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Arulnangai R, Asia Thabassoom H, Vajiha Banu H, Thirugnanasambandham K, Ganesamoorthy R. Recent developments on ursolic acid and its potential biological applications. Toxicol Rep 2025; 14:101900. [PMID: 39897400 PMCID: PMC11786699 DOI: 10.1016/j.toxrep.2025.101900] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Revised: 12/25/2024] [Accepted: 01/06/2025] [Indexed: 02/04/2025] Open
Abstract
A naturally occurring pentacyclic triterpenoid, ursolic acid (UA) has attracted a lot of interest due to its various pharmacological characteristics and its medical uses. The goal of this thorough review is to present a thorough examination of the therapeutic benefits of UA, including its anti-inflammatory, antioxidant, anticancer, antibacterial, and metabolic-regulating properties. We go over its origins, pharmacological characteristics, and advantages in the treatment of several illnesses, including cancer, neurological disorders, metabolic disorders, and cardiovascular diseases. We further emphasize its potential to improve exercise capacity and its growing function as an exercise mimic. UA's therapeutic potential is thoroughly explained in this review, which highlights the compound's potential as a natural remedy for several illnesses.
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Affiliation(s)
- R. Arulnangai
- PG & Research Department of Chemistry, Jamal Mohamed College, Trichy, Tamil Nadu, India
| | - H. Asia Thabassoom
- PG & Research Department of Chemistry, Jamal Mohamed College, Trichy, Tamil Nadu, India
| | - H. Vajiha Banu
- PG and Research Department of Microbiology, Jamal Mohamed College, Trichy, Tamil Nadu, India
| | - K. Thirugnanasambandham
- Nammazhvar Organic Farming Research centre, Tamil Nadu Agricultural University, Lawley Road, Coimbatore, Tamil Nadu 641 003, India
| | - R. Ganesamoorthy
- Department of Chemistry, Vinayaka Mission’s Kirupananda Variyar Arts and Science College, Salem, Tamil Nadu, India
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Tian Y, Wang X, Bi Y, Li X, Zhang Y, Yao Y, Zhang M, Xu T, Zhang Y, Gui C, Zhang W, Zhang C, Yu H, Zhang Y. Interactions of oleanane pentacyclic triterpenoids with human organic anion transporting polypeptide 1B1 and 1B3. Toxicol In Vitro 2024; 98:105842. [PMID: 38761881 DOI: 10.1016/j.tiv.2024.105842] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Revised: 04/29/2024] [Accepted: 05/07/2024] [Indexed: 05/20/2024]
Abstract
Oleanane pentacyclic triterpenoids have been widely used in clinical practice. However, studies on their interactions with hepatic transporters remain limited. In this study, we systematically investigated the inhibitory effects of 14 oleanane pentacyclic triterpenoids on organic anion transporting polypeptide 1B1 and 1B3 (OATP1B1 and OATP1B3), two liver-specific uptake transporters. Through fluorescence-based cellular uptake assays, we identified three potent OATP1B1 inhibitors (saikosaponin B1, saikosaponin A and 18β-glycyrrhetinic acid) and five potent OATP1B3 inhibitors (echinocystic acid, 3-oxo-16α-hydroxy-olean-12-en-28β-oic acid, chikusetsu saponin IVa, saikosaponin B1 and 18β-glycyrrhetinic acid). Structural analysis revealed that free oleanane triterpenoids inhibited OATP1B1/1B3 more potently than triterpene glycosides. Despite their similar structures, 18β-glycyrrhetinic acid exhibited much stronger inhibition on OATP1B1/1B3 than 18α-glycyrrhetinic acid, while both were substrates of OATP1B3. Interestingly, OATP1B3 overexpression significantly increased reactive oxygen species (ROS) levels in HepG2 cells after treatment with 18β-glycyrrhetinic acid. To conclude, this study highlights the potential interactions of oleanane pentacyclic triterpenoids with OATP1B1/1B3, and provides novel insights into the anti-cancer activity of 18β-glycyrrhetinic acid.
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Affiliation(s)
- Yiqing Tian
- School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China
| | - Xue Wang
- Cancer Biology Program, University of Hawaii Cancer Center, Honolulu, HI 96813, USA
| | - Yajuan Bi
- School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China
| | - Xuejuan Li
- College of Pharmaceutical Engineering of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yang Zhang
- College of Pharmaceutical Engineering of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yao Yao
- Department of Colorectal Surgery, Tianjin, Union Medical Center, Tianjin 30021, China
| | - Mingzhe Zhang
- School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China
| | - Tong Xu
- School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China
| | - Youheng Zhang
- Department of General Practice, Nanjing Tianyinshan Hospital, Jiangsu 211100, China
| | - Chunshan Gui
- College of Pharmaceutical Sciences, Soochow University, Jiangsu 215123, China
| | | | - Chunze Zhang
- Department of Colorectal Surgery, Tianjin, Union Medical Center, Tianjin 30021, China
| | - Heshui Yu
- College of Pharmaceutical Engineering of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China.
| | - Youcai Zhang
- School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China.
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Multivariate assessment of anticancer oleanane triterpenoids lipophilicity. J Chromatogr A 2021; 1656:462552. [PMID: 34571283 DOI: 10.1016/j.chroma.2021.462552] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 09/09/2021] [Accepted: 09/10/2021] [Indexed: 12/24/2022]
Abstract
Naturally occurring molecules are excellent sources of lead compounds. A series of oleanolic acid (OA) derivatives previously synthesized in our laboratory, which show promising antitumor activity, have been analyzed in terms of lipophilicity evaluation applying chromatographic and computational approaches. Retention data obtained on three reversed-phase liquid chromatography stationary phases (RP-HPLC) and immobilized artificial membrane chromatography (IAM-HPLC) were compared with computational methods using chemometric tools such as cluster analysis, principal component analysis and sum of ranking differences. To investigate the molecular mechanism of retention quantitive structure retention relationship analysis was performed, based on the genetic algorithm coupled with multiple linear regression (GA-MLR). The obtained results suggested that the ionization potential of studied molecules significantly affects their retention in classical RP-HPLC. In IAM-HPLC additionally, polarizability-related descriptors also play an essential role in that process. The lipophilicity indices comparison shows significant differences between the computational lipophilicity and chromatographically determined ones.
