang, Chang-hong

2015-03-01

To investigate the chemical constituents of Melissa officinalis leaves. The chemical constituents were separated by silica gel column chromatography and their structures were determined by spectroscopic experiments. 13 compounds were isolated and identified as protocatechuyl aldehyde(1), serratagenic acid(2), vanillin(3), 2α,3β-dihydroxy-urs-12-en-28-oic acid(4), ursolic acid(5), oleanolic acid(6), daucosterol(7),2α,3β,23,29-tetrahydroxyolean-12-en-28-oic acid-29-O-β-D-gluco- pyranoside(8), luteolin(9) rosmarinic acid(10), luteolin-7-O-β-D-glucoside (11), β-stitosterol(12) and palmitic acid(13). Compounds 1 ~ 8 are separated from this plant for the first time and compounds 1-4 and 8 are isolated from this genus for the first time.

Fingerprint of Hedyotis diffusa Willd. by HPLC-MS.

PubMed

Yang, Ting; Yang, Yi-Hua; Yang, Ju-Yun; Chen, Ben-Mei; Duan, Ju-Ping; Yu, Shu-Yi; Ouyang, Hong-Tao; Cheng, Jun-Ping; Chen, Yu-Xiang

2008-01-01

A HPLC-MS fingerprint method has been developed based on the consistent chromatographic features of the major chemical constituents among 10 batches of Hedyotis diffusa Willd. Chromatographic separation was conducted on a Hypersil-Keystone Hypurity C(18) column using methanol:water:acetic acid as the mobile phase. Major compounds, including oleanolic acid, ursolic acid and ferulic acid, were analysed by HPLC-MS. Their analysis was ascertained by comparison with data derived from the standard compounds. The HPLC-MS fingerprint was successfully applied to analyse and differentiate samples from different geographical origins, or processing methods. H. diffusa was well distinguished from Hedyotis chrysotricha by HPLC-MS. Therefore the establishment of fingerprint of H. diffusa is critical in assessing and controlling its overall quality.

Ursolic and oleanolic acids as antimicrobial and immunomodulatory compounds for tuberculosis treatment.

PubMed

Jiménez-Arellanes, Adelina; Luna-Herrera, Julieta; Cornejo-Garrido, Jorge; López-García, Sonia; Castro-Mussot, María Eugenia; Meckes-Fischer, Mariana; Mata-Espinosa, Dulce; Marquina, Brenda; Torres, Javier; Hernández-Pando, Rogelio

2013-10-07

New alternatives for the treatment of Tuberculosis (TB) are urgently needed and medicinal plants represent a potential option. Chamaedora tepejilote and Lantana hispida are medicinal plants from Mexico and their hexanic extracts have shown antimycobacterial activity. Bioguided investigation of these extracts showed that the active compounds were ursolic acid (UA) and oleanolic acid (OA). The activity of UA and OA against Mycobacterium tuberculosis H37Rv, four monoresistant strains, and two drug-resistant clinical isolates were determined by MABA test. The intracellular activity of UA and OA against M. tuberculosis H37Rv and a MDR clinical isolate were evaluated in a macrophage cell line. Finally, the antitubercular activity of UA and OA was tested in BALB/c mice infected with M. tuberculosis H37Rv or a MDR strain, by determining pulmonary bacilli loads, tissue damage by automated histomorphometry, and expression of IFN-γ, TNF-α, and iNOS by quantitative RT-PCR. The in vitro assay showed that the UA/OA mixture has synergistic activity. The intracellular activity of these compounds against M. tuberculosis H37Rv and a MDR clinical isolate in a macrophage cell line showed that both compounds, alone and in combination, were active against intracellular mycobacteria even at low doses. Moreover, when both compounds were used to treat BALB/c mice with TB induced by H37Rv or MDR bacilli, a significant reduction of bacterial loads and pneumonia were observed compared to the control. Interestingly, animals treated with UA and OA showed a higher expression of IFN-γ and TNF-α in their lungs, than control animals. UA and OA showed antimicrobial activity plus an immune-stimulatory effect that permitted the control of experimental pulmonary TB.

Ursolic and oleanolic acids as antimicrobial and immunomodulatory compounds for tuberculosis treatment

PubMed Central

2013-01-01

Background New alternatives for the treatment of Tuberculosis (TB) are urgently needed and medicinal plants represent a potential option. Chamaedora tepejilote and Lantana hispida are medicinal plants from Mexico and their hexanic extracts have shown antimycobacterial activity. Bioguided investigation of these extracts showed that the active compounds were ursolic acid (UA) and oleanolic acid (OA). Methods The activity of UA and OA against Mycobacterium tuberculosis H37Rv, four monoresistant strains, and two drug-resistant clinical isolates were determined by MABA test. The intracellular activity of UA and OA against M. tuberculosis H37Rv and a MDR clinical isolate were evaluated in a macrophage cell line. Finally, the antitubercular activity of UA and OA was tested in BALB/c mice infected with M. tuberculosis H37Rv or a MDR strain, by determining pulmonary bacilli loads, tissue damage by automated histomorphometry, and expression of IFN-γ, TNF-α, and iNOS by quantitative RT-PCR. Results The in vitro assay showed that the UA/OA mixture has synergistic activity. The intracellular activity of these compounds against M. tuberculosis H37Rv and a MDR clinical isolate in a macrophage cell line showed that both compounds, alone and in combination, were active against intracellular mycobacteria even at low doses. Moreover, when both compounds were used to treat BALB/c mice with TB induced by H37Rv or MDR bacilli, a significant reduction of bacterial loads and pneumonia were observed compared to the control. Interestingly, animals treated with UA and OA showed a higher expression of IFN-γ and TNF-α in their lungs, than control animals. Conclusion UA and OA showed antimicrobial activity plus an immune-stimulatory effect that permitted the control of experimental pulmonary TB. PMID:24098949

A Novel Multifunctional C-23 Oxidase, CYP714E19, is Involved in Asiaticoside Biosynthesis.

PubMed

Kim, Ok Tae; Um, Yurry; Jin, Mei Lan; Kim, Jang Uk; Hegebarth, Daniela; Busta, Lucas; Racovita, Radu C; Jetter, Reinhard

2018-06-01

Centella asiatica is widely used as a medicinal plant due to accumulation of the ursane-type triterpene saponins asiaticoside and madecassoside. The molecular structure of both compounds suggests that they are biosynthesized from α-amyrin via three hydroxylations, and the respective Cyt P450-dependent monooxygenases (P450 enzymes) oxidizing the C-28 and C-2α positions have been reported. However, a third enzyme hydroxylating C-23 remained elusive. We previously identified 40,064 unique sequences in the transcriptome of C. asiatica elicited by methyl jasmonate, and among them we have now found 149 unigenes encoding putative P450 enzymes. In this set, 23 full-length cDNAs were recognized, 13 of which belonged to P450 subfamilies previously implicated in secondary metabolism. Four of these genes were highly expressed in response to jasmonate treatment, especially in leaves, in accordance with the accumulation patterns of asiaticoside. The functions of these candidate genes were tested using heterologous expression in yeast cells. Gas chromatography-mass spectrometry (GC-MS) analysis revealed that yeast expressing only the oxidosqualene synthase CaDDS produced the asiaticoside precursor α-amyrin (along with its isomer β-amyrin), while yeast co-expressing CaDDS and CYP716A83 also contained ursolic acid along with oleanolic acid. This P450 enzyme thus acts as a multifunctional triterpenoid C-28 oxidase converting amyrins into corresponding triterpenoid acids. Finally, yeast strains co-expressing CaDDS, CYP716A83 and CYP714E19 produced hederagenin and 23-hydroxyursolic acid, showing that CYP714E19 is a multifunctional triterpenoid oxidase catalyzing the C-23 hydroxylation of oleanolic acid and ursolic acid. Overall, our results demonstrate that CaDDS, CYP716A83 and CYP714E19 are C. asiatica enzymes catalyzing consecutive steps in asiaticoside biosynthesis.

Regulation of microRNA using promising dietary phytochemicals: Possible preventive and treatment option of malignant mesothelioma.

PubMed

Sayeed, Md Abu; Bracci, Massimo; Lucarini, Guendalina; Lazzarini, Raffaella; Di Primio, Roberto; Santarelli, Lory

2017-10-01

Malignant mesothelioma (MM) is a very aggressive, lethal cancer, and its incidence is increasing worldwide. Development of multi-drug resistance, therapy related side-effects, and disease recurrence after therapy are the major problems for the successful treatment of MM. Emerging evidence indicates that dietary phytochemicals can exert anti-cancer activities by regulating microRNA expression. Until now, only one dietary phytochemical (ursolic acid) has been reported to have MM microRNA regulatory ability. A large number of dietary phytochemicals still remain to be tested. In this paper, we have introduced some dietary phytochemicals (curcumin, epigallocatechin gallate, quercetin, genistein, pterostilbene, resveratrol, capsaicin, ellagic acid, benzyl isothiocyanate, phenethyl isothiocyanate, sulforaphane, indole-3-carbinol, 3,3'-diindolylmethane, diallyl disulphide, betulinic acid, and oleanolic acid) which have shown microRNA regulatory activities in various cancers and could regulate MM microRNAs. In addition to microRNA regulatory activities, curcumin, epigallocatechin gallate, quercetin, genistein, resveratrol, phenethyl isothiocyanate, and sulforaphane have anti-mesothelioma potentials, and pterostilbene, capsaicin, ellagic acid, benzyl isothiocyanate, indole-3-carbinol, 3,3'-diindolylmethane, diallyl disulphide, betulinic acid, and oleanolic acid have potentials to inhibit cancer by regulating the expression of various genes which are also known to be aberrant in MM. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

[Study on chemical constituents from rhizome of Rabdosia flavida].

PubMed

Zhao, Ming-Zao; Li, Jin-Qiang; Zhang, Yu; Zhang, Xue-Jiao; Jiang, Bei

2014-07-01

To study the chemical constituents from the rhizome of Rabdosia flavida. The compounds were isolated and purified by various chromatographic methods, and their structures were elucidated on the basis of spectral data and physicochemical properties. Ten compounds were obtained from ethyl acetate fraction of the 70% acetone extract of Rabdosia flavida rhizome and identified as ferruginol (1), dehydrocostuslactone (2), taraxasterol (3), oleic acid (4), ursolic cid (5), coniferyl aldehyde (6), oleanolic acid (7), 6,12, 15-trihydroxy-5, 8,11, 13-abietetra-7-one (8), 5α, 8α-epidioxyergosta-6,22-dien-3β-ol (9), and daucosterol (10). All the compounds are isolated from Rabdosia flavida for the first time.

Changes in the triterpenoid content of cuticular waxes during fruit ripening of eight grape (Vitis vinifera) cultivars grown in the Upper Rhine Valley.

PubMed

Pensec, Flora; Pączkowski, Cezary; Grabarczyk, Marta; Woźniak, Agnieszka; Bénard-Gellon, Mélanie; Bertsch, Christophe; Chong, Julie; Szakiel, Anna

2014-08-13

Triterpenoids present in grape cuticular waxes are of interest due to their potential role in protection against biotic stresses, their impact on the mechanical toughness of the fruit surface, and the potential industrial application of these biologically active compounds from grape pomace. The determination of the triterpenoid profile of cuticular waxes reported here supplements existing knowledge of the chemical diversity of grape, with some compounds reported in this species for the first time. Common compounds identified in eight examined cultivars grown in the Upper Rhine Valley include oleanolic acid, oleanolic and ursolic acid methyl esters, oleanolic aldehyde, α-amyrin, α-amyrenone, β-amyrin, cycloartanol, 24-methylenecycloartanol, erythrodiol, germanicol, lupeol accompanied by lupeol acetate, campesterol, cholesterol, sitosterol, stigmasterol, and stigmasta-3,5-dien-7-one, whereas 3,12-oleandione was specific for the Muscat d'Alsace cultivar. Changes in the triterpenoid content of cuticular waxes were determined at three different phenological stages: young grapes, grapes at véraison (the onset of ripening), and mature grapes. The results reveal a characteristic evolution of triterpenoid content during fruit development, with a high level of total triterpenoids in young grapes that gradually decreases with a slight increase in the level of neutral triterpenoids. This phenomenon may partially explain changes in the mechanical properties of the cuticle and possible modulations in the susceptibility to pathogens of mature grapes.

Ethnomedicinal, phytochemical and pharmacological profile of a mangrove plant Ceriops Decandra GriffDin Hou.

PubMed

Mahmud, Imran; Shahria, Naznin; Yeasmin, Sabina; Iqbal, Asif; Mukul, Emdadul Hasan; Gain, Sudipta; Shilpi, Jamil Ahmad; Islam, Md Khirul

2018-06-22

Ceriops decandra is a mangrove tree species, reputed for its folkloric uses in the treatment of gastrointestinal disorders, infection, snakebites, inflammation, and cancer. Different parts of the plant are rich with various phytoconstituents which include diterpenoids (ceriopsin A-G), triterpenoids (lupeol, α-amyrin, oleanolic acid, ursolic acid), and phenolics (catechin, procyanidins).These phytoconstituents and their derivatives could form a new basis for developing new drugs against various diseases. The objective of the present study is to compile the phytochemical, ethnobotanical, biological, and pharmacological significance of the plant to provide directions for future research to find out therapeutically active lead compounds for developing new drugs against diseases of current interest including diabetes, inflammation, and cancer.

Pentacyclic triterpene in Olea europaea L: A simultaneous determination by high-performance liquid chromatography coupled to mass spectrometry.

PubMed

Giménez, Estela; Juan, M Emília; Calvo-Melià, Sara; Barbosa, José; Sanz-Nebot, Victoria; Planas, Joana M

2015-09-04

Pentacyclic triterpenes are gaining interest due to their beneficial health effects, as anti-inflammatory, anti-diabetic and anti-tumoral, among others. In this study, an analytical LC-MS method was developed for the simultaneous determination of maslinic, oleanolic and ursolic acids along with erythrodiol and uvaol, which are the main triterpenic compounds present in the fruits and leaves of Olea europaea L. A Zorbax Eclipse PAH column at 30°C with mobile phase of water (17%) and methanol (83%) at 0.8mL/min conformed the optimal chromatographic conditions that allowed the separation of the compounds of interest, two pairs of which are isomers differing only in the position of one methyl group (oleanolic-ursolic and erythrodiol-uvaol). The ionization was performed in an APCI source at 450°C programmed in negative mode for the triterpenic acids, and in positive for the alcohols. An ion trap (LC-IT-MS) and a triple quadrupole (LC-QqQ-MS) were assessed for maximal sensitivity that was achieved with LC-QqQ-MS. The LODs of triterpenic acids were lower than 1nM, whereas for erythrodiol and uvaol were 4.5 and 7.5nM, respectively. The method was linear for the five analytes in the range of concentrations from 0.005 to 15μM with correlation coefficients exceeding 0.99. The precision and accuracy were ≤9.90% and ≤9.57%, respectively. The applicability of the validated method was assessed in the analysis of the pentacyclic triterpenes in Marfil table olives, after the optimization of the extraction procedure. The developed method constitutes the first step for future studies of triterpenic compounds present in foods that would allow establishing their effects on human health. Copyright © 2015 Elsevier B.V. All rights reserved.

Triterpenoid Acids as Important Antiproliferative Constituents of European Elderberry Fruits.

PubMed

Gleńsk, Michał; Czapińska, Elżbieta; Woźniak, Marta; Ceremuga, Ireneusz; Włodarczyk, Maciej; Terlecki, Grzegorz; Ziółkowski, Piotr; Seweryn, Ewa

2017-01-01

In Europe, both the fruits and flowers of Sambucus nigra L. have been used against cold, as well as laxative, diaphoretic, and diuretic remedies. There are also a number of commercially available food products that contain elderberry juice, puréed or dried elderberries. Recent comprehensive literature data on pharmacology and chemistry of Sambuci fructus have encouraged us to screen extracts with different polarities from this plant material against cancer cell lines. The cytotoxic activity of the ethyl acetate and aqueous acetone extracts from elderberries as well as detected triterpenoids on human colon adenocarcinoma cell line (LoVo) and human breast cancer cell line (MCF-7) was investigated by sulforhodamine B assay. Moreover, cell migration assay was conducted for triterpenoid fraction and pure compounds. Aqueous acetone extract possessed much lower IC 50 value in cancer cell lines compared to ethyl acetate extract. The latter manifested high cytotoxicity against studied cell lines, suggesting that nonpolar compounds are responsible for the cytotoxic activity. Indeed, the phytochemical analysis revealed that ursolic and oleanolic acids are the main triterpenoids in the mentioned extract of which ursolic acid showed the highest activity with IC 50 values of 10.7 µg/mL on MCF-7 and 7.7 µg/mL on LoVo cells.

Conformation of flexibly linked triterpene dimers by using RDC-enhanced NMR spectroscopy

NASA Astrophysics Data System (ADS)

Lakshmi, Jerripothula K.; Pattnaik, Banita; Kavitha, Rachineni; Mallavadhani, Uppuluri V.; Jagadeesh, Bharatam

2018-06-01

Dimers of flexibly linked pentacyclic triterpene ursolic acid (UA) and its related frameworks such as asiatic acid (AA) and oleanolic acid (OA) have recently attracted significant attention due to their enhanced anti-cancer and anti-HCV activity compared to their respective monomers. Determination of conformation/inter-monomer orientation of these molecules is very important to understand their structure-activity relationship and to develop new scaffolds, which, however, is difficult through conventional NOE based solution-state NMR spectroscopy, due to lack of long-range NOEs. In the present work, we report a precise determination of conformation of two 1,2,3-triazole-linked triterpene dimer molecules, UA-AA and UA-OA, by employing one-bond Csbnd H residual dipolar couplings (RDCs) as additional long-range orientational restraints, measured in anisotropic PDMS/CDCl3 solvent medium.

Active compounds, antioxidant activity and α-glucosidase inhibitory activity of different varieties of Chaenomeles fruits.

PubMed

Miao, Jing; Li, Xia; Zhao, Chengcheng; Gao, Xiaoxiao; Wang, Ying; Gao, Wenyuan

2018-05-15

Chaenomeles is an important source for food industry in China, and its planting area is expanding year by year. This study was conducted to evaluate different varieties of Chaenomeles by comparing the chemical compositions, antioxidant activity and α-glucosidase inhibitory activity of peels and fleshes from twelve varieties of Chaenomeles. In the results, peels of Chaenomeles contain more phenolics, flavonoids and triterpenes, and show better antioxidant activity and α-glucosidase inhibitory activity than their fleshes. All varieties of Chaenomeles perform different depend on cultivar and climatic conditions. Oleanolic acid, ursolic acid, protocatechuic acid, rutin, catechin, caffeic acid, syringic acid, epicatechin, hyperin, quercetin, kaempferol and chlorogenic acid are main active compounds in Chaenomeles. Zheng'an, Liufu, Zimugua1, Qijiang and Changjun get Top five scores. This is the first study on the peels and fleshes of twelve varieties of Chaenomeles, and it gives insights into variety selection in the planting and production of Chaenomeles. Copyright © 2017 Elsevier Ltd. All rights reserved.

Recent progress in the antiviral activity and mechanism study of pentacyclic triterpenoids and their derivatives.

PubMed

Xiao, Sulong; Tian, Zhenyu; Wang, Yufei; Si, Longlong; Zhang, Lihe; Zhou, Demin

2018-05-01

Viral infections cause many serious human diseases with high mortality rates. New drug-resistant strains are continually emerging due to the high viral mutation rate, which makes it necessary to develop new antiviral agents. Compounds of plant origin are particularly interesting. The pentacyclic triterpenoids (PTs) are a diverse class of natural products from plants composed of three terpene units. They exhibit antitumor, anti-inflammatory, and antiviral activities. Oleanolic, betulinic, and ursolic acids are representative PTs widely present in nature with a broad antiviral spectrum. This review focuses on the recent literatures in the antiviral efficacy of this class of phytochemicals and their derivatives. In addition, their modes of action are also summarized. © 2018 Wiley Periodicals, Inc.

Targeting mitochondria: Esters of rhodamine B with triterpenoids are mitocanic triggers of apoptosis.

PubMed

Wolfram, Ratna Kancana; Heller, Lucie; Csuk, René

2018-05-25

Triterpenoic acids, ursolic acid (1), oleanolic acid (2), glycyrrhetinic acid (3) and betulinic acid (4) were converted into their corresponding methyl 5-8 and benzyl esters 9-12 or benzyl amides 21-24. These derivatives served as starting materials for the synthesis of pink colored rhodamine B derivatives 25-36 which were screened for cytotoxicity in colorimetric SRB assays. All of the compounds were cytotoxic for a variety of human tumor cell lines. The activity of the benzyl ester derivatives 29-32 was lower than the cytotoxicity of the methyl esters 25-28. The benzyl amides 33-36 were the most cytotoxic compounds of this series. The most potential compound was a glycyrrhetinic acid rhodamine B benzyl amide 35. This compound showed activity against the different cancer cell lines in a two-digit to low three-digit nano-molar range. Staining experiments combined with fluorescence microscopy showed that this compound triggered apoptosis in A2780 ovarian carcinoma cells and acted as a mitocan. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

A new anthraquinone and eight constituents from Hedyotis caudatifolia Merr. et Metcalf: isolation, purification and structural identification.

PubMed

Luo, Peng; Su, Jiale; Zhu, Yilin; Wei, Jianhua; Wei, Wanxing; Pan, Weigao

2016-10-01

Hedyotis caudatifolia Merr. et Metcalf. (HC), a folk medicine in Yao nationalities areas in China, was used to investigate the chemical constituents. Through silica gel and Sephadex LH-20 column chromatography, nine compounds were isolated and purified. By physical and chemical properties, IR, MS (EI-MS, high resolution EI-MS), 1D NMR ((1)H NMR, (13)C NMR) and 2D NMR (HSQC, (1)H-(1)H COSY, HMBC), their structures were identified as β-sitosterol (1), stigmasterol (2), scopolin (3), 2-hydroxy-1,7,8-trimethoxyanthracene-9,10-dione (4), oleanolic acid (5), ursolic acid (6), methyl barbinervate (7), β-daucosterol (8) and p-Hydroxybenzoic acid (9). These compounds were isolated from HC for the first time, and 4 a new anthraquinone whose biological activities are worth to be investigated in future. These compounds may contribute to the HC's pharmacological effects on treating diseases, and may be used as candidates for control index in establishing the quality control standard of HC.

Chemical composition and antioxidant and anti-inflammatory potential of peels and flesh from 10 different pear varieties (Pyrus spp.).

PubMed

Li, Xia; Wang, Tingting; Zhou, Bin; Gao, Wenyuan; Cao, Jingguo; Huang, Luqi

2014-01-01

This study was performed to compare the contents of total phenolics, total flavonoids, and total triterpenes between peel and flesh of ten different pear cultivars. The monomeric compounds were analyzed by HPLC, their antioxidant and anti-inflammatory activities were also measured. Peel and flesh from Yaguang, Hongpi, Qingpi and Guifei varieties contained relatively more total phenolic, total flavonoids and total triterpene, and showed stronger antioxidant and anti-inflammatory activities, while Lvbaoshi and Youran appeared to be weakest among them. All the chemical components found in the pear peel were approximately 6-20 times higher than those in the flesh of pear. For the monomeric compounds, arbutin, oleanolic acid, ursolic acid, chlorogenic acid, epicatechin, and rutin were the dominant components contained in the ten pear cultivars both in peel and in flesh. All of the analyses suggested that the peel of pear might be an excellent polyphenol and triterpenes source. Copyright © 2013 Elsevier Ltd. All rights reserved.

Chemical constituents of gold-red apple and their α-glucosidase inhibitory activities.

PubMed

He, Qian-Qian; Yang, Liu; Zhang, Jia-Yu; Ma, Jian-Nan; Ma, Chao-Mei

2014-10-01

Ten compounds were isolated and purified from the peels of gold-red apple (Malus domestica) for the 1st time. The identified compounds are 3β, 20β-dihydroxyursan-28-oic acid (1), 2α-hydroxyoleanolic acid (2), euscaphic acid (3), 3-O-p-coumaroyl tormentic acid (4), ursolic acid (5), 2α-hydroxyursolic acid (6), oleanolic acid (7), betulinic acid (8), linolic acid (9), and α-linolenic acid (10). Their structures were determined by interpreting their nuclear magnetic resonance and mass spectrometry (MS) spectra, and by comparison with literature data. Compound 1 is new, and compound 2 is herein reported for the 1st time for the genus Malus. α-Glucosidase inhibition assay revealed 6 of the triterpenoid isolates as remarkable α-glucosidase inhibitors, with betulinic acid showing the strongest inhibition (IC50 = 15.19 μM). Ultra-performance liquid chromatography-electrospray ionization MS analysis of the fruit peels, pomace, flesh, and juice revealed that the peels and pomace contained high levels of triterpenes, suggesting that wastes from the fruit juice industry could serve as rich sources of bioactive triterpenes. © 2014 Institute of Food Technologists®

Antibacterial and antiparasitic activity of oleanolic acid and its glycosides isolated from marigold (Calendula officinalis).

PubMed

Szakiel, Anna; Ruszkowski, Dariusz; Grudniak, Anna; Kurek, Anna; Wolska, Krystyna I; Doligalska, Maria; Janiszowska, Wirginia

2008-11-01

The antibacterial and antiparasitic activities of free oleanolic acid and its glucosides and glucuronides isolated from marigold (Calendula officinalis) were investigated. The MIC of oleanolic acid and the effect on bacterial growth were estimated by A600 measurements. Oleanolic acid's influence on bacterial survival and the ability to induce autolysis were measured by counting the number of cfu. Cell morphology and the presence of endospores were observed under electron and light microscopy, respectively. Oleanolic acid inhibited bacterial growth and survival, influenced cell morphology and enhanced the autolysis of Gram-positive bacteria suggesting that bacterial envelopes are the target of its activity. On the other hand, glycosides of oleanolic acid inhibited the development of L3 Heligmosomoides polygyrus larvae, the infective stage of this intestinal parasitic nematode. In addition, both oleanolic acid and its glycosides reduced the rate of L3 survival during prolonged storage, but only oleanolic acid glucuronides affected nematode infectivity. The presented results suggest that oleanolic acid and its glycosides can be considered as potential therapeutic agents.

[Study on solid dispersion of precipitated calcium carbonate-based oleanolic acid].

PubMed

Yan, Hong-mei; Zhang, Zhen-hai; Jia, Xiao-bin; Jiang, Yan-rong; Sun, E

2015-05-01

Oleanolic acid-precipitated calcium carbonate solid dispersion was prepared by using solvent evaporation method. The microscopic structure and physicochemical properties of solid dispersion were analyzed using differential scanning calorimetry and scanning electron microscopy (SEM). And its in vitro release also was investigated. The properties of the precipitated calcium carbonate was studied which was as a carrier of oleanolic acid solid dispersion. Differential scanning calorimetry analysis suggested that oleanolic acid may be present in solid dispersion as amorphous substance. The in vitro release determination results of oleanolic acid-precipitated calcium carbonate (1: 5) solid dispersion showed accumulated dissolution rate of.oleanolic acid was up to 90% at 45 min. Accelerating experiment showed that content and in vitro dissolution of oleanolic acid solid dispersion did not change after storing over 6 months. The results indicated that in vitro dissolution of oleanolic acid was improved greatly by the solid dispersion with precipitated calcium carbonate as a carrier. The solid dispersion is a stabilizing system which has actual applied value.

Suppression of AMF/PGI-mediated tumorigenic activities by ursolic acid in cultured hepatoma cells and in a mouse model.

PubMed

Shih, Wen-Ling; Yu, Feng-Ling; Chang, Ching-Dong; Liao, Ming-Huei; Wu, Hung-Yi; Lin, Ping-Yuan

2013-10-01

Our previous studies demonstrated that autocrine motility factor/phosphoglucose isomerase (AMF/PGI) possesses tumorigenic activities through the modulation of intracellular signaling. We then investigated the effects of ursolic acid (UA), oleanolic acid (OA), tangeretin, and nobiletin against AMF/PGI-mediated oncogenesis in cultured stable Huh7 and Hep3B cells expressing wild-type or mutated AMF/PGI and in a mouse model in this study. The working concentrations of the tested compounds were lower than their IC10 , which was determined by Brdu incorporation and colony formation assay. Only UA efficiently suppressed the AMF/PGI-induced Huh7 cell migration and MMP-3 secretion. Additionally, UA inhibited the AMF/PGI-mediated protection against TGF-β-induced apoptosis in Hep3B cells, whereas OA, tangeretin, and nobiletin had no effect. In Huh7 cells and tumor tissues, UA disrupted the Src/RhoA/PI 3-kinase signaling and complex formation induced by AMF/PGI. In the Hep3B system, UA dramatically suppressed AMF/PGI-induced anti-apoptotic signaling transmission, including Akt, p85, Bad, and Stat3 phosphorylation. AMF/PGI enhances tumor growth, angiogenesis, and pulmonary metastasis in mice, which is correlated with its enzymatic activity, and critically, UA intraperitoneal injection reduces the tumorigenesis in vivo, enhances apoptosis in tumor tissues and also prolongs mouse survival. Combination of sub-optimal dose of UA and cisplatin, a synergistic tumor cell-killing effects was found. Thus, UA modulates intracellular signaling and might serve as a functional natural compound for preventing or alleviating hepatocellular carcinoma. © 2012 Wiley Periodicals, Inc.

[Studies on chemical constituents from rhizome of Anemone flaccida].

PubMed

Zhang, Lan-tian; Takaishi, Yoshihisa; Zhang, Yan-wen; Duan, Hong-quan

2008-07-01

To study the chemical constituents from Anemone flaccida. Chemical constituents were isolated by repeated column chromatography (silica gel, Toyopearl HW-40C and preparative HPLC). The structures were elucidated on the basis of spectral data analysis. Twelve triterpenes were isolated and their structures were identified as follow: oleanolic acid (1), oleanolic acid 3-O-beta-D-glccopyranosyl-(1-->2)-beta-D-xylopyranoside (2), eleutheroside K (3), oleanolic acid 3-O-alpha-L-rhamnopyranosyl-(1-->2)-beta-D-xylopyranoside (4), oleanolic acid 3-O-beta-D-glccopyranosyl-(1-->2)-alpha-L-arabinofurnoside (5), oleanolic acid 3-O-beta-D-glccuronopyranose (6), oleanolic acid 3-O-beta-D-glccuronopyranose methyl ester (7), oleanolic acid 28-O-alpha-L-rhamnopyranosyl(1-->4)-beta-D-glccopyranosyl (1-->6)-beta-D-glccopyranosyl (8), oleanolic acid 3-O-beta-D-glccuronopyranose 28-O-alpha-L-rhamnopyranosyl (1-->4)-beta-D-glccopyranosyl (1-->6)-beta-D-glccopyranoside (9), oleanolic acid 3-O-beta-D-glccopyranosyl methyl ester 28-O-alpha-L-rhamnopyranosyl (1-->4)-beta-D-glccopyranosyl (1-->6)-beta-D-glccopyranoside (10), oleanolic acid 3-O-beta-D-glccopyranosyl-(1-->2)-beta-D-xylopyranosyl-28-O-alpha-L-rhamnopyranosyl (1-->4)-beta-D-glccopyranosyl (1-->6)-beta-D-glccopyranoside (11), oleanolic acid 3-O-alpha-L-rh-amnopyranosyl-(1-->2)-alpha-L-arabinopyrnosyl-28-O-alpha-L-rhamnopyranosyl (1-->4)-beta-D-glccopyranosyl (1-->6)-beta-D-glccopyranoside (12). compounds 5-8, 10, 12 were isolated from this plant for the first time. Compounds 2, 5 and 11 showed positive anti-tumor activities.

p21 induction plays a dual role in anti-cancer activity of ursolic acid

PubMed Central

Zhang, Xudong; Song, Xinhua; Yin, Shutao; Zhao, Chong; Fan, Lihong

2015-01-01

Previous studies have shown that induction of G1 arrest and apoptosis by ursolic acid is associated with up-regulation of cyclin-dependent kinase inhibitor (CDKI) protein p21 in multiple types of cancer cells. However, the functional role of p21 induction in G1 cell cycle arrest and apoptosis, and the mechanisms of p21 induction by ursolic acid have not been critically addressed. In the current study, we demonstrated that p21 played a mediator role in G1 cell cycle arrest by ursolic acid, whereas p21-mediated up-regulation of Mcl-1 compromised apoptotic effect of ursolic acid. These results suggest that p21 induction plays a dual role in the anti-cancer activity of ursolic acid in terms of cell cycle and apoptosis regulation. p21 induction by ursolic acid was attributed to p53 transcriptional activation. Moreover, we found that ursolic acid was able to inhibit murine double minute-2 protein (MDM2) and T-LAK cell-originated protein kinase (TOPK), the two negative regulator of p53, which in turn contributed to ursolic acid-induced p53 activation. Our findings provided novel insights into understanding of the mechanisms involved in cell cycle arrest and apoptosis induction in response to ursolic acid exposure. PMID:26582056

Ursolic Acid Increases Skeletal Muscle and Brown Fat and Decreases Diet-Induced Obesity, Glucose Intolerance and Fatty Liver Disease

PubMed Central

Kunkel, Steven D.; Elmore, Christopher J.; Bongers, Kale S.; Ebert, Scott M.; Fox, Daniel K.; Dyle, Michael C.; Bullard, Steven A.; Adams, Christopher M.

2012-01-01

Skeletal muscle Akt activity stimulates muscle growth and imparts resistance to obesity, glucose intolerance and fatty liver disease. We recently found that ursolic acid increases skeletal muscle Akt activity and stimulates muscle growth in non-obese mice. Here, we tested the hypothesis that ursolic acid might increase skeletal muscle Akt activity in a mouse model of diet-induced obesity. We studied mice that consumed a high fat diet lacking or containing ursolic acid. In skeletal muscle, ursolic acid increased Akt activity, as well as downstream mRNAs that promote glucose utilization (hexokinase-II), blood vessel recruitment (Vegfa) and autocrine/paracrine IGF-I signaling (Igf1). As a result, ursolic acid increased skeletal muscle mass, fast and slow muscle fiber size, grip strength and exercise capacity. Interestingly, ursolic acid also increased brown fat, a tissue that shares developmental origins with skeletal muscle. Consistent with increased skeletal muscle and brown fat, ursolic acid increased energy expenditure, leading to reduced obesity, improved glucose tolerance and decreased hepatic steatosis. These data support a model in which ursolic acid reduces obesity, glucose intolerance and fatty liver disease by increasing skeletal muscle and brown fat, and suggest ursolic acid as a potential therapeutic approach for obesity and obesity-related illness. PMID:22745735

Ursolic acid, a natural pentacyclic triterpenoid, inhibits intracellular trafficking of proteins and induces accumulation of intercellular adhesion molecule-1 linked to high-mannose-type glycans in the endoplasmic reticulum

PubMed Central

Mitsuda, Satoshi; Yokomichi, Tomonobu; Yokoigawa, Junpei; Kataoka, Takao

2014-01-01

Ursolic acid (3β-hydroxy-urs-12-en-28-oic acid) is a natural pentacyclic triterpenoid that is present in many plants, including medicinal herbs, and foods. Ursolic acid was initially identified as an inhibitor of the expression of intercellular adhesion molecule-1 (ICAM-1) in response to interleukin-1α (IL-1α). We report here a novel biological activity: ursolic acid inhibits intracellular trafficking of proteins. Ursolic acid markedly inhibited the IL-1α-induced cell-surface ICAM-1 expression in human cancer cell lines and human umbilical vein endothelial cells. By contrast, ursolic acid exerted weak inhibitory effects on the IL-1α-induced ICAM-1 expression at the protein level. Surprisingly, we found that ursolic acid decreased the apparent molecular weight of ICAM-1 and altered the structures of N-linked oligosaccharides bound to ICAM-1. Ursolic acid induced the accumulation of ICAM-1 in the endoplasmic reticulum, which was linked mainly to high-mannose-type glycans. Moreover, in ursolic-acid-treated cells, the Golgi apparatus was fragmented into pieces and distributed over the cells. Thus, our results reveal that ursolic acid inhibits intracellular trafficking of proteins and induces the accumulation of ICAM-1 linked to high-mannose-type glycans in the endoplasmic reticulum. PMID:24649404

Ursolic acid induces neural regeneration after sciatic nerve injury

PubMed Central

Liu, Biao; Liu, Yan; Yang, Guang; Xu, Zemin; Chen, Jiajun

2013-01-01

In this study, we aimed to explore the role of ursolic acid in the neural regeneration of the injured sciatic nerve. BALB/c mice were used to establish models of sciatic nerve injury through unilateral sciatic nerve complete transection and microscopic anastomosis at 0.5 cm below the ischial tube-rosity. The successfully generated model mice were treated with 10, 5, or 2.5 mg/kg ursolic acid via intraperitoneal injection. Enzyme-linked immunosorbent assay results showed that serum S100 protein expression level gradually increased at 1–4 weeks after sciatic nerve injury, and significantly decreased at 8 weeks. As such, ursolic acid has the capacity to significantly increase S100 protein expression levels. Real-time quantitative PCR showed that S100 mRNA expression in the L4–6 segments on the injury side was increased after ursolic acid treatment. In addition, the muscular mass index in the soleus muscle was also increased in mice treated with ursolic acid. Toluidine blue staining revealed that the quantity and average diameter of myelinated nerve fibers in the injured sciatic nerve were significantly increased after treatment with ursolic acid. 10 and 5 mg/kg of ursolic acid produced stronger effects than 2.5 mg/kg of ursolic acid. Our findings indicate that ursolic acid can dose-dependently increase S100 expression and promote neural regeneration in BALB/c mice following sciatic nerve injury. PMID:25206561

Ursolic acid inhibits the invasive phenotype of SNU-484 human gastric cancer cells

PubMed Central

KIM, EUN-SOOK; MOON, AREE

2015-01-01

Metastasis is a major cause of cancer-related mortality in patients with gastric cancer. Ursolic acid, a pentacyclic triterpenoid compound derived from medicinal herbs, has been demonstrated to exert anticancer effects in various cancer cell systems. However, to the best of our knowledge, the inhibitory effect of ursolic acid on the invasive phenotype of gastric cancer cells has yet to be reported. Therefore, the aim of the present study was to investigate the effect of ursolic acid on the invasiveness of SNU-484 human gastric cancer cells. Ursolic acid efficiently induced apoptosis, possibly via the downregulation of B-cell lymphoma 2 (Bcl-2), the upregulation of Bcl-2-associated X protein and the proteolytic activation of caspase-3. Furthermore, the activation of p38 mitogen-activated protein kinase and c-Jun N-terminal kinase was increased by the administration of ursolic acid. In addition, ursolic acid significantly suppressed the invasive phenotype of the SNU-484 cells and significantly decreased the expression of matrix metalloproteinase (MMP)-2, indicating that MMP-2 may be responsible for the anti-invasive activity of ursolic acid. Taken together, the results of the present study demonstrate that ursolic acid induces apoptosis and inhibits the invasive phenotype of gastric cancer cells; therefore, ursolic acid may have a potential application as a chemopreventive agent to prevent the metastasis of gastric cancer or to alleviate the process of metastasis. PMID:25621065

Chemical constituents from Hericium erinaceus and their ability to stimulate NGF-mediated neurite outgrowth on PC12 cells.

PubMed

Zhang, Cheng-Chen; Yin, Xia; Cao, Chen-Yu; Wei, Jing; Zhang, Qiang; Gao, Jin-Ming

2015-11-15

One new meroterpenoid, named hericenone K (11), along with 10 known compounds (1-10), ergosterol peroxide (1), cerevisterol (2), 3β,5α,9α-trihydroxy-ergosta-7,22-dien-6-one (3), inoterpene A (4), astradoric acid C (5), betulin (6), oleanolic acid (7), ursolic acid (8), hemisceramide (9), and 3,4-dihydro-5-methoxy-2-methyl-2-(4'-methyl-2'-oxo-3'-pentenyl)-9(7H)-oxo-2H-furo[3,4-h]benzopyran (10), was isolated from the fruiting bodies of the mushroom Hericium erinaceus. Their structures were characterized on the basis of spectroscopic methods, as well as through comparison with previously reported data. Compounds 3-6, 8, and 9 were isolated from Hericium species for the first time. Compounds 10 and 11 was suggested to be racemic by the CD spectrum data and specific rotations, which ware resolved by chiral HPLC into respective enantiomers. Compounds 1-3, (±)-10, (-)-10 and (+)-10 in the presence of NGF (20 ng/mL) exerted a significant increase in neurite-bearing cells. Copyright © 2015 Elsevier Ltd. All rights reserved.

Oleanolic acid supplement attenuates liquid fructose-induced adipose tissue insulin resistance through the insulin receptor substrate-1/phosphatidylinositol 3-kinase/Akt signaling pathway in rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, Ying; Wang, Jianwei, E-mail: wangjianwei1968@gmail.com; Gu, Tieguang

Oleanolic acid, a triterpenoid contained in more than 1620 plants including various fruits and foodstuffs, has numerous metabolic effects, such as hepatoprotection. However, its underlying mechanisms remain poorly understood. Adipose tissue insulin resistance (Adipo-IR) may contribute to the development and progress of metabolic abnormalities through release of excessive free fatty acids from adipose tissue. This study investigated the effect of oleanolic acid on Adipo-IR. The results showed that supplement with oleanolic acid (25 mg/kg, once daily, by oral gavage) over 10 weeks attenuated liquid fructose-induced increase in plasma insulin concentration and the homeostasis model assessment of insulin resistance (HOMA-IR) indexmore » in rats. Simultaneously, oleanolic acid reversed the increase in the Adipo-IR index and plasma non-esterified fatty acid concentrations during the oral glucose tolerance test assessment. In white adipose tissue, oleanolic acid enhanced mRNA expression of the genes encoding insulin receptor, insulin receptor substrate (IRS)-1 and phosphatidylinositol 3-kinase. At the protein level, oleanolic acid upregulated total IRS-1 expression, suppressed the increased phosphorylated IRS-1 at serine-307, and restored the increased phosphorylated IRS-1 to total IRS-1 ratio. In contrast, phosphorylated Akt to total Akt ratio was increased. Furthermore, oleanolic acid reversed fructose-induced decrease in phosphorylated-Akt/Akt protein to plasma insulin concentration ratio. However, oleanolic acid did not affect IRS-2 mRNA expression. Therefore, these results suggest that oleanolic acid supplement ameliorates fructose-induced Adipo-IR in rats via the IRS-1/phosphatidylinositol 3-kinase/Akt pathway. Our findings may provide new insights into the mechanisms of metabolic actions of oleanolic acid. - Highlights: • Adipose insulin resistance (Adipo-IR) contributes to metabolic abnormalities. • We investigated the effect of oleanolic acid (OA) on adipo-IR in fructose-fed rats. • OA attenuated fructose-induced increase in Adipo-IR index and NEFA concentrations. • OA modulated adipose IRS-1/phosphatidylinositol 3-kinase/Akt signaling. • OA ameliorates Adipo-IR via the IRS-1/PI3K/Akt signaling pathway in rats.« less

Composition and morphology of cuticular wax in blueberry (Vaccinium spp.) fruits.

PubMed

Chu, Wenjing; Gao, Haiyan; Cao, Shifeng; Fang, Xiangjun; Chen, Hangjun; Xiao, Shangyue

2017-03-15

The chemical composition and morphology of cuticular wax in mature fruit of nine blueberry cultivars were investigated using gas chromatography-mass spectrometry (GC-MS) and scanning electron microscope (SEM). Triterpenoids and β-diketones were the most prominent compounds, accounting for on average 64.2% and 16.4% of the total wax, respectively. Ursolic or oleanolic acid was identified as the most abundant triterpenoids differing in cultivars. Two β-diketones, hentriacontan-10,12-dione and tritriacontan-12,14-dione, were detected in cuticular wax of blueberry fruits for the first time. Notably, hentriacontan-10,12-dione and tritriacontan-12,14-dione were only detected in highbush (V. corymbosum) and rabbiteye (V. ashei) blueberries, respectively. The results of SEM showed that a large amount of tubular wax deposited on the surface of blueberry fruits. There was no apparent difference in wax morphology among the nine cultivars. Copyright © 2016 Elsevier Ltd. All rights reserved.

Anabolic activity of ursolic acid in bone: Stimulating osteoblast differentiation in vitro and inducing new bone formation in vivo.

PubMed

Lee, Su-Ui; Park, Sang-Joon; Kwak, Han Bok; Oh, Jaemin; Min, Yong Ki; Kim, Seong Hwan

2008-01-01

In the field of osteoporosis, there has been growing interest in anabolic agents that enhance bone mass and improve bone architecture. In this study, we demonstrated that the ubiquitous plant triterpenoid, ursolic acid, enhances differentiation and mineralization of osteoblasts in vitro. We found that ursolic acid induced the expression of osteoblast-specific genes with the activation of mitogen-activated protein kinases, nuclear factor-kappaB, and activator protein-1. Additionally, noggin, an antagonist of bone morphogenetic proteins (BMPs), inhibited ursolic acid-induced osteoblast differentiation. Noggin also inhibited the activation of Smad and the induction of BMP-2 mRNA expression by ursolic acid in the late stage of osteoblast differentiation. Importantly, ursolic acid was shown to have bone-forming activity in vivo in a mouse calvarial bone formation model. A high proportion of positive immunostaining of BMP-2 was found in the nuclear region of woven bone formed by ursolic acid. These results suggested that ursolic acid has the anabolic potential to stimulate osteoblast differentiation and enhance new bone formation.

The Pleiotropic Antibacterial Mechanisms of Ursolic Acid against Methicillin-Resistant Staphylococcus aureus (MRSA).

PubMed

Wang, Chao-Min; Jhan, Yun-Lian; Tsai, Shang-Jie; Chou, Chang-Hung

2016-07-07

(1) BACKGROUND: Several triterpenoids were found to act synergistically with classes of antibiotic, indicating that plant-derived chemicals have potential to be used as therapeutics to enhance the activity of antibiotics against multidrug-resistant pathogens. However, the mode of action of triterpenoids against bacterial pathogens remains unclear. The objective of this study is to evaluate the interaction between ursolic acid against methicillin-resistant Staphylococcus aureus (MRSA); (2) METHODS: The ability of ursolic acid to damage mammalian and bacterial membranes was examined. The proteomic response of methicillin-resistant S. aureus in ursolic acid treatment was investigated using two-dimensional (2D) proteomic analysis; (3) RESULTS: Ursolic acid caused the loss of staphylococcal membrane integrity without hemolytic activity. The comparison of the protein pattern of ursolic acid-treated and normal MRSA cells revealed that ursolic acid affected a variety of proteins involved in the translation process with translational accuracy, ribonuclease and chaperon subunits, glycolysis and oxidative responses; (4) CONCLUSION: The mode of action of ursolic acid appears to be the influence on the integrity of the bacterial membrane initially, followed by inhibition of protein synthesis and the metabolic pathway. These findings reflect that the pleiotropic effects of ursolic acid against MRSA make it a promising antibacterial agent in pharmaceutical research.

Anti-cancer effect of ursolic acid activates apoptosis through ROCK/PTEN mediated mitochondrial translocation of cofilin-1 in prostate cancer

PubMed Central

Gai, Wen-Tao; Yu, Da-Peng; Wang, Xin-Sheng; Wang, Pei-Tao

2016-01-01

Ursolic acid is a type of pentacyclic triterpene compound with multiple pharmacological activities including cancer resistance, protection from liver injury, antisepsis, anti-inflammation and antiviral activity. The present study aimed to investigate the anticancer effect of ursolic acid. Ursolic acid activates cell apoptosis and its pro-apoptotic mechanism remains to be fully elucidated. Cell Counting kit-8 assays, flow cytometric analysis and analysis of caspase-3 and caspase-9 activity were used to estimate the anticancer effect of ursolic acid on DU145 prostate cancer cells. The protein expression of cytochrome c, rho-associated protein kinase (ROCK), phosphatase and tensin homolog (PTEN) and cofilin-1 were examined using western blot analysis. In the present study, ursolic acid significantly suppressed cell growth and induced apoptosis, as well as increasing caspase-3 and caspase-9 activities of DU145 cells. Furthermore, cytoplasmic and mitochondrial cytochrome c protein expression was significantly activated and suppressed, respectively, by ursolic acid. Ursolic acid significantly suppressed the ROCK/PTEN signaling pathway and inhibited cofilin-1 protein expression in DU145 cells. The results of the present study indicate that the anticancer effect of ursolic acid activates cell apoptosis through ROCK/PTEN mediated mitochondrial translocation of cofilin-1 in prostate cancer. PMID:27698874

Ursolic Acid Inhibits Na+/K+-ATPase Activity and Prevents TNF-α-Induced Gene Expression by Blocking Amino Acid Transport and Cellular Protein Synthesis

PubMed Central

Yokomichi, Tomonobu; Morimoto, Kyoko; Oshima, Nana; Yamada, Yuriko; Fu, Liwei; Taketani, Shigeru; Ando, Masayoshi; Kataoka, Takao

2011-01-01

Pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α, induce the expression of a wide variety of genes, including intercellular adhesion molecule-1 (ICAM-1). Ursolic acid (3β-hydroxy-urs-12-en-28-oic acid) was identified to inhibit the cell-surface ICAM-1 expression induced by pro-inflammatory cytokines in human lung carcinoma A549 cells. Ursolic acid was found to inhibit the TNF-α-induced ICAM-1 protein expression almost completely, whereas the TNF-α-induced ICAM-1 mRNA expression and NF-κB signaling pathway were decreased only partially by ursolic acid. In line with these findings, ursolic acid prevented cellular protein synthesis as well as amino acid uptake, but did not obviously affect nucleoside uptake and the subsequent DNA/RNA syntheses. This inhibitory profile of ursolic acid was similar to that of the Na+/K+-ATPase inhibitor, ouabain, but not the translation inhibitor, cycloheximide. Consistent with this notion, ursolic acid was found to inhibit the catalytic activity of Na+/K+-ATPase. Thus, our present study reveals a novel molecular mechanism in which ursolic acid inhibits Na+/K+-ATPase activity and prevents the TNF-α-induced gene expression by blocking amino acid transport and cellular protein synthesis. PMID:24970122

Matrix metalloproteinase, hyaluronidase and elastase inhibitory potential of standardized extract of Centella asiatica.

PubMed

Nema, Neelesh Kumar; Maity, Niladri; Sarkar, Birendra Kumar; Mukherjee, Pulok Kumar

2013-09-01

Centella asiatica (L.) Urban (Apiaceae), a valuable herb described in Ayurveda, is used in the indigenous system of medicine as a tonic to treat skin diseases. Centella asiatica methanol extract and its ethyl acetate, n-butanol and aqueous fraction, were subjected for the evaluation of skin care potential through the in vitro hyaluronidase, elastase and matrix metalloproteinase-1 (MMP-1) inhibitory assay. The C. asiatica plant was extracted with methanol and fractionated with ethyl acetate, n-butanol and water. The enzymatic activities were evaluated using ursolic acid and oleanolic acid as standards. Isolate molecule asiaticoside was quantified in the crude extract and fractions through high-performance liquid chromatography (HPLC) and structural was characterized by liquid chromatography-mass spectroscopy (LC-MS) and ¹H nuclear magnetic resonance (NMR). Isolated compound was also evaluated for in vitro enzyme assays. Extract exhibited anti-hyaluronidase and anti-elastase activity with IC₅₀ of 19.27 ± 0.37 and 14.54 ± 0.39 µg/mL, respectively, as compared to ursolic acid. Centella asiatica n-butanol fraction (CAnB) and isolated compound showed significant hyaluronidase (IC₅₀ = 27.00 ± 0.43 and 18.63 ± 0.33 µg/mL) and elastase (IC₅₀ = 29.15 ± 0.31 and 19.45 ± 0.25 µg/mL) inhibitory activities, respectively, and also showed significant MMP-1 inhibition (p < 0.05 and p < 0.01). n-Butanol fraction was found to be most effective among the all fractions from which asiaticoside was isolated and further quantified by HPLC. This work concludes that the asiaticoside from C. asiatica may be a prospective agent for skin care.

Evaluation of Anti-Toxoplasma gondii Effect of Ursolic Acid as a Novel Toxoplasmosis Inhibitor.

PubMed

Choi, Won Hyung; Lee, In Ah

2018-05-09

This study was carried out to evaluate the anti-parasitic effect of ursolic acid against Toxoplasma gondii ( T. gondii ) that induces toxoplasmosis, particularly in humans. The anti-parasitic effects of ursolic acid against T. gondii -infected cells and T. gondii were evaluated through different specific assays, including immunofluorescence staining and animal testing. Ursolic acid effectively inhibited the proliferation of T. gondii when compared with sulfadiazine, and consistently induced anti- T. gondii activity/effect. In particular, the formation of parasitophorous vacuole membrane (PVM) in host cells was markedly decreased after treating ursolic acid, which was effectively suppressed. Moreover, the survival rate of T. gondii was strongly inhibited in T. gondii group treated with ursolic acid, and then 50% inhibitory concentration (IC 50 ) against T. gondii was measured as 94.62 μg/mL. The T. gondii -infected mice treated with ursolic acid indicated the same survival rates and activity as the normal group. These results demonstrate that ursolic acid causes anti- T. gondii action and effect by strongly blocking the proliferation of T. gondii through the direct and the selective T. gondii -inhibitory ability as well as increases the survival of T. gondii -infected mice. This study shows that ursolic acid has the potential to be used as a promising anti- T. gondii candidate substance for developing effective anti-parasitic drugs.

Differential Gene Expression for Investigation of Escherichia coli Biofilm Inhibition by Plant Extract Ursolic Acid

PubMed Central

Ren, Dacheng; Zuo, Rongjun; González Barrios, Andrés F.; Bedzyk, Laura A.; Eldridge, Gary R.; Pasmore, Mark E.; Wood, Thomas K.

2005-01-01

After 13,000 samples of compounds purified from plants were screened, a new biofilm inhibitor, ursolic acid, has been discovered and identified. Using both 96-well microtiter plates and a continuous flow chamber with COMSTAT analysis, 10 μg of ursolic acid/ml inhibited Escherichia coli biofilm formation 6- to 20-fold when added upon inoculation and when added to a 24-h biofilm; however, ursolic acid was not toxic to E. coli, Pseudomonas aeruginosa, Vibrio harveyi, and hepatocytes. Similarly, 10 μg of ursolic acid/ml inhibited biofilm formation by >87% for P. aeruginosa in both complex and minimal medium and by 57% for V. harveyi in minimal medium. To investigate the mechanism of this nontoxic inhibition on a global genetic basis, DNA microarrays were used to study the gene expression profiles of E. coli K-12 grown with or without ursolic acid. Ursolic acid at 10 and 30 μg/ml induced significantly (P < 0.05) 32 and 61 genes, respectively, and 19 genes were consistently induced. The consistently induced genes have functions for chemotaxis and mobility (cheA, tap, tar, and motAB), heat shock response (hslSTV and mopAB), and unknown functions (such as b1566 and yrfHI). There were 31 and 17 genes repressed by 10 and 30 μg of ursolic acid/ml, respectively, and 12 genes were consistently repressed that have functions in cysteine synthesis (cysK) and sulfur metabolism (cysD), as well as unknown functions (such as hdeAB and yhaDFG). Ursolic acid inhibited biofilms without interfering with quorum sensing, as shown with the V. harveyi AI-1 and AI-2 reporter systems. As predicted by the differential gene expression, deleting motAB counteracts ursolic acid inhibition (the paralyzed cells no longer become too motile). Based on the differential gene expression, it was also discovered that sulfur metabolism (through cysB) affects biofilm formation (in the absence of ursolic acid). PMID:16000817

Ursolic Acid Inhibits Superoxide Production in Activated Neutrophils and Attenuates Trauma-Hemorrhage Shock-Induced Organ Injury in Rats

PubMed Central

Hwang, Tsong-Long; Shen, Hsin-I; Liu, Fu-Chao; Tsai, Hsin-I; Wu, Yang-Chang; Chang, Fang-Rong; Yu, Huang-Ping

2014-01-01

Neutrophil activation is associated with the development of organ injury after trauma–hemorrhagic shock. In the present study, ursolic acid inhibited the superoxide anion generation and elastase release in human neutrophils. Administration of ursolic acid attenuated trauma–hemorrhagic shock-induced hepatic and lung injuries in rats. In addition, administration of ursolic acid attenuated the hepatic malondialdehyde levels and reduced the plasma aspartate aminotransferase and alanine aminotransferase levels after trauma–hemorrhagic shock. In conclusion, ursolic acid, a bioactive natural compound, inhibits superoxide anion generation and elastase release in human neutrophils and ameliorates trauma–hemorrhagic shock-induced organ injury in rats. PMID:25360589

Fragment-based discovery of novel pentacyclic triterpenoid derivatives as cholesteryl ester transfer protein inhibitors.

PubMed

Chang, Yongzhi; Zhou, Shuxi; Li, Enqin; Zhao, Wenfeng; Ji, Yanpeng; Wen, Xiaoan; Sun, Hongbin; Yuan, Haoliang

2017-01-27

Cholesteryl Ester Transfer Protein (CETP) is an important therapeutic target for the treatment of atherosclerotic cardiovascular disease. Our molecular modeling study revealed that pentacyclic triterpenoid compounds could mimic the protein-ligand interactions of the endogenous ligand cholesteryl ester (CE) by occupying its binding site. Alignment of the docking conformations of oleanolic acid (OA), ursolic acid (UA) and the crystal conformations of known CETP inhibitor Torcetrapib in the active site proposed the applicability of fragment-based drug design (FBDD) approaches in this study. Accordingly, a series of pentacyclic triterpenoid derivatives have been designed and synthesized as novel CETP inhibitors. The most potent compound 12e (IC 50 :0.28 μM) validated our strategy for molecular design. Molecular dynamics simulations illustrated that the more stable hydrogen bond interaction of the UA derivative 12e with Ser191 and stronger hydrophobic interactions with Val198, Phe463 than those of OA derivative 12b mainly led to their significantly different CETP inhibitory activity. These novel potent CETP inhibitors based on ursane-type scaffold should deserve further investigation. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Supercritical Fluid Extraction of Eucalyptus globulus Bark—A Promising Approach for Triterpenoid Production

PubMed Central

Domingues, Rui M. A.; Oliveira, Eduardo L. G.; Freire, Carmen S. R.; Couto, Ricardo M.; Simões, Pedro C.; Neto, Carlos P.; Silvestre, Armando J. D.; Silva, Carlos M.

2012-01-01

Eucalyptus bark contains significant amounts of triterpenoids with demonstrated bioactivity, namely triterpenic acids and their acetyl derivatives (ursolic, betulinic, oleanolic, betulonic, 3-acetylursolic, and 3-acetyloleanolic acids). In this work, the supercritical fluid extraction (SFE) of Eucalyptus globulus deciduous bark was carried out with pure and modified carbon dioxide to recover this fraction, and the results were compared with those obtained by Soxhlet extraction with dichloromethane. The effects of pressure (100–200 bar), co-solvent (ethanol) content (0, 5 and 8% wt), and multistep operation were studied in order to evaluate the applicability of SFE for their selective and efficient production. The individual extraction curves of the main families of compounds were measured, and the extracts analyzed by GC-MS. Results pointed out the influence of pressure and the important role played by the co-solvent. Ethanol can be used with advantage, since its effect is more important than increasing pressure by several tens of bar. At 160 bar and 40 °C, the introduction of 8% (wt) of ethanol greatly improves the yield of triterpenoids more than threefold. PMID:22837719

Ursolic acid and its esters: occurrence in cranberries and other Vaccinium fruit and effects on matrix metalloproteinase activity in DU145 prostate tumor cells.

PubMed

Kondo, Miwako; MacKinnon, Shawna L; Craft, Cheryl C; Matchett, Michael D; Hurta, Robert A R; Neto, Catherine C

2011-03-30

Ursolic acid and its cis- and trans-3-O-p-hydroxycinnamoyl esters have been identified as constituents of American cranberries (Vaccinium macrocarpon), which inhibit tumor cell proliferation. Since the compounds may contribute to berry anticancer properties, their content in cranberries, selected cranberry products, and three other Vaccinium species (V. oxycoccus, V. vitis-idaea and V. angustifolium) was determined by liquid chromatography-mass spectroscopy. The ability of these compounds to inhibit growth in a panel of tumor cell lines and inhibit matrix metalloproteinase (MMP) activity associated with tumor invasion and metastasis was determined in DU145 prostate tumor cells. The highest content of ursolic acid and esters was found in V. macrocarpon berries (0.460-1.090 g ursolic acid and 0.040-0.160 g each ester kg(-1) fresh weight). V. vitis-idaea and V. angustifolium contained ursolic acid (0.230-0.260 g kg(-1) ), but the esters were not detected. V. oxycoccus was lowest (0.129 g ursolic acid and esters per kg). Ursolic acid content was highest in cranberry products prepared from whole fruit. Ursolic acid and its esters inhibited tumor cell growth at micromolar concentrations, and inhibited MMP-2 and MMP-9 activity at concentrations below those previously reported for cranberry polyphenolics. Cranberries (V. macrocarpon) were the best source of ursolic acid and its esters among the fruit and products tested. These compounds may limit prostate carcinogenesis through matrix metalloproteinase inhibition. Copyright © 2011 Society of Chemical Industry.

Interaction of Synuclein and Inflammation in Dopaminergic Neurodegeneration

DTIC Science & Technology

2014-06-01

are less responsive to the blocking effects of anti-CD36 antibodies. The CD36 inhibitor, ursolic acid , at concentrations of 10-5 and 10-6, reduced...N9 chemotaxis across native synuclein by almost 50%. Equally interesting is the fact that ursolic acid had a small effect on CD36-deficient N9 cell...chemotaxis across synuclein which suggests that ursolic acid may also inhibit other scavenger receptors such as SR1 and RAGE. Ursolic acid was

Ursolic acid activates the apoptosis of prostate cancer via ROCK/PTEN mediated mitochondrial translocation of cofilin-1

PubMed Central

Mu, Dawei; Zhou, Gaobiao; Li, Jianye; Su, Bin; Guo, Heqing

2018-01-01

Ursolic acid has various pharmacological activities, and can reduce blood fat as well as having antihepatic, antitumoral, anti-inflammatory and antiviral properties. However, the pro-apoptotic mechanism by which ursolic acid influences human prostate cancer requires additional study. The aim of the present study was to assess whether ursolic acid activates the apoptosis of prostate cancer and to investigate the mechanism by which the Rho-associated protein kinase 1 (ROCK1)/phosphatase and tensin homolog (PTEN) signaling pathway performs a role in ursolic acid-mediated cofilin-1 to induce apoptosis in human prostate cancer. Firstly, the present study determined the pro-apoptotic mechanism by which ursolic acid influences the cell proliferation and apoptosis of human prostate LNCaP cancer cells. Caspase-3/9 activities and ROCK1, PTEN, Cofilin-1 and cytochrome c protein expression levels were also analyzed. In the present study, it is reported that the pro-apoptotic mechanism of ursolic acid potently suppressed the cell proliferation of human prostate LNCaP cancer cells. The present study revealed that the mediation of ROCK1/PTEN-cofilin-1/cytochrome c protein expression activates caspase-3/9 activities which subsequently induced the apoptosis of human prostate cancer cells. In conclusion, these findings demonstrated that ursolic acid activates the apoptosis of prostate cancer via ROCK/PTEN mediated cofilin-1/cytochrome c which mediated caspase-3/9 activities. PMID:29435058

Constituents of the Vietnamese medicinal plant Orthosiphon stamineus.

PubMed

Tezuka, Y; Stampoulis, P; Banskota, A H; Awale, S; Tran, K Q; Saiki, I; Kadota, S

2000-11-01

From the MeOH extract of the aerial part of Vietnamese Orthosiphon stamineus, five new isopimarane-type diterpenes [orthosiphols F-J (1-5)] and two new diterpenes [staminols A (6) and B (7)] with a novel carbon-framework, to which we proposed the name "staminane", and three new highly-oxygenated staminane-type diterpenes [staminolactones A (8) and B (9) and norstaminol A (10)1 were isolated. Moreover, staminolactone A (8) is 8,14-secostaminane-type and staminolactone B (9) is 13,14-secostaminane-type, while norstaminol A (10) is 14-norstaminen-type. Together with these new diterpenes, sixteen known compounds were also isolated and identified to be: 7,3',4'-tri-O-methylluteolin (11), eupatorin (12), sinensetin (13), 5-hydroxy-6,7,3',4'-tetramethoxyflavone (14), salvigenin (15), ladanein (16), tetramethylscutellarein (17), 6-hydroxy-5,7,4'-trimethoxyflavone (18), vomifoliol (19), aurantiamide acetate (20), rosmarinic acid (21), caffeic acid (22), oleanolic acid (23), ursolic acid (24), betulinic acid (25), and beta-sitosterol (26). All the isolated compounds were tested for their cytotoxicity towards highly liver metastatic murine colon 26-L5 carcinoma cells, and the new diterpenes, except for 4, and flavonoids (11, 12, 16, 18) showed cytotoxicity with an ED50 value between 10 and 90 microg/ml.

Ursolic acid isolated from Uncaria rhynchophylla activates human dendritic cells via TLR2 and/or TLR4 and induces the production of IFN-gamma by CD4+ naïve T cells.

PubMed

Jung, Tae-Young; Pham, Thanh Nhan Nguyen; Umeyama, Akemi; Shoji, Noboru; Hashimoto, Toshihiro; Lee, Je-Jung; Takei, Masao

2010-09-25

Ursolic acid is triterpene isolated from Uncaria rhynchophylla and is a pharmacologically active substance. The induction of dendritic cell maturation is critical for the induction of Ag-specific T-lymphocyte response and may be essential for the development of human vaccine relying on T cell immunity. In this study, we investigated that the effect of Ursolic acid on the phenotypic and functional maturation of human monocyte-derived dendritic cells in vitro. Dendritic cells harvested on day 8 were examined using functional assay. The expression levels of CD1a, CD80, CD83, CD86, HLA-DR and CCR7 on Ursolic acid-primed dendritic cells was slightly enhanced. Ursolic acid dose-dependently enhanced the T cell stimulatory capacity in an allogeneic mixed lymphocyte reaction, as measured by T cell proliferation. The production of IL-12p70 induced by Ursolic acid-primed dendritic cells was inhibited by the anti-Toll-like receptor-2 (TLR2) mAb and anti-TLR4 mAb. Moreover, Ursolic acid-primed dendritic cells expressed levels of mRNA coding for both TLR2 and TLR4. The majority of cells produced considerable interferon-gamma (IFN-gamma), but also small amounts of interleukin (IL-4)-4. Ursolic acid-primed dendritic cells have an intermediate migratory capacity towards CCL19 and CCL21. These results suggest that Ursolic acid modulates human dendritic cells function in a fashion that favors Th1 polarization via the activation of IL-12p70 dependent on TLR2 and/or TLR4, and may be used on dendritic cells-based vaccines for cancer immunotherapy. 2010 Elsevier B.V. All rights reserved.

Therapeutic potentials of Crataegus azarolus var. eu- azarolus Maire leaves and its isolated compounds.

PubMed

Abu-Gharbieh, Eman; Shehab, Naglaa Gamil

2017-04-18

Hyperglycemia is a complicated condition accompanied with high incidence of infection and dyslipidemia. This study aimed to explore the phyto-constituents of Crataegus azarolus var. eu- azarolus Maire leaves, and to evaluate the therapeutic potentials particularly antimicrobial, antihyperglycemic and antihyperlipidemic of the extract and the isolated compound (3β-O-acetyl ursolic acid). Total phenolics and flavonoidal contents were measured by RP-HPLC analysis. Free radicals scavenging activity of different extraction solvents was tested in-vitro on DPPH free radicals. The antimicrobial activity of the ethanolic extract and its fractions as well as the isolated compounds were evaluated in-vitro on variable microorganisms. Animal models were used to evaluate the antihyperglycemic and antihyperlipidemic activities of the ethanolic extract along with the isolated compound (3β-O acetyl ursolic acid). RP- HPLC analysis of the phenolics revealed high content of rutin, salicylic and ellagic acids. Six compounds belonging to triterpenes and phenolics were isolated from chloroform and n-butanol fractions namely: ursolic acid, 3β-O-acetyl ursolic acid, ellagic acid, quercetin 3-O-β methyl ether, rutin and apigenin7-O-rutinoside. Ethanolic extract showed the highest DPPH radical scavenger activity compared to other solvents. Ethanolic extract, hexane fraction, ursolic acid, 3β-O acetyl ursolic acid and quercetin 3-O-methyl ether showed variable antimicrobial activity against E. coli, P. aeruginosa, S. aureus, and C. albicans. Administration of the ethanolic extract or 3β-O acetyl ursolic acid orally to the mice reduced blood glucose significantly in a time- and dose-dependent manner. Ethanolic extract significantly reduced LDL-C, VLDL-C, TC and TG and increased HDL-C in rats. Ethanolic extract and 3β-O acetyl ursolic acid reduced in-vitro activity of pancreatic lipase. This study reveals that Crataegus azarolus var. eu- azarolus Maire has the efficiency to control hyperglycemia with its associated complications. This study is the first to evaluate antihyperglycemic and antihyperlipidemic potentials of 3β-O acetyl ursolic acid.

Ursolic acid inhibits proliferation and induces apoptosis of HT-29 colon cancer cells by inhibiting the EGFR/MAPK pathway*

PubMed Central

Shan, Jian-zhen; Xuan, Yan-yan; Zheng, Shu; Dong, Qi; Zhang, Su-zhan

2009-01-01

Objective: To investigate the effects of ursolic acid on the proliferation and apoptosis of human HT-29 colon cancer cells. Methods: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and flow cytometry assays were performed to evaluate the effects of ursolic acid on the growth and apoptosis of HT-29 cells. Western blot analysis was applied to investigate the inhibitory effects of ursolic acid on the phosphorylation of the epidermal growth factor receptor (EGFR), extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (p38 MAPK), and the activity of B cell leukemia-2 (Bcl-2), B cell leukemia-xL (Bcl-xL), caspase-3, and caspase-9. Results: Ursolic acid inhibited the growth of HT-29 cells in dose- and time-dependent manners. The median inhibition concentration (IC50) values for 24, 48, and 72 h treatment were 26, 20, and 18 μmol/L, respectively. The apoptotic rates of 10, 20, and 40 μmol/L ursolic acid treatments for 24 h were 5.74%, 14.49%, and 33.05%, and for 48 h were 9%, 21.39%, and 40.49%, respectively. Ursolic acid suppressed the phosphorylation of EGFR, ERK1/2, p38 MAPK, and JNK, which is well correlated with its growth inhibitory effect. 10, 20, and 40 μmol/L ursolic acid significantly inhibited the proliferation of EGF-stimulated HT-29 cells (P<0.05). Cell proliferation was most significantly inhibited when treated with 10 and 20 μmol/L ursolic acid combined with 200 nmol/L AG 1478 or 10 μmol/L U0126 (P<0.01). Besides, it also down-regulated the expression of Bcl-2 and Bcl-xL and activated caspase-3 and caspase-9. Conclusion: Ursolic acid induces apoptosis in HT-29 cells by suppressing the EGFR/MAPK pathway, suggesting that it may be a potent agent for the treatment of colorectal cancer. PMID:19735099

Anxiolytic-like effects of ursolic acid in mice.

PubMed

Colla, André R S; Rosa, Julia M; Cunha, Mauricio P; Rodrigues, Ana Lúcia S

2015-07-05

Ursolic acid is a pentacyclic triterpenoid that possesses several biological and neuropharmacological effects including antidepressant-like activity. Anxiety disorders represent common and disability psychiatric conditions that are often associated with depressive symptoms. This work investigated the anxiolytic-like effects of ursolic acid administration in different behavioral paradigms that evaluate anxiety in mice: open field test, elevated plus maze test, light/dark box test and marble burying test. To this end, mice were administered with ursolic acid (0.1, 1 and 10mg/kg, p.o.) or diazepam (2mg/kg, p.o.), positive control, and submitted to the behavioral tests. The results show that ursolic acid (10mg/kg) elicited an anxiolytic-like effect observed by the increased total time in the center and decreased number of rearings responses in the open field test and an increased percentage of entries and total time spent in the open arms of elevated plus maze, similarly to diazepam. No significant effects of ursolic acid were shown in the light/dark box and marble burying test. These data indicate that ursolic acid exhibits anxiolytic-like effects in the open field and elevated plus maze test, but not in the light/dark box and marble burying test, showing the relevance of testing several behavioral paradigms in the evaluation of anxiolytic-like actions. Of note, the results extend the understanding on the effects of ursolic acid in the central nervous system and suggest that it may be a novel approach for the management of anxiety-related disorders. Copyright © 2015. Published by Elsevier B.V.

Oral administration of oleanolic acid, isolated from Swertia mussotii Franch, attenuates liver injury, inflammation, and cholestasis in bile duct-ligated rats

PubMed Central

Chai, Jin; Du, Xiaohuang; Chen, Sheng; Feng, XinChan; Cheng, Ying; Zhang, Liangjun; Gao, Yu; Li, Shaoxue; He, Xiaochong; Wang, Rongquan; Zhou, Xiangdong; Yang, Yong; Luo, Weizao; Chen, Wensheng

2015-01-01

Background & aims: Oleanolic acid is abundantly distributed in Swertia mussotii Franch, a Chinese traditional herb for the treatment of jaundice. However, the hepatoprotective role of oleanolic acid in obstructive cholestasis and its underlying molecular mechanism are unclear. Methods: Normal rats and bile duct-ligated (BDL) rats were given oleanolic acid and serum biochemistry, bile salts, and pro-inflammatory factors were measured, as well as the expression levels of liver bile acid synthesis and detoxification enzymes, membrane transporters, nuclear receptors, and transcriptional factors. Results: Oral administration of oleanolic acid at 100 mg/kg did not cause rat liver injury. However, it significantly reduced the serum levels of alanine aminotransferase (ALT) on days 7 and 14, aspartate aminotransferase (AST) and TNF-α on day 14, and alkaline phosphatase (ALP) and IL-1β on days 3, 7, and 14 in the BDL rats. Furthermore, the serum levels of total bile acid (TBA) and bile acids, including CDCA, CA, DCA, and Tα/βMCA were significantly reduced by oleanolic acid on day 3 in the BDL rats. In addition, the expression levels of detoxification enzymes Cyp3a, Ugt2b, Sult2a1, Gsta1-2, and Gstm1-3, membrane transporters Mrp3, Mrp4, Ostβ, Mdr1, Mdr2, and Bsep, nuclear receptors Pxr, Vdr, Hnf4α, Rxrα, Rarα, Lxr, and Lrh-1, and transcriptional factors Nrf2, Hnf3β, and Ahr were significantly increased in oleanolic acid-treated rats. Conclusion: We demonstrated that the oral administration of oleanolic acid attenuates liver injury, inflammation, and cholestasis in BDL rats. The anti-cholestatic effect may be associated with the induction of hepatic detoxification enzymes and efflux transporters mediated by nuclear receptors and transcriptional factors. PMID:25932098

Protective effect of ursolic acid from Cornus officinalis on the hydrogen peroxide-induced damage of HEI-OC1 auditory cells.

PubMed

Yu, Hyeon-Hee; Hur, Jong-Moon; Seo, Se-Jeong; Moon, Hae-Dalma; Kim, Hyun-Jin; Park, Rae-Kil; You, Yong-Ouk

2009-01-01

The fruits of Cornus officinalis have been used in traditional oriental medicine for treatment of inner ear diseases, such as tinnitus and hearing loss. In the present study, we investigated the protective effect of C. officinalis on hydrogen peroxide-induced cytotoxicity in HEI-OC1 auditory cells. The results from bioassay-guided fractionation of methanol extract of C. officinalis fruits showed that ursolic acid is a major active component. Ursolic acid (0.05-2 microg/ml) had protective effect against the HEI-OC1 cell damage and reduced lipid peroxidation in a dose-dependent manner. In addition, pre-treatment with ursolic acid significantly attenuated the decrease of activities of catalase (CAT) and glutathione peroxidase (GPX), but superoxide dismutase (SOD) activity was not significantly affected by ursolic acid. These results indicate that ursolic acid protects hydrogen peroxide-induced HEI-OC1 cell damage through inhibition of lipid peroxidation and induction of antioxidant enzymes, CAT and GPX, and may be one of the active components responsible for these effects of C. officinalis fruits.

Screening of plant extracts for antimicrobial activity against bacteria and yeasts with dermatological relevance.

PubMed

Weckesser, S; Engel, K; Simon-Haarhaus, B; Wittmer, A; Pelz, K; Schempp, C M

2007-08-01

There is cumulative resistance against antibiotics of many bacteria. Therefore, the development of new antiseptics and antimicrobial agents for the treatment of skin infections is of increasing interest. We have screened six plant extracts and isolated compounds for antimicrobial effects on bacteria and yeasts with dermatological relevance. The following plant extracts have been tested: Gentiana lutea, Harpagophytum procumbens, Boswellia serrata (dry extracts), Usnea barbata, Rosmarinus officinalis and Salvia officinalis (supercritical carbon dioxide [CO2] extracts). Additionally, the following characteristic plant substances were tested: usnic acid, carnosol, carnosic acid, ursolic acid, oleanolic acid, harpagoside, boswellic acid and gentiopicroside. The extracts and compounds were tested against 29 aerobic and anaerobic bacteria and yeasts in the agar dilution test. U. barbata-extract and usnic acid were the most active compounds, especially in anaerobic bacteria. Usnea CO2-extract effectively inhibited the growth of several Gram-positive bacteria like Staphylococcus aureus (including methicillin-resistant strains - MRSA), Propionibacterium acnes and Corynebacterium species. Growth of the dimorphic yeast Malassezia furfur was also inhibited by Usnea-extract. Besides the Usnea-extract, Rosmarinus-, Salvia-, Boswellia- and Harpagophytum-extracts proved to be effective against a panel of bacteria. It is concluded that due to their antimicrobial effects some of the plant extracts may be used for the topical treatment of skin disorders like acne vulgaris and seborrhoic eczema.

Blockage of epithelial to mesenchymal transition and upregulation of let 7b are critically involved in ursolic acid induced apoptosis in malignant mesothelioma cell

PubMed Central

Sohn, Eun Jung; Won, Gunho; Lee, Jihyun; Yoon, Sang Wook; Lee, Ilho; Kim, Hee Jeong; Kim, Sung-Hoon

2016-01-01

Malignant pleural mesothelioma (MPN), which is caused by asbestos exposure, is one of aggressive lung tumors. In the present study, we elucidated the anti-tumor mechanism of ursolic acid in malignant mesotheliomas. Ursolic acid significantly exerted cytotoxicity in a time and dose dependent manner in H28, H2452 and MSTO-211H mesothelioma cells and inhibited cell proliferation by colony formation assay in a dose-dependent fashion. Also, ursolic acid treatment accumulated the sub-G1 population, attenuated the expression of procapase 9, cyclin D1, pAKT, p-glycogen synthase kinase 3-alpha/beta (pGSK3α/β), β-catenin and nuclear factor kappa-light-chain-enhancer of activated B cells (NFkB) and also cleaved caspase 3 and poly (ADP-ribose) polymerase (PARP) in mesothelioma cells. Furthermore, ursolic acid treatment blocked epithelial and mesenchymal transition (EMT) molecules by activating E-cadherin as an epithelial marker and attenuating Vimentin, and Twist as mesenchymal molecules. Interestingly, miRNA array revealed that 23 miRNAs (>2 folds) including let-7b and miRNA3613-5p, miRNA134 and miRNA196b were significantly upregulated while 33 miRNAs were downregulated in ursolic acid treated H2452 cells. Furthermore, overexpression of let 7b using let-7b mimics enhanced the antitumor effect of ursolic acid to attenuate the expression of procaspases 3, pro-PARP, pAKT, β-catenin and Twist and increase sub-G1 accumulation in H2452 mesothelioma cells. Overall, our findings suggest that ursolic acid induces apoptosis via inhibition of EMT and activation of let7b in mesothelioma cells as a potent chemotherapeutic agent for treatment of malignant mesotheliomas. PMID:28090191

Multihydroxylation of ursolic acid by Pestalotiopsis microspora isolated from the medicinal plant Huperzia serrata.

PubMed

Fu, Shao-bin; Yang, Jun-shan; Cui, Jin-long; Meng, Qing-feng; Feng, Xu; Sun, Di-An

2011-10-01

The structural modification of ursolic acid by an endophytic fungus Pestalotiopsis microspora, isolated from medicinal plant Huperzia serrata was reported for the first time. The structure diversity was very important for the SAR study of ursolic acid and its derivatives. Incubation of ursolic acid 1 with P. microspora afforded four metabolites: 3-oxo-15α, 30-dihydroxy-urs-12-en-28-oic acid (2), 3β, 15α-dihydroxy-urs-12-en-28-oic acid (3), 3β, 15α, 30- trihydroxy-urs-12-en-28-oic acid (4) and 3,4-seco-ursan-4,30-dihydroxy-12-en-3,28-dioic acid (5). All products were new compounds and their structures elucidation was mainly based on the spectroscopic data. Copyright © 2011 Elsevier B.V. All rights reserved.

The Effect of Ursolic Acid on Leishmania (Leishmania) amazonensis Is Related to Programed Cell Death and Presents Therapeutic Potential in Experimental Cutaneous Leishmaniasis

PubMed Central

Yamamoto, Eduardo S.; Campos, Bruno L. S.; Jesus, Jéssica A.; Laurenti, Márcia D.; Ribeiro, Susan P.; Kallás, Esper G.; Rafael-Fernandes, Mariana; Santos-Gomes, Gabriela; Silva, Marcelo S.; Sessa, Deborah P.; Lago, João H. G.; Levy, Débora; Passero, Luiz F. D.

2015-01-01

Among neglected tropical diseases, leishmaniasis is one of the most important ones, affecting more than 12 million people worldwide. The available treatments are not well tolerated, and present diverse side effects, justifying the search for new therapeutic compounds. In the present study, the activity of ursolic acid (UA) and oleanolic acid (OA) were assayed in experimental cutaneous leishmaniasis (in vitro and in vivo). Promastigote forms of L. amazonensis were incubated with OA and UA for 24h, and effective concentration 50% (EC50) was estimated. Ultraestructural alterations in Leishmania amazonensis promastigotes after UA treatment were evaluated by transmission electron microscopy, and the possible mode of action was assayed through Annexin V and propidium iodide staining, caspase 3/7 activity, DNA fragmentation and transmembrane mitochondrial potential. The UA potential was evaluated in intracellular amastigotes, and its therapeutic potential was evaluated in L. amazonensis infected BALB/c mice. UA eliminated L. amazonensis promastigotes with an EC50 of 6.4 μg/mL, comparable with miltefosine, while OA presented only a marginal effect on promastigote forms at 100 μg/mL. The possible mechanism by which promastigotes were eliminated by UA was programmed cell death, independent of caspase 3/7, but it was highly dependent on mitochondria activity. UA was not toxic for peritoneal macrophages from BALB/c mice, and it was able to eliminate intracellular amastigotes, associated with nitric oxide (NO) production. OA did not eliminate amastigotes nor trigger NO. L. amazonensis infected BALB/c mice submitted to UA treatment presented lesser lesion size and parasitism compared to control. This study showed, for the first time, that UA eliminate promastigote forms through a mechanism associated with programed cell death, and importantly, was effective in vivo. Therefore, UA can be considered an interesting candidate for future tests as a prototype drug for the treatment of cutaneous leishmaniasis. PMID:26674781

[Study on triterpenoid saponins in the rhizome of Anemone hofengensis].

PubMed

Han, Lin-Tao; Li, Ming-Ming; Huang, Fang; Hou, An-Wei

2013-10-01

To study the triterpenoid saponins in the rhizome of Anemone hofengensis. The constituents were separated with various chromatographic techniques and their structures were elucidated by physicochemical properties and spectral data. Five compounds were isolated and identified as 3-O-alpha-L-rhamnopyranosyl-(1 --> 2)-alpha-L-arabino-pyranosyl-oleanolic acid (1), 3-O-alpha-L-rhamnopyranosyl-(1 --> 2)-beta-D-glucopyranosyl-(1 --> 2)-alpha-L-rhamnopyranosyl-oleanolic acid 28-O-alpha-L-rhamnopyranosyl-(1 --> 4) -beta-D-glucopyranosyl-(1 --> 6)-beta-D-glucopyranoside (2), 3-O-alpha-L-rhamnopyranosyl-(1 --> 2) [beta-D-glucopyranosyl-(1 --> 4)]-alpha-L-rhamnopyranosyl-oleanolic acid-28-O-beta-D-glucopyranosyl-(1 --> 6)-beta-D-gluco-pyranoside (3), 3-O-beta-D-glucopyranosyl-(1 --> 2)-beta-D-xylopyranosyl-oleanolic acid 28-O-beta-D-glucopyranosyl-(1 --> 6)-beta-D-glucopyranoside (4), oleanolic acid-28-O-alpha-L-rhamnopyra-nosyl-(1 --> 4)-beta-D-glucopyranosyl-(1 --> 6)-beta-D-glucopyranoside (5). Compound 1 - 5 are isolated from this plant for the first time.