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Fruits of Vitex doniana sweet: toxicity profile, anti-inflammatory and antioxidant activities, and quantification of one of its bioactive constituents oleanolic acid. Heliyon 2021; 7:e07910. [PMID: 34522807 PMCID: PMC8424515 DOI: 10.1016/j.heliyon.2021.e07910] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Revised: 08/06/2021] [Accepted: 08/30/2021] [Indexed: 11/20/2022] Open
Abstract
Background Vitex doniana Sweet fruit, an under-utilised crop specie of Ghana, has not been validated for its ethnomedical use in managing inflammatory conditions. Therefore, the study sought to investigate its anti-inflammatory and antioxidant activities as well as isolate and quantify one of its active constituents. Materials and methods In-vivo anti-inflammatory activity of the methanol fruit extract was evaluated using the carrageenan-induced oedema model in chicks. The in-vitro antioxidant property was also investigated using the 2, 2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay. The acute and subacute toxicity studies of the fruit extract were evaluated in rodent models. Results No signs of autonomic and central nervous system stimulation/depression were recorded. The LD50 by oral route, was estimated to be beyond 3000 mg/kg. Subacute studies revealed an increase in red blood cell and lymphocyte counts. Liver enzymes, serum proteins and bilirubin levels did not significantly increase. The crude extracts at doses of 10, 30 and 100 mg/kg inhibited paw oedema considerably. The ethyl acetate fraction showed the highest antioxidant activity (IC50 = 99.35 ± 0.77 μg/mL). Oleanolic acid, isolated from the ethyl acetate extract, showed significant anti-inflammatory and antioxidant activities. A sensitive high-performance liquid chromatography method for the detection and estimation of oleanolic acid, as a biomarker compound for V. doniana fruit, was developed and validated for quality assurance purposes. Conclusion The extract of V. doniana fruits possesses considerable anti-inflammatory and antioxidant properties and was non-toxic under laboratory conditions.
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Heidari S, Mehri S, Hosseinzadeh H. The genus Glycyrrhiza (Fabaceae family) and its active constituents as protective agents against natural or chemical toxicities. Phytother Res 2021; 35:6552-6571. [PMID: 34414608 DOI: 10.1002/ptr.7238] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 06/28/2021] [Accepted: 07/27/2021] [Indexed: 12/27/2022]
Abstract
Licorice is the dried roots and rhizomes of various species of the genus Glycyrrhiza (Fabaceae) that have been used in folk medicine from ancient times. Many important research projects have established several beneficial effects for this medicinal herb, including antiinflammatory, antimicrobial, antiviral, antiprotozoal, antioxidant, antihyperglycemic, antihyperlipidemic, hepatoprotective, and neuroprotective. Licorice contains important bioactive components, such as glycyrrhizin (glycyrrhizic, glycyrrhizinic acid), liquiritigenin, liquiritin, and glycyrrhetinic acid. The protective effects of licorice and its main chemical components against toxins and toxicants in several organs including the brain, heart, liver, kidney, and lung have been shown. In this comprehensive review article, the protective effects of these constituents against natural, industrial, environmental, and chemical toxicities with attention on the cellular and molecular mechanism are introduced. Also, it has been revealed that this plant and its main compounds can inhibit the toxicity of different toxins by the antioxidant, antiinflammatory, and anti-apoptotic properties as well as the modulation of Inhibitor of kappaB kinase (IKK), Extracellular signal-regulated protein kinase1/2 (ERK1/2), p38, inducible nitric oxide synthase, and nuclear factor-κB (NF-κB) signaling pathways. More high-quality investigations in both experimental and clinical studies need to firmly establish the efficacy of licorice and its main constituents against toxic agents.
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Affiliation(s)
- Somaye Heidari
- Pharmaceutical Research Center, Department of Pharmacodynamics and Toxicology, School of Pharmacy, Zabol University of Medical Sciences, Zabol, Iran.,Toxicology and Addiction Research Center, Zabol University of Medical Sciences, Zabol, Iran
| | - Soghra Mehri
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Pharmacodynamics and Toxicology, School pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hossein Hosseinzadeh
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Pharmacodynamics and Toxicology, School pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
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Ursolic Acid and Related Analogues: Triterpenoids with Broad Health Benefits. Antioxidants (Basel) 2021; 10:antiox10081161. [PMID: 34439409 PMCID: PMC8388988 DOI: 10.3390/antiox10081161] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Revised: 06/04/2021] [Accepted: 06/22/2021] [Indexed: 12/14/2022] Open
Abstract
Ursolic acid (UA) is a well-studied natural pentacyclic triterpenoid found in herbs, fruit and a number of traditional Chinese medicinal plants. UA has a broad range of biological activities and numerous potential health benefits. In this review, we summarize the current data on the bioavailability and pharmacokinetics of UA and review the literature on the biological activities of UA and its closest analogues in the context of inflammation, metabolic diseases, including liver and kidney diseases, obesity and diabetes, cardiovascular diseases, cancer, and neurological disorders. We end with a brief overview of UA’s main analogues with a special focus on a newly discovered naturally occurring analogue with intriguing biological properties and potential health benefits, 23-hydroxy ursolic acid.