Evaluation of the Cytotoxicity of Satureja spicigera and Its Main Compounds

PubMed Central

Gohari, Ahmad Reza; Ostad, Seyed Nasser; Moradi-Afrapoli, Fahimeh; Malmir, Maryam; Tavajohi, Shohreh; Akbari, Hassan; Saeidnia, Soodabeh

2012-01-01

Satureja spicigera (Lamiaceae) grows wildly in Northwest of Iran. In this study, bioassay-guided isolation and identification of the main compounds has been reported using various chromatographic methods and comparison of their spectral data with those reported in the literature. Brine shrimp lethality and four cancerous cell lines HT29/219, Caco2, NIH-3T3, and T47D were used for cytotoxicity evaluations. From the aerial parts of S. spicigera, nine known compounds including two flavanones, 5,7,3′,5′-tetrahydroxy flavanone (8) and 5,4′-dihydroxy-3′-methoxyflavanone-7-(6′′-O-α-L-rhamnopyranosyl)-β-D-glucopyranoside (9), one dihydrochalcone, nubigenol (7), together with thymoquinone (1), thymol (2), carvacrol (3), β-sitosterol (4), ursolic acid (5) and oleanolic acid (6) were identified. Among the isolated chalcone and flavanones, compound 8 was effective against Artemia salina larva (LC50= 2 μg/mL) and only the compound 9 demonstrated IC50 value of 98.7 μg/mL on the T47D (human, breast, ductal carcinoma). Other compounds did not show significant inhibition of the cell growth. PMID:22623883

Oleanolic acid liposomes with polyethylene glycol modification: promising antitumor drug delivery

PubMed Central

Gao, Dawei; Tang, Shengnan; Tong, Qi

2012-01-01

Background Oleanolic acid is a pentacyclic triterpene present in many fruits and vegetables, and has received much attention on account of its biological properties. However, its poor solubility and low bioavailability limit its use. The objective of this study was to encapsulate oleanolic acid into nanoliposomes using the modified ethanol injection method. Methods The liposomes contain a hydrophobic oleanolic acid core, an amphiphilic soybean lecithin monolayer, and a protective hydrophilic polyethylene glycol (PEG) coating. During the preparation process, the formulations described were investigated by designing 34 orthogonal experiments as well as considering the effects of different physical characteristics. The four factors were the ratios of drug to soybean phosphatidylcholine (w/w), cholesterol (w/w), PEG-2000 (w/w), and temperature of phosphate-buffered saline at three different levels. We identified the optimized formulation which showed the most satisfactory lipid stability and particle formation. The morphology of the liposomes obtained was determined by transmission electron microscopy and atomic force microscopy. The existence of PEG in the liposome component was validated by Fourier transform infrared spectrum analysis. Results The PEGylated liposomes dispersed individually and had diameters of around 110–200 nm. Encapsulation efficiency was more than 85%, as calculated by high-performance liquid chromatography and Sephadex® gel filtration. Furthermore, when compared with native oleanolic acid, the liposomal formulations showed better stability in vitro. Finally, the cytotoxicity of the oleanolic acid liposomes was evaluated using a microtiter tetrazolium assay. Conclusion These results suggest that PEGylated liposomes would serve as a potent delivery vehicle for oleanolic acid in future cancer therapy. PMID:22848175

BDNF–ERK–CREB signalling mediates the role of miR-132 in the regulation of the effects of oleanolic acid in male mice

PubMed Central

Yi, Li-Tao; Li, Jing; Liu, Bin-Bin; Luo, Liu; Liu, Qing; Geng, Di

2014-01-01

Background Although previous study has demonstrated that brain-derived neurotrophic factor (BDNF) is involved in the antidepressant-like effect of oleanolic acid, there is little information regarding the details of the molecular mechanism involved in this effect. Methods We used a chronic unpredictable mild stress (CUMS) model to test the antidepressant-like effect of oleanolic acid on depressant-like behaviour, miR-132 expression and synaptic protein expression in the male mouse hippocampus. Furthermore, we explored the possible signalling pathways associated with miR-132 expression that mediate the effect of oleanolic acid on neuronal proliferation. Results The results demonstrated that a 3-week treatment with oleanolic acid ameliorated CUMS-induced anhedonic and anxiogenic behaviours. Furthermore, we found that oleanolic acid led to the BDNF-related phosphorylation and activation of extracellular signal-regulated kinases (ERK) and cyclic adenosine monophosphate response element binding protein (CREB), which was associated with the upregulation of miR-132 and hippocampal neuronal proliferation. Moreover, experiments with an miR-132 antagomir revealed that targeting miR-132 led to inhibition of neuronal proliferation and the postsynaptic density protein 95, but did not affect presynaptic protein synapsin I. Limitations Several other stimuli can also induce CREB phosphorylation in the hippocampus. Thus, regulation of miR-132 may not be restricted to neurotrophic signalling. Conclusion Our results show that oleanolic acid induces the upregulation of miR-132, which serves as an important regulator of neurotrophic actions, mainly through the activation of the hippocampal BDNF–ERK–CREB signalling pathways. PMID:25079084

Distribution and expression characteristics of triterpenoids and OSC genes in white birch (Betula platyphylla suk.).

PubMed

Yin, Jing; Ren, Chun-Lin; Zhan, Ya-Guang; Li, Chun-Xiao; Xiao, Jia-Lei; Qiu, Wei; Li, Xin-Yu; Peng, Hong-Mei

2012-03-01

Betulin and oleanolic acids (pentacyclic triterpenoid secondary metabolites) have broad pharmacological activities and can be potentially used for the development of anti-cancer and anti-AIDS drugs. In this study, we detected the accumulation and the distribution characteristics of betulin and oleanolic acid in various organs of white birch at different ages. We also determined the expression of 4 OSC genes (LUS, β-AS, CAS1 and CAS2) involved in the triterpenoid synthesis pathways by real time RT-PCR. The result showed that the 1-year old birch can synthesize betulin and oleanolic acid. In addition, betulin and oleanolic acids were mainly distributed in the bark, while the content in the root skin and leaf was very low. The content of betulin and oleanolic acid in birch varied in different seasons. The content of betulin and oleanolic acid and their corresponding LUS and β-AS gene expression were very low in 1-year old birch. With increasing age of birch, betulin content was increased, while oleanolic acid was decreased. Similar changes were also observed for their corresponding synthesis genes LUS and β-AS. In the leaf of 1-year old plant, the highest expression of CAS1 and CAS2 occurred at end of September, while expression of LUS and the β-AS was low from June to October. In the stem skin,high expression of β-AS and the LUS genes occurred from the end of July to September. In the root, high expression of the β-AS gene was observed at the end of October. These results indicated that triterpenoid gene expression was similar to the triterpene accumulation. Expression of LUS gene and β-AS gene in birch with different ages were corresponding to the betulinic and oleanolic acid accumulation. Expression of CAS1 and CAS2 genes were elevated with increasing age of birch. This study provides molecular mechanisms of triterpenes synthesis in birch plants.

Ursolic acid isolated from guava leaves inhibits inflammatory mediators and reactive oxygen species in LPS-stimulated macrophages.

PubMed

Kim, Min-Hye; Kim, Jin Nam; Han, Sung Nim; Kim, Hye-Kyeong

2015-06-01

Psidium guajava (guava) leaves have been frequently used for the treatment of rheumatism, fever, arthritis and other inflammatory conditions. The purpose of this study was to identify major anti-inflammatory compounds from guava leaf extract. The methanol extract and its hexane-, dichloromethane-, ethylacetate-, n-butanol- and water-soluble phases derived from guava leaves were evaluated to determine their inhibitory activity on nitric oxide (NO) production by RAW 264.7 cells stimulated with lipopolysaccharide (LPS). The methanol extract decreased NO production in a dose-dependent manner without cytotoxicity at a concentration range of 0-100 μg/mL. The n-butanol soluble phase was the most potent among the five soluble phases. Four compounds were isolated by reversed-phase HPLC from the n-butanol soluble phase and identified to be avicularin, guaijaverin, leucocyanidin and ursolic acid by their NMR spectra. Among these compounds, ursolic acid inhibited LPS-induced NO production in a dose-dependent manner without cytotoxity at a concentration range of 1-10 µM, but the other three compounds had no effect. Ursolic acid also inhibited LPS-induced prostaglandin E2 production. A western blot analysis showed that ursolic acid decreased the LPS-stimulated inducible nitric oxide synthase and cyclooxygenase protein levels. In addition, ursolic acid suppressed the production of intracellular reactive oxygen species in LPS-stimulated RAW 264.7 cells, as measured by flow cytometry. Taken together, these results identified ursolic acid as a major anti-inflammatory compound in guava leaves.

Comparative protective effect of hawthorn berry hydroalcoholic extract, atorvastatin, and mesalamine on experimentally induced colitis in rats.

PubMed

Malekinejad, Hassan; Shafie-Irannejad, Vahid; Hobbenaghi, Rahim; Tabatabaie, Seyed Hamed; Moshtaghion, Seyed-Mehdi

2013-07-01

The protective effect of hydroalcoholic extract of hawthorn berries (HBE) on acetic acid (AA)-induced colitis in rats was investigated. Forty-two Wistar rats were divided into seven groups, including control and test groups (n=6). The control animals received saline, and the test animals were treated with saline (sham group), mesalamine (50 mg/kg; M group), atorvastatin (20 mg/kg; A group), HBE (100 mg/kg; H group), mesalamine and HBE (HM group), or atorvastatin plus HBE (HA group), 3 days before and a week after colitis induction. Colitis was induced by administration of 1 mL AA (4%) via a polyethylene catheter intrarectally. High-performance liquid chromatography analyses showed that HBE contained 0.13% and 0.5% oleanolic acid and ursolic acid, respectively. Elevated myeloperoxidase activity and lipid peroxidation were attenuated in the HA group. The H and HM groups showed marked reductions in colitis-induced decreases in total thiol molecules and body weight. The histopathological studies revealed that HBE decreased colitis-induced edema and infiltration of neutrophils. Our data suggest the anti-inflammatory and antioxidant effects of HBE and atorvastatin protect against AA-induced colitis. The anti-inflammatory effect of HBE may be attributable to its ability to decrease myeloperoxidase activity as a biomarker of neutrophil infiltration.

Ursolic acid inhibits breast cancer growth by inhibiting proliferation, inducing autophagy and apoptosis, and suppressing inflammatory responses via the PI3K/AKT and NF-κB signaling pathways in vitro

PubMed Central

Luo, Juan; Hu, Yan-Ling; Wang, Hong

2017-01-01

Breast cancer, which is the second leading cause of cancer-associated mortality in women worldwide, develops from breast tissue. Chemotherapy is the most commonly used therapy to treat breast cancer. However, a number of natural plant-derived products have been suggested as alternative therapies to treat different types of cancer, such as breast cancer. The aim of the present study was to determine the anti-tumor effects of ursolic acid and its effect on apoptosis and inflammation in breast cancer cells. The anti-cancer effects of ursolic acid were evaluated in vitro using flow cytometry, western blotting and reverse transcription-quantitative polymerase chain reaction. The results suggest that ursolic acid inhibits the viability of breast cancer cells by inducing autophagy and apoptosis without inducing cell death. Cellular migration assays demonstrated that ursolic acid was able to suppress the invasive ability of breast cancer cells (P<0.05). In addition, the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway was downregulated following ursolic acid administration (P<0.05), leading to an upregulation of glycogen synthase kinase activity (P<0.05) and downregulation of B-cell lymphoma 2 (P<0.05), subsequently causing autophagy and apoptosis via cyclin-D1 inhibition and caspase-3 stimulation (P<0.05). Furthermore, the inflammatory response of breast cancer cells was assessed by measuring levels of nuclear factor (NF)-κB. Ursolic acid was found to downregulate NF-κB in breast cancer cells, thus inhibiting inflammation and preventing the progression of breast cancer (P<0.05). To the best of our knowledge, the present study is the first to assess the effect of ursolic acid on breast cancer cells through PI3K/AKT-regulated GSK and caspase-3 accompanied by NF-κB signaling pathways. The results of the present study regarding the potential underlying molecular mechanisms of ursolic acid may be used to develop novel therapeutic strategies for breast cancer treatment. PMID:29042957

Syntheses and mucosal adjuvant activity of simplified oleanolic acid saponins possessing cinnamoyl ester.

PubMed

Shirahata, Tatsuya; Nagai, Takayuki; Hirata, Nozomu; Yokoyama, Masaki; Katsumi, Tatsuya; Konishi, Naruki; Nishino, Takashi; Makino, Kazuishi; Yamada, Haruki; Kaji, Eisuke; Kiyohara, Hiroaki; Kobayashi, Yoshinori

2017-03-15

A series of new simplified oleanolic acid saponins with a glycosyl ester moiety at C28, were efficiently prepared. Furthermore, the effect of nasal administration of the synthetic oleanolic acid saponins on the nasal anti-influenza virus antibody titer against secondary nasal inoculation of the influenza split vaccine was examined. The result revealed cinnamoyl saponin as a suitable candidate vaccine adjuvant. Copyright © 2016. Published by Elsevier Ltd.

Transepithelial transport of rosuvastatin and effect of ursolic acid on its transport in Caco-2 monolayers.

PubMed

Hua, Wen Jin; Fang, Hu Jin; Hua, Wei Xiao

2012-09-01

The aim of this study was to determine transepithelial transport characteristics of rosuvastatin and effect of ursolic acid (P-gp potential inhibitor) and ko143 (ABC transporters selective inhibitor) on its transport in Caco-2 monolayers. A reliable Caco-2 cell monolayers model was established. The TEER value was used to inspect integrity of cell model. Apparent permeability coefficients (Papp(BL-AP) and Papp(AP-BL)) were used to analyze transepithelial transport of rosuvastatin. Uptake of rosuvastatin was time- and concentration-dependent in Caco-2 cell. The ko143 but not ursolic acid had effect on the uptake of rosuvastatin in Caco-2 cell monolayer model and affected apparent permeability coefficient and apparent permeability of rosuvastatin. Active transport and passive diffusion absorption existed in transepithelial transport of rosuvastatin in Caco-2 cell model. Ursolic acid had no effect on transport of rosuvastatin in Caco-2 cell monolayer. The result indicated that ursolic acid may not cause effect on intestinal absorption of rosuvastatin.

[Effects of triterpenoid from Psidium guajava leaves ursolic acid on proliferation, differentiation of 3T3-L1 preadipocyte and insulin resistance].

PubMed

Lin, Juan-Na; Kuang, Qiao-Ting; Ye, Kai-He; Ye, Chun-Ling; Huang, Yi; Zhang, Xiao-Qi; Ye, Wen-Cai

2013-08-01

To investigate the influences of triterpenoid from Psidium guajava Leaves (ursolic acid) on the proliferation, differentiation of 3T3-L1 preadipocyte, and its possible mechanism treat for insulin resistance. 3T3-L1 preadipocyte was cultured in vitro. After adding ursolic acid to the culture medium for 48h, the cell viability was tested by MTT assay. Induced for 6 days, the lipid accumulation of adipocyte was measured by Oil Red O staining. The insulin resistant cell model was established with Dexamethasone. Cellular glucose uptake was determined with GOD-POD assays and FFA concentration was determined at the time of 48h. Secreted adiponectin were measured by ELISA. The protein levels of PPARgamma and PTP1B in insulin resistant adipocyte were measured by Western Blotting. Compared with medium control group, 30, 100 micromol/L ursolic acid could increase its proliferation and differentiation significantly (P < 0.05 or P < 0.01). Compared with the model group, ursolic acid at 100 micromol/L could enhance cellular glucose uptake of insulin resistant adipocyte significantly both in basic and insulin stimulation state (P < 0.01), while ursolic acid at 30 micromol/L could already enhance its glucose uptake significantly (P < 0.05), and could already decrease its FFA production significantly (P < 0.05). Ursolic acid at 30 micromol/L could increase the secretion of adiponectin on insulin resistant adipocyte significantly (P < 0.05), up-regulate the expression of PPARgamma protein (P < 0.05), but showed no effect on the PTP1B protein expression (P > 0.05). Ursolic acid can improve the proliferation and differentiation of 3T3-L1 preadipocyte, enhance cellular glucose uptake, inhibit the production of FFA, promote the secretion of adiponectin insulin resistant adipocyte, its mechanism may be related to upregulating the expression of PPARgamma protein.

Pentacyclic triterpenoids from Cyclocarya paliurus and their antioxidant activities in FFA-induced HepG2 steatosis cells.

PubMed

Yang, Hui-Min; Yin, Zhi-Qi; Zhao, Meng-Ge; Jiang, Cui-Hua; Zhang, Jian; Pan, Ke

2018-04-18

Six undescribed pentacyclic triterpenoids including four triterpenoid aglycones, 1β,2a,3β,23-tetrahydroxyurs-12-en-28-ursolic acid, 2a,3a,6β,19α,23-pentahydroxyurs-12-en-28-ursolic acid, 2α,3α,20β,23-tetrahydroxyurs-12-en-28-ursolic acid and 1β,2a,3β,23-tetrahydroxyurs-12,20(30)-dien-28-ursolic acid, and two triterpenoid glucosides, 2a,3a,23-trihydroxy-12,20(30)-dien-28-ursolic acid 28-O-β-d-glucopyranoside and 1-oxo-3β,23-dihydroxyolean-12-en-28-oic acid 28-O-β-d-xylopyranoside, along with 5 known triterpenoids were isolated from a CH 3 Cl-soluble extract of the leaves of Cyclocarya paliurus. Their structures were established on the basis of chemical and spectroscopic approaches. These compounds were assessed for their antioxidant effects on FFA-induced hepatic steatosis in HepG2 cells. The results revealed that three saponins and two aglycones markedly increased SOD activity and reduced MDA level. Copyright © 2018 Elsevier Ltd. All rights reserved.

[Studies on triterpenoid saponins in the rhizome of Anemone flaccida].

PubMed

Han, Lin-Tao; Huang, Fang

2009-07-01

To study the triterpenoid saponins in the rhizome of Anemone flaccida. The constituents were separated with various chromatographic techniques and their structures were elucidated by means of physicochemical properties and the analysis of their spectral datas. Five compounds were isolated and identified as 3-O-beta-D-glucuronypyranosyl-oleanolic acid-28-O-alpha-L-rhamnopyranosyl (1 --> 4)-beta-D-glucopyranosyl(1 --> 6)-beta-D-glucopyra noside (1), 3-O-beta-D-glucuronypyranosyl-oleanolic acid-28-O-beta-D-glucopyranosyl (1 --> 6)-beta-D-glucopyranoside (2), 3-O-alpha-L-rhamnopyranosy (1 --> 2)-beta-D-glucopyranosyl-oleanolic acid-28-O-alpha-L-rhamnopyranosyl (1 --> 4)-beta-D-glucopyranosyl (1 --> 6)-beta-D-glucopyranoside (3), 3-O-alpha-L-rhamnopyranosyl (1 --> 2)-alpha-L-arabinopyrano-syl-oleanolic acid-28-O-alpha-L-rhamnopyranosyl (1 -->4)-beta-D-glucopyranosyl (1 --> 6)-beta-D-glucopyranoside (4), 3-O-alpha-L-rhamnopyranosyl (1 --> 2)-beta-D-xylopyranosyl-oleanolic acid-28-O-alpha-L-rhamnopyranosyl (1 --> 4)-beta-D-glucopyranosyl (1 --> 6)-beta-D-glucopyranoside (5). Compound 1 - 4 are isolated from this plant for the first time. Compound 1,2 are isolated from this genus for the first time.

Cytochrome P450 CYP716A254 catalyzes the formation of oleanolic acid from β-amyrin during oleanane-type triterpenoid saponins biosynthesis in Anemone flaccida.

PubMed

Zhan, Chuansong; Ahmed, Shakeel; Hu, Sheng; Dong, Shuang; Cai, Qian; Yang, Tewu; Wang, Xuekui; Li, Xiaohua; Hu, Xuebo

2018-01-01

Anemone flaccida Fr. Shmidt (Ranunculaceae), known as 'Di Wu' in China, is a perennial herb which has long been used to treat arthritis. The rhizome of A. flaccida contains pharmacologically active components i.e. oleanane-type triterpenoid saponins. Oleanolic acid is natural triterpenoid in plants with diverse biological activities. The biosynthesis of oleanolic acid involves cyclization of 2,3-oxidosqualene to the oleanane-type triterpenoid skeleton, followed by a series of oxidation reactions catalyzed by cytochrome P450 monooxygenase (CYP450). Previously, we identified four possible cytochrome P450 genes belonging to CYP716A subfamily from the transcriptome of A. flaccida. In this study, we identified one of those genes "CYP716A254" encoding a cytochrome P450 monooxygenase from A. flaccida that catalyzes the conversion of the β-amyrin into oleanolic acid. The heterologous expression of CYP716A254 in yeast resulted in oxidation of β-amyrin at the C-18 position to oleanolic acid production. These results provide an important basis for further studies of oleanane-type triterpenoid saponins synthesis in A. flaccida. Copyright © 2017 Elsevier Inc. All rights reserved.

Ameliorative effects of oleanolic acid on fluoride induced metabolic and oxidative dysfunctions in rat brain: Experimental and biochemical studies.

PubMed

Sarkar, Chaitali; Pal, Sudipta; Das, Niranjan; Dinda, Biswanath

2014-04-01

Beneficial effects of oleanolic acid on fluoride-induced oxidative stress and certain metabolic dysfunctions were studied in four regions of rat brain. Male Wistar rats were treated with sodium fluoride at a dose of 20 mg/kg b.w./day (orally) for 30 days. Results indicate marked reduction in acidic, basic and neutral protein contents due to fluoride toxicity in cerebrum, cerebellum, pons and medulla. DNA, RNA contents significantly decreased in those regions after fluoride exposure. Activities of proteolytic enzymes (such as cathepsin, trypsin and pronase) were inhibited by fluoride, whereas transaminase enzyme (GOT and GPT) activities increased significantly in brain tissue. Fluoride appreciably elevated brain malondialdehyde level, free amino acid nitrogen, NO content and free OH radical generation. Additionally, fluoride perturbed GSH content and markedly reduced SOD, GPx, GR and CAT activities in brain tissues. Oral supplementation of oleanolic acid (a plant triterpenoid), at a dose of 5mg/kgb.w./day for last 14 days of fluoride treatment appreciably ameliorated fluoride-induced alteration of brain metabolic functions. Appreciable counteractive effects of oleanolic acid against fluoride-induced changes in protein and nucleic acid contents, proteolytic enzyme activities and other oxidative stress parameters indicate that oleanolic acid has potential antioxidative effects against fluoride-induced oxidative brain damage. Copyright © 2014 Elsevier Ltd. All rights reserved.

Study of isomeric pentacyclic triterpene acids in traditional Chinese medicine of Forsythiae Fructus and their binding constants with β-cyclodextrin by capillary electrophoresis.

PubMed

Ren, Tingjun; Xu, Zhongqi

2018-04-01

In this study, a capillary zone electrophoresis (CZE) method was first developed to identify three microconstituents of isomeric pentacyclic triterpene acids (PTAs including oleanolic acid (OA), ursolic acid (UA) and betulinic acid (BA)) in Forsythiae Fructus (FF). The baseline separation of PTAs by CZE were eventually achieved in a background electrolyte (BGE) containing 50.0 mmol/L borax and 0.5 mmol/L β-cyclodextrin (β-CD) at pH 9.5 within 13.0 min. Herein, it was not only the compositions of BGE were detail investigated for rapid and good separation, but also the binding ratio and the equilibrium constants (K) for OA, UA and BA with β-CD was estimated by double reciprocal equation to well understand the separation mechanism. The proposed method allowed the LODs of PTAs were averaged at 1.50 μg/mL with UV detection (at 200 nm). The interday RSD of migration time and peak area were around 2.0 and 4.7% (n = 5), respectively. Thus, the content of PTAs in 19 FF real samples distinguished from maturation stages and geographical areas in China was quantified with the proposed method. Depending on the amount of each PTA in FF, it was demonstrated these microconstituents might benefit to identify their harvested time even qualities. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Permeability of rosmarinic acid in Prunella vulgaris and ursolic acid in Salvia officinalis extracts across Caco-2 cell monolayers

USDA-ARS?s Scientific Manuscript database

Rosmarinic acid (RA), a caffeic acid derivative found in high concentrations in Prunella vulgaris (self-heal), and ursolic acid (UA), a pentacyclic triterpene acid concentrated in Salvia officinalis (sage), have been traditionally used to treat inflammation in the mouth, and may also be of benefit t...

Protection and sensitization of normal and malignant cells by a naturally occurring compound in a model of photochemical damage

NASA Astrophysics Data System (ADS)

Lee, Yuan-Hao; Kumar, Neeru; Glickman, Randolph D.

2012-03-01

Certain phytonutrients are known to confer protection and immunosuppression against radiation insults. Radiation-induced reactive oxygen species (ROS) can either lead to the destruction of normal tissue cells, or induce tumor radioresistance by activating ROS scavenging proteins. To identify whether the triterpene phytonutrient, ursolic acid, reduces radiation-induced damage in normal cells and promotes the apoptosis of malignant cells, we investigated the biologic mechanisms and effect of radiation-cell interaction with or without treatment with ursolic acid in human skin melanoma cells (ATCC CRL-11147TM) and transformed human retinal pigment epithelial (hTERT-RPE) cells. UV-VIS light was employed to investigate the efficacy of ursolic acid in altering cellular viability by modulations of p53 and NF-κB p65 signaling. Cell response was investigated by changes in proliferative activity and free radical generation assessed by 2',7'-dichlorofluorescin liquid chromatography. Ursolic acid pretreatment strongly increased the level of p53 and decreased the level of phosphorylated p65 leading to enhanced cell death of skin melanoma cells in response to UV-VIS exposure. In contrast, ursolic acid appeared to downregulate p53 levels without disturbing NF-κB activation along with an increase of oxidative stress in hTERT-RPE cells. These findings indicate that ursolic acid may beneficially increase the radiosensitivity of tumor cells while potentiating a photoprotective effect on benign cells through differential effects on the NF-κB and p53 signaling pathways.

Comparison of the interaction between lactoferrin and isomeric drugs

NASA Astrophysics Data System (ADS)

Guo, Ming; Lu, Xiaowang; Wang, Yan; Brodelius, Peter E.

2017-02-01

The binding properties of pentacyclic triterpenoid isomeric drugs, i.e. ursolic acid (UA) and oleanolic acid (OA), to bovine lactoferrin (BLF) have been studied by molecule modeling, fluorescence spectroscopy, UV-visible absorbance spectroscopy and infrared spectroscopy (IR). Molecular docking, performed to reveal the possible binding mode or mechanism, suggested that hydrophobic interaction and hydrogen bonding play important roles to stabilize the complex. The results of spectroscopic measurements showed that the two isomeric drugs both strongly quenched the intrinsic fluorescence of BLF through a static quenching procedure although some differences between UA and OA binding strength and non-radiation energy transfer occurred within the molecules. The number of binding sites was 3.44 and 3.10 for UA and OA, respectively, and the efficiency of Förster energy transfer provided a distance of 0.77 and 1.21 nm for UA and OA, respectively. The conformation transformation of BLF affected by the drugs conformed to the ;all-or-none; pattern. In addition, the changes of the ratios of α-helices, β-sheets and β-turns of BLF during the process of the interaction were obtained. The results of the experiments in combination with the calculations showed that there are two modes of pentacyclic triterpenoid binding to BLF instead of one binding mode only governed by the principle of the lowest bonding energy.

Phytochemical Study of the Ecuadorian Species Lepechinia mutica (Benth.) Epling and High Antifungal Activity of Carnosol against Pyricularia oryzae.

PubMed

Ramírez, Jorge; Gilardoni, Gianluca; Ramón, Erika; Tosi, Solveig; Picco, Anna Maria; Bicchi, Carlo; Vidari, Giovanni

2018-04-19

The plant Lepechinia mutica (Benth.) Epling (family Lamiaceae) is endemic to Ecuador. In the present study, we report some major non-volatile secondary metabolites from the leaves and the chemistry of the essential oil distilled from the flowers. The main identified compounds were carnosol, viridiflorol, ursolic acid, oleanolic acid, chrysothol, and 5-hydroxy-4′,7-dimethoxy flavone. Their structures were determined by X-ray diffraction and NMR and MS techniques. The essential oil showed a chemical composition similar to that distilled from the leaves, but with some qualitative and quantitative differences regarding several minor compounds. The main constituents (>4%) were: δ-3-carene (24.23%), eudesm-7(11)-en-4-ol (13.02%), thujopsan-2-α-ol (11.90%), β-pinene (7.96%), valerianol (5.19%), and co-eluting limonene and β-phellandrene (4.47%). The volatile fraction was also submitted to enantioselective analysis on a β-cyclodextrin column, obtaining the separation and identification of the enantiomers for α-thujene, β-pinene, sabinene, α-phellandrene, limonene and β-phellandrene. Furthermore, the anti-fungal activity of non-volatile secondary metabolites was tested in vitro, with carnosol resulting in being very active against the “blast disease” caused by the fungus Pyricularia oryzae .

Differential Lipid Composition and Gene Expression in the Semi-Russeted “Cox Orange Pippin” Apple Variety

PubMed Central

Legay, Sylvain; Cocco, Emmanuelle; André, Christelle M.; Guignard, Cédric; Hausman, Jean-Francois; Guerriero, Gea

2017-01-01

Russeting is characterized by a particular rough and brown phenotype, which is mainly due to the accumulation of suberin in the inner part of the epidermal cell walls. In our previous bulk transcriptomic analysis, comparing fully russeted, and waxy apple varieties, showed, in apple fruit skin, a massive decreased expression of cutin, wax and some pentacyclic triterpene biosynthesis genes in the russeted varieties, with an expected concomitant enhanced expression of the suberin biosynthetic genes. In the present work, we performed a deep investigation of the aliphatic composition of the cutin, suberin, waxes, and triterpenes in the waxy and russeted patches of the semi-russeted apple variety “Cox Orange Pippin.” A targeted gene expression profiling was performed to validate candidate genes which were identified in our previous work and might be involved in the respective metabolic pathways. Our results showed that a decrease of cuticular waxes, ursolic acid and oleanolic acid, accompanied by an accumulation of alkyl-hydroxycinamates and betulinic acid, occurs in the russeted patches. The suberin monomer composition is characterized by specific occurrence of 20, 22, and 24 carbon aliphatic chains, whereas cutin is mainly represented by common C16 and C18 aliphatic chains. This work depicts, for the first time in apple, the complex composition of suberin, cutin, waxes and triterpenes, and confirms the strong interplay between these epidermal polymers in apple fruit skin. PMID:29018466

Differential Lipid Composition and Gene Expression in the Semi-Russeted "Cox Orange Pippin" Apple Variety.

PubMed

Legay, Sylvain; Cocco, Emmanuelle; André, Christelle M; Guignard, Cédric; Hausman, Jean-Francois; Guerriero, Gea

2017-01-01

Russeting is characterized by a particular rough and brown phenotype, which is mainly due to the accumulation of suberin in the inner part of the epidermal cell walls. In our previous bulk transcriptomic analysis, comparing fully russeted, and waxy apple varieties, showed, in apple fruit skin, a massive decreased expression of cutin, wax and some pentacyclic triterpene biosynthesis genes in the russeted varieties, with an expected concomitant enhanced expression of the suberin biosynthetic genes. In the present work, we performed a deep investigation of the aliphatic composition of the cutin, suberin, waxes, and triterpenes in the waxy and russeted patches of the semi-russeted apple variety "Cox Orange Pippin." A targeted gene expression profiling was performed to validate candidate genes which were identified in our previous work and might be involved in the respective metabolic pathways. Our results showed that a decrease of cuticular waxes, ursolic acid and oleanolic acid, accompanied by an accumulation of alkyl-hydroxycinamates and betulinic acid, occurs in the russeted patches. The suberin monomer composition is characterized by specific occurrence of 20, 22, and 24 carbon aliphatic chains, whereas cutin is mainly represented by common C16 and C18 aliphatic chains. This work depicts, for the first time in apple, the complex composition of suberin, cutin, waxes and triterpenes, and confirms the strong interplay between these epidermal polymers in apple fruit skin.

Comparative Protective Effect of Hawthorn Berry Hydroalcoholic Extract, Atorvastatin, and Mesalamine on Experimentally Induced Colitis in Rats

PubMed Central

Shafie-Irannejad, Vahid; Hobbenaghi, Rahim; Tabatabaie, Seyed Hamed; Moshtaghion, Seyed-Mehdi

2013-01-01

Abstract The protective effect of hydroalcoholic extract of hawthorn berries (HBE) on acetic acid (AA)–induced colitis in rats was investigated. Forty-two Wistar rats were divided into seven groups, including control and test groups (n=6). The control animals received saline, and the test animals were treated with saline (sham group), mesalamine (50 mg/kg; M group), atorvastatin (20 mg/kg; A group), HBE (100 mg/kg; H group), mesalamine and HBE (HM group), or atorvastatin plus HBE (HA group), 3 days before and a week after colitis induction. Colitis was induced by administration of 1 mL AA (4%) via a polyethylene catheter intrarectally. High-performance liquid chromatography analyses showed that HBE contained 0.13% and 0.5% oleanolic acid and ursolic acid, respectively. Elevated myeloperoxidase activity and lipid peroxidation were attenuated in the HA group. The H and HM groups showed marked reductions in colitis-induced decreases in total thiol molecules and body weight. The histopathological studies revealed that HBE decreased colitis-induced edema and infiltration of neutrophils. Our data suggest the anti-inflammatory and antioxidant effects of HBE and atorvastatin protect against AA-induced colitis. The anti-inflammatory effect of HBE may be attributable to its ability to decrease myeloperoxidase activity as a biomarker of neutrophil infiltration. PMID:23875899

LC-UV assay method and UPLC/Q-TOF-MS characterisation of saponins from Ilex paraguariensis A. St. Hil. (mate) unripe fruits.

PubMed

Peixoto, Maria Paula Garofo; Kaiser, Samuel; Verza, Simone Gasparin; de Resende, Pedro Ernesto; Treter, Janine; Pavei, Cabral; Borré, Gustavo Luís; Ortega, George González

2012-01-01

Ilex paraguariensis A. St. Hil. (mate) is known in several South American countries because of the use of its leaves in stimulant herbal beverages. High saponin contents were reported in mate leaves and unripe fruits that possess a dissimilar composition. Two LC-UV methods previously reported for mate saponins assay focused on mate leaves and the quantification of the less polar saponin fraction in mate fruits. To develop and validate a LC-UV method to assay the total content of saponins in unripe mate fruits and characterise the chemical structure of triterpenic saponins by UPLC/Q-TOF-MS. From unripe fruits of mate a crude ethanolic extract was prepared (EX40) and the mate saponin fraction (MSF) purified by solid phase extraction. The LC-UV method was validated using ilexoside II as external standard. UPLC/Q-TOF-MS was adjusted from the LC-UV method to obtain the fragmentation patterns of the main saponins present in unripe fruits. Both LC-UV and UPLC/Q-TOF-MS methods indicate a wide range of Ilex saponins polarity. The ilexoside II and total saponin content of EX40 were 8.20% (w/w) and 47.60% (w/w), respectively. The total saponin content in unripe fruits was 7.28% (w/w). The saponins present in MSF characterised by UPLC/Q-TOF-MS are derived mainly from ursolic/oleanolic, acetyl ursolic or pomolic acid. The validated LC-UV method was shown to be linear, precise, accurate and to cover several saponins previously isolated from Ilex species and could be applied for the quality control of unripe fruit saponins. Copyright © 2011 John Wiley & Sons, Ltd.

Structure elucidation of two triterpenoid saponins from rhizome of Anemone raddeana Regel.

PubMed

Lu, Jincai; Xu, Beibei; Gao, Song; Fan, Li; Zhang, Hongfen; Liu, Runxiang; Kodama, Hiroyuki

2009-09-01

Two new 27-hydroxy-oleanolic acid type triterpenoid saponins, raddeanoside 20 (1) and raddeanoside 21(2) were isolated from the rhizome of Anemone raddeana Regel. The structures of the two compounds were elucidated as 27-hydroxy-oleanolic acid 3-O-alpha-L-rhamnopyranosyl(1-->2) [beta-D-glucopyranosyl (1-->4)]-alpha-L-arabinopyranoside (1) and 3-O-alpha-L-rhamnopyranosyl (1-->2)-alpha-L-arabinopyranosyl-27-hydroxy-oleanolic acid 28-O-alpha-L-rhamnopyranosyl(1-->4)-beta-D-glucopyranosyl (1-->6)-beta-D-glucopyranoside (2) on the basis of chemical and spectral evidence.

Antidepressant-like effect of oleanolic acid in mice exposed to the repeated forced swimming test.

PubMed

Yi, Li-Tao; Li, Jing; Liu, Qing; Geng, Di; Zhou, Ya-Fei; Ke, Xiao-Qing; Chen, Huan; Weng, Lian-Jin

2013-05-01

The study aimed to explore the antidepressant-like effect of oleanolic acid and its possible mechanism related to the monoaminergic system and neurotrophin in mice exposed to the repeated forced swimming test (FST). Both the duration and the latency of immobility affected by oleanolic acid (10, 20 and 40 mg/kg) were evaluated in the FST repeated at intervals on days 1, 7 and 14, followed by neurochemical and brain-derived neurotrophic factor (BDNF) analyses in the mouse brain regions of frontal cortex and whole hippocampus. A repeated analysis of variance (ANOVA) indicated that over retesting the immobility time increased, whereas latency to immobility tended to decrease. Minute-by-minute analysis showed that immobility time also increased during the 4-min course of the test. In addition, post-hoc Dunnett's test demonstrated that sub-chronic and chronic, but not acute, oleanolic acid treatment reduced the immobility time (sub-chronic: 20 mg/kg, 43.5%; chronic: 10 mg/kg, 19.3%; 20 mg/kg, 31.8%) and increased the latency to immobility (sub-chronic: 10 mg/kg, 60.6%; 20 mg/kg, 80.1%; chronic: 10 mg/kg, 121.8%; 20 mg/kg, 140.8%; 40 mg/kg, 80.0%). Furthermore, chronic administration of oleanolic acid significantly increased serotonin (5-HT) levels (frontal cortex: 44.5%, 41.9%, 27.5% for 10, 20, 40 mg/kg; hippocampus: 57.2%, 80.9% for 10, 20 mg/kg), decreased 5-hydroxyindoleacetic acid (5-HIAA)/5-HT ratio (frontal cortex: 31.6%, 30.1%, 23.5%; hippocampus: 40.6%, 47.7%, 29.2% for 10, 20, 40 mg/kg) and elevated norepinephrine (NE) levels (hippocampus: 20 mg/kg, 45.4%) but did not alter dopamine (DA) levels. Moreover, BDNF levels in the two brain regions were also elevated by chronic oleanolic acid treatment (frontal cortex: 20 mg/kg, 67.2%; hippocampus: 10 mg/kg, 36.4%; 20 mg/kg, 55.1%). Taken together, these findings imply that functions of 5-HT, NE and BDNF may be involved in the antidepressant-like effect of oleanolic acid.

Triterpenic Acids Present in Hawthorn Lower Plasma Cholesterol by Inhibiting Intestinal ACAT Activity in Hamsters

PubMed Central

Lin, Yuguang; Vermeer, Mario A.; Trautwein, Elke A.

2011-01-01

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. PMID:19228775

Triterpenic Acids Present in Hawthorn Lower Plasma Cholesterol by Inhibiting Intestinal ACAT Activity in Hamsters.

PubMed

Lin, Yuguang; Vermeer, Mario A; Trautwein, Elke A

2011-01-01

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.

RNA-Seq-based transcriptome analysis of methicillin-resistant Staphylococcus aureus biofilm inhibition by ursolic acid and resveratrol

PubMed Central

Qin, Nan; Tan, Xiaojuan; Jiao, Yinming; Liu, Lin; Zhao, Wangsheng; Yang, Shuang; Jia, Aiqun

2014-01-01

Bacterial biofilms are particularly problematic since they become resistant to most available antibiotics. Hence, novel potential antagonists to inhibit biofilm formation are urgent. Here the influences of two natural products, ursolic acid and resveratrol, on biofilm of the clinical methicillin-resistant Staphylococcus aureus (MRSA) isolate were investigated using RNA-seq, and the differentially expressed genes were analyzed using Cuffdiff. The results showed that ursolic acid inhibition of biofilm formation may reduce amino acids metabolism and adhesins expression and resveratrol may disturb quorum sensing (QS) and the synthesis of surface proteins and capsular polysaccharides. In addition, the transcriptome analysis of resveratrol and the combination of resveratrol with vancomycin inhibition of established biofilm revealed that resveratrol would disturb the expression of genes related to QS, surface and secreted proteins, and capsular polysaccharides. These findings suggest that ursolic acid and resveratrol could be useful to be adjunct therapies for the treatment of MRSA biofilm-involved infections. PMID:24970710

Role of modifier in microwave assisted extraction of oleanolic acid from Gymnema sylvestre: application of green extraction technology for botanicals.

PubMed

Mandal, Vivekananda; Dewanjee, Saikat; Mandal, Subhash C

2009-08-01

This work highlights the development of a green extraction technology for botanicals with the use of microwave energy. Taking into consideration the extensive time involved in conventional extraction methods, coupled with usage of large volumes of organic solvent and energy resources, an ecofriendly green method that can overcome the above problems has been developed. The work compares the effect of sample pretreatment with untreated sample for improved yield of oleanolic acid from Gymnema sylvestre leaves. The pretreated sample with water produced 0.71% w/w oleanolic acid in one extraction cycle with 500 W microwave power, 25 mL methanol and only an 8 min extraction time. On the other hand, a conventional heat reflux extraction for 6 hours could produce only 0.62% w/w oleanolic acid. The detailed mechanism of extraction has been studied through scanning electron micrographs. The environmental impact of the proposed green method has also been evaluated.

Ursolic Acid, a Natural Pentacylcic Triterpene from Ochrosia elliptica and Its Role in The Management of Certain Neglected Tropical Diseases

PubMed Central

Labib, Rola M.; Ebada, Sherif S.; Youssef, Fadia S.; Ashour, Mohamed L.; Ross, Samir A.

2016-01-01

Background: Leishmaniasis and African trypanosomiasis are recognized as the leading causes of mortality and morbidity with the greatest prevalence in the developing countries. They affect more than one billion of the poorest people on the globe. Objective: To find a cheap, affordable, safe, and efficacious antileshmanial and antitrypanosomal natural drug and to elucidate its probable mode of action. Materials and Methods: Phytochemical investigation of the non-polar fraction of the methanol extract of leaves of Ochrosia elliptica Labill. (Apocyanaceae) resulted in the isolation of ursolic acid, which was unambiguously determined based on HR-ESI-FTMS, extensive 1D and 2D NMR spectroscopy. It was further tested for its cytotoxicity, antimicrobial, antimalarial, antileishmanial, and trypanocidal potency. in-silico molecular modeling studies were conducted on six vital parasitic enzymes including farnesyl diphosphate synthase, N-myristoyl transferase, pteridine reductase 1, trypanothione reductase, methionyl-tRNA synthetase, and inosine–adenosine–guanosine nucleoside hydrolase to discover its potential mode of action as antitrypanosomal and antileishmanial agent. Results: Ursolic acid displayed considerable antitrypanosomal and antileishmanial activities with IC50 values ranging between 1.53 and 8.79 μg/mL. It showed superior antitrypanosomal activity as compared to the standard drug difluoromethylornithine (DFMO), with higher binding affinities towards trypanothione reductase and pteridine reductase 1. It displayed free binding energy of -30.73 and -50.08 kcal/mole towards the previously mentioned enzymes, respectively. In addition, ursolic acid exhibited considerable affinities to farnesyl diphosphate synthase, N-myristoyl transferase and methionyl-tRNA synthetase with free binding energies ranging from -42.54 to -63.93 kcal/mole. Conclusion: Ursolic acid offers a safe, effective and cheap antitrypanosomal and antileishmanial candidate acting on several key parasitic enzymes. SUMMARY The fresh leaves of Ochrosia elleptica Labill., family Apocyanaceae are a reliable source of ursolic acid.Ursolic acid displayed considerable antitrypanosomal and antileishmanial activities. It showed superior antitrypanosomal activity as compared to difluoromethylornithine (DFMO), potent antitrypanosomal reference drug.In silico molecular modeling studies revealed that the antileishmanial and antitrypanosomal activities of ursolic acid could be partially explained in view of its multiple inhibitory effects on vital parasitic enzymes with the highest potency exerted in the inhibition of pteridine reductase 1 and trypanothione reductase. Abbreviations used: AHT: African Human Trypanosomiasis, ATCC: American type cell culture, BuOH: n-butanol, DCM: dichloromethane, DFMO: difluoromethylornithine, EtOAc: ethyl acetate, FCS: fetal calf serum, HMBC: Heteronuclear Multiple Bond Correlation, HMQC: Heteronuclear Multiple-Quantum Correlation, HR-ESI-FTMS: High Resolution Electrospray ionozation Mass Spectrometry, MENA: Middle East and North Africa, MeOH: Methanol, MRSA: Methicillin-resistant Staphylococcus aureus, NTDs: Neglected tropical diseases, TLC: Thin layer chromatography, UA: Ursolic acid, UV: Ultra violet, WHO: World Health Organization. PMID:27867276

Production of oleanolic acid glycosides by hairy root established cultures of Calendula officinalis L.

PubMed

Długosz, Marek; Wiktorowska, Ewa; Wiśniewska, Anita; Pączkowski, Cezary

2013-01-01

In order to initiate hairy root culture initiation cotyledons and hypocotyls of Calendula officinalis L. were infected with Agrobacterium rhizogenes strain ATCC 15834 or the same strain containing pCAMBIA 1381Z vector with β-glucuronidase reporter gene under control of promoter of NIK (Nematode Induced Kinase) gene. The efficiency of induction of hairy roots reached 33.8% for cotyledons and 66.6% for hypocotyls together for both transformation experiments. Finally, eight control and nine modified lines were established as a long-term culture. The hairy root cultures showed the ability to synthesize oleanolic acid mainly (97%) as glycosides; control lines contained it at the average 8.42 mg · g(-1) dry weight in tissue and 0.23 mg · dm(-3) in medium; modified lines: 4.59 mg · g(-1) for the tissue, and 0.48 mg · dm(-3) for the medium. Additionally lines showed high positive correlation between dry/fresh weight and oleanolic acid concentration in tissue. Using the Killiani mixture in acidic hydrolysis of oleanolic acid glycosides released free aglycones that were partially acetylated in such conditions.

Phytochemical composition and in vitro pharmacological activity of two rose hip (Rosa canina L.) preparations.

PubMed

Wenzig, E M; Widowitz, U; Kunert, O; Chrubasik, S; Bucar, F; Knauder, E; Bauer, R

2008-10-01

The aim of the present study was to compare powdered rose hip with and without fruits (Rosae pseudofructus cum/sine fructibus, Rosa canina L., Rosaceae) with regard to their phytochemical profile and their in vitro anti-inflammatory and radical-scavenging properties. The two powders were subsequently extracted with solvents of increasing polarity and tested for inhibition of cyclooxygenase (COX-1, COX-2) and of 5-LOX-mediated leukotriene B(4) (LTB(4)) formation as well as for DPPH-radical-scavenging capacity. While the water and methanol extracts were inactive in the COX-1, COX-2 and LTB(4) inhibition assays, the n-hexane and the dichloromethane extracts inhibited all three enzymes. In the active extracts, the triterpenoic acids ursolic acid, oleanolic acid and betulinic acid were identified, although only in minute amounts. Furthermore, oleic, linoleic and alpha-linolenic acid were identified apart from several saturated fatty acids. Even though unsaturated fatty acids are known to be good inhibitors of COX-1, COX-2 and LT formation, no clear correlation between their concentration in the extracts and their activity was found. We suggest that other, yet unidentified, lipophilic constituents might play a more important role for the observed in vitro inhibitory activity on arachidonic acid metabolism. Some of the extracts also showed considerable DPPH radical scavenging activity, the methanolic extracts being most potent. The radical scavenging activity of the extracts correlated very well with their total phenolic content, while ascorbic acid contributes only little to the radical-scavenging activity due to its low concentration present in the extracts. In summary, extracts derived from powdered rose hip without fruits were more effective in all assays carried out compared with extracts derived from powdered rose hip with fruits.

Constituents of the root of Anemone tomentosa.

PubMed

Hu, Hao-Bin; Zheng, Xu-Dong; Jian, Yu-Feng; Liu, Jian-Xin; Zhu, Ji-Hua

2011-07-01

A new diterpene glycoside, tomentoside I (1), along with eleven known compounds, including the four coumarins, 4,5-dimethoxyl-7-methylcoumarin (2), 4,7-dimethoxyl-5-methylcoumarin (3), isofraxidin (4) and fraxidin (5) as well as the seven triterpenoids, oleanolic acid (6), oleanolic acid 3-O-α-L-arabinopyranoside (7), oleanolic acid 3-O-β-D-galactopyranosyl-(1→3)-β-D-glucopyranoside (8), hederagenin 3-O-α-L-arabinopyranoside (9), betulinic acid (10), 18-hydroxyursolic acid (11) and 2α,3β,23-trihydroxyurs-12-en-28-oic acid (12) were isolated from the ethanolic extract of the root of Anemone tomentosa and their chemical structures were elucidated by spectroscopic methods. The antimicrobial activities of compounds 1-12 were measured using the agar disc-diffusion method. Also, their antioxidant activities against 1,1-diphenyl-2-picrylhydrazyl (DPPH) were evaluated.

A High Content Drug Screen Identifies Ursolic Acid as an Inhibitor of Amyloid β Protein Interactions with Its Receptor CD36*

PubMed Central

Wilkinson, Kim; Boyd, Justin D.; Glicksman, Marcie; Moore, Kathryn J.; El Khoury, Joseph

2011-01-01

A pathological hallmark of Alzheimer disease (AD) is deposition of amyloid β (Aβ) in the brain. Aβ binds to microglia via a receptor complex that includes CD36 leading to production of proinflammatory cytokines and neurotoxic reactive oxygen species and subsequent neurodegeneration. Interruption of Aβ binding to CD36 is a potential therapeutic strategy for AD. To identify pharmacologic inhibitors of Aβ binding to CD36, we developed a 384-well plate assay for binding of fluorescently labeled Aβ to Chinese hamster ovary cells stably expressing human CD36 (CHO-CD36) and screened an Food and Drug Administration-approved compound library. The assay was optimized based on the cells' tolerance to dimethyl sulfoxide, Aβ concentration, time required for Aβ binding, reproducibility, and signal-to-background ratio. Using this assay, we identified four compounds as potential inhibitors of Aβ binding to CD36. These compounds were ursolic acid, ellipticine, zoxazolamine, and homomoschatoline. Of these compounds, only ursolic acid, a naturally occurring pentacyclic triterpenoid, successfully inhibited binding of Aβ to CHO-CD36 cells in a dose-dependent manner. The ursolic acid effect reached a plateau at ∼20 μm, with a maximal inhibition of 64%. Ursolic acid also blocked binding of Aβ to microglial cells and subsequent ROS production. Our data indicate that cell-based high-content screening of small molecule libraries for their ability to block binding of Aβ to its receptors is a useful tool to identify novel inhibitors of receptors involved in AD pathogenesis. Our data also suggest that ursolic acid is a potential therapeutic agent for AD via its ability to block Aβ-CD36 interactions. PMID:21835916

Identification and Small Molecule Inhibition of an Activating Transcription Factor 4 (ATF4)-dependent Pathway to Age-related Skeletal Muscle Weakness and Atrophy*

PubMed Central

Ebert, Scott M.; Dyle, Michael C.; Bullard, Steven A.; Dierdorff, Jason M.; Murry, Daryl J.; Fox, Daniel K.; Bongers, Kale S.; Lira, Vitor A.; Meyerholz, David K.; Talley, John J.; Adams, Christopher M.

2015-01-01

Aging reduces skeletal muscle mass and strength, but the underlying molecular mechanisms remain elusive. Here, we used mouse models to investigate molecular mechanisms of age-related skeletal muscle weakness and atrophy as well as new potential interventions for these conditions. We identified two small molecules that significantly reduce age-related deficits in skeletal muscle strength, quality, and mass: ursolic acid (a pentacyclic triterpenoid found in apples) and tomatidine (a steroidal alkaloid derived from green tomatoes). Because small molecule inhibitors can sometimes provide mechanistic insight into disease processes, we used ursolic acid and tomatidine to investigate the pathogenesis of age-related muscle weakness and atrophy. We found that ursolic acid and tomatidine generate hundreds of small positive and negative changes in mRNA levels in aged skeletal muscle, and the mRNA expression signatures of the two compounds are remarkably similar. Interestingly, a subset of the mRNAs repressed by ursolic acid and tomatidine in aged muscle are positively regulated by activating transcription factor 4 (ATF4). Based on this finding, we investigated ATF4 as a potential mediator of age-related muscle weakness and atrophy. We found that a targeted reduction in skeletal muscle ATF4 expression reduces age-related deficits in skeletal muscle strength, quality, and mass, similar to ursolic acid and tomatidine. These results elucidate ATF4 as a critical mediator of age-related muscle weakness and atrophy. In addition, these results identify ursolic acid and tomatidine as potential agents and/or lead compounds for reducing ATF4 activity, weakness, and atrophy in aged skeletal muscle. PMID:26338703

Suppression of muscle wasting by the plant‐derived compound ursolic acid in a model of chronic kidney disease

PubMed Central

Yu, Rizhen; Chen, Ji‐an; Xu, Jing; Cao, Jin; Wang, Yanlin; Thomas, Sandhya S.

2016-01-01

Abstract Background Muscle wasting in chronic kidney disease (CKD) and other catabolic disorders contributes to morbidity and mortality, and there are no therapeutic interventions that regularly and safely block losses of muscle mass. We have obtained evidence that impaired IGF‐1/insulin signalling and increases in glucocorticoids, myostatin and/or inflammatory cytokines that contribute to the development of muscle wasting in catabolic disorders by activating protein degradation. Methods Using in vitro and in vivo models of muscle wasting associated with CKD or dexamethasone administration, we measured protein synthesis and degradation and examined mechanisms by which ursolic acid, derived from plants, could block the loss of muscle mass stimulated by CKD or excessive levels of dexamethasone. Results Using cultured C2C12 myotubes to study muscle wasting, we found that exposure to glucocorticoids cause loss of cell proteins plus an increase in myostatin; both responses are significantly suppressed by ursolic acid. Results from promoter and ChIP assays demonstrated a mechanism involving ursolic acid blockade of myostatin promoter activity that is related to CEBP/δ expression. In mouse models of CKD‐induced or dexamethasone‐induced muscle wasting, we found that ursolic acid blocked the loss of muscle mass by stimulating protein synthesis and decreasing protein degradation. These beneficial responses included decreased expression of myostatin and inflammatory cytokines (e.g. TGF‐β, IL‐6 and TNFα), which are initiators of muscle‐specific ubiquitin‐E3 ligases (e.g. Atrogin‐1, MuRF‐1 and MUSA1). Conclusions Ursolic acid improves CKD‐induced muscle mass by suppressing the expression of myostatin and inflammatory cytokines via increasing protein synthesis and reducing proteolysis. PMID:27897418

Identification and Small Molecule Inhibition of an Activating Transcription Factor 4 (ATF4)-dependent Pathway to Age-related Skeletal Muscle Weakness and Atrophy.

PubMed

Ebert, Scott M; Dyle, Michael C; Bullard, Steven A; Dierdorff, Jason M; Murry, Daryl J; Fox, Daniel K; Bongers, Kale S; Lira, Vitor A; Meyerholz, David K; Talley, John J; Adams, Christopher M

2015-10-16

Aging reduces skeletal muscle mass and strength, but the underlying molecular mechanisms remain elusive. Here, we used mouse models to investigate molecular mechanisms of age-related skeletal muscle weakness and atrophy as well as new potential interventions for these conditions. We identified two small molecules that significantly reduce age-related deficits in skeletal muscle strength, quality, and mass: ursolic acid (a pentacyclic triterpenoid found in apples) and tomatidine (a steroidal alkaloid derived from green tomatoes). Because small molecule inhibitors can sometimes provide mechanistic insight into disease processes, we used ursolic acid and tomatidine to investigate the pathogenesis of age-related muscle weakness and atrophy. We found that ursolic acid and tomatidine generate hundreds of small positive and negative changes in mRNA levels in aged skeletal muscle, and the mRNA expression signatures of the two compounds are remarkably similar. Interestingly, a subset of the mRNAs repressed by ursolic acid and tomatidine in aged muscle are positively regulated by activating transcription factor 4 (ATF4). Based on this finding, we investigated ATF4 as a potential mediator of age-related muscle weakness and atrophy. We found that a targeted reduction in skeletal muscle ATF4 expression reduces age-related deficits in skeletal muscle strength, quality, and mass, similar to ursolic acid and tomatidine. These results elucidate ATF4 as a critical mediator of age-related muscle weakness and atrophy. In addition, these results identify ursolic acid and tomatidine as potential agents and/or lead compounds for reducing ATF4 activity, weakness, and atrophy in aged skeletal muscle. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

[Studies on chemical constituents of Valeriana officinalis].

PubMed

Jiang, Xia; Zhang, Jian-chao; Liu, Yan-wen; Fang, Yin

2007-11-01

From Valeriana officinalis L., 4 compounds were isolated and identified by various spectral analysis and chemical conversion, as valerenic acid, beta-sitosterol, ursolic acid, 4, 4', 8, 8'-tetrahydroxy-3, 3'-dimethoxyl-dibenzyl-ditetrahydrofuran and caryophyllene acide,valerane, naphthalene, linoleic acid, ethyl ester, myrtenyl acetate were identified by GC-MS. Ursolic acid and 4, 4', 8, 8'-tetrahydroxy-3, 3'-dimethoxyl-dibenzyl-ditetrahydrofuran were discovered in this plant for the first time.

Simple amides of oleanolic acid as effective penetration enhancers.

PubMed

Bednarczyk-Cwynar, Barbara; Partyka, Danuta; Zaprutko, Lucjusz

2015-01-01

Transdermal transport is now becoming one of the most convenient and safe pathways for drug delivery. In some cases it is necessary to use skin penetration enhancers in order to allow for the transdermal transport of drugs that are otherwise insufficiently skin-permeable. A series of oleanolic acid amides as potential transdermal penetration enhancers was formed by multistep synthesis and the synthesis of all newly prepared compounds is presented. The synthetized amides of oleanolic acid were tested for their in vitro penetration promoter activity. The above activity was evaluated by means of using the Fürst method. The relationships between the chemical structure of the studied compounds and penetration activity are presented.

Simple Amides of Oleanolic Acid as Effective Penetration Enhancers

PubMed Central

Bednarczyk-Cwynar, Barbara; Partyka, Danuta; Zaprutko, Lucjusz

2015-01-01

Transdermal transport is now becoming one of the most convenient and safe pathways for drug delivery. In some cases it is necessary to use skin penetration enhancers in order to allow for the transdermal transport of drugs that are otherwise insufficiently skin-permeable. A series of oleanolic acid amides as potential transdermal penetration enhancers was formed by multistep synthesis and the synthesis of all newly prepared compounds is presented. The synthetized amides of oleanolic acid were tested for their in vitro penetration promoter activity. The above activity was evaluated by means of using the Fürst method. The relationships between the chemical structure of the studied compounds and penetration activity are presented. PMID:26010090

Development and Validation of High-performance Thin Layer Chromatographic Method for Ursolic Acid in Malus domestica Peel

PubMed Central

Nikam, P. H.; Kareparamban, J. A.; Jadhav, A. P.; Kadam, V. J.

2013-01-01

Ursolic acid, a pentacyclic triterpenoid possess a wide range of pharmacological activities. It shows hypoglycemic, antiandrogenic, antibacterial, antiinflammatory, antioxidant, diuretic and cynogenic activity. It is commonly present in plants especially coating of leaves and fruits, such as apple fruit, vinca leaves, rosemary leaves, and eucalyptus leaves. A simple high-performance thin layer chromatographic method has been developed for the quantification of ursolic acid from apple peel (Malus domestica). The samples dissolved in methanol and linear ascending development was carried out in twin trough glass chamber. The mobile phase was selected as toluene:ethyl acetate:glacial acetic acid (70:30:2). The linear regression analysis data for the calibration plots showed good linear relationship with r2=0.9982 in the concentration range 0.2-7 μg/spot with respect to peak area. According to the ICH guidelines the method was validated for linearity, accuracy, precision, and robustness. Statistical analysis of the data showed that the method is reproducible and selective for the estimation of ursolic acid. PMID:24302805

Selective and cost-effective protocol to separate bioactive triterpene acids from plant matrices using alkalinized ethanol: Application to leaves of Myrtaceae species

PubMed Central

Lima, Adélia M. Belem; Siani, Antonio Carlos; Nakamura, Marcos Jun; D’Avila, Luiz Antonio

2015-01-01

Background: Triterpenes as betulinic (BA), oleanolic (OA) and ursolic acids (UA) have increasingly gained therapeutic relevance due to their wide scope of pharmacological activities. To fit large-scale demands, exploitable sources of these compounds have to be found and simple, cost-effective methods to extract them developed. Leaf material represents the best plant sustainable raw material. To obtain triterpene acid-rich extracts from leaves of Eugenia, Psidium and Syzygium species (Myrtaceae) by directly treating the dry plant material with alkalinized hydrated ethanol. This procedure was adapted from earlier methods to effect depolymerization of the leaf cutin. Materials and Methods: Extracts were prepared by shaking the milled dry leaves in freshly prepared 2% NaOH in 95% EtOH solution (1:4 w/v) at room temperature for 6 h. Working up the product in acidic aqueous medium led to clear precipitates in which BA, OA and UA were quantified by gas chromatography. Results: Pigment-free and low-polyphenol content extracts (1.2–2.8%) containing 6–50% of total triterpene acids were obtained for the six species assayed. UA (7–20%) predominated in most extracts, but BA preponderated in Eugenia florida (39%). Carried out in parallel, n-hexane defatted leaves led to up to 9% enhancement of total acids in the extracts. The hydroalcoholate treatment of Myrtaceae species dry leaves proved to be a cost-effective and environmentally friendly method to obtain triterpene acids, providing them be resistant to alkaline medium. These combined techniques might be applicable to other plant species and tissues. PMID:26246721

Synergistic antinociceptive interaction of Syzygium aromaticum or Rosmarinus officinalis coadministered with ketorolac in rats.

PubMed

Beltrán-Villalobos, Karla Lyzet; Déciga-Campos, Myrna; Aguilar-Mariscal, Hidemi; González-Trujano, María Eva; Martínez-Salazar, María Fernanda; Ramírez-Cisneros, María de Los Ángeles; Rios, María Yolanda; López-Muñoz, Francisco Javier

2017-10-01

Syzygium aromaticum (L.) Merr. & L.M. Perry (Mirtaceae) and Rosmarinus officinalis L. (Lamiaceae) are both medicinal plants used for centuries to alleviate pain. The aim of the study was to demonstrate the therapeutic potential utility of herb-drug association of S. aromaticum essential oil or R. officinalis ethanolic extract coadministered with ketorolac. Antinociceptive pharmacological interaction was investigated by an isbolographic study using the formalin test in rats. Both alone and in combination with ketorolac; S. aromaticum and R. officinalis produced a dose-dependent antinociceptive response. To plot the isobologram, we used the effective dose 50 of each one component in a fixed 1:1 ratio. The isobolographic analysis showed that, in both combinations, ketorolac plus essential oil S. aromaticum and ketorolac plus ethanolic extract R. officinalis, the experimental value (Z exp ) was lower than the theoretical value (Z add ). In addition, this study shows that eugenol, a metabolite present in S. aromaticum, and ursolic acid, a metabolite present in R. officinalis, also synergized the antinociceptive effect of ketorolac. While, the oleanolic acid present in both medicinal species did not show a synergistic antinociceptive effect in combination with ketorolac. No adverse effects were observed with these herb-drug interactions. These findings suggest that essential oil S. aromaticum and ethanolic extract R. officinalis could be useful in combination with ketorolac for the treatment of inflammatory pain. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Selective activity of Oleanolic and Maslinic Acids on the Amastigote form of Leishmania Spp

PubMed Central

Sifaoui, Ines; López-Arencibia, Atteneri; Martín-Navarro, Carmen M; Reyes-Batlle, María; Mejri, Mondher; Valladares, Basilio; Lorenzo-Morales, Jacob; Abderabba, Manef; Piñero, José Enrique

2017-01-01

Leishmaniasis represents a serious threat to the health as one of the most important neglected tropical diseases as designated by the World Health Organization. The disease is endemic in 82 countries, among them Tunisia is an indigenous area for cutaneous Leishmaniasis. In a previous work, two tritepenic acids namely oleanolic and maslinic acids have been isolated from olive leaf extract. In the present paper, the in vitro activity against amastigotes stage of Leishmania (L.) infantum and Leishmania (L.) amazonensis was investigated. Maslinic acid showed the highest activity, against L. amazonensis, with an IC50 of 1.417 ± 0.401 µg/mL and a selectivity index of 9.405. Although, the oleanolic acid exhibit a better activity against L. infantum with an IC50 of 0.999 ± 0.089 µg/mL and selectivity index of 8.111. PMID:29201107

Constituents of antibacterial extract of Caesalpinia paraguariensis Burk.

PubMed

Woldemichael, Girma M; Singh, Maya P; Maiese, William M; Timmermann, Barbara N

2003-01-01

The Argentinean legume Caesalpinia paraguariensis Burk. (Fabaceae) was selected for further fractionation work based on the strong antimicrobial activity of its CH2Cl2-MeOH (1:1 v/v) extract against a host of clinically significant microorganisms, including antibiotic resistant strains. 1D and 2D NMR enabled the identification of the novel benzoxecin derivative caesalpinol along with the known compounds bilobetin, stigma-5-en-3-O-beta-6'-stearoylglucopyranoside, stigma-5-en-3-beta-6'-palmitoylglucopyranoside, stigma-5-en-3-beta-glucopyranoside, oleanolic acid, 3-O-(E)-hydroxycinnamoyl oleanolic acid, betulinic acid, 3-O-(E)-hydroxycinnamoyl betulinic acid, and lupeol from the active fractions. Oleanolic acid was found active against Bacillus subtilis and both methicillin-sensitive and -resistant Staphylococcus aureus with MICs of 8 (17.5 microM), 8 and 64 (140 microM) microg/ml, respectively. The rest of the compounds, however, did not show activity.

High Triterpenic Acids Production in Callus Cultures from Fruit Pulp of Two Apple Varieties.

PubMed

Verardo, Giancarlo; Gorassini, Andrea; Ricci, Donata; Fraternale, Daniele

2017-01-01

Very rarely fruit pulp has been used in in vitro culture to produce secondary metabolites useful in promoting health. The aims of this work were the study of the best conditions to obtain the callus cultures from the pulp of two varieties of apples, Golden Delicious (GD) and "Mela Rosa Marchigiana" (MRM), and the quali-quantitative analysis of secondary metabolites produced by the two in vitro callus cultures. Callus was induced on both Murashige and Skoog and Gamborg B5 media containing various combinations of supplements. To achieve the maximum recovery of secondary metabolites produced, preliminary extraction tests were carried out on GD apple culture using two different organic solvents (MeOH and EtOAc). The quali-quantitative analysis of the methanolic extract of both cultures was carried out by ESI-MS n and GC-MS techniques. The GC-MS analysis revealed the presence of triterpenic acids, in particular, oleanolic, ursolic, maslinic, pomolic, tormentic, corosolic and annurcoic acid along with a phytosterol, β-sitosterol. In addition, GD callus culture produced phloridzin, absent in the MRM culture. In this last culture, however, the total amount of secondary metabolites was markedly higher. The in vivo production of these bioactive compounds were also quantified in the GD and MRM apple pulps. Apple pulps produced higher amounts of triterpenic acids in vitro than in vivo. The present work can be considered a method to amplify the production of important secondary metabolites which exert beneficial effects on human health. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Ursolic Acid Inhibits Adipogenesis in 3T3-L1 Adipocytes through LKB1/AMPK Pathway

PubMed Central

He, Yonghan; Li, Ying; Zhao, Tiantian; Wang, Yanwen; Sun, Changhao

2013-01-01

Background Ursolic acid (UA) is a triterpenoid compound with multiple biological functions. This compound has recently been reported to possess an anti-obesity effect; however, the mechanisms are less understood. Objective As adipogenesis plays a critical role in obesity, the present study was conducted to investigate the effect of UA on adipogenesis and mechanisms of action in 3T3-L1 preadipocytes. Methods and Results The 3T3-L1 preadipocytes were induced to differentiate in the presence or absence of UA for 6 days. The cells were determined for proliferation, differentiation, fat accumulation as well as the protein expressions of molecular targets that regulate or are involved in fatty acid synthesis and oxidation. The results demonstrated that ursolic acid at concentrations ranging from 2.5 µM to 10 µM dose-dependently attenuated adipogenesis, accompanied by reduced protein expression of CCAAT element binding protein β (C/EBPβ), peroxisome proliferator-activated receptor γ (PPARγ), CCAAT element binding protein α (C/EBPα) and sterol regulatory element binding protein 1c (SREBP-1c), respectively. Ursolic acid increased the phosphorylation of acetyl-CoA carboxylase (ACC) and protein expression of carnitine palmitoyltransferase 1 (CPT1), but decreased protein expression of fatty acid synthase (FAS) and fatty acid-binding protein 4 (FABP4). Ursolic acid increased the phosphorylation of AMP-activated protein kinase (AMPK) and protein expression of (silent mating type information regulation 2, homolog) 1 (Sirt1). Further studies demonstrated that the anti-adipogenic effect of UA was reversed by the AMPK siRNA, but not by the Sirt1 inhibitor nicotinamide. Liver kinase B1 (LKB1), the upstream kinase of AMPK, was upregulated by UA. When LKB1 was silenced with siRNA or the inhibitor radicicol, the effect of UA on AMPK activation was diminished. Conclusions Ursolic acid inhibited 3T3-L1 preadipocyte differentiation and adipogenesis through the LKB1/AMPK pathway. There is potential to develop UA into a therapeutic agent for the prevention or treatment of obesity. PMID:23922935

Effect of Ursolic Acid on Metabolic Syndrome, Insulin Sensitivity, and Inflammation.

PubMed

Ramírez-Rodríguez, Alejandra M; González-Ortiz, Manuel; Martínez-Abundis, Esperanza; Acuña Ortega, Natalhie

2017-09-01

To evaluate the effect of ursolic acid on metabolic syndrome, insulin sensitivity, and inflammation, a randomized, double-blind, placebo-controlled clinical trial was carried out in 24 patients (30-60 years) with a diagnosis of metabolic syndrome without treatment. They were randomly assigned to two groups of 12 patients, each to receive orally 150 mg of ursolic acid or homologated placebo once a day for 12 weeks. Before and after the intervention, the components of metabolic syndrome, insulin sensitivity (Matsuda index), and inflammation profile (interleukin-6 and C-reactive protein) were evaluated. After ursolic acid administration, the remission of metabolic syndrome occurred in 50% of patients (P = .005) with significant differences in body weight (75.7 ± 11.5 vs. 71 ± 11 kg, P = .002), body mass index (BMI) (29.9 + 3.6 vs. 24.9 ± 1.2 kg/m 2 , P = .049), waist circumference (93 ± 8.9 vs. 83 + 8.6 cm, P = .008), fasting glucose (6.0 ± 0.5 vs. 4.7 ± 0.4 mmol/L, P = .002), and insulin sensitivity (3.1 ± 1.1 vs. 4.2 ± 1.2, P = .003). Ursolic acid administration leads to transient remission of metabolic syndrome, reducing body weight, BMI, waist circumference and fasting glucose, as well as increasing insulin sensitivity.

Hyaluronidase Inhibitory Activity of Pentacylic Triterpenoids from Prismatomeris tetrandra (Roxb.) K. Schum: Isolation, Synthesis and QSAR Study

PubMed Central

Abdullah, Nor Hayati; Thomas, Noel Francis; Sivasothy, Yasodha; Lee, Vannajan Sanghiran; Liew, Sook Yee; Noorbatcha, Ibrahim Ali; Awang, Khalijah

2016-01-01

The mammalian hyaluronidase degrades hyaluronic acid by the cleavage of the β-1,4-glycosidic bond furnishing a tetrasaccharide molecule as the main product which is a highly angiogenic and potent inducer of inflammatory cytokines. Ursolic acid 1, isolated from Prismatomeris tetrandra, was identified as having the potential to develop inhibitors of hyaluronidase. A series of ursolic acid analogues were either synthesized via structure modification of ursolic acid 1 or commercially obtained. The evaluation of the inhibitory activity of these compounds on the hyaluronidase enzyme was conducted. Several structural, topological and quantum chemical descriptors for these compounds were calculated using semi empirical quantum chemical methods. A quantitative structure activity relationship study (QSAR) was performed to correlate these descriptors with the hyaluronidase inhibitory activity. The statistical characteristics provided by the best multi linear model (BML) (R2 = 0.9717, R2cv = 0.9506) indicated satisfactory stability and predictive ability of the developed model. The in silico molecular docking study which was used to determine the binding interactions revealed that the ursolic acid analog 22 had a strong affinity towards human hyaluronidase. PMID:26907251

Ursolic Acid Attenuates Diabetic Mesangial Cell Injury through the Up-Regulation of Autophagy via miRNA-21/PTEN/Akt/mTOR Suppression

PubMed Central

Lu, Xinxing; Fan, Qiuling; Xu, Li; Li, Lin; Yue, Yuan; Xu, Yanyan; Su, Yan; Zhang, Dongcheng; Wang, Lining

2015-01-01

Objective To investigate the effect of ursolic acid on autophagy mediated through the miRNA-21-targeted phosphoinositide 3 kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway in rat mesangial cells cultured under high glucose (HG) conditions. Methods Rat glomerular mesangial cells were cultured under normal glucose, HG, HG with the PI3K inhibitor LY294002 or HG with ursolic acid conditions. Cell proliferation and hypertrophy were assayed using an MTT assay and the ratio of total protein to cell number, respectively. The miRNA-21 expression was detected using RT-qPCR. The expression of phosphatase and tensin homolog (PTEN)/AKT/mTOR signaling signatures, autophagy-associated protein and collagen I was detected by western blotting and RT-qPCR. Autophagosomes were observed using electron microscopy. Results Compared with mesangial cells cultured under normal glucose conditions, the cells exposed to HG showed up-regulated miRNA-21 expression, down-regulated PTEN protein and mRNA expression, up-regulated p85PI3K, pAkt, pmTOR, p62/SQSTMI, and collagen I expression and down-regulated LC3II expression. Ursolic acid and LY294002 inhibited HG-induced mesangial cell hypertrophy and proliferation, down-regulated p85PI3K, pAkt, pmTOR, p62/SQSTMI, and collagen I expression and up-regulated LC3II expression. However, LY294002 did not affect the expression of miRNA-21 and PTEN. Ursolic acid down-regulated miRNA-21 expression and up-regulated PTEN protein and mRNA expression. Conclusions Ursolic acid inhibits the glucose-induced up-regulation of mesangial cell miRNA-21 expression, up-regulates PTEN expression, inhibits the activation of PI3K/Akt/mTOR signaling pathway, and enhances autophagy to reduce the accumulation of the extracellular matrix and ameliorate cell hypertrophy and proliferation. PMID:25689721

Oleanane triterpenoids in the prevention and therapy of breast cancer: current evidence and future perspectives

PubMed Central

Parikh, Nisha R.; Mandal, Animesh; Bhatia, Deepak; Siveen, Kodappully Sivaraman; Sethi, Gautam

2014-01-01

Breast cancer is one of the most frequently diagnosed cancers and major cause of death in women in the world. Emerging evidence underscores the value of dietary and non-dietary phytochemicals, including triterpenoids, in the prevention and treatment of breast cancer. Oleanolic acid, an oleanane-type pentacyclic triterpenoid, is present in a large number of dietary and medicinal plants. Oleanolic acid and its derivatives exhibit several promising pharmacological activities, including antioxidant, anti-inflammatory, hepatoprotective, cardioprotective, antipruritic, spasmolytic, antiallergic, antimicrobial and antiviral effects. Numerous studies indicate that oleanolic acid and other oleanane triterpenoids modulate multiple intracellular signaling pathways and exert chemopreventive and antitumor activities in various in vitro and in vivo model systems. A series of novel synthetic oleanane triterpenoids have been prepared by chemical modifications of oleanolic acid and some of these compounds are considered to be the most potent anti-inflammatory and anticarcinogenic triterpenoids. Accumulating studies provide extensive evidence that synthetic oleanane derivatives inhibit proliferation and induce apoptosis of various cancer cells in vitro and demonstrate cancer preventive or antitumor efficacy in animal models of blood, breast, colon, connective tissue, liver, lung, pancreas, prostate and skin cancer. This review critically examines the potential role of oleanolic acid, oleanane triterpenoids and related synthetic compounds in the chemoprevention and treatment of mammary neoplasia. Both in vitro and in vivo studies on these agents and related molecular mechanisms are presented. Several challenges and future directions of research to translate already available impressive preclinical knowledge to clinical practice of breast cancer prevention and therapy are also presented. PMID:25395898

Fruit quality and olive leaf and stone addition affect Picual virgin olive oil triterpenic content.

PubMed

Allouche, Yosra; Uceda, Marino; Jiménez, Antonio; Aguilera, M Paz; Gaforio, José Juan; Beltrán, Gabriel

2009-10-14

The present research aimed to evaluate whether Picual virgin olive oil triterpenic compounds are affected by the addition of variable quantities of stones and leaves before processing or by fruit resting on the ground during 3 months. Results showed that stone addition did not influence triterpenic dialcohol content (uvaol and erythrodiol), whereas triterpenic acids (oleanolic and maslinic) increased significantly when 20 and 30% stones were added. Leaves added at 2% increased significantly oleanolic acid, maslinic acid, and erythrodiol content by 83, 41, and 36%, respectively. During fruit resting on the ground, olive oils showed no differences in uvaol content, a slight increase in erythrodiol, and a gradual increase in both oleanolic and maslinic acids, obtaining at the end of the experiment contents nearly 10- and 3-fold higher than control oils. These results confirm that olive oil triterpenic composition is modified by the factors analyzed.

Identification and pharmacological characterization of the anti-inflammatory principal of the leaves of dwarf elder (Sambucus ebulus L.)

PubMed Central

Schwaiger, Stefan; Zeller, Iris; Pölzelbauer, Petra; Frotschnig, Sandra; Laufer, Günther; Messner, Barbara; Pieri, Valerio; Stuppner, Hermann; Bernhard, David

2011-01-01

Aim of the study The performed investigations aimed on the identification of the anti-inflammatory principal of extracts of leaves of Sambucus ebulus L. (dwarf elder) in order to rationalize the traditional use of this plant for the treatment of chronically inflammatory diseases. Materials and methods Dwarf elder leaf extract was subjected to activity guided fractionation using inhibition of TNFα induced expression of vascular cell adhesion molecule 1 (VCAM-1) on the surface of human umbilical vein endothelial cells (HUVECs) as monitoring tool (positive control: parthenolide 10 μM, VCAM-1 expression (% of control): 5.35 ± 0.38%). Results Bio-guided isolation resulted in identification of ursolic acid as anti-inflammatory principal. Besides its inhibitory effects against TNFα induced expression of VCAM-1 (IC50 6.25 μM), ursolic acid inhibits also TNFα induced expression of ICAM-1 (IC50 value between 3.13 and 6.25 μM) (positive control: parthenolide 10 μM, ICAM-1 expression (% of control): 38.89 ± 16.6%). Toxic effects of ursolic acid on HUVECs can be drastically reduced using an enriched extract instead of the pure compound. Conclusions Our findings suggest an additional mechanism of the anti-inflammatory activity of ursolic acid by demonstrating its ability to inhibit TNFα-stimulated expression of VCAM-1 and ICAM-1 and support the traditional use of extracts and preparations of Sambucus ebulus L., rich in ursolic acid, for the treatment of chronically inflammatory processes. PMID:21040770

Inhibition of key enzymes linked to type 2 diabetes by compounds isolated from Aframomum melegueta fruit.

PubMed

Mohammed, Aminu; Gbonjubola, Victoria Awolola; Koorbanally, Neil Anthony; Islam, Md Shahidul

2017-12-01

The use of Aframomum melegueta K. Schum. (Zingiberaceae) fruit for treatment of diabetes has recently been established in Nigeria. However, compounds responsible for the antidiabetic action have not been identified. The present study carried out the bioassay-guided isolation of possible bioactive compounds responsible for the antidiabetic action of A. melegueta fruit. The A. melegueta fruit was sequentially extracted using ethyl acetate (EtOAc), ethanol and water, and the most active extract (EtOAc) was subjected to column chromatography on a silica gel column using solvent gradient systems of hexane (HEX):EtOAc and EtOAc:MeOH and the isolation of compounds was guided by α-glycosidase and α-amylase inhibitory activities at various concentrations (30-240 μg/mL). According to the results, 3 arylalkanes, 6-paradol (1), 6-shogaol (2) and 6-gingerol (3) and a pentacyclic triterpene, oleanolic acid (4) were isolated from A. melegueta fruit. All the compounds exhibited inhibitory effects against α-amylase and α-glucosidase. 6-Gingerol (3) and oleanolic acid (4) showed higher inhibitory activity against α-amylase (IC 50 : 6-gingerol: 81.78 ± 7.79 μM; oleanolic acid: 91.72 ± 1.63 μM) and α-glucosidase (IC 50 : 6-gingerol: 21.55 ± 0.45 μM; oleanolic acid: 17.35 ± 0.88 μM) compared to the standard drug, acarbose and other isolated compounds. The kinetics of the enzyme action of the compounds showed a noncompetitive mode of inhibition. The data of this study suggest that the 6-gingerol (3) and oleanolic acid (4) showed higher α-amylase and α-glucosidase inhibitory action and therefore could be responsible for the antidiabetic activity of A. melegueta fruit.

Increased synthesis of a new oleanane-type saponin in hairy roots of marigold (Calendula officinalis) after treatment with jasmonic acid.

PubMed

Markowski, Michał; Długosz, Marek; Szakiel, Anna; Durli, Mathieu; Poinsignon, Sophie; Bouguet-Bonnet, Sabine; Vernex-Loset, Lionel; Krier, Gabriel; Henry, Max

2018-04-18

Native plant of marigold (Calendula officinalis L.) synthesizes oleanolic acid saponins classified as glucosides or glucuronides according to the first residue in sugar chain bound to C-3 hydroxyl group. Hairy root culture, obtained by transformation with Agrobacterium rhizogenes strain 15834, exhibit a potent ability of synthesis of oleanolic acid glycosides. The HPLC profile of saponin fraction obtained from C. officinalis hairy roots treated with plant stress hormone, jasmonic acid, showed the 10-times increase of the content of one particular compound, determined by NMR and MALDI TOF as a new bisdesmoside saponin, 3-O-β-d-glucuronopyranosyl-28-O-β-d-galactopyranosyl-oleanolic acid. Such a diglycoside does not occur in native C. officinalis plant. It is a glucuronide, whereas in the native plant glucuronides are mainly accumulated in flowers, while glucosides are the most abundant saponins in roots. Thus, our results revealed that the pathways of saponin biosynthesis, particularly reactions of glycosylation, are altered in C. officinalis hairy root culture.

Microbial hydroxylation and glycosidation of oleanolic acid by Circinella muscae and their anti-inflammatory activities.

PubMed

Yan, Sensen; Lin, Haijun; Huang, Huilian; Yang, Min; Xu, Bohui; Chen, Guangtong

2018-05-29

Biotransformation of oleanolic acid (OA) by Circinella muscae AS 3.2695 was investigated. Nine hydroxylated and glycosylated metabolites (1-9) were obtained. Their structures were elucidated as 3β,7β-dihydroxyolean-12-en-28-oic acid (1), 3β,7β,21β-trihydroxyolean-12-en-28-oic acid (2), 3β,7α,21β-trihydroxyolean-12-en- 28-oic acid (3), 3β,7β,15α-trihydroxyolean-12-en-28-oic acid (4), 7β,15α-dihydroxy- 3-oxo-olean-12-en-28-oic acid (5), 7β-hydroxy-3-oxo-olean-12-en-28-oic acid (6), oleanolic acid-28-O-β-D-glucopyranosyl ester (7), 3β,21β-dihydroxyolean-12-en-28- oic acid-28-O-β-D-glucopyranosyl ester (8), and 3β,7β,15α-trihydroxyolean-12-en- 28-oic acid-28-O-β-D-glucopyranosyl ester (9) by spectroscopic analysis. Among them, compounds 4 and 9 were new compounds. In addition, anti-inflammatory activities were assayed and evaluated for the isolated metabolites. Most of the metabolites exhibited significant inhibitory activities on lipopolysaccharides-induced NO production in RAW 264.7 cells.

Psychotria viridis: Chemical constituents from leaves and biological properties.

PubMed

Soares, Débora B S; Duarte, Lucienir P; Cavalcanti, André D; Silva, Fernando C; Braga, Ariadne D; Lopes, Miriam T P; Takahashi, Jacqueline A; Vieira-Filho, Sidney A

2017-01-01

The phytochemical study of hexane, chloroform and methanol extracts from leaves of Psychotria viridis resulted in the identification of: the pentacyclic triterpenes, ursolic and oleanolic acid; the steroids, 24-methylene-cycloartanol, stigmasterol and β-sitosterol; the glycosylated steroids 3-O-β-D-glucosyl-β-sitosterol and 3-O-β-D-glucosyl-stigmasterol; a polyunsaturated triterpene, squalene; the esters of glycerol, 1-palmitoylglycerol and triacylglycerol; a mixture of long chain hydrocarbons; the aldehyde nonacosanal; the long chain fat acids hentriacontanoic, hexadecanoic and heptadenoic acid; the ester methyl heptadecanoate; the 4-methyl-epi-quinate and two indole alkaloids, N,N-dimethyltryptamine (DMT) and N-methyltryptamine. The chemical structures were determined by means of spectroscopic (IR, 1H and 13C NMR, HSQC, HMBC and NOESY) and spectrometric (CG-MS and LCMS-ESI-ITTOF) methods. The study of biologic properties of P. viridis consisted in the evaluation of the acetylcholinesterase inhibition and cytotoxic activities. The hexane, chloroform, ethyl acetate and methanol extracts, the substances 24-methylene-cycloartanol, DMT and a mixture of 3-O-β-D-glucosyl-β-sitosterol and 3-O-β-D-glucosyl-stigmasterol showed cholinesterase inhibiting activity. This activity induced by chloroform and ethyl acetate extracts was higher than 90%. The methanol and ethyl acetate extracts inhibit the growth and/or induce the death of the tumor cells strains B16F10 and 4T1, without damaging the integrity of the normal cells BHK and CHO. DMT also demonstrated a marked activity against tumor cell strains B16F10 and 4T1.