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Nyakudya TT, Isaiah S, Ayeleso A, Ndhlala AR, Mukwevho E, Erlwanger KH. Short-Term Neonatal Oral Administration of Oleanolic Acid Protects against Fructose-Induced Oxidative Stress in the Skeletal Muscles of Suckling Rats. Molecules 2019; 24:E661. [PMID: 30781794 PMCID: PMC6413042 DOI: 10.3390/molecules24040661] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2018] [Revised: 01/22/2019] [Accepted: 01/28/2019] [Indexed: 02/06/2023] Open
Abstract
Nutritional manipulations in the neonatal period are associated with the development of negative or positive health outcomes later in life. Excessive fructose consumption has been attributed to the increase in the global prevalence of metabolic syndrome (MetS) and the development of oxidative stress. Oleanolic acid (OA) has anti-diabetic and anti-obesity effects. We investigated the protective potential of orally administering OA in the neonatal period, to prevent fructose-induced oxidative stress, adverse health outcomes and maturation of the gastrointestinal tract (GIT) in suckling rats. Seven-day old Sprague-Dawley rats (N = 30) were gavaged daily with 10 mL/kg of: distilled water (DW), oleanolic acid (OA; 60 mg/kg), high fructose solution (HF; 20% w/v), or OAHF for 7 days. On day 14, tissue samples were collected to determine clinical health profiles, hepatic lipid content, and activity of anti-oxidant enzymes. Furthermore, biomarkers of oxidative stress and anti-oxidant capacity in the skeletal muscles were assessed. The gastrointestinal tract (GIT) morphometry was measured. Rats in all groups grew over the 7-day treatment period. There were no significant differences in the terminal body masses, GIT morphometry, surrogate markers of general health, liver lipid content across all treatment groups (p < 0.05). Neonatal fructose administration decreased the activity of catalase, depleted GSH and increased lipid peroxidation. However, the level of GSH and catalase activity were improved by neonatal OA treatment. Short-term oral OA administration during the critical developmental period protects against fructose-induced oxidative stress without adverse effects on health outcomes associated with MetS or precocious development of the GIT in suckling male and female rats.
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Affiliation(s)
- Trevor Tapiwa Nyakudya
- Department of Human Anatomy and Physiology, Faculty of Health Sciences, University of Johannesburg, Doornfontein, Johannesburg 2028, South Africa.
| | - Simon Isaiah
- Department of Biochemistry, Faculty of Natural Sciences & Agriculture, North West University, Mafikeng, Mmabatho 2735, South Africa.
| | - Ademola Ayeleso
- Department of Biochemistry, Faculty of Science, Adeleke University, P.M.B. 250, Ede 232, Osun State, Nigeria.
| | - Ashwell Rungano Ndhlala
- Agricultural Research Council, Vegetable and Ornamental Plants (VOP), Private Bag X293, Pretoria 0001, South Africa.
| | - Emmanuel Mukwevho
- Department of Biochemistry, Faculty of Natural Sciences & Agriculture, North West University, Mafikeng, Mmabatho 2735, South Africa.
| | - Kennedy Honey Erlwanger
- School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, Parktown, Johannesburg 2193, South Africa.
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Wang C, Wang X, Zhao S, Sun W, Tong S. Preparative separation of structural isomeric pentacyclic triterpene oleanolic acid and ursolic acid from natural products by pH-zone-refining countercurrent chromatography. RSC Adv 2019; 9:38860-38866. [PMID: 35540200 PMCID: PMC9076006 DOI: 10.1039/c9ra06082k] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2019] [Accepted: 11/11/2019] [Indexed: 11/21/2022] Open
Abstract
In this work, pH-zone-refining countercurrent chromatography was investigated in the preparative separation of two bioactive components, oleanolic acid and ursolic acid, from three different natural products, Aralia chinensis, apple peels and Eriobotrya japonica Thunb. Oleanolic acid and ursolic acid are structurally isomeric pentacyclic triterpene acids that are widely distributed in many natural products. However, it was difficult to separate these components with high purity by conventional methods. A biphasic solvent system composed of n-hexane–dichloromethane–methanol–water (7 : 3 : 2 : 8, v/v) was selected, in which an optimized concentration of 10 mmol L−1 trifluoroacetic acid was added in the upper phase as the retainer and 10 mmol L−1 ammonia (with 25–28% NH3) was added in the aqueous phase as the eluter. Consequently, 38.56 mg of oleanolic acid with 99.01% purity was separated from 100 mg of the crude extract of Aralia chinensis, while 65.6 mg of a mixture of ursolic acid (90.98%) and oleanolic acid (6.51%) and 46.6 mg of a mixture of ursolic acid (74.35%) and oleanolic acid (23.61%) were separated from 100 mg of the crude extract of apple peels and 100 mg of the crude extract of Eriobotrya japonica Thunb., respectively, by pH-zone-refining countercurrent chromatography using the above selected biphasic solvent system. The results showed that pH-zone-refining countercurrent chromatography is an efficient method for the preparative separation of pentacyclic triterpene acids from natural products. pH-zone-refining countercurrent chromatography was investigated in preparative separation of oleanolic acid and ursolic acid from three different natural products, Aralia chinensis, apple peels and Eriobotrya japonica Thunb.![]()
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Affiliation(s)
- Chaoyue Wang
- College of Pharmaceutical Science
- Zhejiang University of Technology
- Hangzhou
- China
| | - Xiang Wang
- College of Pharmaceutical Science
- Zhejiang University of Technology
- Hangzhou
- China
| | - Shanshan Zhao
- College of Pharmaceutical Science
- Zhejiang University of Technology
- Hangzhou