Anti-inflammatory, antioxidant and anti-acetylcholinesterase activities of Bouvardia ternifolia: potential implications in Alzheimer's disease.

PubMed

García-Morales, Giovanni; Huerta-Reyes, Maira; González-Cortazar, Manasés; Zamilpa, Alejandro; Jiménez-Ferrer, Enrique; Silva-García, Raúl; Román-Ramos, Rubén; Aguilar-Rojas, Arturo

2015-07-01

Bouvardia ternifolia has been used medicinally to treat inflammation. In the present study, we investigate the anti-Alzheimer's potential effect of the hydroalcoholic extract of B. ternifolia through evaluation of anti-inflammatory and antioxidant activities, quantification of the percentage inhibition of acetylcholinesterase activity, protection effect against β-amyloid fibrillar-induce neurotoxicity, and the identification of the main constituents. Our results show that B. ternifolia extract and ethyl acetate fraction induced anti-inflammatory effects by reducing inflammation by >70 %, while antioxidant test revealed significant IC50 values for flavonoid content fraction (30.67 ± 2.09 μg/ml) and ethyl acetate fraction (42.66 ± 0.93 μg/ml). The maximum inhibition of acetylcholinesterase was exhibited by scopoletin content fraction (38.43 ± 3.94 %), while ethyl acetate fraction exerted neuroprotective effect against β-amyloid peptide (83.97 ± 5.03 %). Phytochemical analysis, showed the presence of 3-O-quercetin glucopyranoside (415 mg/g), rutin (229.9 mg/g), ursolic and oleanolic acid (54 and 20.8 mg/g respectively), 3-O-quercetin rhamnopyranoside (12.8 mg/g), chlorogenic acid (9.5 mg/g), and scopoletin (1.38 mg/g). Our findings support the use of B. ternifolia since the extract induced significant neuroprotection against β-amyloid peptide, anti-inflammatory, antioxidant and anti-acetylcholinesterase effects that could be attributed to its contents of polyphenols, coumarins, and triterpenes, and encourage further studies for development of this extract as therapeutic agent in treatment of Alzheimer's disease.

In Vitro Schistosomicidal Activity of Some Brazilian Cerrado Species and Their Isolated Compounds

PubMed Central

Cunha, Nayanne Larissa; Uchôa, Camila Jacintho de Mendonça; Cintra, Lucas Silva; de Souza, Herbert Cristian; Peixoto, Juliana Andrade; Silva, Claudia Peres; Magalhães, Lizandra Guidi; Gimenez, Valéria Maria Meleiro; Groppo, Milton; Rodrigues, Vanderlei; da Silva Filho, Ademar Alves; Andrade e Silva, Márcio Luís; Cunha, Wilson Roberto; Pauletti, Patrícia Mendonça; Januário, Ana Helena

2012-01-01

Miconia langsdorffii Cogn. (Melastomataceae), Roupala montana Aubl. (Proteaceae), Struthanthus syringifolius (Mart.) (Loranthaceae), and Schefflera vinosa (Cham. & Schltdl.) Frodin (Araliaceae) are plant species from the Brazilian Cerrado whose schistosomicidal potential has not yet been described. The crude extracts, fractions, the triterpenes betulin, oleanolic acid, ursolic acid and the flavonoids quercetin 3-O-β-D-rhamnoside, quercetin 3-O-β-D-glucoside, quercetin 3-O-β-D-glucopyranosyl-(1-2)-α-L-rhamnopyranoside and isorhamnetin 3-O-β-D-glucopyranosyl-(1-2)-α-L-rhamnopyranoside were evaluated in vitro against Schistosoma mansoni adult worms and the bioactive n-hexane fractions of the mentioned species were also analyzed by GC-MS. Betulin was able to cause worm death percentage values of 25% after 120 h (at 100 μM), and 25% and 50% after 24 and 120 h (at 200 μM), respectively; besides the flavonoid quercetin 3-O-β-D-rhamnoside promoted 25% of death of the parasites at 100 μM. Farther the flavonoids quercetin 3-O-β-D-glucoside and quercetin 3-O-β-D-rhamnoside at 100 μM exhibited significantly reduction in motor activity, 75% and 87.5%, respectively. Biological results indicated that crude extracts of R. montana, S. vinosa, and M. langsdorffii and some n-hexane and EtOAc fractions of this species were able to induce worm death to some extent. The results suggest that lupane-type triterpenes and flavonoid monoglycosides should be considered for further antiparasites studies. PMID:22924053

Discovery and Development of Therapeutic Drugs against Lethal Human RNA Viruses: a Multidisciplinary Assault.

DTIC Science & Technology

1991-07-16

germacranolides, they also identified the two pentacyclic trzterpenes, lupeol and lupenone. In the present study, we found betulinic and ursolic acids as...O07 . tFurther elution with the same solvents yielded another minor product (22 mg), which proved to be ursolic acid , mp 26G-265’. Both triterpene...performed with ceric sulfate-sulfuric acid spray alcohol 5b (1.0 mg) in pyridine (0.2 mL) was added thionyl chloride reagent (heated at approximately 150 0 C

Structural basis for 18-β-glycyrrhetinic acid as a novel non-GSH analog glyoxalase I inhibitor.

PubMed

Zhang, Hong; Huang, Qiang; Zhai, Jing; Zhao, Yi-ning; Zhang, Li-ping; Chen, Yun-yun; Zhang, Ren-wei; Li, Qing; Hu, Xiao-peng

2015-09-01

Glyoxalase I (GLOI), a glutathione (GSH)-dependent enzyme, is overexpressed in tumor cells and related to multi-drug resistance in chemotherapy, making GLOI inhibitors as potential anti-tumor agents. But the most studied GSH analogs exhibit poor pharmacokinetic properties. The aim of this study was to discover novel non-GSH analog GLOI inhibitors and analyze their binding mechanisms. Mouse GLOI (mGLOI) was expressed in BL21 (DE3) pLysS after induction with isopropyl-β-D-1-thiogalactopyranoside and purified using AKTA FPLC system. An in vitro mGLOI enzyme assay was used to screen a small pool of compounds containing carboxyl groups. Crystal structure of the mGLOI-inhibitor complex was determined at 2.3 Å resolution. Molecular docking study was performed using Discovery Studio 2.5 software package. A natural compound 18-β-glycyrrhetinic acid (GA) and its derivative carbenoxolone were identified as potent competitive non-GSH analog mGLOI inhibitors with Ki values of 0.29 μmol/L and 0.93 μmol/L, respectively. Four pentacyclic triterpenes (ursolic acid, oleanolic acid, betulic acid and tripterine) showed weak activities (mGLOI inhibition ratio <25% at 10 μmol/L) and other three (maslinic acid, corosolic acid and madecassic acid) were inactive. The crystal structure of the mGLOI-GA complex showed that the carboxyl group of GA mimicked the γ-glutamyl residue of GSH by hydrogen bonding to the glutamyl sites (residues Arg38B, Asn104B and Arg123A) in the GSH binding site of mGLOI. The extensive van der Waals interactions between GA and the surrounding residues also contributed greatly to the binding of GA and mGLOI. This work demonstrates a carboxyl group to be an important functional feature of non-GSH analog GLOI inhibitors.

A new ursane triterpene from Monochaetum vulcanicum that inhibits DNA polymerase beta lyase.

PubMed

Chaturvedula, V S Prakash; Gao, Zhijie; Jones, Shannon H; Feng, Xizhi; Hecht, Sidney M; Kingston, David G I

2004-05-01

Bioassay-directed fractionation of a butanone extract of Monochaetum vulcanicum resulted in the isolation of a new triterpene (1) and four known compounds, ursolic acid (2), 2alpha-hydroxyursolic acid (3), 3-(p-coumaroyl)ursolic acid (4), and beta-sitosteryl-beta-d-galactoside (5). The structure of the new compound 1 was established as 3beta-acetoxy-2alpha-hydroxyurs-12-en-28-oic acid on the basis of extensive 1D and 2D NMR spectroscopic interpretation and chemical derivatization. Compounds 1-3 and 5 exhibited polymerase beta lyase activity.

A rapid LC/MS/MS method for the analysis of nonvolatile antiinflammatory agents from Mentha spp.

PubMed

Shen, Diandian; Pan, Min-Hsiung; Wu, Qing-Li; Park, Chung-Heon; Juliani, H Rodolfo; Ho, Chi-Tang; Simon, James E

2011-08-01

Mints (Mentha spp.), aromatic crops grown largely for their essential oils, also are rich sources of nonvolatile antiinflammatory agents. Identification and quantitation of the constituents responsible for their antiinflammatory activity is challenging owing to the lack of suitable chromatographic methodology. In the present research, the simultaneous quantitation of antiinflammatory constituents rosmarinic acid, oleanolic acid, and ursolic acid in mints was attained by using a unique tandem HPLC column system coupled with an electrospray ionization mass detection (MRM mode). The ion mode optimization for rosmarinic acid under negative and triterpenoid acids under positive was achieved by setting 2 time segments in a single run where the polarity mode was switched from negative (0 to 10 min) to positive (10 to 40 min). For the investigated concentration ranges of antiinflammatory agents in mints, good linearities (r² ≥ 0.998) were obtained for each calibration curve. Validation of precision and accuracy for this method showed that intra- and inter-day repeatabilities for all analytes were less than 5.51%, and the recoveries varied from 97.8% to 99.3%. The developed LC/MS/MS assay provides a suitable quality control method for the determination of antiinflammatory constituents in Mentha spp. There is a wide range of diversity in the natural product composition for these acids across the Mentha germplasm collection evaluated. The presence of these antiinflammatory acids in post-distilled mints shows that value-added nutraceutical enriched products can be developed with proper processing and recovery systems in addition to the distillation and capture of the valuable volatile essential oils. Results from this research would benefit both commercial farmers growing mint for essential oil and those in the food industry where value-added phytopharmaceutical enriched products can be developed with proper processing, quality control, and recovery systems during mint essential oil distillation. © 2011 Institute of Food Technologists®

Biological Activities of Oleanolic Acid Derivatives from Calendula officinalis Seeds.

PubMed

Zaki, Ahmed; Ashour, Ahmed; Mira, Amira; Kishikawa, Asuka; Nakagawa, Toshinori; Zhu, Qinchang; Shimizu, Kuniyoshi

2016-05-01

Phytochemical examination of butanol fraction of Calendula officinalis seeds led to the isolation of two compounds identified as 28-O-β-D-glucopyranosyl-oleanolic acid 3-O-β-D-glucopyranosyl (1→3)-β-D-glucopyranosiduronic acid (CS1) and oleanolic acid 3-O-β-D-glucopyranosyl (1→3)-β-D-glucopyranosiduronic acid (CS2). Biological evaluation was carried out for these two compounds such as melanin biosynthesis inhibitory, hyaluronic acid production activities, anti obesity using lipase inhibition and adipocyte differentiation as well as evaluation of the protective effect against hydrogen peroxide induced neurotoxicity in neuro-2A cells. The results showed that, compound CS2 has a melanin biosynthesis stimulatory activity; however, compound CS1 has a potent stimulatory effect for the production of hyaluronic acid on normal human dermal fibroblast from adult (NHDF-Ad). Both compounds did not show any inhibitory effect on both lipase and adipocyte differentiation. Compound CS2 could protect neuro-2A cells and increased cell viability against H2 O2 . These activities (melanin biosynthesis stimulatory and protective effect against H2 O2 of CS2 and hyaluronic acid productive activities of these triterpene derivatives) have been reported for the first time. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Producing aglycons of ginsenosides in bakers' yeast

PubMed Central

Dai, Zhubo; Wang, Beibei; Liu, Yi; Shi, Mingyu; Wang, Dong; Zhang, Xianan; Liu, Tao; Huang, Luqi; Zhang, Xueli

2014-01-01

Ginsenosides are the primary bioactive components of ginseng, which is a popular medicinal plant that exhibits diverse pharmacological activities. Protopanaxadiol, protopanaxatriol and oleanolic acid are three basic aglycons of ginsenosides. Producing aglycons of ginsenosides in Saccharomyces cerevisiae was realized in this work and provides an alternative route compared to traditional extraction methods. Synthetic pathways of these three aglycons were constructed in S. cerevisiae by introducing β-amyrin synthase, oleanolic acid synthase, dammarenediol-II synthase, protopanaxadiol synthase, protopanaxatriol synthase and NADPH-cytochrome P450 reductase from different plants. In addition, a truncated 3-hydroxy-3-methylglutaryl-CoA reductase, squalene synthase and 2,3-oxidosqualene synthase genes were overexpressed to increase the precursor supply for improving aglycon production. Strain GY-1 was obtained, which produced 17.2 mg/L protopanaxadiol, 15.9 mg/L protopanaxatriol and 21.4 mg/L oleanolic acid. The yeast strains engineered in this work can serve as the basis for creating an alternative way for producing ginsenosides in place of extractions from plant sources. PMID:24424342

An integrated global chemomics and system biology approach to analyze the mechanisms of the traditional Chinese medicinal preparation Eriobotrya japonica - Fritillaria usuriensis dropping pills for pulmonary diseases.

PubMed

Tao, Jin; Hou, Yuanyuan; Ma, Xiaoyao; Liu, Dan; Tong, Yongling; Zhou, Hong; Gao, Jie; Bai, Gang

2016-01-08

Traditional Chinese medicine (TCM) herbal formulae provide valuable therapeutic strategies. However, the active ingredients and mechanisms of action remain unclear for most of these formulae. Therefore, the identification of complex mechanisms is a major challenge in TCM research. This study used a network pharmacology approach to clarify the anti-inflammatory and cough suppressing mechanisms of the Chinese medicinal preparation Eriobotrya japonica - Fritillaria usuriensis dropping pills (ChuanbeiPipa dropping pills, CBPP). The chemical constituents of CBPP were identified by high-quality ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC/Q-TOF-MS), and anti-inflammatory ingredients were selected and analyzed using the PharmMapper and Kyoto Encyclopedia of Genes and Genomes (KEGG) bioinformatics websites to predict the target proteins and related pathways, respectively. Then, an RNA-sequencing (RNA-Seq) analysis was carried out to investigate the different expression of genes in the lung tissue of rats with chronic bronchitis. Six main constituents affected 19 predicted pathways, including ursolic acid and oleanolic acid from Eriobotrya japonica (Thunb.) Lindl. (Eri), peiminine from Fritillaria usuriensis Maxim. (Fri), platycodigenin and polygalacic acid from Platycodon grandiflorum (Jacq.) A. DC. (Pla) and guanosine from Pinellia ternata (Thunb.) Makino. (Pin). Expression of 34 genes was significantly decreased after CBPP treatment, affecting four therapeutic functions: immunoregulation, anti-inflammation, collagen formation and muscle contraction. The active components acted on the mitogen activated protein kinase (MAPK) pathway, transforming growth factor (TGF)-beta pathway, focal adhesion, tight junctions and the action cytoskeleton to exert anti-inflammatory effects, resolve phlegm, and relieve cough. This novel approach of global chemomics-integrated systems biology represents an effective and accurate strategy for the study of TCM with multiple components and multiple target mechanisms.

Effect of Sunlight Radiation on the Growth and Chemical Constituents of Salvia plebeia R.Br.

PubMed

Jang, Hyun-Jae; Lee, Seung-Jae; Kim, Cha Young; Hwang, Joo Tae; Choi, Jung Ho; Park, Jee Hun; Lee, Seung Woong; Rho, Mun-Chual

2017-08-01

This study investigated the chemical composition changes of Salvia plebeia R.Br. cultivated under different light sources, including florescent light and sunlight. The plants were exposed to fluorescent light for four months and sunlight and then examined for the next 5-7 months. Plants were harvested monthly during the seven months, and we examined whether the difference in light source affected the phenolic and flavonoid contents and antioxidant activity. A simple and reliable HPLC method using a PAH C 18 column was applied for the quantitative analysis of two triterpenoids from the S. plebeia groups. Oleanolic acid (OA) and ursolic acid (UA) showed good linearity ( R ² > 0.9999) within the test ranges (0.005-0.05 mg/mL), and the average percentage recoveries of the OA and UA were 95.1-104.8% and 97.2-107.1%, respectively. The intra- and inter-day relative standard deviations (RSDs) were less than 2.0%. After exposure to sunlight, the phenolic contents, including rosmarinic acid, showed a reduced tendency, whereas the flavonoid contents, including homoplantaginin and luteolin 7-glucoside, were increased. The content of the triterpenoids also showed an increased tendency under sunlight irradiation, but the variance was not larger than those of the phenolic and flavonoid contents. Among experimental groups, the group harvested at six months, having been exposed to sunlight for two months, showed the most potent antioxidant activity. Therefore, these results showed that the chemical composition and antioxidant activities of S. plebeia R.Br. was affected from environmental culture conditions, such as light source. Our studies will be useful for the development of functional materials using S. plebeia R.Br.

Cytotoxic agents for KB and SiHa cells from n-hexane fraction of Cissampelos pareira and its chemical composition.

PubMed

Bala, Manju; Pratap, Kunal; Verma, Praveen Kumar; Padwad, Yogendra; Singh, Bikram

2015-01-01

Eleven constituents were characterised by gas chromatography-mass spectrometry analysis, and five molecules were isolated using column chromatography. The in vitro study of the extract and isolated molecules against KB and SiHa cell lines revealed oleanolic acid (1) and oleic acid (2) as potent cytotoxic molecules with potential anticancer activity. The IC50 values of n-hexane extract (CPHF), oleanolic acid (1) and oleic acid (2) were >300, 56.08 and 70.7 μg/mL (μM), respectively, against KB cell lines and >300, 47.24 and 80.2 μg/mL (μM), respectively, against SiHa cell lines.

Oleanolic acid alters bile acid metabolism and produces cholestatic liver injury in mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu, Jie, E-mail: JLiu@kumc.edu; Zunyi Medical College, Zunyi 563003; Lu, Yuan-Fu

2013-11-01

Oleanolic acid (OA) is a triterpenoids that exists widely in plants. OA is effective in protecting against hepatotoxicants. Whereas a low dose of OA is hepatoprotective, higher doses and longer-term use of OA produce liver injury. This study characterized OA-induced liver injury in mice. Adult C57BL/6 mice were given OA at doses of 0, 22.5, 45, 90, and 135 mg/kg, s.c., daily for 5 days, and liver injury was observed at doses of 90 mg/kg and above, as evidenced by increases in serum activities of alanine aminotransferase and alkaline phosphatase, increases in serum total bilirubin, as well as by livermore » histopathology. OA-induced cholestatic liver injury was further evidenced by marked increases of both unconjugated and conjugated bile acids (BAs) in serum. Gene and protein expression analysis suggested that livers of OA-treated mice had adaptive responses to prevent BA accumulation by suppressing BA biosynthetic enzyme genes (Cyp7a1, 8b1, 27a1, and 7b1); lowering BA uptake transporters (Ntcp and Oatp1b2); and increasing a BA efflux transporter (Ostβ). OA increased the expression of Nrf2 and its target gene, Nqo1, but decreased the expression of AhR, CAR and PPARα along with their target genes, Cyp1a2, Cyp2b10 and Cyp4a10. OA had minimal effects on PXR and Cyp3a11. Taken together, the present study characterized OA-induced liver injury, which is associated with altered BA homeostasis, and alerts its toxicity potential. - Highlights: • Oleanolic acid at higher doses and long-term use may produce liver injury. • Oleanolic acid increased serum ALT, ALP, bilirubin and bile acid concentrations. • OA produced feathery degeneration, inflammation and cell death in the liver. • OA altered bile acid homeostasis, affecting bile acid synthesis and transport.« less

Evaluation and prevention of the negative matrix effect of terpenoids on pesticides in apples quantification by gas chromatography-tandem mass spectrometry.

PubMed

Giacinti, Géraldine; Raynaud, Christine; Capblancq, Sophie; Simon, Valérie

2016-12-21

The sample matrix can enhance the gas chromatography signal of pesticide residues relative to that obtained with the same concentration of pesticide in solvent. This paper is related to negative matrix effects observed in coupled gas chromatography-mass spectrometry ion trap (GC/MS 2 ) quantification of pesticides in concentrated extracts of apple peel prepared by the Quick Easy Cheap Effective Rugged and Safe (QuEChERS) method. It is focused on the pesticides most frequently used on the apple varieties studied, throughout the crop cycle, right up to harvest, to combat pests and diseases and to improve fruit storage properties. Extracts from the fleshy receptacle (flesh), the epiderm (peel) and fruit of three apple varieties were studied by high-performance thin-layer chromatography hyphenated with UV-vis light detection (HPTLC/UV visible). The peel extracts had high concentrations of triterpenic acids (oleanolic and ursolic acids), reaching 25mgkg -1 , whereas these compounds were not detected in the flesh extracts (<0.05mgkg -1 ). A significant relationship has been found between the levels of these molecules and negative matrix effects in GC/MS 2 . The differences in the behavior of pesticides with respect to matrix effects can be accounted for by the physicochemical characteristics of the molecules (lone pairs, labile hydrogen, conjugation). The HPTLC/UV visible method developed here for the characterization of QuEChERS extracts acts as a complementary clean-up method, aimed to decrease the negative matrix effects of such extracts. Copyright © 2016 Elsevier B.V. All rights reserved.

Molecular recognition of emerald ash borer infestation using leaf spray mass spectrometry.

PubMed

Falcone, Caitlin E; Cooks, R Graham

2016-06-15

The introduction of the emerald ash borer (Agrilus planipennis) (EAB) from Asia to Michigan, USA, in the 1990s caused the widespread death of ash trees in two Canadian provinces and 24 US states. The three current methods for the detection of emerald ash borer infestation, visual surveys, tree girdling and artificial traps, can be unreliable, and there is clearly a need for a rapid, dependable technique for the detection of emerald ash borer infestation. Leaf spray, an ambient ionization method for mass spectrometry (MS), gives direct chemical information on a leaf sample by applying a high voltage to a naturally or artificially sharply pointed leaf piece causing ions to be generated directly from the leaf tip for MS analysis. Leaflets from 23 healthy and EAB-infested ash trees were analyzed by leaf spray mass spectrometry in an attempt to distinguish healthy and EAB-infested ash trees. In negative ion mode, healthy ash trees showed an increased abundance of ions m/z 455.5, 471.5 and 487.5, and ash trees infested with the EAB displayed an increased abundance of ions m/z 181 and 217. The identities of the chemical discriminators ursolic acid and oleanolic acid in healthy ash trees, and six-carbon sugar alcohols in infested ash trees, were determined by tandem mass spectrometry and confirmed with standards. This preliminary study suggests that leaf spray mass spectrometry of ash tree leaflets provides a potential tool for the early detection of ash tree infestation by the emerald ash borer. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Evaluation and prevention of the negative matrix effect of terpenoids on pesticides in apples quantification by gas chromatography-tandem mass spectrometry.

PubMed

Giacinti, Géraldine; Raynaud, Christine; Capblancq, Sophie; Simon, Valérie

2017-02-03

The sample matrix can enhance the gas chromatography signal of pesticide residues relative to that obtained with the same concentration of pesticide in solvent. This paper is related to negative matrix effects observed in coupled gas chromatography-mass spectrometry ion trap (GC/MS 2 ) quantification of pesticides in concentrated extracts of apple peel prepared by the Quick Easy Cheap Effective Rugged and Safe (QuEChERS) method. It is focused on the pesticides most frequently used on the apple varieties studied, throughout the crop cycle, right up to harvest, to combat pests and diseases and to improve fruit storage properties. Extracts from the fleshy receptacle (flesh), the epiderm (peel) and fruit of three apple varieties were studied by high-performance thin-layer chromatography hyphenated with UV-vis light detection (HPTLC/UV visible). The peel extracts had high concentrations of triterpenic acids (oleanolic and ursolic acids), reaching 25mgkg -1 , whereas these compounds were not detected in the flesh extracts (<0.05mgkg -1 ). A significant relationship has been found between the levels of these molecules and negative matrix effects in GC/MS 2 . The differences in the behavior of pesticides with respect to matrix effects can be accounted for by the physicochemical characteristics of the molecules (lone pairs, labile hydrogen, conjugation). The HPTLC/UV visible method developed here for the characterization of QuEChERS extracts acts as a complementary clean-up method, aimed to decrease the negative matrix effects of such extracts. Copyright © 2016 Elsevier B.V. All rights reserved.

Anti-Trichomonas vaginalis activity of ursolic acid derivative: a promising alternative.

PubMed

Bitencourt, Fernanda Gobbi; de Brum Vieira, Patrícia; Meirelles, Lucia Collares; Rigo, Graziela Vargas; da Silva, Elenilson Figueiredo; Gnoatto, Simone Cristina Baggio; Tasca, Tiana

2018-05-01

Trichomonas vaginalis is an extracellular parasite that binds to the epithelium of the human urogenital tract and causes the sexually transmitted infection, trichomoniasis. In view of increased resistance to drugs belonging to the 5-nitroimidazole class, new treatment alternatives are urgently needed. In this study, eight semisynthetized triterpene derivatives were evaluated for in vitro anti-T. vaginalis activity. Ursolic acid and its derivative, 3-oxime-urs-12-en-28-oic-ursolic acid (9), presented the best anti-T. vaginalis activity when compared to other derivatives, with minimum inhibitory concentration (MIC) at 25 μM. Moreover, 9 was active against several T. vaginalis fresh clinical isolates. Hemolysis assay demonstrated that 9 presented a low hemolytic effect. Importantly, 25 μM 9 was not cytotoxic against the Vero cell lineage. Finally, we demonstrated that compound 9 acts synergistically with metronidazole against a T. vaginalis metronidazole-resistant isolate. This report reveals the high potential of the triterpenoid derivative 9 as trichomonicidal agent.

Anti-herpes virus activities of bioactive fraction and isolated pure constituent of Mallotus peltatus: an ethnomedicine from Andaman Islands

PubMed Central

2012-01-01

Background Viral infections, particularly the infections caused by herpes simplex virus (HSV), represent one of the most serious public health concerns globally because of their devastating impact. The aim of this study was to evaluate the antiviral potential of methanolic crude extract of an ethnomedicine Mallotus peltatus, its active fraction and pure compound, against HSV-1 F and HSV-2 G. Result The cytotoxicity (CC50, the concentration of 50% cellular toxicity), antiviral effective concentration (EC50, the concentration required to achieve 50% protection against virus-induced cytopathic effect), plaque reduction and the selectivity index (SI, the ratio of CC50 and EC50) was determined. Results showed that the crude methanolic extract of M. peltatus possessed weak anti-HSV activity. In contrast, the active fraction A and isolated ursolic acid from fraction A exhibited potent antiherpesvirus activity against both HSV-1 (EC50 = 7.8 and 5.5 μg/ml; SI = 22.3 and 20) and HSV-2 (EC50 = 8.2 and 5.8 μg/ml, and SI = 21.2 and 18.97). The fraction A and isolated ursolic acid (10 μg/ml) inhibited plaque formation of HSV-1 and HSV-2 at more than 80% levels, with a dose dependent antiviral activity, compared to acyclovir. The time response study revealed that the anti-HSV activity of fraction A and isolated ursolic acid is highest at 2–5 h post-infection. Moreover, the time kinetics study by indirect immunofluorescence assay showed a characteristic pattern of small foci of single fluorescent cells in fraction A- treated virus infected cells at 2 h and 4 h post-infection, suggesting drug inhibited viral dissemination. Further, the PCR study with infected cell cultures treated with fraction A and isolated ursolic acid at various time intervals, failed to show amplification at 48–72 h, like acyclovir treated HSV-infected cells. Moreover, fraction A or isolated ursolic acid showed no interaction in combination with acyclovir. Conclusion This study revealed that bioactive fraction A and isolated ursolic acid of M. peltatus has good anti-HSV activity, probably by inhibiting the early stage of multiplication (post-infection of 0–5 h), with SI value of 20, suggesting its potential use as anti-HSV agents. PMID:22624581

Oleanolic Acid Alters Multiple Cell Signaling Pathways: Implication in Cancer Prevention and Therapy.

PubMed

Žiberna, Lovro; Šamec, Dunja; Mocan, Andrei; Nabavi, Seyed Fazel; Bishayee, Anupam; Farooqi, Ammad Ahmad; Sureda, Antoni; Nabavi, Seyed Mohammad

2017-03-16

Nowadays, much attention has been paid to diet and dietary supplements as a cost-effective therapeutic strategy for prevention and treatment of a myriad of chronic and degenerative diseases. Rapidly accumulating scientific evidence achieved through high-throughput technologies has greatly expanded the understanding about the multifaceted nature of cancer. Increasingly, it is being realized that deregulation of spatio-temporally controlled intracellular signaling cascades plays a contributory role in the onset and progression of cancer. Therefore, targeting regulators of oncogenic signaling cascades is essential to prevent and treat cancer. A plethora of preclinical and epidemiological evidences showed promising role of phytochemicals against several types of cancer. Oleanolic acid, a common pentacyclic triterpenoid, is mainly found in olive oil, as well as several plant species. It is a potent inhibitor of cellular inflammatory process and a well-known inducer of phase 2 xenobiotic biotransformation enzymes. Main molecular mechanisms underlying anticancer effects of oleanolic acid are mediated by caspases, 5' adenosine monophosphate-activated protein kinase, extracellular signal-regulated kinase 1/2, matrix metalloproteinases, pro-apoptotic Bax and bid, phosphatidylinositide 3-kinase/Akt1/mechanistic target of rapamycin, reactive oxygen species/apoptosis signal-regulating kinase 1/p38 mitogen-activated protein kinase, nuclear factor-κB, cluster of differentiation 1, CKD4, s6k, signal transducer and activator of transcription 3, as well as aforementioned signaling pathways . In this work, we critically review the scientific literature on the molecular targets of oleanolic acid implicated in the prevention and treatment of several types of cancer. We also discuss chemical aspects, natural sources, bioavailability, and safety of this bioactive phytochemical.

Effects of five oleanolic acid triterpenoid saponins from the rhizome of Anemone raddeana on stimulus-induced superoxide generation, phosphorylation of proteins and translocation of cytosolic compounds to cell membrane in human neutrophils.

PubMed

Wei, Shihu; He, Wenfei; Lu, Jincai; Wang, Zhonghuan; Yamashita, Koichi; Yokoyama, Masanori; Kodama, Hiroyuki

2012-03-01

Five oleanolic acid triterpenoid saponins (OTS-1, 2, 3, 4 and 5) were isolated from the rhizome of Anemone raddeana. The effect of these triterpenoid saponins on stimulus-induced superoxide generation in human neutrophils was assayed by measuring the reduction of ferricytochrome c using a dual-beam spectrophotometer. The phosphorylation of neutrophil proteins, and translocation of p67(phox), p47(phox) and Rac to plasma membrane were investigated using specific monoclonal antibodies. The five oleanolic acid triterpenoid saponins used in this experiment suppressed N-formyl-methionyl-leucyl-phenylalanine (fMLP)-induced superoxide generation in a concentration-dependent manner. OTS-1, 2 and 4 suppressed phorbol 12-myristate 13-acetate (PMA)- and arachidonic acid (AA)-induced superoxide generation in a concentration-dependent manner, but OTS-3 and 5 showed no effect. fMLP- and PMA-induced tyrosyl or serine/threonine phosphorylation, and fMLP-, PMA- and AA-induced translocation of p67(phox), p47(phox) and Rac to plasma membrane were in parallel with the suppression of the stimulus-induced superoxide generation. Copyright © 2011 Elsevier B.V. All rights reserved.

Triterpene saponin hemi-biosynthesis of a leaf beetle's (Platyphora kollari) defensive secretion

NASA Astrophysics Data System (ADS)

Ghostin, Jean; Habib-Jiwan, Jean-Louis; Rozenberg, Raoul; Daloze, Désiré; Pasteels, Jacques M.; Braekman, Jean-Claude

2007-07-01

The adults of the leaf beetle Platyphora kollari (Chrysomelidae) are able to metabolise the oleanane triterpene β-amyrin (1) into the glycoside 3-O-β-d-glucopyranosyl-(1→4)-β-d-glucuronopyranosyl-hederagenin (2) that is stored in their defensive glands. The aim of this study was to test the hypothesis that oleanolic acid (3) is an intermediate in the conversion of 1 into 2 and to check whether the sequestration of pentacyclic triterpenes is selective in favour of β-amyrin (1). To this end, adults of P. kollari were fed with Ipomoea batatas leaf disks painted with a solution of [2,2,3-2H3]oleanolic acid or [2,2,3-2H3]α-amyrin and the secretion of their defensive glands analysed by HPLC ESIMS. The data presented in this work indicated that the first step of the transformation of β-amyrin (1) into the sequestered glycoside 2 is its oxidation into oleanolic acid (3) and that this conversion is selective but not specific in favour of β-amyrin (1).

Antimycobacterial triterpenes from the Canadian medicinal plant Sarracenia purpurea.

PubMed

Morrison, Steven A; Li, Haoxin; Webster, Duncan; Johnson, John A; Gray, Christopher A

2016-07-21

The purple pitcher plant, Sarracenia purpurea, is a medicinal plant used by the Canadian First Nations to treat a wide variety of illnesses. The Mi'kmaq and Wolastoqiyik (Maliseet) peoples of Eastern Canada have traditionally used infusions of S. purpurea for the treatment of tuberculosis-like symptoms. Previous investigations have shown methanolic extracts of S. purpurea to possess antimycobacterial activity. To isolate and identify antimycobacterial constituents from S. purpurea. Methanolic extracts of S. purpurea were subjected to bioassay guided fractionation using the microplate resazurin assay (MRA) to assess inhibitory activity against Mycobacterium tuberculosis strain H37Ra. The antimycobacterial constituents were identified by NMR, MS and polarimetry. The triterpenes betulinaldehyde, β-sitosterol, betulinic acid, and ursolic acid were isolated from S. purpurea. Betulinaldehyde, betulinic acid, and ursolic acid exhibited MICs of 450, 950, and 450μM and IC50s of 98, 169, and 93μM against M. tuberculosis H37Ra respectively whilst β-sitosterol was inactive (MIC and IC50 of >1000μM). Betulinaldehyde, betulinic acid, and ursolic acid were identified as the principal constituents responsible for the antimycobacterial activity of S. purpurea. This work is consistent with the ethnopharmacological use of S. purpurea by Canadian First Nations as a treatment against infectious diseases. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

[Ursolic acid inhibits corneal graft rejection following orthotopic allograft transplantation in rats].

PubMed

Wang, Bo; Wu, Jing; Ma, Ming; Li, Ping-Ping; Yu, Jian

2015-04-01

To investigate the effects of ursolic acid on corneal graft rejection in a rat model of othotopic corneal allograft transplantation. Forty-eight recipient Wistar rats were divided into normal control group with saline treatment (group A), autograft group with saline treatment (group B), SD rat allograft group with saline treatment (group C), and SD rat allograft group with intraperitoneal ursolic acid (UA) treatment group (group D). The rats received saline or UC (20 mg·kg(-1)·d(-1)) treatment for 12 days following othotopic graft transplantation. The grafts were evaluated using the Larkin corneal rejection rating system, and the graft survival was assessed with Kaplan-Meier analysis. On day 14, the grafts were harvested for histological examination, Western blotting, and assessment of expressions of interlukin-2 (IL-2), interferon-γ (IFN-γ), nuclear transcription factor-κB (NF-κB) p65, vascular endothelial growth factor (VEGF) and intercellular adhesion molecule-1 (ICAM-1). The allograft survival was significantly longer in group D than in group C (29.12±9.58 vs 9.67±2.16 days, P<0.05). UC treatment obviously reduced the expression levels of IL-2, IFN-γ, NF-κBp65, ICAM-1 and VEGF and increased inhibitory kappa B alpha (IκB-α) expression in the grafts, where no obvious inflammatory cell infiltration or corneal neovascularization was found. As a NF-κB inhibitor, ursolic acid can prevent corneal neovascularization and corneal allograft rejection to promote graft survival in rats following orthotopic corneal allograft transplantation.

Ursolic acid promotes robust tolerance to cardiac allografts in mice

PubMed Central

Liu, Y; Huang, X; Li, Y; Li, C; Hu, X; Xue, C; Meng, F; Zhou, P

2011-01-01

Nuclear factor (NF)-κB is an important molecule in T cell activation. Our previous work has found that T cell-restricted NF-κB super-repressor (IκBαΔN-Tg) mice, expressing an inhibitor of NF-κB restricted to the T cell compartment, can permanently accept fully allogeneic cardiac grafts and secondary donor skin grafts. In this study, we explore if transient NF-κB inhibition by a small molecular inhibitor could induce permanent graft survival. Ursolic acid, a small molecular compound, dose-dependently inhibited T cell receptor (TCR)-triggered NF-κB nuclear translocation and T cell activation in vitro. In vivo, ursolic acid monotherapy prolonged significantly the survival of cardiac allograft in mice. Assisted with donor-specific transfusion (DST) on day 0, ursolic acid promoted 84·6% of first cardiac grafts to survive for more than 150 days. While the mice with long-term surviving grafts (LTS) did not reject the second donor strain hearts for more than 100 days without any treatment, they all promptly rejected the third-party strain hearts within 14 days. Interestingly, this protocol did not result in an increased proportion of CD4+CD25+forkhead box P3+ regulatory T cells in splenocytes. That adoptive transfer experiments also did not support regulation was the main mechanism in this model. Splenocytes from LTS showed reduced alloreactivity to donor antigen. However, depletion of CD4+CD25+ regulatory T cells did not alter the donor-reactivity of LTS splenocytes. These data suggest that depletion of donor-reactive T cells may play an important role in this protocol. PMID:21391985

Ursolic Acid Hydrazide Based Organometallic Complexes: Synthesis, Characterization, Antibacterial, Antioxidant and Docking Studies

NASA Astrophysics Data System (ADS)

Jabeen, Muafia; Ahmad, Sajjad; Shahid, Khadija; Sadiq, Abdul; Rashid, Umer

2018-03-01

In the current research work,eleven metal complexes were synthesized from the hydrazide derivative of ursolic acid. Metal complexes of tin, antimony and iron were synthesized and characterized by FT-IR and NMR spectroscopy. The antibacterial and antioxidant activities were performed for these complexes, which revealed that the metal complexes synthesized are more potent than their parent compounds. We observed that antioxidant activity showed by triphenyltin complex was significant and least activity have been shown by antimony trichloride complex.The synthesized metal complexes were then evaluated against two Gram-negative and two Gram-positive bacterial strains. Triphenyl tin complex emerged as potent antibacterial agent with MIC value of 8 μg/ml each against Shigellaspp, S. typhi and S. aureus. While, the MIC value againstS. pneumoniae is 4 μg/ml.Computational docking studies were carried out on molecular targets to interpret the results of antioxidant and antibacterial activities. Based on the results, it may be inferred that the metal complexes of ursolic acid are more active as compared to the parent drug and may be proved for some other pharmacological potential by further analysis.

Effect-directed analysis of fresh and dried elderberry (Sambucus nigra L.) via hyphenated planar chromatography.

PubMed

Krüger, S; Mirgos, M; Morlock, G E

2015-12-24

A healthy diet is an important factor in a healthy lifestyle that is becoming increasingly important in today's society. The fruits of European elder (Sambucus nigra L.) are a rich source of bioactive compounds like anthocyanins. In this study, dried and fresh fruits of four cultivated and six wild growing plants were investigated for their anthocyanin pattern and content as well as their bioactive compounds. After separation on HPTLC plates silica gel 60 F254 with a mixture of ethyl acetate, 2-butanone, formic acid and water, the plates were quantitatively evaluated by densitometry and also subjected to various (bio)assays to investigate the samples for compounds acting as radical-scavengers, antimicrobials, estrogens, and acetylcholinesterase or tyrosinase inhibitors. The mean contents for the two most abundant anthocyanins in European elderberries, confirmed by HPTLC-ESI-MS, ranged from 159 to 647mg/100g in fresh and from 166 to 2764mg/100g in dried fruits for cyanidin-3-sambubioside, and from 112 to 521mg/100g in fresh and 95 to 226mg/100g in dried fruits for cyanidin-3-glucoside. Additionally, the anthocyanin content was higher in berries of cultivars than of wild growing plants. The anthocyanins' radical scavenging activity and antimicrobial effect against Aliivibrio fischeri were confirmed. Further, a radical scavenging compound affecting A. fischeri and acting as acetylcholinesterase inhibitor was tentatively assigned by its protonated molecule at m/z 456 as either ursolic or oleanolic acid by HPTLC-ESI-MS. HPTLC hyphenated with bioassays and mass spectrometry was selected as method of choice for fingerprinting, pattern recognition, and bioprofiling of elderberry samples as well as quantitation and confirmation of bioactive compounds therein. Copyright © 2015 Elsevier B.V. All rights reserved.

Antiviral activities of extracts and selected pure constituents of Ocimum basilicum.

PubMed

Chiang, Lien-Chai; Ng, Lean-Teik; Cheng, Pei-Win; Chiang, Win; Lin, Chun-Ching

2005-10-01

1. Ocimum basilicum (OB), also known as sweet basil, is a well known medicinal herb in traditional Chinese medicine preparations. In the present study, extracts and purified components of OB were used to identify possible antiviral activities against DNA viruses (herpes viruses (HSV), adenoviruses (ADV) and hepatitis B virus) and RNA viruses (coxsackievirus B1 (CVB1) and enterovirus 71 (EV71)). 2. The results show that crude aqueous and ethanolic extracts of OB and selected purified components, namely apigenin, linalool and ursolic acid, exhibit a broad spectrum of antiviral activity. Of these compounds, ursolic acid showed the strongest activity against HSV-1 (EC50 = 6.6 mg/L; selectivity index (SI) = 15.2), ADV-8 (EC50 = 4.2 mg/L; SI = 23.8), CVB1 (EC50 = 0.4 mg/L; SI = 251.3) and EV71 (EC50 = 0.5 mg/L; SI = 201), whereas apigenin showed the highest activity against HSV-2 (EC50 = 9.7 mg/L; SI = 6.2), ADV-3 (EC50 = 11.1 mg/L; SI = 5.4), hepatitis B surface antigen (EC50 = 7.1 mg/L; SI = 2.3) and hepatitis B e antigen (EC50 = 12.8 mg/L; SI = 1.3) and linalool showed strongest activity against AVD-II (EC50 = 16.9 mg/L; SI = 10.5). 3. No activity was noted for carvone, cineole, beta-caryophyllene, farnesol, fenchone, geraniol, beta-myrcene and alpha-thujone. 4. The action of ursolic acid against CVB1 and EV71 was found to occur during the infection process and the replication phase. 5. With SI values greater than 200, the potential use of ursolic acid for treating infection with CVB1 and EV71 merits further investigation.

mRNA Expression Signatures of Human Skeletal Muscle Atrophy Identify a Natural Compound that Increases Muscle Mass

PubMed Central

Kunkel, Steven D.; Suneja, Manish; Ebert, Scott M.; Bongers, Kale S.; Fox, Daniel K.; Malmberg, Sharon E.; Alipour, Fariborz; Shields, Richard K.; Adams, Christopher M.

2011-01-01

SUMMARY Skeletal muscle atrophy is a common and debilitating condition that lacks a pharmacologic therapy. To develop a potential therapy, we identified 63 mRNAs that were regulated by fasting in both human and mouse muscle, and 29 mRNAs that were regulated by both fasting and spinal cord injury in human muscle. We used these two unbiased mRNA expression signatures of muscle atrophy to query the Connectivity Map, which singled out ursolic acid as a compound whose signature was opposite to those of atrophy-inducing stresses. A natural compound enriched in apples, ursolic acid reduced muscle atrophy and stimulated muscle hypertrophy in mice. It did so by enhancing skeletal muscle insulin/IGF-I signaling, and inhibiting atrophy-associated skeletal muscle mRNA expression. Importantly, ursolic acid’s effects on muscle were accompanied by reductions in adiposity, fasting blood glucose and plasma cholesterol and triglycerides. These findings identify a potential therapy for muscle atrophy and perhaps other metabolic diseases. PMID:21641545

Oleanolic-bioenhancer coloaded chitosan modified nanocarriers attenuate breast cancer cells by multimode mechanism and preserve female fertility.

PubMed

Sharma, Monika; Sharma, Shweta; Sharma, Vikas; Sharma, Komal; Yadav, Santosh Kumar; Dwivedi, Pankaj; Agrawal, Satish; Paliwal, Sarvesh Kumar; Dwivedi, Anil Kumar; Maikhuri, Jagdamba Prasad; Gupta, Gopal; Mishra, Prabhat Ranjan; Rawat, Ajay Kumar Singh

2017-11-01

Addressing multidrug resistant stage of breast cancer is an impediment for chemotherapy. Moreover, breast cancer chemotherapy has potential enduring confrontations i.e. related toxicity including effect on fertility of young female patients. The co-delivery of polyphenolic bio-enhancers with oleanolic acid in chitosan coated PLGA nanoparticles was designed for oral delivery with enhanced antitumor effect consecutively preserving the female fertility. The optimized oleanolic- bio-enhancer nano formulation CH-OA-B-PLGA with particle size was 342.2±3.7nm and zeta potential of 34.2±3.1mV was capable of lowering viability in MDAMB 231 cell line 16 times than OA. Further, mechanistic studies in MDAMB-231 cells revealed that CH-OA-PLGA induces apoptosis by mitochondrial membrane disruption; follows ROS mediated and caspase dependent apoptosis. The antitumor effect studied in 4-T1 induced Balb/c mice mammary tumor model displayed augmented antitumor potency by CH-OA-B-PLGA in comparison to OA. In the in vivo toxicity on Sprague-Dawley rat model, CH-OA-B-PLGA significantly displayed the safe profile and also preserves fertility in female rats. The experiment result suggests co-delivery of oleanolic acid with bio-enhancers as a breakthrough for developing safe chemotherapy for hormone independent breast cancer therapy countering the toxicity issues. Copyright © 2017. Published by Elsevier B.V.

Anti-inflammatory activity of extract and fractions from Nepeta sibthorpii Bentham.

PubMed

Miceli, N; Taviano, M F; Giuffrida, D; Trovato, A; Tzakou, O; Galati, E M

2005-02-28

Several species of Nepeta genus are utilized in folk medicine for treatment of contusions, rheumatic pains, fever, cutaneous eruptions. Some species are employed for their anti-inflammatory properties. In this paper, we report the results of phytochemical studies on aerial parts of Nepeta sibthorpii Bentham (Lamiaceae), an endemic plant of Greece. The bioassay-guided fractionation of methanol extract led to the isolation of ursolic acid and polyphenol fraction. By HPLC, we determined some phenolics: chlorogenic acid (0.315 mg/g) and the flavonoids rutin (0.091 mg/g), luteolin-7-O-glucoside (0.387 mg/g) and a luteolin derivative. We assayed the radical scavenging activity of Nepeta sibthorpii methanol extract by the 1,1-diphenyl-2-picrylhydrazyl (DPPH) method. Moreover, we studied the anti-inflammatory activity of Nepeta sibthorpii methanol extract (50 mg/kg, os), ursolic acid and polyphenol fraction (dose corresponding to 50 mg/kg of methanol extract, os) in the carrageenan-induced paw oedema in rat. In this experimental model, we observed a significant inhibition of paw oedema. We suppose that the anti-inflammatory effect of methanol extract could be related to the free radical scavenging activity and that it depends on a synergic action of all the components of the methanol extract, even if ursolic acid can be considered the main responsible for this activity.

Search for constituents with neurotrophic factor-potentiating activity from the medicinal plants of paraguay and Thailand.

PubMed

Li, Yushan; Ohizumi, Yasushi

2004-07-01

20 medicinal plants of Paraguay and 3 medicinal plants of Thailand were examined on nerve growth factor (NGF)-potentiating activities in PC12D cells. The trail results demonstrated that the methanol extracts of four plants, Verbena littoralis, Scoparia dulcis, Artemisia absinthium and Garcinia xanthochymus, markedly enhanced the neurite outgrowth induced by NGF from PC12D cells. Furthermore, utilizing the bioactivity-guided separation we successfully isolated 32, 4 and 5 constituents from V. littoralis, S. dulcis and G. xanthochymus, respectively, including nine iridoid and iridoid glucosides (1-9), two dihydrochalcone dimers (10 and 11), two flavonoids and three flavonoid glycosides (12-16), two sterols (17 and 18), ten triterpenoids (19-28), five xanthones (29-33), one naphthoquinone (34), one benzenepropanamide (35), four phenylethanoid glycosides (36-39) and two other compounds (40 and 41). Among which, 15 compounds (1-4, 10-11, 14-18, 29-31 and 34) were new natural products. The results of pharmacological trails verified that littoralisone (1), gelsemiol (5), 7a-hydroxysemperoside aglucone (6), verbenachalcone (10), littorachalcone (11), stigmast-5-ene 3beta,7alpha,22alpha-triol (18), ursolic acid (19), 3beta-hydroxyurs-11-en-28,13beta-olide (24), oleanolic acid (25), 2alpha,3beta-dihydroxyolean-12-en-28-oic acid (26), 1,4,5,6-tetrahydroxy-7,8-di(3-methylbut-2-enyl)xanthone (29), 1,2,6-trihydroxy-5-methoxy-7-(3-methylbut-2-enyl)xanthone (30), 1,3,5,6-tetrahydroxy-4,7,8-tri(3-methyl-2-butenyl)xanthone (31), 12b-hydroxy-des-D-garcigerrin A (32), garciniaxanthone E (33) and (4R)-4,9-dihydroxy-8-methoxy-alpha-lapachone (34) elicited marked enhancement of NGF-mediated neurite outgrowth in PC12D cells. These substances may contribute to the basic study and the medicinal development for the neurodegenerative disorder.

Comparative pharmacokinetics of swertiamarin in rats after oral administration of swertiamarin alone, Qing Ye Dan tablets and co-administration of swertiamarin and oleanolic acid.

PubMed

Xu, Gui-li; Li, Hong-liang; He, Jian-chang; Feng, En-fu; Shi, Pan-pan; Liu, Yue-qiong; Liu, Chang-xiao

2013-08-26

Qing Ye Dan is a well-known herbal drug that is widely used to treat viral hepatitis in the Yi and Hani minority regions in the Yunnan province of China. An LC-MS/MS method was developed to determine the levels of swertiamarin in rat plasma. Swertiamarin and naringin (internal standard, IS) were extracted from rat plasma using solid-phase extraction (SPE) to purify the samples. The pharmacokinetics of the following different administration methods of swertiamarin in rats were studied: oral administration of swertiamarin alone, a Qing Ye Dan tablet (QYDT) and co-administration of swertiamarin and oleanolic acid, with each method delivering approximately 20mg/kg of swertiamarin. Non-compartmental pharmacokinetic profiles were constructed by using the software DAS (version 2.1.1), and the pharmacokinetic parameters were compared using an unpaired Student's t-test. The results showed that the pharmacokinetic parameters Cmax, AUC0-∞, Vz/F and CLz/F were significantly different (P<0.05) among the three types of swertiamarin administration. The data indicate that oleanolic acid and the other ingredients present in QYDT could affect the pharmacokinetic behaviour of swertiamarin in rats. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

UDP-Glycosyltransferases from the UGT73C Subfamily in Barbarea vulgaris Catalyze Sapogenin 3-O-Glucosylation in Saponin-Mediated Insect Resistance1[W][OA

PubMed Central

Augustin, Jörg M.; Drok, Sylvia; Shinoda, Tetsuro; Sanmiya, Kazutsuka; Nielsen, Jens Kvist; Khakimov, Bekzod; Olsen, Carl Erik; Hansen, Esben Halkjær; Kuzina, Vera; Ekstrøm, Claus Thorn; Hauser, Thure; Bak, Søren

2012-01-01

Triterpenoid saponins are bioactive metabolites that have evolved recurrently in plants, presumably for defense. Their biosynthesis is poorly understood, as is the relationship between bioactivity and structure. Barbarea vulgaris is the only crucifer known to produce saponins. Hederagenin and oleanolic acid cellobioside make some B. vulgaris plants resistant to important insect pests, while other, susceptible plants produce different saponins. Resistance could be caused by glucosylation of the sapogenins. We identified four family 1 glycosyltransferases (UGTs) that catalyze 3-O-glucosylation of the sapogenins oleanolic acid and hederagenin. Among these, UGT73C10 and UGT73C11 show highest activity, substrate specificity and regiospecificity, and are under positive selection, while UGT73C12 and UGT73C13 show lower substrate specificity and regiospecificity and are under purifying selection. The expression of UGT73C10 and UGT73C11 in different B. vulgaris organs correlates with saponin abundance. Monoglucosylated hederagenin and oleanolic acid were produced in vitro and tested for effects on P. nemorum. 3-O-β-d-Glc hederagenin strongly deterred feeding, while 3-O-β-d-Glc oleanolic acid only had a minor effect, showing that hydroxylation of C23 is important for resistance to this herbivore. The closest homolog in Arabidopsis thaliana, UGT73C5, only showed weak activity toward sapogenins. This indicates that UGT73C10 and UGT73C11 have neofunctionalized to specifically glucosylate sapogenins at the C3 position and demonstrates that C3 monoglucosylation activates resistance. As the UGTs from both the resistant and susceptible types of B. vulgaris glucosylate sapogenins and are not located in the known quantitative trait loci for resistance, the difference between the susceptible and resistant plant types is determined at an earlier stage in saponin biosynthesis. PMID:23027665

Ellagic acid, sulforaphane, and ursolic acid in the prevention and therapy of breast cancer: current evidence and future perspectives.

PubMed

Jaman, Md Sadikuj; Sayeed, Md Abu

2018-05-03

Globally, breast cancer is the most common cancer and the second leading cause of cancer-related death among women. Surgery, chemotherapy, hormonal therapy, and radiotherapy are currently available treatment options for breast cancer therapy. However, chemotherapy, hormonal therapy, and radiotherapy are often associated with side effects and multidrug resistance, recurrence, and lack of treatment in metastasis are the major problems in the treatment of breast cancer. Recently, dietary phytochemicals have emerged as advantageous agents for the prevention and therapy of cancer due to their safe nature. Ellagic acid (EA), sulforaphane (SF), and ursolic acid (UA), which are found in widely consumed fruits and vegetables, have been shown to inhibit breast cancer cell proliferation and to induce apoptosis. This review encompasses the role of EA, SF, and UA in the fight against breast cancer. Both in vitro and in vivo effects of these agents are presented.

Synthesis and biological evaluation of Raddeanin A, a triterpene saponin isolated from Anemone raddeana.

PubMed

Qian, Shan; Chen, Quan Long; Guan, Jin Long; Wu, Yong; Wang, Zhou Yu

2014-01-01

First, Raddeanin A, a cytotoxic oleanane-type triterpenoid saponin isolated from Anemone raddeana REGEL, was synthesized. Stepwise glycosylation was adopted in the synthesis from oleanolic acid, employing arabinosyl, glucosyl and rhamnosyl trichloroacetimidate as donors. The chemical structure of Raddeanin A was confirmed by means of (1)H-NMR, (13)C-NMR, IR, MS and elemental analysis, which elucidated the structure to be 3-O-α-L-rhamnopyranosyl-(1→2)-β-D-glucopyranosyl-(1→2)-α-L-arabinopyranoside oleanolic acid. Biological activity tests showed that in the range of low concentrations, Raddeanin A displayed moderate inhibitory activity against histone deacetylases (HDACs), indicating that the HDACs' inhibitory activity of Raddeanin A may contribute to its cytotoxicity.

Yields and content of ursolic acid in pearl grass (Hedyotis corymbosa) when utilizing cow manure fertilizer in different shades

NASA Astrophysics Data System (ADS)

Jayanti, L. D.; Yunus, A.; Pujiasmanto, B.; Widyastuti, Y.

2018-03-01

This study aims to examine the intensity of shade and proper dosage of fertilizer to maximize the content of ursolic acid and pearl grass yield. The field-run study was carried out at the Medicinal Plant Garden of the Research and Development of Medicinal Plants and Traditional Medicines (B2P2TOOT) and the laboratory research was conducted at the B2P2TOOT Phytochemistry Laboratory. The experiment design was Randomized Complete Block Design with Split Plot pattern with the intensity (three levels) as main plot and fertilizer dosage (four levels) as sub plot. The data obtained were analyzed using the variance analysis, if there were significant differences tested further by using Duncan’s Multiple Range Test (DMRT) with 95% confidence level. The results showed that shade treatment gave significant effects on plant height, number of branches, root length, fresh weight and dry weight. The treatment of a fertilizer dosage 15 tons/ha gave the best results on fresh weight and dry weight. The combination of N0K0 treatment (without shade, without cow manure) resulted in the highest quality of ursolic acid as it featured a light blue color when detected under UV366 light.

A 70% Ethanol Extract of Mistletoe Rich in Betulin, Betulinic Acid, and Oleanolic Acid Potentiated β-Cell Function and Mass and Enhanced Hepatic Insulin Sensitivity

PubMed Central

Ko, Byoung-Seob; Kang, Suna; Moon, Bo Reum; Ryuk, Jin Ah; Park, Sunmin

2016-01-01

We investigated that the long-term consumption of the water (KME-W) and 70% ethanol (KME-E) mistletoe extracts had antidiabetic activities in partial pancreatectomized (Px) rats. Px rats were provided with a high-fat diet containing 0.6% KME-E, 0.6% KME-W, and 0.6% dextrin (control) for 8 weeks. As normal-control, Sham-operated rats were provided with 0.6% dextrin. In cell-based studies, the effects of its main terpenoids (betulin, betulinic acid, and oleanolic acid) on glucose metabolism were measured. Both KME-W and KME-E decreased epididymal fat mass by increasing fat oxidation in diabetic rats. KME-E but not KME-W exhibited greater potentiation of first-phase insulin secretion than the Px-control in a hyperglycemic clamp. KME-E also made β-cell mass greater than the control by increasing β-cell proliferation and decreasing its apoptosis. In a euglycemic-hyperinsulinemic clamp, whole-body glucose infusion rate and hepatic glucose output increased with potentiating hepatic insulin signaling in the following order: Px-control, KME-W, KME-E, and normal-control. Betulin potentiated insulin-stimulated glucose uptake via increased PPAR-γ activity and insulin signaling in 3T3-L1 adipocytes, whereas oleanolic acid enhanced glucose-stimulated insulin secretion and cell proliferation in insulinoma cells. In conclusion, KME-E prevented the deterioration of glucose metabolism in diabetic rats more effectively than KME-W and KME-E can be a better therapeutic agent for type 2 diabetes than KME-W. PMID:26884795

Oleanolic acid and its synthetic derivatives for the prevention and therapy of cancer: Preclinical and clinical evidence

PubMed Central

Shanmugam, Muthu K.; Dai, Xiaoyun; Kumar, Alan Prem; Tan, Benny KH; Sethi, Gautam; Bishayee, Anupam

2014-01-01

Oleanolic acid (OA, 3β-hydroxyolean-12-en-28-oic acid) is a ubiquitous pentacyclic multifunctional triterpenoid, widely found in several dietary and medicinal plants. Natural and synthetic OA derivatives can modulate multiple signaling pathways including nuclear factor-κB, AKT, signal transducer and activator of transcription 3, mammalian target of rapamycin, caspases, intercellular adhesion molecule 1, vascular endothelial growth factor, and poly (ADP-ribose) polymerase in a variety of tumor cells. Importantly, synthetic derivative of OA, 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO), and its C-28 methyl ester (CDDO-Me) and C28 imidazole (CDDO-Im) have demonstrated potent antiangiogenic and antitumor activities in rodent cancer models. These agents are presently under evaluation in phase I studies in cancer patients. This review summarizes the diverse molecular targets of OA and its derivatives and also provides clear evidence on their promising potential in preclinical and clinical situations. PMID:24486850

The construction of the multifunctional targeting ursolic acids liposomes and its apoptosis effects to C6 glioma stem cells

PubMed Central

Ying, Xue; Wang, Yahua; Xu, Haolun; Li, Xia; Yan, Helu; Tang, Hui; Wen, Chen; Li, Yingchun

2017-01-01

Brain gliomas, one of the most fatal tumors to human, severely threat the health and life of human. They are capable of extremely strong invasion ability. And invasive glioma cells could rapidly penetrate into normal brain tissues and break them. We prepared a kind of functional liposomes, which could be transported acrossing the blood-brain barrier (BBB) and afterwards induce the apoptosis of glioma stem cells. In this research, we chose ursolic acids (UA) as an anti-cancer drug to inhibit the growth of C6 glioma cells, while epigallocatechin 3-gallate(EGCG) as the agent that could induce the apoptosis of C6 glioma stem cells. With the targeting ability of MAN, the liposomes could be delivered through the BBB and finally were concentrated on the brain gliomas. Cell experiments in vitro demonstrated that the functional liposomes were able to significantly enhance the anti-cancer effects of the drugs due to promoting the apoptosis and endocytosis effects of C6 glioma cells and C6 glioma stem cells at the same time. Furthermore, the evaluations through animal models showed that the drugs could obviously prolong the survival period of brain glioma-bearing mice and inhibit the tumor growth. Consequently, multifunctional targeting ursolic acids liposomes could potentially improve the therapeutic effects on C6 glioma cells and C6 glioma stem cells. PMID:28969057

Effects of Different Extraction Methods on the Extraction Rates of Five Chemical Ingredients of Swertia mussotii Franch by UPLC-ESI-MS/MS

NASA Astrophysics Data System (ADS)

Xiong, Yaokun; Zhou, Lifen; Zhao, Yonghong; Liu, Yun; Liu, Xia; Zhu, Genhua; Yan, Zhihong; Liu, Zhiyong

2018-01-01

Objective: To compare the effects of three extraction methods (ultrasound, reflux and percolation) on the contents of gentiopicroside, mangiferin, swertiamain, sweroside and oleanolic acid in Swertia mussotii Franch. Method: The contents of five components were determined by UPLC-ESI/MS. In the solvent system, eluent A was 0.05% (v: v) formic acid with 1mM/L ammonium acetate aqueous solution and eluent B was acetonitrile. Chromatographic separations were achieved using an Agilent EC-C18 column (4.6×100 mm, 2.7 um) at 30 °C. The flow rate was set at 0.8mL/min. The compound ionization was adopted at negative ionization mode by electro spray ionization (ESI). The quantification was performed in multiple reaction monitoring (MRM). Results: The linear ranges of swertiamarin, gentiopicroside, mangiferin, sweroside and oleanolic acid are 80∼7450 ng/mL, 103∼6600 ng/mL, 100∼8000 ng/mL, 130∼8450 ng/mL, 100∼7000 ng/mL, respectively. As a result, the content of oleanolic acid was the highest extracted by ultrasonic extraction and the content of mangiferin was the highest extracted by reflux extraction. For percolation extraction, the contents of five components were between ultrasound and reflux extraction. Conclusion: For five components, there are significant differences between the three different extraction methods. The results could provide a reference for the quality control of Swertia mussotii Franch and the research and development of new drugs.

Unusual immuno-modulatory triterpene-caffeates in the skins of russeted varieties of apples and pears.

PubMed

Andre, Christelle M; Larsen, Lesley; Burgess, Elaine J; Jensen, Dwayne J; Cooney, Janine M; Evers, Danièle; Zhang, Jingli; Perry, Nigel B; Laing, William A

2013-03-20

Three triterpene-caffeates have been isolated from skins of a russeted apple cultivar "Merton Russet" and identified by LC-MS and NMR as betulinic acid-3-cis-caffeate, betulinic acid-3-trans-caffeate, and oleanolic acid-3-trans-caffeate. Betulinic acid-3-trans-caffeate and oleanolic acid-3-trans-caffeate were also found in russeted pear skins. These compounds have not been previously reported in apples or pears, or in any other foods. Their presence was related to suberized tissue as they were only found in russet portions of the partially russeted apple cultivar "Cox's Orange Pippin" and were not detected in the waxy apple cultivar "Royal Gala". High concentrations of betulinic acid-3-trans-caffeate were found in the bark of both "Merton Russet" and "Royal Gala" trees. The three triterpene-caffeates showed anti-inflammatory activity in vitro, inhibiting NF-κB activation with IC50's of 6-9 μM. Betulinic acid-3-trans-caffeate, the predominant compound in the apples, was immuno-modulatory at around 10 μM in the in vitro and ex vivo bioassays, boosting production of the pro-inflammatory cytokine TNFα in cells stimulated with bacterial lipopolysaccharides.

Two new triterpenoid saponins from rhizome of Anemone amurensis.

PubMed

Lv, Chong-Ning; Fan, Li; Wang, Jing; Qin, Ru-Lan; Xu, Tan-Ye; Lei, Tian-Li; Lu, Jin-Cai

2015-01-01

Two new triterpenoid saponins were isolated from the 70% ethanol extract of the rhizome of Anemone amurensis, they are oleanolic acid 28-O-β-d-glucopyranosyl-(1 → 3)-α-l-rhamnopyranosyl-(1 → 4)-β-d-glucopyranosyl-(1 → 6)-β-d-glucopyranosyl ester (1) and 23,27-dihydroxy oleanolic acid 3-O-α-l-arabinopyranoside (2). The structures of 1 and 2 were elucidated on the basis of chemical and spectral analysis, including 1D and 2D NMR data and HR-ESI-MS. Compounds 1 and 2 were tested for cytotoxicities against three human cancer cell lines (A549, Hep-G2, and MCF-7). Compound 1 showed potent cytotoxicity with IC50 values of 34.76, 41.17, and 28.92 μM, respectively, while compound 2 with IC50>100 μM.

Ursolic acid improves domoic acid-induced cognitive deficits in mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wu, Dong-mei; Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Xuzhou Normal University, Xuzhou 221116, Jiangsu Province; Lu, Jun, E-mail: lu-jun75@163.com

Our previous findings suggest that mitochondrial dysfunction is the mechanism underlying cognitive deficits induced by domoic acid (DA). Ursolic acid (UA), a natural triterpenoid compound, possesses many important biological functions. Evidence shows that UA can activate PI3K/Akt signaling and suppress Forkhead box protein O1 (FoxO1) activity. FoxO1 is an important regulator of mitochondrial function. Here we investigate whether FoxO1 is involved in the oxidative stress-induced mitochondrial dysfunction in DA-treated mice and whether UA inhibits DA-induced mitochondrial dysfunction and cognitive deficits through regulating the PI3K/Akt and FoxO1 signaling pathways. Our results showed that FoxO1 knockdown reversed the mitochondrial abnormalities and cognitivemore » deficits induced by DA in mice through decreasing HO-1 expression. Mechanistically, FoxO1 activation was associated with oxidative stress-induced JNK activation and decrease of Akt phosphorylation. Moreover, UA attenuated the mitochondrial dysfunction and cognitive deficits through promoting Akt phosphorylation and FoxO1 nuclear exclusion in the hippocampus of DA-treated mice. LY294002, an inhibitor of PI3K/Akt signaling, significantly decreased Akt phosphorylation in the hippocampus of DA/UA mice, which weakened UA actions. These results suggest that UA could be recommended as a possible candidate for the prevention and therapy of cognitive deficits in excitotoxic brain disorders. - Highlights: • Ursolic acid (UA) is a naturally triterpenoid compound. • UA attenuated the mitochondrial dysfunction and cognitive deficits. • Mechanistically, UA activates PI3K/Akt signaling and suppresses FoxO1 activity. • UA could be recommended as a possible candidate for anti-excitotoxic brain disorders.« less

Allspice and Clove As Source of Triterpene Acids Activating the G Protein-Coupled Bile Acid Receptor TGR5

PubMed Central

Ladurner, Angela; Zehl, Martin; Grienke, Ulrike; Hofstadler, Christoph; Faur, Nadina; Pereira, Fátima C.; Berry, David; Dirsch, Verena M.; Rollinger, Judith M.

2017-01-01

Worldwide, metabolic diseases such as obesity and type 2 diabetes have reached epidemic proportions. A major regulator of metabolic processes that gained interest in recent years is the bile acid receptor TGR5 (Takeda G protein-coupled receptor 5). This G protein-coupled membrane receptor can be found predominantly in the intestine, where it is mainly responsible for the secretion of the incretins glucagon-like peptide 1 (GLP-1) and peptide YY (PYY). The aim of this study was (i) to identify plant extracts with TGR5-activating potential, (ii) to narrow down their activity to the responsible constituents, and (iii) to assess whether the intestinal microbiota produces transformed metabolites with a different activity profile. Chenodeoxycholic acid (CDCA) served as positive control for both, the applied cell-based luciferase reporter gene assay for TGR5 activity and the biotransformation assay using mouse fecal slurry. The suitability of the workflow was demonstrated by the biotransformation of CDCA to lithocholic acid resulting in a distinct increase in TGR5 activity. Based on a traditional Tibetan formula, 19 plant extracts were selected and investigated for TGR5 activation. Extracts from the commonly used spices Syzygium aromaticum (SaroE, clove), Pimenta dioica (PdioE, allspice), and Kaempferia galanga (KgalE, aromatic ginger) significantly increased TGR5 activity. After biotransformation, only KgalE showed significant differences in its metabolite profile, which, however, did not alter its TGR5 activity compared to non-transformed KgalE. UHPLC-HRMS (high-resolution mass spectrometry) analysis revealed triterpene acids (TTAs) as the main constituents of the extracts SaroE and PdioE. Identification and quantification of TTAs in these two extracts as well as comparison of their TGR5 activity with reconstituted TTA mixtures allowed the attribution of the TGR5 activity to TTAs. EC50s were determined for the main TTAs, i.e., oleanolic acid (2.2 ± 1.6 μM), ursolic acid (1.1 ± 0.2 μM), as well as for the hitherto unknown TGR5 activators corosolic acid (0.5 ± 1.0 μM) and maslinic acid (3.7 ± 0.7 μM). In conclusion, extracts of clove, allspice, and aromatic ginger activate TGR5, which might play a pivotal role in their therapeutic use for the treatment of metabolic diseases. Moreover, the TGR5 activation of SaroE and PdioE could be pinpointed solely to TTAs. PMID:28769799

[Studies on chemical constitutents in roots of Jasminum sambac].

PubMed

Zhang, Zheng-fu; Bian, Bao-lin; Yang, Jian; Tian, Xiu-feng

2004-03-01

To isolate and identify the chemical constitutents in roots of Jasminum sambac. The compounds were isolated by means of chromatography and the structures were identified on the basis of physical and spectral data. Dotriacontanoic acid, dotriacontanol, oleanolic acid, daucosterol and hesperidin were elucidated. All compounds were found in this plant for the first time.

Ursolic acid attenuates oxidative stress-mediated hepatocellular carcinoma induction by diethylnitrosamine in male Wistar rats.

PubMed

Gayathri, Renganathan; Priya, D Kalpana Deepa; Gunassekaran, G R; Sakthisekaran, Dhanapal

2009-01-01

Hepatocellular carcinoma is the most common primary cancer of the liver in Asian countries. For more than a decade natural dietary agents including fruits, vegetables and spices have drawn a great deal of attention in the prevention of diseases, preferably cancer. Ursolic acid is a natural triterpenoid widely found in food, medicinal herbs, apple peel and other products it has been extensively studied for its anticancer and antioxidant properties. The purpose of this study was to evaluate the effect of ursolic acid in diethylnitrosamine (DEN) induced and phenobarbital promoted hepatocarcinogenesis in male Wistar rats. Antioxidant status was assessed by alterations in level of lipid peroxides and protein carbonyls. Damage to plasma membranes was assessed by levels of membrane and tissue ATPases. Liver tissue was homogenized and utilized for estimation of lipid peroxides, protein carbonyls and glycoproteins. Anticoagulated blood was utilized for erythrocyte membrane isolation. Oral administration of UA 20 mg/kg bodyweight for 6 weeks decreased the levels of lipid peroxides and protein carbonyls at a significance of p< 0.05. Activities of membrane and tissue ATPases returned to normal after UA administration. Levels of glycoproteins were also restored after treatment. Histopathological observations were recorded. The findings from the above study suggest the effectiveness of UA in reducing the oxidative stress mediated changes in liver of rats. Since UA has been found to be a potent antioxidant, it can be suggested as an excellent chemopreventive agent in overcoming diseases like cancer which are mediated by free radicals.

Killing of Serratia marcescens biofilms with chloramphenicol.

PubMed

Ray, Christopher; Shenoy, Anukul T; Orihuela, Carlos J; González-Juarbe, Norberto

2017-03-29

Serratia marcescens is a Gram-negative bacterium with proven resistance to multiple antibiotics and causative of catheter-associated infections. Bacterial colonization of catheters mainly involves the formation of biofilm. The objectives of this study were to explore the susceptibility of S. marcescens biofilms to high doses of common antibiotics and non-antimicrobial agents. Biofilms formed by a clinical isolate of S. marcescens were treated with ceftriaxone, kanamycin, gentamicin, and chloramphenicol at doses corresponding to 10, 100 and 1000 times their planktonic minimum inhibitory concentration. In addition, biofilms were also treated with chemical compounds such as polysorbate-80 and ursolic acid. S. marcescens demonstrated susceptibility to ceftriaxone, kanamycin, gentamicin, and chloramphenicol in its planktonic form, however, only chloramphenicol reduced both biofilm biomass and biofilm viability. Polysorbate-80 and ursolic acid had minimal to no effect on either planktonic and biofilm grown S. marcescens. Our results suggest that supratherapeutic doses of chloramphenicol can be used effectively against established S. marcescens biofilms.

Ursolic acid facilitates apoptosis in rheumatoid arthritis synovial fibroblasts by inducing SP1-mediated Noxa expression and proteasomal degradation of Mcl-1.

PubMed

Kim, Eugene Y; Sudini, Kuladeep; Singh, Anil K; Haque, Mahamudul; Leaman, Douglas; Khuder, Sadik; Ahmed, Salahuddin

2018-05-25

Rheumatoid arthritis (RA) is characterized by hyperplastic pannus formation mediated by activated synovial fibroblasts (RASFs) that cause joint destruction. We have shown earlier that RASFs exhibit resistance to apoptosis, primarily as a result of enhanced expression of myeloid cell leukemia-1 (Mcl-1). In this study, we discovered that ursolic acid (UA), a plant-derived pentacyclic triterpenoid, selectively induces B-cell lymphoma 2 homology 3-only protein Noxa in human RASFs. We observed that UA-induced Noxa expression was followed by a consequent decrease in Mcl-1 expression in a dose-dependent manner. Subsequent evaluation of the signaling pathways showed that UA-induced Noxa is primarily mediated by the JNK pathway in human RASFs. Chromatin immunoprecipitation (IP) studies into the promoter region of Noxa indicated the role of transcription factor specificity protein 1 in JNK-mediated Noxa expression. Furthermore, the results from IP studies and proximity ligation assays indicated that UA-induced Noxa colocalizes and associates with Mcl-1 to prime it for proteasomal degradation through K 48 -linked ubiquitination by the selective recruitment of Mcl-1 ubiquitin ligase E3, a homologous to E6-associated protein C terminus domain-containing E3 ubiquitin ligase. These findings unveil a novel mechanism of inducing apoptosis in RASFs and a potential adjunct therapeutic strategy of regulating synovial hyperplasia in RA.-Kim, E. Y., Sudini, K., Singh, A. K., Haque, M., Leaman, D., Khuder, S., Ahmed, S. Ursolic acid facilitates apoptosis in rheumatoid arthritis synovial fibroblasts by inducing SP1-mediated Noxa expression and proteasomal degradation of Mcl-1.

Purity-activity relationships of natural products: the case of anti-TB active ursolic acid.

PubMed

Jaki, Birgit U; Franzblau, Scott G; Chadwick, Lucas R; Lankin, David C; Zhang, Fangqiu; Wang, Yuehong; Pauli, Guido F

2008-10-01

The present study explores the variability of biological responses from the perspective of sample purity and introduces the concept of purity-activity relationships (PARs) in natural product research. The abundant plant triterpene ursolic acid (1) was selected as an exemplary natural product due to the overwhelming number yet inconsistent nature of its approximate 120 reported biological activities, which include anti-TB potential. Nine different samples of ursolic acid with purity certifications were obtained, and their purity was independently assessed by means of quantitative 1H NMR (qHNMR). Biological evaluation consisted of determining MICs against two strains of virulent Mycobacterium tuberculosis and IC50 values in Vero cells. Ab initio structure elucidation provided unequivocal structural confirmation and included an extensive 1H NMR spin system analysis, determination of nearly all J couplings and the complete NOE pattern, and led to the revision of earlier reports. As a net result, a sigmoid PAR profile of 1 was obtained, demonstrating the inverse correlation of purity and anti-TB bioactivity. The results imply that synergistic effects of 1 and its varying impurities are the likely cause of previously reported antimycobacterial potential. Generating PARs is a powerful extension of the routinely performed quantitative correlation of structure and activity ([Q]SAR). Advanced by the use of primary analytical methods such as qHNMR, PARs enable the elucidation of cases like 1 when increasing purity voids biological activity. This underlines the potential of PARs as a tool in drug discovery and synergy research and accentuates the need to routinely combine biological testing with purity assessment.

Phytochemical investigations and antioxidant potential of roots of Leea macrophylla (Roxb.).

PubMed

Mahmud, Zobaer Al; Bachar, Sitesh C; Hasan, Choudhury Mahmood; Emran, Talha Bin; Qais, Nazmul; Uddin, Mir Muhammad Nasir

2017-07-06

Oleanolic acid (NZ-15), 7 α, 28-olean diol (NZ-38) and Stigmasterol (NZ-14) were isolated from the ethanolic extracts of the roots of Leea macrophylla (Family: Leeaceae) by using chromatographic analysis. This is the first report of isolation of these compounds from this plant. Their structures were constructed by spectroscopic analysis and by comparing the data with the published one. Subsequently the ethanolic extract was fractionated with two organic solvents and all the fractions were studied to evaluate their in vitro antioxidant property. The ethanolic extract was fractionated with two organic solvents and all the fractions were studied to evaluate their in vitro antioxidant property by DPPH free radical scavenging assay, superoxide anion radical scavenging assay, nitric oxide radical scavenging assay, and reducing power assay. In the DPPH free radical scavenging assay and superoxide radical scavenging assay, the ethyl acetate soluble fraction of ethanolic extract revealed the highest free radical scavenging activity with IC 50 value of 2.65 and 155.62 μg/ml, respectively as compared to standard ascorbic acid (IC 50 value of 5.8 and 99.66 μg/ml). Ethyl acetate fraction also possessed highest reducing power activity with an EC50 value of 15.27 μg/ml compared to ascorbic acid (EC 50 0.91 μg/ml). On the other hand, the carbon tetrachloride fraction exhibited most significant NO scavenging activity with IC 50 value of 277.8 μg/ml that was even higher than that of standard ascorbic acid (IC 50 value 356.04 μg/ml). In addition, the total phenolic contents of these extract and fractions were evaluated using Folin-Ciocalteu reagent and varied from 7.93 to 50.21 mg/g dry weight expressed as gallic acid equivalents (GAE). This study showed that different extracts of roots of L. macrophylla possess potential DPPH, superoxide, and NO free radical scavenging activities. The antioxidant activities of the plant extracts might be due to the presence of oleanolic acid, oleanolic acid derivative 7 α, 28-olean diol and stigmasterol.

In vitro propagation and analysis of secondary metabolites in Glossogyne tenuifolia (Hsiang-Ju) - a medicinal plant native to Taiwan.

PubMed

Chen, Chia-Chen; Chang, Hung-Chi; Kuo, Chao-Lin; Agrawal, Dinesh Chandra; Wu, Chi-Rei; Tsay, Hsin-Sheng

2014-12-01

Glossogyne tenuifolia Cassini (Hsiang-Ju in Chinese) is a perennial herb native to Penghu Islands, Taiwan. The herb is a traditional anti-pyretic and hepatoprotective used in Chinese medicine. Several studies on G. tenuifolia have demonstrated its pharmacological values of antioxidation, anti-inflammation, immunomodulation, and cytotoxicity on several human cancer cell lines. Active compounds, oleanolic acid and luteolin in G. tenuifolia are affected by several factors, including climatic change, pathogens and agricultural practices. Plant population of G. tenuifolia has been severely affected and reduced considerably in natural habitat due to the use of herbicides by farmers. Also, collection of plant material from the natural habitat is restricted to a few months in a year. Therefore, the objective of the present study was to develop an efficient micropropagation protocol for G. tenuifolia. The study also aimed to investigate the influence of in vitro growth environment on the active compounds in in vitro shoots, tissue culture raised greenhouse plants; compare the values with wild plants and commercially available crude drug. Half-strength MS (Murashige and Skoog) basal medium supplemented with 0.1 mg/L 6-benzyladenine (BA) and 0.1 mg/L α-naphthaleneacetic acid (NAA) induced the maximum average number of shoots (7.3) per shoot tip explant excised from in vitro grown seedlings. Induction of rooting in cent percent in vitro shoots with an average number of 6.6 roots/shoot was achieved on ½ strength MS medium supplemented with 3.0 mg/L indole-3-acetic acid (IAA). The rooted plantlets acclimatized successfully in the greenhouse with a 100% survival rate. HPLC analysis revealed that the quantity of oleanolic acid and luteolin in in vitro shoots, tissue culture plants in the greenhouse, wild type plants and commercial crude drug varied depending upon the source. The oleanolic acid and luteolin contents were found to be significantly higher (16.89 mg/g and 0.84 mg/g, respectively) in 3-month old tissue culture raised plants in greenhouse compared to commercially available crude drug (6.51 mg/g, 0.13 mg/g, respectively). We have successfully developed an in vitro propagation protocol for G. tenuifolia which can expedite its plant production throughout the year. The contents of oleanolic acid and luteolin in the tissue culture raised plants in the greenhouse were significantly higher than the marketed crude drug demonstrating the practical application of the tissue culture technology. These findings may be very useful in micropropagation, germplasm conservation and commercial cultivation of G. tenuifolia. So far, there is no published report on tissue culture propagation of this important medicinal plant species.

Oleanolic acid activates daf-16 to increase lifespan in Caenorhabditis elegans

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, Jiaolong; Lu, Lulu; Zhou, Lijun, E-mail: lijunzhou@tju.edu.cn

Oleanolic acid (OA) is an active ingredient in natural plants. It has been reported to possess a variety of pharmacological activities, but very little is known about its effects of anti-aging. We investigate here whether OA has an impact on longevity in vivo, and more specifically, we have examined effects of OA on the lifespan and stress tolerance in Caenorhabditis elegans (C. elegans). Our results showed that OA could extend the lifespan, increase its stress resistance and reduce the intracellular reactive oxygen species (ROS) in wild-type worms. Moreover, we have found that OA-induced longevity may not be associated with the calorie restrictionmore » (CR) mechanism. Our mechanistic studies using daf-16 loss-of-function mutant strains (GR1307) indicated that the extension of lifespan by OA requires daf-16. In addition, OA treatment could also modulate the nuclear localization, and the quantitative real-time PCR results revealed that up-regulation of daf-16 target genes such as sod-3, hsp-16.2 and ctl-1 could prolong lifespan and increase stress response in C. elegans. This study overall uncovers the longevity effect of OA and its underpinning mechanisms. - Graphical abstract: Oleanolic acid modulates the activity of DAF-16 to promote longevity and increase stress resistance in Caenorhabditis elegans. - Highlights: • OA extends the lifespan of wild-type Caenorhabditis elegans. • OA improves the stress resistance and reduces the intracellular ROS level in C. elegans. • OA induces lifespan extension may not proceed through the CR mechanism. • OA extends the lifespan in C. elegans is modulated by daf-16.« less

[Accumulation dynamic of triterpenoid saponins in Akebia trifoliata stem].

PubMed

Zhang, Zheng; Feng, Hang; Wang, Zhe-Zhi

2014-07-01

In order to understand the accumulation dynamic of triterpenoid saponins in Akebia trifoliata stem to determine the suitable harvesting time and the growth age of stem. The contents of effective components, oleanolic acid and hederagenin in Akebia trifoliata stems, collected at the same growth condition of different growth ages and different harvesting time, were compared by high performance liquid chromatography (HPLC). The accumulation period of oleanolic acid was from the first year to the sixth year, the content rose quickly in the seventh year, and reached the greatest at the ninth year, then declined quickly, the contents in stem of more than 10 years had no significant difference compared with that of 1 - 6 years. The content of herderagenin had no great change by the age of stem. Comprehensive consideration,the triterpenoid saponins contents of the eight to nine years old Akebia trifoliata stems were higher. The most appropriate harvesting time for Akebia trifoliata was from later August to later September in the eighth years.

Flavonoids and terpenoids from Luma gayana (Barn.) Burret.

PubMed

Wächter, G A; Wangmaneerat, A; Caple, K M; Montenegro, G; Timmermann, B N

1999-12-01

The flavonoids 5-hydroxy-7-methoxyflavanone, 6,8-dimethyl-5,7-dihydroxyflavanone and 2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone, a mixture of alkyl esters of p-coumaric acid, the triterpenoids oleanolic acid and maslinic acid, the monoterpenoid 1 alpha,2 beta,4 beta-trihydroxy-p-menthane, the sesquiterpenoid clovandiol and beta-sitosterol were isolated from the aerial parts of Luma gayana (Barn.) Burret. This is the first report on the chemistry of this species.

Towards an efficient protocol for the determination of triterpenic acids in olive fruit: a comparative study of drying and extraction methods.

PubMed

Goulas, Vlasios; Manganaris, George A

2012-01-01

Triterpenic acids, such as maslinic acid and oleanolic acid, are commonly found in olive fruits and have been associated with many health benefits. The drying and extraction methods, as well as the solvents used, are critical factors in the determination of their concentration in plant tissues. Thus, there is an emerging need for standardisation of an efficient extraction protocol that determines triterpenic acid content in olive fruits. To evaluate common extraction methods of triterpenic acids from olive fruits and to determine the effect of the drying method on their content in order to propose an optimum protocol for their quantification. The efficacy of different drying and extraction methods was evaluated through the quantification of maslinic acid and oleanolic acid contents using the reversed-phase HPLC technique. Data showed that ultrasonic assisted extraction with ethanol or a mixture of ethanol:methanol (1:1, v/v) resulted in the recovery of significantly higher amounts of triterpenic acids than other methods used. The drying method also affected the estimated triterpenic acid content; frozen or lyophilised olive fruit material gave higher yields of triterpenic acids compared with air-dried material at both 35°C and 105°C. This study provides a rapid and low-cost extraction method, i.e. ultrasonic assisted extraction with an eco-friendly solvent such as ethanol, from frozen or lyophilised olive fruit for the accurate determination of the triterpenic acid content in olive fruit. Copyright © 2011 John Wiley & Sons, Ltd.

Radioprotective effect of ursolic acid in radiation-induced impairment of neurogenesis, learning and memory in adolescent BALB/c mouse.

PubMed

Tang, Feng Ru; Loke, Weng Keong; Wong, Peiyan; Khoo, Boo Cheong

2017-06-01

The effect of acute irradiation with 5Gy or fractionated exposure with 0.5Gy continuously for 10days (a total dose of 5Gy) was evaluated in an immature BALB/c mouse model. Radioprotective effect of ursolic acid (at 25mg/kg/daily administered 1h after acute or each of fractionated irradiations, and continuously for 30days) was also investigated. We found that both acute and fractionated irradiation at a total dose of 5Gy did not induce any mortality within 30days after exposure to postnatal day 26 (P26) BALB/c mice, but reduced animal weigh gain in the first few weeks. At 90days after irradiation, the weight of animals with acute irradiation was still significantly lower than the control group; no significant difference though was observed for those fractionatedly exposed mice compared to the control group. Behavioral tests indicated that acute irradiation at 5Gy induced deficits in learning and memory in the contextual fear conditioning test. The memory for novel object recognition was also impaired. Similar changes were not observed in mice with fractionated irradiation. Immunohistochemical study demonstrated clearly that acute and fractionated irradiations induced impairment of neurogenesis in the subgranular zone (SGZ) of the dentate gyrus although fractionated exposure induced much lesser loss of newly generated neurons. Ursolic acid administered at 25mg/kg/daily for 30days after irradiation greatly improved acute irradiation-induced deficits in contextual learning and memory and in novel object recognition memory although it exacerbated radiation-induced reduction of neurogenesis in SGZ. Copyright © 2017. Published by Elsevier Inc.

Evaluation of Antitumor Activity of Long-Circulating and pH-Sensitive Liposomes Containing Ursolic Acid in Animal Models of Breast Tumor and Gliosarcoma.

PubMed

Rocha, Talita Guieiro Ribeiro; Lopes, Sávia Caldeira de Araújo; Cassali, Geovani Dantas; Ferreira, Ênio; Veloso, Emerson Soares; Leite, Elaine Amaral; Braga, Fernão Castro; Ferreira, Lucas Antônio Miranda; Balvay, Daniel; Garofalakis, Anikitos; Oliveira, Mônica Cristina; Tavitian, Bertrand

2016-12-01

Background Ursolic acid (UA) is a triterpene found in different plant species, possessing antitumor activity, which may be a result of its antiangiogenic effect. However, UA has low water solubility, which limits its use because the bioavailability is impaired. To overcome this inconvenience, we developed long-circulating and pH-sensitive liposomes containing ursolic acid (SpHL-UA). We investigated the antiangiogenic effect of free UA and SpHL-UA in murine brain cancer and human breast tumor models by means of determination of the relative tumor volume, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), and histopathological analysis. Methods The animals were treated with dimethyl sulfoxide in 0.9% (w/v) NaCl, free UA, long-circulating and pH-sensitive liposomes without drug (SpHL), or SpHL-UA. The animals were submitted to each treatment by intraperitoneal injection for 5 days. The dose of free UA or SpHL-UA was equal to 23 mg/kg. Results Tumor growth inhibition was not observed in human breast tumor-bearing animals. For murine gliosarcoma-bearing animals, a slight tumor growth inhibition was observed in the groups treated with free UA or SpHL-UA (9% and 15%, respectively). No significant change in any of the parameters evaluated by DCE-MRI for both experimental models could be observed. Nevertheless, the evaluation of the mean values of magnetic resonance parameters of human breast tumor-bearing animals showed evidence of a possible antiangiogenic effect induced by SpHL-UA. Histopathological analysis did not present significant change for any treatment. Conclusion SpHL-UA did not show antiangiogenic activity in a gliosarcoma model and seemed to induce an antiangiogenic effect in the human breast tumor model. © The Author(s) 2016.

Effects of cranberry extracts and ursolic acid derivatives on P-fimbriated Escherichia coli, COX-2 activity, pro-inflammatory cytokine release and the NF-κβ transcriptional response in vitro

PubMed Central

Huang, Yue; Nikolic, Dejan; Pendland, Susan; Doyle, Brian J.; Locklear, Tracie D.; Mahady, Gail B.

2010-01-01

Cranberry, the fresh or dried ripe fruit of Vaccinium macrocarpon Ait. (Ericaceae), is currently used as adjunct therapy for the prevention and symptomatic treatment of urinary tract infections. Data from clinical trials suggest that extracts of cranberry or cranberry juice reduce the bacterial load of E. coli and also suppress the inflammatory symptoms induced by E. coli infections. A methanol extract prepared from 10 kg of dehydrated cranberries did not directly inhibit the growth of E coli strains ATCC 700336 or ATCC 25922 in concentrations up to 256 μg/mL in vitro. However, the methanol extract (CR-ME) inhibited the activity of cyclooxygenase-2, with an IC50 of 12.8 μg/mL. Moreover, CR-ME also inhibited the NF-κβ transcriptional activation in human T lymphocytes with an IC50 of 19.4 μg/mL, and significantly (p < 0.01) inhibited the release of interleukin (IL)-1β, IL-6, IL-8 and tumor necrosis factor-α from E. coli lipopolysaccharide (LPS)-stimulated human peripheral blood mononuclear cells in vitro, at a concentration of 50 μg/mL. The extract had no effect on inducible nitric oxide synthase activity in the murine macrophage cell line RAW 264.7. The compounds responsible for this activity were identified using a novel LC-MS based assay as ursolic acid and ursolic acid derivatives. Taken together, these data suggest CR-ME and its constituent chemical compounds target specific pathways involved in E. coli-induced inflammation. PMID:20376297

Evaluation of Antitumor Activity of Long-Circulating and pH-Sensitive Liposomes Containing Ursolic Acid in Animal Models of Breast Tumor and Gliosarcoma

PubMed Central

Rocha, Talita Guieiro Ribeiro; Lopes, Sávia Caldeira de Araújo; Cassali, Geovani Dantas; Ferreira, Ênio; Veloso, Emerson Soares; Leite, Elaine Amaral; Braga, Fernão Castro; Ferreira, Lucas Antônio Miranda; Balvay, Daniel; Garofalakis, Anikitos; Oliveira, Mônica Cristina; Tavitian, Bertrand

2016-01-01

Background. Ursolic acid (UA) is a triterpene found in different plant species, possessing antitumor activity, which may be a result of its antiangiogenic effect. However, UA has low water solubility, which limits its use because the bioavailability is impaired. To overcome this inconvenience, we developed long-circulating and pH-sensitive liposomes containing ursolic acid (SpHL-UA). We investigated the antiangiogenic effect of free UA and SpHL-UA in murine brain cancer and human breast tumor models by means of determination of the relative tumor volume, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), and histopathological analysis. Methods. The animals were treated with dimethyl sulfoxide in 0.9% (w/v) NaCl, free UA, long-circulating and pH-sensitive liposomes without drug (SpHL), or SpHL-UA. The animals were submitted to each treatment by intraperitoneal injection for 5 days. The dose of free UA or SpHL-UA was equal to 23 mg/kg. Results. Tumor growth inhibition was not observed in human breast tumor–bearing animals. For murine gliosarcoma-bearing animals, a slight tumor growth inhibition was observed in the groups treated with free UA or SpHL-UA (9% and 15%, respectively). No significant change in any of the parameters evaluated by DCE-MRI for both experimental models could be observed. Nevertheless, the evaluation of the mean values of magnetic resonance parameters of human breast tumor–bearing animals showed evidence of a possible antiangiogenic effect induced by SpHL-UA. Histopathological analysis did not present significant change for any treatment. Conclusion. SpHL-UA did not show antiangiogenic activity in a gliosarcoma model and seemed to induce an antiangiogenic effect in the human breast tumor model. PMID:27130721

Antimycobacterial activity of methanolic plant extract of Artemisia capillaris containing ursolic acid and hydroquinone against Mycobacterium tuberculosis.

PubMed

Jyoti, Md Anirban; Nam, Kung-Woo; Jang, Woong Sik; Kim, Young-Hee; Kim, Su-Kyung; Lee, Byung-Eui; Song, Ho-Yeon

2016-04-01

In order to protect against Mycobacterium tuberculosis (MTB) infection, novel drugs and new targets should be screened from the vast source of plants. We investigated the potentiality of the herbal plant of Artemisia capillaris extract (AC) against Mycobacterium tuberculosis. In this study, we isolated ursolic acid and hydroquinone by bio-activity guided fractionation from the methanol extracts of AC, and tested the inhibitory effects against several strains of MTB. Anti-mycobacterial evaluation of these compounds was carried out using the MGIT™ 960 and resazurin assay. Mycobacterial morphological changes due to the treatment of these compounds were further evaluated by Transmission electron microscopy (TEM). Ursolic acid (UA) and hydroquinone (HQ) inhibited the growth of both susceptible and resistant strains of M. tuberculosis. The MIC (minimum inhibitory concentration) values of both UA and HQ were 12.5 μg/ml against the susceptible strains of M. tuberculosis. Also both UA and HQ showed 12.5-25 μg/ml of MIC values against MDR/XDR MTB strains. However, against clinical strains of MTB, UA was found sensitive against those strains that are sensitive against both INH and RFP but resistant against those strains that are resistant to INH. On the other hand HQ was sensitive against all clinical strains. TEM image-analysis of the strain H37Ra after treatment with UA revealed cell wall lysis, whereas HQ-treated cells showed deformed cytoplasmic morphology. All these results indicate that AC extracts containing UA and HQ possess promising chemotherapeutic potency against MTB for future use. Copyright © 2015 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Effects of curcumin and ursolic acid on the mitochondrial coupling efficiency and hydrogen peroxide emission of intact skeletal myoblasts.

PubMed

Tueller, Daniel J; Harley, Jackson S; Hancock, Chad R

2017-10-21

Curcumin may improve blood glucose management, but the mechanism is not fully established. We demonstrated that curcumin (40 μM) reduced the mitochondrial coupling efficiency (percentage of oxygen consumption coupled to ATP synthesis) of intact skeletal muscle cells. A 30-minute pretreatment with curcumin reduced mitochondrial coupling efficiency by 17.0 ± 0.4% relative to vehicle (p < 0.008). Curcumin pretreatment also decreased the rate of hydrogen peroxide emission by 43 ± 13% compared to vehicle (p < 0.05). Analysis of cell respiration in the presence of curcumin revealed a 40 ± 4% increase in the rate of oxygen consumption upon curcumin administration (p < 0.05 compared to vehicle). No difference in mitochondrial coupling efficiency was observed between vehicle- and curcumin-pretreated cells after permeabilization of cell membranes (p > 0.7). The interaction between curcumin and ursolic acid, another natural compound that may improve blood glucose management, was also examined. Pretreatment with ursolic acid (0.12 μM) increased the mitochondrial coupling efficiency of intact cells by 4.1 ± 1.1% relative to vehicle (p < 0.008) and attenuated the effect of curcumin when the two compounds were used in combination. The observed changes to mitochondrial coupling efficiency and hydrogen peroxide emission were consistent with the established effects of curcumin on blood glucose control. Our findings also show that changes to mitochondrial coupling efficiency after curcumin pretreatment may go undetected unless cells are assessed in the intact condition. Copyright © 2017 Elsevier Inc. All rights reserved.

Anti-inflammatory effects of methyl ursolate obtained from a chemically derived crude extract of apple peels: potential use in rheumatoid arthritis.

PubMed

Pádua, Tatiana A; de Abreu, Bianca S S C; Costa, Thadeu E M M; Nakamura, Marcos J; Valente, Lígia M M; Henriques, Maria das Graças; Siani, Antonio C; Rosas, Elaine C

2014-11-01

Ursolic acid (UA), a pentacyclic triterpene acid found in apple peels (Malus domestica, Borkh, Rosaceae), has a large spectrum of pharmacological effects. However, the vegetal matrix usually produces highly viscous and poorly soluble extracts that hamper the isolation of this compound. To overcome this problem, the crude EtOH-AcOEt extract of commercial apple peels was exhaustively treated with diazomethane, after which methyl ursolate (MU) was purified by column chromatography and characterized spectrometrically. The anti-inflammatory effects of UA and MU (50 mg/kg) were analyzed by zymosan-induced paw edema, pleurisy and in an experimental arthritis model. After 4 h of treatment with UA and MU, paw edema was reduced by 46 and 44 %, respectively. Both UA and MU inhibited protein extravasation into the thoracic cavity; tibio-femoral edema by 40 and 48 %, respectively; and leukocyte influx into the synovial cavity after 6 h by 52 and 73 %, respectively. Additionally, both UA and MU decreased the levels of mediators related to synovial inflammation, such as KC/CXCL-1 levels by 95 and 90 %, TNF-α levels by 76 and 71 %, and IL-1β levels by 57 and 53 %, respectively. Both the compounds were equally effective when assayed in different inflammatory models, including experimental arthritis. Hence, MU may be considered to be a useful anti-inflammatory derivative to overcome the inherent poor solubility of UA for formulating pharmaceutical products.

Ursolic Acid and Chronic Disease: An Overview of UA's Effects On Prevention and Treatment of Obesity and Cancer.

PubMed

Mancha-Ramirez, Anna M; Slaga, Thomas J

Chronic diseases pose a worldwide problem and are only continuing to increase in incidence. Two major factors contributing to the increased incidence in chronic disease are a lack of physical activity and poor diet. As the link between diet and lifestyle and the increased incidence of chronic disease has been well established in the literature, novel preventive, and therapeutic methods should be aimed at naturally derived compounds such as ursolic acid (UA), the focus of this chapter. As chronic diseases, obesity and cancer share the common thread of inflammation and dysregulation of many related pathways, the focus here will be on these two chronic diseases. Significant evidence in the literature supports an important role for natural compounds such as UA in the prevention and treatment of chronic diseases like obesity and cancer, and here we have highlighted many of the ways UA has been shown to be a beneficial and versatile phytochemical.

Ursolic acid ameliorates CCl4-induced liver fibrosis through the NOXs/ROS pathway.

PubMed

Gan, Dakai; Zhang, Wang; Huang, Chenkai; Chen, Jiang; He, Wenhua; Wang, Anjiang; Li, Bimin; Zhu, Xuan

2018-04-19

Liver fibrosis is a reversible wound-healing response that occurs after liver injury. NADPH oxidases (NOXs) and reactive oxygen species (ROS) which are expressed in hepatocytes (HCs), hepatic stellate cells (HSCs), and Kupffer cells (KCs) play an important role in the development of hepatic fibrosis. In in vitro studies, we had shown that ursolic acid (UA) could reverse liver fibrosis by inhibiting the activation of NOX-mediated fibrotic signaling networks in HSCs. In this study, we verified that UA could alleviate CCl4-induced liver fibrosis by reducing the expression of NOXs/ROS in HCs, HSCs, KCs. Meanwhile, the phagocytic index α and clearance index K which represent phagocytosis of KCs were unchanged. Together, all our data demonstrated that UA induced the proliferation of HCs, promoted apoptosis in HSCs, and prevented activation of KCs in vivo by reducing the expression of NOXs/ROS in HCs, HSCs, KCs. Besides, UA had no effect on the host defense function. © 2018 The Authors. Journal of Cellular Physiology Published by Wiley Periodicals, Inc.

Ursolic acid exerts anti-cancer activity by suppressing vaccinia-related kinase 1-mediated damage repair in lung cancer cells.

PubMed

Kim, Seong-Hoon; Ryu, Hye Guk; Lee, Juhyun; Shin, Joon; Harikishore, Amaravadhi; Jung, Hoe-Yune; Jung, Hoe-Youn; Kim, Ye Seul; Lyu, Ha-Na; Oh, Eunji; Baek, Nam-In; Choi, Kwan-Yong; Yoon, Ho Sup; Kim, Kyong-Tai

2015-09-28

Many mitotic kinases have been targeted for the development of anti-cancer drugs, and inhibitors of these kinases have been expected to perform well for cancer therapy. Efforts focused on selecting good targets and finding specific drugs to target are especially needed, largely due to the increased frequency of anti-cancer drugs used in the treatment of lung cancer. Vaccinia-related kinase 1 (VRK1) is a master regulator in lung adenocarcinoma and is considered a key molecule in the adaptive pathway, which mainly controls cell survival. We found that ursolic acid (UA) inhibits the catalytic activity of VRK1 via direct binding to the catalytic domain of VRK1. UA weakens surveillance mechanisms by blocking 53BP1 foci formation induced by VRK1 in lung cancer cells, and possesses synergistic anti-cancer effects with DNA damaging drugs. Taken together, UA can be a good anti-cancer agent for targeted therapy or combination therapy with DNA damaging drugs for lung cancer patients.

Ursolic acid in health and disease.

PubMed

Seo, Dae Yun; Lee, Sung Ryul; Heo, Jun-Won; No, Mi-Hyun; Rhee, Byoung Doo; Ko, Kyung Soo; Kwak, Hyo-Bum; Han, Jin

2018-05-01

Ursolic acid (UA) is a natural triterpene compound found in various fruits and vegetables. There is a growing interest in UA because of its beneficial effects, which include anti-inflammatory, anti-oxidant, anti-apoptotic, and anti-carcinogenic effects. It exerts these effects in various tissues and organs: by suppressing nuclear factor-kappa B signaling in cancer cells, improving insulin signaling in adipose tissues, reducing the expression of markers of cardiac damage in the heart, decreasing inflammation and increasing the level of anti-oxidants in the brain, reducing apoptotic signaling and the level of oxidants in the liver, and reducing atrophy and increasing the expression levels of adenosine monophosphate-activated protein kinase and irisin in skeletal muscles. Moreover, UA can be used as an alternative medicine for the treatment and prevention of cancer, obesity/diabetes, cardiovascular disease, brain disease, liver disease, and muscle wasting (sarcopenia). In this review, we have summarized recent data on the beneficial effects and possible uses of UA in health and disease managements.

Evolution in Medicinal Chemistry of Ursolic Acid Derivatives as Anticancer Agents

PubMed Central

Chen, Haijun; Gao, Yu; Wang, Ailan; Zhou, Xiaobin; Zheng, Yunquan; Zhou, Jia

2015-01-01

Currently, there is a renewed interest in common dietaries and plant-based traditional medicines for the prevention and treatment of cancer. In the search for potential anticancer agents from natural sources, ursolic acid (UA), a pentacyclic triterpenoid widely found in various medicinal herbs and fruits, exhibits powerful biological effects including its attractive anticancer activity against various types of cancer cells. However, the limited solubility, rapid metabolism and poor bioavailability of UA restricted its further clinical applications. In the past decade, with substantial progress toward the development of new chemical entities for the treatment of cancer, numerous UA derivatives have been designed and prepared to overcome its disadvantages. Despite extensive effort, discovery of effective UA derivatives has so far met with only limited success. This review summarizes the current status of the structural diversity and evolution in medicinal chemistry of UA analogues and provides a detailed discussion of future direction for further research in the chemical modifications of UA. PMID:25617694

Ursolic acid in health and disease

PubMed Central

Seo, Dae Yun; Lee, Sung Ryul; Heo, Jun-Won; No, Mi-Hyun; Rhee, Byoung Doo; Ko, Kyung Soo

2018-01-01

Ursolic acid (UA) is a natural triterpene compound found in various fruits and vegetables. There is a growing interest in UA because of its beneficial effects, which include anti-inflammatory, anti-oxidant, anti-apoptotic, and anti-carcinogenic effects. It exerts these effects in various tissues and organs: by suppressing nuclear factor-kappa B signaling in cancer cells, improving insulin signaling in adipose tissues, reducing the expression of markers of cardiac damage in the heart, decreasing inflammation and increasing the level of anti-oxidants in the brain, reducing apoptotic signaling and the level of oxidants in the liver, and reducing atrophy and increasing the expression levels of adenosine monophosphate-activated protein kinase and irisin in skeletal muscles. Moreover, UA can be used as an alternative medicine for the treatment and prevention of cancer, obesity/diabetes, cardiovascular disease, brain disease, liver disease, and muscle wasting (sarcopenia). In this review, we have summarized recent data on the beneficial effects and possible uses of UA in health and disease managements. PMID:29719446

Physicochemical properties and oral bioavailability of ursolic acid nanoparticles using supercritical anti-solvent (SAS) process.

PubMed

Yang, Lei; Sun, Zhen; Zu, Yuangang; Zhao, Chunjian; Sun, Xiaowei; Zhang, Zhonghua; Zhang, Lin

2012-05-01

The objective of the study was to prepare ursolic acid (UA) nanoparticles using the supercritical anti-solvent (SAS) process and evaluate its physicochemical properties and oral bioavailability. The effects of four process variables, pressure, temperature, drug concentration and drug solution flow rate, on drug particle formation during SAS process, were investigated. Particles with mean particle size ranging from 139.2±19.7 to 1039.8±65.2nm were obtained by varying the process parameters. The UA was characterised by scanning electron microscopy, X-ray diffraction, Fourier-transform infrared spectroscopy, thermal gravimetric analysis, specific surface area, dissolution test and bioavailability test. It was concluded that physicochemical properties and bioavailability of crystalline UA could be improved by physical modification, such as particle size reduction and generation of amorphous state using SAS process. Further, SAS process was a powerful methodology for improving the physicochemical properties and bioavailability of UA. Copyright © 2011 Elsevier Ltd. All rights reserved.

Structure-activity relationships of 3-O-β-chacotriosyl oleanane-type triterpenoids as potential H5N1 entry inhibitors.

PubMed

Song, Gaopeng; Shen, Xintian; Li, Sumei; Li, Yibin; Si, Hongzong; Fan, Jihong; Li, Junhua; Gao, Erqiang; Liu, Shuwen

2016-08-25

A series of 3-O-β-chacotriosyl oleanolic acid analogs have been designed, synthesized and evaluated as H5N1 entry inhibitors based on a small molecule inhibitor saponin 1 previously discovered by us. Detailed structure-activity relationships (SARs) studies on the aglycone of compound 1 indicated that the subtle modification of oleanolic acid as an aglycon has key influences on the antiviral activity. These results suggested that either the introduction of a disubstituted amide structure at the 17-COOH of OA or alteration of the C-3 configuration of OA from 3β-to 3α-forms can significantly improve the selective index while maintaining their antiviral activities in vitro. Compound 8 was selected for further mechanistic study because of its distinguished inhibition activity and good selective index. Molecular simulation study and surface plasmon resonance analysis confirmed that compound 8 stabilized HA2 subunit of hemagglutinin (HA) by binding with amino acid residues LYS-26, ASN-53, ASN-27 and ASN-50, therefore may prevent HA from conformational rearranging, which is a critical step for viral entry. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Pharmacokinetic study of calenduloside E and its active metabolite oleanolic acid in beagle dog using liquid chromatography-tandem mass spectrometry.

PubMed

Shi, Meiyun; Yang, Yan; Sun, Yantong; Cheng, Longmei; Zhao, Sen; Xu, Huibo; Fawcett, J Paul; Sun, Xiaobo; Gu, Jingkai

2014-03-01

Aralia mandshrica is a well-known traditional Chinese medicine from Northeast China commonly used to treat digestive, circulatory and immune system disorders. Calenduloside E is one of its bioactive components currently under evaluation as a pure drug. In this study, a highly sensitive and rapid method based on liquid chromatography-tandem mass spectrometry (LC-MS/MS) for the simultaneous quantitation of calenduloside E and its active metabolite oleanolic acid in beagle dog plasma has been developed and validated. Samples containing the ammonium salt of simvastatin acid as internal standard (IS) were purified by solid phase extraction and separated on a SUPELCO Ascentis-C18 column (50mm×4.6mm i.d., 5μm) using gradient elution with 0.35% formic acid and acetonitrile. Analytes and IS were detected in a cycle time of 5min after ionization in the negative ion mode by multiple reaction monitoring of the precursor-to-product ion transitions at m/z 631.4→455.4 and m/z 435.4→319.0 for calenduloside E and IS respectively and by single ion monitoring of the ion at m/z 455.4 for oleanolic acid. The method was linear over the concentration range 0.4-100ng/mL for both analytes using 0.5mL plasma. Inter- and intra-day precisions were both <6.96% with accuracies <6.40%. In the pharmacokinetic (PK) study, beagle dogs were given oral doses of calenduloside E (1.05, 2.10 and 4.20mg/kg) and an intravenous injection of 2.10mg/kg. The absolute bioavailability of calenduloside E was only 0.58%. Area under the plasma concentration time curve (AUC(0-t)) for the oral doses of calenduloside E was approximately dose proportional while other PK parameters (t1/2, Tmax and MRT) showed no significant differences among the three doses (P>0.05). The PK data provide a useful platform on which to base future clinical studies of calenduloside E. Copyright © 2014 Elsevier B.V. All rights reserved.

A Novel Ellagic Acid Derivative from Desbordesia glaucescens.

PubMed

DongmoMafodong, Faustine L; Tsopmo, Apollinaire; Awouafack, Maurice D; Roland, Tchuenguem T; Dzoyem, Jean P; Tane, Pierre

2015-10-01

One novel ellagic acid derivative, desglauside (1), was isolated from the leaves of Desbordesia glaucescens together with three known compounds [3',4'-di-O-methylellagic acid (2), oleanolic acid (3) and β-sitosterol-3-O-β-D-glucopyranoside (4)]. Their structures were elucidated on the basis of NMR spectroscopic and MS analysis, and by comparison with related published data. The crude extract, fractions and isolated compounds showed no activity against four yeast strains [Candida albicans (ATCC 9002), C. parapsilopsis (ATCC22019), C. tropicalis (ATCC750), Cryptococcus neoformans (IP95026) and one isolate of Candida guilliermondii].

In vitro anti-breast cancer activity of ethanolic extract of Wrightia tomentosa: role of pro-apoptotic effects of oleanolic acid and urosolic acid.

PubMed

Chakravarti, Bandana; Maurya, Ranjani; Siddiqui, Jawed Akhtar; Bid, Hemant Kumar; Rajendran, S M; Yadav, Prem P; Konwar, Rituraj

2012-06-26

Wrightia tomentosa Roem. & Schult. (Apocynaceae) is known in the traditional medicine for anti-cancer activity along with other broad indications like snake and scorpion bites, renal complications, menstrual disorders etc. However, the anti-cancer activity of this plant or its constituents has never been studied systematically in any cancer types so far. To evaluate the anti-cancer activities of the ethanolic extract of W. tomentosa and identified constituent active molecule(s) against breast cancer. Powdered leaves of W. tomentosa were extracted with ethanol. The ethanolic extract, subsequent hexane fractions and fraction F-4 of W. tomentosa were tested for its anti-proliferative and pro-apoptotic effects in breast cancer cells MCF-7 and MDA-MB-231. The ethanolic extract, subsequent hexane fractions and fraction F-4 of W. tomentosa inhibited the proliferation of human breast cancer cell lines, MCF-7 and MDA-MB-231. The fraction F-4 obtained from hexane fraction inhibited proliferation of MCF-7 and MDA-MB-231 cells in concentration and time dependent manner with IC₅₀ of 50 μg/ml and 30 μg/ml for 24 h, 28 μg/ml and 22 μg/ml for 48 h and 25 μg/ml and 20 μg/ml for 72 h respectively. The fraction F-4 induced G1 cell cycle arrest, reactive oxygen species (ROS) generation, loss of mitochondrial membrane potential and subsequent apoptosis. Apoptosis is indicated in terms of increased Bax/Bcl-2 ratio, enhanced Annexin-V positivity, caspase 8 activation and DNA fragmentation. The active molecule isolated from fraction F-4, oleanolic acid and urosolic acid inhibited cell proliferation of MCF-7 and MDA-MB-231 cells at IC₅₀ value of 7.5 μM and 7.0 μM respectively, whereas there is devoid of significant cell inhibiting activity in non-cancer originated cells, HEK-293. In both MCF-7 and MDA-MB-231, oleanolic acid and urosolic acid induced cell cycle arrest and apoptosis as indicated by significant increase in Annexin-V positive apoptotic cell counts. Our results suggest that W. tomentosa extracts has significant anti-cancer activity against breast cancer cells due to induction of apoptosis pathway. Olenolic and urosolic acid are important constituent molecules in the extract responsible for anti-cancer activity of W. tomentosa.

Anti-plasmodial activity of some Zulu medicinal plants and of some triterpenes isolated from them.

PubMed

Simelane, Mthokozisi B C; Shonhai, Addmore; Shode, Francis O; Smith, Peter; Singh, Mogie; Opoku, Andy R

2013-10-08

Mimusops caffra E. Mey. ex A.DC and Mimusops obtusifolia Lam (both members of the Sapotaceae family), and Hypoxis colchicifolia Bak (family Hypoxidaceae) are used by traditional healers in Zululand to manage malaria. Anti-plasmodial investigation of the crude extracts and some triterpenes isolated from the plants showed activity against a chloroquine sensitive (CQS) strain of Plasmodium falciparum (D10). Among the crude extracts the leaves of M. caffra exhibited the highest activity, with an IC₅₀ of 2.14 μg/mL. The pentacyclic tritepenoid ursolic acid (1), isolated from the leaves of M. caffra was the most active compound (IC₅₀ 6.8 μg/mL) as compared to taraxerol (2) and sawamilletin (3) isolated from the stem bark of M. obtusifolia (IC₅₀ > 100). Chemical modification of the ursolic acid (1) to 3β-acetylursolic acid (4) greatly enhanced its anti-plasmodial activity. Compound 4 reduced parasitaemia against Plasmodium berghei by 94.01% in in vivo studies in mice. The cytotoxicity of 3β-acetylursolic acid (IC₅₀) to two human cell lines (HEK293 and HepG2) was 366.00 μg/mL and 566.09 μg/mL, respectively. The results validate the use of these plants in folk medicine.

Novel Intriguing Strategies Attenuating to Sarcopenia

PubMed Central

Sakuma, Kunihiro; Yamaguchi, Akihiko

2012-01-01

Sarcopenia, the age-related loss of skeletal muscle mass, is characterized by a deterioration of muscle quantity and quality leading to a gradual slowing of movement, a decline in strength and power, increased risk of fall-related injury, and, often, frailty. Since sarcopenia is largely attributed to various molecular mediators affecting fiber size, mitochondrial homeostasis, and apoptosis, the mechanisms responsible for these deleterious changes present numerous therapeutic targets for drug discovery. Resistance training combined with amino acid-containing supplements is often utilized to prevent age-related muscle wasting and weakness. In this review, we summarize more recent therapeutic strategies (myostatin or proteasome inhibition, supplementation with eicosapentaenoic acid (EPA) or ursolic acid, etc.) for counteracting sarcopenia. Myostatin inhibitor is the most advanced research with a Phase I/II trial in muscular dystrophy but does not try the possibility for attenuating sarcopenia. EPA and ursolic acid seem to be effective as therapeutic agents, because they attenuate the degenerative symptoms of muscular dystrophy and cachexic muscle. The activation of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) in skeletal muscle by exercise and/or unknown supplementation would be an intriguing approach to attenuating sarcopenia. In contrast, muscle loss with age may not be influenced positively by treatment with a proteasome inhibitor or antioxidant. PMID:22500226

ON012380: A Non-ATP Competitive Inhibitor of BCR-ABL for the Therapy of Imatinib-Resistant CMLs

DTIC Science & Technology

2009-05-01

viability of peripheral mononuclear cells derived from three normal persons was not affected by either TGAY1 or by Ursolic acid compared to...compounds that are capable of inhibiting this particular (as well as other) amino acid substitution. A major goal of our team was to generate a potent...Fichiner I , Schumacher P, Fiebig HH, Unger C. In vitro and in vivo efficacy of acid -sensitive transferrin and albumin doxorubicin conjugates in a 18

Quantification of bioactive compounds in Picual and Arbequina olive leaves and fruit.

PubMed

Romero, Concepción; Medina, Eduardo; Mateo, Mª Antonia; Brenes, Manuel

2017-04-01

Olive leaves and fruit possess bioactive substances such as phenolic compounds and triterpenic acids that can be obtained from olive by-products generated during olive oil extraction. The aim of the present study was the characterization and quantification of these compounds in Picual and Arbequina cultivars from different locations and throughout two seasons in both olive leaves and fruit. The major phenolic compound identified in the leaves was oleuropein, and the total content of phenolic compounds in this material reached 70 g kg -1 fresh weight. The leaves were also rich in triterpenic acids (20 g kg -1 fresh weight), with oleanolic acid being the most concentrated among them. With regard to olives, oleuropein and demethyloleuropein were the main phenolic compounds in the pulp of Picual and Arbequina cultivars, and the total concentration of these phenolic compounds reached 3.5% fresh weight. Olives can also be an important source of triterpenic acids, although this is mainly the skin part, where the maslinic and oleanolic acids are concentrated. Olive leaves can contain up to 70 g kg -1 phenolic compounds and 20 g kg -1 triterpenic acids, and olive fruit can contain up to 35 g kg -1 of the former and 3 g kg -1 of the latter. It must also be noted that this level was constant both between seasons and orchard locations. © 2016 Society of Chemical Industry. © 2016 Society of Chemical Industry.

Hybrid molecule from O2-(2,4-dinitrophenyl)diazeniumdiolate and oleanolic acid: a glutathione S-transferase π-activated nitric oxide prodrug with selective anti-human hepatocellular carcinoma activity and improved stability.

PubMed

Fu, Junjie; Liu, Ling; Huang, Zhangjian; Lai, Yisheng; Ji, Hui; Peng, Sixun; Tian, Jide; Zhang, Yihua

2013-06-13

A series of hybrids from O(2)-(2,4-dinitrophenyl)diazeniumdiolate and oleanolic acid (OA) were designed, synthesized, and biologically evaluated as novel nitric oxide (NO)-releasing prodrugs that could be activated by glutathione S-transferase π (GSTπ) overexpressed in a number of cancer cells. It was discovered that the most active compound, 21, released high levels of NO selectively in HCC cells but not in the normal cells and exhibited potent antiproliferative activity in vitro as well as remarkable tumor-retarding effects in vivo. Compared with the reported GSTπ-activated prodrugs JS-K and PABA/NO, 21 exhibited remarkably improved stability in the absence of GSTπ. Importantly, the decomposition of 21 occurred in the presence of GSTπ and was much more effective than in glutathione S-transferase α. Additionally, 21 induced apoptosis in HepG2 cells by arresting the cell cycle at the G2/M phase, activating both the mitochondrion-mediated pathway and the MAPK pathway and enhancing the intracellular production of ROS.

Oleanolic acid acetate attenuates polyhexamethylene guanidine phosphate-induced pulmonary inflammation and fibrosis in mice.

PubMed

Kim, Min-Seok; Han, Jin-Young; Kim, Sung-Hwan; Jeon, Doin; Kim, Hyeon-Young; Lee, Seung Woong; Rho, Mun-Chual; Lee, Kyuhong

2018-06-01

Oleanolic acid acetate (OAA), triterpenoid compound isolated from Vigna angularis (azuki bean), has been revealed anti-inflammatory in several studies. We investigated the effects of OAA against polyhexamethylene guanidine phosphate (PHMG-P)-induced pulmonary inflammation and fibrosis in mice. OAA treatment effectively alleviated PHMG-P-induced lung injury, including the number of total and differential cell in BAL fluid, histopathological lesions and hydroxyproline content in a dose dependent manner. Moreover, OAA treatment significantly decreased the elevations of IL-1β, IL-6, TNF-α, TGF-β1, and fibronectin, and the activation of the NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome in the lungs of PHMG-P-treated mice. Cytokines are known to be key modulators in the inflammatory responses that drive progression of fibrosis in injured tissues. The activation of NLRP3 inflammasome has been reported to be involved in induction of inflammatory cytokines. These results indicate that OAA may mitigate the inflammatory response and development of pulmonary fibrosis in the lungs of mice treated with PHMG-P. Copyright © 2018. Published by Elsevier B.V.

Effects of oleanolic acid on pulmonary morphofunctional and biochemical variables in experimental acute lung injury.

PubMed

Santos, Raquel S; Silva, Pedro L; Oliveira, Gisele P; Cruz, Fernanda F; Ornellas, Débora S; Morales, Marcelo M; Fernandes, Janaina; Lanzetti, Manuella; Valença, Samuel S; Pelosi, Paolo; Gattass, Cerli R; Rocco, Patricia R M

2011-12-15

We analysed the effects of oleanolic acid (OA) on lung mechanics and histology and its possible mechanisms of action in experimental acute lung injury (ALI). BALB/c mice were randomly divided into Control (saline, ip) and ALI (paraquat, 25 mg/kg, ip) groups. At 1 h, both groups were treated with saline (SAL, 50 μl ip), OA (10 mg/kg ip), or dexamethasone (DEXA, 1 mg/kg ip). At 24 h, lung static elastance, viscoelastic pressure, and alveolar collapse reduced more after OA compared to DEXA administration. Tumour necrosis factor-α, macrophage migration inhibitory factor, interleukin-6, interferon-γ, and transforming growth factor-β mRNA expressions in lung tissue diminished similarly after OA or DEXA. Conversely, only OA avoided reactive oxygen species generation and yielded a significant decrease in nitrite concentration. OA and DEXA restored the reduced glutathione/oxidized glutathione ratio and catalase activity while increasing glutathione peroxidase induced by paraquat. In conclusion, OA improved lung morphofunction by modulating the release of inflammatory mediators and oxidative stress. Copyright © 2011 Elsevier B.V. All rights reserved.

Oleanolic acid improves pulmonary morphofunctional parameters in experimental sepsis by modulating oxidative and apoptotic processes.

PubMed

Santos, Raquel Souza; Silva, Pedro Leme; de Oliveira, Gisele Pena; Santos, Cintia Lourenço; Cruz, Fernanda Ferreira; de Assis, Edson Fernandes; de Castro-Faria-Neto, Hugo Caire; Capelozzi, Vera Luiza; Morales, Marcelo Marcos; Pelosi, Paolo; Gattass, Cerli Rocha; Rocco, Patricia Rieken Macedo

2013-12-01

We compared the effects of oleanolic acid (OA) vs. dexamethasone on lung mechanics and histology, inflammation, and apoptosis in lung and distal organs in experimental sepsis. Seventy-eight BALB/c mice were randomly divided into two groups. Sepsis was induced by cecal ligation and puncture, while the control group underwent sham surgery. 1h after surgery, all animals were further randomized to receive saline (SAL), OA and dexamethasone (DEXA) intraperitoneally. Both OA and DEXA improved lung mechanics and histology, which were associated with fewer lung neutrophils and less cell apoptosis in lung, liver, and kidney than SAL. However, only animals in the DEXA group had lower levels of interleukin (IL)-6 and KC (murine analog of IL-8) in bronchoalveolar lavage fluid than SAL animals. Conversely, OA was associated with lower inducible nitric oxide synthase expression and higher superoxide dismutase than DEXA. In the experimental sepsis model employed herein, OA and DEXA reduced lung damage and distal organ apoptosis through distinct anti-inflammatory mechanisms. Copyright © 2013 Elsevier B.V. All rights reserved.

Species classification and bioactive ingredients accumulation of BaiJiangCao based on characteristic inorganic elements analysis by inductively coupled plasma-mass spectrometry and multivariate analysis

PubMed Central

Wen-Lan, Li; Xue, Zhang; Xin-Xin, Yang; Shuai, Wang; Lin, Zhao; Huan-Jun, Zhao; Yong-Rui, Bao; Chen-Feng, Ji; Ning, Chen; Zheng, Xiang

2015-01-01

Background: Patrinia scabiosaefolia Fisch and Patrinia villosa (Thunb.) Juss., two species herbs with the same Chinese name “BaiJiangCao”, are important ancient herbal medicines widely used for more than 2000 years. The clinical application of two species herb is confused due to the difficult identification. Objective: The objective was to authenticate the species of BaiJiangCao and analyze the accumulation of bioactive ingredients based on characteristic inorganic elements analysis. Materials and Methods: Content of 32 inorganic elements in BaiJiangCao from different habitats were determined by inductively coupled plasma-mass spectrometry (ICP-MS), and the characteristic inorganic elements were picked to distinguish the species of the herb by principal component analysis and cluster analysis. Contents of two bioactive ingredients, luteoloside, and oleanolic acid, in the samples, were also analyzed by high-performance liquid chromatography method. Relationship between accumulation of bioactive ingredients and content of macroelements in BaiJiangCao was established by statistics. Results: A 4 macroelements (Na, Mg, K, Fe) in 32 determined inorganic elements were picked for characteristic inorganic elements. Content of Na, Mg, K and Fe showed positive correlations with that of luteoloside, content of Na, Mg showed positive correlations with that of oleanolic acid, but content of K and Fe showed negative correlations with that of oleanolic acid. Conclusion: It is for the first time to utilize the characteristic inorganic elements as an index to classify the herb species by the method of ICP-MS and multivariate analysis. And it is also the first report to investigate the influence of inorganic elements in herb on the accumulation of bioactive components which could affect the pharmacological efficacy of the herb medicine. And this method could also be utilized in research of corresponding aspects. PMID:26600721

Clinical safety and efficacy of NG440: a novel combination of rho iso-alpha acids from hops, rosemary, and oleanolic acid for inflammatory conditions.

PubMed

Minich, Deanna M; Bland, Jeffrey S; Katke, Jeffrey; Darland, Gary; Hall, Amy; Lerman, Robert H; Lamb, Joseph; Carroll, Brian; Tripp, Matthew

2007-09-01

In this report, we examine the clinical safety and efficacy of NG440, a phytochemical-based antiinflammatory formula consisting of a combination of rho iso-alpha acids from hops, rosemary, and oleanolic acid. In a previous study, we demonstrated that NG440 significantly decreased pain by 50% in patients with osteoarthritis. Consistent with these data, results from a multicentre trial indicate that NG440 reduced pain scores in patients with joint discomfort, as measured by VAS (visual analog scale) methodology. As demonstrated in an ex vivo clinical study, these effects on pain relief may be due to reduced inflammatory cytokine production including lower prostaglandin E2 formation. Finally, strong data exist to suggest that NG440 is a safe formula for human consumption. Animal toxicity data revealed no adverse effects of NG440 at dosages < or =250 mg.kg-1.day-1 for 21 days. Furthermore, human trial data suggest that NG440 does not negatively impact cardiovascular and gastrointestinal markers normally affected by selective COX-2 enzyme inhibitors, including platelet function, blood pressure, blood cell count, or fecal calprotectin, a measure of gastrointestinal injury. In conclusion, NG440 may serve as a safe and efficacious alternative in some areas where specific COX-2 inhibitors have been traditionally used.

[Chemical constituents of the roots of Vaccinium bracteatum].

PubMed

Lv, Xiao-Lan; Mai, Xi; Guo, Hui; Lai, Xiao-Ping

2012-06-01

To study the chemical constituents of the roots of Vaccinium bracteatum. The constituents were separated and purified with chromatographic methods (including silica gel, Sephadex LH-20 and RP-18 column chromatography), and their structures were determined by spectroscopic methods (including MS, 1H-NMR and 13C-NMR). 10 compounds were isolated from the roots of Vaccinium bracteatu and were elucidated as chlorogenic acid (1), pinoresinol (2), ferulic acid (3), kaempferol (4), trans-caffeic acid (5), beta-sitosterol (6), quercetin (7), oleanolic acid (8), apigenin (9) and luteolin (10). Compounds 1 -3 are obtained from this plant for the first time.

A study of the trypanocidal activity of triterpene acids isolated from Miconia species.

PubMed

Cunha, Wilson Roberto; Crevelin, Eduardo J; Arantes, Glenda M; Crotti, Antonio E Miller; Andrade e Silva, Márcio L; Furtado, Niege A J Cardoso; Albuquerque, Sérgio; Ferreira, Daniele Da Silva

2006-06-01

Triterpene acids, including ursolic acid (1), urjinolic acid (4) and oleanoic acid (5) along with a mixture of 2alpha-hydroxyursolic acid (2) and maslic acid (3) were isolated from methylene chloride extracts of the Miconia sellowiana and M. ligustroides species and their activities against the trypomastigote blood forms of Trypanosoma cruzi were evaluated. The potassium salt derivative of ursolic acid (1a) was also tested. The in vitro assays showed that compounds 1, 5 and 1a were the most active (IC(50) 17.1 microm, 12.8 microm and 8.9 microm, respectively). In contrast, a mixture of 2 plus 3, that exhibit a hydroxyl at C-2 and C-3, is much less potent than a mixture of 1 and 5 (IC(50) 48.5 microm and 11.8 microm, respectively). In the same manner, compound 4, that differs from 5 by two additional hydroxyl groups (at C-2 and C-23) displayed weak trypanocidal activity (IC(50) 76.3 microm) when compared with the other triterpenes. These results suggest that the free hydroxyl at C-3 and the polarity of C-28 are the most influential structural features for determining the in vitro trypanocidal activity of triterpenes. In vivo assays were also undertaken for the most active compounds 1, 1a and the mixture of 1 plus 5. The most significant reduction in parasite number in the parasitemic peak were obtained for compound 1 and its salt derivative 1a (75.7% and 70.4%, respectively). Moreover, the survival time was increased for all the treated animals.

A tandem array of UDP-glycosyltransferases from the UGT73C subfamily glycosylate sapogenins, forming a spectrum of mono- and bisdesmosidic saponins.

PubMed

Erthmann, Pernille Østerbye; Agerbirk, Niels; Bak, Søren

2018-05-01

This study identifies six UGT73Cs all able to glucosylate sapogenins at positions 3 and/or 28 which demonstrates that B. vulgaris has a much richer arsenal of UGTs involved in saponin biosynthesis than initially anticipated. The wild cruciferous plant Barbarea vulgaris is resistant to some insects due to accumulation of two monodesmosidic triterpenoid saponins, oleanolic acid 3-O-β-cellobioside and hederagenin 3-O-β-cellobioside. Insect resistance depends on the structure of the sapogenin aglycone and the glycosylation pattern. The B. vulgaris saponin profile is complex with at least 49 saponin-like metabolites, derived from eight sapogenins and including up to five monosaccharide units. Two B. vulgaris UDP-glycosyltransferases, UGT73C11 and UGT73C13, O-glucosylate sapogenins at positions 3 and 28, forming mainly 3-O-β-D-glucosides. The aim of this study was to identify UGTs responsible for the diverse saponin oligoglycoside moieties observed in B. vulgaris. Twenty UGT genes from the insect resistant genotype were selected and heterologously expressed in Nicotiana benthamiana and/or Escherichia coli. The extracts were screened for their ability to glycosylate sapogenins (oleanolic acid, hederagenin), the hormone 24-epibrassinolide and sapogenin monoglucosides (hederagenin and oleanolic acid 3-O-β-D-glucosides). Six UGTs from the UGT73C subfamily were able to glucosylate both sapogenins and both monoglucosides at positions 3 and/or 28. Some UGTs formed bisdesmosidic saponins efficiently. At least four UGT73C genes were localized in a tandem array with UGT73C11 and possibly UGT73C13. This organization most likely reflects duplication events followed by sub- and neofunctionalization. Indeed, signs of positive selection on several amino acid sites were identified and modelled to be localized on the UGT protein surface. This tandem array is proposed to initiate higher order bisdesmosidic glycosylation of B. vulgaris saponins, leading to the recently discovered saponin structural diversity, however, not directly to known cellobiosidic saponins.

[Fat soluble constituents of the leaves of Vaccinium bracteatum Thunb].

PubMed

Tu, P; Liu, J; Li, J

1997-07-01

Four compounds were isolated from the fat soluble fraction of the leaves of Vaccinium bracteatum and identified as friedelin (I), epifriedelinol (II), beta-sitosterol(III) and ursolic acid(IV) by IR, NMR and MS. Compound III and IV are isolated from the leaves of this plant for the first time.

Discovery of antitumor ursolic acid long-chain diamine derivatives as potent inhibitors of NF-κB.

PubMed

Jiang, Wei; Huang, Ri-Zhen; Zhang, Jing; Guo, Tong; Zhang, Meng-Ting; Huang, Xiao-Chao; Zhang, Bin; Liao, Zhi-Xin; Sun, Jing; Wang, Heng-Shan

2018-05-08

A series of inhibitors of NF-κB based on ursolic acid (UA) derivatives containing long-chain diamine moieties were designed and synthesized as well as evaluated the antitumor effects. These compounds exhibited significant inhibitory activity to the NF-κB with IC 50 values at micromolar concentrations in A549 lung cancer cell line. Among them, compound 8c exerted potent activity against the test tumor cell lines including multidrug resistant human cancer lines, with the IC 50 values ranged from 5.22 to 8.95 μM. Moreover, compound 8c successfully suppressed the migration of A549 cells. Related mechanism study indicated compound 8c caused cell cycle arrest at G1 phase and triggered apoptosis in A549 cells through blockage of NF-κB signalling pathway. Molecular docking study revealed that key interactions between 8c and the active site of NF-κB in which the bulky and strongly electrophilic group of long-chain diamine moieties were important for improving activity. Copyright © 2018 Elsevier Inc. All rights reserved.

Ursolic acid and luteolin-7-glucoside improve lipid profiles and increase liver glycogen content through glycogen synthase kinase-3.

PubMed

Azevedo, Marisa F; Camsari, Cagri; Sá, Carla M; Lima, Cristovao F; Fernandes-Ferreira, Manuel; Pereira-Wilson, Cristina

2010-06-01

In the present study, two phytochemicals - ursolic acid (UA) and luteolin-7-glucoside (L7G) - were assessed in vivo in healthy rats regarding effects on plasma glucose and lipid profile (total cholesterol, HDL and LDL), as well as liver glycogen content, in view of their importance in the aetiology of diabetes and associated complications. Both UA and L7G significantly decreased plasma glucose concentration. UA also significantly increased liver glycogen levels accompanied by phosphorylation of glycogen synthase kinase-3 (GSK3). The increase in glycogen deposition induced by UA (mediated by GSK3) could have contributed to the lower plasma glucose levels observed. Both compounds significantly lowered total plasma cholesterol and low-density lipoprotein levels, and, in addition, UA increased plasma high-density lipoprotein levels. Our results show that UA particularly may be useful in preventable strategies for people at risk of developing diabetes and associated cardiovascular complications by improving plasma glucose levels and lipid profile, as well as by promoting liver glycogen deposition.

Design, synthesis, evaluation, and molecular docking of ursolic acid derivatives containing a nitrogen heterocycle as anti-inflammatory agents.

PubMed

Wei, Zhi-Yu; Chi, Ke-Qiang; Wang, Ke-Si; Wu, Jie; Liu, Li-Ping; Piao, Hu-Ri

2018-06-01

Ursolic acid derivatives containing oxadiazole, triazolone, and piperazine moieties were synthesized in an attempt to develop potent anti-inflammatory agents. Structures of the synthesized compounds were elucidated by 1 H NMR, 13 C NMR, and HRMS. Most of the synthesized compounds showed pronounced anti-inflammatory effects at 100 mg/kg. In particular, compound 11b, which displayed the most potent anti-inflammatory activity of all of the compounds prepared, with 69.76% inhibition after intraperitoneal administration, was more potent than the reference drugs indomethacin and ibuprofen. The cytotoxicity of the compounds was also assessed by the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay, and no compounds showed any appreciable cytotoxic activity (IC 50 >100 μmol/L). Furthermore, molecular docking studies of the synthesized compounds were performed to rationalize the obtained biological results. Overall, the results indicate that compound 11b could be a therapeutic candidate for the treatment of inflammation. Copyright © 2018 Elsevier Ltd. All rights reserved.

[Chemical constituents from Ajuga nipponensis].

PubMed

He, Gui-xia; Liang, Xiao-lan; Ouyang, Wen; Yi, Gang-qiang; Li, Yun-yao; Zhao, Jian-ping; Ikhlas, Khan

2013-12-01

To study the chemical constituents of Ajuga nipponensis. The chemical constituents were isolated by repeated silica gel column chromatography and their structures were elucidated by phyisochemical properties and spectral analysis. Ten compounds were isolated and identified as:hexadecanoic acid(1), ajuforrestin A(2), beta-sitosterol(3), acacetin(4), apigenin(5), ajugamacrin B(6), ursolic acid(7), beta-ecdysone(8), 8-acetylharpagide(9) and daucosterol(10). Compounds 1-7 and 10 are isolated from this plant for the first time.

Synthesis and antiplasmodial activity of betulinic acid and ursolic acid analogues.

PubMed

Innocente, Adrine M; Silva, Gloria N S; Cruz, Laura Nogueira; Moraes, Miriam S; Nakabashi, Myna; Sonnet, Pascal; Gosmann, Grace; Garcia, Célia R S; Gnoatto, Simone C B

2012-10-12

More than 40% of the World population is at risk of contracting malaria, which affects primarily poor populations in tropical and subtropical areas. Antimalarial pharmacotherapy has utilised plant-derived products such as quinine and artemisinin as well as their derivatives. However, worldwide use of these antimalarials has caused the spread of resistant parasites, resulting in increased malaria morbidity and mortality. Considering that the literature has demonstrated the antimalarial potential of triterpenes, specially betulinic acid (1) and ursolic acid (2), this study investigated the antimalarial activity against P. falciparum chloroquine-sensitive 3D7 strain of some new derivatives of 1 and 2 with modifications at C-3 and C-28. The antiplasmodial study employed flow cytometry and spectrofluorimetric analyses using YOYO-1, dihydroethidium and Fluo4/AM for staining. Among the six analogues obtained, compounds 1c and 2c showed excellent activity (IC₅₀ = 220 and 175 nM, respectively) while 1a and b demonstrated good activity (IC₅₀ = 4 and 5 μM, respectively). After cytotoxicity evaluation against HEK293T cells, 1a was not toxic, while 1c and 2c showed IC₅₀ of 4 μM and a selectivity index (SI) value of 18 and 23, respectively. Moreover, compound 2c, which presents the best antiplasmodial activity, is involved in the calcium-regulated pathway(s).

[Study on the chemical constituents in roots of Gentiana dahurica].

PubMed

Chen, Qian-Liang; Shi, Zhang-Yan; Zhang, Ya-Hui; Zheng, Jiang-Bin

2011-08-01

To systematically study the chemical constituents in the roots of Gentiana dahurica. Various column chromatographic techniques were used for isolation and purification. The structures were elucidated on the basis of spectral data (UV, IR, MS, NMR) and identified by comparing with the authentic substance. Seven compounds were isolated and identified as: roburic acid (1), oleanolic acid (2), beta-sitosterol (3), daucosterol (4), gentiopicroside(5), swertiamarine (6), sweroside (7). Compounds 1, 2 and 4 are isolated from this plant for the first time.

Antioxidant activity and total phenols from the methanolic extract of Miconia albicans (Sw.) Triana leaves.

PubMed

Pieroni, Laís Goyos; de Rezende, Fernanda Mendes; Ximenes, Valdecir Farias; Dokkedal, Anne Lígia

2011-11-10

Miconia is one of the largest genus of the Melastomataceae, with approximately 1,000 species. Studies aiming to describe the diverse biological activities of the Miconia species have shown promising results, such as analgesic, antimicrobial and trypanocidal properties. M. albicans leaves were dried, powdered and extracted to afford chloroformic and methanolic extracts. Total phenolic contents in the methanolic extract were determined according to modified Folin-Ciocalteu method. The antioxidant activity was measured using AAPH and DPPH radical assays. Chemical analysis was performed with the n-butanol fraction of the methanolic extract and the chloroformic extract, using different chromatographic techniques (CC, HPLC). The structural elucidation of compounds was performed using 500 MHz NMR and HPLC methods. The methanolic extract showed a high level of total phenolic contents; the results with antioxidant assays showed that the methanolic extract, the n-butanolic fraction and the isolated flavonoids from M. albicans had a significant scavenging capacity against AAPH and DPPH. Quercetin, quercetin-3-O-glucoside, rutin, 3-(E)-p-coumaroyl-α-amyrin was isolated from the n-butanolic fraction and α-amyrin, epi-betulinic acid, ursolic acid, epi-ursolic acid from the chloroformic extract. The results presented in this study demonstrate that M. albicans is a promising species in the search for biologically active compounds.

Nutrition Frontiers - Summer 2016 | Division of Cancer Prevention

Cancer.gov

Volume 7, Issue 3 The summer issue of Nutrition Frontiers showcases the combined effects of ursolic acid and resveratrol for skin cancer, the potential chemopreventive effects of the dietary supplement 4-MU, and a method to monitor a heterocyclic aromatic amine in dyed hair. Learn about our spotlight investigators, Drs. Michael Caligiuri and Jianhua Yu, and their research on

Impact Of Obesity On Tamoxifen Chemoprevention In A Model Of Ductal Carcinoma In Situ

DTIC Science & Technology

2011-10-01

Antitumor effects of ursolic acid in a mouse model of postmenopausal breast cancer. Nutrition and Cancer 62(8):1074-86, 2010. Zheng Q, Dunlap SM, Zhu...at the time of sacrifice, including tumor, mammary fat pad, liver, visceral white adipose tissue, skin, and skeletal muscle (Task 1.d). All mice

An evaluation of the anti-tumor efficacy of oleanolic acid-loaded PEGylated liposomes

NASA Astrophysics Data System (ADS)

Tang, Shengnan; Gao, Dawei; Zhao, Tingting; Zhou, Jing; Zhao, Xiaoning

2013-06-01

The effective delivery of oleanolic acid (OA) to the target site has several benefits in therapy for different pathologies. However, the delivery of OA is challenging due to its poor aqueous solubility. The study aims to evaluate the tumor inhibition effect of the PEGylated OA nanoliposome on the U14 cervical carcinoma cell line. In our previous study, OA was successfully encapsulated into PEGylated liposome with the modified ethanol injection method. Oral administration of PEGylated OA liposome was demonstrated to be more efficient in inhibiting xenograft tumors. The results of organ index indicated that PEG liposome exhibited higher anti-tumor activity and lower cytotoxicity. It was also found that OA and OA liposomes induced tumor cell apoptosis detected by flow cytometry. Furthermore, effects of OA on the morphology of tumor and other tissues were observed by hematoxylin and eosin staining. The histopathology sections did not show pathological changes in kidney or liver in tested mice. In contrast, there was a significant difference in tumor tissues between treatment groups and the negative control group. These observations imply that PEGylated liposomes seem to have advantages for cancer therapy in terms of effective delivery of OA.

Oleanolic acid suppresses aerobic glycolysis in cancer cells by switching pyruvate kinase type M isoforms.

PubMed

Liu, Jia; Wu, Ning; Ma, Leina; Liu, Ming; Liu, Ge; Zhang, Yuyan; Lin, Xiukun

2014-01-01

Warburg effect, one of the hallmarks for cancer cells, is characterized by metabolic switch from mitochondrial oxidative phosphorylation to aerobic glycolysis. In recent years, increased expression level of pyruvate kinase M2 (PKM2) has been found to be the culprit of enhanced aerobic glycolysis in cancer cells. However, there is no agent inhibiting aerobic glycolysis by targeting PKM2. In this study, we found that Oleanolic acid (OA) induced a switch from PKM2 to PKM1, and consistently, abrogated Warburg effect in cancer cells. Suppression of aerobic glycolysis by OA is mediated by PKM2/PKM1 switch. Furthermore, mTOR signaling was found to be inactivated in OA-treated cancer cells, and mTOR inhibition is required for the effect of OA on PKM2/PKM1 switch. Decreased expression of c-Myc-dependent hnRNPA1 and hnRNPA1 was responsible for OA-induced switch between PKM isoforms. Collectively, we identified that OA is an antitumor compound that suppresses aerobic glycolysis in cancer cells and there is potential that PKM2 may be developed as an important target in aerobic glycolysis pathway for developing novel anticancer agents.

A New Alkenylmethylresorcinol from the Fruits of Ardisia kivuensis.

PubMed

Nguekeu, Yves M M; Ndontsa, Blanche L; Mbouangouere, Roukayatou; Awouafack, Maurice D; Ito, Takuya; Tane, Pierre; Morita, Hiroyuki

2016-05-01

The phytochemical study of the MeOH extract from the fruits of Ardisia kivuensis was carried out using repeated silica gel column chromatography followed by Sephadex LH-20 to afford a new alkenylmethylresorcinol, ardisinol III (1) along with three known compounds, oleanolic acid, β-sitosterol and pentacosanoic acid. The structure of 1 was elucidated using spectroscopic analysis (NMR and MS), and comparison with published data. Compound 1 had weak antioxidant activity (IC50 109.8 μg/mL) while other compounds were not active as compared to L-ascorbic acid (IC50 3.9 μg/mL).

Permeability of rosmarinic acid in Prunella vulgaris and ursolic acid in Salvia officinalis extracts across Caco-2 cell monolayers.

PubMed

Qiang, Zhiyi; Ye, Zhong; Hauck, Cathy; Murphy, Patricia A; McCoy, Joe-Ann; Widrlechner, Mark P; Reddy, Manju B; Hendrich, Suzanne

2011-10-11

Rosmarinic acid (RA), a caffeic acid-related compound found in high concentrations in Prunella vulgaris (self-heal), and ursolic acid (UA), a pentacyclic triterpene acid concentrated in Salvia officinalis (sage), have been traditionally used to treat inflammation in the mouth, and may also be beneficial for gastrointestinal health in general. To investigate the permeabilities of RA and UA as pure compounds and in Prunella vulgaris and Salvia officinalis ethanol extracts across human intestinal epithelial Caco-2 cell monolayers. The permeabilities and phase II biotransformation of RA and UA as pure compounds and in herbal extracts were compared using Caco-2 cells with HPLC detection. The apparent permeability coefficient (P(app)) for RA and RA in Prunella vulgaris extracts was 0.2 ± 0.05 × 10(-6)cm/s, significantly increased to 0.9 ± 0.2 × 10(-6)cm/s after β-glucuronidase/sulfatase treatment. P(app) for UA and UA in Salvia officinalis extract was 2.7 ± 0.3 × 10(-6)cm/s and 2.3 ± 0.5 × 10(-6)cm/s before and after β-glucuronidase/sulfatase treatment, respectively. Neither compound was affected in permeability by the herbal extract matrix. RA and UA in herbal extracts had similar uptake as that found using the pure compounds, which may simplify the prediction of compound efficacy, but the apparent lack of intestinal glucuronidation/sulfation of UA is likely to further enhance the bioavailability of that compound compared with RA. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Permeability of Rosmarinic acid in Prunella vulgaris and Ursolic acid in Salvia officinalis Extracts across Caco-2 Cell Monolayers

PubMed Central

Qiang, Zhiyi; Ye, Zhong; Hauck, Cathy; Murphy, Patricia A.; McCoy, Joe-Ann; Widrlechner, Mark P.; Reddy, Manju B.; Hendrich, Suzanne

2011-01-01

Ethnopharmacological relevance Rosmarinic acid (RA), a caffeic acid-related compound found in high concentrations in Prunella vulgaris (self-heal), and ursolic acid (UA), a pentacyclic triterpene acid concentrated in Salvia officinalis (sage), have been traditionally used to treat inflammation in the mouth, and may also be beneficial for gastrointestinal health in general. Aim of the study To investigate the permeabilities of RA and UA as pure compounds and in P. vulgaris and S. officinalis ethanol extracts across human intestinal epithelial Caco-2 cell monolayers. Materials and methods The permeabilities and Phase II biotransformation of RA and UA as pure compounds and in herbal extracts were compared using Caco-2 cells with HPLC detection. Results The apparent permeability coefficient (Papp) for RA and RA in P. vulgaris extracts was 0.2 ± 0.05 × 10−6 cm/s, significantly increased to 0.9 ± 0.2 × 10−6 cm/s after β-glucuronidase/sulfatase treatment. Papp for UA and UA in S. officinalis extract was 2.7 ± 0.3 × 10−6 cm/s and 2.3 ± 0.5 × 10−6 cm/s before and after β-glucuronidase/sulfatase treatment, respectively. Neither compound was affected in permeability by the herbal extract matrix. Conclusion RA and UA in herbal extracts had similar uptake as that found using the pure compounds, which may simplify the prediction of compound efficacy, but the apparent lack of intestinal glucuronidation/sulfation of UA is likely to further enhance the bioavailability of that compound compared with RA. PMID:21798330

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

PubMed Central

Kim, Eunkyung; Sy-Cordero, Arlene; Graf, Tyler N.; Brantley, Scott J.; Paine, Mary F.; Oberlies, Nicholas H.

2010-01-01

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, a 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 (IC50) of maslinic acid, corosolic acid, and ursolic acid was 7.4, 8.8, and <10 μM, respectively, using HIM as the enzyme source and was 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. PMID:20717876

Isolation and identification of intestinal CYP3A inhibitors from cranberry (Vaccinium macrocarpon) using human intestinal microsomes.

PubMed

Kim, Eunkyung; Sy-Cordero, Arlene; Graf, Tyler N; Brantley, Scott J; Paine, Mary F; Oberlies, Nicholas H

2011-02-01

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. © Georg Thieme Verlag KG Stuttgart · New York.

[Studies on chemical constituents of Heterosmilax yunnanensis].

PubMed

Qin, Wen-jie; Wang, Gang-li; Lin, Rui-chao

2007-08-01

To study the chemical constituents of Heterosmilax yunianensis. The compounds were isolated and repeatedly purified with chromatograph and the structures were elucidated by physico-chemical properties and spectral analysis. Eight compounds were obtained and elucidated as beta-sitosterol (I), glycerol monopalmitate (II), daucosterol (IIl), hexacosanoic acid (IV), 5-hydroxymethyl furaldehyde (V), hergapen (VI), ursolic acid (VII), liquiritigenin (VIII). They have been isolated from this plant for the first time, and IV - VIII are obtained from the plants of Heterosmilax for the first time.

Hypolipidemic and hypoglycemic activities of a oleanolic acid derivative from Malva parviflora on streptozotocin-induced diabetic mice.

PubMed

Gutiérrez, Rosa Martha Pérez

2017-05-01

One new oleanolic acid derivative, 2α,3β,23α,29α tetrahydroxyolean-12(13)-en-28-oic acid (1) was isolated from the aerial parts of Malva parviflora. Their structure was characterized by spectroscopic methods. The hypolipidemic and hypoglycemic activities of 1 was analyzed in in streptozotocin (STZ)-nicotinamide-induced type 2 diabetes in mice (MD) and type 1 diabetes in streptozotocin-induced diabetic mice (SD). Triterpene was administered orally at doses of 20 mg/kg for 4 weeks. Organ weight, body weight, glucose, fasting insulin, cholesterol-related lipid profile parameters, glutamate oxaloacetate transaminase (SGOT), glutamate pyruvate transaminase (SGPT), serum alkaline phosphatase (SALP), glucokinase, hexokinase, glucose-6-phosphatase activities and glycogen in liver were measured after 4 weeks of treatment. The results indicated that 1 regulate glucose metabolism, lipid profile, lipid peroxidation, increased body weight, glucokinase and hexokinase activities inhibited triglycerides, total cholesterol, low density lipoproteins level, SGOT, SGPT, SALP, glycogen in liver and glucose-6-phosphatase. In addition, improvement of insulin resistance and protective effect for pancreatic β-cells, also 1 may changes the expression of pro-inflammatory cytokine (IL-6 and TNF-α levels) and enzymes (PAL2, COX-2, and LOX). The results suggest that 1 has hypolipidemic and hypoglycemic, anti-inflammatory, activities, improve insulin resistance and hepatic enzymes in streptozotocin-induced diabetic mice.

Ursolic Acid Inhibits Leucine-Stimulated mTORC1 Signaling by Suppressing mTOR Localization to Lysosome

PubMed Central

Ou, Xiang; Liu, Meilian; Luo, Hairong; Dong, Lily Q.; Liu, Feng

2014-01-01

Ursolic acid (UA), a pentacyclic triterpenoid widely found in medicinal herbs and fruits, has been reported to possess a wide range of beneficial properties including anti-hyperglycemia, anti-obesity, and anti-cancer. However, the molecular mechanisms underlying the action of UA remain largely unknown. Here we show that UA inhibits leucine-induced activation of the mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway in C2C12 myotubes. The UA-mediated inhibition of mTORC1 is independent of Akt, tuberous sclerosis complex 1/2 (TSC1/2), and Ras homolog enriched in brain (Rheb), suggesting that UA negatively regulates mTORC1 signaling by targeting at a site downstream of these mTOR regulators. UA treatment had no effect on the interaction between mTOR and its activator Raptor or inhibitor Deptor, but suppressed the binding of RagB to Raptor and inhibited leucine-induced mTOR lysosomal localization. Taken together, our study identifies UA as a direct negative regulator of the mTORC1 signaling pathway and suggests a novel mechanism by which UA exerts its beneficial function. PMID:24740400

Novel nutraceutic therapies for the treatment of metabolic syndrome

PubMed Central

Martínez-Abundis, Esperanza; Méndez-del Villar, Miriam; Pérez-Rubio, Karina G; Zuñiga, Laura Y; Cortez-Navarrete, Marisol; Ramírez-Rodriguez, Alejandra; González-Ortiz, Manuel

2016-01-01

Nutraceutic therapies such as berberine, bitter melon, Gymnema sylvestre, Irvingia gabonensis, resveratrol and ursolic acid have been shown to help control metabolic syndrome (MetS). The effect of berberine on glucose and lipid metabolism, hypertension, obesity and MetS has been evaluated in animal models and humans. Most clinical trials involving bitter melon have been conducted to evaluate its effect on glucose metabolism; nevertheless, some studies have reported favorable effects on lipids and blood pressure although there is little information about its effect on body weight. Gymnema sylvestre helps to decrease body weight and blood sugar levels; however, there is limited information on dyslipidemia and hypertension. Clinical trials of Irvingia gabonensis have shown important effects decreasing glucose and cholesterol concentrations as well decreasing body weight. Resveratrol acts through different mechanisms to decrease blood pressure, lipids, glucose and weight, showing its effects on the population with MetS. Finally, there is evidence of positive effects with ursolic acid in in vitro and in vivo studies on glucose and lipid metabolism and on body weight and visceral fat. Therefore, a review of the beneficial effects and limitations of the above-mentioned nutraceutic therapies is presented. PMID:27076875

Analgesic and Anti-Inflammatory Activities of Rosa taiwanensis Nakai in Mice

PubMed Central

Tsai, Der-Shiang; Huang, Mei-Hsuen; Tsai, Jen-Chieh; Chang, Yuan-Shuang; Chiu, Yung-Jia; Lin, Yen-Chang

2015-01-01

Abstract In this study, we evaluated the analgesic and anti-inflammatory activities of a 70% ethanol extract from Rosa taiwanensis Nakai (RTEtOH). The analgesic effect was determined using acetic acid-induced writhing response and formalin test. The anti-inflammatory activity was evaluated by λ-carrageenan-induced paw edema in mice. The anti-inflammatory mechanism of RTEtOH was examined by measuring the levels of cyclooxygenase-2 (COX-2), nitric oxide (NO), tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, and malondialdehyde (MDA) in the paw edema tissue and the activities of superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione reductase (GRd) in the liver tissue. The betulinic acid and oleanolic acid contents of RTEtOH were assayed by HPLC. The results showed that RTEtOH decreased the acetic acid-induced writhing responses (1.0 g/kg) and the late phase of the formalin-induced licking time (0.5 and 1.0 g/kg). In the anti-inflammatory models, RTEtOH (0.5 and 1.0 g/kg) reduced the paw edema at 3, 4, and 5 h after λ-carrageenan administration. Moreover, the anti-inflammatory mechanisms might be due to the decreased levels of COX-2, TNF-α, IL-1β, and IL-6, as well as the inhibition of NO and MDA levels through increasing the activities of SOD, GPx, and GRd. The contents of two active compounds, betulinic acid and oleanolic acid, were quantitatively determined. This study demonstrated the analgesic and anti-inflammatory activities of RTEtOH and provided evidence to support its therapeutic use in inflammatory diseases. PMID:25494361

Phytochemical Comparison of the Water and Ethanol Leaf Extracts of the Cree medicinal plant, Sarracenia purpurea L. (Sarraceniaceae).

PubMed

Cieniak, Carolina; Walshe-Roussel, Brendan; Liu, Rui; Muhammad, Asim; Saleem, Ammar; Haddad, Pierre S; Cuerrier, Alain; Foster, Brian C; Arnason, John T

2015-01-01

The Cree of Eeyou Istchee in Northern Quebec identified Sarracenia purpurea L. as an important plant for the treatment of Type 2 diabetes. Traditionally the plant is used as a decoction (boiling water extract) of the leaf, however, in order to study the extract in a laboratory setting, an 80% ethanol extract was used. In this study, the phytochemistry of both extracts of the leaves was compared and quantified. Two S. purpurea leaf extracts were prepared, one a traditional hot water extract and the other an 80% ethanol extract. Using UPLC-ESI-MS, the extracts were phytochemically compared for 2 triterpenes, betulinic acid and ursolic acid, using one gradient method and for 10 additional substances, including the actives quercetin-3-O-galactoside and morroniside, using a different method. The concentrations of the nine phenolic substances present, as well as an active principle, the iridoid glycoside morroniside, were very similar between the two extracts, with generally slightly higher concentrations of phenolics in the ethanol extract as expected. However, two triterpenes, betulinic acid and ursolic acid, were 107 and 93 times more concentrated, respectively, in the ethanol extract compared to the water extract. The main phytochemical markers and most importantly the antidiabetic active principles, quercetin-3-O-galactoside and morroniside, were present in similar amounts in the two extracts, which predicts similar bioactivity.This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Ameliorative effect of ursolic acid on renal fibrosis in adenine-induced chronic kidney disease in rats.

PubMed

Thakur, Richa; Sharma, Anshuk; Lingaraju, Madhu C; Begum, Jubeda; Kumar, Dhirendra; Mathesh, Karikalan; Kumar, Pawan; Singh, Thakur Uttam; Kumar, Dinesh

2018-05-01

Ursolic acid (UA), an ursane-type pentacyclic triterpenoid commonly found in apple peels and holy basil has been shown to possess many beneficial effects. Renal fibrosis is a complication of kidney injury and associated with increased risk of morbidity and mortality. In our previous investigation, a lupane-type pentacyclic triterpenoid, betulinic acid (BA) was found to have protective effect on chronic kidney disease (CKD) and renal fibrosis. This prompted us to explore the therapeutic value of UA, a chemically related compound to BA in CKD. CKD was induced by feeding adenine with the feed at a concentration of 0.75% for 28 days. UA at the dose rate of 30 mg/kg in 0.5% carboxy methyl cellulose (CMC) was administered by oral route, simultaneously with adenine feeding for 28 days. Adenine feeding increased the kidney weight to body weight index, decreased the kidney function due to injury as indicated by increased markers like serum urea, uric acid, creatinine, cystatin C and neutrophil gelatinase-associated lipocalin (NGAL) and initiated the fibrotic response in kidney by increasing the profibrotic proteins viz. transforming growth factor-beta (TGF-β), connective tissue growth factor (CTGF), fibronectin and collagen. However, treatment with UA reversed the damage induced by adenine as shown by reduced kidney injury and fibrosis markers which was further clearly evident in histological picture indicating the suitability of UA for use in CKD. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

1H and 13C NMR spectral data of new saponins from Cordia piauhiensis.

PubMed

Santos, Renata P; Silveira, Edilberto R; Uchôa, Daniel Esdras de A; Pessoa, Otília Deusdênia L; Viana, Francisco Arnaldo; Braz-Filho, Raimundo

2007-08-01

Two new bidesmoside triterpenoid saponins were isolated from stems of Cordia piauhiensis. Their structures, characterized as 3-O-alpha-L-rhamnopyranosyl-(1 --> 2)-beta-D-glucopyranosyl pomolic acid 28-O-beta-D-glucopyranosyl ester (1) and 3-O-alpha-L-rhamnopyranosyl-(1 --> 2)-beta-D-glucopyranosyl oleanolic acid 28-O-beta-D-glucopyranosyl-(1 --> 6)-beta-D-glucopyranosyl ester (2), were unequivocally established after extensive NMR (1H, 13C, DEPT 135 degrees, COSY, HSQC, HMBC, TOCSY, and NOESY) studies. Copyright 2007 John Wiley & Sons, Ltd.

Effects of ursolic acid on glucose metabolism, the polyol pathway and dyslipidemia in non-obese type 2 diabetic mice.

PubMed

Lee, Jin; Lee, Hae-In; Seo, Kown-Il; Cho, Hyun Wook; Kim, Myung-Joo; Park, Eun-Mi; Lee, Mi-Kyung

2014-07-01

Ursolic acid (UA) is a pentacyclic triterpenoid compound that naturally occurs in fruits, leaves and flowers of medicinal herbs. This study investigated the dose-response efficacy of UA (0.01 and 0.05%) on glucose metabolism, the polyol pathway and dyslipidemia in streptozotocin/nicotinamide-induced diabetic mice. Supplement with both UA doses reduced fasting blood glucose and plasma triglyceride levels in non-obese type 2 diabetic mice. High-dose UA significantly lowered plasma free fatty acid, total cholesterol and VLDL-cholesterol levels compared with the diabetic control mice, while LDL-cholesterol levels were reduced with both doses. UA supplement effectively decreased hepatic glucose-6-phosphatase activity and increased glucokinase activity, the glucokinase/glucose-6-phosphatase ratio, GLUT2 mRNA levels and glycogen content compared with the diabetic control mice. UA supplement attenuated hyperglycemia-induced renal hypertrophy and histological changes. Renal aldose reductase activity was higher, whereas sorbitol dehydrogenase activity was lower in the diabetic control group than in the non-diabetic group. However, UA supplement reversed the biochemical changes in polyol pathway to normal values. These results demonstrated that low-dose UA had preventive potency for diabetic renal complications, which could be mediated by changes in hepatic glucose metabolism and the renal polyol pathway. High-dose UA was more effective anti-dyslipidemia therapy in non-obese type 2 diabetic mice.

[Study on the chemical constituent from the dichloromethane extract. of the pine needles of Cedrus deodara].

PubMed

Shi, Xiao-Feng; Bai, Zhao-Hui; Liu, Dong-Yan; Li, Shuang

2012-03-01

To study the chemical constituents of the dichloromethane extracted from pine needles of Cedrus deodara. Compounds were isolated and purified from the dichloromethane extract of pine needles by chromatography on silica gel and Sephadex LH-20. Their structures were identified on the basis of spectroscopic analysis and physicochemical property. Nine compounds were isolated and purified. Their structures were identified as stigmasterol (1), oleanolic acid (2), parahydroxybenzaldehyde (3), beta-sitosterol (4), syringaresinol (5), daucosterol (6), p-hydroxybenzoic acid (7), gallicin (8) and gallic acid (9). Compounds 1-3, 5 -9 are isolated from pine needles of this genus for the first time.

Control of water-borne parasitic diseases with natural products: the potential of Dialium guineense as a molluscicide.

PubMed

Houghton, P J; Odukoya, O A; Adelusi, A; Omogbai, E K; Sanderson, L; Whitfield, P J

1997-01-01

The molluscicidal activity of the fruit and leaves of Dialium guineense was found to be due to glycosides of the triterpenoid oleanolic acid. Three glycosides were isolated from the fruit and a fourth from the leaves and are known compounds. The amount of total saponins present in D. guineense makes it a good candidate for a readily available molluscicide in Nigerian villages.

[Studies on preparative technology and quantitative determination for extracts of total saponin in roof of Panax japonicus].

PubMed

He, Yu-min; Lu, Ke-ming; Yuan, Ding; Zhang, Chang-cheng

2008-11-01

To explore the optimum extraction and purification condition of the total saponins in the root of Panax japonicus (RPJ), and establish its quality control methods. Designed L16 (4(5)) orthogonal test with the extraction rate of total saponins as index, to determine the rational extraction process, and the techniques of water-saturated n-butanol extraction and acetone precipitation were applied to purify the alcohol extract of RPJ. Total saponins were detected by spectrophotometry and its triterpenoidal sapogenin oleanolic acid detected by HPLC. The optimum conditions of total saponins from RPJ was as follows: the material was pulverized, dipped in 60% ethanol aqueous solution as extract solvent at 10 times of volume, and refluxed 3 times for 3 h each time. Extractant of water-saturated n-butanol with extraction times of 3 and precipitant of acetone with precipitation amount of 4-5 times were included in the purification process, which would obtain the quality products. The content of total saponins could reach to 83.48%, and oleanolic acid to 38.30%. The optimized preparative technology is stable, convenient and practical. The extract rate of RPJ was high and steady with this technology, which provided new evidence for industrializing production of the plant and developing new drug.

Identification of a novel oxidative stress induced cell death by Sorafenib and oleanolic acid in human hepatocellular carcinoma cells.

PubMed

Lange, Matthias; Abhari, Behnaz Ahangarian; Hinrichs, Tobias M; Fulda, Simone; Liese, Juliane

2016-10-15

The lack of effective chemotherapies in hepatocellular carcinoma (HCC) is still an unsolved problem and underlines the need for new strategies in liver cancer treatment. In this study, we present a novel approach to improve the efficacy of Sorafenib, today's only routinely used chemotherapeutic drug for HCC, in combination with triterpenoid oleanolic acid (OA). Our data show that cotreatment with subtoxic concentrations of Sorafenib and OA leads to highly synergistic induction of cell death. Importantly, Sorafenib/OA cotreatment triggers cell damage in a sustained manner and suppresses long-term clonogenic survival. Sorafenib/OA cotreatment induces DNA fragmentation and caspase-3/7 cleavage and the addition of the pan-caspase inhibitor zVAD.fmk shows the requirement of caspase activation for Sorafenib/OA-triggered cell death. Furthermore, Sorafenib/OA co-treatment stimulates a significant increase in reactive oxygen species (ROS) levels. Most importantly, the accumulation of intracellular ROS is required for cell death induction, since the addition of ROS scavengers (i.e. α-tocopherol, MnTBAP) that prevent the increase of intracellular ROS levels completely rescues cells from Sorafenib/OA-triggered cell death. In conclusion, OA represents a novel approach to increase the sensitivity of HCC cells to Sorafenib via oxidative stress. Copyright © 2016 Elsevier Inc. All rights reserved.

[Studies on chemical constituents of leaves of Psidium guajava].

PubMed

Fu, Huizheng; Luo, Yongming; Zhang, Dongming

2009-03-01

To study the chemical constituents of the leaves of Psidium guajava. The chemical constituents were isolated by column chromatography on silica gel, Sephadex LH-20 and MPLC. Their structures were elucidated on the basis of spectral analysis. Nine compounds were isolated from this plant, and the structure of them were identified as ursolic acid (1), 2alpha-hydroxyursolic acid (2), 2alpha-hydroxyoleanolic acid (3), morin-3-O-alpha-L-arabopyranoside (4), quercetin (5), hyperin (6), myricetin-3-O-beta-D-glucoside (7), quercetin-3-O-beta-D-glucuronopyranoside (8), 1-O-galloyl-beta-D-glucose (9). Compounds 3, 7-9 were isolated from this plant for the first time.

[Study on Chemical Constituents from Roots of Lonicera macranthoides].

PubMed

Liu, Wen-juan; Chen, Yu; Ma, Xin; Zhao, You-yi; Feng, Xu

2014-12-01

To study chemical constituents of the roots of Lonicera macranthoides. The chemical constituents were isolated and purified by means of several chromatographic techniques and their structures were elucidated by spectroscopic methods. Seven compounds were isolated and identified as ribenol (1), excoecarin C (2), 18-hydroxy-13-epi-manoyloxide (3), asiatic acid (4), oleanolic acid (5), β-sitosterol (6) and β-daucosterol (7). Compounds 1-4 are obtained from this genus for the first time. Compound 5 is obtained from this plant for the first time. All the compounds are found from the roots of Lonicera mac- ranthoides for the first time.

Efficient and scalable synthesis of bardoxolone methyl (cddo-methyl ester).

PubMed

Fu, Liangfeng; Gribble, Gordon W

2013-04-05

Bardoxolone methyl (2-cyano-3,12-dioxooleane-1,9(11)-dien-28-oic acid methyl ester; CDDO-Me) (1), a synthetic oleanane triterpenoid with highly potent anti-inflammatory activity (levels below 1 nM), has completed a successful phase I clinical trial for the treatment of cancer and a successful phase II trial for the treatment of chronic kidney disease in type 2 diabetes patients. Our synthesis of bardoxolone methyl (1) proceeds in ∼50% overall yield in five steps from oleanolic acid (2), requires only one to two chromatographic purifications, and can provide gram quantities of 1.

Two new triterpenoid saponins from the leaves of Bupleurum lancifolium (Apiaceae).

PubMed

Achouri, Amel; Derbré, Séverine; Medjroubi, Kamel; Laouer, Hocine; Séraphin, Denis; Akkal, Salah

2017-10-01

Chemical investigation of the leaves of Bupleurum lancifolium led to the isolation and identification of two triterpenoid saponins previously undescribed named 3-O-[α-L-rhamnopyranosyl (1 → 4)-β-D-glucopyranosyl] echinocystic acid 28-O-β-D-glucopyranosyl ester (1) and 3-O-[α-L-rhamnopyranosyl (1 → 4)-β-D-glucopyranosyl] oleanolic acid 28-O-β-D-glucopyranosyl ester (2) along with the two known compounds isorhamnetin 3-rutinoside (3) and rutin (4). Their structures were elucidated by different spectroscopic methods, including HRESIMS analysis as well as 1D and 2D NMR experiments.

Targeted isolation and identification of bioactive compounds lowering cholesterol in the crude extracts of crabapples using UPLC-DAD-MS-SPE/NMR based on pharmacology-guided PLS-DA.