- China
| | - Wenyu Sun
- College of Pharmaceutical Science
- Zhejiang University of Technology
- Hangzhou
- China
| | - Shengqiang Tong
- College of Pharmaceutical Science
- Zhejiang University of Technology
- Hangzhou
- China
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Subramanya SB, Venkataraman B, Meeran MFN, Goyal SN, Patil CR, Ojha S. Therapeutic Potential of Plants and Plant Derived Phytochemicals against Acetaminophen-Induced Liver Injury. Int J Mol Sci 2018; 19:ijms19123776. [PMID: 30486484 PMCID: PMC6321362 DOI: 10.3390/ijms19123776] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2018] [Revised: 09/02/2018] [Accepted: 09/15/2018] [Indexed: 12/18/2022] Open
Abstract
Acetaminophen (APAP), which is also known as paracetamol or N-acetyl-p-aminophenol is a safe and potent drug for fever, pain and inflammation when used at its normal therapeutic doses. It is available as over-the-counter drug and used by all the age groups. The overdose results in acute liver failure that often requires liver transplantation. Current clinical therapy for APAP-induced liver toxicity is the administration of N-acetyl-cysteine (NAC), a sulphydryl compound an approved drug which acts by replenishing cellular glutathione (GSH) stores in the liver. Over the past five decades, several studies indicate that the safety and efficacy of herbal extracts or plant derived compounds that are used either as monotherapy or as an adjunct therapy along with conventional medicines for hepatotoxicity have shown favorable responses. Phytochemicals mitigate necrotic cell death and protect against APAP-induced liver toxicityby restoring cellular antioxidant defense system, limiting oxidative stress and subsequently protecting mitochondrial dysfunction and inflammation. Recent experimental evidences indicat that these phytochemicals also regulate differential gene expression to modulate various cellular pathways that are implicated in cellular protection. Therefore, in this review, we highlight the role of the phytochemicals, which are shown to be efficacious in clinically relevant APAP-induced hepatotoxicity experimental models. In this review, we have made comprehensive attempt to delineate the molecular mechanism and the cellular targets that are modulated by the phytochemicals to mediate the cytoprotective effect against APAP-induced hepatotoxicity. In this review, we have also defined the challenges and scope of phytochemicals to be developed as drugs to target APAP-induced hepatotoxicity.
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Affiliation(s)
- Sandeep B Subramanya
- Department of Physiology, College of Medicine and Health Sciences, PO Box # 17666, United Arab Emirates University, Al Ain 17666, UAE.
| | - Balaji Venkataraman
- Department of Physiology, College of Medicine and Health Sciences, PO Box # 17666, United Arab Emirates University, Al Ain 17666, UAE.
| | - Mohamed Fizur Nagoor Meeran
- Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, PO Box # 17666, United Arab Emirates University, Al Ain 17666, UAE.
| | - Sameer N Goyal
- Department of Pharmacology, SVKM's Institute of Pharmacy, Dhule, Maharashtra 424 001, India.
- Department of Pharmacology, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, Dhule, Maharashtra 425 405, India.
| | - Chandragouda R Patil
- Department of Pharmacology, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, Dhule, Maharashtra 425 405, India.
| | - Shreesh Ojha
- Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, PO Box # 17666, United Arab Emirates University, Al Ain 17666, UAE.
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Nagoor Meeran MF, Goyal SN, Suchal K, Sharma C, Patil CR, Ojha SK. Pharmacological Properties, Molecular Mechanisms, and Pharmaceutical Development of Asiatic Acid: A Pentacyclic Triterpenoid of Therapeutic Promise. Front Pharmacol 2018; 9:892. [PMID: 30233358 PMCID: PMC6131672 DOI: 10.3389/fphar.2018.00892] [Citation(s) in RCA: 95] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2018] [Accepted: 07/23/2018] [Indexed: 12/16/2022] Open
Abstract
Asiatic acid (AA) is a naturally occurring aglycone of ursane type pentacyclic triterpenoids. It is abundantly present in many edible and medicinal plants including Centella asiatica that is a reputed herb in many traditional medicine formulations for wound healing and neuropsychiatric diseases. AA possesses numerous pharmacological activities such as antioxidant and anti-inflammatory and regulates apoptosis that attributes its therapeutic effects in numerous diseases. AA showed potent antihypertensive, nootropic, neuroprotective, cardioprotective, antimicrobial, and antitumor activities in preclinical studies. In various in vitro and in vivo studies, AA found to affect many enzymes, receptors, growth factors, transcription factors, apoptotic proteins, and cell signaling cascades. This review aims to represent the available reports on therapeutic potential and the underlying pharmacological and molecular mechanisms of AA. The review also also discusses the challenges and prospects on the pharmaceutical development of AA such as pharmacokinetics, physicochemical properties, analysis and structural modifications, and drug delivery. AA showed favorable pharmacokinetics and found bioavailable following oral or interaperitoneal administration. The studies demonstrate the polypharmacological properties, therapeutic potential and molecular mechanisms of AA in numerous diseases. Taken together the evidences from available studies, AA appears one of the important multitargeted polypharmacological agents of natural origin for further pharmaceutical development and clinical application. Provided the favorable pharmacokinetics, safety, and efficacy, AA can be a promising agent or adjuvant along with currently used modern medicines with a pharmacological basis of its use in therapeutics.