PubMed

Wen, Chao; Wang, Dongshan; Li, Xing; Huang, Tao; Huang, Cheng; Hu, Kaifeng

2018-02-20

The anti-hyperlipidemic effects of crude crabapple extracts derived from Malus 'Red jade', Malus hupehensis (Pamp.) Rehd. and Malus prunifolia (Willd.) Borkh. were evaluated on high-fat diet induced obese (HF DIO) mice. The results revealed that some of these extracts could lower serum cholesterol levels in HF DIO mice. The same extracts were also parallelly analyzed by LC-MS in both positive and negative ionization modes. Based on the pharmacological results, 22 LC-MS variables were identified to be correlated with the anti-hyperlipidemic effects using partial least square discriminant analysis (PLS-DA) and independent samples t-test. Further, under the guidance of the bioactivity-correlated LC-MS signals, 10 compounds were targetedly isolated and enriched using UPLC-DAD-MS-SPE and identified/elucidated by NMR together with MS/MS as citric acid(1), p-coumaric acid(2), hyperoside(3), myricetin(4), naringenin(5), quercetin(6), kaempferol(7), gentiopicroside(8), ursolic acid(9) and 8-epiloganic acid(10). Among these 10 compounds, 6 compounds, hyperoside(3), myricetin(4), naringenin(5), quercetin(6), kaempferol(7) and ursolic acid(9), were individually studied and reported to indeed have effects on lowering the serum lipid levels. These results demonstrated the efficiency of this strategy for drug discovery. In contrast to traditional routes to discover bioactive compounds in the plant extracts, targeted isolation and identification of bioactive compounds in the crude plant extracts using UPLC-DAD-MS-SPE/NMR based on pharmacology-guided PLS-DA of LC-MS data brings forward a new efficient dereplicated approach to natural products research for drug discovery. Copyright © 2017 Elsevier B.V. All rights reserved.

Folate-Chitosan Nanoparticles Loaded with Ursolic Acid Confer Anti-Breast Cancer Activities in vitro and in vivo

NASA Astrophysics Data System (ADS)

Jin, Hua; Pi, Jiang; Yang, Fen; Jiang, Jinhuan; Wang, Xiaoping; Bai, Haihua; Shao, Mingtao; Huang, Lei; Zhu, Haiyan; Yang, Peihui; Li, Lihua; Li, Ting; Cai, Jiye; Chen, Zheng W.

2016-07-01

Ursolic acid (UA) has proved to have broad-spectrum anti-tumor effects, but its poor water solubility and incompetent targeting property largely limit its clinical application and efficiency. Here, we synthesized a nanoparticle-based drug carrier composed of chitosan, UA and folate (FA-CS-UA-NPs) and demonstrated that FA-CS-UA-NPs could effectively diminish off-target effects and increase local drug concentrations of UA. Using MCF-7 cells as in vitro model for anti-cancer mechanistic studies, we found that FA-CS-UA-NPs could be easily internalized by cancer cells through a folate receptor-mediated endocytic pathway. FA-CS-UA-NPs entered into lysosome, destructed the permeability of lysosomal membrane, and then got released from lysosomes. Subsequently, FA-CS-UA-NPs localized into mitochondria but not nuclei. The prolonged retention of FA-CS-UA-NPs in mitochondria induced overproduction of ROS and destruction of mitochondrial membrane potential, and resulted in the irreversible apoptosis in cancer cells. In vivo experiments showed that FA-CS-UA-NPs could significantly reduce breast cancer burden in MCF-7 xenograft mouse model. These results suggested that FA-CS-UA-NPs could further be explored as an anti-cancer drug candidate and that our approach might provide a platform to develop novel anti-cancer drug delivery system.

Ursolic acid protects against ulcerative colitis via anti-inflammatory and antioxidant effects in mice.

PubMed

Liu, Baohai; Piao, Xuehua; Guo, Lianyi; Liu, Shanshan; Chai, Fang; Gao, Leming

2016-06-01

Ursolic acid (UA) has been reported to have a protective effect in colitis. However, the underlying mechanisms remain to be elucidated. In the present study, experimental ulcerative colitis was induced in male BALB/c mice by the administration of 5% dextran sulfate sodium (DSS) for 7 days, followed by treatment with UA for another 7 days. Hematoxylin & eosin staining was performed to evaluate colon tissue damage, and enzyme assays were used to measure malondialdehyde (MDA) content and superoxide dismutase (SOD) activity in colon homogenate. In addition, serum levels of interleukin (IL)‑1β and tumor necrosis factor (TNF)‑α were measured using an ELISA, and the level of nuclear factor (NF)‑κB p65 in the colonic tissues was assessed by western blotting. The 7‑day DSS administration induced marked colon damage, increased the serum levels of IL‑1β and TNF‑α, increased MDA content and decreased SOD activity in the colon homogenate. These changes were significantly improved by treatment with UA. UA also reduced the DSS‑stimulated high nuclear level of NF‑κB p65 in the colon tissues. These results demonstrate a protective role of UA in ulcerative colitis, and suggest that anti-inflammatory and antioxidant activities are involved in the underlying mechanisms.

The human natural killer-1 (HNK-1) glycan mimetic ursolic acid promotes functional recovery after spinal cord injury in mouse.

PubMed

Sahu, Sudhanshu; Li, Rong; Kadeyala, Praveen Kumar; Liu, Shisong; Schachner, Melitta

2018-05-01

Human natural killer-1 (HNK-1) cell antigen is a glycan epitope involved in several neural events, such as neuritogenesis, myelination, synaptic plasticity and regeneration of the nervous system after injury. We have recently identified the small organic compound ursolic acid (UA) as a HNK-1 mimetic with the aim to test its therapeutic potential in the central nervous system. UA, a plant-derived pentacyclic triterpenoid, is well known for its multiple biological functions, including neuroprotective, antioxidant and anti-inflammatory activities. In the present study, we evaluated its functions in a mouse model of spinal cord injury (SCI) and explored the molecular mechanisms underlying its positive effects. Oral administration of UA to mice 1 h after SCI and thereafter once daily for 6 weeks enhanced the regaining of motor functions and axonal regrowth, and decreased astrogliosis. UA administration decreased levels of proinflammatory markers, including interleukin-6 and tumor necrosis factor-α, in the injured spinal cord at the acute phase of inflammation and activated the mitogen-activated protein kinase and phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin pathways in the injured spinal cord. Taken together, these results suggest that UA may be a candidate for treatment of nervous system injuries. Copyright © 2017. Published by Elsevier Inc.

Targeting RORs nuclear receptors by novel synthetic steroidal inverse agonists for autoimmune disorders.

PubMed

Dal Prà, Matteo; Carta, Davide; Szabadkai, Gyorgy; Suman, Matteo; Frión-Herrera, Yahima; Paccagnella, Nicola; Castellani, Giulia; De Martin, Sara; Ferlin, Maria Grazia

2018-05-01

Designing novel inverse agonists of NR RORγt still represents a challenge for the pharmaceutical community to develop therapeutics for treating immune diseases. By exploring the structure of NRs natural ligands, the representative arotenoid ligands and RORs specific ligands share some chemical homologies which can be exploited to design a novel molecular structure characterized by a polycyclic core bearing a polar head and a hydrophobic tail. Compound MG 2778 (8), a cyclopenta[a]phenantrene derivative, was identified as lead compound which was chemically modified at position 2 in order to obtain a small library for preliminary SARs. Cell viability and estrogenic activity of compounds 7, 8, 19a, 30, 31 and 32 were evaluated to attest selectivity. The selected 7, 8, 19a and 31 compounds were assayed in a Gal4 UAS-Luc co-transfection system in order to determine their ability to modulate RORγt activity in a cellular environment. They were evaluated as inverse agonists taken ursolic acid as reference compound. The potency of compounds was lower than that of ursolic acid, but their efficacy was similar. Compound 19a was the most active, significantly reducing RORγt activity at low micromolar concentrations. Copyright © 2018 Elsevier Ltd. All rights reserved.

Assessment of the Anticonvulsant Potency of Ursolic Acid in Seizure Threshold Tests in Mice.

PubMed

Nieoczym, Dorota; Socała, Katarzyna; Wlaź, Piotr

2018-05-01

Ursolic acid (UA) is a plant derived compound which is also a component of the standard human diet. It possesses a wide range of pharmacological properties, i.e., antioxidant, anti-inflammatory, antimicrobial and antitumor, which have been used in folk medicine for centuries. Moreover, influence of UA on central nervous system-related processes, i.e., pain, anxiety and depression, was proved in experimental studies. UA also revealed anticonvulsant properties in animal models of epilepsy and seizures. The aim of the present study was to investigate the influence of UA on seizure thresholds in three acute seizure models in mice, i.e., the 6 Hz-induced psychomotor seizure threshold test, the maximal electroshock threshold (MEST) test and the timed intravenous pentylenetetrazole (iv PTZ) infusion test. We also examined its effect on the muscular strength (assessed in the grip strength test) and motor coordination (estimated in the chimney test) in mice. UA at doses of 50 and 100 mg/kg significantly increased the seizure thresholds in the 6 Hz and MEST tests. The studied compound did not influence the seizure thresholds in the iv PTZ test. Moreover, UA did not affect the motor coordination and muscular strength in mice. UA displays only a weak anticonvulsant potential which is dependent on the used seizure model.

The Bile Acid Receptor TGR5 Does Not Interact with β-Arrestins or Traffic to Endosomes but Transmits Sustained Signals from Plasma Membrane Rafts*

PubMed Central

Jensen, Dane D.; Godfrey, Cody B.; Niklas, Christian; Canals, Meritxell; Kocan, Martina; Poole, Daniel P.; Murphy, Jane E.; Alemi, Farzad; Cottrell, Graeme S.; Korbmacher, Christoph; Lambert, Nevin A.; Bunnett, Nigel W.; Corvera, Carlos U.

2013-01-01

TGR5 is a G protein-coupled receptor that mediates bile acid (BA) effects on energy balance, inflammation, digestion, and sensation. The mechanisms and spatiotemporal control of TGR5 signaling are poorly understood. We investigated TGR5 signaling and trafficking in transfected HEK293 cells and colonocytes (NCM460) that endogenously express TGR5. BAs (deoxycholic acid (DCA), taurolithocholic acid) and the selective agonists oleanolic acid and 3-(2-chlorophenyl)-N-(4-chlorophenyl)-N, 5-dimethylisoxazole-4-carboxamide stimulated cAMP formation but did not induce TGR5 endocytosis or recruitment of β-arrestins, as assessed by confocal microscopy. DCA, taurolithocholic acid, and oleanolic acid did not stimulate TGR5 association with β-arrestin 1/2 or G protein-coupled receptor kinase (GRK) 2/5/6, as determined by bioluminescence resonance energy transfer. 3-(2-chlorophenyl)-N-(4-chlorophenyl)-N, 5-dimethylisoxazole-4-carboxamide stimulated a low level of TGR5 interaction with β-arrestin 2 and GRK2. DCA induced cAMP formation at the plasma membrane and cytosol, as determined using exchange factor directly regulated by cAMP (Epac2)-based reporters, but cAMP signals did not desensitize. AG1478, an inhibitor of epidermal growth factor receptor tyrosine kinase, the metalloprotease inhibitor batimastat, and methyl-β-cyclodextrin and filipin, which block lipid raft formation, prevented DCA stimulation of ERK1/2. Bioluminescence resonance energy transfer analysis revealed TGR5 and EGFR interactions that were blocked by disruption of lipid rafts. DCA stimulated TGR5 redistribution to plasma membrane microdomains, as localized by immunogold electron microscopy. Thus, TGR5 does not interact with β-arrestins, desensitize, or traffic to endosomes. TGR5 signals from plasma membrane rafts that facilitate EGFR interaction and transactivation. An understanding of the spatiotemporal control of TGR5 signaling provides insights into the actions of BAs and therapeutic TGR5 agonists/antagonists. PMID:23818521

Chemical of Vitex trifolia.

PubMed

Liu, Quan-Yu; Chen, Yong-Sheng; Wang, Fei; Chen, Shi-Wu; Zhang, Yong-Hong

2014-06-01

A new steroidal ester, beta-rosaterol palmitate (1) along with ten known compounds, uvaol(2), 3-epi-ursolic acid (3), 2alpha, 3beta, 24-trihydroxyolean-12-en-28-oic acid (4), 2alpha, 3alpha, 24-trihydroxyurs-12-en-28-oic acid (5), 2alpha, 3alpha, 24-trihydroxyolean-12-en-28-oic acid (6), 2alpha, 3alpha, 24-trihydroxyolean-12-en-28-oic acid-28-O-beta-D-glucopyranosyl ester (7), (Z)-9-hexadecenoic acid (8), octacosyl alcohol (9), beta-sitosterol (10) and beta-daucosterol (11), has been isolated from the stems and leaves of Vitex trifolia. Their structures were elucidated using a combination of 1D and 2D NMR techniques (COSY, HMQC, and HMBC)and HR-ESI-MS analyses. Compounds 2-7 were isolated from this plant for the first time.

A bis-bithiophene from Tridax procumbens L. (Asteraceae).

PubMed

Ali, Muhammad Shaiq; Jahangir, Muhammad

2002-08-01

The ethyl acetate soluble part of hexane extract of Tridax procumbens yielded a new bis-bithiophene named tridbisbithiophene along with four known terpenoids: taraxasteryl acetate, beta-amyrenone, lupeol and oleanolic acid, which have never been reported so far from Tridax procumbens. The structures of all the isolated constituents were elucidated with the aid of 1D-NMR spectroscopy whereas, the structure of new constituent tridbisbithiophene was confirmed via COSY and HMBC interactions.

Ursolic acid-mediated changes in glycolytic pathway promote cytotoxic autophagy and apoptosis in phenotypically different breast cancer cells.

PubMed

Lewinska, Anna; Adamczyk-Grochala, Jagoda; Kwasniewicz, Ewa; Deregowska, Anna; Wnuk, Maciej

2017-06-01

Plant-derived pentacyclic triterpenotids with multiple biological activities are considered as promising candidates for cancer therapy and prevention. However, their mechanisms of action are not fully understood. In the present study, we have analyzed the effects of low dose treatment (5-20 µM) of ursolic acid (UA) and betulinic acid (BA) on breast cancer cells of different receptor status, namely MCF-7 (ER + , PR +/- , HER2 - ), MDA-MB-231 (ER - , PR - , HER2 - ) and SK-BR-3 (ER - , PR - , HER2 + ). UA-mediated response was more potent than BA-mediated response. Triterpenotids (5-10 µM) caused G0/G1 cell cycle arrest, an increase in p21 levels and SA-beta-galactosidase staining that was accompanied by oxidative stress and DNA damage. UA (20 µM) also diminished AKT signaling that affected glycolysis as judged by decreased levels of HK2, PKM2, ATP and lactate. UA-induced energy stress activated AMPK that resulted in cytotoxic autophagy and apoptosis. UA-mediated elevation in nitric oxide levels and ATM activation may also account for AMPK activation-mediated cytotoxic response. Moreover, UA-promoted apoptosis was associated with decreased pERK1/2 signals and the depolarization of mitochondrial membrane potential. Taken together, we have shown for the first time that UA at low micromolar range may promote its anticancer action by targeting glycolysis in phenotypically distinct breast cancer cells.

[Study on Chemical Constituents of Petroleum Ether Fraction from Rubus alceaefolius].

PubMed

Chen, Pan; Fang, Zhi-jian; Yan, Han-jing; Zhou, Hong-bo; Mei, Quan-xi

2015-01-01

To investigate the chemical constituents of Rubus alceaefolius. Nine compounds were isolated and purified from the petroleum ether extract of 95% alcohol extract of Rubus alceaefolius by repeated column chromatography on silica, Sephadex LH-20 and structurally identified by spectral analysis. The compounds were identified as chrysophanol(1), physcion (2), β-sitosterol(3), 3-oxotirucalla-7, 24-dien-21-oic acid(4), myricadiol(5), 19-α-hydroxy-3-acetyl-ursolic acid(6), N-benzoylphenylalaninyl-N-benzoylphenylalaninate(7), aurantiamide acetate(8) and euscaphic acid(9). Compounds land 4~8 are isolated from this plant for the first time, and compounds 4 - 8 are found in plants of Rubus genus for the first time.

Cycloartane glycosides from leaves of Oxyanthus pallidus.

PubMed

Tigoufack, Ignas Bertrand Nzedong; Ngnokam, David; Tapondjou, Leon Azefack; Harakat, Dominique; Voutquenne, Laurence

2010-12-01

From the MeOH extract of leaves of Oxyanthus pallidus, three cycloartane glycosides, named pallidiosides A-C, were isolated together with two known compounds, oleanolic acid and 3-O-β-D-glucopyranosyl-β-sitosterol. The structures of pallidiosides A-C were assigned on the basis of spectral studies and comparison with published literature data. The known compounds were identified by means of Co TLC and confirmed by their physical constants. Copyright © 2010 Elsevier Ltd. All rights reserved.

Determination of oleanolic acid in human plasma and its association with olive oil intake in healthy Spanish adults within the EPIC Spain cohort study.

PubMed

Buckland, Genevieve; Pastor, Antoni; Lujan-Barroso, Leila; Gonzalez, Carlos Alberto; Travier, Noemie; Amiano, Pilar; Huerta, José María; Agudo, Antonio; Navarro, Carmen; Chirlaque, María Dolores; Sánchez, Maria-José; Rodríguez-Barranco, Miguel; Barricarte, Aurelio; Ardanaz, Eva; Dorronsoro, Miren; Molinuevo, Amaia; Quirós, José Ramón; de la Torre, Rafael

2017-08-01

Oleanolic acid (OA) is an important triterpenic compound found in olive oil, however little is known about its concentrations in human plasma. We aimed to determine plasma OA levels in a healthy Spanish population and compare them with estimates of dietary olive oil intake. The final study sample included 141 individuals randomly selected from the European Prospective Investigation into Cancer and Nutrition Spanish cohort. Dietary olive oil intake was estimated using validated dietary history questionnaires. OA concentrations were determined in plasma (from the participants' stored blood samples) using a HPLC-MS method. Correlation coefficients between OA and olive oil intake were calculated, adjusting for center; sex; age; consumption of olives, apples, grapes, and red wine; and fasting state. The mean OA concentration in olive oil nonconsumers was 0.72 ng/mL (SD 0.82), while in the high olive oil intake group it was 1.32 ng/mL (SD 1.14). The fully adjusted partial Spearman correlations coefficients reached 0.36 (p-value < 0.001) overall, varying minimally by sex and fasting state. This is the first study providing steady-state concentrations of triterpenes in humans. The results show that there was low-to-moderate correlation between OA concentrations and olive oil intake in this population. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Antimicrobial steroidal saponin and oleanane-type triterpenoid saponins from Paullinia pinnata.

PubMed

Lunga, Paul K; Qin, Xu-Jie; Yang, Xing W; Kuiate, Jules-Roger; Du, Zhi Z; Gatsing, Donatien

2014-10-02

Paullinia pinnata L. (Sapindaceae) is an African woody vine, which is widely used in traditional medicine for the treatment of human malaria, erectile dysfunction and bacterial infections. A phytochemical investigation of its methanol leaf and stem extracts led to the isolation of seven compounds which were evaluated for their antimicrobial properties. The extracts were fractionated and compounds were isolated by chromatographic methods. Their structures were elucidated from their spectroscopic data in conjunction with those reported in literature. The antimicrobial activities of the crude extracts, fractions and compounds were evaluated against bacteria, yeasts and dermatophytes using the broth micro-dilution technique. Seven compounds: 2-O-methyl-L-chiro-inositol (1), β-sitosterol (2), friedelin (3), 3β-(β-D-Glucopyranosyloxy) stigmast-5-ene (4), (3β)-3-O-(2'-Acetamido-2'-deoxy-β-D-glucopyranosyl) oleanolic acid (5), (3β,16α-hydroxy)-3-O-(2'-Acetamido-2'-deoxy-β-D-glucopyranosyl) echinocystic acid (6) and (3β)-3-O-[β-D-glucopyranosyl-(1″-3')-2'-acetamido-2'-deoxy-β-D-galactopyranosyl]oleanolic acid (7) were isolated. Compounds 5 and 7 showed the best antibacterial and anti-yeast activities respectively (MIC value range of 0.78-6.25 and 1.56-6.25 μg/ml), while 6 exhibited the best anti-dermatophytic activity (MIC value range of 6.25-25 μg/ml). The results of the present findings could be considered interesting, taking into account the global disease burden of these susceptible microorganisms, in conjunction with the search for alternative and complementary medicines.

Ursolic Acid Mediates Hepatic Protection through Enhancing of anti-aging Biomarkers.

PubMed

Gharibi, Shadi; Bakhtiari, Nuredin; Jalalvand, Elham-Moslemee

2017-05-30

Age-associated loss of liver function has been recognized for decades. But, the mechanism driving liver regeneration and its decline with age remains elusive. Hence, to support of our previous studies about anti-aging effects of Ursolic Acid (UA), a compound which extensively present in apple peels. The aim of this study is to address whether UA might alter sensors of the cell metabolic state such as SIRT1, SIRT6, PGC-1β and Klotho proteins. To evaluate the effect of UA on hepatic indicated proteins, mice were administrated with UA twice daily for 7 days. The involvements of these proteins in the UA-mediated effect harmony hepatic protection were investigated by immunofluorescence microscopy technique. Our findings clearly illustrated that UA enhanced SIRT1 (~ 5 ± 0.2 folds) and SIRT6 (~ 8 ± 0.5 folds) proteins levels in hepatic, p<0.001. In addition, the data showed that UA increased PGC-1β (~ 7 ± 0.4 folds) protein overexpression, p<0.001. Moreover, we showed that UA up-regulated Klotho (~ 3.5 ± 0.2 folds) protein in order to improve hepatic performance, p<0.01. Our results suggest that UA through increasing of SIRT1 up-regulation ameliorate reverse cholesterol transport, fatty acid use and oxidative stress defense. In addition, it seems that UA by enhancing of SIRT6 expression promotes cholesterol homeostasis through repressing of SREBP1 and SREBP2. Reciprocally, UA might be involved in VLDL synthesis and exportation through PGC-1β up-regulation. Finally, UA might be as key regulators of mineral homeostasis and bile acid/cholesterol metabolism, by inducing of Klotho overexpression. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

[Study on the chemical constituents in Pouzolzia zeylanica].

PubMed

Fu, Ming; Niu, You-Ya; Yu, Juan; Kong, Qing-Tong

2012-11-01

To study the chemical constituents of Pouzolzia zeylanica. Many chromatography means were used in separation and purification, and the structures of all compounds were identified by the means of spectroscopic analysis and physicochemical properties. 14 compounds were elucidated as: beta-sitosterol (1), daucosterol (2), oleanolic acid (3), epicatechin (4), alpha-amyrin (5), eugenyl-beta-rutinoside (6), 2alpha, 3alpha, 19alpha-trihydroxyurs-12-en-28-oic (7), scopolin (8), scutellarein-7-O-alpha-L-rhamnoside (9), scopoletin (10), quercetin (11), quercetin-3-O-beta-D-glucoside (12), apigenin (13), 2alpha-hydroxyursolic acid (14). All compounds are obtained from this plant for the first time.

Synthesis and Pro-Apoptotic Activity of Novel Glycyrrhetinic Acid Derivatives

PubMed Central

Logashenko, Evgeniya B; Salomatina, Oksana V; Markov, A V; Korchagina, Dina V; Salakhutdinov, Nariman F; Tolstikov, Genrikh A; Vlassov, Valentin V; Zenkova, Marina A

2011-01-01

Triterpenoids are used for medicinal purposes in many countries. Some, such as oleanolic and glycyrrhetinic acids, are known to be anti-inflammatory and anticarcinogenic. However, the biological activities of these naturally occurring molecules against their particular targets are weak, so the synthesis of new synthetic analogues with enhanced potency is needed. By combining modifications to both the A and C rings of 18βH-glycyrrhetinic acid, the novel synthetic derivative methyl 2-cyano-3,12-dioxo-18βH-olean-9(11),1(2)-dien-30-oate was obtained. This derivative displays high antiproliferative activity in cancer cells, including a cell line with a multidrug-resistance phenotype. It causes cell death by inducing the intrinsic caspase-dependent apoptotic pathway. PMID:21328513

Preparation, physicochemical characterization, and cell viability evaluation of long-circulating and pH-sensitive liposomes containing ursolic acid.

PubMed

Caldeira de Araújo Lopes, Sávia; Vinícius Melo Novais, Marcus; Salviano Teixeira, Cláudia; Honorato-Sampaio, Kinulpe; Tadeu Pereira, Márcio; Ferreira, Lucas Antônio Miranda; Braga, Fernão Castro; Cristina Oliveira, Mônica

2013-01-01

Cancer is one of the leading causes of death worldwide. Although several drugs are used clinically, some tumors either do not respond or are resistant to the existing pharmacotherapy, thus justifying the search for new drugs. Ursolic acid (UA) is a triterpene found in different plant species that has been shown to possess significant antitumor activity. However, UA presents a low solubility in aqueous medium, which presents a barrier to its biological applications. In this context, the use of liposomes presents a promising strategy to deliver UA and allow for its intravenous administration. In this work, long-circulating and pH-sensitive liposomes containing UA (SpHL-UA) were developed, and their chemical and physicochemical properties were evaluated. SpHL-UA presented adequate properties, including a mean diameter of 191.1 ± 6.4 nm, a zeta potential of 1.2 ± 1.4 mV, and a UA entrapment of 0.77 ± 0.01 mg/mL. Moreover, this formulation showed a good stability after having been stored for 2 months at 4 °C. The viability studies on breast (MDA-MB-231) and prostate (LNCaP) cancer cell lines demonstrated that SpHL-UA treatment significantly inhibited cancer cell proliferation. Therefore, the results of the present work suggest the applicability of SpHL-UA as a new and promising anticancer formulation.

Inhibition of breast tumor growth and angiogenesis by a medicinal herb: Ocimum sanctum

PubMed Central

Nangia-Makker, Pratima; Tait, Larry; Hogan, Victor; Shekhar, Malathy P.V.; Funasaka, Tatsuyoshi; Raz, Avraham

2013-01-01

Ocimum sanctum (OS) is a traditionally used medicinal herb, which shows anti-oxidant, anti-carcinogenic, radio-protective and free radical scavenging properties. So far no detailed studies have been reported on its effects on human cancers. Thus, we analyzed its effects on human breast cancer utilizing in vitro and in vivo methodologies. Aqueous extracts were prepared from the mature leaves of Ocimum sanctum cultivated devoid of pesticides. Tumor progression and angiogenesis related processes like chemotaxis, proliferation, apoptosis, 3-dimensional growth and morphogenesis, angiogenesis, and tumor growth were studied in the presence or absence of the extract and in some experiments a comparison was made with purified commercially available eugenol, apigenin and ursolic acid. Aqueous OS leaf extract inhibits proliferation, migration, anchorage independent growth, three dimensional growth and morphogenesis, and induction of COX-2 protein in breast cancer cells. A comparative analysis with eugenol, apigenin and ursolic acid showed that the inhibitory effects on chemotaxis and three dimensional morphogenesis of breast cancer cells were specific to OS extract. In addition, OS extracts also reduced tumor size and neoangiogenesis in a MCF10 DCIS.com xenograft model of human DCIS. This is the first detailed report showing that OS leaf extract may be of value as a breast cancer preventive and therapeutic agent and might be considered as additional additive in the arsenal of components aiming at combating breast cancer progression and metastasis. PMID:17437270

Anti-angiogenic activity and antitumor efficacy of amphiphilic twin drug from ursolic acid and low molecular weight heparin

NASA Astrophysics Data System (ADS)

Cheng, Wenming; Zohra Dahmani, Fatima; Zhang, Juan; Xiong, Hui; Wu, Yuanyuan; Yin, Lifang; Zhou, Jianping; Yao, Jing

2017-02-01

Heparin, a potential blood anti-coagulant, is also known for its binding ability to several angiogenic factors through electrostatic interactions due to its polyanionic character. However, the clinical application of heparin for cancer treatment is limited by several drawbacks, such as unsatisfactory therapeutic effects and severe anticoagulant activity that could induce hemorrhaging. Herein, low molecular weight heparin (LMWH) was conjugated to ursolic acid (UA), which is also an angiogenesis inhibitor, by binding the amine group of aminoethyl-UA (UA-NH2) with the carboxylic groups of LMWH. The resulting LMWH-UA conjugate as an amphiphilic twin drug showed reduced anticoagulant activity and could also self-assemble into nanomicelles with a mean particle size ranging from 200-250 nm. An in vitro endothelial tubular formation assay and an in vivo Matrigel plug assay were performed to verify the anti-angiogenic potential of LMWH-UA. Meanwhile, the in vivo antitumor effect of LMWH-UA was also evaluated using a B16F10 mouse melanoma model. LMWH-UA nanomicelles were shown to inhibit angiogenesis both in vitro and in vivo. In addition, the i.v. administration of LMWH-UA to the B16F10 tumor-bearing mice resulted in a significant inhibition of tumor growth as compared to the free drug solutions. These findings demonstrate the therapeutic potential of LMWH-UA as a new therapeutic remedy for cancer therapy.

Ursolic acid suppresses leptin-induced cell proliferation in rat vascular smooth muscle cells.

PubMed

Yu, Ya-Mei; Tsai, Chiang-Chin; Tzeng, Yu-Wen; Chang, Weng-Cheng; Chiang, Su-Yin; Lee, Ming-Fen

2017-07-01

Accumulating lines of evidence indicate that high leptin levels are associated with adverse cardiovascular health in obese individuals. Proatherogenic effects of leptin include endothelial cell activation and vascular smooth muscle cell proliferation and migration. Ursolic acid (UA) has been reported to exhibit multiple biological effects including antioxidant and anti-inflammatory properties. In this study, we investigated the effect of UA on leptin-induced biological responses in rat vascular smooth muscle cells (VSMCs). A-10 VSMCs were treated with leptin in the presence or absence of UA. Intracellular reactive oxygen species (ROS) was probed by 2',7'-dichlorofluorescein diacetate. The expression of extracellular signal-regulated kinase (ERK)1/2, phospho-(ERK)1/2, nuclear factor-kappa B (NF-κB) p65 and p50, and matrix metalloproteinase-2 (MMP2) was determined by Western blotting. Immunocytochemistry and confocal laser scanning microscopy were also used for the detection of NF-κB. The secretion of MMP2 was detected by gelatin zymography. UA exhibited antioxidant activities in vitro. In rat VSMCs, UA effectively inhibited cell growth and the activity of MMP2 induced by leptin. These suppressive effects appeared by decreasing the activation of (ERK)1/2, the nuclear expression and translocation of NF-κB, and the production of ROS. UA appeared to inhibit leptin-induced atherosclerosis, which may prevent the development of obesity-induced cardiovascular diseases.

Mounting evidence validates Ursolic Acid directly activates SIRT1: A powerful STAC which mimic endogenous activator of SIRT1.

PubMed

Bakhtiari, Nuredin; Mirzaie, Sako; Hemmati, Roohullah; Moslemee-Jalalvand, Elham; Noori, Ali Reza; Kazemi, Jahanfard

2018-07-15

Ursolic Acid (UA), a pentacyclic triterpenoid compound, plays a vital role in aging process. However, the role of UA in the regulation of aging and longevity is still controversial as we have previously demonstrated that UA increases SIRT1 protein level in aged-mice. Here, we reveal that UA directly activates SIRT1 in silico, in vitro and in vivo. We have identified that UA binds to outer surface of SIRT1 and leads to tight binding of substrates to enzyme in comparison with Resveratrol (RSV) and control. Furthermore, our results indicate that UA drives the structure of SIRT1 toward a closed state (an active form of enzyme). Interestingly, our experimental findings are in agreement with the molecular dynamic results. Based on our data, UA increases the affinity of enzyme for both substrates with decreasing Km value, while enhances the Vmax of enzyme. Additionally, we have determined that UA heightened SIRT1 catalytic efficiency by 2 folds compared with RSV. Thereby, to identify the endogenous activator of SIRT1, UA was administrated to aged-mice and then the tissues were isolated. According to our results, it can be concluded that UA increases SIRT1 activity and mimics Lamin A and AROS behavior in the living cells. Copyright © 2018 Elsevier Inc. All rights reserved.

Ursolic acid supplementation decreases markers of skeletal muscle damage during resistance training in resistance-trained men: a pilot study

PubMed Central

Bang, Hyun Seok; Seo, Dae Yun; Chung, Young Min; Kim, Do Hyung; Lee, Sam-Jun; Lee, Sung Ryul; Kwak, Hyo-Bum; Kim, Tae Nyun; Kim, Min; Oh, Kyoung-Mo; Son, Young Jin; Kim, Sanghyun

2017-01-01

Ursolic acid (UA) supplementation was previously shown to improve skeletal muscle function in resistance-trained men. This study aimed to determine, using the same experimental paradigm, whether UA also has beneficial effects on exercise-induced skeletal muscle damage markers including the levels of cortisol, B-type natriuretic peptide (BNP), myoglobin, creatine kinase (CK), creatine kinase-myocardial band (CK-MB), and lactate dehydrogenase (LDH) in resistance-trained men. Sixteen healthy participants were randomly assigned to resistance training (RT) or RT+UA groups (n=8 per group). Participants were trained according to the RT program (60~80% of 1 repetition, 6 times/week), and the UA group was additionally given UA supplementation (450 mg/day) for 8 weeks. Blood samples were obtained before and after intervention, and cortisol, BNP, myoglobin, CK, CK-MB, and LDH levels were analyzed. Subjects who underwent RT alone showed no significant change in body composition and markers of skeletal muscle damage, whereas RT+UA group showed slightly decreased body weight and body fat percentage and slightly increased lean body mass, but without statistical significance. In addition, UA supplementation significantly decreased the BNP, CK, CK-MB, and LDH levels (p<0.05). In conclusion, UA supplementation alleviates increased skeletal muscle damage markers after RT. This finding provides evidence for a potential new therapy for resistance-trained men. PMID:29200908

[Chemical constituents from herbs of Swertia delavayi].

PubMed

Xia, Cong-long; Liu, Guang-ming; Zhang, Hao

2008-08-01

To isolate and identify the chemical constituents of 95% alcohol extract from Swertia delavayi. The compounds were isolated and purified by column chromatogrphy and their structures were identified by the physicochemical properties and spectral analyses. Seven compounds were isolated and identified as oleanolic acid (1), gentiopcroside (2), swertiamarin (3), daucosterol (4), swertiadecoraxanthone-II (5), isovitexin (6), isoorientin (7). Compounds 2-7 were isolated from S. delavayi for the first time. While the compound 6 was firstly reported from the genus Swertia.

Bioactive saponins from the fruits of Aesculus pavia L.

PubMed

Sun, Zhen-Liang; Zhang, Ming; Wu, Ying; Wan, Ai-Hong; Zhang, Rong

2011-10-01

Continued chemical investigation on the fruits of Aesculus pavia L. resulted in theisolation and identification of two new oleanolic acid saponins, namely vaccaroside A (1) andvaccaroside B (2). The isolated furostanol saponins were evaluated for cytotoxic activity againsthuman normal amniotic and human lung carcinoma cell lines using neutral red and MTT assays.In vitro experiments showed significant cytotoxicity in a dose dependent manner with IC₅₀ valuesin the range of 27.80-79.02 μM. Copyright © 2011 Elsevier B.V. All rights reserved.

An updated review on the parasitic herb of Cuscuta reflexa Roxb.

PubMed

Patel, Satish; Sharma, Vikas; Chauhan, Nagendra S; Dixit, Vinod K

2012-03-01

Cuscuta reflexa Roxb. is a golden yellow, leafless, perennial, parasitic herb of the family Convolvulaceae. C. reflexa has been investigated for antispasmodic, hemodynamic, anticonvulsant, anti steroidogenic, antihypertensive, muscle relaxant, cardiotonic, antiviral, antibacterial, antioxidant, cholinergic, diuretic and hair growth activities. Many chemical constituents have been isolated from C. reflexa such as cuscutin, amarbelin, β-sitosterol, stigmasterol, kaempferol, dulcitol, myricetin, quercetin, coumarin and oleanolic acid. This review presents a detailed survey of the literature on pharmacognosy, phytochemistry and traditional and biological medicinal uses of C. reflexa.

[Chemical constituents from Exochorda racemosa].

PubMed

Zhang, Jiajia; Li, Xiangmei; Ren, Lihua; Fang, Chengwu; Wang, Fei

2011-05-01

To study the chemical constituents of Exochorda racemosa. Compounds were isolated and purified by silica gel, Sephadex LH-20, MCI gel and RP-18 column chromatography, and their structures were determined by spectroscopic analysis. Twenty compounds were isolated and identified as N-p-coumaroyl-N'-caffeoylputrescine (1), sutherlandin trans-p-coumarate (2), apigenin 7-O-methylglucuronide (3), astragalin (4), nicotiflorin (5), kaempferol 3-neohesperidoside (6), rutin (7), apigenin (8), luteolin (9), linalool-1-oic acid (10), betulalbuside A (11), ursolic acid (12) , corosolic acid (13), gynuramide II (14), beta-sitosterol (15), daucosterol (16), uridine (17), adenosine (18), syringin (19), and trans4-hydroxycinnamic acid (20), respectively. All compounds were obtained from this plant for the first time, moreover, 1 was reported as a new natural product, and 2 is a naturally rare cyanogenic glycoside.

Ursolic Acid-Induced Elevation of Serum Irisin Augments Muscle Strength During Resistance Training in Men

PubMed Central

Bang, Hyun Seok; Seo, Dae Yun; Chung, Yong Min; Oh, Kyoung-Mo; Park, Jung Jun; Arturo, Figueroa; Jeong, Seung-Hun; Kim, Nari

2014-01-01

Ursolic acid (UA), a type of pentacyclic triterpenoid carboxylic acid purified from natural plants, can promote skeletal muscle development. We measured the effect of resistance training (RT) with/without UA on skeletal muscle development and related factors in men. Sixteen healthy male participants (age, 29.37±5.14 years; body mass index=27.13±2.16 kg/m2) were randomly assigned to RT (n=7) or RT with UA (RT+UA, n=9) groups. Both groups completed 8 weeks of intervention consisting of 5 sets of 26 exercises, with 10~15 repetitions at 60~80% of 1 repetition maximum and a 60~90-s rest interval between sets, performed 6 times/week. UA or placebo was orally ingested as 1 capsule 3 times/day for 8 weeks. The following factors were measured pre-and post-intervention: body composition, insulin, insulin-like growth factor-1 (IGF-1), irisin, and skeletal muscle strength. Body fat percentage was significantly decreased (p<0.001) in the RT+UA group, despite body weight, body mass index, lean body mass, glucose, and insulin levels remaining unchanged. IGF-1 and irisin were significantly increased compared with baseline levels in the RT+UA group (p<0.05). Maximal right and left extension (p<0.01), right flexion (p<0.05), and left flexion (p<0.001) were significantly increased compared with baseline levels in the RT+UA group. These findings suggest that UA-induced elevation of serum irisin may be useful as an agent for the enhancement of skeletal muscle strength during RT. PMID:25352765

[Studies on the chemical constituents of Lonicera macranthoides].

PubMed

Jia, Xiao-Dong; Zhao, Xing-Zeng; Wang, Ming; Dong, Yun-Fa; Feng, Xu

2008-07-01

To study the chemical constituents of flower buds of Lonicera macranthoides. The 90% EtOH extract of Lonicera macranthoides. was successively partitioned with petroleum ether and ethyl acetete. Repeated column chromatography of the ethyl acetete fraction afforded the following compounds (1-9): ginnol (1), triacontanol (2), ursolic acid (3), beta-sitosterol (4), triacontane (5), palmitic acid (6), beta-daucosterol (7), 3-decyl-3-octyldocosan-1-ol (8), 3-dodecyl-3-nonyldocosan-1-ol (9). All compounds except 4 are isolated from this plant for the first time while compounds 2, 3, 5, 8 and 9 are their first time been isolated from genus Lonicera.

Chemical constituents from Melastoma dodecandrum and their inhibitory activity on interleukin-8 production in HT-29 cells.

PubMed

Yang, Guo-Xun; Zhang, Rui-Ze; Lou, Bin; Cheng, Ke-Jun; Xiong, Juan; Hu, Jin-Feng

2014-01-01

In search of anti-inflammatory lead compounds from traditional Chinese medicines, a bioassay-guided phytochemical study on Melastoma dodecandrum was carried out. As a result, 18 compounds have been isolated. Their chemical structures were determined on the basis of their physicochemical properties and spectral data. Among the isolates, three pentacyclic triterpenoids, ursolic acid (1), asiatic acid (3) and terminolic acid (6), together with one tannin casuarinin (17), were found to significantly decrease interleukin-8 (IL-8) production in human colon cancer cells. The results imply, at least in part, that the anti-inflammatory effect of M. dodecandrum could be due to inhibition of IL-8 production, demonstrated by these naturally occurring compounds described above.

In vivo effects of diabetes, insulin and oleanolic acid on enzymes of glycogen metabolism in the skin of streptozotocin-induced diabetic male Sprague-Dawley rats.

PubMed

Mukundwa, Andrew; Langa, Silvana O; Mukaratirwa, Samson; Masola, Bubuya

2016-03-04

The skin is the largest organ in the body and diabetes induces pathologic changes on the skin that affect glucose homeostasis. Changes in skin glycogen and glucose levels can mirror serum glucose levels and thus the skin might contribute to whole body glucose metabolism. This study investigated the in vivo effects of diabetes, insulin and oleanolic acid (OA) on enzymes of glycogen metabolism in skin of type 1 diabetic rats. Diabetic and non-diabetic adult male Sprague-Dawley rats were treated with a single daily dose of insulin (4 IU/kg body weight), OA (80 mg/kg body weight) and a combination of OA + insulin for 14 days. Glycogen phosphorylase (GP) expression; and GP, glycogen synthase (GS) and hexokinase activities as well glycogen levels were evaluated. The results suggest that diabetes lowers hexokinase activity, GP activity and GP expression with no change in GS activity whilst the treatments increased GP expression and the activities of hexokinase, GP and GS except for the GS activity in OA treated rats. Glycogen levels were increased slightly by diabetes as well as OA treatment. In conclusion diabetes, OA and insulin can lead to changes in GS and GP activities in skin without significantly altering the glycogen content. We suggest that the skin may contribute to whole body glucose homeostasis particularly in disease states. Copyright © 2016 Elsevier Inc. All rights reserved.

Liquid chromatography tandem mass spectrometric determination of triterpenes in human fluids: Evaluation of markers of dietary intake of olive oil and metabolic disposition of oleanolic acid and maslinic acid in humans.

PubMed

Pozo, Oscar J; Pujadas, Mitona; Gleeson, Sarah Biel; Mesa-García, Maria Dolores; Pastor, Antoni; Kotronoulas, Aristotelis; Fitó, Montserrat; Covas, Maria-Isabel; Navarro, José Ramón Fernández; Espejo, Juan Antonio; Sanchez-Rodriguez, Estefania; Marchal, Rosa; Calleja, Miguel Angel; de la Torre, Rafael

2017-10-16

Olive oil is rich in several minor components like maslinic (MA) and oleanolic (OA) acids which have cardioprotective, antitumor, and anti-inflammatory properties. In order to assess the health benefits in humans provided by the olive oil triterpenes (MA and OA), suitable analytical methods able to quantify the low concentrations expected in human fluids are required. In this study, the LC-MS/MS quantification of both OA and MA in plasma and urine has been evaluated. The plasmatic method is based on the direct determination of the analytes. The urinary detection requires more sensitivity which was reached by derivatization with 2-picolylamine. Additionally, the urinary species present after MA and OA ingestion were evaluated by the direct detection of several phase II metabolites previously synthesized. Our results showed that OA is metabolized as both sulfate and glucuronide conjugates whereas MA is mainly excreted as glucuronide. Based on this information, the method for the urinary detection of MA and OA involved an enzymatic hydrolysis. Both plasmatic and urinary methods were validated with suitable precision and accuracy at all tested levels. Required sensitivity was achieved in both matrices. Up to our knowledge, this is the first method able to quantify the low concentration levels of triterpenes present in urine. Samples from two healthy volunteers who received virgin olive oils with different triterpenes content were analyzed. Some preliminary clues on the metabolic disposition of OA and MA after olive oil intake are provided. Copyright © 2017 Elsevier B.V. All rights reserved.

Oleanolic and maslinic acid sensitize soft tissue sarcoma cells to doxorubicin by inhibiting the multidrug resistance protein MRP-1, but not P-glycoprotein.

PubMed

Villar, Victor Hugo; Vögler, Oliver; Barceló, Francisca; Gómez-Florit, Manuel; Martínez-Serra, Jordi; Obrador-Hevia, Antònia; Martín-Broto, Javier; Ruiz-Gutiérrez, Valentina; Alemany, Regina

2014-04-01

The pentacyclic triterpenes oleanolic acid (OLA) and maslinic acid (MLA) are natural compounds present in many plants and dietary products consumed in the Mediterranean diet (e.g., pomace and virgin olive oils). Several nutraceutical activities have been attributed to OLA and MLA, whose antitumoral effects have been extensively evaluated in human adenocarcinomas, but little is known regarding their effectiveness in soft tissue sarcomas (STS). We assessed efficacy and molecular mechanisms involved in the antiproliferative effects of OLA and MLA as single agents or in combination with doxorubicin (DXR) in human synovial sarcoma SW982 and leiomyosarcoma SK-UT-1 cells. As single compound, MLA (10-100 μM) was more potent than OLA, inhibiting the growth of SW982 and SK-UT-1 cells by 70.3 ± 1.11% and 68.8 ± 1.52% at 80 μM, respectively. Importantly, OLA (80 μM) or MLA (30 μM) enhanced the antitumoral effect of DXR (0.5-10 μM) by up to 2.3-fold. On the molecular level, efflux activity of the multidrug resistance protein MRP-1, but not of the P-glycoprotein, was inhibited. Most probably as a consequence, DXR accumulated in these cells. Kinetic studies showed that OLA behaved as a competitive inhibitor of substrate-mediated MRP-1 transport, whereas MLA acted as a non-competitive one. Moreover, none of both triterpenes induced a compensatory increase in MRP-1 expression. In summary, OLA or MLA sensitized cellular models of STS to DXR and selectively inhibited MRP-1 activity, but not its expression, leading to a higher antitumoral effect possibly relevant for clinical treatment. Copyright © 2014 Elsevier Inc. All rights reserved.

Rauvolfianine, a new antimycobacterial glyceroglycolipid and other constituents from Rauvolfia caffra. Sond (Apocynaceae).

PubMed

Ebeh Messanga, Robert; Dominique Serge, Ngono Bikobo; Abouem A Zintchem, Auguste; Norbert, Mbabi Nyemeck Ii; Esther Del Florence, Moni Ndedi; Patrick Hervé, Betote Diboué; Maximilienne Ascension, Nyegue; Alex De Théodore, Atchadé; Dieudonné Emmanuel, Pegnyemb; Christian G, Bochet; Koert, Ulrich

2017-08-16

The chemical investigation of the extract of the dried leaves of Rauvolfia caffra (Sond) (synonym Rauvolfia macrophylla) (Apocynaceae) led to isolation of a new glycoside derivative, rauvolfianine (1) as well as six known compounds: oleanolic acid (2), sitosterol-3-O-β-D-glucopyranoside (3), betulinic acid (4), vellosimine (5), sarpagine (6) and D-fructofuranosyl-β-(2→1)-α-D-glucopyranoside (7). Compounds 1, 2, 3, 4 and 7 were evaluated for antitubercular activity. Compounds 1 and 2 were the most active (MIC = 7.8125 and 31.25 μg/mL) towards the Isoniazid resistant strain of Mycobacterium tuberculosis AC45. Their structures and relative stereochemistry were elucidated by spectroscopic methods.

Hypoxia pathway and hypoxia-mediated extensive extramedullary hematopoiesis are involved in ursolic acid's anti-metastatic effect in 4T1 tumor bearing mice

PubMed Central

Gao, Jian-Li; Shui, Yan-Mei; Jiang, Wei; Huang, En-Yi; Shou, Qi-Yang; Ji, Xin; He, Bai-Cheng; Lv, Gui-Yuan; He, Tong-Chuan

2016-01-01

Hypoxic in the tumor mass is leading to the myeloproliferative-like disease (leukemoid reaction) and anemia of body, which characterized by strong extensive extramedullary hematopoiesis (EMH) in spleen. As the key transcription factor of hypoxia, hypoxia-inducible factor-1 (HIF-1) activates the expression of genes essential for EMH processes including enhanced blood cell production and angiogenesis. We found ursolic acid (UA), a natural pentacyclic triterpenoid carboxylic acid, inhibited growth of breast cancer both in vivo and in vitro. The suppression was mediated through the inhibition of multiple cell pathways linked to inflammation, proliferation, angiogenesis, and metastasis. UA also suppressed the leukemoid reaction and the EMH phenomenon of the tumor bearing mice without any significant suppression on body weight (i.p. by 20 mg/kg for 28 days). This is associated with the significant decrease in white blood cells (WBC), platelets (PLT) and spleen weight. During this process, we also detected the down-regulation of cell proliferative genes (PCNA, and β-catenin), and metastatic genes (VEGF, and HIF-1α), as well as the depression of nuclear protein intensity of HIF-1α. Furthermore, the expression of E2F1, p53 and MDM2 genes were increased in UA group when the VEGF and HIF-1α was over-expressed. Cancer cells were sensitive to UA treating after the silencing of HIF-1α and the response of Hypoxic pathway reporter to UA was suppressed when HIF-1α was over expressed. Overall, our results from experimental and predictive studies suggest that the anticancer activity of UA may be at least in part caused by suppressing the cancer hypoxia and hypoxia-mediated EMH. PMID:27708244

A smart pH-responsive nano-carrier as a drug delivery system for the targeted delivery of ursolic acid: suppresses cancer growth and metastasis by modulating P53/MMP-9/PTEN/CD44 mediated multiple signaling pathways.

PubMed

Jiang, Kai; Chi, Ting; Li, Tao; Zheng, Guirong; Fan, Lulu; Liu, Yajun; Chen, Xiufen; Chen, Sijia; Jia, Lee; Shao, Jingwei

2017-07-13

Ursolic acid (UA) has been recently used as a promising anti-tumor and cancer metastatic chemo-preventive agent due to its low toxicity and liver-protecting property. However, the low bioavailability and nonspecific tumor targeting restrict its further clinical application. To address the problem, a silica-based mesoporous nanosphere (MSN) controlled-release drug delivery system (denoted UA@M-CS-FA) was designed and successfully synthesized, and was functionalized with folic acid (FA) and pH-sensitive chitosan (CS) for the targeted delivery of UA to folate receptor (FR) positive tumor cells. UA@M-CS-FA were spherical with mean diameter below 150 nm, and showed about -20 mV potential. Meanwhile, UA@M-CS-FA exhibited a pH-sensitive release manner and high cellular uptake in FR over-expressing HeLa cancer cells. Also, in vitro cellular assays suggested that UA@M-CS-FA inhibited cancer cell growth, invasion and migration. Mechanistically, UA@M-CS-FA induced cancer cell apoptosis and inhibited migration via cell cycle arrest in the G0/G1 stage, regulating the PARP/Bcl-2/MMP-9/CD44/PTEN/P53. Importantly, in vivo experiments further confirmed that UA@M-CS-FA significantly suppressed the tumor progression and lung metastasis in tumor-bearing nude mice. Immunohistochemical analysis revealed that UA@M-CS-FA treatment regulated CD44, a biomarker of cancer metastasis. Overall, our data demonstrated that a CS and FA modified MSN controlled-release drug delivery system could help broaden the usage of UA and reflect the great application potential of the UA as an anticancer or cancer metastatic chemopreventive agent.

Ursolic Acid-enriched herba cynomorii extract induces mitochondrial uncoupling and glutathione redox cycling through mitochondrial reactive oxygen species generation: protection against menadione cytotoxicity in h9c2 cells.

PubMed

Chen, Jihang; Wong, Hoi Shan; Ko, Kam Ming

2014-01-27

Herba Cynomorii (Cynomorium songaricum Rupr., Cynomoriaceae) is one of the most commonly used 'Yang-invigorating' tonic herbs in Traditional Chinese Medicine (TCM). An earlier study in our laboratory has demonstrated that HCY2, an ursolic acid-enriched fraction derived from Herba Cynomorii, increased mitochondrial ATP generation capacity (ATP-GC) and induced mitochondrial uncoupling as well as a cellular glutathione response, thereby protecting against oxidant injury in H9c2 cells. In this study, we demonstrated that pre-incubation of H9c2 cells with HCY2 increased mitochondrial reactive oxygen species (ROS) generation in these cells, which is likely an event secondary to the stimulation of the mitochondrial electron transport chain. The suppression of mitochondrial ROS by the antioxidant dimethylthiourea abrogated the HCY2-induced enhancement of mitochondrial uncoupling and glutathione reductase (GR)-mediated glutathione redox cycling, and also protected against menadione-induced cytotoxicity. Studies using specific inhibitors of uncoupling protein and GR suggested that the HCY2-induced mitochondrial uncoupling and glutathione redox cycling play a determining role in the cytoprotection against menadione-induced oxidant injury in H9c2 cells. Experimental evidence obtained thus far supports the causal role of HCY2-induced mitochondrial ROS production in eliciting mitochondrial uncoupling and glutathione antioxidant responses, which offer cytoprotection against oxidant injury in H9c2 cells.

Ursolic Acid Attenuates Atherosclerosis in ApoE-/- Mice: Role of LOX-1 Mediated by ROS/NF-κB Pathway.

PubMed

Li, Qiu; Zhao, Wenwen; Zeng, Xi; Hao, Zhihui

2018-05-07

Atherosclerosis, a chronic inflammatory disease, is a major contributor to cardiovascular diseases. Ursolic acid (UA) is a phytonutrient with widely biological effects including anti-oxidative, anti-inflammatory, and so on. At present, the effect of UA on atherosclerosis and the mechanism of action are still obscure. This study focused on investigating the effects of UA on atherosclerosis both in vivo and in vitro. We first selected LOX-1 as our target, which was reckoned as a new promising receptor for treating atherosclerosis. The evaluation in vitro suggested that UA significantly decreased endothelial LOX-1 expression induced by LPS both in mRNA and protein levels. Pre-treatment of UA also inhibited TLR4/MyD88 signaling activated by LPS. Moreover, UA reduced ROS production and suppressed the activation of NF-κB stimulated by LPS. Particularly, the evaluation in vivo further verified the conclusion obtained in vitro. In ApoE −/− mice fed with an atherogenic diet, both UA (100 mg/kg/day) and simvastatin significantly attenuated atherosclerotic plaque formation and shrunk necrotic core areas. The enhanced expression of LOX-1 in atherosclerotic aorta was also dramatically decreased by administration of UA. Taken together, these results suggested that UA, with anti-atherosclerotic activity through inhibition of LOX-1 mediated by ROS/NF-κB signaling pathways, may become a valuable vascular protective candidate for the treatment of atherosclerosis.

Oral supplementation with ursolic acid ameliorates sepsis-induced acute kidney injury in a mouse model by inhibiting oxidative stress and inflammatory responses.

PubMed

Zhang, Zhenyu; Zhang, Hong; Chen, Rui; Wang, Zhong

2018-05-01

Ursolic acid (UA) as a multiple bioactive native compound has recently been demonstrated to treat sepsis in animal models. However, the beneficial effects of UA in sepsis‑induced acute kidney injury (AKI) are not completely understood. In the present study, the effect of UA on sepsis‑induced AKI in cecal ligation and puncture (CLP) surgery mice was investigated. Renal histomorphological analysis was performed by hematoxylin and eosin staining. The expression of inflammatory markers in the kidney of septic mice was measured by reverse transcription‑quantitative polymerase chain reaction and western blotting. The results demonstrated that UA administration improved survival in septic mice induced by CLP surgery. The treatment with UA revealed protection against AKI induced by CLP surgery, including the alleviation of glomerular damage and vacuolization in the proximal tubules. In addition, the effects of UA on oxidative stress and inflammation in septic mice were determined. The findings suggested that UA may protect against sepsis‑induced AKI by inhibiting reactive oxygen species and inflammatory cytokines, including tumor necrosis factor‑α, interleukin (IL)‑1β and IL‑6, in the kidney from septic mice. Finally, UA inhibited CLP‑induced activation of nuclear factor‑κB signaling in the kidney from septic mice. The findings of the present study demonstrated that UA may be used as a potential therapeutic agent for complications of sepsis, especially for sepsis-induced AKI.

Oral supplementation with ursolic acid ameliorates sepsis-induced acute kidney injury in a mouse model by inhibiting oxidative stress and inflammatory responses

PubMed Central

Zhang, Zhenyu; Zhang, Hong; Chen, Rui; Wang, Zhong

2018-01-01

Ursolic acid (UA) as a multiple bioactive native compound has recently been demonstrated to treat sepsis in animal models. However, the beneficial effects of UA in sepsis-induced acute kidney injury (AKI) are not completely understood. In the present study, the effect of UA on sepsis-induced AKI in cecal ligation and puncture (CLP) surgery mice was investigated. Renal histomorphological analysis was performed by hematoxylin and eosin staining. The expression of inflammatory markers in the kidney of septic mice was measured by reverse transcription-quantitative polymerase chain reaction and western blotting. The results demonstrated that UA administration improved survival in septic mice induced by CLP surgery. The treatment with UA revealed protection against AKI induced by CLP surgery, including the alleviation of glomerular damage and vacuolization in the proximal tubules. In addition, the effects of UA on oxidative stress and inflammation in septic mice were determined. The findings suggested that UA may protect against sepsis-induced AKI by inhibiting reactive oxygen species and inflammatory cytokines, including tumor necrosis factor-α, interleukin (IL)-1β and IL-6, in the kidney from septic mice. Finally, UA inhibited CLP-induced activation of nuclear factor-κB signaling in the kidney from septic mice. The findings of the present study demonstrated that UA may be used as a potential therapeutic agent for complications of sepsis, especially for sepsis-induced AKI. PMID:29568928

A "natural" approach: synthesis and cytoxicity of monodesmosidic glycyrrhetinic acid glycosides.

PubMed

Schwarz, Stefan; Siewert, Bianka; Xavier, Nuno M; Jesus, Ana R; Rauter, Amélia P; Csuk, René

2014-01-24

Several pentacyclic triterpenoic acids have shown noteworthy antitumor activity, among them betulinic acid as well as oleanolic acid and derivatives thereof. Glycyrrhetinic acid (GA) exhibits some cytotoxic activity albeit this compound is not as active as betulinic acid, but GA came in the focus of scientific interest since it triggers apoptosis in tumor cells. In addition, it can be extracted from the roots of liquorice in high yields. Previous studies revealed that the introduction of an extra hydrophilic moiety increases the cytotoxicity of these compounds. Thus, a series of GA glycosides was prepared utilizing hexoses as well as pentoses (in D- and L-configuration) by using glycosyl trichloroacetimidates and TMSOTf as catalyst. The compounds were screened for cytotoxic activity against seven human cancer cell lines and the not malignant murine cell line NIH 3T3using a photometric SRB assay. The compounds trigger apoptosis as shown from extra trypan blue and acridine orange/ethidium bromide staining. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

Monoamine Oxidase and Dopamine β-Hydroxylase Inhibitors from the Fruits of Gardenia jasminoides

PubMed Central

Kim, Ji Ho; Kim, Gun Hee; Hwang, Keum Hee

2012-01-01

This research was designed to determine what components of Gardenia jasminoides play a major role in inhibiting the enzymes related antidepressant activity of this plant. In our previous research, the ethyl acetate fraction of G. jasminosides fruits inhibited the activities of both monoamine oxidase-A (MAO-A) and monoamine oxidase-B (MAO-B), and oral administration of the ethanolic extract slightly increased serotonin concentrations in the brain tissues of rats and decreased MAO-B activity. In addition, we found through in vitro screening test that the ethyl acetate fraction showed modest inhibitory activity on dopamine-β hydroxylase (DBH). The bioassay-guided fractionation led to the isolation of five bio-active compounds, protocatechuic acid (1), geniposide (2), 6'-O-trans-p-coumaroylgeniposide (3), 3,5-d-ihydroxy-1,7-bis (4-hydroxyphenyl) heptanes (4), and ursolic acid (5), from the ethyl acetate fraction of G. jasminoides fruits. The isolated compounds showed different inhibitory potentials against MAO-A, -B, and DBH. Protocatechuic acid showed potent inhibition against MAO-B (IC50 300 μmol/L) and DBH (334 μmol/L), exhibiting weak MAO-A inhibition (2.41 mmol/L). Two iridoid glycosides, geniposide (223 μmol/L) and 6'-O-trans-p-coumaroylgeniposide (127μmol/L), were selective MAO-B inhibitor. Especially, 6'-O-trans-p-coumaroylgeniposide exhibited more selective MAO-B inhibition than deprenyl, well-known MAO-B inhibitor for the treatment of early-stage Parkinson’s disease. The inhibitory activity of 3,5-di-hydroxy-1,7-bis (4-hydroxyphenyl) heptane was strong for MAO-B (196 μmol/L), modest for MAO-A (400 μmol/L), and weak for DBH (941 μmol/L). Ursolic acid exhibited significant inhibition of DBH (214 μmol/L), weak inhibition of MAO-B (780 μmol/L), and no inhibition against MAO-A. Consequently, G. jasminoides fruits are considerable for development of biofunctional food materials for the combination treatment of depression and neurodegenerative disorders. PMID:24116298

Protective effects of pretreatment with oleanolic acid in rats in the acute phase of hepatic ischemia-reperfusion injury: role of the PI3K/Akt pathway.

PubMed

Gui, Bo; Hua, Fuzhou; Chen, Jie; Xu, Zeping; Sun, Hongbin; Qian, Yanning

2014-01-01

Oleanolic acid (OA) has been used to treat liver disorders, but whether it can attenuate hepatic ischemia-reperfusion- (IR-) associated liver dysfunction remains unexplored. In the present study, 160 male Sprague-Dawley rats were equally divided into five groups: group SH received neither hepatic IR nor drugs; group IR received hepatic IR without drugs; group CM and group OA received 0.5% sodium carboxymethylcellulose and 100 mg/kg OA, intragastrically, once a day for seven days before the hepatic IR, respectively; on the basis of treatment in group OA, group OA+wortmannin further received 15 μg/kg of PI3K inhibitor wortmannin, intraperitoneally, 30 min before the hepatic IR. Then each group was equally divided into four subgroups according to four time points (preoperation, 0 h, 3 h, and 6 h after reperfusion). Serum ALT activity, IL-1β concentration, and hepatic phosphorylation of PI3K, Akt, and GSK-3β protein expression were serially studied. We found that OA pretreatment improved histological status and decreased serum ALT and IL-1β levels. It also increased p-PI3K, p-Akt, and p-GSK-3β protein expression at all the four time points. Prophylactic wortmannin partially reversed OA's protective effects. The data indicate that OA pretreatment protects liver from IR injury during the acute phase partially through PI3K/Akt-mediated inactivation of GSK-3β.

Therapeutic role of ursolic acid on ameliorating hepatic steatosis and improving metabolic disorders in high-fat diet-induced non-alcoholic fatty liver disease rats.

PubMed

Li, Songtao; Liao, Xilu; Meng, Fanyu; Wang, Yemei; Sun, Zongxiang; Guo, Fuchuan; Li, Xiaoxia; Meng, Man; Li, Ying; Sun, Changhao

2014-01-01

Non-alcoholic fatty liver disease (NAFLD) is one of the most prevalent liver diseases around the world, and is closely associated with obesity, diabetes, and insulin resistance. Ursolic acid (UA), an ubiquitous triterpenoid with multifold biological roles, is distributed in various plants. This study was conducted to investigate the therapeutic effect and potential mechanisms of UA against hepatic steatosis in a high-fat diet (HFD)-induced obese non-alcoholic fatty liver disease (NAFLD) rat model. Obese NAFLD model was established in Sprague-Dawley rats by 8-week HFD feeding. Therapeutic role of UA was evaluated using 0.125%, 0.25%, 0.5% UA-supplemented diet for another 6 weeks. The results from both morphologic and histological detections indicated that UA significantly reversed HFD-induced hepatic steatosis and liver injury. Besides, hepatic peroxisome proliferator-activated receptor (PPAR)-α was markedly up-regulated at both mRNA and protein levels by UA. Knocking down PPAR-α significantly inhibited the anti-steatosis role of UA in vitro. HFD-induced adverse changes in the key genes, which participated in hepatic lipid metabolism, were also alleviated by UA treatment. Furthermore, UA significantly ameliorated HFD-induced metabolic disorders, including insulin resistance, inflammation and oxidative stress. These results demonstrated that UA effectively ameliorated HFD-induced hepatic steatosis through a PPAR-α involved pathway, via improving key enzymes in the controlling of lipids metabolism. The metabolic disorders were accordingly improved with the decrease of hepatic steatosis. Thereby, UA could be a promising candidate for the treatment of NAFLD.

Compounds from Sedum caeruleum with antioxidant, anticholinesterase, and antibacterial activities.

PubMed

Bensouici, Chawki; Kabouche, Ahmed; Karioti, Anastasia; Öztürk, Mehmet; Duru, Mehmet Emin; Bilia, Anna Rita; Kabouche, Zahia

2016-01-01

This is the first study on the phytochemistry, antioxidant, anticholinesterase, and antibacterial activities of Sedum caeruleum L. (Crassulaceae). The objective of this study is to isolate the secondary metabolites and determine the antioxidant, anticholinesterase, and antibacterial activities of S. caeruleum. Six compounds (1-6) were isolated from the extracts of S. caeruleum and elucidated using UV, 1D-, 2D-NMR, and MS techniques. Antioxidant activity was investigated using DPPH(•), CUPRAC, and ferrous-ions chelating assays. Anticholinesterase activity was determined against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes using the Ellman method. Antibacterial activity was performed according to disc diffusion and minimum inhibitory concentration (MIC) methods. Isolated compounds were elucidated as ursolic acid (1), daucosterol (2), β-sitosterol-3-O-β-D-galactopyranoside (3), apigenin (4), apigetrin (5), and apiin (6). The butanol extract exhibited highest antioxidant activity in all tests (IC50 value: 28.35 ± 1.22 µg/mL in DPPH assay, IC50 value: 40.83 ± 2.24 µg/L in metal chelating activity, and IC50 value: 23.52 ± 0.44 µg/L in CUPRAC), and the highest BChE inhibitory activity (IC50 value: 36.89 ± 0.15 µg/L). Moreover, the chloroform extract mildly inhibited (MIC value: 80 µg/mL) the growth of all the tested bacterial strains. Ursolic acid (1), daucosterol (2), β-sitosterol-3-O-β-D-galactopyranoside (3), apigenin (4), apigetrin (5), and apiin (6) were isolated from Sedum caeruleum for the first time. In addition, a correlation was observed between antioxidant and anticholinesterase activities of bioactive ingredients of this plant.

α-Glucosidase Inhibition and Antibacterial Activity of Secondary Metabolites from the Ecuadorian Species Clinopodium taxifolium (Kunth) Govaerts.

PubMed

Morocho, Vladimir; Valle, Andrea; García, Jessica; Gilardoni, Gianluca; Cartuche, Luis; Suárez, Alírica I

2018-01-11

The phytochemical investigation of both volatile and fixed metabolites of Clinopodium taxifolium (Kunth) Govaerts (Lamiaceae) was performed for the first time. It allowed the isolation and characterization of the essential oil and six known compounds: carvacrol ( 1 ), squalane ( 2 ), uvaol ( 3 ), erythrodiol ( 4 ), ursolic acid ( 5 ), and salvigenin ( 6 ). Their structures were identified and characterized by Nuclear Magnetic Resonance (NMR) and Gas Chromatography coupled to Mass Spectroscopy (GC-MS), and corroborated by literature. The essential oil of the leaves was obtained by hydrodistillation in two different periods and analyzed by GC-MS and GC coupled to Flame Ionization Detector (GC-FID). A total of 54 compounds were detected, of which 42 were identified (including trace constituents). The major constituents were carvacrol methyl ether (18.9-23.2%), carvacrol (13.8-16.3%) and, carvacryl acetate (11.4-4.8%). The antibacterial activities were determined as Minimum Inhibition Concentration (MIC) against Staphylococcus aureus , Enterococcus faecalis , Escherichia coli , Klebsiella pneumoniae , Proteus vulgaris , Pseudomonas aeruginosa and Micrococcus luteus . The hexane and methanol extracts exhibited activity only against Klebsiella pneumoniae (250 and 500 μg/mL respectively), while the ethyl acetate extract was inactive. The hypoglycemic activity was evaluated by the in vitro inhibition of α-glucosidase. The ethyl acetate (EtOAc) extract showed strong inhibitory activity with IC 50 = 24.88 µg/mL, however methanolic and hexanic extracts showed weak activity. As a pure compound, only ursolic acid showed a strong inhibitory activity, with IC 50 = 72.71 μM.

Resistance to ursolic acid-induced apoptosis through involvement of melanogenesis and COX-2/PGE{sub 2} pathways in human M4Beu melanoma cancer cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hassan, Lama; Pinon, Aline; Limami, Youness

Melanoma is one of the most aggressive forms of cancer with a continuously growing incidence worldwide and is usually resistant to chemotherapy agents, which is due in part to a strong resistance to apoptosis. Previously, we had showed that B16-F0 murine melanoma cells undergoing apoptosis are able to delay their own death induced by ursolic acid (UA), a natural pentacyclic triterpenoid compound. We had demonstrated that tyrosinase and TRP-1 up-regulation in apoptotic cells and the subsequent production of melanin were implicated in an apoptosis resistance mechanism. Several resistance mechanisms to apoptosis have been characterized in melanoma such as hyperactivation ofmore » DNA repair mechanisms, drug efflux systems, and reinforcement of survival signals (PI3K/Akt, NF-κB and Raf/MAPK pathways). Otherwise, other mechanisms of apoptosis resistance involving different proteins, such as cyclooxygenase-2 (COX-2), have been described in many cancer types. By using a strategy of specific inhibition of each ways, we suggested that there was an interaction between melanogenesis and COX-2/PGE{sub 2} pathway. This was characterized by analyzing the COX-2 expression and activity, the expression of tyrosinase and melanin production. Furthermore, we showed that anti-proliferative and proapoptotic effects of UA were mediated through modulation of multiple signaling pathways including Akt and ERK-1/2 proteins. Our study not only uncovers underlying molecular mechanisms of UA action in human melanoma cancer cells but also suggest its great potential as an adjuvant in treatment and cancer prevention.« less

Antioxidant activity against H2O2-induced cytotoxicity of the ethanol extract and compounds from Pyrola decorate leaves.

PubMed

Yang, Xiliang; Peng, Qingyun; Liu, Qian; Hu, Jie; Tang, Zhipeng; Cui, Lianjie; Lin, Zonghao; Xu, Bing; Lu, Kuojian; Yang, Fang; Sheng, Zhizheng; Yuan, Qiong; Liu, Song; Zhang, Jiuliang; Zhou, Xuefeng

2017-12-01

The leaves of Pyrola decorate H. Andr (Pyrolaceae), known as Luxiancao, have long been used for treating kidney deficiency, gastric haemorrhage and rheumatic arthritic diseases in traditional Chinese medicine. The phytochemicals and antioxidant capacities in vitro of P. decorate leaves were investigated. Ethanol, petroleum ether, acetidin, n-butyl alcohol and aqueous extracts of Pyrola decorate leaves were prepared by solvent sequential process, and then isolated and purified to obtain phytochemicals. Cell viability was measured by MTT assay. PC12 cells were pretreated for 24 h with different extractions of P. decorate leaves at concentrations of 0.1, 0.5, 1, 5 and 10 mg/mL, then H 2 O 2 of 0.4 mM was added in all samples for an additional 2 h. The antioxidant capacities of betulin, ursolic acid and monotropein were determined in PC12 cells against H 2 O 2 induced cytotoxicity in vitro as well. Nine compounds (1-9) were isolated and structurally determined by spectroscopic methods, especially 2D NMR analyses. Ethanol extract treated groups showed inhibitory activity with IC 50 value of 10.83 mg/mL. Betulin, ursolic acid and monotropein were isolated from P. decorate, and demonstrated with IC 50 values of 6.88, 6.15 and 6.13 μg/mL, respectively. In conclusion, Pyrola decorate is a potential antioxidative natural plant and worth testing for further pharmacological investigation in the treatment of oxidative stress related neurological disease.

A novel co-drug of aspirin and ursolic acid interrupts adhesion, invasion and migration of cancer cells to vascular endothelium via regulating EMT and EGFR-mediated signaling pathways: multiple targets for cancer metastasis prevention and treatment

PubMed Central

Tang, Qiao; Liu, Yajun; Li, Tao; Yang, Xiang; Zheng, Guirong; Chen, Hongning; Jia, Lee; Shao, Jingwei

2016-01-01

Metastasis currently remains the predominant cause of breast carcinoma treatment failure. The effective targeting of metastasis-related-pathways in cancer holds promise for a new generation of therapeutics. In this study, we developed an novel Asp-UA conjugate, which was composed of classical “old drug” aspirin and low toxicity natural product ursolic acid for targeting breast cancer metastasis. Our results showed that Asp-UA could attenuate the adhesion, migration and invasion of breast cancer MCF-7 and MDA-MB-231 cells in a more safe and effective manner in vitro. Molecular and cellular study demonstrated that Asp-UA significantly down-regulated the expression of cell adhesion and invasion molecules including integrin α6β1, CD44, MMP-2, MMP-9, COX-2, EGFR and ERK proteins, and up-regulated the epithelial markers “E-cadherin” and “β-catenin”, and PTEN proteins. Furthermore, Asp-UA (80 mg/kg) reduced lung metastasis in a 4T1 murine breast cancer metastasis model more efficiently, which was associated with a decrease in the expression of CD44. More importantly, we did not detect side effects with Asp-UA in mice such as weight loss and main viscera tissues toxicity. Overall, our research suggested that co-drug Asp-UA possessed potential metastasis chemoprevention abilities via influencing EMT and EGFR-mediated pathways and could be a more promising drug candidate for the prevention and/or treatment of breast cancer metastasis. PMID:27683033

Potential Protective Effects of Ursolic Acid against Gamma Irradiation-Induced Damage Are Mediated through the Modulation of Diverse Inflammatory Mediators

PubMed Central

Wang, Hong; Sim, Meng-Kwoon; Loke, Weng Keong; Chinnathambi, Arunachalam; Alharbi, Sulaiman Ali; Tang, Feng Ru; Sethi, Gautam

2017-01-01

This study was aimed to evaluate the possible protective effects of ursolic acid (UA) against gamma radiation induced damage both in vitro as well as in vivo. It was observed that the exposure to gamma radiation dose- and time-dependently caused a significant decrease in the cell viability, while the treatment of UA attenuated this cytotoxicity. The production of free radicals including reactive oxygen species (ROS) and NO increased significantly post-irradiation and further induced lipid peroxidation and oxidative DNA damage in cells. These deleterious effects could also be effectively blocked by UA treatment. In addition, UA also reversed gamma irradiation induced inflammatory responses, as indicated by the decreased production of TNF-α, IL-6, and IL-1β. NF-κB signaling pathway has been reported to be a key mediator involved in gamma radiation-induced cellular damage. Our results further demonstrated that gamma radiation dose- and time-dependently enhanced NF-κB DNA binding activity, which was significantly attenuated upon UA treatment. The post-irradiation increase in the expression of both phospho-p65, and phospho-IκBα was also blocked by UA. Moreover, the treatment of UA was found to significantly prolong overall survival in mice exposed to whole body gamma irradiation, and reduce the excessive inflammatory responses. Given its radioprotective efficacy as described here, UA as an antioxidant and NF-κB pathway blocker, may function as an important pharmacological agent in protecting against gamma irradiation-induced injury. PMID:28670276

A novel co-drug of aspirin and ursolic acid interrupts adhesion, invasion and migration of cancer cells to vascular endothelium via regulating EMT and EGFR-mediated signaling pathways: multiple targets for cancer metastasis prevention and treatment.

PubMed

Tang, Qiao; Liu, Yajun; Li, Tao; Yang, Xiang; Zheng, Guirong; Chen, Hongning; Jia, Lee; Shao, Jingwei

2016-11-08

Metastasis currently remains the predominant cause of breast carcinoma treatment failure. The effective targeting of metastasis-related-pathways in cancer holds promise for a new generation of therapeutics. In this study, we developed an novel Asp-UA conjugate, which was composed of classical "old drug" aspirin and low toxicity natural product ursolic acid for targeting breast cancer metastasis. Our results showed that Asp-UA could attenuate the adhesion, migration and invasion of breast cancer MCF-7 and MDA-MB-231 cells in a more safe and effective manner in vitro. Molecular and cellular study demonstrated that Asp-UA significantly down-regulated the expression of cell adhesion and invasion molecules including integrin α6β1, CD44 ,MMP-2, MMP-9, COX-2, EGFR and ERK proteins, and up-regulated the epithelial markers "E-cadherin" and "β-catenin", and PTEN proteins. Furthermore, Asp-UA (80 mg/kg) reduced lung metastasis in a 4T1 murine breast cancer metastasis model more efficiently, which was associated with a decrease in the expression of CD44. More importantly, we did not detect side effects with Asp-UA in mice such as weight loss and main viscera tissues toxicity. Overall, our research suggested that co-drug Asp-UA possessed potential metastasis chemoprevention abilities via influencing EMT and EGFR-mediated pathways and could be a more promising drug candidate for the prevention and/or treatment of breast cancer metastasis.

Glycosides from Bougainvillea glabra.

PubMed

Simon, András; Tóth, Gábor; Duddeck, Helmut; Soliman, Hesham S M; Mahmoud, Ibrahim I; Samir, Hanan

2006-01-01

Three glycosides were isolated from Bougainvillea glabra and their structures were determined by extensive use of 1D and 2D NMR spectroscopy ((1)H and (13)C). First compound was identical to momordin IIc (quinoside D) [beta-D-glucopyranosyl 3-O-[beta-D-xylopyranosyl-(1 --> 3)-O-(beta-D-glucopyranosyluronic acid)] oleanolate], second compound was quercetin 3-O-alpha-L-(rhamnopyranosyl)(1 --> 6)-[alpha-L-rhamnopy-ranosyl(1 --> 2)]-beta-D-galactopyranoside and third compound was its derivative quercetin 3-O-alpha-L-(4-caffeoylrhamnopyranosyl)(1 --> 6)-[alpha-L-rhamnopyranosyl (1 --> 2)]-beta-D-galactopyranoside, a new natural product.

Secoiridoids from Gentiana siphonantha.

PubMed

Tan, R X; Kong, L D

1997-11-01

Repeated fractionations of the methanol extract of the subterranean parts (rhizomes and roots) of Gentiana siphonantha afforded two new and five known secoiridoids, in addition to the widespread plant constituents beta-sitiosterol, daucosterol and oleanolic acid. The structures of the new acyl secoiridoid glycosides were elucidated as 6'-gentisoyl 8-epikingiside and 2'-gentisoyl gelidoside mainly by a combination of high field NMR techniques. The known secoiridoids were identified as gentiolactone, gentiopicroside, sweroside, gelidoside and trifloroside. None of these constituents was active against human pathogenic fungi (Candida albican, Aspergillus flavus and Trichoderma viride). The chemotaxonomic significance of the isolates is discussed briefly.

Targeting Inflammatory Pathways by Triterpenoids for Prevention and Treatment of Cancer

PubMed Central

Yadav, Vivek R.; Prasad, Sahdeo; Sung, Bokyung; Kannappan, Ramaswamy; Aggarwal, Bharat B.

2010-01-01

Traditional medicine and diet has served mankind through the ages for prevention and treatment of most chronic diseases. Mounting evidence suggests that chronic inflammation mediates most chronic diseases, including cancer. More than other transcription factors, nuclear factor-kappaB (NF-κB) and STAT3 have emerged as major regulators of inflammation, cellular transformation, and tumor cell survival, proliferation, invasion, angiogenesis, and metastasis. Thus, agents that can inhibit NF-κB and STAT3 activation pathways have the potential to both prevent and treat cancer. In this review, we examine the potential of one group of compounds called triterpenes, derived from traditional medicine and diet for their ability to suppress inflammatory pathways linked to tumorigenesis. These triterpenes include avicins, betulinic acid, boswellic acid, celastrol, diosgenin, madecassic acid, maslinic acid, momordin, saikosaponins, platycodon, pristimerin, ursolic acid, and withanolide. This review thus supports the famous adage of Hippocrates, “Let food be thy medicine and medicine be thy food”. PMID:22069560

Two new flavones from Tridax procumbens Linn.

PubMed

Xu, Runsheng; Zhang, Jing; Yuan, Ke

2010-09-09

Two new flavones, 8,3'-dihydroxy-3,7,4'-trimethoxy-6-O-β-D-glucopyranosyl flavone (1) and 6,8,3'-trihydroxy-3,7,4'-trimethoxyflavone (2) were isolated from Tridax procumbens Linn., together with the four known compounds puerarin (3), esculetin (4), oleanolic acid (5) and betulinic acid (6). The structures of the two new flavones were elucidated based on chemical analysis and spectral methods (IR, 1D and 2D NMR, ESI-MS, HR-ESI-MS). The antioxidant activity of the two new flavones were evaluated by two methods, the 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity and ferric reducing antioxidant power (FRAP) assays, and the data showed that compounds 1 and 2 have certain antioxidant activity, with the antioxidant activity of compound 2 being stronger than that of compound 1.

[Studies on the chemical constituents of the stems of Piper betle].

PubMed

Yin, Yan; Huang, Xiang-Zhong; Wang, Jiong; Dai, Jian-Hui; Liang, Hui; Dai, Yun

2009-06-01

To study the chemical constituents from the stems of Piper betle. Various chromatographic techniques were used to isolate and purify the constituents. The structures of these compounds were elucidated on the basis of spectral analysis. Nine compounds were isolated from the petroleum ester and ethyl acetate soluble fractions of the 70% acetone extract and their structures were identified as 6beta-hydroxystigmast-4-en-3-one (1), beta-sitosterol (2), stigmasterol (3), oleanolic acid (4), 23-hydroxyursan-12-en-28-oic acid (5), beta-sitosterol-3-O-beta-D-glucoside-6'-O-palmitate (6), beta-daucosterol (7), (2S) -4'-hydroxy- 2,3-dihydroflavonone-7-O-beta-D-glucoside (8) and alpha-ethyl glucoside (9). Among these compounds, 1, 3 -9 are isolated from this plant for the first time.

Simultaneous determination of six bioactive saponins from Rhizoma Panacis Japonici in rat plasma by UHPLC-MS/MS: Application to a pharmacokinetic study.

PubMed

Zheng, Hong; Qiu, Feng; Zhao, Hui; Chen, Jie; Wang, Lei; Zou, Haiyan

2018-06-07

A specific, sensitive and rapid ultra high performance liquid chromatography-tandem mass spectrometric (UHPLC-MS/MS) method was developed and validated for simultaneous determination of six major bioactive constituents in Rhizoma Panacis Japonici (RPJ), including oleanolic acid-type chikusetsusaponin V, IV, hemsgiganoside B, damarane-type ginsenoside Rb1, Rg1 and Re in rat plasma, using estazolam as the internal standard (IS). Plasma samples were pretreated with methanol/acetonitrile (1:1, V/V) for protein precipitation. Chromatographic separation was performed on an Agilent Eclipse Plus C 18 column, using a gradient mobile phase consisting of methanol and 0.1% formic acid aqueous solution. A tandem mass spectrometric detection with an electrospray ionization (ESI) interface was conducted via multiple reaction monitoring (MRM) under positive ionization mode. For all the six analytes of interest, the calibration curves were linear in the concentration range of 2.00-500 ng/mL with r ≥ 0.9956. The intra- and inter-day precisions (in terms of relative standard deviation, RSD) were all below 10.2% and the accuracies (in terms of relative error, RE) were within -5.0% to 6.3% for all six analytes. Extraction recovery, matrix effect and stability data all met the acceptance criteria of FDA guideline for bioanalytical method validation. The developed method was applied to the pharmacokinetic study in rat. After oral administration of the total saponins from RPJ, six analytes were quickly absorbed into the blood and presented the phenomenon of double peaks. Among the six analytes, ginsenoside Rb1 showed slowest elimination from plasma with a t 1/2z of 16.00 h, while that of the others were between 1.72 and 5.62 h. In conclusion, the developed method was successfully used to simultaneously analyze major oleanolic acid-type and damarane-type saponins of RPJ in rat plasma after oral administration. Copyright © 2018. Published by Elsevier B.V.

Simultaneous determination of flavonoids, isochlorogenic acids and triterpenoids in Ilex hainanensis Using high performance liquid chromatography coupled with diode array and evaporative light scattering detection.

PubMed

Peng, Bo; Qiao, Chun-Feng; Zhao, Jing; Huang, Wei-Hua; Hu, De-Jun; Liu, Hua-Gang; Li, Shao-Ping

2013-03-04

A high performance liquid chromatography coupled with diode array and evaporative light scattering detection (HPLC-DAD-ELSD) method for simultaneous determination of eight major bioactive compounds including two flavonoids (rutin and eriodictyol-7-O-β-D-glucopyranoside), two isochlorogenic acids (isochlorogenic acid A and isochlorogenic acid C) and four triterpenoids (ilexhainanoside D, ilexsaponin A1, ilexgenin A and ursolic acid) in Ilex hainanensis has been developed for the first time. The 283 nm wavelength was chosen for determination of two flavonoids and two isochlorogenic acids. ELSD was applied to determine four triterpenoids. The analysis was performed on an Agilent Zorbax SB-C18 column (250 × 4.6 mm i.d., 5 µm) with gradient elution of 0.2% formic acid in water and acetonitrile. The method was validated for linearity, limit of detection, limit of quantification, precision, repeatability and accuracy. The proposed method has been successfully applied for simultaneous quantification of the analytes in four samples of Ilex hainanensis, which is helpful for quality control of this plant.

Synthesis, Antiviral and Cytotoxic Activity of Novel Terpenyl Hybrid Molecules Prepared by Click Chemistry.