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Affiliation(s)
- Mohamed Fizur Nagoor Meeran
- Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
| | | | - Kapil Suchal
- Department of Pharmacology, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, India
| | - Charu Sharma
- Department of Internal Meicine, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Chandragouda R. Patil
- Department of Pharmacology, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, India
| | - Shreesh K. Ojha
- Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
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Alfei S, Taptue GB, Catena S, Bisio A. Synthesis of Water-soluble, Polyester-based Dendrimer Prodrugs for Exploiting Therapeutic Properties of Two Triterpenoid Acids. CHINESE JOURNAL OF POLYMER SCIENCE 2018. [DOI: 10.1007/s10118-018-2124-9] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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López-Hortas L, Pérez-Larrán P, González-Muñoz MJ, Falqué E, Domínguez H. Recent developments on the extraction and application of ursolic acid. A review. Food Res Int 2018; 103:130-149. [PMID: 29389599 DOI: 10.1016/j.foodres.2017.10.028] [Citation(s) in RCA: 103] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2016] [Revised: 10/10/2017] [Accepted: 10/12/2017] [Indexed: 01/02/2023]
Abstract
Ursolic acid (UA) is a pentacyclic triterpenoid widely found in herbs, leaves, flowers and fruits; update information on the major natural sources or agro-industrial wastes is presented. Traditional (maceration, Soxhlet and heat reflux) and modern (microwave-, ultrasound-, accelerated solvent- and supercritical fluid) extraction and purification technologies of UA, as well as some patented process, are summarized. The great interest in this bioactive compound is related to the beneficial effects in human health due to antioxidant, antimicrobial, anti-inflammatory, hepatoprotective, immunomodulatory, anti-tumor, chemopreventive, cardioprotective, antihyperlipidemic and hypoglycemic activities, and others. UA may augment the resistance of the skin barrier to irritants, prevent dry skin and could be suitable to develop antiaging products. The development of nanocrystals and nanoparticle-based drugs could reduce the side effects of high doses of UA in organisms, and increase its limited solubility and poor bioavailability of UA which limit the potential of this bioactive and the further applications. Commercial patented applications in relation to cosmetical and pharmaceutical uses of UA and its derivatives are surveyed.
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Affiliation(s)
- Lucía López-Hortas
- Departamento de Enxeñería Química, Facultad de Ciencias, Universidade de Vigo, As Lagoas s/n, 32004 Ourense, Spain; Departamento de Química Analítica, Facultad de Ciencias, Universidade de Vigo, As Lagoas s/n, 32004 Ourense, Spain
| | - Patricia Pérez-Larrán
- Departamento de Enxeñería Química, Facultad de Ciencias, Universidade de Vigo, As Lagoas s/n, 32004 Ourense, Spain
| | - María Jesús González-Muñoz
- Departamento de Enxeñería Química, Facultad de Ciencias, Universidade de Vigo, As Lagoas s/n, 32004 Ourense, Spain
| | - Elena Falqué
- Departamento de Química Analítica, Facultad de Ciencias, Universidade de Vigo, As Lagoas s/n, 32004 Ourense, Spain
| | - Herminia Domínguez
- Departamento de Enxeñería Química, Facultad de Ciencias, Universidade de Vigo, As Lagoas s/n, 32004 Ourense, Spain.
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Das J, Sarkar A, Ghosh P. Friedelane triterpenoids: transformations toward A-ring modifications including 2-homoderivatives. NEW J CHEM 2018. [DOI: 10.1039/c8nj00009c] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Common reaction strategies were employed on suitable substrates to achieve a series of C2,C3-; C3,C4- and C2,C3,C4-functionalized (including 2-homo-) friedelane triterpenoids with just one to four efficient steps.
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Affiliation(s)
- Jayanta Das
- Natural Products and Polymer Chemistry Laboratory
- Department of Chemistry
- North Bengal University
- Darjeeling-734013
- India
| | - Antara Sarkar
- Natural Products and Polymer Chemistry Laboratory
- Department of Chemistry
- North Bengal University
- Darjeeling-734013
- India
| | - Pranab Ghosh
- Natural Products and Polymer Chemistry Laboratory
- Department of Chemistry
- North Bengal University
- Darjeeling-734013
- India
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Wang H, Sim MK, Loke WK, Chinnathambi A, Alharbi SA, Tang FR, Sethi G. Potential Protective Effects of Ursolic Acid against Gamma Irradiation-Induced Damage Are Mediated through the Modulation of Diverse Inflammatory Mediators. Front Pharmacol 2017; 8:352. [PMID: 28670276 PMCID: PMC5472704 DOI: 10.3389/fphar.2017.00352] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2017] [Accepted: 05/23/2017] [Indexed: 01/08/2023] Open
Abstract
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.
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Affiliation(s)
- Hong Wang
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of SingaporeSingapore, Singapore
- Singapore Nuclear Research and Safety Initiative, National University of SingaporeSingapore, Singapore
| | - Meng-Kwoon Sim
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of SingaporeSingapore, Singapore
| | - Weng Keong Loke
- Agent Diagnostic and Therapeutic Laboratory, Defence and Environmental Research Institute, DSO National LaboratoriesSingapore, Singapore
| | - Arunachalam Chinnathambi
- Department of Botany and Microbiology, College of Science, King Saud UniversityRiyadh, Saudi Arabia
| | - Sulaiman Ali Alharbi
- Department of Botany and Microbiology, College of Science, King Saud UniversityRiyadh, Saudi Arabia
| | - Feng Ru Tang
- Singapore Nuclear Research and Safety Initiative, National University of SingaporeSingapore, Singapore
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of SingaporeSingapore, Singapore
- Department of Botany and Microbiology, College of Science, King Saud UniversityRiyadh, Saudi Arabia
- School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, PerthWA, Australia
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15
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Mancha-Ramirez AM, Slaga TJ. Ursolic Acid and Chronic Disease: An Overview of UA's Effects On Prevention and Treatment of Obesity and Cancer. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 928:75-96. [PMID: 27671813 DOI: 10.1007/978-3-319-41334-1_4] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
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.