PubMed

Pertino, Mariano Walter; Petrera, Erina; Alché, Laura Edith; Schmeda-Hirschmann, Guillermo

2018-06-03

Naturally occurring terpenes were combined by click reactions to generate sixteen hybrid molecules. The diterpene imbricatolic acid (IA) containing an azide group was used as starting compound for the synthesis of all the derivatives. The alkyne group in the terpenes cyperenoic acid, dehydroabietinol, carnosic acid γ-lactone, ferruginol, oleanolic acid and aleuritolic acid was obtained by esterification using appropriate alcohols or acids. The hybrid compounds were prepared by combining the IA azide function with the different terpene-alkynes under click chemistry conditions. The cytotoxic activity of the terpene hybrids 1 ⁻ 16 was assessed against Vero cells and tumour cell lines (HEP-2, C6 and Raw 264.7). Compounds 1 , 2 , 3 and 7 showed cytotoxic activity against the tested cell lines. The antiviral activity of the compounds was evaluated against HSV-1 KOS, Field and B2006 strain. For the pairs of hybrid compounds formed between IA-diterpene (compounds 3 ⁻ 8 , except for compound 7 ), a moderate activity was observed against the three HSV-1 strains with an interesting selectivity index (SI ≥10, SI = CC 50 /CE 50 ) for some compounds.

[Studies on the chemical constituents of ethyl acetate extract from the roots of Actinidia chrysantha].

PubMed

Meng, Li-Li; Huang, Chu-Sheng; Liu, Hong-Xing; Chen, Xi-Hui

2009-10-01

To study the chemical constituents of ethyl acetate extract from the roots of Actinidia chrysantha. Chromatographic methods were used to isolate the compounds from ethyl acetate extract from the roots of Actinidia chrysantha and chemical and spectral methods were used to elucidate the structures of the isolated compounds. Five compounds were identified as stigmast-3, 6-dione (I), beta-sitosterol (II), ursolicacid (III), beta-daucosterol (IV), 2alpha, 3beta, 23-triol-12-en-28-ursolic acid (V). Those compounds are obtained from the plant for the first time.

Differential Partitioning of Triterpenes and Triterpene Esters in Apple Peel.

PubMed

Poirier, Brenton C; Buchanan, David A; Rudell, David R; Mattheis, James P

2018-02-28

Apple peel is a rich source of secondary metabolites, and several studies have outlined the dietary health benefits of ursane-type triterpenes in apple. Changes in triterpene metabolism have also been associated with the development of superficial scald, a postharvest apple peel browning disorder, and postharvest applications of diphenylamine and 1-methylcyclopropene. Previously, studies have generated metabolite profiles for whole apple peel or apple wax. In this study, we report separate metabolic analyses of isolated wax fractions and peel epidermis to investigate the spatial distribution of secondary metabolites in peel. In addition to examining previously reported triterpenes, we identified several unreported fatty acid esters of ursane-type triterpenes (C14-C22). All free pentacyclic triterpenes and triterpenic acids, with the exception of β-amyrin, were localized in the wax layer, along with esters of ursolic acid and uvaol. All sterols, sterol derivatives and α-amyrin esters were localized in the dewaxed peel epidermis.

Secondary Metabolite Accumulation Associates with Ecological Succession of Endophytic Fungi in Cynomorium songaricum Rupr.

PubMed

Cui, Jin-Long; Zhang, Yan-Yan; Vijayakumar, Vinod; Zhang, Gang; Wang, Meng-Liang; Wang, Jun-Hong

2018-06-06

Cynomorium songaricum Rupr. is a rare root-parasitic plant distributed in the desert ecosystem. Little is known about the role of endophytes in accumulation of metabolites in C. songaricum. Here, the correlations between the seven active components (total sugars, flavonoids, protocatechuic acid, catechins, tannins, gallic acid, and ursolic acid) and the endophytic fungi of C. songaricum were investigated, and their causal relationships are discussed further. The results showed that the accumulation of these components and the assembly of endophytic fungi changed with different plant developmental stages. Diverse relationships including positive and negative correlation were found among chemicals and endophytic fungal operational taxonomic units based on correlation coefficient matrices, which demonstrated that the accumulation of secondary metabolites in C. songaricum is closely related to the endophytic fungal community composition. These results present new opportunities to deeply understand plant-fungal symbioses and secondary metabolite productions.

Adsorption of saponin compound in Carica papaya leaves extract using weakly basic ion exchanger resin

NASA Astrophysics Data System (ADS)

Abidin, Noraziani Zainal; Janam, Anathasia; Zubairi, Saiful Irwan

2016-11-01

Adsorption of saponin compound in papaya leaves juice extract using Amberlite® IRA-67 resin was not reported in previous studies. In this research, Amberlite® IRA-67 was used to determine the amount of saponin that can be adsorbed using different weights of dry resin (0.1 g and 0.5 g). Peleg model was used to determine the maximum yield of saponin (43.67 mg) and the exhaustive time (5.7 days) prior to a preliminary resin-saponin adsorption study. After adsorption process, there was no significant difference (p>0.05) in total saponin content (mg) for sample treated with 0.1 g (3.79 ± 0.55 mg) and sample treated with 0.5 g (3.43 ± 0.51 mg) dry weight resin. Long-term kinetic adsorption of resin-saponin method (>24 hours) should be conducted to obtain optimum freed saponin extract. Besides that, sample treated with 0.1 g dry weight resin had high free radical scavenging value of 50.33 ± 2.74% compared to sample treated with 0.5 g dry weight resin that had low free radical scavenging value of 24.54 ± 1.66% dry weights. Total saponin content (mg), total phenolic content (mg GAE) and free radical scavenging activity (%) was investigated to determine the interaction of those compounds with Amberlite® IRA-67. The RP-HPLC analysis using ursolic acid as standard at 203 nm showed no peak even though ursolic acid was one of the saponin components that was ubiquitous in plant kingdom. The absence of peak was due to weak solubility of ursolic acid in water and since it was only soluble in solvent with moderate polarity. The Pearson's correlation coefficient for total saponin content (mg) versus total phenolic content (mg GAE) and radical scavenging activity (%) were +0.959 and +0.807. Positive values showed that whenever there was an increase in saponin content (mg), the phenolic content (mg GAE) and radical scavenging activity (%) would also increase. However, as the resin-saponin adsorption was carried out, there was a significant decrease of radical scavenging activity (%) as the amount of the resin increased. Moreover, the saponin amount did not show any reduction as the amount of resin resin increased. Therefore, there was other active ingredient which has the antioxidant properties were affected by the adsoprtion process. For that reason, the kinetic equilibrium of resin-saponin adsorption studies against the ratio of resin-to-extract has to be carried out to determine the efficacy of the extract therapeutic properties prior to the cell culture studies.

Pharmacokinetics in Vitro and in Vivo of Two Novel Prodrugs of Oleanolic Acid in Rats and Its Hepatoprotective Effects against Liver Injury Induced by CCl4.

PubMed

Yu, Zongjiang; Sun, Weizhi; Peng, Weibing; Yu, Rilei; Li, Guoqiang; Jiang, Tao

2016-05-02

Oleanolic acid (OA) is a well-known pentacyclic triterpenoid compound, which has been used as a dietary supplement and is supplied as an over-the-counter drug for the treatment of human liver diseases. These are reasons for the low bioavailability of OA which have restricted its wider application. In this study, two OA prodrugs (1,3-cyclic propanyl phosphate esters of OA) were designed and synthesized. The hepatoprotective effects of these prodrugs were evaluated against carbon tetrachloride (CCl4) induced liver injury in mice; the levels of alanine aminotransferase (ALT), lactic dehydrogenase (LDH), and aspartate aminotransferase (AST) were significantly increased, and the level of the hepatic malondialdehyde (MDA) was increased. The metabolism, in vitro, of the prodrugs was studied by incubation in rat liver microsome; the plasma pharmacokinetics and the biodistribution in vivo after intravenous (iv) injection to six rats were investigated, respectively. The prodrugs diminished gradually with time; most of the parent drugs were released within 30 min in vitro, and the presumed mechanism of the in vitro metabolism was confirmed. The plasma-concentration data in vivo was analyzed by a compartmental method: both the prodrugs and the corresponding released parent drugs existed at up to 48 h in rats. The t1/2 improved after intravenous administration in rats compared with direct injection of the parent drugs. All analyte concentrations were highest in the liver, and most of the prodrugs were excreted in feces (>47.11%). Therefore, 1,3-cyclic propanyl phosphate esters of OA can serve as a promising lead candidate for drugs.

Effect of a controlled-release drug delivery system made of oleanolic acid formulated into multivesicular liposomes on hepatocellular carcinoma in vitro and in vivo

PubMed Central

Luo, Yuling; Liu, Zhongbing; Zhang, Xiaoqin; Huang, Juan; Yu, Xin; Li, Jinwei; Xiong, Dan; Sun, Xiaoduan; Zhong, Zhirong

2016-01-01

The aim of the present study was to develop a novel dosage form of multivesicular liposomes for oleanolic acid (OA) to overcome its poor solubility, prolong therapeutic drug levels in the blood, and enhance the antitumor effect on hepatocellular carcinoma. OA-encapsulated multivesicular liposomes (OA-MVLs) were prepared by a double-emulsion method, and the formulation was optimized by the central composite design. The morphology, particle size, and drug-loading efficiency of OA-MVLs were investigated. Furthermore, OA-MVLs were also characterized both in vitro and in vivo. The results showed that OA-MVLs were spherical particles with an average particle size of 11.57 μm and an encapsulation efficiency of 82.3%±0.61%. OA-MVLs exhibited a sustained-release pattern in vitro, which was fitted to Ritger–Peppas equation. OA-MVLs inhibited the growth of human HepG2 cells which was confirmed by the MTT assay and fluorescence microscopy detection. The in vivo release of OA from OA-MVLs exhibited a sustained manner, indicating a longer circulation time compared to OA solution. The in vivo toxicity study indicated that medium-dose OA-MVLs exerted no toxic effect on the hosts. Importantly, OA-MVLs suppressed the growth of murine H22 hepatoma and prolonged the survival of tumor-bearing mice. In conclusion, the poorly soluble OA could be encapsulated into MVLs to form a novel controlled-release drug delivery system. The present study may hold promise for OA-MVLs as a new dosage form for sustained-release drug delivery in cancer therapy. PMID:27471381

Oleanolic Acid Ameliorates Aβ25-35 Injection-induced Spatial Learning and Memory Deficit in Alzheimer's Disease Model Rats.

PubMed

Wang, Kai; Sun, Weiming; Zhang, Linlin; Guo, Wei; Xu, Jiachun; Liu, Shuang; Zhou, Zhen; Zhang, Yulian

2018-05-24

Abnormal amyloid β (Aβ) accumulation and deposition in hippocampus is an essential process in Alzheimer's disease (AD). To investigate whether Oleanolic acid (OA) could improve learning and memory deficit and its possible mechanism. Forty-five SD rats were randomly divided into sham operation group, model group, and OA group. AD models by injection of Aβ25-35 were built. Morris water maze (MWM) was applied to investigate learning and memory, transmission electron microscope (TEM) to observe the ultrastructure of synapse, western blot to the key targets of synapse, electrophysiology for long-term potentiation (LTP), and Ca2+ concentration in synapse was also measured. The latency time in model group was significantly longer than that in sham operation group (P=0.0001<0.05); while it was significantly shorter in the OA group than that in model group (P=0.0001<0.05); compared with model group, the times of cross-platform in OA group significantly increased (P = 0.0001 <0.05). TEM results showed OA couldalleviate neuron damage and synapses changes induced by Aβ25-35. The expression of CaMKII, PKC, NMDAR2B, BDNF, TrkB, and CREB protein were significantly improved by OA; the concentration of Ca2+ were significantly lower and the slope and amplitude of f-EPSP increased in OA group. OA could ameliorate Aβ-induced spatial learning and memory loss of AD rats, and the mechanism might be involved with maintaining synaptic integrity to restore synaptic plasticity and increasing the NMDAR2B protein, CaMKII and PKC protein in postsynaptic density (PSD), reducing synaptic Ca2+ concentration, enhancing LTP by up-regulating BDNF, TrkB, CREB proteins. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Oleanolic acid acetate inhibits rheumatoid arthritis by modulating T cell immune responses and matrix-degrading enzymes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Choi, Jin Kyeong; Molecular Immunology Section, Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892; Kim, Sung-Wan

ABSTRACT: Rheumatoid arthritis (RA) is a chronic autoimmune disease associated with a combination of synovium joint inflammation, synovium hyperplasia, and destruction of cartilage and bone. Oleanolic acid acetate (OAA), a compound isolated from Vigna angularis, has been known to possess pharmacological activities, including anti-inflammation and anti-bone destruction. In this study, we investigated the effects of OAA on RA and the underlying mechanisms of action by using a type-II collagen-induced arthritis (CIA) mouse model and tumor necrosis factor (TNF)-α-stimulated RA synovial fibroblasts. Oral administration of OAA decreased the clinical arthritis symptoms, paw thickness, histologic and radiologic changes, and serum total andmore » anti-type II collagen IgG, IgG1, and IgG2a levels. OAA administration reduced Th1/Th17 phenotype CD4{sup +} T lymphocyte expansions and inflammatory cytokine productions in T cell activated draining lymph nodes and spleen. OAA reduced the expression and production of inflammatory mediators, such as cytokines and matrix metalloproteinase (MMP)-1/3, in the ankle joint tissue and RA synovial fibroblasts by down-regulating Akt, mitogen-activated protein kinases, and nuclear factor-κB. Our results clearly support that OAA plays a therapeutic role in RA pathogenesis by modulating helper T cell immune responses and matrix-degrading enzymes. The immunosuppressive effects of OAA were comparable to dexamethasone and ketoprofen. We provide evidences that OAA could be a potential therapeutic candidate for RA. - Highlights: • OAA attenuated chronic CIA symptoms. • OAA had a regulating effect on the T helper cell immune reaction for CIA. • The effect of OAA on the RA was comparable to the dexamethasone or ketoprofen. • OAA might be a candidate for the treatment of arthritic diseases.« less

Potent Anti-Inflammatory Activity of Ursolic Acid, a Triterpenoid Antioxidant, Is Mediated through Suppression of NF-κB, AP-1 and NF-AT

PubMed Central

Checker, Rahul; Sandur, Santosh K.; Sharma, Deepak; Patwardhan, Raghavendra S.; Jayakumar, S.; Kohli, Vineet; Sethi, Gautam; Aggarwal, Bharat B.; Sainis, Krishna B.

2012-01-01

Background Ursolic acid (UA), a pentacyclic triterpenoid carboxylic acid, is the major component of many plants including apples, basil, cranberries, peppermint, rosemary, oregano and prunes and has been reported to possess antioxidant and anti-tumor properties. These properties of UA have been attributed to its ability to suppress NF-κB (nuclear factor kappa B) activation. Since NF-κB, in co-ordination with NF-AT (nuclear factor of activated T cells) and AP-1(activator protein-1), is known to regulate inflammatory genes, we hypothesized that UA might exhibit potent anti-inflammatory effects. Methodology/Principal Findings The anti-inflammatory effects of UA were assessed in activated T cells, B cells and macrophages. Effects of UA on ERK, JNK, NF-κB, AP-1 and NF-AT were studied to elucidate its mechanism of action. In vivo efficacy of UA was studied using mouse model of graft-versus-host disease. UA inhibited activation, proliferation and cytokine secretion in T cells, B cells and macrophages. UA inhibited mitogen-induced up-regulation of activation markers and co-stimulatory molecules in T and B cells. It inhibited mitogen-induced phosphorylation of ERK and JNK and suppressed the activation of immunoregulatory transcription factors NF-κB, NF-AT and AP-1 in lymphocytes. Treatment of cells with UA prior to allogenic transplantation significantly delayed induction of acute graft-versus-host disease in mice and also significantly reduced the serum levels of pro-inflammatory cytokines IL-6 and IFN-γ. UA treatment inhibited T cell activation even when added post-mitogenic stimulation demonstrating its therapeutic utility as an anti-inflammatory agent. Conclusions/Significance The present study describes the detailed mechanism of anti-inflammatory activity of UA. Further, UA may find application in the treatment of inflammatory disorders. PMID:22363615

In vitro evaluation of the comprehensive antimicrobial and antioxidant properties of Curtisia dentata (Burm.f) C.A. Sm: toxicological effect on the Human embryonic kidney (HEK293) and Human hepatocellular carcinoma (HepG2) cell lines

PubMed Central

Fadipe, VO; Mongalo, NI; Opoku, AR

2015-01-01

Curtisia dentata is used in African traditional medicine to treat variety of infections. C. dentata leaves were collected from Buffelskloof Nature Reserve, South Africa. The ethanol, chloroform, ethyl acetate and acetone extracts were evaluated for antimicrobial activity using micro dilution assay against Escherichia coli, Pseudomonas aeruginosa, Mycobacterium smegmatis, Mycoplasma hominis, Candida albicans and some clinical isolates of Moraxella catarrhalis, Proteus mirabilis and Staphylococcus aureus isolated from HIV patient. Acetone extract exhibited lowest MIC of 0.01 mg/ml against Candida albicans compared to other extracts. Besides lupeol, betulinic acid and ursolic acid, β-sitosterol was isolated for the first time from C. dentata leaves and exhibited antimicrobial activity with MIC values ranging from 0.20 to 6.25 mg/ml. Furthermore, the ethanol extract and the four isolated compounds revealed microbicidal effect, with MIC index of less than 4. Ethanol extract revealed the best total activity of 2400 ml/g against Mycoplasma hominis. Cytotoxicity of the isolated compounds was further investigated against the Human embryonic kidney (HEK293) and Human hepatocellular carcinoma (HepG2) cell lines using the MTT assay. Ursolic acid exhibited the lowest LD50 of 122.4 µg/ml against HEK293 cell line while lupeol exhibited LD50 of 278.8 and 289.4 µg/ml against HEK293 and HepG2 respectively. Lupeol exhibited low selectivity index. Ethyl acetate and acetone extracts were further investigated for antioxidant activity against 2,2-diphenyl-1-picrylhydrazyl (DPPH). The acetone extract exhibited potent inhibition of DPPH compared to ethyl acetate extract. The findings of the current work validate the use of the plant species in the treatment of various human infections. PMID:27065768

Antibacterial and anti-inflammatory effects of Syzygium jambos L. (Alston) and isolated compounds on acne vulgaris

PubMed Central

2013-01-01

Background Acne vulgaris is a chronic skin disorder leading to inflammation as a result of the production of reactive oxygen species due to the active involvement of Propionibacterium acnes (P. acnes) in the infection site of the skin. The current study was designed to assess the potential of the leaf extract of Syzygium jambos L. (Alston) and its compounds for antibacterial and anti-inflammatory activity against the pathogenic P. acnes. Methods The broth dilution method was used to assess the antibacterial activity. The cytotoxicity investigation on mouse melanocyte (B16-F10) and human leukemic monocyte lymphoma (U937) cells was done using sodium 3’-[1-(phenyl amino-carbonyl)-3,4-tetrazolium]-bis-[4-methoxy-6-nitrobenzene sulfonic acid hydrate (XTT) reagent. The non-toxic concentrations of the samples was investigated for the suppression of cytokines interleukin 8 (IL 8) and tumour necrosis factor (TNF α) by testing the supernatants in the co-culture of the human U937 cells and heat killed P. acnes using enzyme immunoassay kits (ELISA). The statistical analysis was done using the Graph Pad Prism 4 program. Results Bioassay guided isolation of ethanol extract of the leaves of S. jambos led to the isolation of three known compounds namely; squalene, an anacardic acid analogue and ursolic acid which are reported for the first time from this plant. The ethanol extract of S. jambos and one of the isolated compound namely, anacardic acid analogue were able to inhibit the growth of P. acnes with a noteworthy minimum inhibitory concentration (MIC) value of 31.3 and 7.9 μg/ml, respectively. The ethanol extract and three commercially acquired compounds namely; myricetin, myricitrin, gallic acid exhibited significant antioxidant activity with fifty percent inhibitory concentration (IC50) ranging between 0.8-1.9 μg/ml which was comparable to that of vitamin C, the reference antioxidant agent. The plant extract, compounds ursolic acid and myricitrin (commercially acquired) significantly inhibited the release of inflammatory cytokines IL 8 and TNF α by suppressing them by 74 - 99%. TEM micrographs showed the lethal effects of selected samples against P. acnes. Conclusions The interesting antibacterial, antioxidant and anti-inflammatory effects of S. jambos shown in the present study warrant its further investigation in clinical studies for a possible alternative anti-acne agent. PMID:24168697

Epigenetic modifications of triterpenoid ursolic acid in activating Nrf2 and blocking cellular transformation of mouse epidermal cells

PubMed Central

Kim, Hyuck; Ramirez, Christina N.; Su, Zheng-Yuan; Kong, Ah-Ng Tony

2016-01-01

Ursolic acid (UA), a well-known natural triterpenoid found in abundance in blueberries, cranberries and apple peels, has been reported to possess many beneficial health effects. These effects include anti-cancer activity in various cancers, such as skin cancer. Skin cancer is the most common cancer in the world. Nuclear factor E2-related factor 2 (Nrf2) is a master regulator of anti-oxidative stress response with anti-carcinogenic activity against UV- and chemical-induced tumor formation in the skin. Recent studies show that epigenetic modifications of Nrf2 play an important role in cancer prevention. However the epigenetic impact of UA on Nrf2 signaling remains poorly understood in skin cancer. In this study, we investigated the epigenetic effects of UA on mouse epidermal JB6 P+ cells. UA inhibited cellular transformation by 12-O-tetradecanoylphorbol-13-acetate (TPA) at a concentration at which the cytotoxicity was no more than 25%. Under this condition, UA induced the expression of the Nrf2-mediated detoxifying/antioxidant enzymes heme oxygenase-1 (HO-1), NAD(P)H:quinone oxidoreductase 1 (NQO1), and UDP-glucuronosyltransferase 1A1 (UGT1A1). DNA methylation analysis revealed that UA demethylated the first 15 CpG sites of the Nrf2 promoter region, which correlated with the re-expression of Nrf2. Furthermore, UA reduced the expression of epigenetic modifying enzymes, including the DNA methyltransferases (DNMTs) DNMT1 and DNMT3a and the histone deacetylases (HDACs) HDAC1, 2, 3, and 8 (Class I) and HDAC6 and 7 (Class II), and HDAC activity. Taken together, these results suggest that the epigenetic effects of the triterpenoid UA could potentially contribute to its beneficial effects, including the prevention of skin cancer. PMID:27260468

Ursolic acid inhibits the growth of human pancreatic cancer and enhances the antitumor potential of gemcitabine in an orthotopic mouse model through suppression of the inflammatory microenvironment

PubMed Central

Prasad, Sahdeo; Yadav, Vivek R.; Sung, Bokyung; Gupta, Subash C.; Tyagi, Amit K.; Aggarwal, Bharat B.

2016-01-01

The development of chemoresistance in human pancreatic cancer is one reason for the poor survival rate for patients with this cancer. Because multiple gene products are linked with chemoresistance, we investigated the ability of ursolic acid (UA) to sensitize pancreatic cancer cells to gemcitabine, a standard drug used for the treatment of pancreatic cancer. These investigations were done in AsPC-1, MIA PaCa-2, and Panc-28 cells and in nude mice orthotopically implanted with Panc-28 cells. In vitro, UA inhibited proliferation, induced apoptosis, suppressed NF-κB activation and its regulated proliferative, metastatic, and angiogenic proteins. UA (20 μM) also enhanced gemcitabine (200 nM)-induced apoptosis and suppressed the expression of NF-κB-regulated proteins. In the nude mouse model, oral administration of UA (250 mg/kg) suppressed tumor growth and enhanced the effect of gemcitabine (25 mg/kg). Furthermore, the combination of UA and gemcitabine suppressed the metastasis of cancer cells to distant organs such as liver and spleen. Immunohistochemical analysis showed that biomarkers of proliferation (Ki-67) and microvessel density (CD31) were suppressed by the combination of UA and gemcitabine. UA inhibited the activation of NF-κB and STAT3 and the expression of tumorigenic proteins regulated by these inflammatory transcription factors in tumor tissue. Furthermore, the combination of two agents decreased the expression of miR-29a, closely linked with tumorigenesis, in the tumor tissue. UA was found to be bioavailable in animal serum and tumor tissue. These results suggest that UA can inhibit the growth of human pancreatic tumors and sensitize them to gemcitabine by suppressing inflammatory biomarkers linked to proliferation, invasion, angiogenesis, and metastasis. PMID:26909608

Ursolic acid incorporation does not prevent the formation of a non-lamellar phase in pH-sensitive and long-circulating liposomes.

PubMed

Lopes, Sávia C A; Novais, Marcus V M; Ferreira, Diêgo S; Braga, Fernão C; Magalhães-Paniago, Rogério; Malachias, Ângelo; Oliveira, Mônica C

2014-12-23

Ursolic acid (UA) is a triterpene found in different plant species that has been shown to possess significant antitumor activity. However, UA presents a low water solubility, which limits its biological applications. In this context, our research group has proposed the incorporation of UA in long-circulating and pH-sensitive liposomes (SpHL-UA).These liposomes, composed of dioleylphosphatidylethanolamine (DOPE), cholesteryl hemisuccinate (CHEMS), and distearoylphosphatidylethanolamine-polyethylene glycol2000 (DSPE-PEG2000), were shown to be very promising carriers for UA. Considering that the release of UA from SpHL-UA and its antitumor activity depend upon the occurrence of the lamellar to non-lamellar phase transition of DOPE, in the present work, the interactions of UA with the components of the liposomes were evaluated, aiming to clarify their role in the structural organization of DOPE. The study was carried out by differential scanning calorimetry (DSC) and small-angle X-ray scattering (SAXS) under low hydration conditions. DSC studies revealed that DOPE phase transition temperatures did not shift significantly upon UA addition. On the other hand, in SAXS studies, a different pattern of DOPE phase organization was observed in the presence of UA, with the occurrence of the cubic phase Im3m at 20 °C and the cubic phase Pn3m at 60 °C. These findings suggest that UA interacts with the lipids and changes their self-assembly. However, these interactions between the lipids and UA were unable to eliminate the lamellar to non-lamellar phase transition, which is essential for the cytoplasmic delivery of UA molecules from SpHL-UA.

Synthesis and Biological Evaluation of Novel N-Aryl-ω-(Benzoazol-2-yl)-Sulfanylalkanamides as Dual Inhibitors of α-Glucosidase and Protein Tyrosine Phosphatase 1B.

PubMed

Wang, Mei-Yan; Cheng, Xian-Chao; Chen, Xiu-Bo; Li, Yu; Zang, Lan-Lan; Duan, Yu-Qing; Chen, Ming-Zhu; Yu, Peng; Sun, Hua; Wang, Run-Ling

2018-05-09

α-Glucosidase is known to catalyze the digestion of carbohydrates and release free glucose into the digestive tract. Protein tyrosine phosphatase 1B (PTP1B) is engaged in the dephosphorylation of the insulin receptor and regulation of insulin sensitivity. Therefore, dual antagonists by targeting both α-glucosidase and PTP1B may be potential candidates for type 2 diabetes therapy. In this work, three series of novel N-aryl-ω-(benzoazol-2-yl)-sulfanylalkanamides were synthesized and assayed for their α-glucosidase and PTP1B inhibitory activities, respectively. Compound 3l, exhibiting the most effective α-glucosidase inhibitory activity (IC 50 = 10.96 μM (3l), IC 50 = 51.32 μM (Acarbose), IC 50 = 18.22 μM (Ursolic acid)) and potent PTP1B inhibitory activity (IC 50 = 13.46 μM (3l), IC 50 = 14.50 μM (Ursolic acid)), was identified as a novel dual inhibitor of α-glucosidase and PTP1B. Furthermore, 3l is a highly selective PTP1B inhibitor since no inhibition was showed by 3l at 100 μM against PTP-MEG2, TCPTP, SHP2, or SHP1. Subsequent kinetic analysis revealed 3l inhibited α-glucosidase in a reversible and mixed manner. Molecular docking study indicated that hydrogen bonds, van der Waals, charge interactions and Pi-cation interactions all contributed to interactions between 3l and α-glucosidase/PTP1B. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Ursolic acid derivatives as potential antidiabetic agents: In vitro, in vivo, and in silico studies.

PubMed

Guzmán-Ávila, Ricardo; Flores-Morales, Virginia; Paoli, Paolo; Camici, Guido; Ramírez-Espinosa, Juan José; Cerón-Romero, Litzia; Navarrete-Vázquez, Gabriel; Hidalgo-Figueroa, Sergio; Yolanda Rios, Maria; Villalobos-Molina, Rafael; Estrada-Soto, Samuel

2018-03-01

Hit, Lead & Candidate Discovery Protein tyrosine phosphatase 1B (PTP-1B) has attracted interest as a novel target for the treatment of type 2 diabetes, this because its role in the insulin-signaling pathway as a negative regulator. Thus, the aim of current work was to obtain seven ursolic acid derivatives as potential antidiabetic agents with PTP-1B inhibition as main mechanism of action. Furthermore, derivatives 1-7 were submitted in vitro to enzymatic PTP-1B inhibition being 3, 5, and 7 the most active compounds (IC 50  = 5.6, 4.7, and 4.6 μM, respectively). In addition, results were corroborated with in silico docking studies with PTP-1B orthosteric site A and extended binding site B, showed that 3 had polar and Van der Waals interactions in both sites with Lys120, Tyr46, Ser216, Ala217, Ile219, Asp181, Phe182, Gln262, Val49, Met258, and Gly259, showing a docking score value of -7.48 Kcal/mol, being more specific for site A. Moreover, compound 7 showed polar interaction with Gln262 and Van der Waals interactions with Ala217, Phe182, Ile219, Arg45, Tyr46, Arg47, Asp48, and Val49 with a predictive docking score of -6.43 kcal/mol, suggesting that the potential binding site could be localized in the site B adjacent to the catalytic site A. Finally, derivatives 2 and 7 (50 mg/kg) were selected to establish their in vivo antidiabetic effect using a noninsulin-dependent diabetes mice model, showing significant blood glucose lowering compared with control group (p < .05). © 2018 Wiley Periodicals, Inc.

In vitro, in silico and in vivo studies of ursolic acid as an anti-filarial agent.

PubMed

Kalani, Komal; Kushwaha, Vikas; Sharma, Pooja; Verma, Richa; Srivastava, Mukesh; Khan, Feroz; Murthy, P K; Srivastava, Santosh Kumar

2014-01-01

As part of our drug discovery program for anti-filarial agents from Indian medicinal plants, leaves of Eucalyptus tereticornis were chemically investigated, which resulted in the isolation and characterization of an anti-filarial agent, ursolic acid (UA) as a major constituent. Antifilarial activity of UA against the human lymphatic filarial parasite Brugia malayi using in vitro and in vivo assays, and in silico docking search on glutathione-s-transferase (GST) parasitic enzyme were carried out. The UA was lethal to microfilariae (mf; LC100: 50; IC50: 8.84 µM) and female adult worms (LC100: 100; IC50: 35.36 µM) as observed by motility assay; it exerted 86% inhibition in MTT reduction potential of the adult parasites. The selectivity index (SI) of UA for the parasites was found safe. This was supported by the molecular docking studies, which showed adequate docking (LibDock) scores for UA (-8.6) with respect to the standard antifilarial drugs, ivermectin (IVM -8.4) and diethylcarbamazine (DEC-C -4.6) on glutathione-s-transferase enzyme. Further, in silico pharmacokinetic and drug-likeness studies showed that UA possesses drug-like properties. Furthermore, UA was evaluated in vivo in B. malayi-M. coucha model (natural infection), which showed 54% macrofilaricidal activity, 56% female worm sterility and almost unchanged microfilaraemia maintained throughout observation period with no adverse effect on the host. Thus, in conclusion in vitro, in silico and in vivo results indicate that UA is a promising, inexpensive, widely available natural lead, which can be designed and developed into a macrofilaricidal drug. To the best of our knowledge this is the first ever report on the anti-filarial potential of UA from E. tereticornis, which is in full agreement with the Thomson Reuter's 'Metadrug' tool screening predictions.

Therapeutic Role of Ursolic Acid on Ameliorating Hepatic Steatosis and Improving Metabolic Disorders in High-Fat Diet-Induced Non-Alcoholic Fatty Liver Disease Rats

PubMed Central

Meng, Fanyu; Wang, Yemei; Sun, Zongxiang; Guo, Fuchuan; Li, Xiaoxia; Meng, Man; Li, Ying; Sun, Changhao

2014-01-01

Background Non-alcoholic fatty liver disease (NAFLD) is one of the most prevalent liver diseases around the world, and is closely associated with obesity, diabetes, and insulin resistance. Ursolic acid (UA), an ubiquitous triterpenoid with multifold biological roles, is distributed in various plants. This study was conducted to investigate the therapeutic effect and potential mechanisms of UA against hepatic steatosis in a high-fat diet (HFD)-induced obese non-alcoholic fatty liver disease (NAFLD) rat model. Methodology/Principal Findings Obese NAFLD model was established in Sprague-Dawley rats by 8-week HFD feeding. Therapeutic role of UA was evaluated using 0.125%, 0.25%, 0.5% UA-supplemented diet for another 6 weeks. The results from both morphologic and histological detections indicated that UA significantly reversed HFD-induced hepatic steatosis and liver injury. Besides, hepatic peroxisome proliferator-activated receptor (PPAR)-α was markedly up-regulated at both mRNA and protein levels by UA. Knocking down PPAR-α significantly inhibited the anti-steatosis role of UA in vitro. HFD-induced adverse changes in the key genes, which participated in hepatic lipid metabolism, were also alleviated by UA treatment. Furthermore, UA significantly ameliorated HFD-induced metabolic disorders, including insulin resistance, inflammation and oxidative stress. Conclusions/Significance These results demonstrated that UA effectively ameliorated HFD-induced hepatic steatosis through a PPAR-α involved pathway, via improving key enzymes in the controlling of lipids metabolism. The metabolic disorders were accordingly improved with the decrease of hepatic steatosis. Thereby, UA could be a promising candidate for the treatment of NAFLD. PMID:24489777

Ursolic acid sensitizes cisplatin-resistant HepG2/DDP cells to cisplatin via inhibiting Nrf2/ARE pathway

PubMed Central

Wu, Shouhai; Zhang, Tianpeng; Du, Jingsheng

2016-01-01

Background Combinations of adjuvant sensitizers with anticancer drugs is a promising new strategy to reverse chemoresistance. Ursolic acid (UA) is one of the natural pentacyclic triterpene compounds known to have many pharmacological characteristics such as anti-inflammatory and anticancer properties. This study investigates whether UA can sensitize hepatocellular carcinoma cells to cisplatin. Materials and methods Cells were transfected with nuclear factor erythroid-2-related factor 2 (Nrf2) small interfering RNA and Nrf2 complementary DNA by using Lipofectin 2000. The cytotoxicity of cells was investigated by Cell Counting Kit 8 assay. Cell apoptosis, cell cycle, reactive oxygen species, and mitochondrial membrane potential were detected by flow cytometry fluorescence-activated cell sorting. The protein level of Nrf2, NAD(P)H quinone oxidoreductase 1 (NQO1), glutathione S-transferase (GST), and heme oxygenase-1 (HO-1) was detected by Western blot analysis. Results The results showed that the reverse index was 2.9- and 9.69-fold by UA of 1.125 μg/mL and 2.25 μg/mL, respectively, for cisplatin to HepG2/DDP cells. UA–cisplatin combination induced cell apoptosis and reactive oxygen species, blocked the cell cycle in G0/G1 phase, and reduced the mitochondrial membrane potential. Mechanistically, UA–cisplatin dramatically decreased the expression of Nrf2 and its downstream genes. The sensibilization of UA–cisplatin combination was diminished in Nrf2 small interfering RNA-transfected HepG2/DDP cells, as well as in Nrf2 complementary DNA-transfected HepG2/DDP cells. Conclusion The results confirmed the sensibilization of UA on HepG2/DDP cells to cisplatin, which was possibly mediated via the Nrf2/antioxidant response element pathway. PMID:27822011

Inhibition of Streptococcus mutans biofilm formation on composite resins containing ursolic acid

PubMed Central

Kim, Soohyeon; Song, Minju; Roh, Byoung-Duck; Park, Sung-Ho

2013-01-01

Objectives To evaluate the inhibitory effect of ursolic acid (UA)-containing composites on Streptococcus mutans (S. mutans) biofilm. Materials and Methods Composite resins with five different concentrations (0.04, 0.1, 0.2, 0.5, and 1.0 wt%) of UA (U6753, Sigma Aldrich) were prepared, and their flexural strengths were measured according to ISO 4049. To evaluate the effect of carbohydrate source on biofilm formation, either glucose or sucrose was used as a nutrient source, and to investigate the effect of saliva treatment, the specimen were treated with either unstimulated whole saliva or phosphate-buffered saline (PBS). For biofilm assay, composite disks were transferred to S. mutans suspension and incubated for 24 hr. Afterwards, the specimens were rinsed with PBS and sonicated. The colony forming units (CFU) of the disrupted biofilm cultures were enumerated. For growth inhibition test, the composites were placed on a polystyrene well cluster, and S. mutans suspension was inoculated. The optical density at 600 nm (OD600) was recorded by Infinite F200 pro apparatus (TECAN). One-way ANOVA and two-way ANOVA followed by Bonferroni correction were used for the data analyses. Results The flexural strength values did not show significant difference at any concentration (p > 0.01). In biofilm assay, the CFU score decreased as the concentration of UA increased. The influence of saliva pretreatment was conflicting. The sucrose groups exhibited higher CFU score than glucose group (p < 0.05). In bacterial growth inhibition test, all experimental groups containing UA resulted in complete inhibition. Conclusions Within the limitations of the experiments, UA included in the composite showed inhibitory effect on S. mutans biofilm formation and growth. PMID:23741708

Inhibition of cell surface expression of endothelial adhesion molecules by ursolic acid prevents intimal hyperplasia of venous bypass grafts in rats

PubMed Central

Zeller, Iris; Wiedemann, Dominik; Schwaiger, Stefan; Stelzmüller, Marlies; Kreutmayer, Simone; Leberfing, Oliver; Stuppner, Hermann; Bernhard, David

2012-01-01

OBJECTIVES Despite rapid progress in surgical techniques, there is still a significant lack of surgery-supportive pharmacological treatments. The aim of this study was to test the hypothesis that ursolic acid (UA) may prevent intimal hyperplasia of venous bypass grafts. METHODS The hypothesis was tested by means of primary cell isolation and culture followed by real-time polymerase chain reaction, western blotting, fluorescence microscopy and fluorescence-activated cell sorting analyses, as well as an in vivo rat model for intimal hyperplasia of venous bypass grafts and immunohistochemistry and histochemistry. RESULTS The local application of UA significantly inhibited intimal hyperplasia in vivo (intimal thickness control: 25 μm, UA group: 18 μM–8 weeks after surgery). The UA treatment of grafts significantly resulted in reduced endothelial vascular cell adhesion molecule-1 (VCAM-1) expression, reduced infiltration of the grafts vessel wall by CD45-positive cells and increased smooth muscle cell (SMC) death. In in vitro condition, it could be shown that UA inhibits VCAM-1 expression downstream of NFκB and is likely to interfere with VCAM-1 protein synthesis in endothelial cells. Quantification of cell death in vascular smooth muscle cells treated with UA indicated that UA is a potent inducer of SMC apoptosis. CONCLUSIONS Our results suggest that UA-mediated inhibition of endothelial VCAM-1 expression reduces the infiltration of venous bypass grafts by CD45-positive cells and inhibits intimal hyperplasia. Apoptosis induction in SMCs may be another method in which UA reduces intimal thickening. UA may constitute a surgery-supportive pharmacon that reduces intimal hyperplasia of vein grafts. PMID:22551965

Ursolic acid protects monocytes against metabolic stress-induced priming and dysfunction by preventing the induction of Nox4☆

PubMed Central

Ullevig, Sarah L.; Kim, Hong Seok; Nguyen, Huynh Nga; Hambright, William S.; Robles, Andrew J.; Tavakoli, Sina; Asmis, Reto

2014-01-01

Aims Dietary supplementation with ursolic acid (UA) prevents monocyte dysfunction in diabetic mice and protects mice against atherosclerosis and loss of renal function. The goal of this study was to determine the molecular mechanism by which UA prevents monocyte dysfunction induced by metabolic stress. Methods and results Metabolic stress sensitizes or “primes” human THP-1 monocytes and murine peritoneal macrophages to the chemoattractant MCP-1, converting these cells into a hyper-chemotactic phenotype. UA protected THP-1 monocytes and peritoneal macrophages against metabolic priming and prevented their hyper-reactivity to MCP-1. UA blocked the metabolic stress-induced increase in global protein-S-glutathionylation, a measure of cellular thiol oxidative stress, and normalized actin-S-glutathionylation. UA also restored MAPK phosphatase-1 (MKP1) protein expression and phosphatase activity, decreased by metabolic priming, and normalized p38 MAPK activation. Neither metabolic stress nor UA supplementation altered mRNA or protein levels of glutaredoxin-1, the principal enzyme responsible for the reduction of mixed disulfides between glutathione and protein thiols in these cells. However, the induction of Nox4 by metabolic stress, required for metabolic priming, was inhibited by UA in both THP-1 monocytes and peritoneal macrophages. Conclusion UA protects THP-1 monocytes against dysfunction by suppressing metabolic stress-induced Nox4 expression, thereby preventing the Nox4-dependent dysregulation of redox-sensitive processes, including actin turnover and MAPK-signaling, two key processes that control monocyte migration and adhesion. This study provides a novel mechanism for the anti-inflammatory and athero- and renoprotective properties of UA and suggests that dysfunctional blood monocytes may be primary targets of UA and related compounds. PMID:24494201

Antinociceptive Activity of Borreria verticillata: In vivo and In silico Studies

PubMed Central

Silva, Rosa H. M.; Lima, Nathália de Fátima M.; Lopes, Alberto J. O.; Vasconcelos, Cleydlenne C.; de Mesquita, José W. C.; de Mesquita, Ludmilla S. S.; Lima, Fernando C. V. M.; Ribeiro, Maria N. de S.; Ramos, Ricardo M.; Cartágenes, Maria do Socorro de S.; Garcia, João B. S.

2017-01-01

Borreria verticillata (L.) G. Mey. known vassourinha has antibacterial, antimalarial, hepatoprotective, antioxidative, analgesic, and anti-inflammatory, however, its antinociceptive action requires further studies. Aim of the study evaluated the antinociceptive activity of B. verticillata hydroalcoholic extract (EHBv) and ethyl acetate fraction (FAc) by in vivo and in silico studies. In vivo assessment included the paw edema test, writhing test, formalin test and tail flick test. Wistar rats and Swiss mice were divided into 6 groups and given the following treatments oral: 0.9% NaCl control group (CTRL), 10 mg/kg memantine (MEM), 10 mg/kg indomethacin (INDO), 500 mg/kg EHBv (EHBv 500), 25 mg/kg FAc (FAc 25) and 50 mg/kg FAc (FAc 50). EHBv, FAc 25 and 50 treatments exhibited anti-edematous and peripheral antinociceptive effects. For in silico assessment, compounds identified in FAc were subjected to molecular docking with COX-2, GluN1a and GluN2B. Ursolic acid (UA) was the compound with best affinity parameters (binding energy and inhibition constant) for COX-2, GluN1a, GluN2B, and was selected for further analysis with molecular dynamics (MD) simulations. In MD simulations, UA exhibited highly frequent interactions with residues Arg120 and Glu524 in the COX-2 active site and NMDA, whereby it might prevent COX-2 and NMDA receptor activation. Treatment with UA 10 mg/Kg showed peripheral and central antinociceptive effect. The antinociceptive effect of B. verticillata might be predominantly attributed to peripheral actions, including the participation of anti-inflammatory components. Ursolic acid is the main active component and seems to be a promising source of COX-2 inhibitors and NMDA receptor antagonists. PMID:28588488

Ursolic acid mediates photosensitization by initiating mitochondrial-dependent apoptosis

NASA Astrophysics Data System (ADS)

Lee, Yuan-Hao; Wang, Exing; Kumar, Neeru; Glickman, Randolph D.

2013-02-01

The signaling pathways PI3K/Akt and MAPK play key roles in transcription, translation and carcinogenesis, and may be activated by light exposure. These pathways may be modulated or inhibited by naturally-occurring compounds, such as the triterpenoid, ursolic acid (UA). Previously, the transcription factors p53 and NF-kB, which transactivate mitochondrial apoptosis-related genes, were shown to be differentially modulated by UA. Our current work indicates that UA causes these effects via the mTOR and insulin-mediated pathways. UA-modulated apoptosis, following exposure to UV radiation, is observed to correspond to differential levels of oxidative stress in retinal pigment epithelial (RPE) and skin melanoma (SM) cells. Flow cytometry analysis, DHE (dihydroethidium) staining and membrane permeability assay showed that UA pretreatment potentiated cell cycle arrest and radiation-induced apoptosis selectively on SM cells while DNA photo-oxidative damage (i.e. strand breakage) was reduced, presumably by some antioxidant activity of UA in RPE cells. The UA-mediated NF-κB activation in SM cells was reduced by rapamycin pretreatment, which indicates that these agents exert inter-antagonistic effects in the PI3K/Akt/mTOR pathway. In contrast, the antagonistic effect of UA on the PI3K/Akt pathway was reversed by insulin leading to greater NF-κB and p53 activation in RPE cells. MitoTracker, a mitochondrial functional assay, indicated that mitochondria in RPE cells experienced reduced oxidative stress while those in SM cells exhibited increased oxidative stress upon UA pretreatment. When rapamycin administration was followed by UA, mitochondrial oxidative stress was increased in RPE cells but decreased in SM cells. These results indicate that UA modulates p53 and NF-κB, initiating a mitogenic response to radiation that triggers mitochondria-dependent apoptosis.

Ursolic acid improves podocyte injury caused by high glucose.

PubMed

Xu, Li; Fan, Qiuling; Wang, Xu; Li, Lin; Lu, Xinxing; Yue, Yuan; Cao, Xu; Liu, Jia; Zhao, Xue; Wang, Lining

2017-08-01

Autophagy plays an important role in the maintenance of podocyte homeostasis. Reduced autophagy may result in limited renal cell function during exposure to high glucose conditions. In this study we investigated the effects of ursolic acid (UA) on autophagy and podocyte injury, which were induced by high glucose. Conditionally immortalized murine podocytes were cultured in media supplemented with high glucose and the effects of the PI3K inhibitor LY294002 and UA on protein expression were determined. miR-21 expression was detected by real-time RT-PCR. Activation of the PTEN-PI3K/Akt/mTOR pathway, expression of autophagy-related proteins and expression of podocyte marker proteins were determined by western blot. Immunofluorescence was used to monitor the accumulation of LC3 puncta. Autophagosomes were also observed by transmission electron microscopy. During exposure to high glucose conditions, the normal level of autophagy was reduced in podocytes, and this defective autophagy induced podocyte injury. Increased miR-21 expression, decreased PTEN expression and abnormal activation of the PI3K/Akt/mTOR pathway were observed in cells that were cultured in high glucose conditions. UA and LY294002 reduced podocyte injury through the restoration of defective autophagy. Our data suggest that UA inhibits miR-21 expression and increases PTEN expression, which in turn inhibits Akt and mTOR and restores normal levels of autophagy. Our data suggest that podocyte injury is associated with reduced levels of autophagy during exposure to high glucose conditions, UA attenuated podocyte injury via an increase in autophagy through miR-21 inhibition and PTEN expression, which inhibit the abnormal activation of the PI3K/Akt/mTOR pathway. © The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

Bioactive properties of the main triterpenes found in olives, virgin olive oil, and leaves of Olea europaea.

PubMed

Sánchez-Quesada, Cristina; López-Biedma, Alicia; Warleta, Fernando; Campos, María; Beltrán, Gabriel; Gaforio, José J

2013-12-18

Oleanolic acid, maslinic acid, uvaol, and erythrodiol are the main triterpenes present in olives, olive tree leaves, and virgin olive oil. Their concentration in virgin olive oil depends on the quality of the olive oil and the variety of the olive tree. These triterpenes are described to present different properties, such as antitumoral activity, cardioprotective activity, anti-inflammatory activity, and antioxidant protection. Olive oil triterpenes are a natural source of antioxidants that could be useful compounds for the prevention of multiple diseases related to cell oxidative damage. However, special attention has to be paid to the concentrations used, because higher concentration may lead to cytotoxic or biphasic effects. This work explores all of the bioactive properties so far described for the main triterpenes present in virgin olive oil.

Beckmann rearrangement within the ring C of oleanolic acid lactone: Synthesis, structural study and reaction mechanism analysis

NASA Astrophysics Data System (ADS)

Froelich, Anna; Bednarczyk-Cwynar, Barbara; Zaprutko, Lucjusz; Gzella, Andrzej

2017-05-01

Synthesis, spectral and X-ray analysis of three compounds, i.e. 3β-acetoxy-12-hydroxyimino-18β-oleanan-28,13β-olide (substrate) and 3β-acetoxy-12-nitrile-12,13-seco-15(14 → 13)-abeoolean-14(27)-en-28,13β-olide and 3β-acetoxy-12-oxo-12a-aza-C-homoolean-13(18)-en-28-oic acid (Beckmann rearrangement reaction products) are described. Structural analysis revealed that the oxime group in the ring C in substrate molecule had an E-configuration. The nitrile product with retained lactone group was a result of major transformations within rings C and D of oleanane skeleton. In lactam product free carboxyl group and a double bond in ring D instead of lactone system were formed in Beckmann rearrangement reaction.

Anti-Helicobacter pylori activity of anacardic acids from Amphipterygium adstringens.

PubMed

Castillo-Juárez, Israel; Rivero-Cruz, Fausto; Celis, Heliodoro; Romero, Irma

2007-10-08

Amphipterygium adstringens (Schltdl.) Standl. (Anacardiaceae) is widely used in traditional Mexican medicine for the treatment of gastritis and ulcers. In this work, we studied the anti-Helicobacter pylori activity of its bark, this Gram-negative bacterium is considered the major etiological agent of chronic active gastritis and peptic ulcer disease, and it is linked to gastric carcinoma. From a bio-guided assay of the fractions obtained form a continuous Soxhlet extraction of the bark, we identified that petroleum ether fraction had significant antimicrobial activity against Helicobacter pylori. From this fraction, we isolated an anacardic acids mixture and three known triterpenes: masticadienonic acid; 3alpha-hydroxymasticadienonic acid; 3-epi-oleanolic; as well as the sterol beta-sitosterol. Only the anacardic acids mixture exhibits a potent dose-dependent antibacterial activity (MIC=10 microg/ml in broth cultures). It is enriched in saturated alkyl phenolic acids (C15:0, C16:0, C17:0 C19:0) which represents a novel source of these compounds with potent anti-Helicobacter pylori activity. The promising use of anacardic acids and Amphipterygium adstringens bark in the development of an integral treatment of Helicobacter pylori diseases is discussed.

Chromatographic and mass spectrometric characterization of essential oils and extracts from Lippia (Verbenaceae) aromatic plants.

PubMed

Stashenko, Elena E; Martínez, Jairo R; Cala, Mónica P; Durán, Diego C; Caballero, Deyanira

2013-01-01

Analytical methodologies based on GC and HPLC were developed for the separation and quantification of carnosic acid, ursolic acid, caffeic acid, p-coumaric acid, rosmarinic acid, apigenin, luteolin, quercetin, kaempferol, naringenin, and pinocembrin. These methods were used to characterize essential oils and extracts obtained by solvent (methanol) and by supercritical fluid (CO(2)) extraction from stems and leaves of Lippia (Verbenaceae family) aromatic plants (Lippia alba, Lippia origanoides, Lippia micromera, Lippia americana, Lippia graveolens, and Lippia citriodora). Supercritical CO(2) extraction isolated solely pinocembrin and narigenin from three L. origanoides chemotypes. Solvent extracts possessed a more varied composition that additionally included apigenin, quercetin, and luteolin. Solvent extraction afforded higher overall flavonoid yields from all species in comparison with supercritical CO(2) extraction. Pinocembrin was determined in L. origanoides extract at a concentration of 30 mg/g of plant material, which is more than ten times higher than the amount at which polyphenols are regularly found in aromatic plant extracts. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Are all phytochemicals useful in the preventing of DNA damage?

PubMed

Bacanlı, Merve; Aydın, Sevtap; Başaran, A Ahmet; Başaran, Nurşen

2017-11-01

Phytochemicals derived from natural plants have been used commonly for the prevention and/or treatment of different diseases due to the belief of their safety. Many plant species synthesize toxic chemicals. New natural chemicals are being discovered but their toxic effects are unknown. Phytochemicals have been regarded as possible antioxidants. But on the other hand it is suggested that various phenolic antioxidants can display pro-oxidant properties at high doses. In this review, the role of some phytochemicals (epigallocathecin gallate, carvacrol, galangin, limonene, lycopene, naringin, puerarin, terpinene, thymol and ursolic acid) on the prevention of DNA damage will be discussed. Copyright © 2017 Elsevier Ltd. All rights reserved.

Bioactive oleanane-type saponins from the rhizomes of Anemone taipaiensis.

PubMed

Wang, Xiao-Yang; Gao, Hui; Zhang, Wei; Li, Yuan; Cheng, Guang; Sun, Xiao-Li; Tang, Hai-Feng

2013-10-15

Investigation of the n-BuOH extract of the rhizomes of Anemone taipaiensis led to the isolation of five new oleanane-type triterpenoid saponins (1-5), together with seven known saponins (6-12). Their structures were determined by the extensive use of (1)D and (2)D NMR experiments along with ESIMS analyses and acid hydrolysis. The aglycone of 1, 2 and 4 was determined as siaresinolic acid, which was reported in this genus for the first time. The cytotoxicities of the saponins 1-12, prosapogenins 4a, 5a, 10a-12a and sapogenins siaresinolic acid (SA), oleanolic acid (OA), hederagenin (HE) were evaluated against five human cancer cell lines, including HepG2, HL-60, A549, HeLa and U87MG. The monodesmosidic saponins 6-8, 5a, 10a-12a and sapogenins SA, OA, HE exhibited cytotoxic activity toward all cancer cell lines, with IC50 values ranging from 2.25 to 57.28 μM. Remarkably, the bisdesmosidic saponins 1-4 and 9 showed selective cytotoxicity against the U87MG cells. Copyright © 2013 Elsevier Ltd. All rights reserved.

Isolation, characterization, and in rats plasma pharmacokinetic study of a new triterpenoid saponin from Dianthus superbus.

PubMed

Ren, Yina; Xu, Xiaobao; Zhang, Qianlan; Lu, Yongzhuang; Li, Ximin; Zhang, Lin; Tian, Jingkui

2017-02-01

One new oleanolic acid triterpenoid saponin, 3-O-β-D-glucopyranosyl olean-11, 13(18)-diene-23,28-dioic acid, (hereafter referred to as DS-1) was isolated from the traditional Chinese medicinal plant Dianthus superbus (D. superbus). DS-1 plays an important role in the bioactivity of D. superbus. Thus, a sensitive, reliable and accurate reversed-phased liquid chromatography with tandem mass spectrometry (LC-MS/MS) in negative ion mode was developed and validated for the quantification and pharmacokinetic study of DS-1 in rats plasma. The pharmacokinetic profile showed that DS-1 was rapidly absorbed and eliminated in plasma, indicating that significant accumulation of the compound in biological specimen is unlikely. In addition, poor absorption into systemic circulation was observed after oral administration of DS-1, resulting in low absolute bioavailability (0.92 %).

An access to a library of novel triterpene derivatives with a promising pharmacological potential by Ugi and Passerini multicomponent reactions.

PubMed

Wiemann, Jana; Heller, Lucie; Csuk, René

2018-04-25

The promising combination of natural product leads and their derivatization by isocyanide-based multicomponent reactions (IMCRs) has gained interest in accessing diversity-oriented libraries with auspicious pharmacological potential. Therefore, a set of 34 Ugi and 3 Passerini products was successfully synthesized starting from naturally occurring triterpenoids, i.e. oleanolic acid (OA) and maslinic acid (MA), followed by a biological evaluation of the novel α-acylamino carboxamides and the α-acyloxy carboxamides in colorimetric SRB assays to determine their cytotoxic potential. Especially, the MA-Ugi products 6a, 6b and 7b showed a remarkable cytotoxicity for A2780 ovarian carcinoma cells in a low μM range. Compounds 6a and 7b induced programmed cell death in part through the apoptosis pathway. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Characterization of two minor saponins from Cordia piauhiensis by 1H and 13C NMR spectroscopy.

PubMed

Santos, Renata P; Silveira, Edilberto R; Lemos, Telma Leda G; Viana, Francisco Arnaldo; Braz-Filho, Raimundo; Pessoa, Otília Deusdênia L

2005-06-01

A careful NMR analysis with full assignment of the 1H and 13C spectral data for two minor saponins isolated from stems of Cordia piauhiensis is reported. These saponins were isolated by high-performance liquid chromatography and characterized as 3beta-O-[alpha-L-rhamnopyranosyl-(1 --> 2)-beta-D-glucopyranosyl]pomolic acid 28-O-[beta-D-glucopyranosyl-(1 --> 6)-beta-D-glucopyranosyl] ester (1) and 3beta-O-[alpha-L-rhamnopyranosyl-(1 --> 2)-beta-D-glucopyranosyl]oleanolic acid 28-O-[beta-D-xylopyranosyl-(1 --> 2)-beta-D-glucopyranosyl-(1 --> 6)-beta-D-glucopyranosyl] ester (2). Their structures were established using a combination of 1D and 2D (1H, 1H-COSY, TOCSY, NOESY, gs-HMQC and gs-HMBC) NMR techniques, electrospray ionization mass spectrometry and chemical evidence. Copyright 2005 John Wiley & Sons, Ltd.

Phytotoxic and Nematicidal Components of Lavandula luisieri.

PubMed

Julio, Luis F; Barrero, Alejandro F; Herrador del Pino, M Mar; Arteaga, Jesús F; Burillo, Jesús; Andres, Maria Fe; Díaz, Carmen E; González-Coloma, Azucena

2016-02-26

Several preparations were obtained from the aerial parts of predomesticated Lavandula luisieri, including the essential oil and ethanolic, hexane, and ethyl acetate extractives. Additionally, pilot plant vapor pressure extraction was carried out at a pressure range of 0.5-1.0 bar to give a vapor pressure oil and an aqueous residue. A chemical study of the hexane extract led to the isolation of six necrodane derivatives (1, 2, and 4-7), with four of these (1, 2, 5, and 7) being new, as well as camphor, a cadinane sesquiterpene (9), tormentic acid, and ursolic acid. The EtOAc and EtOH extracts contained a mixture of phenolic compounds with rosmarinic acid being the major component. Workup of the aqueous residue resulted in the isolation of the necrodane 3 and (1R*,2S*,4R*)-p-menth-5-ene-1,2,8-triol (8), both new natural compounds. The structures of the new compounds were established based on their spectroscopic data. The phytotoxic and nematicidal activities of these compounds were evaluated.

Rapid Determination of Two Triterpenoid Acids in Chaenomelis Fructus Using Supercritical Fluid Extraction On-line Coupled with Supercritical Fluid Chromatography.

PubMed

Zhang, Xiaotian; Ji, Feng; Li, Yueqi; He, Tian; Han, Ya; Wang, Daidong; Lin, Zongtao; Chen, Shizhong

2018-01-01

In this study, an on-line supercritical fluid extraction (SFE) and supercritical fluid chromatography (SFC) method was developed for the rapid determination of oleanoic acid and ursolic acid in Chaenomelis Fructus. After optimization of the conditions, the two triterpenoid acids was obtained by SFE using 20% methanol as a modifier at 35°C in 8 min. They were resolved on a Shim-pack UC-X Diol column (4.6 × 150 mm, 3 μm) in 14 min (0 - 10 min, 5 - 10%; 10 - 14 min, 10% methanol in CO 2 ) with a backpressure of 15 MPa at 40°C. The on-line SFE-SFC method could be completed within 40 min (10.79 mg/g dry plant, R s = 2.36), while the ultrasound-assisted extraction and HPLC method required at least 90 min (3.55 mg/g dry plant, R s = 1.92). This on-line SFE-SFC method is powerful to simplify the pre-processing and quantitative analysis of natural products.

Phenolic and triterpenoid antioxidants from Origanum majorana L. herb and extracts obtained with different solvents.

PubMed

Vági, E; Rapavi, E; Hadolin, M; Vásárhelyiné Perédi, K; Balázs, A; Blázovics, A; Simándi, B

2005-01-12

Antioxidant properties of marjoram (Origanum majorana L.) herb and extracts obtained with ethanol, n-hexane, and supercritical CO2 extraction are presented. Individual antioxidants, ursolic acid, carnosic acid, and carnosol, were quantified with high-performance liquid chromatography. The effects of different parameters (temperature and pressure) of high-pressure extraction on the yield of carnosol were studied. Furthermore, two marjoram herbs from Hungary and Egypt were compared measuring hydrogen-donating abilities with 1,1-diphenyl-2-picrylhydrazyl by spectrophotometric and the total scavenger capacities by chemiluminometric methods from the aqueous extracts of the herbs. The antioxidant activities of the solvent extracts were performed using the Rancimat method. The Egyptian herb and its extracts possessed better antioxidant activities than Hungarian ones. Applying supercritical CO2 extraction, the highest value of carnosol was obtained at 400 bar and 60 degrees C.

[Studies on the chemical constituents of Pharbitis purpurea].

PubMed

Wang, Jin-Lan; Hua, Zhun; Zhao, Bao-Ying; Tang, Wan-Xia; Zhang, Shu-Jun

2010-10-01

To study the chemical constituents of Pharbitis purpurea. The constituents were isolated by silica gel column chromatography, HPLC and recrystallization and their structures were elucidated on the basis of spectral analysis. Fourteen compounds were isolated and identified as daucosterol (1), umbelliferone (2), ursolic acid (3), N-p-hydroxy-cis-coumaroyltyramine (4), N-p-hydroxy-trans-coumaroyltyramine (5), N-cis-feruloyltyramine (6), N-trans-feruloyltyramine (7), (3R, 5R, 6S, 7E, 9S)-megastigman-5,6-epoxy-7-ene-3,9-diol (8), (6S,9R)-vomifoliol (9), (+)-syringaresinol (10), isovitexin (11), syringopicroside( 12), uricil (13), (6S,9R)-roseoside (14). Compounds 3, 8-2,14 are isolated from the genus for the first time.

Inhibitory effects of constituents of Morinda citrifolia seeds on elastase and tyrosinase.

PubMed

Masuda, Megumi; Murata, Kazuya; Fukuhama, Akiko; Naruto, Shunsuke; Fujita, Tadashi; Uwaya, Akemi; Isami, Fumiyuki; Matsuda, Hideaki

2009-07-01

A 50% ethanolic extract (MCS-ext) from seeds of Morinda citrifolia ("noni" seeds) showed more potent in vitro inhibition of elastase and tyrosinase, and 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity than extracts of M. citrifolia leaves or flesh. Activity-guided fractionation of MCS-ext using in vitro assays led to the isolation of ursolic acid as an active constituent of elastase inhibitory activity. 3,3'-Bisdemethylpinoresinol, americanin A, and quercetin were isolated as active constituents having both tyrosinase inhibitory and radical scavenging activities. Americanin A and quercetin also showed superoxide dismutase (SOD)-like activity. These active compounds were isolated from noni seeds for the first time.

Identification and genome organization of saponin pathway genes from a wild crucifer, and their use for transient production of saponins in Nicotiana benthamiana.

PubMed

Khakimov, Bekzod; Kuzina, Vera; Erthmann, Pernille Ø; Fukushima, Ery Odette; Augustin, Jörg M; Olsen, Carl Erik; Scholtalbers, Jelle; Volpin, Hanne; Andersen, Sven Bode; Hauser, Thure P; Muranaka, Toshiya; Bak, Søren

2015-11-01

The ability to evolve novel metabolites has been instrumental for the defence of plants against antagonists. A few species in the Barbarea genus are the only crucifers known to produce saponins, some of which make plants resistant to specialist herbivores, like Plutella xylostella, the diamondback moth. Genetic mapping in Barbarea vulgaris revealed that genes for saponin biosynthesis are not clustered but are located in different linkage groups. Using co-location with quantitative trait loci (QTLs) for resistance, transcriptome and genome sequences, we identified two 2,3-oxidosqualene cyclases that form the major triterpenoid backbones. LUP2 mainly produces lupeol, and is preferentially expressed in insect-susceptible B. vulgaris plants, whereas LUP5 produces β-amyrin and α-amyrin, and is preferentially expressed in resistant plants; β-amyrin is the backbone for the resistance-conferring saponins in Barbarea. Two loci for cytochromes P450, predicted to add functional groups to the saponin backbone, were identified: CYP72As co-localized with insect resistance, whereas CYP716As did not. When B. vulgaris sapogenin biosynthesis genes were transiently expressed by CPMV-HT technology in Nicotiana benthamiana, high levels of hydroxylated and carboxylated triterpenoid structures accumulated, including oleanolic acid, which is a precursor of the major resistance-conferring saponins. When the B. vulgaris gene for sapogenin 3-O-glucosylation was co-expressed, the insect deterrent 3-O-oleanolic acid monoglucoside accumulated, as well as triterpene structures with up to six hexoses, demonstrating that N. benthamiana further decorates the monoglucosides. We argue that saponin biosynthesis in the Barbarea genus evolved by a neofunctionalized glucosyl transferase, whereas the difference between resistant and susceptible B. vulgaris chemotypes evolved by different expression of oxidosqualene cyclases (OSCs). © 2015 The Authors The Plant Journal © 2015 John Wiley & Sons Ltd.

Protective effects of oleanolic acid on oxidative stress and the expression of cytokines and collagen by the AKT/NF‑κB pathway in silicotic rats.

PubMed

Peng, Hai-Bing; Wang, Rui-Xun; Deng, Hai-Jing; Wang, Yong-Heng; Tang, Jun-Dong; Cao, Fu-Yuan; Wang, Jian-Hui

2017-05-01

Oleanolic acid (OA), a natural pentacyclic triterpenoid, has been reported to have several benefits and medicinal properties. However, its protective effects against silica‑induced lung injury and fibrosis remain to be elucidated. The aim of the present study was to investigate the effects of OA on oxidative stress, and the expression of cytokines and collagen in silicotic rats. Male rats were induced by intratracheal instillation of silicosis (250 mg/kg), with the exception of the control group (NS). The rats in the OA group were intragastrically administered with OA (60 mg/kg/d). The rats in the solvent control group were gavaged daily with 0.6% sodium carboxymethyl cellulose (10 ml/kg) solution for 56 consecutive days. The data showed that OA significantly attenuated the extent of silicosis fibrosis by histopathologic analysis of the lung tissues. In addition, oxidative stress activated by silica exposure, as evidenced by increasing of malondialdehyde content, and activities of superoxide dismutase and glutathione peroxidase in the lung, was regulated by treatment with OA. Furthermore, enzyme‑linked immunosorbent assay analysis showed that OA significantly decreased the levels of tumor necrosis factor‑α and transforming growth factor‑β1. Immunohistochemistry analysis showed that OA significantly decreased collagen types I and III. In investigating the mechanisms underlying the action of OA, it was found that OA decreased the level of phosphorylated AKT1, which in turn inactivated the transcriptional of nuclear factor (NF)‑κB in the development and progress of silicosis. In conclusion, these results suggested that the protective effects of OA were due, at least in part, to its anti‑oxidant activity and its ability to decrease the expression of cytokines and collagen by modulating the AKT/NF‑κB pathway.

Oleanolic acid induces p53-dependent apoptosis via the ERK/JNK/AKT pathway in cancer cell lines in prostatic cancer xenografts in mice.

PubMed

Kim, Gyeong-Ji; Jo, Hyeon-Ju; Lee, Kwon-Jai; Choi, Jeong Woo; An, Jeung Hee

2018-05-29

We evaluated oleanolic acid (OA)-induced anti-cancer activity, apoptotic mechanism, cell cycle status, and MAPK kinase signaling in DU145 (prostate cancer), MCF-7 (breast cancer), U87 (human glioblastoma), normal murine liver cell (BNL CL.2) and human foreskin fibroblast cell lines (Hs 68). The IC50 values for OA-induced cytotoxicity were 112.57 in DU145, 132.29 in MCF-7, and 163.60 in U87 cells, respectively. OA did not exhibit toxicity in BNL CL. 2 and Hs 68 cell lines in our experiments. OA, at 100 µg/mL, increased the number of apoptotic cells to 27.0% in DU145, 27.0% in MCF-7, and 15.7% in U87, when compared to control cells. This enhanced apoptosis was due to increases in p53, cytochrome c, Bax, PARP-1 and caspase-3 expression in DU145, MCF-7 and U87 cell lines. OA-treated DU145 cells were arrested in G2 because of the activation of p-AKT, p-JNK, p21 and p27, and the decrease in p-ERK, cyclin B1 and CDK2 expression; OA-treated MCF-7 cells were arrested in G1 owing to the activation of p-JNK, p-ERK, p21, and p27, and the decrease in p-AKT, cyclin D1, CDK4, cyclin E, and CDK2; and OA-treated U87 cells also exhibited G1 phase arrest caused by the increase in p-ERK, p-JNK, p-AKT, p21, and p27, and the decrease in cyclin D1, CDK4, cyclin E and CDK2. Thus, OA arrested the cell cycle at different phases and induced apoptosis in cancer cells. These results suggested that OA possibly altered the expression of the cell cycle regulatory proteins differently in varying types of cancer.

Apoptosis caused by triterpenes and phytosterols and antioxidant activity of an enriched flavonoid extract and from Passiflora mucronata.

PubMed

da Silva, Isabel Cristina Vieira; Kaluderovic, Goran; de Oliveira, Pollyana Felix; Guimaraes, Denise Oliveira; Quaresma, Carla Holandino; Porzel, Andrea; Muzitano, Michelle Frazao; Wessjohann, Ludger A; Leal, Ivana Correa Ramos

2018-03-14

The genus Passiflora is knew for food consumption mainly and it extracts present a variety of methabolites, including flavones, alkaloids and triterpenes usually correlated with their antioxidant and antitumoral activities. P. mucronata (Pm) is from Brazil South America and is characterized as "Maracujá de Restinga", being used in the folk medicine for treating insomnia and soothing. The present study evaluated in the first time, the antioxidant and cytotoxicity of the hydroalcoholic leaves extract and fractions from Pm. Their cytotoxic effects were against human prostate cancer (PC3) and mouse malignant melanoma (B16F10) cell lines, by the MTT and CV assays. β-Amyrin, oleanolic acid, β-sitosterol and stigmasterol were isolated as the main components of the most active hexane fraction. These substances were tested individually against the tumor cell lines, whereby β-sitosterol and stigmasterol showed the most relevant activity to PC3 in CV assay and, oleanolic acid to B16F10 by the MTT assay. In addition, these compounds were analysed to cell cycle arrest, and stigmasterol decreased the number of cells in B16F10 line in the G1/G0 phase and subsequently, increased the cell number in sub-G1 phase, presumably indicating apoptosis as possible mode of cell death.The antioxidant activity by the DPPH method showed that the hydroalcoholic extract from the leaves presented higher antioxidant activity (EC50= 133.3 µg/mL) compared to the flowers (EC50= 152.3 µg/mL) and fruits (EC50=207.9 µg/mL) extracts. By the HPLC-MS it was possible to identify the main flavones present in the leaf extract (isoschaftoside, schaftoside, isovitexin, vitexin, isoorientin, orientin). Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Bioactive Phytochemicals from Wild Arbutus unedo L. Berries from Different Locations in Portugal: Quantification of Lipophilic Components

PubMed Central

Fonseca, Daniela F. S.; Salvador, Ângelo C.; Santos, Sónia A. O.; Vilela, Carla; Freire, Carmen S. R.; Silvestre, Armando J. D.; Rocha, Sílvia M.

2015-01-01

The lipophilic composition of wild Arbutus unedo L. berries, collected from six locations in Penacova (center of Portugal), as well as some general chemical parameters, namely total soluble solids, pH, titratable acidity, total phenolic content and antioxidant activity was studied in detail to better understand its potential as a source of bioactive compounds. The chemical composition of the lipophilic extracts, focused on the fatty acids, triterpenoids, sterols, long chain aliphatic alcohols and tocopherols, was investigated by gas chromatography–mass spectrometry (GC–MS) analysis of the dichloromethane extracts. The lipophilic extractives of the ripe A. unedo berries ranged from 0.72% to 1.66% (w/w of dry weight), and consisted mainly of triterpenoids, fatty acids and sterols. Minor amounts of long chain aliphatic alcohols and tocopherols were also identified. Forty-one compounds were identified and among these, ursolic acid, lupeol, α-amyrin, linoleic and α-linolenic acids, and β-sitosterol were highlighted as the major components. To the best of our knowledge the current research study provides the most detailed phytochemical repository for the lipophilic composition of A. unedo, and offers valuable information for future valuation and exploitation of these berries. PMID:26110390

Ursolic acid differentially modulates apoptosis in skin melanoma and retinal pigment epithelial cells exposed to UV-VIS broadband radiation.

PubMed

Lee, Yuan-Hao; Wang, Exing; Kumar, Neeru; Glickman, Randolph D

2014-05-01

The signaling pathways via mTOR (mammalian target of rapamycin) and AMPK (AMP-activated protein kinase) play key roles in transcription, translation and carcinogenesis, and may be activated by light exposure. These pathways can be modulated by naturally occurring compounds, such as the triterpenoid, ursolic acid (UA). Previously, the transcription factors p53 and NF-κB, which transactivate mitochondrial apoptosis-related genes, were shown to be differentially modulated by UA. UA-modulated apoptosis, following exposure to UV-VIS radiation (ultraviolet to visible light broadband radiation, hereafter abbreviated to UVR), is observed to correspond to differential levels of oxidative stress in retinal pigment epithelial (RPE) and skin melanoma (SM) cells. The cellular response to this phytochemical was characterized using western blot, flow cytometry, microscopy with reactive oxidative species probes MitoTracker and dihydroethidium, and membrane permeability assay. UA pretreatment potentiated cell cycle arrest and UVR-induced apoptosis selectively in SM cells while reducing photo-oxidative stress in the DNA of RPE cells presumably by antioxidant activity of UA. Mechanistically, the nuclear transportation of p65 and p53 was reduced by UA administration prior to UVR exposure while the levels of p65 and p53 nuclear transportation in SM cells were sustained at a substantially higher level. Finally, the mitochondrial functional assay showed that UVR induced the collapse of the mitochondrial membrane potential, and this effect was exacerbated by rapamycin or UA pretreatment in SM preferentially. These results were consistent with reduced proliferation observed in the clonogenic assay, indicating that UA treatment enhanced the phototoxicity of UVR, by modulating the activation of p53 and NF-κB and initiating a mitogenic response to optical radiation that triggered mitochondria-dependent apoptosis, particularly in skin melanoma cells. The study indicates that this compound has multiple actions with the potential for protecting normal cells while sensitizing skin melanoma cells to UV irradiation.

Ursolic Acid Increases Glucose Uptake through the PI3K Signaling Pathway in Adipocytes

PubMed Central

He, Yonghan; Li, Wen; Li, Ying; Zhang, Shuocheng; Wang, Yanwen; Sun, Changhao

2014-01-01

Background Ursolic acid (UA), a triterpenoid compound, is reported to have a glucose-lowering effect. However, the mechanisms are not fully understood. Adipose tissue is one of peripheral tissues that collectively control the circulating glucose levels. Objective The objective of the present study was to determine the effect and further the mechanism of action of UA in adipocytes. Methods and Results The 3T3-L1 preadipocytes were induced to differentiate and treated with different concentrations of UA. NBD-fluorescent glucose was used as the tracer to measure glucose uptake and Western blotting used to determine the expression and activity of proteins involved in glucose transport. It was found that 2.5, 5 and 10 µM of UA promoted glucose uptake in a dose-dependent manner (17%, 29% and 35%, respectively). 10 µM UA-induced glucose uptake with insulin stimulation was completely blocked by the phosphatidylinositol (PI) 3-kinase (PI3K) inhibitor wortmannin (1 µM), but not by SB203580 (10 µM), the inhibitor of mitogen-activated protein kinase (MAPK), or compound C (2.5 µM), the inhibitor of AMP-activated kinase (AMPK) inhibitor. Furthmore, the downstream protein activities of the PI3K pathway, phosphoinositide-dependent kinase (PDK) and phosphoinositide-dependent serine/threoninekinase (AKT) were increased by 10 µM of UA in the presence of insulin. Interestingly, the activity of AS160 and protein kinase C (PKC) and the expression of glucose transporter 4 (GLUT4) were stimulated by 10 µM of UA under either the basal or insulin-stimulated status. Moreover, the translocation of GLUT4 from cytoplasm to cell membrane was increased by UA but decreased when the PI3K inhibitor was applied. Conclusions Our results suggest that UA stimulates glucose uptake in 3T3-L1 adipocytes through the PI3K pathway, providing important information regarding the mechanism of action of UA for its anti-diabetic effect. PMID:25329874

Ursolic acid rich Ocimum sanctum L leaf extract loaded nanostructured lipid carriers ameliorate adjuvant induced arthritis in rats by inhibition of COX-1, COX-2, TNF-α and IL-1: Pharmacological and docking studies

PubMed Central

Abuzinadah, Mohammed F.; Alkreathy, Huda M.; Banaganapalli, Babajan; Mujeeb, Mohd

2018-01-01

Background Ursolic acid (UA) is a promising molecule with anti-inflammatory, analgesic and potential anti-arthritic activity. Methods This study was undertaken to make formulation and evaluation of Ocimum sanctum L. leaf extract (OLE) loaded nano-structured lipid carriers (OLE-NLCs) for improved transdermal delivery of UA. Different surfactants, solid lipids and liquid lipids were used for the preparation of NLCs. The NLCs were developed using emulsion solvent diffusion and evaporation method. Different physicochemical properties, entrapment efficacy, in vitro release evaluation, and ex vivo permeation studies of the prepared NLCs were carried out. The in vivo anti-arthritic activity of OLE-loaded NLC gel and control gel formulation (OLE free NLC gel) against Complete Freund's Adjuvant (CFA) induced arthritis in wister albino rats was also carried out. Results OLE-NLCs were composed of spherical particles having a mean particle size of ~120 nm, polydispersity index of ~0.162 and zeta potential of ~ -27 mV. The high entrapment efficiency (EE) of UA ~89.56% was attained. The in vitro release study demonstrated a prolonged release of UA from the NLCs up to 12 h. The developed formulation was found to be significantly better with respect to the drug permeation amount with an enhancement ratio of 2.69 as compared with marketed formulation. The in vivo biological activity investigations, studies showed that the newly prepared NLCs formulation of OLE showed excellent anti-arthritic activity and the results were found at par with standard marketed diclofenac gel for its analgesic and anti-arthritic activities. These results were also supported by radiological analysis and molecular docking studies. Conclusion The overall results proved that the prepared OLE-NLCs were very effective for the treatment of arthritis and the results were found at par with standard marketed the standard formulation of diclofenac gel. PMID:29558494

Ursolic acid reduces the metalloprotease/anti-metalloprotease imbalance in cerebral ischemia and reperfusion injury.

PubMed

Wang, Yanzhe; He, Zhiyi; Deng, Shumin

2016-01-01

Activators of PPARs, particularly PPARγ, may be effective neuroprotective drugs against inflammatory responses in cerebral ischemia and reperfusion injury. Ursolic acid (UA) may act as a PPARγ agonist and serve as an anti-inflammatory agent. In this study, we used a rat middle cerebral artery occlusion and reperfusion model to examine how UA acts as a neuroprotective agent to modulate the metalloprotease/anti-metalloprotease balance. The middle cerebral artery occlusion and reperfusion model (occlusion for 2 hours followed by reperfusion for 48 hours) was induced in male Sprague Dawley rats. UA was administered intragastrically 0.5, 24, and 47 hours after reperfusion. Bisphenol A diglycidyl ether (a PPARγ antagonist) was intraperitoneally administered 1, 24.5, and 47.5 hours after reperfusion. Forty-eight hours after reperfusion, neurological deficits and infarct volume were estimated. The PPARγ level and the metalloprotease/anti-metalloprotease balance were examined by Western blotting and immunohistochemistry. The activation of MAPK signaling pathways was also assessed. UA-treated (5, 10, or 20 mg/kg) rats showed significant improvement in neurological deficit score, infarct volume, and the number of intact neurons compared with control rats (P<0.01). Both the PPARγ protein level and the percentage of PPARγ-positive cells were increased in the UA-treated groups (P<0.01). Compared with the control group, the UA-treated groups exhibited reduced protein levels of MMP2, MMP9, and activated MAPKs (P<0.01) but an increased level of TIMP1 (P<0.01). UA exerted its protective effects in a dose-dependent manner. Co-treatment with UA and bisphenol A diglycidyl ether completely abolished the UA-induced changes in PPARγ expression; however UA continued to exert a significant but partial neuroprotective effect. UA can act as a PPARγ agonist to improve the metalloprotease/anti-metalloprotease balance, possibly by inhibiting the activation of the MAPK signaling pathway, thereby attenuating cerebral ischemia and reperfusion injury. Therefore, UA may serve as a novel neuroprotective therapeutic agent.

Synthesis and proapoptotic activity of oleanolic acid derived amides.

PubMed

Heller, Lucie; Knorrscheidt, Anja; Flemming, Franziska; Wiemann, Jana; Sommerwerk, Sven; Pavel, Ioana Z; Al-Harrasi, Ahmed; Csuk, René

2016-10-01

Thirty-one different 3-O-acetyl-OA derived amides have been prepared and screened for their cytotoxic activity. In the SRB assays nearly all the carboxamides displayed good cytotoxicity in the low μM range for several human tumor cell lines. Low EC50 values were obtained especially for the picolinylamides 14-16, for a N-[2-(dimethylamino)-ethyl] derivative 27 and a N-[2-(pyrrolinyl)-ethyl] carboxamide 28. These compounds were submitted to an extensive biological testing and proved compound 15 to act mainly by an arrest of the tumor cells in the S phase of the cell cycle. Cell death occurred by autophagy while compounds 27 and 28 triggered apoptosis. Copyright © 2016 Elsevier Inc. All rights reserved.

Interactions of antiparasitic sterols with sterol 14α-demethylase (CYP51) of human pathogens.

PubMed

Warfield, Jasmine; Setzer, William N; Ogungbe, Ifedayo Victor

2014-01-01

Sterol 14α-demethylase is a validated and an attractive drug target in human protozoan parasites. Pharmacological inactivation of this important enzyme has proven very effective against fungal infections, and it is a target that is being exploited for new antitrypanosomal and antileishmanial chemotherapy. We have used in silico calculations to identify previously reported antiparasitic sterol-like compounds and their structural congeners that have preferential and high docking affinity for CYP51. The sterol 14α-demethylase from Trypanosoma cruzi and Leishmania infantum, in particular, preferentially dock to taraxerol, epi-oleanolic acid, and α/β-amyrim structural scaffolds. These structural information and predicted interactions can be exploited for fragment/structure-based antiprotozoal drug design.

Ethylene glycol-linked amino acid diester prodrugs of oleanolic acid for PepT1-mediated transport: synthesis, intestinal permeability and pharmacokinetics.

PubMed

Cao, Feng; Jia, Jinghao; Yin, Zhi; Gao, Yahan; Sha, Lei; Lai, Yisheng; Ping, Qineng; Zhang, Yihua

2012-08-06

The purposes of this study were to expand the structure of parent drugs selected for peptide transporter 1 (PepT1)-targeted ester prodrug design and to improve oral bioavailability of oleanolic acid (OA), a Biopharmaceutics Classification System (BCS) class IV drug. Through an ethoxy linker the carboxylic acid group of OA was conjugated with the carboxylic acid group of different amino acid promoieties to form six diester prodrugs. The effective permeability (P(eff)) of prodrugs was screened by in situ rat single-pass intestinal perfusion (SPIP) model in two buffers with different pH (6.0 and 7.4) as PepT1 employs a proton-gradient as the driving force. Compared to OA, 2.5-fold, 2.3-fold, 2.2-fold, 2.1-fold, and 1.9-fold enhancement of P(eff) in buffer with pH 6.0 was observed for L-Phe ester (5c), L-Val ester (5a), L-Lys ester (5e), D-Phe ester (5d), and D-Val ester (5b), respectively. Furthermore, P(eff) of 5a, 5c, 5d and 5e in pH 6.0 was significantly higher than that in pH 7.4 (p < 0.01), respectively. These results showed that the H(+) concentration of perfusion solution had great effect on the transport of the prodrugs across intestinal membrane. For the further evaluation of affinity to PepT1, inhibition studies were performed by coperfusing 0.1 mM prodrug with 50 mM glycyl-sarcosine (Gly-Sar, a typical substrate of PepT1). It turned out that the P(eff) of 5a, 5b, 5c and L-Tyr ester (6f) significantly reduced in the presence of Gly-Sar (1.7-fold, 2.2-fold, 1.9-fold, and 1.4-fold, respectively). We supposed that it may be attributed to PepT1 mediated transport of these prodrugs. 5a and 6f were selected as the optimal target prodrugs for oral absorption in vivo. Following intragastric administration of 300 mg/kg (calculated as OA) 5a, 6f and OA in three groups of rats, compared with group OA, Cmax for the group of 5a and 6f was enhanced by 1.56-fold and 1.54-fold, respectively. Fapp of group 5a and 6f was 2.21- and 2.04-fold increased, respectively, indicating that 5a and 6f had better oral absorption than OA. The combined results also suggest that diester prodrugs which conjugated two carboxylic acid groups of proper amino acid promoieties and parent drug through a linker can be used for PepT1-targeted prodrug design. With this strategy, oral bioavailability of OA in rats could be improved significantly.

[Chemical Compositions from Stems and Branches of Sorbaria arborea].

PubMed

Wang, Jian; Ma, Yang-min; Yan, Meng-ru; Xu, Qian; Qu, Zi-rui; Miao, Zhi

2015-10-01

To investigate the chemical constituents from the stems and branches of Sorbaria arborea. The chemical constituents were isolated and purified by silica gel column chromatography, Sephadex LH-20 column chromatography and recrystallization. Their structures were identified by physicochemical properties and spectra analysis. Ten compounds were isolated and identified as ursolic acid (1), cucurbitacin F (2), (-) -epicatechin (3), daucosterol (4), arbutin (5), 3-O-β-anthemisol (6), 2,6-dimethoxy-p-hydroquinone-4-O-β-D-glucopyranoside (7), lupeol (8), betulin (9) and lup-20 (29) -en-3β, 30-diol (10). All the compounds are isolated from this plant for the first time, and compounds 1, 6 - 8 and 10 are obtained from Sorbaria genus for the first time.