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Affiliation(s)
- Anna M Mancha-Ramirez
- Department of Cellular and Structural Biology, The University of Texas Health Science Center San Antonio, 7703 Floyd Curl Drive, San Antonio, TX, 78229, USA
| | - Thomas J Slaga
- Department of Pharmacology, The University of Texas Health Science Center San Antonio, 7703 Floyd Curl Drive, San Antonio, TX, 78229, USA.
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16
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Chigurupati H, Auddy B, Biyani M, Stohs SJ. Hepatoprotective Effects of a Proprietary Glycyrrhizin Product during Alcohol Consumption: A Randomized, Double-Blind, Placebo-Controlled, Crossover Study. Phytother Res 2016; 30:1943-1953. [DOI: 10.1002/ptr.5699] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2016] [Revised: 07/18/2016] [Accepted: 07/22/2016] [Indexed: 12/14/2022]
Affiliation(s)
| | - Biswajit Auddy
- Chigurupati Technologies Private Limited; Hyderabad India
| | - M. Biyani
- Chigurupati Technologies Private Limited; Hyderabad India
| | - Sidney J. Stohs
- Creighton University; 7068 Maumee Valley Court Frisco TX 75034 USA
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17
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Gutiérrez-Rebolledo GA, Siordia-Reyes AG, Meckes-Fischer M, Jiménez-Arellanes A. Hepatoprotective properties of oleanolic and ursolic acids in antitubercular drug-induced liver damage. ASIAN PAC J TROP MED 2016; 9:644-51. [DOI: 10.1016/j.apjtm.2016.05.015] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2016] [Revised: 05/16/2016] [Accepted: 05/23/2016] [Indexed: 12/11/2022] Open
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18
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Bachhav SS, Bhutada MS, Patil SP, Sharma KS, Patil SD. Oleanolic Acid Prevents Increase in Blood Pressure and Nephrotoxicity in Nitric Oxide Dependent Type of Hypertension in Rats. Pharmacognosy Res 2015; 7:385-92. [PMID: 26692754 PMCID: PMC4660519 DOI: 10.4103/0974-8490.159575] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
Abstract
Background: Recently, we have reported antihypertensive activity of oleanolic acid (OA) in glucocorticoid-induced hypertension with restoration of nitric oxide (NO) level. However, the involvement of NO-releasing action of OA was unclear. Objective: To explore antihypertensive activity of OA in Nω-nitro-L-arginine methyl ester (L-NAME) hypertensive rats wherein NO is completely blocked, which would allow exploring the possibility of involvement of NO-releasing action of OA. Materials and Methods: Five groups of rats were investigated as normal control, L-NAME (40 mg/kg/day), L-NAME + enalapril (15 mg/kg/day), L-NAME + l-arginine (100 mg/kg/day), and L-NAME + OA (60 mg/kg/day) for 4 weeks. The systolic blood pressure, body weight, and heart rate were measured weekly for 4 weeks. Serum nitrate/nitrite (NOx) level, urine electrolytes concentration, cardiac mass index, and serum creatinine level were determined followed by organ histopathology. Results: OA and enalapril delayed the rise in blood pleasure following L-NAME administration. Decreased serum NOx level was not significantly increased with any of the treatment. OA produced a small, though nonsignificant, increase in the NOx level. L-NAME administration did not affect cardiac mass index. There was an increase in serum creatinine upon L-NAME administration which was prevented by OA. Decreased urine volume, urine sodium and potassium were reversed by OA. Conclusion: These results suggest that the antihypertensive effect of OA in L-NAME hypertension is due to diuresis and nephroprotection. However, OA has nonsignificantly affected the NO levels.
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Affiliation(s)
- Sagar S Bachhav
- Department of Pharmacology, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, Dhule, Maharashtra, India
| | - Mukesh S Bhutada
- Department of Pharmacology, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, Dhule, Maharashtra, India
| | - Sachin P Patil
- Department of Pharmacology, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, Dhule, Maharashtra, India
| | - Kinjal S Sharma
- Department of Pharmacology, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, Dhule, Maharashtra, India
| | - Savita D Patil
- Department of Pharmacology, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, Dhule, Maharashtra, India
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19
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Jesus JA, Lago JHG, Laurenti MD, Yamamoto ES, Passero LFD. Antimicrobial activity of oleanolic and ursolic acids: an update. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2015; 2015:620472. [PMID: 25793002 PMCID: PMC4352472 DOI: 10.1155/2015/620472] [Citation(s) in RCA: 117] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/30/2014] [Accepted: 01/22/2015] [Indexed: 12/14/2022]
Abstract
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.
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Affiliation(s)
- Jéssica A. Jesus
- Laboratório de Patologia de Moléstias Infecciosas, Departamento de Patologia, Faculdade de Medicina da Universidade de São Paulo, Avenue Dr. Arnaldo 455, 06780-210 Cerqueira César, SP, Brazil
- Instituto de Ciências Ambientais, Químicas e Farmacêuticas, Universidade Federal de São Paulo, Rua Professor Artur Riedel 275, 09972-270 Diadema, SP, Brazil
| | - João Henrique G. Lago
- Instituto de Ciências Ambientais, Químicas e Farmacêuticas, Universidade Federal de São Paulo, Rua Professor Artur Riedel 275, 09972-270 Diadema, SP, Brazil
| | - Márcia D. Laurenti
- Laboratório de Patologia de Moléstias Infecciosas, Departamento de Patologia, Faculdade de Medicina da Universidade de São Paulo, Avenue Dr. Arnaldo 455, 06780-210 Cerqueira César, SP, Brazil
| | - Eduardo S. Yamamoto
- Laboratório de Patologia de Moléstias Infecciosas, Departamento de Patologia, Faculdade de Medicina da Universidade de São Paulo, Avenue Dr. Arnaldo 455, 06780-210 Cerqueira César, SP, Brazil
| | - Luiz Felipe D. Passero
- Laboratório de Patologia de Moléstias Infecciosas, Departamento de Patologia, Faculdade de Medicina da Universidade de São Paulo, Avenue Dr. Arnaldo 455, 06780-210 Cerqueira César, SP, Brazil
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20
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Camer D, Yu Y, Szabo A, Huang XF. The molecular mechanisms underpinning the therapeutic properties of oleanolic acid, its isomer and derivatives for type 2 diabetes and associated complications. Mol Nutr Food Res 2014; 58:1750-9. [PMID: 24740831 DOI: 10.1002/mnfr.201300861] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2013] [Revised: 03/04/2014] [Accepted: 03/06/2014] [Indexed: 01/02/2023]
Abstract
Recent research has uncovered the molecular mechanisms responsible for the therapeutic properties of oleanolic acid (OA), its isomer ursolic acid (UA), and derivatives. In particular, recent reports have highlighted the benefits of these compounds in the prevention and treatment of type 2 diabetes and associated life-threatening complications, such as nonalcoholic fatty liver disease, nephropathy, retinopathy, and atherosclerosis. The prevalence of type 2 diabetes is of major concern since it is reaching global epidemic levels. Treatments targeting the signaling pathways altered in type 2 diabetes are being actively investigated, and OA and UA in natural and derivative forms are potential candidates to modulate these pathways. We will explore the findings from in vitro and in vivo studies showing that these compounds: (i) improve insulin signaling and reduce hyperglycemia; (ii) reduce oxidative stress by upregulating anti-oxidants and; (iii) reduce inflammation by inhibiting proinflammatory signaling. We will discuss the molecular mechanisms underpinning these therapeutic properties in this review in order to provide a rationale for the future use of OA, UA, and their derivatives for the prevention and treatment of type 2 diabetes and associated comorbidities.
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Affiliation(s)
- Danielle Camer
- Centre for Translational Neuroscience, School of Medicine, Illawarra Health and Medical Research Institute, University of Wollongong, NSW, Australia
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21
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Triterpenes from the Protium heptaphyllum resin – chemical composition and cytotoxicity. REVISTA BRASILEIRA DE FARMACOGNOSIA-BRAZILIAN JOURNAL OF PHARMACOGNOSY 2014. [DOI: 10.1016/j.bjp.2014.06.003] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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22
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Ma JQ, Ding J, Zhang L, Liu CM. Ursolic acid protects mouse liver against CCl4-induced oxidative stress and inflammation by the MAPK/NF-κB pathway. ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2014; 37:975-83. [PMID: 24727148 DOI: 10.1016/j.etap.2014.03.011] [Citation(s) in RCA: 94] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/07/2014] [Revised: 03/12/2014] [Accepted: 03/16/2014] [Indexed: 06/03/2023]
Abstract
Ursolic acid (UA), a natural pentacyclic triterpenoid, has been reported to have many benefits and medicinal properties. However, its protective effects against carbon tetrachloride (CCl(4)) induced hepatotoxicity have not been clarified. The aim of the present study was to investigate the effects of UA on oxidative stress and inflammation in liver of CCl(4) treated mice. Male ICR mice were injected with CCl(4) with or without UA co-administration (25 and 50 mg/kg intragastrically once daily) for one week. Our data showed that UA significantly prevented CCl(4)-induced hepatotoxicity in a dose-dependent manner, indicated by both diagnostic indicators of liver damage (serum aminotransferase activities) and histopathological analysis. Moreover, CCl(4)-induced profound elevation of reactive oxygen species (ROS) production and oxidative stress, as evidenced by increasing of lipid peroxidation level and depleting of the total antioxidant capacity (TAC) level in liver, were suppressed by treatment with UA. Furthermore, western blot analysis showed that UA significantly decreased CYP2E1 expression levels and production of pro-inflammatory markers including TNF-α, IL-1β and COX-2 in CCl(4)-treated mouse liver. In exploring the underlying mechanisms of UA action, we found that UA decreased the activation of mitogen-activated protein kinases (JNK, p38 MAPK, ERK), which in turn inactivated the immunoregulatory transcription factor nuclear factor kappa B (NF-κB) in liver of CCl(4) treated mice. In conclusion, these results suggested that the inhibition of CCl(4)-induced inflammation by UA is due at least in part to its anti-oxidant activity and its ability to modulate the MAPK and NF-κB signaling pathway.
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Affiliation(s)
- Jie-Qiong Ma
- School of Chemistry and Pharmaceutical, Sichuan University of Science and Engineering, 643000 Zigong City, Sichuan Province, PR China.