An Overview of Structurally Modified Glycyrrhetinic Acid Derivatives as Antitumor Agents.

PubMed

Xu, Bing; Wu, Gao-Rong; Zhang, Xin-Yu; Yan, Meng-Meng; Zhao, Rui; Xue, Nan-Nan; Fang, Kang; Wang, Hui; Chen, Meng; Guo, Wen-Bo; Wang, Peng-Long; Lei, Hai-Min

2017-06-02

Glycyrrhetinic Acid ( GA ), a triterpenoid aglycone component of the natural product glycyrrhizinic acid, was found to possess remarkable anti-proliferative and apoptosis-inducing activity in various cancer cell lines. Though GA was not as active as other triterpenes, such as betulinic acid and oleanolic acid, it could trigger apoptosis in tumor cells and it can be obtained easily and cheaply, which has stimulated scientific interest in using GA as a scaffold to synthesize new antitumor agents. The structural modifications of GA reported in recent decades can be divided into four groups, which include structural modifications on ring-A, ring-C, ring-E and multiple ring modifications. The lack of a comprehensive and recent review on this topic prompted us to gather more new information. This overview is dedicated to summarizing and updating the structural modification of GA to improve its antitumor activity published between 2005 and 2016. We reviewed a total of 210 GA derivatives that we encountered and compiled the most active GA derivatives along with their activity profile in different series. Furthermore, the structure activity relationships of these derivatives are briefly discussed. The included information is expected to be of benefit to further studies of structural modifications of GA to enhance its antitumor activity.

[Chemical constituents of Swertia macrosperma].

PubMed

Wang, Hongling; Geng, Changan; Zhang, Xuemei; Ma, Yunbao; Jiang, Zhiyong; Chen, Jijun

2010-12-01

To study the chemical constituents of Swertia macrosperma. The air-dried whole plants of Swertia macrosperma were extracted with boiling water. The extract was concentrated to a small amount of volume and extracted with petroleum ether, EtOAc and n-BuOH, successively. The compounds were isolated and purified by column chromatography from the EtOAc fraction, and identified based on spectral analyses (MS, 1H-NMR, 13C-NMR). Thirteen compounds were isolated from S. macrosperma, and were characterized as norbellidifolin (1), 1-hydroxy-3,7, 8-trimethoxy-xanthone (2), norswertianolin (3), swertianolin (4), 1,3,7,8-tetrahydroxyxanthone-8-O-beta-D-glucopyranoside (5), swertiamatin (6), decentapicrin (7), coniferl aldehyde (8), sinapaldehyde (9), balanophonin (10), together with beta-sitosterol, daucosterol, and oleanolic acid . Compounds 2, 4-10 were obtained from Swertia macrosperma for the first time.

A new glucosidic phthalide from Helichrysum microphyllum subsp. tyrrhenicum from La Maddalena Island (Sardinia, Italy).

PubMed

Venditti, Alessandro; Lattanzi, Claudia; Ornano, Luigi; Maggi, Filippo; Sanna, Cinzia; Ballero, Mauro; Alvino, Antonello; Serafini, Mauro; Bianco, Armandodoriano

2016-01-01

In this study, we reported the analysis of the medium polarity fraction obtained from an accession of Helichrysum microphyllum subsp. tyrrhenicum from La Maddalena Island. Besides several compounds already evidenced in this species and related genera, i.e. micropyrone (1), arzanol (2), helipyrone (3), acetyl-bitalin derivatives (4, 5), gnaphaliol (6), caffeic acid (7), ursolic acid (8), 7-O-β-(D-glucopyranosyl)-5-methoxy-1(3H)-isobenzofuranone (9), gnaphaliol-9-O-β-D-glucopyranoside (11) and gnaphaliol-3-O-β-D-glucopyranoside (12), the presence of a new glycosidic phthalide, 6-O-β-(D-glucopyranosyl)-4-methoxy-1(3H)-benzofuranone (10), was evidenced for the first time, which resulted in a structural isomer of compound (9). The occurrence of this new benzofuranone derivative is an additional evidence of the deep intraspecific variability expressed by this species, which was also stated for the non-volatile components, and may be a distinctive trait of the population growing on La Maddalena Island.

Ritual Black Drink consumption at Cahokia

PubMed Central

Crown, Patricia L.; Emerson, Thomas E.; Gu, Jiyan; Hurst, W. Jeffrey; Pauketat, Timothy R.; Ward, Timothy

2012-01-01

Chemical analyses of organic residues in fragments of pottery from the large site of Cahokia and surrounding smaller sites in Illinois reveal theobromine, caffeine, and ursolic acid, biomarkers for species of Ilex (holly) used to prepare the ritually important Black Drink. As recorded during the historic period, men consumed Black Drink in portions of the American Southeast for ritual purification. This first demonstrated discovery of biomarkers for Ilex occurs in beaker vessels dating between A.D. 1050 and 1250 from Cahokia, located far north of the known range of the holly species used to prepare Black Drink during historic times. The association of Ilex and beaker vessels indicates a sustained ritual consumption of a caffeine-laced drink made from the leaves of plants grown in the southern United States. PMID:22869743

[Effect of soil phenolic acids on soil microbe of coal-mining depressed land after afforestation restoration by different tree species].

PubMed

Ji, Li; Yang, Li Xue

2017-12-01

Phenolic acids are one of the most important factors that influence microbial community structure. Investigating the dynamic changes of phenolic acids and their relationship with the microbial community structure in plantation soils with different tree species could contribute to better understanding and revealing the mechanisms of microbial community changes under afforestation restoration in coal-mining subsidence areas. In this study, plantations of three conifer and one deciduous species (Pinus koraiensis, Larix gmelinii, Pinus sylvestris var. mongolica, and Populus ussuriensis) were established on abandoned coal-mining subsidence areas in Baoshan District, Shuangyashan City. The contents of soil phenols, 11 types of phenolic acids, and microbial communities in all plots were determined. The results showed that the contents of soil complex phenol in plantations were significantly higher than that of abandoned land overall. Specifically, soils in larch and poplar plantations had higher contents of complex phenol, while soils in larch and Korean pine plantations had greater contents of total phenol. Moreover, soil in the P. koraiensis plantation had a higher content of water-soluble phenol compared with abandoned lands. The determination of 11 phenolic acids indicated that the contents of ferulic acid, abietic acid, β-sitosterol, oleanolic acid, shikimic acid, linoleic acid, and stearic acid were higher in plantation soils. Although soil phenol contents were not related with soil microbial biomass, the individual phenolic acids showed a significant relationship with soil microbes. Ferulic acid, abietic acid, and β-sitosterol showed significant promoting effects on soil microbial biomass, and they showed positive correlations with fungi and fungi/bacteria ratio. These three phenolic acids had higher contents in the poplar plantation, suggesting that poplar affo-restation had a beneficial effect on soil quality in coal-mining subsidence areas.

Bardoxolone methyl prevents high-fat diet-induced alterations in prefrontal cortex signalling molecules involved in recognition memory.

PubMed

Camer, Danielle; Yu, Yinghua; Szabo, Alexander; Fernandez, Francesca; Dinh, Chi H L; Huang, Xu-Feng

2015-06-03

High fat (HF) diets are known to induce changes in synaptic plasticity in the forebrain leading to learning and memory impairments. Previous studies of oleanolic acid derivatives have found that these compounds can cross the blood-brain barrier to prevent neuronal cell death. We examined the hypothesis that the oleanolic acid derivative, bardoxolone methyl (BM) would prevent diet-induced cognitive deficits in mice fed a HF diet. C57BL/6J male mice were fed a lab chow (LC) (5% of energy as fat), a HF (40% of energy as fat), or a HF diet supplemented with 10mg/kg/day BM orally for 21weeks. Recognition memory was assessed by performing a novel object recognition test on the treated mice. Downstream brain-derived neurotrophic factor (BDNF) signalling molecules were examined in the prefrontal cortex (PFC) and hippocampus of mice via Western blotting and N-methyl-d-aspartate (NMDA) receptor binding. BM treatment prevented HF diet-induced impairment in recognition memory (p<0.001). In HF diet fed mice, BM administration attenuated alterations in the NMDA receptor binding density in the PFC (p<0.05), however, no changes were seen in the hippocampus (p>0.05). In the PFC and hippocampus of the HF diet fed mice, BM administration improved downstream BDNF signalling as indicated by increased protein levels of BDNF, phosphorylated tropomyosin related kinase B (pTrkB) and phosphorylated protein kinase B (pAkt), and increased phosphorylated AMP-activated protein kinase (pAMPK) (p<0.05). BM administration also prevented the HF diet-induced increase in the protein levels of inflammatory molecules, phosphorylated c-Jun N-terminal kinase (pJNK) in the PFC, and protein tyrosine phosphatase 1B (PTP1B) in both the PFC and hippocampus. In summary, these findings suggest that BM prevents HF diet-induced impairments in recognition memory by improving downstream BDNF signal transduction, increasing pAMPK, and reducing inflammation in the PFC and hippocampus. Copyright © 2015 Elsevier Inc. All rights reserved.

Study of oleanolic acid on the estrodiol production and the fat production of mouse preadipocyte 3T3-L1 in vitro.

PubMed

Wan, Qian; Lu, Hua; Liu, Xia; Yie, Shangmian; Xiang, Junbei; Yao, Zouying

2015-01-01

The women during the menopause period have an increased tendency for the obesity, which represents the more fat production than during the premenopausal period. Although this is not beneficial overall, it could provide a compensatory source for the estrogen production for the menopausal women. So it would be meaningful to find an agent that could inhibit the fat production while does not disturb the total estrogen production by fat tissues. In the present study, the effect of oleanolic acid (OA) on the fat production and the total estrogen production of the differentiating mouse preadipocyte 3T3-L1 as well as the mechanisms behind those effects were preliminarily investigated. The cell line 3T3-L1 was chosen as the model cell because it is usually used for the research about the obesity. During the induced differentiation of 3T3-L1 cells, cells were intervened continuously with OA. The fat production was determined with the oil red staining assay and the total estrogen production was measured with the ELISA assay. Finally, the expression patterns for important genes of the fat production and the estrogen production were studied, respectively with the real-time fluorescence quantitative PCR (qPCR). The results showed that for the differentiating 3T3-L1 cells, OA could significantly inhibit the fat production and did not disturb the total estrogen production significantly. In the mechanism studies, OA was found to significantly down-regulate ACC, the key gene for fat synthesis, which could explain the inhibitory effect of OA on the fat production; OA was also found to significantly up-regulate CYP11A1, CYP17, CYP19, the key genes for the estrogen synthesis and significantly down-regulate CYP1A1, the key gene for the estrogen decomposition, which preliminarily explained the lack of the effect of OA on the total estrogen production. In conclusion, OA was found able to inhibit the fat production while maintaining the total estrogen level and the mechanisms for the above findings were preliminarily clarified, which suggests that OA may be useful to treat the menopausal obesity.

Oleanolic acid acetate inhibits atopic dermatitis and allergic contact dermatitis in a murine model

DOE Office of Scientific and Technical Information (OSTI.GOV)

Choi, Jin Kyeong; Oh, Hyun-Mee; Lee, Soyoung

2013-05-15

Atopic dermatitis (AD) and allergic contact dermatitis (ACD) are common allergic and inflammatory skin diseases caused by a combination of eczema, scratching, pruritus, and cutaneous sensitization with allergens. This paper examines whether oleanolic acid acetate (OAA) modulates AD and ACD symptoms by using an existing AD model based on the repeated local exposure of mite extract (Dermatophagoides farinae extract, DFE) and 2,4-dinitrochlorobenzene to the ears of BALB/c mice. In addition, the paper uses a 2,4-dinitrofluorobenzene-sensitized local lymph node assay (LLNA) for the ACD model. The oral administration of OAA over a four-week period attenuated AD symptoms in terms of decreasedmore » skin lesions, epidermal thickness, the infiltration of immune cells (CD4{sup +} cells, eosinophils, and mast cells), and serum IgE, IgG2a, and histamine levels. The gene expression of Th1, Th2, Th17, and Th22 cytokines was reduced by OAA in the lymph node and ear tissue, and the LLNA verified that OAA suppressed ACD. The oral administration of OAA over a three-day period attenuated ACD symptoms in terms of ear thickness, lymphocyte proliferation, and serum IgG2a levels. The gene expression of Th1, Th2, and Th17 cytokines was reduced by OAA in the thymus and ear tissue. Finally, to define the underlying mechanism, this paper uses a TNF-α/IFN-γ-activated human keratinocyte (HaCaT) model. OAA inhibited the expression of cytokines and chemokines through the downregulation of NF-κB and MAPKs in HaCaT cells. Taken together, the results indicate that OAA inhibited AD and ACD symptoms, suggesting that OAA may be effective in treating allergic skin disorders. - Highlights: • OAA reduced both acute and chronic AD symptoms. • OAA had a controlling effect on the immune reaction for ACD. • The effect of OAA on allergic skin disorders was comparable to the cyclosporine A. • OAA might be a candidate for the treatment of allergic skin disorders.« less

Cytotoxic and Immunomodulatory Potential Activity of Physalis peruviana Fruit Extracts on Cervical Cancer (HeLa) and Fibroblast (L929) Cells.

PubMed

Mier-Giraldo, Helen; Díaz-Barrera, Luis Eduardo; Delgado-Murcia, Lucy Gabriela; Valero-Valdivieso, Manuel Fernando; Cáez-Ramírez, Gabriela

2017-10-01

It was purposed to evaluate the biological potential of ethanol and isopropanol crude extracts of ripe Physalis peruviana fruits. Cytotoxic and immunomodulatory effects of the expression of interleukin-6, interleukin-8, and monocyte chemoattractant protein-1 (MCP-1) were evaluated on human cervical cancer (HeLa) and murine fibroblast (L929) cells. The composition was evaluated by high-performance liquid chromatography diode-array detection and high-performance liquid chromatography ultraviolet/visible detection. The presence of ursolic acid and rosmarinic acid was found in both solvents. However, gallic acid, quercetin, and epicatechin were higher in isopropanol extracts ( P < .05). The results indicated a relationship among the total polyphenol content, antioxidant activity, and cytotoxic activity that was dependent on the solvent used. Isopropanol extracts presented a half-maximal inhibition concentration value (IC 50 ) of 60.48 ± 3.8 μg/mL for HeLa cells and 66.62 ± 2.67 μg/mL for L929 fibroblasts. The extracts reduced the release of interleukin-6, interleukin-8, and MCP-1 in a dose-dependent manner. Extracts showed anticancer and immunomodulatory potential for new complementary pharmaceutical products development.

Cytotoxic and Immunomodulatory Potential Activity of Physalis peruviana Fruit Extracts on Cervical Cancer (HeLa) and Fibroblast (L929) Cells

PubMed Central

Mier-Giraldo, Helen; Díaz-Barrera, Luis Eduardo; Delgado-Murcia, Lucy Gabriela; Valero-Valdivieso, Manuel Fernando; Cáez-Ramírez, Gabriela

2017-01-01

It was purposed to evaluate the biological potential of ethanol and isopropanol crude extracts of ripe Physalis peruviana fruits. Cytotoxic and immunomodulatory effects of the expression of interleukin-6, interleukin-8, and monocyte chemoattractant protein-1 (MCP-1) were evaluated on human cervical cancer (HeLa) and murine fibroblast (L929) cells. The composition was evaluated by high-performance liquid chromatography diode-array detection and high-performance liquid chromatography ultraviolet/visible detection. The presence of ursolic acid and rosmarinic acid was found in both solvents. However, gallic acid, quercetin, and epicatechin were higher in isopropanol extracts (P < .05). The results indicated a relationship among the total polyphenol content, antioxidant activity, and cytotoxic activity that was dependent on the solvent used. Isopropanol extracts presented a half-maximal inhibition concentration value (IC50) of 60.48 ± 3.8 μg/mL for HeLa cells and 66.62 ± 2.67 μg/mL for L929 fibroblasts. The extracts reduced the release of interleukin-6, interleukin-8, and MCP-1 in a dose-dependent manner. Extracts showed anticancer and immunomodulatory potential for new complementary pharmaceutical products development. PMID:28719984

Ursolic acid reduces the metalloprotease/anti-metalloprotease imbalance in cerebral ischemia and reperfusion injury

PubMed Central

Wang, Yanzhe; He, Zhiyi; Deng, Shumin

2016-01-01

Background Activators of PPARs, particularly PPARγ, may be effective neuroprotective drugs against inflammatory responses in cerebral ischemia and reperfusion injury. Ursolic acid (UA) may act as a PPARγ agonist and serve as an anti-inflammatory agent. In this study, we used a rat middle cerebral artery occlusion and reperfusion model to examine how UA acts as a neuroprotective agent to modulate the metalloprotease/anti-metalloprotease balance. Methods The middle cerebral artery occlusion and reperfusion model (occlusion for 2 hours followed by reperfusion for 48 hours) was induced in male Sprague Dawley rats. UA was administered intragastrically 0.5, 24, and 47 hours after reperfusion. Bisphenol A diglycidyl ether (a PPARγ antagonist) was intraperitoneally administered 1, 24.5, and 47.5 hours after reperfusion. Forty-eight hours after reperfusion, neurological deficits and infarct volume were estimated. The PPARγ level and the metalloprotease/anti-metalloprotease balance were examined by Western blotting and immunohistochemistry. The activation of MAPK signaling pathways was also assessed. Results UA-treated (5, 10, or 20 mg/kg) rats showed significant improvement in neurological deficit score, infarct volume, and the number of intact neurons compared with control rats (P<0.01). Both the PPARγ protein level and the percentage of PPARγ-positive cells were increased in the UA-treated groups (P<0.01). Compared with the control group, the UA-treated groups exhibited reduced protein levels of MMP2, MMP9, and activated MAPKs (P<0.01) but an increased level of TIMP1 (P<0.01). UA exerted its protective effects in a dose-dependent manner. Co-treatment with UA and bisphenol A diglycidyl ether completely abolished the UA-induced changes in PPARγ expression; however UA continued to exert a significant but partial neuroprotective effect. Conclusion UA can act as a PPARγ agonist to improve the metalloprotease/anti-metalloprotease balance, possibly by inhibiting the activation of the MAPK signaling pathway, thereby attenuating cerebral ischemia and reperfusion injury. Therefore, UA may serve as a novel neuroprotective therapeutic agent. PMID:27274199

Ursolic acid suppresses TGF-β1-induced quiescent HSC activation and transformation by inhibiting NADPH oxidase expression and Hedgehog signaling

PubMed Central

Yu, Shan-Shan; Chen, Biao; Huang, Chen-Kai; Zhou, Juan-Juan; Huang, Xin; Wang, An-Jiang; Li, Bi-Min; He, Wen-Hua; Zhu, Xuan

2017-01-01

Activation of quiescent hepatic stellate cells (q-HSCs) and their transformation to myofibroblasts (MFBs) is a key event in liver fibrosis. Hedgehog (Hh) signaling stimulates q-HSCs to differentiate into MFBs, and NADPH oxidase (NOX) may be involved in regulating Hh signaling. The author's preliminary study demonstrated that ursolic acid (UA) selectively induces apoptosis in activated HSCs and inhibits their proliferation in vitro via negative regulation of NOX activity and expression. However, the effect of UA on q-HSCs remains to be elucidated. The present study aimed to investigate the effect of UA on q-HSC activation and HSC transformation and to observe alterations in the NOX and Hh signaling pathways during q-HSC activation. q-HSC were isolated from adult male Sprague-Dawley rats. Following culture for 3 days, the cells were treated with or without transforming growth factor-β1 (TGF-β1; 5 µg/l); intervention groups were pretreated with UA (40 µM) or diphenyleneiodonium chloride (DPI; 10 µM) for 30 min prior to addition of TGF-β1. mRNA and protein expression of NOX and Hh signaling components and markers of q-HSC activation were examined by western blotting and reverse transcription-polymerase chain reaction. TGF-β1 induced activation of q-HSCs, with increased expression of α-smooth muscle actin (α-SMA) and type I collagen. In addition, expression of NOX subunits (gp91phox, p67phox, p22phox, and Rac1) and Hh signaling components, including sonic Hh, sterol-4-alpha-methyl oxidase, and Gli family zinc finger 2, were upregulated in activated HSCs. Pretreatment of q-HSCs with UA or DPI prior to TGF-β1 significantly downregulated expression of NOX subunits and Hh signaling components and additionally inhibited expression of α-SMA and type I collagen, thereby preventing transformation to MFBs. UA inhibited TGF-β1-induced activation of q-HSCs and their transformation by inhibiting expression of NOX subunits and the downstream Hh pathway. PMID:29042951

Characterization and Quantitation of Triterpenoid Saponins in Raw and Sprouted Chenopodium berlandieri spp. (Huauzontle) Grains Subjected to Germination with or without Selenium Stress Conditions.

PubMed

Lazo-Vélez, Marco A; Guajardo-Flores, Daniel; Mata-Ramírez, Daniel; Gutiérrez-Uribe, Janet A; Serna-Saldivar, Sergio O

2016-01-01

Pseudocereal Chenopodium berlandieri spp. (huauzontle) was evaluated to determine saponin composition. Saponins were evaluated in raw and germinated grains subjected to chemical stress induced by sodium selenite. Analysis by liquid chromatography coupled with ELSD detector revealed the presence of 12 saponins, identified according to compounds previously assayed in Chenopodium quinoa. Saponins found at the highest concentrations in raw grains were derived from oleanolic and phytolaccagenic acids. Total saponin concentration significantly decreased in germinated compared to raw grains due to the significant loss of 90.1% and 95.7% of the phytolaccagenic acid without and with chemical selenium stress, respectively. The most abundant saponin in germinated sprouts decreased during normal germination. Interestingly, the concentration of this particular saponin significantly increased during the Se-induced stress germination. Chemical stress with selenium salts proved to change the saponin composition in geminated Chenopodium berlandieri spp. grains, therefore affecting their potential use as ingredient in the food industry. © 2015 Institute of Food Technologists®

Time course of pentacyclic triterpenoids from fruits and leaves of olive tree (Olea europaea L.) cv. Picual and cv. Cornezuelo during ripening.

PubMed

Peragón, Juan

2013-07-10

Pentacyclic triterpenoids are plant secondary metabolites of great interest for health and disease prevention. HPLC-UV/vis was used to determine the concentration of the pentacyclic triterpenoids present in fruits and leaves of Picual and Cornezuelo olive tree cultivars. Maslinic acid (MA) and oleanolic acid (OA) are the only two compounds present in fruits, MA being the more abundant. In leaves, in addition to MA and OA, uvaol (UO), and erythrodiol (EO) are found, with OA being the most abundant. In this work, the changes in the concentrations of these compounds during ripening as well as the effect of Jaén-style table-olive processing are reported. The amount of MA and OA found in Picual and Cornezuelo olives after processing was 1.26 ± 0.06, 1.30 ± 0.06, 0.31 ± 0.02, and 0.23 ± 0.01 mg per fruit, respectively. These results enable us to calculate the average intake of pentacyclic triterpenoids and reinforce the importance of table olives as a source of healthy compounds.

Synthesis, Formulation, and Adjuvanticity of Monodesmosidic Saponins with Olenanolic Acid, Hederagenin and Gypsogenin Aglycones, and some C‐28 Ester Derivatives†

PubMed Central

Greatrex, Ben W.; Daines, Alison M.; Hook, Sarah; Lenz, Dirk H.; McBurney, Warren; Rades, Thomas

2015-01-01

Abstract In an attempt to discover a new synthetic vaccine adjuvant, the glycosylation of hederagenin, gypsogenin, and oleanolic acid acceptors with di‐ and trisaccharide donors to generate a range of mimics of natural product QS‐21 was carried out. The saponins were formulated with phosphatidylcholine and cholesterol, and the structures analyzed by transmission electron microscopy. 3‐O‐(Manp(1→3)Glcp)hederagenin was found to produce numerous ring‐like micelles when formulated, while C‐28 choline ester derivatives preferred self‐assembly and did not interact with the liposomes. When alone and in the presence of cholesterol and phospholipid, the choline ester derivatives produced nanocrystalline rods or helical micelles. The effects of modifying sugar stereochemistry and the aglycone on the immunostimulatory effects of the saponins was then evaluated using the activation markers MHC class II and CD86 in murine bone marrow dendritic cells. The most active saponin, 3‐O‐(Manp(1→3)Glcp)hederagenin, was stimulatory at high concentrations in cell culture, but this did not translate to strong responses in vivo. PMID:27308200

[Chemical constituents of Halenia elliptica].

PubMed

Wang, Hongling; Chen, Hao; Geng, Chang'an; Zhang, Xuemei; Ma, Yunbao; Jiang, Zhiyong; Chen, Jijun

2011-06-01

To study the chemical constituents of Halenia elliptica. The air-dried whole plants of Halenia elliptica were extracted with 90% EtOH. The EtOH extract was condensed to a small amount of volume and extracted with petroleum ether, EtOAc and n-BuOH, successively. The compounds were isolated and purified by column chromatography from the EtOAc fraction, and identified based on spectral analyses (MS, 1H-NMR, 13C-NMR). 12 compounds were isolated from H. elliptica, and characterized as 8-hydroxy-2-methylchromone (1), 5-methoxy-2-methylchromone (2), 7-epi-vogeloside (3), coniferl aldehyde (4), sinapaldehyde (5), norbellidifolin (6), 1-hydroxyl-2,3,4,6-tetramethoxyxanthone (7), 1-hydroxyl-2,3,4,7-tetramethoxyxanthone (8), 1-hydroxyl-2,3,5-trimethoxyxanthone (9), together with azelaic acid, beta-sitosterol, and oleanolic acid. Compounds 1, 2 were new natural compounds and compounds 3-6, 10 were obtained from H. elliptica for the first time and compound 6 showed inhibitory activities against HBsAg and HBeAg secretion with IC50 value of 0.77 and < 0.62 mmol x L(-1), respectively.

Oleanane-type triterpene saponins from Calendula stellata.

PubMed

Lehbili, Meryem; Alabdul Magid, Abdulmagid; Kabouche, Ahmed; Voutquenne-Nazabadioko, Laurence; Abedini, Amin; Morjani, Hamid; Sarazin, Thomas; Gangloff, Sophie C; Kabouche, Zahia

2017-12-01

Five previously undescribed bisdesmosidic triterpenoid saponins named calendustellatosides A-E, along with fifteen known compounds were isolated from the 70% ethanol whole plant extract of Calendula stellata Cav. (Asteraceae). Their structures were determined by 1D- and 2D-NMR spectroscopy as well as high resolution mass spectrometry and acid hydrolysis. The saponins comprised oleanolic acid, echinocystic acid, morolic acid or mesembryanthemoidigenic acid as the aglycones and saccharide moieties at C-3 and C-28. Like most Calendula saponins, the sugar moiety linked at C-3 was either β-d-glucose or β-d-glucuronic acid which could be substituted at C-3 by a β-d-galactose and/or C-2 by a supplementary β-d-galactose or a β-d-glucose. The sugar moiety linked to C-28 was determined as β-d-glucose. The antibacterial evaluation of compounds 1-20 by bioautography on Staphylococcus aureus followed by the determination of MIC values of active compounds by serial dilution technique against 5 bacteria revealed that; calendustellatoside D was the most active against Enterococcus faecalis with an antibacterial effect comparable to antibiotics. The cytotoxic activities of isolated compounds were evaluated against fibrosarcoma cell line (HT1080) and human lung cancer cell line (A549). Calendustellatosides B and D exhibited a low cytotoxic activity against HT1080 cell line with IC 50 values of 47 ± 0.6 and 39 ± 0.5 μM, respectively. Copyright © 2017 Elsevier Ltd. All rights reserved.

Identification of triterpene hydroxycinnamates with in vitro antitumor activity from whole cranberry fruit (Vaccinium macrocarpon).

PubMed

Murphy, Brian T; MacKinnon, Shawna L; Yan, Xiaojun; Hammond, Gerald B; Vaisberg, Abraham J; Neto, Catherine C

2003-06-04

Bioactivity-guided fractionation of cranberry fruit was used to determine the identity of triterpenoid esters from Vaccinium macrocarpon, which inhibit tumor cell growth and may play a role in cancer prevention. In our previous study, a fraction from whole fruit exhibited tumor cell growth inhibition in vitro. The major components of this fraction were isolated by chromatographic separation of ethyl acetate extracts, purified by semipreparative HPLC, and identified by NMR as cis- (1) and trans- (2) isomers of 3-O-p-hydroxycinnamoyl ursolic acid. These triterpenoid esters have not been previously reported in Vaccinium fruit. Bioassay of the purified triterpene cinnamates in tumor cell lines in vitro showed slightly greater activity of compound 1 in most cell lines, with GI(50) values of approximately 20 microM in MCF-7 breast, ME180 cervical and PC3 prostate tumor cell lines. Quercetin was slightly less active than 1, while cyanidin-3-galactoside exhibited much lower cytotoxicity, with GI(50) greater than 250 microM in all cell lines. Phenylboronic acid (3) was also isolated from the fruit but showed insignificant antitumor activity.

Aortic relaxant activity of Crataegus gracilior Phipps and identification of some of its chemical constituents.

PubMed

Hernández-Pérez, Abigail; Bah, Moustapha; Ibarra-Alvarado, César; Rivero-Cruz, José Fausto; Rojas-Molina, Alejandra; Rojas-Molina, Juana Isela; Cabrera-Luna, José Alejandro

2014-12-15

This study focused on the assessment of the vasorelaxant activity of the organic and aqueous extracts obtained from leaves and fruits of a Mexican hawthorn (Crataegus gracilior) on isolated rat aorta, and on the purification and identification of some of their secondary metabolites by the use of chromatographic and spectroscopic techniques. The results obtained showed that the methanol extract has a significantly more potent and effective vasorelaxant effect than the other tested extracts, with an EC50 = 8.69 ± 4.34 µg/mL and an Emax = 94.6% ± 11.30%, values that are close to that of acetylcholine, the positive control. From the same extract, two major triterpenes were isolated and identified as ursolic and corosolic acids by comparison of their experimental NMR spectroscopic data with those reported in the literature. Chlorogenic acid, rutin, quercetin, kaempferol and (+)-catechin were also identified using HPLC coupled with PDAD. All these compounds have already been proven to possess on their own antihypertensive effect and other benefits on cardiovascular diseases and they can support, at least in part, the traditional use of this plant species.

Variation of active constituents of an important Tibet folk medicine Swertia mussotii Franch. (Gentianaceae) between artificially cultivated and naturally distributed.

PubMed

Yang, Huiling; Ding, Chenxu; Duan, Yuanwen; Liu, Jianquan

2005-04-08

Concentrations of seven phytochemical constituents (swertiamarin, mangiferin, swertisin, oleanolic acid, 1,5,8-trihydroxy-3-methoxyxanthone, 1,8-dihydroxy-3,7-dimethoxyxanthone and 1,8-dihydroxy-3,5-dimethoxyxanthone) of "ZangYinChen" (Swertia mussotii, a herb used in Tibetan folk medicine) were determined and compared in plants collected from naturally distributed high-altitude populations and counterparts that had been artificially cultivated at low altitudes. Levels of mangiferin, the most abundant active compound in this herb, were significantly lower in cultivated samples and showed a negative correlation with altitude. The other constituents were neither positively nor negatively correlated with cultivation at low altitude. Concentrations of all of the constituents varied substantially with growth stage and were highest at the bud stage in the cultivars, but there were no distinct differences between flowering and fruiting stages in this respect.

GC-MS Profiling of Triterpenoid Saponins from 28 Quinoa Varieties (Chenopodium quinoa Willd.) Grown in Washington State.

PubMed

Medina-Meza, Ilce G; Aluwi, Nicole A; Saunders, Steven R; Ganjyal, Girish M

2016-11-16

Quinoa (Chenopodium quinoa Willd) contains 2 to 5% saponins in the form of oleanane-type triterpenoid glycosides or sapogenins found in the external layers of the seeds. These saponins confer an undesirable bitter flavor. This study maps the content and profile of glycoside-free sapogenins from 22 quinoa varieties and 6 original breeding lines grown in North America under similar agronomical conditions. Saponins were recovered using a novel extraction protocol and quantified by GC-MS. Oleanolic acid (OA), hederagenin (HD), serjanic acid (SA), and phytolaccagenic acid (PA) were identified by their mass spectra. Total saponin content ranged from 3.81 to 27.1 mg/g among the varieties studied. The most predominant sapogenin was phytolaccagenic acid with 16.72 mg/g followed by hederagenin at 4.22 mg/g representing the ∼70% and 30% of the total sapogenin content. Phytolaccagenic acid and the total sapogenin content had a positive correlation of r 2 = 0.88 (p < 0.05). Results showed that none of the varieties we studied can be classified as "sweet". Nine varieties were classified as "low-sapogenin". We recommend six of the varieties be subjected to saponin removal process before consumption. A multivariate analysis was conducted to evaluate and cluster the different genotypes according their sapogenin profile as a way of predicting the possible utility of separate quinoa in food products. The multivariate analysis showed no correlations between origin of seeds and saponin profile and/or content.

Functional analyses on antioxidant, anti-inflammatory, and antiproliferative effects of extracts and compounds from Ilex latifolia Thunb., a Chinese bitter tea.

PubMed

Hu, Ting; He, Xiao-Wei; Jiang, Jian-Guo

2014-08-27

Ilex latifolia Thunb., widely distributed in China, has been used as a functional food and drunk for a long time. This study was aimed to identify the bioactive constituents with antioxidant, antitumor, and anti-inflammatory properties. I. latifolia was extracted with 95% ethanol and then partitioned into four fractions: petroleum ether fraction, ethyl acetate fraction, n-butanol fraction, and water fraction. Results showed that the ethyl acetate fraction was found to have significant ferric reducing antioxidant power activity, DPPH radical scavenging activity, and oxygen radical absorbance capacity, cytotoxicity against human cervix carcinoma HeLa cells, and inhibitory effect on NO production in macrophage RAW 264.7 cells. Five compounds were isolated from the ethyl acetate fraction, and they were identified as ethyl caffeate (1), ursolic acid (2), chlorogenic acid (3), 3,4-di-O-caffeoylquinic acid methyl ester (4), and 3,5-di-O-caffeoylquinic acid methyl ester (5), the last two of which were isolated for the first time from I. latifolia. Compounds 4 and 5 exhibited cytotoxicity actions against tumor cell line. Compound 3 showed the strongest anti-inflammatory activity of all the compounds. The results obtained in this work might contribute to the understanding of biological activities of I. latifolia and further investigation on its potential application values for food and drug.

Chemical constituents and antibacterial activity of Melastoma malabathricum L.

PubMed

Wong, Keng-Chong; Hag Ali, Dafaalla Mohamed; Boey, Peng-Lim

2012-01-01

The aqueous methanolic extracts of Melastoma malabathricum L. exhibited antibacterial activity when assayed against seven microorganisms by the agar diffusion method. Solvent fractionation afforded active chloroform and ethyl acetate fractions from the leaves and the flowers, respectively. A phytochemical study resulted in the identification of ursolic acid (1), 2α-hydroxyursolic acid (2), asiatic acid (3), β-sitosterol 3-O-β-D-glucopyranoside (4) and the glycolipid glycerol 1,2-dilinolenyl-3-O-β-D-galactopyanoside (5) from the chloroform fraction. Kaempferol (6), kaempferol 3-O-α-L-rhamnopyranoside (7), kaempferol 3-O-β-D-glucopyranoside (8), kaempferol 3-O-β-D-galactopyranoside (9), kaempferol 3-O-(2″,6″-di-O-E-p-coumaryl)-β-D-galactopyranoside (10), quercetin (11) and ellagic acid (12) were found in the ethyl acetate fraction. The structures of these compounds were determined by chemical and spectral analyses. Compounds 1-4, the flavonols (6 and 11) and ellagic acid (12) were found to be active against some of the tested microorganisms, while the kaempferol 3-O-glycosides (7-9) did not show any activity, indicating the role of the free 3-OH for antibacterial activity. Addition of p-coumaryl groups results in mild activity for 10 against Staphylococcus aureus and Bacillus cereus. Compounds 2-5, 7 and 9-12 are reported for the first time from M. malabathricum. Compound 10 is rare, being reported only once before from a plant, without assignment of the double bond geometry in the p-coumaryl moiety.

[Study on anti-tumor chemical constituents from pericarps of Juglans mandshurica].

PubMed

Zhou, Yuan-yuan; Meng, Ying; Jiang, Yan-qiu; Liu, Zhao-xi; Yang, Bing-you

2014-11-01

To study the anti-tumor chemical components of the pericarps of Juglans mandshurica. The chemical constituents were isolated and purified by AB-8 macroporous adsorption resin, silica gel, Sephadex LH-20 columns and recrystallization. The structures were elucidated on the basis of physicochemical properties and NMR spectral data analysis. From the pericarps of Juglans mandshurica, twelve compounds were separated and identified as 3-methoxy juglone(1), 3-ethoxy juglone(2), 1,8-di-hydroxy anthraquinone (3), juglone (4), 2α, 3α, 19α-trihydroxy ursolic acid (5), 1α, 3β-dihydroxy-olean-18-ene (6), methyl gallate (7), pterocarine(8), quercetin(9), kaempferol(10), daucosterol(11), and β-sitosterol(12). Compounds 1 - 3 and 6 are isolated from the pericarps of Juglans mandshurica for the first time. Compounds 5 and 7 are isolated from Juglans genus for the first time.

Retention of cytoplasmic droplet by rat cauda epididymal spermatozoa after treatment with cytotoxic and xenobiotic agents.

PubMed

Akbarsha, M A; Latha, P N; Murugaian, P

2000-11-01

Spermatozoa leaving the testis contain a cytoplasmic droplet which they release during transit through the epididymis before reaching the cauda epididymidis. The cytoplasmic droplet shows P450 aromatase activity, which plays a role in synthesis of oestrogen from androgen. In the present study, 3-month-old Wistar strain male albino rats were administered with the organophosphate insecticides malathion or dichlorvos, or the phytotherapeutics andrographolide or ursolic acid. Segments of the epididymis were subjected to histopathological and ultrastructural analyses and it was found that 60-95% of the spermatozoa residing in the lumen of the cauda epididymidis retained the cytoplasmic droplet. The motility of the spermatozoa released from the cauda epididymidis was inhibited. One of the mechanisms of action of these toxicants on male reproductive function may be attributed to the retention of the cytoplasmic droplet and the resultant impairment of sperm motility.

Transcriptomics and the Mediterranean Diet: A Systematic Review

PubMed Central

Herrera-Marcos, Luis V.; Lou-Bonafonte, José M.; Arnal, Carmen; Navarro, María A.; Osada, Jesús

2017-01-01

The Mediterranean diet has been proven to be highly effective in the prevention of cardiovascular diseases and cancer and in decreasing overall mortality. Nowadays, transcriptomics is gaining particular relevance due to the existence of non-coding RNAs capable of regulating many biological processes. The present work describes a systematic review of current evidence supporting the influence of the Mediterranean diet on transcriptomes of different tissues in various experimental models. While information on regulatory RNA is very limited, they seem to contribute to the effect. Special attention has been given to the oily matrix of virgin olive oil. In this regard, monounsaturated fatty acid-rich diets prevented the expression of inflammatory genes in different tissues, an action also observed after the administration of olive oil phenolic compounds. Among these, tyrosol, hydroxytyrosol, and secoiridoids have been found to be particularly effective in cell cycle expression. Less explored terpenes, such as oleanolic acid, are important modulators of circadian clock genes. The wide range of studied tissues and organisms indicate that response to these compounds is universal and poses an important level of complexity considering the different genes expressed in each tissue and the number of different tissues in an organism. PMID:28486416

Quantitative analysis of anti-inflammatory and radical scavenging triterpenoid esters in evening primrose seeds.

PubMed

Zaugg, Janine; Potterat, Olivier; Plescher, Andreas; Honermeier, Bernd; Hamburger, Matthias

2006-09-06

Lipophilic triterpenoidal esters with radical scavenging and cyclooxygenase inhibitory properties were recently found in cold-pressed, nonraffinated evening primrose oil (EPO). A quantitative assay for the analysis of 3-O-trans-caffeoyl derivatives of betulinic, morolic, and oleanolic acid in evening primrose seeds was developed and validated. Extraction efficiency >99% was achieved by means of pressurized liquid extraction with two extraction cycles and 80% (v/v) ethanol at 120 degrees C. Analysis of esters was by normal-phase high-performance liquid chromatography on a Diol column and hexane/ethyl acetate (containing 0.1% formic acid) (65:35) as the eluent. The analytes were determined without further prepurification. Seeds from defined cultures of Oenothera biennis, Oenothera lamarckiana, and Oenothera ammophila, grown under identical conditions, were analyzed. The cultures originated from seeds from eight collections in the wild and from selections from five cultivars. The content of total triterpenoidal esters in seeds varied between 1.34 and 2.78 mg/g. Three types of qualitative patterns were observed for the triterpenoidal esters. The influence of different harvest times and plant treatments was studied with the cultivar Anothera. Variations between 1.5 and 2.3 mg/g were found.

Inhibition of amyloid β aggregation and protective effect on SH-SY5Y cells by triterpenoid saponins from the cactus Polaskia chichipe.

PubMed

Fujihara, Koji; Koike, Shin; Ogasawara, Yuki; Takahashi, Kunio; Koyama, Kiyotaka; Kinoshita, Kaoru

2017-07-01

Alzheimer's disease (AD) destroys brain function, especially in the hippocampus, and is a social problem worldwide. A major pathogenesis of AD is related to the accumulation of amyloid beta (Aβ) peptides, resulting in neuronal cell death in the brain. Here, we isolated four saponins (1-4) and elucidated their structures from 1D and 2D NMR and HRFABMS spectral data. The structures of 1 and 2 were determined as new saponins which have cochalic acid as the aglycon, and 3 was determined as a new saponin with oleanolic acid as the aglycon. Compound 4 was confirmed as the known saponin chikusetsusaponin V (=ginsenoside R 0 ). Isolated saponins (1-4) and six previously reported saponins (5-10) were tested for their inhibitory effects of Aβ aggregation and their protective effects on SH-SY5Y cells against Aβ-associated toxicity. As the results, compounds 3 and 4 showed inhibitory effect of Aβ aggregation and compounds 5-8 exerted the protective effects on SH-SY5Y cells against Aβ-associated toxicity. Copyright © 2017 Elsevier Ltd. All rights reserved.

Transcriptomics and the Mediterranean Diet: A Systematic Review.

PubMed

Herrera-Marcos, Luis V; Lou-Bonafonte, José M; Arnal, Carmen; Navarro, María A; Osada, Jesús

2017-05-09

The Mediterranean diet has been proven to be highly effective in the prevention of cardiovascular diseases and cancer and in decreasing overall mortality. Nowadays, transcriptomics is gaining particular relevance due to the existence of non-coding RNAs capable of regulating many biological processes. The present work describes a systematic review of current evidence supporting the influence of the Mediterranean diet on transcriptomes of different tissues in various experimental models. While information on regulatory RNA is very limited, they seem to contribute to the effect. Special attention has been given to the oily matrix of virgin olive oil. In this regard, monounsaturated fatty acid-rich diets prevented the expression of inflammatory genes in different tissues, an action also observed after the administration of olive oil phenolic compounds. Among these, tyrosol, hydroxytyrosol, and secoiridoids have been found to be particularly effective in cell cycle expression. Less explored terpenes, such as oleanolic acid, are important modulators of circadian clock genes. The wide range of studied tissues and organisms indicate that response to these compounds is universal and poses an important level of complexity considering the different genes expressed in each tissue and the number of different tissues in an organism.

Nonsterol Triterpenoids as Major Constituents of Olea europaea

PubMed Central

Stiti, Naïm; Hartmann, Marie-Andrée

2012-01-01

Plant triterpenoids represent a large and structurally diverse class of natural products. A growing interest has been focused on triterpenoids over the past decade due to their beneficial effects on human health. We show here that these bioactive compounds are major constituents of several aerial parts (floral bud, leaf bud, stem, and leaf) of olive tree, a crop exploited so far almost exclusively for its fruit and oil. O. europaea callus cultures were analyzed as well. Twenty sterols and twenty-nine nonsteroidal tetra- and pentacyclic triterpenoids belonging to seven types of carbon skeletons (oleanane, ursane, lupane, taraxerane, taraxastane, euphane, and lanostane) were identified and quantified by GC and GC-MS as free and esterified compounds. The oleanane-type compounds, oleanolic acid and maslinic acid, were largely predominant in all the organs tested, whereas they are practically absent in olive oil. In floral buds, they represented as much as 2.7% of dry matter. In callus cultures, lanostane-type compounds were the most abundant triterpenoids. In all the tissues analyzed, free and esterified triterpene alcohols exhibited different distribution patterns of their carbon skeletons. Taken together, these data provide new insights into largely unknown triterpene secondary metabolism of Olea europaea. PMID:22523691

Chemical and biological study of Manilkara zapota (L.) Van Royen leaves (Sapotaceae) cultivated in Egypt

PubMed Central

Fayek, Nesrin M.; Monem, Azza R. Abdel; Mossa, Mohamed Y.; Meselhy, Meselhy R.; Shazly, Amani H.

2012-01-01

Background: Manilkara zapota (L.) Van Royen is an evergreen tree, native to the tropical Americas and introduced to Egypt as a fruiting tree in 2002. No previous study was reported on the plant cultivated in Egypt. Materials and Methods: In this study, the leaves of the plant cultivated in Egypt were subjected to phytochemical and biological investigations. The lipoidal matter was analyzed by GLC. Five compounds were isolated from the petroleum ether and ethyl acetate fractions of the alcoholic extract of the leaves by chromatographic fractionation on silica gel and sephadex, the structures of these compounds were identified using IR, UV, MS, 1H-NMR and 13C-NMR. The LD50 of the alcoholic and aqueous extracts of the leaves was determined and their antihyperglycemic, hypocholesterolemic and antioxidant activities were tested by enzymatic colorimetric methods using specific kits. Results: Unsaturated fatty acids represent 32.32 % of the total fatty acids, oleic acid (13.95%), linoleidic acid (10.18 %) and linoleic acid (5.96 %) were the major ones. The isolated compounds were identified as lupeol acetate, oleanolic acid, apigenin-7-O-α-L-rhamnoside, myricetin-3-O-α-L-rhamnoside and caffeic acid. This is the first report about isolation of these compounds from Manilkara zapota except myricetin-3-O-α-L-rhamnoside, which was previously isolated from the plant growing abroad. The LD50 recorded 80 g/Kg b. wt. for both the tested extracts, so they could be considered to be safe. They exhibited antihyperglycemic, hypocholesterolemic and antioxidant activities. Conclusion: The observed biological activities were attributed to the different chemical constituents present in the plant mainly its phenolic constituents. PMID:22518080

Ursolic Acid Ameliorates Inflammation in Cerebral Ischemia and Reperfusion Injury Possibly via High Mobility Group Box 1/Toll-Like Receptor 4/NFκB Pathway.

PubMed

Wang, Yanzhe; Li, Lei; Deng, Shumin; Liu, Fang; He, Zhiyi

2018-01-01

Toll-like receptors (TLRs) play key roles in cerebral ischemia and reperfusion injury by inducing the production of inflammatory mediators, such as interleukins (ILs) and tumor necrosis factor-alpha (TNF-α). According to recent studies, ursolic acid (UA) regulates TLR signaling and exhibits notable anti-inflammatory properties. In the present study, we explored the mechanism by which UA regulates inflammation in the rat middle cerebral artery occlusion and reperfusion (MCAO/R) model. The MCAO/R model was induced in male Sprague-Dawley rats (MCAO for 2 h, followed by reperfusion for 48 h). UA was administered intragastrically at 0.5, 24, and 47 h after reperfusion. The direct high mobility group box 1 (HMGB1) inhibitor glycyrrhizin (GL) was injected intravenously after 0.5 h of ischemia as a positive control. The degree of brain damage was estimated using the neurological deficit score, infarct volume, histopathological changes, and neuronal apoptosis. We assessed IL-1β, TNF-α, and IL-6 levels to evaluate post-ischemic inflammation. HMGB1 and TLR4 expression and phosphorylation of nuclear factor kappa-light-chain-enhancer of activated B cell (NFκB) were also examined to explore the underlying mechanism. UA (10 and 20 mg/kg) treatment significantly decreased the neurological deficit scores, infarct volume, apoptotic cells, and IL-1β, TNF-α, and IL-6 concentrations. The infarct area ratio was reduced by (33.07 ± 1.74), (27.05 ± 1.13), (27.49 ± 1.87), and (39.74 ± 2.14)% in the 10 and 20 mg/kg UA, GL, and control groups, respectively. Furthermore, UA (10 and 20 mg/kg) treatment significantly decreased HMGB1 release and the TLR4 level and inactivated NFκB signaling. Thus, the effects of intragastric administration of 20 mg/kg of UA and 10 mg/kg of GL were similar. We provide novel evidence that UA reduces inflammatory cytokine production to protect the brain from cerebral ischemia and reperfusion injury possibly through the HMGB1/TLR4/NFκB signaling pathway.

Ursolic Acid-Regulated Energy Metabolism—Reliever or Propeller of Ultraviolet-Induced Oxidative Stress and DNA Damage?

PubMed Central

Lee, Yuan-Hao; Sun, Youping; Glickman, Randolph D.

2014-01-01

Ultraviolet (UV) light is a leading cause of diseases, such as skin cancers and cataracts. A main process mediating UV-induced pathogenesis is the production of reactive oxygen species (ROS). Excessive ROS levels induce the formation of DNA adducts (e.g., pyrimidine dimers) and result in stalled DNA replication forks. In addition, ROS promotes phosphorylation of tyrosine kinase-coupled hormone receptors and alters downstream energy metabolism. With respect to the risk of UV-induced photocarcinogenesis and photodamage, the antitumoral and antioxidant functions of natural compounds become important for reducing UV-induced adverse effects. One important question in the field is what determines the differential sensitivity of various types of cells to UV light and how exogenous molecules, such as phytochemicals, protect normal cells from UV-inflicted damage while potentiating tumor cell death, presumably via interaction with intracellular target molecules and signaling pathways. Several endogenous molecules have emerged as possible players mediating UV-triggered DNA damage responses. Specifically, UV activates the PIKK (phosphatidylinositol 3-kinase-related kinase) family members, which include DNA-PKcs, ATM (ataxia telangiectasia mutated) and mTOR (mammalian target of rapamycin), whose signaling can be affected by energy metabolism; however, it remains unclear to what extent the activation of hormone receptors regulates PIKKs and whether this crosstalk occurs in all types of cells in response to UV. This review focuses on proteomic descriptions of the relationships between cellular photosensitivity and the phenotypic expression of the insulin/insulin-like growth receptor. It covers the cAMP-dependent pathways, which have recently been shown to regulate the DNA repair machinery through interactions with the PIKK family members. Finally, this review provides a strategic illustration of how UV-induced mitogenic activity is modulated by the insulin sensitizer, ursolic acid (UA), which results in the metabolic adaptation of normal cells against UV-induced ROS, and the metabolic switch of tumor cells subject to UV-induced damage. The multifaceted natural compound, UA, specifically inhibits photo-oxidative DNA damage in retinal pigment epithelial cells while enhancing that in skin melanoma. Considering the UA-mediated differential effects on cell bioenergetics, this article reviews the disparities in glucose metabolism between tumor and normal cells, along with (peroxisome proliferator-activated receptor-γ coactivator 1α)-dependent mitochondrial metabolism and redox (reduction-oxidation) control to demonstrate UA-induced synthetic lethality in tumor cells. PMID:28250388

A bioinformatic and mechanistic study elicits the antifibrotic effect of ursolic acid through the attenuation of oxidative stress with the involvement of ERK, PI3K/Akt, and p38 MAPK signaling pathways in human hepatic stellate cells and rat liver

PubMed Central

He, Wenhua; Shi, Feng; Zhou, Zhi-Wei; Li, Bimin; Zhang, Kunhe; Zhang, Xinhua; Ouyang, Canhui; Zhou, Shu-Feng; Zhu, Xuan

2015-01-01

NADPH oxidases (NOXs) are a predominant mediator of redox homeostasis in hepatic stellate cells (HSCs), and oxidative stress plays an important role in the pathogenesis of liver fibrosis. Ursolic acid (UA) is a pentacyclic triterpenoid with various pharmacological activities, but the molecular targets and underlying mechanisms for its antifibrotic effect in the liver remain elusive. This study aimed to computationally predict the molecular interactome and mechanistically investigate the antifibrotic effect of UA on oxidative stress, with a focus on NOX4 activity and cross-linked signaling pathways in human HSCs and rat liver. Drug–drug interaction via chemical–protein interactome tool, a server that can predict drug–drug interaction via chemical–protein interactome, was used to predict the molecular targets of UA, and Database for Annotation, Visualization, and Integrated Discovery was employed to analyze the signaling pathways of the predicted targets of UA. The bioinformatic data showed that there were 611 molecular proteins possibly interacting with UA and that there were over 49 functional clusters responding to UA. The subsequential benchmarking data showed that UA significantly reduced the accumulation of type I collagen in HSCs in rat liver, increased the expression level of MMP-1, but decreased the expression level of TIMP-1 in HSC-T6 cells. UA also remarkably reduced the gene expression level of type I collagen in HSC-T6 cells. Furthermore, UA remarkably attenuated oxidative stress via negative regulation of NOX4 activity and expression in HSC-T6 cells. The employment of specific chemical inhibitors, SB203580, LY294002, PD98059, and AG490, demonstrated the involvement of ERK, PI3K/Akt, and p38 MAPK signaling pathways in the regulatory effect of UA on NOX4 activity and expression. Collectively, the antifibrotic effect of UA is partially due to the oxidative stress attenuating effect through manipulating NOX4 activity and expression. The results suggest that UA may act as a promising antifibrotic agent. More studies are warranted to evaluate the safety and efficacy of UA in the treatment of liver fibrosis. PMID:26347199

Phytochemical Analysis and Antimicrobial, Antinociceptive, and Anti-Inflammatory Activities of Two Chemotypes of Pimenta pseudocaryophyllus (Myrtaceae)

PubMed Central

de Paula, Joelma Abadia Marciano; Silva, Maria do Rosário Rodrigues; Costa, Maysa P.; Diniz, Danielle Guimarães Almeida; Sá, Fabyola A. S.; Alves, Suzana Ferreira; Costa, Élson Alves; Lino, Roberta Campos; de Paula, José Realino

2012-01-01

Preparations from Pimenta pseudocaryophyllus (Gomes) L.R. Landrum (Myrtaceae) have been widely used in Brazilian folk medicine. This study aims to evaluate the antimicrobial activity of the crude ethanol extracts, fractions, semipurified substances, and essential oils obtained from leaves of two chemotypes of P. pseudocaryophyllus and to perform the antinociceptive and anti-inflammatory screening. The ethanol extracts were purified by column chromatography and main compounds were spectrally characterised (1D and 2D 1H and 13C NMR). The essential oils constituents were identified by GC/MS. The broth microdilution method was used for testing the antimicrobial activity. The abdominal contortions induced by acetic acid and the ear oedema induced by croton oil were used for screening of antinociceptive and anti-inflammatory activities, respectively. The phytochemical analysis resulted in the isolation of pentacyclic triterpenes, flavonoids, and phenol acids. The oleanolic acid showed the best profile of antibacterial activity for Gram-positive bacteria (31.2–125 μg mL−1), followed by the essential oil of the citral chemotype (62.5–250 μg mL−1). Among the semipurified substances, Ppm5, which contained gallic acid, was the most active for Candida spp. (31.2 μg mL−1) and Cryptococcus spp. (3.9–15.6 μg mL−1). The crude ethanol extract and fractions from citral chemotype showed antinociceptive and anti-inflammatory effects. PMID:23082081

Cancer Cell Signaling Pathways Targeted by Spice-Derived Nutraceuticals

PubMed Central

Sung, Bokyung; Prasad, Sahdeo; Yadav, Vivek R.; Aggarwal, Bharat B.

2012-01-01

Extensive research within the last half a century has revealed that cancer is caused by dysregulation of as many as 500 different gene products. Most natural products target multiple gene products and thus are ideally suited for prevention and treatment of various chronic diseases, including cancer. Dietary agents such as spices have been used extensively in the Eastern world for a variety of ailments for millennia, and five centuries ago they took a golden journey to the Western world. Various spice-derived nutraceuticals, including 1′-acetoxychavicol acetate, anethole, capsaicin, car-damonin, curcumin, dibenzoylmethane, diosgenin, eugenol, gambogic acid, gingerol, thymoquinone, ursolic acid, xanthohumol, and zerumbone derived from galangal, anise, red chili, black cardamom, turmeric, licorice, fenugreek, clove, kokum, ginger, black cumin, rosemary, hop, and pinecone ginger, respectively, are the focus of this review. The modulation of various transcription factors, growth factors, protein kinases, and inflammatory mediators by these spice-derived nutraceuticals are described. The anticancer potential through the modulation of various targets is also the subject of this review. Although they have always been used to improve taste and color and as a preservative, they are now also used for prevention and treatment of a wide variety of chronic inflammatory diseases, including cancer. PMID:22149093

Propylene glycol-linked amino acid/dipeptide diester prodrugs of oleanolic acid for PepT1-mediated transport: synthesis, intestinal permeability, and pharmacokinetics.

PubMed

Cao, Feng; Gao, Yahan; Wang, Meng; Fang, Lei; Ping, Qineng

2013-04-01

In our previous studies, ethylene glycol-linked amino acid diester prodrugs of oleanolic acid (OA), a Biopharmaceutics Classification System (BCS) class IV drug, designed to target peptide transporter 1 (PepT1) have been synthesized and evaluated. Unlike ethylene glycol, propylene glycol is of very low toxicity in vivo. In this study, propylene glycol was used as a linker to further compare the effect of the type of linker on the stability, permeability, affinity, and bioavailability of the prodrugs of OA. Seven diester prodrugs with amino acid/dipeptide promoieties containing L-Val ester (7a), L-Phe ester (7b), L-Ile ester (7c), D-Val-L-Val ester (9a), L-Val-L-Val ester (9b), L-Ala-L-Val ester (9c), and L-Ala-L-Ile ester (9d) were designed and successfully synthesized. In situ rat single-pass intestinal perfusion (SPIP) model was performed to screen the effective permeability (P(eff)) of the prodrugs. P(eff) of 7a, 7b, 7c, 9a, 9b, 9c, and 9d (6.7-fold, 2.4-fold, 1.24-fold, 1.22-fold, 4.15-fold, 2.2-fold, and 1.4-fold, respectively) in 2-(N-morpholino)ethanesulfonic acid buffer (MES) with pH 6.0 showed significant increase compared to that of OA (p < 0.01). In hydroxyethyl piperazine ethanesulfonic acid buffer (HEPES) of pH 7.4, except for 7c, 9a, and 9d, P(eff) of the other prodrugs containing 7a (5.2-fold), 7b (2.0-fold), 9b (3.1-fold), and 9c (1.7-fold) exhibited significantly higher values than that of OA (p < 0.01). In inhibition studies with glycyl-sarcosine (Gly-Sar, a typical substrate of PepT1), P(eff) of 7a (5.2-fold), 7b (2.0-fold), 9b (3.1-fold), and 9c (2.3-fold) had significantly reduced values (p < 0.01). Compared to the apparent permeability coefficient (P(app)) of OA with Caco-2 cell monolayer, significant enhancement of the P(app) of 7a (5.27-fold), 9b (3.31-fold), 9a (2.26-fold), 7b (2.10-fold), 7c (2.03-fold), 9c (1.87-fold), and 9d (1.39-fold) was also observed (p < 0.01). Inhibition studies with Gly-Sar (1 mM) showed that P(app) of 7a, 9b, and 9c significantly reduced by 1.3-fold, 1.6-fold, and 1.4-fold (p < 0.01), respectively. These results may be attributed to PepT1-mediated transport and their differential affinity toward PepT1. According to the permeability and affinity, 7a and 9b were selected in the pharmacokinetic studies in rats. Compared with group OA, C(max) for group 7a and 9b was enhanced to 3.04-fold (p < 0.01) and 2.62-fold (p < 0.01), respectively. AUC(0→24) was improved to 3.55-fold (p < 0.01) and 3.39-fold (p < 0.01), respectively. Compared to the ethylene glycol-linked amino acid diester prodrugs of OA in our previous work, results from this study revealed that part of the propylene glycol-linked amino acid/dipeptide diester prodrugs showed better stability, permeability, affinity, and bioavailability. In conclusion, propylene glycol-linked amino acid/dipeptide diester prodrugs of OA may be suitable for PepT1-targeted prodrugs of OA to improve the oral bioavailability of OA.

Targeting arachidonic acid pathway by natural products for cancer prevention and therapy.

PubMed

Yarla, Nagendra Sastry; Bishayee, Anupam; Sethi, Gautam; Reddanna, Pallu; Kalle, Arunasree M; Dhananjaya, Bhadrapura Lakkappa; Dowluru, Kaladhar S V G K; Chintala, Ramakrishna; Duddukuri, Govinda Rao

2016-10-01

Arachidonic acid (AA) pathway, a metabolic process, plays a key role in carcinogenesis. Hence, AA pathway metabolic enzymes phospholipase A 2 s (PLA 2 s), cyclooxygenases (COXs) and lipoxygenases (LOXs) and their metabolic products, such as prostaglandins and leukotrienes, have been considered novel preventive and therapeutic targets in cancer. Bioactive natural products are a good source for development of novel cancer preventive and therapeutic drugs, which have been widely used in clinical practice due to their safety profiles. AA pathway inhibitory natural products have been developed as chemopreventive and therapeutic agents against several cancers. Curcumin, resveratrol, apigenin, anthocyans, berberine, ellagic acid, eugenol, fisetin, ursolic acid, [6]-gingerol, guggulsteone, lycopene and genistein are well known cancer chemopreventive agents which act by targeting multiple pathways, including COX-2. Nordihydroguaiaretic acid and baicalein can be chemopreventive molecules against various cancers by inhibiting LOXs. Several PLA 2 s inhibitory natural products have been identified with chemopreventive and therapeutic potentials against various cancers. In this review, we critically discuss the possible utility of natural products as preventive and therapeutic agents against various oncologic diseases, including prostate, pancreatic, lung, skin, gastric, oral, blood, head and neck, colorectal, liver, cervical and breast cancers, by targeting AA pathway. Further, the current status of clinical studies evaluating AA pathway inhibitory natural products in cancer is reviewed. In addition, various emerging issues, including bioavailability, toxicity and explorability of combination therapy, for the development of AA pathway inhibitory natural products as chemopreventive and therapeutic agents against human malignancy are also discussed. Copyright © 2016 Elsevier Ltd. All rights reserved.

Isolation and identification of antibacterial compound from the leaves of Cassia auriculata.

PubMed

Senthilkumar, P K; Reetha, D

2011-09-01

Antimicrobial properties of medicinal plants and plant parts such as flowers, roots, fruits, seeds and oils are being used to cure some chronic and acute diseases throughout the world. In the present study, an attempt has been made to isolate and identify the antibacterial compound present in the leaves of the Cassia auriculata. A preliminary screening of antibacterial activity was carried out with fine different plant extracts viz., Aegle marmelos, Chloris Virgata, Clausena anisata, Feronia limonia and Cassia auriculata against different human pathogenic bacteriae such as Escherichia coil, Salmonella typhi, Proteus mirabilis and Klebsiella pneumoniae at different concentrations. Based on the results, the plant Cassia auriculata was selected as the efficient plant, which shows antibacterial activity against the tested organisms. Further compound responsible for its antibacterial activity was isolated and identified by IR spectrum, 1HNMR, 13CNMR and Mass spectrum studies, as oleanolic acid, which has the molecular formula of C30H48O3.

CDDO and Its Role in Chronic Diseases.

PubMed

Mathis, Bryan J; Cui, Taixing

2016-01-01

There has been a continued interest in translational research focused on both natural products and manipulation of functional groups on these compounds to create novel derivatives with higher desired activities. Oleanolic acid, a component of traditional Chinese medicine used in hepatitis therapy, was modified by chemical processes to form 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO). This modification increased anti-inflammatory activity significantly and additional functional groups on the CDDO backbone have shown promise in treating conditions ranging from kidney disease to obesity to diabetes. CDDO's therapeutic effect is due to its upregulation of the master antioxidant transcription factor Nuclear factor erythroid 2-related factor 2 (Nrf2) through conformational change of Nrf2-repressing, Kelch-like erythroid cell-derived protein with CNC homology-associated protein 1 (Keap1) and multiple animal and human studies have verified subsequent activation of Nrf2-controlled antioxidant genes via upstream Antioxidant Response Element (ARE) regions. At the present time, positive results have been obtained in the laboratory and clinical trials with CDDO derivatives treating conditions such as lung injury, inflammation and chronic kidney disease. However, clinical trials for cancer and cardiovascular disease have not shown equally positive results and further exploration of CDDO and its derivatives is needed to put these shortcomings into context for the purpose of future therapeutic modalities.

Viscum articulatum Burm. f.: a review on its phytochemistry, pharmacology and traditional uses.

PubMed

Patel, Bhishma P; Singh, Pawan K

2018-02-01

The aim of this study was to review and highlight traditional and ethnobotanical uses, phytochemical constituents, IP status, biological activity and pharmacological activity of Viscum articulatum. Thorough literature searches were performed on Viscum articulatum, and data were analysed for reported traditional uses, pharmacological activity, phytochemicals present and patents filed. Scientific and patent databases such as PubMed, Science Direct, Google Scholar, Google patents, USPTO and Espacenet were searched using different keywords. Viscum articulatum has been traditionally used in different parts of the world for treatment of various ailments. Almost all the parts such as leaves, root, stem and bark are having medicinal values and are reported for their uses in Ayurvedic and Chinese system of medicine for the management of various diseases. Modern scientific studies demonstrate efficacy of this plant against hypertension, ulcer, epilepsy, inflammation, wound, nephrotoxicity, HIV, cancer, etc. Major bioactive phytochemicals include oleanolic acid, betulinic acid, eriodictyol, naringenin, β-amyrin acetate, visartisides, etc. Side effects of allopathic medicines have created a global opportunity, acceptance and demand for phytomedicines. Viscum articulatum could be an excellent source of effective and safe phytomedicine for various ailments if focused translational efforts are undertaken by integrating the existing outcomes of researches. © 2017 Royal Pharmaceutical Society.

Formulation and characterization of Turkish oregano microcapsules prepared by spray-drying technology.

PubMed

Baranauskaite, Juste; Ivanauskas, Liudas; Masteikova, Ruta; Kopustinskiene, Dalia; Baranauskas, Algirdas; Bernatoniene, Jurga

2017-09-01

The aim of this study was optimization of spray-drying process conditions for microencapsulation of Turkish oregano extract. Different concentrations of maltodextrin and gum arabic as encapsulating agents (wall material) as well as influence of selected processing variables were evaluated. The optimal conditions were maintained on the basis of the load of main bioactive compounds - ursolic, rosmarinic acids and carvacrol - in prepared microparticles after comparison of all significant response variables using desirability function. Physicomechanical properties of powders such as flowability, wettability, solubility, moisture content as well as product yield, encapsulation efficiency (EE), density, morphology and size distribution of prepared microparticles have been determined. The results demonstrated that the optimal conditions for spray-drying mixture consisted of two parts of wall material solution and one part of ethanolic oregano extract when the feed flow rate was 40 mL/min and air inlet temperature -170 °C. Optimal concentration of wall materials in solution was 20% while the ratio of maltodextrin and gum arabic was 8.74:1.26.

Simultaneous quantitative determination of multiple bioactive markers in Ocimum sanctum obtained from different locations and its marketed herbal formulations using UPLC-ESI-MS/MS combined with principal component analysis.

PubMed

Pandey, Renu; Chandra, Preeti; Srivastava, Mukesh; Mishra, D K; Kumar, Brijesh

2015-01-01

Ocimum sanctum L., with phenolic acids, flavonoids, propenyl phenols and terpenoids as active pharmacological constituents, is a popular medicinal herb and is present as an ingredient in many herbal formulations. Therefore, development of a reliable analytical method for simultaneous determination of the pharmacologically active constituents of O. sanctum is of high importance. To develop and validate a new, rapid, sensitive and selective UPLC-ESI/MS/MS method for simultaneous determination of 23 bioactive markers including phenolic acids, flavonoids, propenyl phenol and terpenoid in the leaf extract and marketed herbal formulations of O. sanctum. An UPLC-ESI/MS/MS method using negative electrospray ionisation (ESI) in multiple-reaction-monitoring (MRM) mode was used for simultaneous determination. Chromatographic separation was achieved on an Acquity UPLC BEH C18 -column using a gradient elution with 0.1% formic acid in water and 0.1% formic acid in acetonitrile. Principal component analysis (PCA) was applied to correlate and discriminate eight geographical collections of O. sanctum based on quantitative data of the analytes. The developed method was validated as per International Conference on Harmonization guidelines and found to be accurate, with overall recovery in the range 95.09-104.84% (RSD ≤ 1.85%), precise (RSD ≤ 1.98%) and linear (r(2)  ≥ 0.9971) over the concentration range of 0.5-1000 ng/mL. Ursolic acid was found to be the most abundant marker in all the samples investigated, except for the marketed tablet. The method established is simple, rapid and sensitive, hence it can be reliably utilised for the quality control of O. sanctum and derived herbal formulations. Copyright © 2015 John Wiley & Sons, Ltd.

Active ingredients from natural botanicals in the treatment of obesity.

PubMed

Zhang, W-L; Zhu, L; Jiang, J-G

2014-12-01

Obesity is considered as a chronic disease that can induce a series of comorbidities and complications. Chinese medicine has long clinical experiences in the treatment of obesity. This review summarizes the natural products from traditional Chinese medicine (TCM) that are reported to have anti-obesity effects in the past two decades. Botanic TCM comprises 90% of total Chinese crude drugs, and generally contains various active ingredients, in which the effective anti-obesity ingredients identified can be divided into saponins, polysaccharides, alkaloids, polyphenols and others. Astragaloside IV, glycyrrhizin, macrostemonoside A, berberine, betaine, capsaicin, matrine, methyl piperate, piperine, rutaecarpine, asimilobine, epigallocatechingallate, magnolol, resveratrol, soybean-isoflavone, α-linolenic acid, emodin, geniposide, phillyrin, salidroside and ursolic acid are specified in this review, and their sources, models, efficacy are described. It is concluded that the mechanisms of these components for the treatment of obesity include: (i) suppression of appetite, increase of satiety, reduction of energy intake; (ii) reduction in the digestion and absorption of exogenous lipid; (iii) attenuation of the synthesis of endogenous lipid; (iv) promotion of the oxidation and expenditure of lipid and (v) improvement of lipid metabolism disorder. Authors believe that the effective compounds from TCM will provide an alternative and hopeful way for the treatment of obesity. © 2014 World Obesity.

Chemical constituents of Phragmanthera austroarabica A. G. Mill and J. A. Nyberg with potent antioxidant activity

PubMed Central

Badr, Jihan M.

2015-01-01

Background: Phragmanthera austroarabica A.G. Mill. and J. A. Nyberg is a semi parasitic plant belonging to family Loranthaceae. It was collected from Saudi Arabia. It is widely used in folk medicine among the kingdom in treatment of various diseases including diabetes mellitus. Objective: The total alcoholic extract of P. austroarabica collected from Saudi Arabia was investigated for the chemical structure and prominent biological activity of the main constituents. Materials and Methods: Isolation of the active constituents was performed using different chromatographic techniques including column chromatography packed with silica or sephadex and preparative thin layer chromatography. The structures of the isolated compounds were established based on different spectroscopic data as mass spectrum, one-dimensional and two-dimensional nuclear magnetic resonance (correlation spectroscopy, heteronuclear single quantum coherence, and heteronuclear multiple-bond correlation). Results: Phytochemical investigation of the plant resulted in isolation of 12 compounds. The isolated compounds were identified as chrysophanic acid, emodin, chrysophanic acid-8-O-glucoside, emodin-8-O-glucoside, pectolinarigenin, quercetin, dillenetin-3-O-glucoside, catechin, catechin-4’-O-gallate, methyl gallate, lupeol and ursolic acid. All the isolated phenolic compounds revealed significant free radical scavenging activities when tested using 2,2-diphenyl-1-picrylhydrazyl reagent. Conclusion: The antioxidant activities of the isolated compounds can justify the use of P. austroarabica in traditional medicine for treatment of diabetes and verify its possible application as an antihyperglycemic drug. PMID:26692747

The bile acid receptor GPBAR1 (TGR5) is expressed in human gastric cancers and promotes epithelial-mesenchymal transition in gastric cancer cell lines

PubMed Central

Cipriani, Sabrina; Marchianò, Silvia; Marino, Elisabetta; Zampella, Angela; Rende, Mario; Mosci, Paolo; Distrutti, Eleonora; Donini, Annibale; Fiorucci, Stefano

2016-01-01

GPBAR1 (also known as TGR5) is a bile acid activated receptor expressed in several adenocarcinomas and its activation by secondary bile acids increases intestinal cell proliferation. Here, we have examined the expression of GPBAR1 in human gastric adenocarcinomas and investigated whether its activation promotes the acquisition of a pro-metastatic phenotype. By immunohistochemistry and RT-PCR analysis we found that expression of GPBAR1 associates with advanced gastric cancers (Stage III-IV). GPBAR1 expression in tumors correlates with the expression of N-cadherin, a markers of epithelial-mesenchymal transition (EMT) (r=0.52; P<0.01). Expression of GPBAR1, mRNA and protein, was detected in cancer cell lines, with MKN 45 having the higher expression. Exposure of MKN45 cells to GPBAR1 ligands, TLCA, oleanolic acid or 6-ECDCA (a dual FXR and GPBAR1 ligand) increased the expression of genes associated with EMT including KDKN2A, HRAS, IGB3, MMP10 and MMP13 and downregulated the expression of CD44 and FAT1 (P<0.01 versus control cells). GPBAR1 activation in MKN45 cells associated with EGF-R and ERK1 phosphorylation. These effects were inhibited by DFN406, a GPBAR1 antagonist, and cetuximab. GPBAR1 ligands increase MKN45 migration, adhesion to peritoneum and wound healing. Pretreating MKN45 cells with TLCA increased propensity toward peritoneal dissemination in vivo. These effects were abrogated by cetuximab. In summary, we report that GPBAR1 is expressed in advanced gastric cancers and its expression correlates with markers of EMT. GPBAR1 activation in MKN45 cells promotes EMT. These data suggest that GPBAR1 antagonist might have utility in the treatment of gastric cancers. PMID:27409173

Investigation of cytochrome P450 inhibitory properties of maslinic acid, a bioactive compound from Olea europaea L., and its structure-activity relationship.

PubMed

Sun, Min; Tang, Yu; Ding, Tonggui; Liu, Mingyao; Wang, Xin

2015-01-15

Maslinic acid (MA), the main pentacyclic triterpene of Olea europaea L. fruit, possesses a variety of pharmacological actions, including hypoglycemic, antioxidant, cardioprotective and antitumoral activities. Despite its importance, little is known about its effects on the cytochrome P450 (CYP) activity in both humans and animals. Therefore, the aim of this study was to investigate the effects of MA on the CYP 1A2, 2C9/11, 2D1/6, 2E1 and 3A2/4 activities by human and rat liver microsomes and specific CYP isoforms. In humans, MA only weakly inhibited CYP3A4 activity in human liver microsomes and specific CYP3A4 isoform with IC50 value at 46.1 and 62.3µM, respectively. In rats, MA also exhibited weak inhibition on CYP2C11, CYP2E1 and CYP3A2 activities with IC50 values more than 100µM. Enzyme kinetic studies showed that the MA was not only a competitive inhibitor of CYP3A4 in humans, but also a competitive inhibitor of CYP2C11 and 3A2 in rats, with Ki of 18.4, 98.7 and 66.3µM, respectively. Moreover, the presence of hydroxyl group at C-2 position of triterpenic acid in MA compared with oleanolic acid could magnify its competitive inhibition on human CYP3A4 activity. The relatively high Ki values of MA would have a low potential to cause the possible toxicity and drug interactions involving CYP enzymes, thus suggesting a sufficient safety for its putative use as a nutraceutical taken together with drugs. Copyright © 2014 Elsevier GmbH. All rights reserved.

Electrophilic Triterpenoid Enones: A Comparative Thiol-Trapping and Bioactivity Study.

PubMed

Del Prete, Danilo; Taglialatela-Scafati, Orazio; Minassi, Alberto; Sirignano, Carmina; Cruz, Cristina; Bellido, Maria L; Muñoz, Eduardo; Appendino, Giovanni

2017-08-25

Bardoxolone methyl (1) is the quintessential member of triterpenoid cyanoacrylates, an emerging class of bioactive compounds capable of transient covalent binding to thiols. The mechanistic basis for this unusual "pulsed reactivity" profile and the mode of its biological translation are unknown. To provide clues on these issues, a series of Δ 1 -dehydrooleanolates bearing an electron-withdrawing group at C-2 (7a-m) were prepared from oleanolic acid (3a) and comparatively investigated in terms of reactivity with thiols and bioactivity against a series of electrophile-sensitive transcription factors (Nrf2, NF-κB, STAT3). The emerging picture suggests that the triterpenoid scaffold sharply decreases the reactivity of the enone system by steric encumbrance and that only strongly electrophilic and sterically undemanding substituents such as a cyanide or a carboxylate group can re-establish Michael reactivity, albeit in a transient way for the cyanide group. In general, a substantial dissection between the thiol-trapping ability and the modulation of biological end-points sensitive to thiol alkylation was observed, highlighting the role of shape complementarity for the activity of triterpenoid thia-Michael acceptors.

Synthesis and biological evaluation of novel thiadiazole amides as potent Cdc25B and PTP1B inhibitors.

PubMed

Li, Yingjun; Yu, Yang; Jin, Kun; Gao, Lixin; Luo, Tongchuan; Sheng, Li; Shao, Xin; Li, Jia

2014-09-01

A series of novel thiadiazole amide derivatives have been synthesized and evaluated for inhibitory activities against Cdc25B and PTP1B. Most of them showed inhibitory activities against Cdc25B (IC50=1.18-8.01 μg/mL) and PTP1B (IC50=0.85-8.75 μg/mL), respectively. Moreover, compounds 5b and 4l were most potent with IC50 values of 1.18 and 0.85 μg/mL for Cdc25B and PTP1B, respectively, compared with reference drugs Na3VO4 (IC50=0.93 μg/mL) and oleanolic acid (IC50=0.85 μg/mL). The results of selectivity experiments showed that the target compounds were selective inhibitors against PTP1B and Cdc25B. Enzyme kinetic experiments demonstrated that compound 5k was a specific inhibitor with the typical characteristics of a mixed inhibitor. Copyright © 2014 Elsevier Ltd. All rights reserved.

Bioactivities and chemical constituents of a Vietnamese medicinal plant Che Vang, Jasminum subtriplinerve Blume (Oleaceae).

PubMed

Ngan, Dai Hue; Hoai, Ho Thi Cam; Huong, Le Mai; Hansen, Poul Erik; Vang, Ole

2008-01-01

Five crude extracts were made from leaves and stems of Jasminum subtriplinerve Blume (Oleaceae) and investigated for antimicrobial, antioxidant and cytotoxic activities. The extractions were done with petroleum ether, ethyl acetate, ethanol, methanol or water. All extracts exhibited anti-bacterial activity except the water fraction. On the other hand, all extracts exhibit antioxidant activity except the petroleum ether fraction using the DPPH radical scavenging assay. Only the petroleum ether fraction showed a cytotoxicity activity against tested cell-lines, Hep-G2 and RD with IC(50) values of 19.2 and 20 microg mL(-1), respectively. From the petroleum ether and ethyl acetate extracts, two triterpenes namely 3beta-acetyl-oleanolic acid and lup-20-en-3beta-ol and a sterol, stigmast-5-en-3beta-ol were isolated. The structure of those compounds were elucidated by spectrometric methods IR, MS, 1D-NMR, 2D-NMR and simulated ACD/NMR spectra. The data presented here indicate that J. subtriplinerve do contain compounds with interesting biological activity.

Triterpenoid saponins from the root of Anemone tomentosa.

PubMed

Wang, Yi; Kang, Wei; Hong, Liang-jian; Hai, Wen-li; Wang, Xiao-yang; Tang, Hai-feng; Tian, Xiang-rong

2013-01-01

Three new triterpenoid saponins, tomentoside A (1), B (2) and C (3), along with four known saponins (4-7) were isolated from the root of Anemone tomentosa. The structures of the new compounds were elucidated as 3-O-β-D-ribopyranosyl-(1→3)-α-L-rhamnopyranosyl-(1→2)-[β-D-glucopyranosyl-(1→4)]-α-L-arabinopyranosyl hederagenin 28-O-α-L-rhamnopyranosyl-(1→4)-β-D-glucopyranosyl-(1→6)-β-D-glucopyranoside (1), 3-O-β-D-ribopyranosyl-(1→3)-α-L-rhamnopyranosyl-(1→2)-[β-D-glucopyranosyl-(1→4)]-β-D-xylopyranosyl hederagenin 28-O-α-L-rhamnopyranosyl-(1→4)-β-D-glucopyranosyl-(1→6)-β-D-glucopyranoside (2) and 3-O-β-D-galactopyranosyl-(1→3)-α-L-rhamnopyranosyl-(1→2)-β-D-xylopyranosyl oleanolic acid 28-O-α-L-rhamnopyranosyl-(1→4)-β-D-glucopyranosyl-(1→6)-β-D-glucopyranoside (3) on the basis of chemical and spectral evidence. In the oligosaccharide chains of compound 3, the characteristic D-galactose residue is a rare structural feature and secondly encountered among triterpenoid saponins from Anemone.

Comparison of cardioprotective effects of labeled and unlabeled oleanoic acids with new BOPIM dye on primary neonatal rat cardiomyocytes following hypoxia/reoxygenation injury.

PubMed

Wang, Sa; He, Hai-bo; Xiao, Shu-zhang; Wang, Jun-zhi; Bai, Cai-hong; Wei, Na; Zou, Kun

2014-08-01

It is well known that fluorescent labeling has recently become a major research tool in molecular and cellular biology for demonstrating therapeutic mechanisms and metabolic pathways. However, few studies have reported the use of fluorescent labeling of natural products. We recently explored the boron 2-(2'-pyridyl) imidazole (BOPIM) derivative analogs, which are highly fluorescent, non-aggregated, and nontoxic. In the present study, the natural product oleanolic acid (OA) was functionalized and labeled with BOPIM, thus yielding a highly fluorescent probe, the comparison of cardioprotective effects of labeled and unlabeled OAs with BOPIM on primary neonatal rat cardiomyocytes with hypoxia/reoxygenation (H/R) injury were investigated. Pretreatment with OA and BOPIM-OA significantly prevented the H/R induced cell death in primary neonatal rat cardiomyocytes. However, BOPIM exhibited no improvements on the H/R injury cardiomyocytes, and which were similar to those of the H/R group. The results of comparison of cardioprotective effects between labeled and unlabeled OAs with BOPIM showed that introducing the BOPIM chromophore did not make a difference with H/R injury cardiomyocytes. BOPIM chromophore is a suitable probe for investigating the pharmacological mechanisms of natural products. Copyright © 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

Antifungal and antibacterial activity and chemical composition of polar and non-polar extracts of Athrixia phylicoides determined using bioautography and HPLC

PubMed Central

2013-01-01

Background Athrixia phylicoides DC. (Asteraceae) is used medicinally in South Africa to treat a plethora of ailments, including heart problems, diabetes, diarrhoea, sores and infected wounds. It is also prepared in the form of a tea (hot decoction) taken as a refreshing, pleasant-tasting beverage with commercialization potential. Methods Extracts of the dried ground aerial parts were prepared using organic solvents (diethyl ether, dichloromethane/methanol, ethyl acetate and ethanol) and water. These extracts were subjected to HPLC, TLC and bioautography analysis with the aim of linking a range of peaks visualized in HPLC chromatography profiles to antibacterial and antifungal activity of the same extracts. Results HPLC revealed a group of compounds extracted by more than one solvent. Compounds identified include inositol, caffeic acid, quercetin, kaempferol, apigenin, hymenoxin and oleanolic acid. The organic extracts displayed similar TLC profiles, and bioautography indicated approximately five antibacterial compounds, but only two antifungal compounds in these extracts. Bioautography indicated that cold water extracted the least antimicrobial compounds. Conclusions Several previously unknown compounds were identified in Athrixia phylicoides extracts, and bioautography indicated a number of antibacterial and antifungal compounds. There were notable differences in chemical composition and bioactivity between the organic and aqueous extracts. Further research is necessary to fully characterize the active components of the extracts. PMID:24330447

Identification of a Multicomponent Traditional Herbal Medicine by HPLC-MS and Electron and Light Microscopy.

PubMed

Liu, Ju-Han; Cheng, Yung-Yi; Hsieh, Chen-Hsi; Tsai, Tung-Hu

2017-12-15

Commercial pharmaceutical herbal products have enabled people to take traditional Chinese medicine (TCM) in a convenient and accessible form. However, the quantity and quality should be additionally inspected. To address the issue, a combination of chemical and physical inspection methods were developed to evaluate the amount of an herbal formula, Xiang-Sha-Liu-Jun-Zi-Tang (XSLJZT), in clinical TCM practice. A high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS) method with electrospray ionization was developed to measure the herbal biomarkers of guanosine, atractylenolide III, glycyrrhizic acid, dehydrocostus lactone, hesperidin, and oleanolic acid from XSLJZT. Scanning electron microscopy (SEM) photographs and light microscopy photographs with Congo red and iodine-KI staining were used to identify the cellulose fibers and starch content. Furthermore, solubility analysis, swelling power test, and crude fiber analysis were contributed to measure the starch additive in pharmaceutical products. The results demonstrated large variations in the chemical components of different pharmaceutical brands. The SEM photographs revealed that the starch was oval, smooth, and granular, and that the raw herbal powder appears stripy, stretched, and filiform. The stained light microscopy photographs of all of the pharmaceutical products showed added starch and raw herbal powder as extenders. The developed chemical and physical methods provide a standard operating procedure for the quantity control of the herbal pharmaceutical products of XSLJZT.

Neurologically Potent Molecules from Crataegus oxyacantha; Isolation, Anticholinesterase Inhibition, and Molecular Docking

PubMed Central

Ali, Mumtaz; Muhammad, Sultan; Shah, Muhammad R.; Khan, Ajmal; Rashid, Umer; Farooq, Umar; Ullah, Farhat; Sadiq, Abdul; Ayaz, Muhammad; Ali, Majid; Ahmad, Manzoor; Latif, Abdul

2017-01-01

Crataegus oxyacantha is an important herbal supplement and famous for its antioxidant potential. The antioxidant in combination with anticholinesterase activity can be considered as an important target in the management of Alzheimer’s disease. The compounds isolated from C. oxyacantha were evaluated for cholinesterases inhibitory activity using Ellman’s assay with Galantamine as standard drug. Total of nine (1–9) compounds were isolated. Compounds 1 and 2 were isolated for the first time from natural source. Important natural products like β-Sitosterol-3-O-β-D-Glucopyranoside (3), lupeol (4), β-sitosterol (5), betulin (6), betulinic acid (7), oleanolic acid (8), and chrysin (9) have also been isolated from C. oxyacantha. Overall, all the compounds exhibited an overwhelming acetylcholinesterase (AChE) inhibition potential in the range 5.22–44.47 μM. The compound 3 was prominent AChE inhibitor with IC50 value of 5.22 μM. Likewise, all the compounds were also potent in butyrylcholinesterase (BChE) inhibitions with IC50s of up to 0.55–15.36 μM. All the compounds, except 3, were selective toward BChE. Mechanism of the inhibition of both the enzymes were further studied by docking procedures using Genetic Optimization for Ligand Docking suit v5.4.1. Furthermore, computational blood brain barrier prediction of the isolated compounds suggest that these are BBB+. PMID:28638340

Inflammation and Immune Regulation as Potential Drug Targets in Antidepressant Treatment

PubMed Central

Schmidt, Frank M.; Kirkby, Kenneth C.; Lichtblau, Nicole

2016-01-01

Growing evidence supports a mutual relationship between inflammation and major depression. A variety of mechanisms are outlined, indicating how inflammation may be involved in the pathogenesis, course and treatment of major depression. In particular, this review addresses 1) inflammatory cytokines as markers of depression and potential predictors of treatment response, 2) findings that cytokines interact with antidepressants and non-pharmacological antidepressive therapies, such as electroconvulsive therapy, deep brain stimulation and physical activity, 3) the influence of cytokines on the cytochrome (CYP) p450-system and drug efflux transporters, and 4) how cascades of inflammation might serve as antidepressant drug targets. A number of clinical trials have focused on agents with immunmodulatory properties in the treatment of depression, of which this review covers nonsteroidal anti-inflammatory drugs (NSAIDs), cytokine inhibitors, ketamine, polyunsaturated fatty acids, statins and curcumin. A perspective is also provided on possible future immune targets for antidepressant therapy, such as toll-like receptor-inhibitors, glycogen synthase kinase-3 inhibitors, oleanolic acid analogs and minocycline. Concluding from the available data, markers of inflammation may become relevant factors for more personalised planning and prediction of response of antidepressant treatment strategies. Agents with anti-inflammatory properties have the potential to serve as clinically relevant antidepressants. Further studies are required to better define and identify subgroups of patients responsive to inflammatory agents as well as to define optimal time points for treatment onset and duration. PMID:26769225

Structure-activity relationships of 3-O-β-chacotriosyl oleanic acid derivatives as entry inhibitors for highly pathogenic H5N1 influenza virus.

PubMed

Li, Sumei; Jia, Xiuhua; Shen, Xintian; Wei, Zhuwen; Jiang, Zhiyan; Liao, Yixian; Guo, Yiming; Zheng, Xiaojun; Zhong, Guohua; Song, Gaopeng

2017-08-15

Highly pathogenic H5N1 virus (H5N1) entry is a key target for the development of novel anti-influenza agents with new mechanisms of action. In our continuing efforts to identify novel potential anti-H5N1 entry inhibitors, a series of 3-O-β-chacotriosyl oleanolic acid analogs have been designed, synthesized and evaluated as H5N1 entry inhibitors based on two small molecule inhibitors 1 and 2 previously discovered by us. The anti-H5N1 entry activities were determined based on HA/HIV and VSVG/HIV entry assays. Compound 15 displayed the most promising anti-H5N1 entry activities with average IC 50 values of 4.05μM and good selective index (22.9). Detailed structure-activity relationships (SARs) studies suggested that either the introduction of an additional oxo group to position 11 at OA or alteration of the C-3 configuration of OA from 3β- to 3α-forms can significantly enhance the selective index while maintaining their antiviral activities in vitro. Molecular simulation analysis confirmed that the compounds exert their inhibitory activity through binding tightly to hemagglutinin (HA2) protein near the fusion peptide and prevent virus entry. Copyright © 2017 Elsevier Ltd. All rights reserved.

Mice Behavioral Phenotype Changes after Administration of Anani (Symphonia globulifera, Clusiaceae), an Alternative Latin American and African Medicine.

PubMed

Suffredini, Ivana Barbosa; Paciencia, Mateus Luís Barradas; Díaz, Ingrit E C; Frana, Sergio Alexandre; Bernardi, Maria Martha

2017-01-01

Anani , ( Symphonia globulifera , Clusiaceae), known as chewstick, is a traditional plant occurring in Africa and in Central and South Americas that is used against parasites and microorganisms. Although its use is popular in some of these countries, there is a lack of information related to its influence over behavioral phenotype (BP). The objective of this study is to evaluate the influence of the administration of the extract obtained from the aerial organs of Anani (EB1257) to male Balb-c mice over BP. Open cage observation, open field, and elevated-plus maze apparatuses were used. Evaluations were done 15, 30, 60, 120, and 180 min after intraperitoneal administration of Anani extract. Impairment of general behavior activity, response to touch, tail squeeze, defecation, locomotion and rearing frequency were observed although no signs of hemorrhage or macroscopical alterations of internal organs. Anani is harmful, but not toxic if used in the appropriate doses, yet to be determined to male mice. Impairment of locomotion and defecation was observed, indicating some degree of influence over locomotion, but no alterations in anxiety levels were assessed. Three compounds were previously found in the plant-lupeol (1), β-amyrin (2) and 3-β-hydroxyglutin-5-ene (3), and one is being described for the first time to occur in the species: oleanolic acid (4). The present work contributes in the support of the rational use of Anani , an important Latin American and African alternative medicine, presenting findings that are being reported for the first time. Symphonia globulifera impairs locomotion and defecatin in behavior analysesNo alterations in anxiety was observedOleanolic acid occurs in the species. Abbreviations used: BP: Behavioral phenotype; OF: Open field, EPM: Elevated-plus maze, MMA/ICMBio/SISBIO: Ministério do Meio Ambiente/Instituto Chico Mendes de Conservação da Biodiversidade/Sistema de Autorização e Informação em Biodiversidade, IBAMA/MMA/CGen: Instituto Brasileiro do Meio Ambiente e dos Recursos Naturais Renováveis/Ministério do Meio Ambiente/Conselho de Gestão do Patrimônio Genético, AM: Amazonas State, UNIP: Universidade Paulista, mg: milligram, kg: kilogram, I.P: Intraperitoneal, CEUA/ICS/UNIP: Comissão de Ética no Uso de Animais/Instituto de Ciências da Saúde/Universidade Paulista, LD: Lethal dose, NLD: Nonlethal dose, GBA: General behavior activity, FCHCL 3 : Fraction chloroform, FBuOH: Fraction buthanol, FH 2 O: Fraction water, FrHEX: Fraction hexane, FrDCM: Fraction dichloromethane, FrMeOH: Fraction methanol, 13 C NMR: Carbon nuclear magnetic resonance, EPA: United States Environmental Protection Agency.

Anti-inflammatory and analgesic components from "hierba santa," a traditional medicine in Peru.

PubMed

Kawano, Marii; Otsuka, Mayumi; Umeyama, Kazuhiro; Yamazaki, Mikio; Shiota, Tetsuo; Satake, Motoyoshi; Okuyama, Emi

2009-04-01

"Hierba santa," a Peruvian herbal medicine, is used to alleviate many symptoms, including headache, hemorrhoids, fever, and rheumatism. Several Cestrum species are said to be the origin of hierba santa. Three lots of hierba santa: Cestrum auriculatum (herb 1 and herb 2) and C. hediundinum (herb 3), which were purchased from Peruvian markets at Cuzco (Andes area) and Equitos (Amazon area), respectively, were examined for their pharmacological activities and active components. Herbs 1-3 showed anti-inflammatory and analgesic activities in the in vivo writhing inhibition test in mouse and inhibited prostaglandin E(1)-, E(2)-, or ACh-induced contractions of guinea pig ileum in the Magnus method. Activity-based separation of each extract yielded cestrumines A and B, cestrusides A and B, a mixture of (+)- and (-)-pinoresinol glucosides, nicotiflorin, rutin, sinapoyl glucose, ursolic acid, beta-sitosteryl glucoside, and 2-sec-butyl-4,6-dihydroxyphenyl-beta-D: -glucopyranoside. Among them, cestrumine A and cestrusides A and B are new compounds. All three lots of hierba santa do not contain exactly the same active components.

Therapeutic effect of Northern Labrador tea extracts for acute myeloid leukemia.

PubMed

McGill, Colin M; Tomco, Patrick L; Ondrasik, Regina M; Belknap, Kaitlyn C; Dwyer, Gaelen K; Quinlan, Daniel J; Kircher, Thomas A; Andam, Cheryl P; Brown, Timothy J; Claxton, David F; Barth, Brian M

2018-04-27

Acute myeloid leukemia (AML) is an aggressive hematological malignancy that is one of the more common pediatric malignancies in addition to occurring with high incidence in the aging population. Unfortunately, these patient groups are quite sensitive to toxicity from chemotherapy. Northern Labrador tea, or Rhododendron tomentosum Harmaja (a.k.a. Ledum palustre subsp. decumbens) or "tundra tea," is a noteworthy medicinal plant used by indigenous peoples in Alaska, Canada, and Greenland to treat a diversity of ailments. However, laboratory investigations of Northern Labrador tea, and other Labrador tea family members, as botanical sources for anticancer compounds have been limited. Utilizing an AML cell line in both in vitro and in vivo studies, as well as in vitro studies using primary human AML patient samples, this study demonstrated for the first time that Northern Labrador tea extracts can exert anti-AML activity and that this may be attributed to ursolic acid as a constituent component. Therefore, this medicinal herb holds the potential to serve as a source for further drug discovery efforts to isolate novel anti-AML compounds. Copyright © 2018 John Wiley & Sons, Ltd.

Major constituents of the foliar epicuticular waxes of species from the Caatinga and Cerrado.

PubMed

Oliveira, A F; Salatino, A

2000-01-01

The epicuticular waxes of leaves of four species (Aspidosperma pyrifolium, Capparis yco, Maytenus rigida and Ziziphus joazeiro) from the Caatinga, (a semi-arid ecosystem of Northeast Brazil) and four species (Aristolochia esperanzae, Didymopanax vinosum, Strychnos pseudoquina and Tocoyena formosa) from the Cerrado, (a savanna ecosystem covering one third of the Brazilian territory), were analyzed. Six species contained a high content (above 60 microg x cm(-2)) of wax, four of them from the Caatinga. Triterpenoids and n-alkanes were the most frequent and abundant constituents found in the species from both habitats. The distribution of n-alkanes predominated by homologues with 27, 29, 31 and 33 carbon atoms, displayed no consistent differences between species from the two habitats. Lupeol, beta-amyrin, epifriedelinol and ursolic acid were the triterpenoids found. Triterpenoids clearly predominate over alkanes in the waxes from the Cerrado species. The waxes of two evergreen species from the Caatinga yielded n-alkanes as predominant constituents. A comparison of foliar epicuticular waxes of native plants from ecosystems with different hydric constraints is discussed.

Carrier-Free, Pure Nanodrug Formed by the Self-Assembly of an Anticancer Drug for Cancer Immune Therapy.

PubMed

Fan, Lulu; Zhang, Bingchen; Xu, Aixiao; Shen, Zhichun; Guo, Yan; Zhao, Ruirui; Yao, Huilu; Shao, Jing-Wei

2018-06-04

Ursolic acid (UA) is a food-plant-derived natural product which has good anticancer activities and low toxicity. However, the poor water solubility of UA limits its application in clinic. To address this issue, we developed a carrier-free nanodrug by self-assembly of UA. Here, we showed that UA nanoparticles (NPs) have a near-spherical shape with a diameter of ∼150 nm. UA NPs exhibited higher antiproliferative activity; significantly caused apoptosis; decreased the expression of COX-2/VEGFR2/VEGFA; and increased the immunostimulatory activity of TNF-α, IL-6, and IFN-β and decreased the activity of STAT-3 in A549 cells in vitro. Furthermore, UA NPs could inhibit tumor growth and have the ability of liver protection in vivo. More importantly, UA NPs could significantly improve the activation of CD4+ T-cells, which indicated that UA NPs have the potential for immunotherapy. Overall, a carrier-free UA nanodrug may be a promising drug to further enhance their anticancer efficacy and immune function.

Cytotoxicity, antimicrobial and antioxidant activity of eight compounds isolated from Entada abyssinica (Fabaceae).

PubMed

Dzoyem, Jean P; Melong, Raduis; Tsamo, Armelle T; Tchinda, Alembert T; Kapche, Deccaux G W F; Ngadjui, Bonaventure T; McGaw, Lyndy J; Eloff, Jacobus N

2017-03-06

Entada abyssinica is a plant traditionally used against gastrointestinal bacterial infections. Eight compounds including three flavonoids, three terpenoids, a monoglyceride and a phenolic compound isolated from E. abyssinica were investigated for their cytotoxicity, antibacterial and antioxidant activity. Compounds 7 and 2 had remarkable activity against Salmonella typhimurium with the lowest respective minimum inhibitory concentration (MIC) values of 1.56 and 3.12 µg/mL. The antioxidant assay gave IC 50 values varied from 0.48 to 2.87 μg/mL in the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay, from 2.53 to 17.04 μg/mL in the 2,2'-Azino-bis (3-ethylbenzothiazoline-6-sulphonic acid) diammonium salt (ABTS) assay and from 1.43 to 103.98 µg/mL in the FRAP assay. Compounds had relatively low cytotoxicity (LC 50 values ranging from 22.42 to 80.55 µg/mL) towards Vero cells. Ursolic acid had the most potent cytotoxicity against THP-1 and RAW 264.7 cells with LC 50 values of 9.62 and 4.56 μg/mL respectively, and selectivity index values of 7.32 and 15.44 respectively. Our findings suggest that among the terpenoid and flavonoid compounds studied, entadanin (compound 7) possess tremendous antibacterial activity against S. typhimurium and could be developed for the treatment of bacterial diseases.

3β-Hydroxy-urs-12-en-28-oic Acid Modulates Dietary Restriction Mediated Longevity and Ameliorates Toxic Protein Aggregation in C. elegans.

PubMed

Negi, Hema; Saikia, Shilpi Khare; Pandey, Rakesh

2017-11-09

Species from lower invertebrates to a spectrum of mammals show antiaging health benefits of phytochemical(s). Here, we explored the pro-longevity effects of a natural triterpenoid, ursolic acid (3β-hydroxy-urs-12-en-28-oic acid; UA) in Caenorhabditis elegans with maximal life span being evident at 25 µM UA. Similar to eat-2 mutants, UA uptake by worm results in reduced fat storage and attenuation of reactive oxygen species (ROS), independent of superoxide dismutase(s) activation. The genetic requirements for UA-mediated longevity are quite similar to dietary restriction (DR) achieved through SKN-1/NRF-2 exhibiting upregulation of downstream target genes gcs-1 and daf-9. Longevity mechanism was independent of PHA-4/FOXA and attributed to partial dependence on sir-2.1. Altogether, our study suggests differential use of UA-elicited signaling cascades in nutrient sensing for longevity. Both the redox state and the proteostasis of an organism play critical role in aging and disease resistance. Interestingly, we observed a reduction of toxic protein aggregation in transgenic polyglutamine (polyQ) C. elegans model and UA-mediated JNK-1 (c-Jun-NH2-terminal kinase) activation in wild-type animals. Thus, our study demonstrates a small extent of prevention against proteotoxic stress by UA coupled with positive aspects of DR-mediated longevity. © The Author 2017. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Impact of Mistletoe Triterpene Acids on the Uptake of Mistletoe Lectin by Cultured Tumor Cells

PubMed Central

Mulsow, Katharina; Enzlein, Thomas; Delebinski, Catharina; Jaeger, Sebastian; Seifert, Georg; Melzig, Matthias F.

2016-01-01

Complementary treatment possibilities for the therapy of cancer are increasing in demand due to the severe side effects of the standard cytostatics used in the first-line therapy. A common approach as a complementary treatment is the use of aqueous extracts of Viscum album L. (Santalaceace). The therapeutic activity of these extracts is attributed to Mistletoe lectins which are Ribosome-inactivating proteins type II. Besides these main constituents the extract of Viscum album L. comprises also a mixture of lipophilic ingredients like triterpene acids of the oleanane, lupane and ursane type. However, these constituents are not contained in commercially available aqueous extracts due to their high lipophilicity and insolubility in aqueous extraction media. To understand the impact of the extract ingredients in cancer therapy, the intracellular uptake of the mistletoe lectin I (ML) by cultured tumor cells was investigated in relation to the mistletoe triterpene acids, mainly oleanolic acid. Firstly, these hydrophobic triterpene acids were solubilized using cyclodextrins (“TT” extract). Afterwards, the uptake of either single compounds (isolated ML and the aqueous “viscum” extract) or in combination with the TT extract (ML+TT, viscumTT), was analyzed. The uptake of ML was studied inTHP-1-, HL-60-, 143B- and Ewing TC-71-cells and determined after 30, 60 and 120 minutes by an enzyme linked immunosorbent assay which quantifies the A-chain of the hololectin. It could be shown that the intracellular uptake after 120 minutes amounted to 20% in all cell lines after incubation with viscumTT. The studies further revealed that the uptake in THP-1-, HL-60- and Ewing TC-71-cells was independent of the addition of TT extract. Interestingly, the uptake of ML by 143B-cells could only be measured after addition of triterpenes pointing to resistance to mistletoe lectin. PMID:27088729

A two-step ultra-high-performance liquid chromatography-quadrupole/time of flight mass spectrometry with mass defect filtering method for rapid identification of analogues from known components of different chemical structure types in Fructus Gardeniae-Fructus Forsythiae herb pair extract and in rat's blood.

PubMed

Zhou, Wei; Shan, Jinjun; Meng, Minxin

2018-08-17

Fructus Gardeniae-Fructus Forsythiae herb pair is an herbal formula used extensively to treat inflammation and fever, but few systematic identification studies of the bioactive components have been reported. Herein, the unknown analogues in the first-step screening were rapidly identified from representative compounds in different structure types (geniposide as iridoid type, crocetin as crocetin type, jasminoside B as monocyclic monoterpene type, oleanolic acid as saponin type, 3-caffeoylquinic acid as organic acid type, forsythoside A as phenylethanoid type, phillyrin as lignan type and quercetin 3-rutinoside as flavonoid type) by UPLC-Q-Tof/MS combined with mass defect filtering (MDF), and further confirmed with reference standards and published literatures. Similarly, in the second step, other unknown components were rapidly discovered from the compounds identified in the first step by MDF. Using the two-step screening method, a total of 58 components were characterized in Fructus Gardeniae-Fructus Forsythiae (FG-FF) decoction. In rat's blood, 36 compounds in extract and 16 metabolites were unambiguously or tentatively identified. Besides, we found the principal metabolites were glucuronide conjugates, with the glucuronide conjugates of caffeic acid, quercetin and kaempferol confirmed as caffeic acid 3-glucuronide, quercetin 3-glucuronide and kaempferol 3-glucuronide by reference standards, respectively. Additionally, most of them bound more strongly to human serum albumin than their respective prototypes, predicted by Molecular Docking and Simulation, indicating that they had lower blood clearance in vivo and possibly more contribution to pharmacological effects. This study developed a novel two-step screening method in addressing how to comprehensively screen components in herbal medicine by UPLC-Q-Tof/MS with MDF. Copyright © 2018 Elsevier B.V. All rights reserved.

The NUTRAOLEOUM Study, a randomized controlled trial, for achieving nutritional added value for olive oils.

PubMed

Biel, Sara; Mesa, Maria-Dolores; de la Torre, Rafael; Espejo, Juan-Antonio; Fernández-Navarro, Jose-Ramón; Fitó, Montserrat; Sánchez-Rodriguez, Estefanía; Rosa, Carmen; Marchal, Rosa; Alche, Juan de Dios; Expósito, Manuela; Brenes, Manuel; Gandul, Beatriz; Calleja, Miguel Angel; Covas, María-Isabel

2016-10-22

Virgin olive oil, a recognized healthy food, cannot be consumed in great quantities. We aim to assess in humans whether an optimized virgin olive oil with high phenolic content (OVOO, 429 mg/Kg) and a functional one (FOO), both rich in phenolic compounds (429 mg/Kg) and triterpenic acids (389 mg/kg), could provide health benefits additional to those supplied a by a standard virgin olive oil (VOO). A randomized, double-blind, crossover, controlled study will be conducted. Healthy volunteers (aged 20 to 50) will be randomized into one of three groups of daily raw olive oil consumption: VOO, OVOO, and FOO (30 mL/d). Olive oils will be administered over 3-week periods preceded by 2-week washout ones. The main outcomes will be markers of lipid and DNA oxidation, inflammation, and vascular damage. A bioavailability and dose-response study will be nested within this sustained- consumption one. It will be made up of 18 volunteers and be performed at two stages after a single dose of each olive oil. Endothelial function and nitric oxide will be assessed at baseline and at 4 h and 6 h after olive oil single dose ingestion. For the first time the NUTRAOLEUM Study will provide first level evidence on the health benefits in vivo in humans of olive oil triterpenes (oleanolic and maslinic acid) in addition to their bioavailability and disposition. The Trial has been registered in ClinicalTrials.gov ID: NCT02520739 .

Lithium adduct as precursor ion for sensitive and rapid quantification of 20 (S)-protopanaxadiol in rat plasma by liquid chromatography/quadrupole linear ion trap mass spectrometry and application to rat pharmacokinetic study.

PubMed

Bao, Yuanwu; Wang, Quanying; Tang, Pingming

2013-03-01

A novel, rapid and sensitive liquid chromatography/quadrupole linear ion trap mass spectrometry [LC-ESI-(QqLIT)MS/MS] method was developed and validated for the quantification of protopanaxadiol (PPD) in rat plasma. Oleanolic acid (OA) was used as internal standard (IS). A simple protein precipitation based on acetonitrile (ACN) was employed. Chromatographic separation was performed on a Sepax GP-C18 column (50 × 2.1 mm, 5 μM) with a mobile phase consisting of ACN-water and 1.5 μM formic acid and 25 mM lithium acetate (90 : 10, v/v) at a flow rate of 0.4 ml/min for 3.0 min. Multiple-reaction-monitoring mode was performed using lithium adduct ion as precursor ion of m/z 467.5/449.4 and 455.6/407.4 for the drug and IS, respectively. Calibration curve was recovered over a concentration range of 0.5-100 ng/ml with a correlation coefficient >0.99. The limit of detection was 0.2 ng/ml in rat plasma for PPD. The results of the intraday and interday precision and accuracy studies were well within the acceptable limits. The validated method was successfully applied to investigate the pharmacokinetic study of PPD after intravenous and gavage administration to rat. Copyright © 2013 John Wiley & Sons, Ltd.

Nutritional evaluation and health promoting activities of nuts and seeds cultivated in Greece.

PubMed

Kalogeropoulos, Nick; Chiou, Antonia; Ioannou, Maria S; Karathanos, Vaios T

2013-09-01

Available data suggest that genetic as well as environmental factors may influence nuts and seeds nutrients content. In this context nuts and seeds cultivated in Greece were studied. Macronutrients content was in agreement with that from other areas. Total phenolics content was in the range of 43.0 ± 2.1-1512.7 ± 60.7 mg GAE/100 g for chestnut and walnut, respectively. Thirteen to 22 individual phenolics were identified in the studied species. Oleanolic acid was in the range of 0.10-9.03 mg/100 g. Pumpkin seeds contained the higher squalene content (71.6 mg/100 g). β-Sitosterol predominated in all samples except pumpkin seeds. Tocopherols ranged from 8.9 mg/100 g (chestnut) to 29.3 mg/100 g (almond). Nuts and seeds hydrophilic extracts at quantities corresponding to the estimated daily consumption by the Greeks succeeded in inhibiting LDL oxidation in vitro by increasing lag time 1.1-14.1 times. One serving of nuts or seeds may cover a significant fraction of health promoting microconstituents daily intake.

Preliminary pharmacognostic screening of Achyranthes coynei stem.

PubMed

Upadhya, Vinayak; Ankad, Gireesh M; Pai, Sandeep R; Hegde, Shruti V; Hegde, Harsha V

2015-01-01

Achyranthes coynei is a rare, endemic perennial shrub reported from Karnataka and Maharashtra states of India. The plant is used to treat various disorders by folk healers and was proven to have antimicrobial and antioxidant properties. The present study was undertaken to evaluate microscopic and macroscopic characters of A. coynei stem, along with its physicochemical parameters. ProgRes(®) CapturePro and Microsoft Excel were used for statistical analysis. Perennial, shrubby nature and woody stem were the distinguishing morphological characters observed. Transverse section (TS) illustrated quadrangular outline of the stem and showed the presence of two types of trichomes on the thick-walled epidermis. TS also showed number of rosette calcium oxalates crystals; prismatic and microsphenoid crystals; conjoint, collateral open secondary vascular bundles; and two amphixylic medullary bundles in the pith. Ash and extractive values, micro and macro elements and nutritive factors were estimated in the present study. The presence of alkaloids, saponins and triterpenoids were observed in preliminary phytochemical screening. High-performance thin layer chromatographic analysis yielded different bands and also indicated the presence of oleanolic acid. The studied parameters for A. coynei stem will be useful for identification and authentication of the plant material.

[Chemical constituents from petroleum ether fraction of Swertia chirayita and their activities in vitro].

PubMed

You, Rong-Rong; Chen, Xue-Qing; He, Dan-Dan; Huang, Chang-Gao; Jin, Yang; Qian, Shi-Hui; Ju, Jian-Ming; Fan, Jun-Ting

2017-10-01

The present work is to study the chemical constituents from petroleum ether fraction of Tibetan medicine Swertia chirayita by column chromatography and recrystallization. The structures were identified by physical and chemical properties and spectral data as swerchirin (1), decussatin (2), 1,8-dihydroxy-3,5,7-trimethoxyxanthone (3), 1-hydroxy-3,5,7,8-tetramethoxyxanthone (4), bellidifolin (5), 1-hydroxy-3, 7-dimethoxyxanthone (6), methylswertianin (7), 1-hydroxy-3,5-dimethoxyxanthone (8), erythrodiol (9), oleanolic acid (10), gnetiolactone (11), scopoletin (12), sinapaldehyde (13), syringaldehyde (14), and β-sitosterol (15). Compounds 3, 4, 9, 11-14 were isolated from S. chirayita for the first time. Compounds 9 and 12 were firstly isolated from the genus Swertia. The cytotoxic activities of compounds 1, 2, 5, 7 and 8 against human pancreatic cancer cell lines SW1990 and BxPC-3,and the protective effects of these compounds against hydrogen peroxide (H2O2)-induced oxidative stress in human endothelium-derived EA.hy926 were investigated in vitro. The results showed no obvious effect at the high concentration of 50 μmol•L⁻¹. Copyright© by the Chinese Pharmaceutical Association.

Chemical constituents from the stems of Gymnema sylvestre.

PubMed

Liu, Yue; Xu, Tun-Hai; Zhang, Man-Qi; Li, Xue; Xu, Ya-Juan; Jiang, Hong-Yu; Liu, Tong-Hua; Xu, Dong-Ming

2014-04-01

To study the chemical constituents of stems of Gymnema sylvestre (Retz.) Schult. Chromatographic techniques using silica gel, C18 reversed phase silica gel, and prep-HPLC were used. The structures were elucidated on the basis of MS and spectroscopic analysis (1D and 2D NMR), as well as chemical methods. Seven compounds were isolated and their structures were elucidated as conduritol A (1), stigmasterol (2), lupeol (3), stigmasterol-3-O-β-D-glucoside (4), the sodium salt of 22α-hydroxy-longispinogenin-3-O-β-D-glucopyranosyl-(1→3)-β-D-glu-curono-pyranosyl-28-O-α-L-rhamnopyranoside (5), oleanolic acid-3-O-β-D-glucopyranosyl-(1→6)-β-D-glucopyranoside (6), and the sodium salt of 22α-hydroxy-longispinogenin 3-O-β-D-glucuronopyranosyl-28-O-α-L-rhamnopyranoside (7). The inhibition activities of compounds 1, 5-7 on non-enzymatic glycation of protein in vitro were evaluated. Compound 7 is a new triterpenoid saponin. It was shown that compounds 1, 5-7 have weak inhibition activities for non-enzymatic glycation of protein in vitro. Copyright © 2014 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.

[Advance in chemical constituents of genus Clematis].

PubMed

Sun, Feng; Yang, Depo

2009-10-01

Progresses in the studies on chemical constituents of Clematis L. (belonging to the family Ranunculaceae) were systematiically reviewed in this article. The plants in this genus have a wide spectrum of constituents as follows: triterpenes, flavonoids, lignans, coumarins, alkaloids, volatile oils, steroids, organic acids, macrocyclic compounds and phenols, etc., among which triterpenoid saponins, flavonoids and lignans are the main components. The triterpenoid saponins are mainly oleanolic type and hederagenin type, most of which are bidesmosidic saponins, substituted with oligosaccharide chains at both C-3 and C-28, and some are substituted with acetyl, caffeoyl, isoferuloyl, p-methoxy cinnamyl and 3,4-dimethoxy cinnamyl groups in the oligosaccharide chains. The flavonoids from Clematis species are mainly flavones, flavonols, flavanones, isoflavones, xanthones and their glucosides (sugar moieties are connected to the aglycone through either the oxygen or the carbon atoms), the aglycones of which are mainly apigenin, kaempferol, luteolin and quercetin. The lignans from Clematis are mainly eupomatene lignans, cyclolignans, monoepoxylignans, bisepoxylignans and lignanolides. Clematis spp. are rich in resources, however, studies on their chemical constituents have only been carried out on twenty or so spp. As a result, it is necessary to expand our study on other spp. from this genus for better utilization of medicinal resources.

Genome sequencing of herb Tulsi (Ocimum tenuiflorum) unravels key genes behind its strong medicinal properties.

PubMed

Upadhyay, Atul K; Chacko, Anita R; Gandhimathi, A; Ghosh, Pritha; Harini, K; Joseph, Agnel P; Joshi, Adwait G; Karpe, Snehal D; Kaushik, Swati; Kuravadi, Nagesh; Lingu, Chandana S; Mahita, J; Malarini, Ramya; Malhotra, Sony; Malini, Manoharan; Mathew, Oommen K; Mutt, Eshita; Naika, Mahantesha; Nitish, Sathyanarayanan; Pasha, Shaik Naseer; Raghavender, Upadhyayula S; Rajamani, Anantharamanan; Shilpa, S; Shingate, Prashant N; Singh, Heikham Russiachand; Sukhwal, Anshul; Sunitha, Margaret S; Sumathi, Manojkumar; Ramaswamy, S; Gowda, Malali; Sowdhamini, Ramanathan

2015-08-28

Krishna Tulsi, a member of Lamiaceae family, is a herb well known for its spiritual, religious and medicinal importance in India. The common name of this plant is 'Tulsi' (or 'Tulasi' or 'Thulasi') and is considered sacred by Hindus. We present the draft genome of Ocimum tenuiflurum L (subtype Krishna Tulsi) in this report. The paired-end and mate-pair sequence libraries were generated for the whole genome sequenced with the Illumina Hiseq 1000, resulting in an assembled genome of 374 Mb, with a genome coverage of 61 % (612 Mb estimated genome size). We have also studied transcriptomes (RNA-Seq) of two subtypes of O. tenuiflorum, Krishna and Rama Tulsi and report the relative expression of genes in both the varieties. The pathways leading to the production of medicinally-important specialized metabolites have been studied in detail, in relation to similar pathways in Arabidopsis thaliana and other plants. Expression levels of anthocyanin biosynthesis-related genes in leaf samples of Krishna Tulsi were observed to be relatively high, explaining the purple colouration of Krishna Tulsi leaves. The expression of six important genes identified from genome data were validated by performing q-RT-PCR in different tissues of five different species, which shows the high extent of urosolic acid-producing genes in young leaves of the Rama subtype. In addition, the presence of eugenol and ursolic acid, implied as potential drugs in the cure of many diseases including cancer was confirmed using mass spectrometry. The availability of the whole genome of O.tenuiflorum and our sequence analysis suggests that small amino acid changes at the functional sites of genes involved in metabolite synthesis pathways confer special medicinal properties to this herb.

New strategies in sport nutrition to increase exercise performance.

PubMed

Close, G L; Hamilton, D L; Philp, A; Burke, L M; Morton, J P

2016-09-01

Despite over 50 years of research, the field of sports nutrition continues to grow at a rapid rate. Whilst the traditional research focus was one that centred on strategies to maximise competition performance, emerging data in the last decade has demonstrated how both macronutrient and micronutrient availability can play a prominent role in regulating those cell signalling pathways that modulate skeletal muscle adaptations to endurance and resistance training. Nonetheless, in the context of exercise performance, it is clear that carbohydrate (but not fat) still remains king and that carefully chosen ergogenic aids (e.g. caffeine, creatine, sodium bicarbonate, beta-alanine, nitrates) can all promote performance in the correct exercise setting. In relation to exercise training, however, it is now thought that strategic periods of reduced carbohydrate and elevated dietary protein intake may enhance training adaptations whereas high carbohydrate availability and antioxidant supplementation may actually attenuate training adaptation. Emerging evidence also suggests that vitamin D may play a regulatory role in muscle regeneration and subsequent hypertrophy following damaging forms of exercise. Finally, novel compounds (albeit largely examined in rodent models) such as epicatechins, nicotinamide riboside, resveratrol, β-hydroxy β-methylbutyrate, phosphatidic acid and ursolic acid may also promote or attenuate skeletal muscle adaptations to endurance and strength training. When taken together, it is clear that sports nutrition is very much at the heart of the Olympic motto, Citius, Altius, Fortius (faster, higher, stronger). Copyright © 2016 Elsevier Inc. All rights reserved.

Spectral characterization and antibacterial activity of an isolated compound from Memecylon edule leaves.

PubMed

Srinivasan, R; Natarajan, D; Shivakumar, M S

2017-03-01

Memecylon edule Roxb. (Melastamataceae family) is a small evergreen tree reported as having ethnobotanical and pharmacological properties. The present study was aimed to investigate the spectral characterization and antibacterial activity of isolated pure compound (3β-hydroxyurs-12-en-28-oic acid (ursolic acid)) from Memecylon edule leaves by performing bioassay guided isolation method. The structure derivation of isolated compound was done by different spectral studies like UV, FT-IR, LC-MS, CHNS analysis, 1D ( 1 H, 13 C and DEPT-135) and 2D-NMR (HSQC and HMBC), respectively. About 99.29% purity of the compound was found in LC analysis. 1 H NMR spectrum results of compound shown 48 protons appear at different shielded region and most of the protons were present in aliphatic region. Whereas, 13 C NMR spectral data resulted seven methyl carbons (CH3), nine methylene carbons (CH2), seven methine carbons (CH) and six non-hydrogenated carbons (C) which are characteristic of pentacyclic triterpene. The isolated pure compound was tested for its antibacterial properties against targeted human pathogens by performing agar well diffusion, MIC and MBC assays and the result exhibits better growth inhibitory effects against S. epidermidis and S. pneumoniae, with the MIC values of 1.56 and 3.15μg/ml. The outcome of this study suggests that the bioactive compound is used for development of plant based drugs in pharmaceutical industry for combating microbial mediated diseases. Copyright © 2017 Elsevier B.V. All rights reserved.

“Nutraceuticals” in relation to human skeletal muscle and exercise

PubMed Central

Deane, Colleen S.; Wilkinson, Daniel J.; Phillips, Bethan E.; Smith, Kenneth; Etheridge, Timothy

2017-01-01

Skeletal muscles have a fundamental role in locomotion and whole body metabolism, with muscle mass and quality being linked to improved health and even lifespan. Optimizing nutrition in combination with exercise is considered an established, effective ergogenic practice for athletic performance. Importantly, exercise and nutritional approaches also remain arguably the most effective countermeasure for muscle dysfunction associated with aging and numerous clinical conditions, e.g., cancer cachexia, COPD, and organ failure, via engendering favorable adaptations such as increased muscle mass and oxidative capacity. Therefore, it is important to consider the effects of established and novel effectors of muscle mass, function, and metabolism in relation to nutrition and exercise. To address this gap, in this review, we detail existing evidence surrounding the efficacy of a nonexhaustive list of macronutrient, micronutrient, and “nutraceutical” compounds alone and in combination with exercise in relation to skeletal muscle mass, metabolism (protein and fuel), and exercise performance (i.e., strength and endurance capacity). It has long been established that macronutrients have specific roles and impact upon protein metabolism and exercise performance, (i.e., protein positively influences muscle mass and protein metabolism), whereas carbohydrate and fat intakes can influence fuel metabolism and exercise performance. Regarding novel nutraceuticals, we show that the following ones in particular may have effects in relation to 1) muscle mass/protein metabolism: leucine, hydroxyl β-methylbutyrate, creatine, vitamin-D, ursolic acid, and phosphatidic acid; and 2) exercise performance: (i.e., strength or endurance capacity): hydroxyl β-methylbutyrate, carnitine, creatine, nitrates, and β-alanine. PMID:28143855

The Bile Acid Receptor GPBAR-1 (TGR5) Modulates Integrity of Intestinal Barrier and Immune Response to Experimental Colitis

PubMed Central

Cipriani, Sabrina; Mencarelli, Andrea; Chini, Maria Giovanna; Distrutti, Eleonora; Renga, Barbara; Bifulco, Giuseppe; Baldelli, Franco; Donini, Annibale; Fiorucci, Stefano

2011-01-01

Background GP-BAR1, a member G protein coupled receptor superfamily, is a cell surface bile acid-activated receptor highly expressed in the ileum and colon. In monocytes, ligation of GP-BAR1 by secondary bile acids results in a cAMP-dependent attenuation of cytokine generation. Aims To investigate the role GP-BAR1 in regulating intestinal homeostasis and inflammation-driven immune dysfunction in rodent models of colitis. Methods Colitis was induced in wild type and GP-BAR1−/− mice by DSS and TNBS administration. Potential GP-BAR1 agonists were identified by in silico screening and computational docking studies. Results GP-BAR1−/− mice develop an abnormal morphology of colonic mucous cells and an altered molecular architecture of epithelial tight junctions with increased expression and abnormal subcellular distribution of zonulin 1 resulting in increased intestinal permeability and susceptibility to develop severe colitis in response to DSS at early stage of life. By in silico screening and docking studies we identified ciprofloxacin as a GP-BAR1 ligand. In monocytes, ciprofloxacin increases cAMP concentrations and attenuates TNFα release induced by TLR4 ligation in a GP-BAR1 dependent manner. Treating mice rendered colitic by TNBS with ciprofloxacin and oleanolic acid, a well characterized GP-BAR1 ligand, abrogates signs and symptoms of colitis. Colonic expression of GP-BAR1 mRNA increases in rodent models of colitis and tissues from Crohn's disease patients. Flow cytometry analysis demonstrates that ≈90% of CD14+ cells isolated from the lamina propria of TNBS-treated mice stained positively for GP-BAR1. Conclusions GP-BAR1 regulates intestinal barrier structure. Its expression increases in rodent models of colitis and Crohn's disease. Ciprofloxacin is a GP-BAR1 ligand. PMID:22046243

Plants of Brazilian restingas with tripanocide activity against Trypanosoma cruzi strains.

PubMed

Faria, Robson Xavier; Souza, André Luis Almeida; Lima, Barbara; Tietbohl, Luis Armando Candido; Fernandes, Caio Pinho; Amaral, Raquel Rodrigues; Ruppelt, Bettina Monika; Santos, Marcelo Guerra; Rocha, Leandro

2017-12-01

Chagas disease is caused by the Trypanosoma cruzi affecting millions of people, and widespread throughout Latin America. This disease exhibits a problematic chemotherapy. Benznidazole, which is the drug currently used as standard treatment, lamentably evokes several adverse reactions. Among other options, natural products have been tested to discover a novel therapeutic drug for this disease. A lot of plants from the Brazilian flora did not contain studies about their biological effects. Restinga de Jurubatiba from Brazil is a sandbank ecosystem poorly studied in relation to plant biological activity. Thus, three plant species from Restinga de Jurubatiba were tested against in vitro antiprotozoal activity. Among six extracts obtained from leaves and stem parts and 2 essential oils derived from leave parts, only 3 extracts inhibited epimastigote proliferation. Substances present in the extracts with activity were isolated (quercetin, myricetin, and ursolic acid), and evaluated in relation to antiprotozoal activity against epimastigote Y and Dm28 Trypanosoma cruzi strains. All isolated substances were effective to reduce protozoal proliferation. Essentially, quercetin and myricetin did not cause mammalian cell toxicity. In summary, myricetin and quercetin molecule can be used as a scaffold to develop new effective drugs against Chagas's disease.

Lipid peroxidation, cyclooxygenase enzyme and tumor cell proliferation inhibitory compounds in Cornus kousa fruits.

PubMed

Vareed, Shaiju K; Schutzki, Robert E; Nair, Muraleedharan G

2007-10-01

The genus Cornus is well known for its medicinal properties. Bioassay-guided isolation and characterization of C. kousa fruits afforded kaempferol 3-O-rhamnoside (1), myricetin 3-O-rhamnoside (2), kaempferol 3-O-glucoside (3), cornin (4) and stenophyllin (5) in addition to ursolic acid and beta-sitosterol. These compounds are isolated for the first time from C. kousa. Compounds 1-5 inhibited Fe(2+) catalyzed lipid peroxidation by 63%, 57%, 61%, 53%, and 51%, at 23, 22, 23, 129, and 108 microM, respectively. Similarly, they inhibited COX-1 and -2 enzymes activities by 24% and 47%, 40% and 37%, 20% and 37%, 52% and 63%, and 48% and 55% respectively, at 231, 215, 226, 258, and 217 microM, respectively. At 129 microM, compound 4 displayed growth inhibition of HCT-116 (colon), MCF-7 (breast), NCI-H460 (lung), SF-268 (central nervous system CNS), and AGS (stomach) human tumor cell lines by 31%, 29%, 40%, 9%, and 28%, respectively. Similarly, compound 5 inhibited the growth of colon, breast, lung, CNS, and stomach tumor cell lines by 0%, 27%, 35%, 16%, and 27%, respectively, at 108 microM.

Use of mRNA expression signatures to discover small molecule inhibitors of skeletal muscle atrophy

PubMed Central

Adams, Christopher M.; Ebert, Scott M.; Dyle, Michael C.

2017-01-01

Purpose of review Here, we discuss a recently developed experimental strategy for discovering small molecules with potential to prevent and treat skeletal muscle atrophy. Recent findings Muscle atrophy involves and requires widespread changes in skeletal muscle gene expression, which generate complex but measurable patterns of positive and negative changes in skeletal muscle mRNA levels (a.k.a. mRNA expression signatures of muscle atrophy). Many bioactive small molecules generate their own characteristic mRNA expression signatures, and by identifying small molecules whose signatures approximate mirror images of muscle atrophy signatures, one may identify small molecules with potential to prevent and/or reverse muscle atrophy. Unlike a conventional drug discovery approach, this strategy does not rely on a predefined molecular target but rather exploits the complexity of muscle atrophy to identify small molecules that counter the entire spectrum of pathological changes in atrophic muscle. We discuss how this strategy has been used to identify two natural compounds, ursolic acid and tomatidine, that reduce muscle atrophy and improve skeletal muscle function. Summary Discovery strategies based on mRNA expression signatures can elucidate new approaches for preserving and restoring muscle mass and function. PMID:25807353

Use of mRNA expression signatures to discover small molecule inhibitors of skeletal muscle atrophy.

PubMed

Adams, Christopher M; Ebert, Scott M; Dyle, Michael C

2015-05-01

Here, we discuss a recently developed experimental strategy for discovering small molecules with potential to prevent and treat skeletal muscle atrophy. Muscle atrophy involves and requires widespread changes in skeletal muscle gene expression, which generate complex but measurable patterns of positive and negative changes in skeletal muscle mRNA levels (a.k.a. mRNA expression signatures of muscle atrophy). Many bioactive small molecules generate their own characteristic mRNA expression signatures, and by identifying small molecules whose signatures approximate mirror images of muscle atrophy signatures, one may identify small molecules with potential to prevent and/or reverse muscle atrophy. Unlike a conventional drug discovery approach, this strategy does not rely on a predefined molecular target but rather exploits the complexity of muscle atrophy to identify small molecules that counter the entire spectrum of pathological changes in atrophic muscle. We discuss how this strategy has been used to identify two natural compounds, ursolic acid and tomatidine, that reduce muscle atrophy and improve skeletal muscle function. Discovery strategies based on mRNA expression signatures can elucidate new approaches for preserving and restoring muscle mass and function.

Phytochemical investigations and antiproliferative secondary metabolites from Thymus alternans growing in Slovakia.

PubMed

Dall'Acqua, Stefano; Peron, Gregorio; Ferrari, Sara; Gandin, Valentina; Bramucci, Massimo; Quassinti, Luana; Mártonfi, Pavol; Maggi, Filippo

2017-12-01

Thymus alternans Klokov (Lamiaceae) is a neglected species of the genus Thymus (Sect. Serpyllum) endemic to Carpathian area, where it is used as a flavouring agent and for medicinal purposes. The aim of the work was to identify antiproliferative constituents from the flowering aerial parts of this plant. Thymus alternans extracts were analyzed by HPLC-MS n and subjected to extensive chromatographic separations. The isolated compounds (phenolics and triterpenes) were structurally elucidated by MS and 1D and 2D NMR experiments. Essential oil (EO) composition was determined by GC-FID and GC-MS. Six purified triterpenes and EO were assayed for in vitro antiproliferative activity against a panel of human cancer cells, namely, breast (MDA-MB 231), colon (HCT-15 and HCT116), lung (U1810), pancreatic (BxPC3), melanoma (A375) and cervical carcinoma (A431) cells. The structures of the isolated compounds were achieved on the basis of H-NMR and MS experiments. Luteolin-4'-O-β-d-glucopyranoside (P1), chrysoeriol-7-O-β-d-glucopyranoside (P2), chrysoeriol-5-O-β-d-glucopyranoside (P3), apigenin-7-O-β-d-glucopyranoside (P4), rosmarinic acid (P5), rosmarinic acid-3'-O-β-d-glucopyranoside (P6), caffeic acid-3-O-β-d-glucopyranoside (P7), 3α-hydroxy-urs-12,15-diene (T1), α-amyrin (T2), β-amyrin (T3), isoursenol (T4), epitaraxerol (T5), and oleanolic acid (T6). GC-MS analysis revealed that the EO of T. alternans was devoid of phenols and belonged to the nerolidol-chemotype, that is typical of the Sect. Serpyllum. The six purified triterpenes (T1-T6) were active with IC 50 ranging from 0.5 to 5 μM being comparable or better than those of reference compounds betulinic acid and cisplatin. The EO exhibited significant effects on A375, MDA-MB 231 and HCT116 cell lines with IC 50 in the range of 5-8 μg/mL. The reported results suggest that T. alternans can be considered as a good source of phytoconstituents with possible importance in the pharmaceutical field.

EGFR inhibition by pentacyclic triterpenes exhibit cell cycle and growth arrest in breast cancer cells.

PubMed

Sathya, Shanmugaraj; Sudhagar, Selvaraj; Sarathkumar, Baskaran; Lakshmi, Baddireddi Subhadra

2014-01-24

Pentacyclic triterpenes are a group of molecules with promising anticancer potential, although their precise molecular target remains elusive. The current work aims to investigate the antiproliferative and associated mechanisms of triterpenes in breast cancer cells in vitro. Effect of triterpenes on cell cycle distribution, ROS and key regulatory proteins were analyzed in three breast cancer cells in vitro. Growth inhibition, new DNA synthesis, colony formation assays and Western blot analysis were performed to assess the EGFR inhibitory effect of triterpenes. Molecular docking was performed to study the interaction between EGFR and triterpenes. We have demonstrated the ability of dimethyl melaleucate (DMM), a pentacyclic triterpene to exhibit cell cycle arrest at G0/G1 phase by down-regulation of cyclin D1 through PI3K/AKT inhibition. Further, to identify the upstream target of DMM, potential EGFR inhibitory activity of DMM and three structurally related pentacyclic triterpenes, ursolic acid, 18α-glycyrrhetinic acid and carbenoxolone was investigated. Interestingly, pentacyclic triterpenes limit EGF mediated breast cancer proliferation through sustained inhibition of EGFR and its downstream effectors STAT3 and cyclin D1 in breast cancer lines. We also show pentacyclic triterpenes to bind at the ATP binding pocket of tyrosine kinase domain of EGFR leading to the hypothesis that pentacyclic triterpenes could be a novel class of EGFR inhibitors. In conclusion, pentacyclic triterpenes inhibit EGFR activation through binding with tyrosine kinase domain thereby suppressing breast cancer proliferation. Pentacyclic triterpenes may serve as a potential platform for development of novel drugs against breast cancer. Copyright © 2013 Elsevier Inc. All rights reserved.

Competitive protein tyrosine phosphatase 1B (PTP1B) inhibitors, prenylated caged xanthones from Garcinia hanburyi and their inhibitory mechanism.

PubMed

Tan, Xue Fei; Uddin, Zia; Park, Chanin; Song, Yeong Hun; Son, Minky; Lee, Keun Woo; Park, Ki Hun

2017-04-15

Protein tyrosine phosphatase 1B (PTP1B) plays important role in diabetes, obesity and cancer. The methanol extract of the gum resin of Garcinia hanburyi (G. hanburyi) showed potent PTP1B inhibition at 10µg/ml. The active compounds were identified as prenylated caged xanthones (1-9) which inhibited PTP1B in dose-dependent manner. Carboxybutenyl group within caged motif (A ring) was found to play a critical role in enzyme inhibition such as 1-6 (IC 50 s=0.47-4.69µM), whereas compounds having hydroxymethylbutenyl 7 (IC 50 =70.25µM) and methylbutenyl 8 (IC 50 >200µM) showed less activity. The most potent inhibitor, gambogic acid 1 (IC 50 =0.47µM) showed 30-fold more potency than ursolic acid (IC 50 =15.5µM), a positive control. In kinetic study, all isolated xanthones behaved as competitive inhibitors which were fully demonstrated with K m , V max and K ik /K iv ratio. It was also proved that inhibitor 1 operated under the enzyme isomerization model having k 5 =0.0751µM - 1 S - 1 , k 6 =0.0249µM - 1 S - 1 and K i app =0.499µM. To develop a pharmacophore model, we explored the binding sites of compound 1 and 7 in PTP1B. These modeling results were in agreement with our findings, which revealed that the inhibitory activities are tightly related to caged motif and prenyl group in A ring. Copyright © 2017 Elsevier Ltd. All rights reserved.

Selection of chemical markers for the quality control of medicinal plants of the genus Cecropia.

PubMed

Rivera-Mondragón, Andrés; Ortíz, Orlando O; Bijttebier, Sebastiaan; Vlietinck, Arnold; Apers, Sandra; Pieters, Luc; Caballero-George, Catherina

2017-12-01

Several Cecropia (Cecropiaceae) species are traditionally used in Latin America for the treatment of a variety of diseases including diabetes, arterial hypertension, asthma, bronchitis, anxiety, and inflammation. At present, a number of commercial products based on these plants have been introduced into the market with very little information on methods for guaranteeing their quality and safety. This work proposes potential chemical markers for the quality control of the raw materials of Cecropia obtusifolia Bertol., Cecropia peltata L., Cecropia glaziovii Snethl., Cecropia pachystachya Trécul, and Cecropia hololeuca Miq. The Herbal Chemical Marker Ranking System (Herb MaRS) developed by the National Institute of Complementary Medicine (NICM) at the University of Western Sydney was used for selecting chemical markers for the quality control of selected medicinal species of Cecropia. This review covers the period from 1982 to 2016. Chlorogenic acid, flavonoidal glycosides (orientin, isoorientin, vitexin, isovitexin, and rutin), catechin, epicatechin, procyanidins (B2, B5, and C1), steroids (β-sitosterol), and triterpenoids (α-amyrin, pomolic, tormentic and ursolic acids) were selected as chemical markers for the quality control of the leaves. It is necessary to establish comprehensive standards for guaranteeing quality, safety and efficacy of herbal drugs. The selection of adequate chemical markers for quality control purposes requires a good knowledge about the chemical composition of medicinal plants and their associated biological properties. To the best of our knowledge this review article is the first to address the identification and quantitative determination of the chemical markers for the genus Cecropia.

"Nutraceuticals" in relation to human skeletal muscle and exercise.

PubMed

Deane, Colleen S; Wilkinson, Daniel J; Phillips, Bethan E; Smith, Kenneth; Etheridge, Timothy; Atherton, Philip J

2017-04-01

Skeletal muscles have a fundamental role in locomotion and whole body metabolism, with muscle mass and quality being linked to improved health and even lifespan. Optimizing nutrition in combination with exercise is considered an established, effective ergogenic practice for athletic performance. Importantly, exercise and nutritional approaches also remain arguably the most effective countermeasure for muscle dysfunction associated with aging and numerous clinical conditions, e.g., cancer cachexia, COPD, and organ failure, via engendering favorable adaptations such as increased muscle mass and oxidative capacity. Therefore, it is important to consider the effects of established and novel effectors of muscle mass, function, and metabolism in relation to nutrition and exercise. To address this gap, in this review, we detail existing evidence surrounding the efficacy of a nonexhaustive list of macronutrient, micronutrient, and "nutraceutical" compounds alone and in combination with exercise in relation to skeletal muscle mass, metabolism (protein and fuel), and exercise performance (i.e., strength and endurance capacity). It has long been established that macronutrients have specific roles and impact upon protein metabolism and exercise performance, (i.e., protein positively influences muscle mass and protein metabolism), whereas carbohydrate and fat intakes can influence fuel metabolism and exercise performance. Regarding novel nutraceuticals, we show that the following ones in particular may have effects in relation to 1 ) muscle mass/protein metabolism: leucine, hydroxyl β-methylbutyrate, creatine, vitamin-D, ursolic acid, and phosphatidic acid; and 2 ) exercise performance: (i.e., strength or endurance capacity): hydroxyl β-methylbutyrate, carnitine, creatine, nitrates, and β-alanine. Copyright © 2017 the American Physiological Society.

Bardoxolone methyl prevents obesity and hypothalamic dysfunction.

PubMed

Camer, Danielle; Yu, Yinghua; Szabo, Alexander; Wang, Hongqin; Dinh, Chi H L; Huang, Xu-Feng

2016-08-25

High-fat (HF) diet-induced obesity is associated with hypothalamic leptin resistance and low grade chronic inflammation, which largely impairs the neuroregulation of negative energy balance. Neuroregulation of negative energy balance is largely controlled by the mediobasal and paraventricular nuclei regions of the hypothalamus via leptin signal transduction. Recently, a derivative of oleanolic acid, bardoxolone methyl (BM), has been shown to have anti-inflammatory effects. We tested the hypothesis that BM would prevent HF diet-induced obesity, hypothalamic leptin resistance, and inflammation in mice fed a HF diet. Oral administration of BM via drinking water (10 mg/kg daily) for 21 weeks significantly prevented an increase in body weight, energy intake, hyperleptinemia, and peripheral fat accumulation in mice fed a HF diet. Furthermore, BM treatment prevented HF diet-induced decreases in the anorexigenic effects of peripheral leptin administration. In the mediobasal and paraventricular nuclei regions of the hypothalamus, BM administration prevented HF diet-induced impairments of the downstream protein kinase b (Akt) pathway of hypothalamic leptin signalling. BM treatment also prevented an increase in inflammatory cytokines, tumour necrosis factor alpha (TNFα) and interleukin 6 (IL-6) in these two hypothalamic regions. These results identify a potential novel neuropharmacological application for BM in preventing HF diet-induced obesity, hypothalamic leptin resistance, and inflammation. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Physicochemical characterization and an injection formulation study of water insoluble ZCVI₄-2, a novel NO-donor anticancer compound.

PubMed

Gao, Yuan; Li, Li; Zhang, Jianjun; Su, Feng; Gong, Zhenhua; Lai, Yisheng; Zhang, Yihua

2012-07-01

ZCVI(4)-2 was a novel nitric oxide-releasing glycosyl derivative of oleanolic acid that displayed strong cytotoxicity selectively against human hepatocellular carcinoma in vitro and in vivo. In this study, ZCVI(4)-2 was characterized by FT-IR spectroscopy, differential scanning calorimetry, powder X-ray diffractometry, Raman spectroscopy, hygroscopicity and stability. A high performance liquid chromatography method was also established for the quantitative determination of solubility and additional stability profile of ZCVI(4)-2. ZCVI(4)-2 was found to be an amorphous and stable solid with low solubility of less than 10 μg/mL. Based on the solubilization tests that included methods of cosolvency and micellization, the solution mixture of 5% Solutol HS-15, 5% 1, 2-propylene glycol and 5% anhydrous ethanol was determined to be the system for the preparation of the ZCVI(4)-2 early injection solution. The effect of pH, temperature, light and injectable isotonic glucose or NaCl solution on ZCVI(4)-2 injection was also investigated. Good stability was observed at all testing conditions. Under the conditions studied, the NO-releasing rate and amount of ZCVI(4)-2 from the early injection solution in rat plasma demonstrated a promising therapeutic efficacy while maintaining a good safety profile.

Voulkensin C-E, new 11-oxocassane-type diterpenoids and a steroid glycoside from Caesalpinia volkensii stem bark and their antiplasmodial activities.

PubMed

Ochieng, Charles O; Manguro, Lawrence A O; Owuor, Philip O; Akala, Hosea

2013-05-15

A bioassay guided isolation of potential antimalarial molecules from the stem bark of Caesalpinia volkensii Harms (Fabaceae) achieved three new 11-oxocassane-type diterpenoids named voulkensin C (1), D (2) and E (3) together with one steroid glycoside named 3-O-[β-glucopyranosyl(1→2)-O-β-xylopyranosyl]-stigmasterol (4) and seven other known compounds including stigmasterol (5), β-sitosterol (6), oleanolic acid (7), 3-β-acetoxyolean-12-en-28-methyl ester (8), voucap-5-ol (9), caesadekarin C (10), deoxycaesaldekarin C (11). The structures of the new compounds were determined on the basis of extensive spectroscopic data (IR, MS, (1)H and (13)C NMR and 2D NMR) analyses. The polar extracts revealed moderate to good antiplasmodial activities against chloquine-sensitive (D6) and -resistant strains (W2) of Plasmodium falciparum. Whereas the pure isolates exhibited limited to moderate antiplasmodial activities with compound 4 showing the highest antiplasmodial activities (IC50 values of 4.44±0.88 and 2.74±1.10μM against D6 and W2 strains, respectively). These results suggest a possible contribution of phytochemicals from C. volkensii stem bark towards inhibition of plasmodial parasites' growth hence potential antimalarial. Copyright © 2013 Elsevier Ltd. All rights reserved.

Oleanane triterpenes with protein tyrosine phosphatase 1B inhibitory activity from aerial parts of Lantana camara collected in Indonesia and Japan.

PubMed

Abdjul, Delfly B; Yamazaki, Hiroyuki; Maarisit, Wilmar; Rotinsulu, Henki; Wewengkang, Defny S; Sumilat, Deiske A; Kapojos, Magie M; Losung, Fitje; Ukai, Kazuyo; Namikoshi, Michio

2017-12-01

During the search for new protein tyrosine phosphatase (PTP) 1B inhibitors, EtOH extracts from the aerial parts of Lantana camara L. (lantana) collected at Manado (Indonesia) and two subtropical islands in Japan (Ishigaki and Iriomote Islands, Okinawa) exhibited potent inhibitory activities against PTP1B in an enzyme assay. Four previously undescribed oleanane triterpenes were isolated together with known triterpenes and flavones from the Indonesian lantana. The EtOH extracts of lantana collected in Ishigaki and Iriomote Islands exhibited different phytochemical profiles from each other and the Indonesian lantana. Triterpenes with a 24-OH group were isolated from the Indonesian lantana only. Five known triterpene compounds were detected in the Ishigaki lantana, and two oleanane triterpenes with an ether linkage between 3β and 25 were the main components together with five known triterpenes as minor components in the Iriomote lantana. The structures of previously undescribed compounds were assigned on the basis of their spectroscopic data. Among the compounds obtained in this study, oleanolic acid exhibited the most potent activity against PTP1B, and is used as a positive control in studies on PTP1B. Copyright © 2017 Elsevier Ltd. All rights reserved.

Efficacy of bioactive compounds from extra virgin olive oil to modulate atherosclerosis development.

PubMed

Lou-Bonafonte, José M; Arnal, Carmen; Navarro, María A; Osada, Jesús

2012-07-01

As olive oil is the main source of calories in the Mediterranean diet, a great deal of research has been devoted to characterizing its role in atherosclerosis. Virgin olive oil is an oily matrix that contains hydrocarbons, mainly squalene; triterpenes such as uvaol, erythrodiol, oleanolic, and maslinic acid; phytosterols; and a wide range of phenolic compounds comprising simple phenols, flavonoids, secoiridoids, and lignans. In this review, we analyze the studies dealing with atherosclerosis and olive oil in several species. A protective role of virgin olive oil against atherosclerosis has been shown in ApoE-deficient mice and hamsters. In the former animal, sex, dose, and dietary cholesterol are modulators of the outcome. Contradictory findings have been reported for rabbits, a circumstance that could be due to the profusion of experimental designs, differing in terms of doses and animal strains, as well as sources of olive oils. This role has yet to be fully validated in humans. Minor components of olive oil have been shown to be involved in atherosclerosis protection. Nevertheless, evidence of the potential of isolated compounds or the right combination of them to achieve the antiatherosclerotic effect of virgin olive oil is inconclusive and will undoubtedly require further experimental support. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

[Studies on ethyl acetate soluble constituents of Huanglian Jiedutang].

PubMed

Ma, Zhao-Tang; Yang, Xiu-Wei

2008-09-01

To study the ethyl acetate soluble constituents from the water extractive of Huanglian Jiedutang decoction, which are composed of Rhizoma Coptidis, Radix Scutellariae, Cortex Phellodendri and Fructus Gardeniae, and provide substances foundation for its pharmacokinetic and pharmacodynamic investigation. The chemical constituents were isolated by various column chromatographic methods and structurally elucidated by NMR and MS techniques. Thirty-five compounds were isolated, among which twenty compounds have been identified as beta-sitosterol (1), oroxylin A (2), wogonin (3), ursolic acid (4), skullcapflavone I (5), tenaxin I (6), skullcapflavone II (7), limonin (8), 5, 2'-dihydroxy-6, 7, 8, 3'-tetramethoxyflavone (9), chrysin (12), baicalein (17), tenaxin II (19), 5, 7, 2'-trihydroxy-6, 8-dimethoxyflavone (21), shihulimonin A (22), 6, 2'-dihydroxy-5, 7, 8, 6'-tetramethoxyflavone (26), viscidulin II (28), 5, 7, 4'-trihydroxy-8-methoxyflavone (29), 5, 7, 2', 6'-tetrahydroxyflavone (30), wogonin-7-O-beta-D-glucuronide methyl ester (31) and daucosterol (34). On the basis of reported results of the chemical constituents of Rhizoma Coptidis, Radix Scutellariae, Cortex Phellodendri and Fructus Gardeniae, it was estimated that all flavonoid compounds rised from the Radix Scutellariae, and compounds 8 and 22 rised from Cortex Phellodendri. Compound 22 was identified in the Cortex Phellodendri for the first time.

Caatinga plants: Natural and semi-synthetic compounds potentially active against Trichomonas vaginalis.

PubMed

Vieira, Patrícia de Brum; Silva, Nícolas Luiz Feijó; da Silva, Gloria Narjara Santos; Silva, Denise Brentan; Lopes, Norberto Peporine; Gnoatto, Simone Cristina Baggio; da Silva, Márcia Vanusa; Macedo, Alexandre José; Bastida, Jaume; Tasca, Tiana

2016-05-01

Trichomonas vaginalis causes trichomoniasis; the most common but overlooked non-viral sexually transmitted disease worldwide. The treatment is based at 5'-nitroimidazoles, however, failure are related to resistance of T. vaginalis to chemotherapy. Caatinga is a uniquely Brazilian region representing a biome with type desert vegetation and plants present diverse biological activity, however, with few studies. The aim of this study was to investigate the activity against T. vaginalis of different plants from Caatinga and identify the compounds responsible by the activity. A bioguided fractionation of Manilkara rufula was performed and four major compounds were identified: caproate of α-amyrin (1b), acetate of β-amyrin (2a), caproate of β-amyrin (2b), and acetate of lupeol (3a). In addition, six derivatives of α-amyrin (1), β-amyrin (2) and lupeol (3) were synthesized and tested against the parasite. Ursolic acid (5) reduced about 98% of parasite viability after 2h of incubation and drastic ultrastructural alterations were observed by scanning electron microscopy. Moreover, 5 presented high cytotoxicity to HMVII and HeLa cell line and low cytotoxicity against Vero line at 50 μM (MIC against the parasite). Metronidazole effect against T. vaginalis resistant isolate was improved when in association with 5. Copyright © 2016 Elsevier Ltd. All rights reserved.

Molluscicidal activity of Manilkara subsericea (Mart.) dubard on Biomphalaria glabrata (Say, 1818).

PubMed

Faria, Robson Xavier; Rocha, Leandro Machado; Souza, Eloísa Portugal Barros Silva Soares; Almeida, Fernanda Borges; Fernandes, Caio Pinho; Santos, José Augusto Albuquerque

2018-02-01

Schistosomiasis is promoted for species from Schistosoma genus affecting over 200 million people worldwide. Molluscicides are an efficient method to control this disease, being able to reduce intermediate host snail Biomphalaria glabrata number. In function of resistance cases using niclosamide, natural products are promisors to discover new drugs. Manilkara subsericea is endemic to Brazilian sandbanks of Rio de Janeiro State and wide ranges of biological activities. However, there is no studies evaluating its effects as molluscicidal agent. We tested crude extract from leaves of M. subsericea molluscicidal action, as well it ethyl-acetate fraction and isolated substances against B. glabrata. M. subsericea leaves crude extract and ethyl acetate fraction induced 80±4.13% and 86.66±4.59% mortality of adult snails at concentrations of 250ppm after 96h, and their LD 50 values were 118.7±1.62 and 23.41±1.15ppm respectively. Isolated substances from M. subsericea were also considered active. Quercetin, myricetin and ursolic acid, at concentration of 100ppm (96h), were able to induce mortality levels of 100%, 80% and 53.33%, respectively. Our results suggest that M. subsericea can be considered promising as a molluscicide agent. Copyright © 2017. Published by Elsevier B.V.

Matrix metalloproteinase-1 inhibitory activities of Morinda citrifolia seed extract and its constituents in UVA-irradiated human dermal fibroblasts.

PubMed

Masuda, Megumi; Murata, Kazuya; Naruto, Shunsuke; Uwaya, Akemi; Isami, Fumiyuki; Matsuda, Hideaki

2012-01-01

The objective of this study was to examine whether a 50% ethanolic extract (MCS-ext) of the seeds of Morinda citrifolia (noni) and its constituents have matrix metalloproteinase-1 (MMP-1) inhibitory activity in UVA-irradiated normal human dermal fibroblasts (NHDFs). The MCS-ext (10 μg/mL) inhibited MMP-1 secretion from UVA-irradiated NHDFs, without cytotoxic effects, at 48 h after UV exposure. The ethyl acetate-soluble fraction of MCS-ext was the most potent inhibitor of MMP-1 secretion. Among the constituents of the fraction, a lignan, 3,3'-bisdemethylpinoresinol (1), inhibited the MMP-1 secretion at a concentration of 0.3 μM without cytotoxic effects. Furthermore, 1 (0.3 μM) reduced the level of intracellular MMP-1 expression. Other constituents, namely americanin A (2), quercetin (3) and ursolic acid (4), were inactive. To elucidate inhibition mechanisms of MMP-1 expression and secretion, the effect of 1 on mitogen-activated protein kinases (MAPKs) phosphorylation was examined. Western blot analysis revealed that 1 (0.3 μM) reduced the phosphorylations of p38 and c-Jun-N-terminal kinase (JNK). These results suggested that 1 suppresses intracellular MMP-1 expression, and consequent secretion from UVA-irradiated NHDFs, by down-regulation of MAPKs phosphorylation.

Antifungal Compound Isolated from Catharanthus roseus L. (Pink) for Biological Control of Root Rot Rubber Diseases.

PubMed

Zahari, R; Halimoon, N; Ahmad, M F; Ling, S K

2018-01-01

Rigidoporus microporus, Ganoderma philippii, and Phellinus noxius are root rot rubber diseases and these fungi should be kept under control with environmentally safe compounds from the plant sources. Thus, an antifungal compound isolated from Catharanthus roseus was screened for its effectiveness in controlling the growth of these fungi. The antifungal compound isolated from C. roseus extract was determined through thin layer chromatography (TLC) and nuclear magnetic resonance (NMR) analysis. Each C. roseus of the DCM extracts was marked as CRD1, CRD2, CRD3, CRD4, CRD5, CRD6, and CRD7, respectively. TLC results showed that all of the C. roseus extracts peaked with red colour at Rf = 0.61 at 366 nm wavelength, except for CRD7. The CRD4 extract was found to be the most effective against R. microporus and G. philippii with inhibition zones of 3.5 and 1.9 mm, respectively, compared to that of other extracts. These extracts, however, were not effective against P. noxius. The CRD4 extract contained ursolic acid that was detected by NMR analysis and the compound could be developed as a biocontrol agent for controlling R. microporus and G. philippii. Moreover, little or no research has been done to study the effectiveness of C. roseus in controlling these fungi.

Activation of G protein-coupled bile acid receptor, TGR5, induces smooth muscle relaxation via both Epac- and PKA-mediated inhibition of RhoA/Rho kinase pathway.

PubMed

Rajagopal, Senthilkumar; Kumar, Divya P; Mahavadi, Sunila; Bhattacharya, Sayak; Zhou, Ruizhe; Corvera, Carlos U; Bunnett, Nigel W; Grider, John R; Murthy, Karnam S

2013-03-01

The present study characterized the TGR5 expression and the signaling pathways coupled to this receptor that mediates the relaxation of gastric smooth muscle. TGR5 was detected in gastric muscle cells by RT-PCR and Western blotting. Treatment of cells with the TGR5-selective ligand oleanolic acid (OA) activated Gαs, but not Gαq, Gαi1, Gαi2, or Gαi3, and increased cAMP levels. OA did not elicit contraction, but caused relaxation of carbachol-induced contraction of gastric muscle cells from wild-type mice, but not tgr5(-/-) mice. OA, but not a selective exchange protein activated by cAMP (Epac) ligand (8-pCPT-2'-O-Me-cAMP), caused phosphorylation of RhoA and the phosphorylation was blocked by the PKA inhibitor, myristoylated PKI, and by the expression of phosphorylation-deficient mutant RhoA (S188A). Both OA and Epac ligand stimulated Ras-related protein 1 (Rap1) and inhibited carbachol (CCh)-induced Rho kinase activity. Expression of RhoA (S188A) or PKI partly reversed the inhibition of Rho kinase activity by OA but had no effect on inhibition by Epac ligand. However, suppression of Rap1 with siRNA blocked the inhibition of Rho kinase by Epac ligand, and partly reversed the inhibition by OA; the residual inhibition was blocked by PKI. Muscle relaxation in response to OA, but not Epac ligand, was partly reversed by PKI. We conclude that activation of TGR5 causes relaxation of gastric smooth muscle and the relaxation is mediated through inhibition of RhoA/Rho kinase pathway via both cAMP/Epac-dependent stimulation of Rap1 and cAMP/PKA-dependent phosphorylation of RhoA at Ser(188). TGR5 receptor activation on smooth muscle reveals a novel mechanism for the regulation of gut motility by bile acids.

A comprehensive analysis on Symplocos racemosa Roxb.: Traditional uses, botany, phytochemistry and pharmacological activities.

PubMed

Acharya, Niyati; Acharya, Sanjeev; Shah, Unnati; Shah, Ripal; Hingorani, Lal

2016-04-02

Symplocos racemosa Roxb. belongs to a unigeneric family Symplocaceae, known as lodhra in Sanskrit; is a small evergreen tree, found throughout the tropical and sub-tropical countries. Ethnobotanical literature indicates use of S. racemosa in treatment of eye disease, skin diseases, ear diseases, liver and bowel complaints, tumors, uterine disorders, spongy and bleeding gums, asthma, fever, snake-bite, gonorrhea and arthritis. The main aim of this review is to provide detailed phytopharmacological profile on S. racemosa in support with the traditional practices and ethnomedicinal uses. All relevant worldwide accepted databases have been searched for the name "S. racemosa" along with other literature from Indian Classical texts and Pharmacopoeias. The accessible literatures available on S. racemosa, were collected through electronic search on Pub med, Scopus, Science direct and traditional reports. S. racemosa is important Indian traditional drug used in many Ayurvedic and herbal formulations for treatment of liver as well as uterine disorders and leucorrhea. Majority of phytopharmacological reports are on stem bark of the plant which include anti-cancer, hepatoprotective, anti-oxidant, anti-androgenic effect, anti-inflammatory, wound healing activity and anti-diabetic effects. Phytochemical studies indicated presence of many phenolic glycosides like symplocoside, triterpenoids like betulinic acid, acetyloleanolic acid and oleanolic acid and flavonoids like quercetin which might have contributed to the observed protective effects. Many ethnobotanical claims have been confirmed through systematic in-vitro and in-vivo pharmacological studies on different extracts of stem bark and isolated constituents. However, systematic studies on the bio-markers are desirable to establish mode of action and to validate the traditional claim in clinical practice after proper safety assessment. The conservation data of genus Symplocos showed risk of extinction due to restricted distribution in the wild hence systematic techniques should be developed for the maintenance of this plant. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Activation of G protein-coupled bile acid receptor, TGR5, induces smooth muscle relaxation via both Epac- and PKA-mediated inhibition of RhoA/Rho kinase pathway

PubMed Central

Rajagopal, Senthilkumar; Kumar, Divya P.; Mahavadi, Sunila; Bhattacharya, Sayak; Zhou, Ruizhe; Corvera, Carlos U.; Bunnett, Nigel W.; Grider, John R.

2013-01-01

The present study characterized the TGR5 expression and the signaling pathways coupled to this receptor that mediates the relaxation of gastric smooth muscle. TGR5 was detected in gastric muscle cells by RT-PCR and Western blotting. Treatment of cells with the TGR5-selective ligand oleanolic acid (OA) activated Gαs, but not Gαq, Gαi1, Gαi2, or Gαi3, and increased cAMP levels. OA did not elicit contraction, but caused relaxation of carbachol-induced contraction of gastric muscle cells from wild-type mice, but not tgr5−/− mice. OA, but not a selective exchange protein activated by cAMP (Epac) ligand (8-pCPT-2′-O-Me-cAMP), caused phosphorylation of RhoA and the phosphorylation was blocked by the PKA inhibitor, myristoylated PKI, and by the expression of phosphorylation-deficient mutant RhoA (S188A). Both OA and Epac ligand stimulated Ras-related protein 1 (Rap1) and inhibited carbachol (CCh)-induced Rho kinase activity. Expression of RhoA (S188A) or PKI partly reversed the inhibition of Rho kinase activity by OA but had no effect on inhibition by Epac ligand. However, suppression of Rap1 with siRNA blocked the inhibition of Rho kinase by Epac ligand, and partly reversed the inhibition by OA; the residual inhibition was blocked by PKI. Muscle relaxation in response to OA, but not Epac ligand, was partly reversed by PKI. We conclude that activation of TGR5 causes relaxation of gastric smooth muscle and the relaxation is mediated through inhibition of RhoA/Rho kinase pathway via both cAMP/Epac-dependent stimulation of Rap1 and cAMP/PKA-dependent phosphorylation of RhoA at Ser188. TGR5 receptor activation on smooth muscle reveals a novel mechanism for the regulation of gut motility by bile acids. PMID:23275618

Chemical constituents of Swertia longifolia Boiss. with α-amylase inhibitory activity.

PubMed

Saeidnia, Soodabeh; Ara, Leila; Hajimehdipoor, Homa; Read, Roger W; Arshadi, Sattar; Nikan, Marjan

2016-01-01

α-Amylase inhibitors play a critical role in the control of diabetes and many of medicinal plants have been found to act as α-amylase inhibitors. Swertia genus, belonging to the family Gentianaceae, comprises different species most of which have been used in traditional medicine of several cultures as antidiabetic, anti-pyretic, analgesic, liver and gastrointestinal tonic. Swertia longifolia Boiss. is the only species of Swertia growing in Iran. In the present investigation, phytochemical study of S. longifolia was performed and α-amylase inhibitory effects of the plant fractions and purified compounds were determined. Aerial parts of the plant were extracted with hexane, chloroform, methanol and water, respectively. The components of the hexane and chloroform fractions were isolated by different chromatographic methods and their structures were determined by (1)H NMR and (13)C NMR data. α-Amylase inhibitory activity was determined by a colorimetric assay using 3,5-dinitro salysilic acid. During phytochemical examination, α-amyrin, β-amyrin and β-sitosterol were purified from the hexane fraction, while ursolic acid, daucosterol and swertiamarin were isolated from chloroform fraction. The results of the biochemical assay revealed α-amylase inhibitory activity of hexane, chloroform, methanol and water fractions, of which the chloroform and methanol fractions were more potent (IC50 16.8 and 18.1 mg/ml, respectively). Among examined compounds, daucosterol was found to be the most potent α-amylase inhibitor (57.5% in concentration 10 mg/ml). With regard to α-amylase inhibitory effects of the plant extracts, purified constituents, and antidiabetic application of the species of Swertia genus in traditional medicine of different countries, S. longifolia seems more appropriate species for further mechanistic antidiabetic evaluations.

Chemical constituents of Swertia longifolia Boiss. with α-amylase inhibitory activity

PubMed Central

Saeidnia, Soodabeh; Ara, Leila; Hajimehdipoor, Homa; Read, Roger W.; Arshadi, Sattar; Nikan, Marjan

2016-01-01

α-Amylase inhibitors play a critical role in the control of diabetes and many of medicinal plants have been found to act as α-amylase inhibitors. Swertia genus, belonging to the family Gentianaceae, comprises different species most of which have been used in traditional medicine of several cultures as antidiabetic, anti-pyretic, analgesic, liver and gastrointestinal tonic. Swertia longifolia Boiss. is the only species of Swertia growing in Iran. In the present investigation, phytochemical study of S. longifolia was performed and α-amylase inhibitory effects of the plant fractions and purified compounds were determined. Aerial parts of the plant were extracted with hexane, chloroform, methanol and water, respectively. The components of the hexane and chloroform fractions were isolated by different chromatographic methods and their structures were determined by 1H NMR and 13C NMR data. α-Amylase inhibitory activity was determined by a colorimetric assay using 3,5-dinitro salysilic acid. During phytochemical examination, α-amyrin, β-amyrin and β-sitosterol were purified from the hexane fraction, while ursolic acid, daucosterol and swertiamarin were isolated from chloroform fraction. The results of the biochemical assay revealed α-amylase inhibitory activity of hexane, chloroform, methanol and water fractions, of which the chloroform and methanol fractions were more potent (IC50 16.8 and 18.1 mg/ml, respectively). Among examined compounds, daucosterol was found to be the most potent α-amylase inhibitor (57.5% in concentration 10 mg/ml). With regard to α-amylase inhibitory effects of the plant extracts, purified constituents, and antidiabetic application of the species of Swertia genus in traditional medicine of different countries, S. longifolia seems more appropriate species for further mechanistic antidiabetic evaluations. PMID:27051429

Therapeutic effect of enhancing endothelial nitric oxide synthase (eNOS) expression and preventing eNOS uncoupling

PubMed Central

Förstermann, Ulrich; Li, Huige

2011-01-01

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. PMID:21198553

The anti-inflammatory effect of Sonchus oleraceus aqueous extract on lipopolysaccharide stimulated RAW 264.7 cells and mice.

PubMed

Li, Qi; Dong, Dan-Dan; Huang, Qiu-Ping; Li, Jing; Du, Yong-Yong; Li, Bin; Li, Huan-Qing; Huyan, Ting

2017-12-01

Sonchus oleraceus L. (Asteraceae) (SO) is a dietary and traditional medicinal plant in China. However, its underlying mechanism of action as an anti-inflammatory agent is not known. This study evaluates the anti-inflammatory activity of aqueous extract of SO. The extract of SO was used to treat RAW 264.7 cells (in the working concentrations of 500, 250, 125, 62.5, 31.3 and 15.6 μg/mL) for 24 h. Pro-inflammatory cytokines and mediators produced in LPS-stimulated RAW 264.7 cells were assessed. Meanwhile, the expression level of TLR-4, COX-2, pSTATs and NF-κB was tested. Moreover, the anti-inflammatory activity of the extract in vivo was assessed using xylene-induced mouse ear oedema model and the anti-inflammatory compounds in the extracts were analyzed by HPLC-MS. SO extract significantly inhibited the production of pro-inflammatory cytokines and mediators at gene and protein levels with the concentration of 31.3 μg/mL, and suppressed the expression of TLR-4, COX-2, NF-κB and pSTAT in RAW 264.7 cells. The anti-inflammatory activity of SO in vivo has significant anti-inflammatory effects with the concentration of 250 and 125 mg/kg, and less side effect on the weights of the mice at the concentration of 250 mg/kg. Moreover, HPLC-MS analysis revealed that the anti-inflammatory compounds in the extract were identified as villosol, ferulaic acid, β-sitosterol, ursolic acid and rutin. This study indicated that SO extract has anti-inflammatory effects in vitro and in vivo, which will be further developed as novel pharmacological strategies in order to defeat inflammatory diseases.

Diuretic and natriuretic activity of two mistletoe species in rats

PubMed Central

Jadhav, Namita; Patil, C. R.; Chaudhari, K. B.; Wagh, J. P.; Surana, S. J.; Jadhav, R. B.

2010-01-01

In different cultural groups, the hemiparasitic plants of the families Loranthaceae and Viscaceae (mistletoes) are frequently used in the treatment of hypertension and/or as diuretic agents. However, it remains unclear as to what commonality makes them diuretic agents or a remedy for hypertension. In this article, the diuretic activity of methanol extracts of Viscum articulatum (VA) Burm. f. and Helicanthus elastica (HE) (Ders.) Dans. in rats is reported. The extracts were administered orally at doses of 100, 200 and 400 mg/kg to rats that had been fasted and deprived of water for 18 hours. Investigations were carried out for diuretic, saluretic and natriuretic effects. The polyphenolic and triterpenoid contents were determined quantitatively using chemical assays and high performance liquid chromatography (HPLC) analysis, respectively. The extracts of VA and HE demonstrated significant and dose-dependent diuretic activity in rats. It was found that while VA mimics the furosemide pattern, HE demonstrated a dose-dependent increase in diuresis, along with an increase in potassium-sparing effects. Phytochemical analysis revealed that polyphenolics and triterpenoids, such as oleanolic acid and lupeol, are the major phytochemicals involved. It was also found that in different combinations, these phytochemicals differed in the way they influenced the electrolyte excretion. A higher content of polyphenolics in association with lower triterpenoid content was found to favor potassium-sparing effects. PMID:21808540

Inhibition of cell proliferation and induction of apoptosis by oleanane triterpenoid (CDDO-Me) in pancreatic cancer cells is associated with the suppression of hTERT gene expression and its telomerase activity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Deeb, Dorrah; Gao, Xiaohua; Liu, Yongbo

2012-06-15

Highlights: Black-Right-Pointing-Pointer CDDO-Me inhibits hTERT gene expression. Black-Right-Pointing-Pointer CDDO-Me inhibits hTERT protein expression. Black-Right-Pointing-Pointer CDDO-Me inhibits hTERT telomerase activity. Black-Right-Pointing-Pointer CDDO-Me inhibits hTERT regulatory proteins. -- Abstract: Methyl-2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oate (CDDO-Me) is a multifunctional oleanane synthetic triterpenoid with potent anti-inflammatory and antitumorigenic properties. The mechanisms of the antisurvival and apoptosis-inducing activities of CDDO-Me and related derivatives of oleanolic acid have been defined; however, to date, no study has been carried out on the effect of CDDOs on human telomerase reverse transcriptase (hTERT) gene or telomerase activity. Here we report for the first time that inhibition of cell proliferation and induction of apoptosismore » by CDDO-Me in pancreatic cancer cell lines is associated with the inhibition of hTERT gene expression, hTERT telomerase activity and a number of proteins that regulate hTERT expression and activity. Furthermore, abrogation or overexpression of hTERT protein altered the susceptibility of tumor cells to CDDO-Me. These findings suggest that telomerase (hTERT) is a relevant target of CDDO-Me in pancreatic cancer cells.« less