| | - Jie Ding
- School of Chemistry and Pharmaceutical, Sichuan University of Science and Engineering, 643000 Zigong City, Sichuan Province, PR China
| | - Li Zhang
- School of Chemistry and Pharmaceutical, Sichuan University of Science and Engineering, 643000 Zigong City, Sichuan Province, PR China
| | - Chan-Min Liu
- School of Life Science, Jiangsu Normal University, No. 101, Shanghai Road, Tangshan New Area, Xuzhou City 221116, Jiangsu Province, PR China
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Loboda A, Rojczyk-Golebiewska E, Bednarczyk-Cwynar B, Lucjusz Z, Jozkowicz A, Dulak J. Targeting nrf2-mediated gene transcription by triterpenoids and their derivatives. Biomol Ther (Seoul) 2014; 20:499-505. [PMID: 24009841 PMCID: PMC3762293 DOI: 10.4062/biomolther.2012.20.6.499] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2012] [Revised: 11/09/2012] [Accepted: 11/09/2012] [Indexed: 12/13/2022] Open
Abstract
Chemoprevention represents a strategy designed to protect cells or tissues against various carcinogens and carcinogenic metabolites derived from exogenous or endogenous sources. Recent studies indicate that plant-derived triterpenoids, like oleanolic acid, may exert cytoprotective functions via regulation of the activity of different transcription factors. The chemopreventive effects may be mediated through induction of the nuclear factor erythroid 2-related factor 2 (Nrf2) transcription factor. Activation of Nrf2 by triterpenoids induces the expression of phase 2 detoxifying and antioxidant enzymes such as NAD(P)H quinone oxidoreductase 1 (NQO1) and heme oxygenase-1 (HO-1) - proteins which can protect cells or tissues against various toxic metabolites. On the other hand, inhibition of other transcription factors, like NF-κB leads to the decrease in the pro-inflammatory gene expression. Moreover, the modulation of microRNAs activity may constitute a new mechanism responsible for valuable effects of triterpenoids. Recently, based on the structure of naturally occurring triterpenoids and with involvement of bioinformatics and computational chemistry, many synthetic analogs with improved biological properties have been obtained. Data from in vitro and in vivo experiments strongly suggest synthetic derivatives as promising candidates in the chemopreventive and chemotherapeutic strategies.
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Affiliation(s)
- Agnieszka Loboda
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland
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24
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Ullevig SL, Kim HS, Nguyen HN, Hambright WS, Robles AJ, Tavakoli S, Asmis R. Ursolic acid protects monocytes against metabolic stress-induced priming and dysfunction by preventing the induction of Nox4. Redox Biol 2014; 2:259-66. [PMID: 24494201 PMCID: PMC3909821 DOI: 10.1016/j.redox.2014.01.003] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2013] [Accepted: 01/03/2014] [Indexed: 01/11/2023] Open
Abstract
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.
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Key Words
- Atherosclerosis
- GSH, reduced glutathione
- Grx, glutaredoxin
- HFD, high-fat diet
- HG, high d-glucose
- LDL, low-density lipoprotein
- MAPK, mitogen-activated protein kinase
- MCP-1, monocyte chemoattractant protein-1
- MKP-1, MAPK phosphatase-1
- Monocyte
- Nox4
- Nox4, NADPH oxidase 4
- OA, oleanolic acid
- PSSG, protein–glutathione mixed disulfide
- ROS, reactive oxygen species
- S-glutathionylation
- UA, ursolic acid
- Ursolic acid
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Affiliation(s)
- Sarah L. Ullevig
- Department of Kinesiology, Health, and Nutrition, University of Texas at San Antonio, United States
| | - Hong Seok Kim
- Department of Clinical Laboratory Sciences, University of Texas Health Science Center, San Antonio, United States
| | - Huynh Nga Nguyen
- Department of Biochemistry, University of Texas Health Science Center, San Antonio, United States
| | - William S. Hambright
- Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, United States
| | - Andrew J. Robles
- Department of Pharmacology, University of Texas Health Science Center, San Antonio, United States
| | - Sina Tavakoli
- Department of Radiology, University of Texas Health Science Center, San Antonio, United States
| | - Reto Asmis
- Department of Clinical Laboratory Sciences, University of Texas Health Science Center, San Antonio, United States
- Department of Biochemistry, University of Texas Health Science Center, San Antonio, United States
- Department of Radiology, University of Texas Health Science Center, San Antonio, United States
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Xu R, Wang Q, Zhang J, Zang M, Liu X, Yang J. Changes in pharmacokinetic profiles of acetaminophen and its glucuronide after pretreatment with combinations of N-acetylcysteine and either glycyrrhizin, silibinin or spironolactone in rat. Xenobiotica 2013; 44:541-6. [PMID: 24251357 DOI: 10.3109/00498254.2013.858849] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
1. The present study was to investigate the effects of giving N-acetylcysteine (NAC) alone and in combination with either glycyrrhizin (GL), silibinin (SIB) or spironolactone (SL) on the plasma pharmacokinetic (PK) profiles, hepatic exposure, biliary excretion and urinary excretion of acetaminophen (APAP) and its major metabolite, acetaminophen glucuronide (AG). 2. Groups of rats (n = 5) were pretreated with oral doses of either NAC, NAC + GL, NAC + SIB or NAC + SL on five occasions every 12 h. At 1 h, after the last dose, they received APAP (200 mg/kg) by intraperitoneal injection. Blood, bile, liver and urine samples were collected at various times after APAP injection and analyzed for APAP and AG by HPLC. NAC alone and NAC + SIB did not significantly change the PK profiles of APAP and AG. In contrast, NAC + GL decreased the biliary excretion of APAP and AG leading to accumulation of APAP in the liver and systemic circulation whereas NAC + SL [multidrug resistance associated 2 (Mrp2) inducer] increased the biliary excretion of AG and decreased the hepatic exposure to APAP and AG. 3. Our results suggest that Mrp2 inhibitor GL should be discouraged with NAC to treat APAP hepatotoxicity. Such PK drug-drug interactions should be considered in the treatment of APAP-induced liver injury.
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Affiliation(s)
- Ruijuan Xu
- Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University , Nanjing , China
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Liu J, Lu YF, Zhang Y, Wu KC, Fan F, Klaassen CD. Oleanolic acid alters bile acid metabolism and produces cholestatic liver injury in mice. Toxicol Appl Pharmacol 2013; 272:816-24. [PMID: 23948738 DOI: 10.1016/j.taap.2013.08.003] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2013] [Revised: 07/31/2013] [Accepted: 08/02/2013] [Indexed: 12/11/2022]
Abstract
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 liver 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.
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Affiliation(s)
- Jie Liu
- University of Kansas Medical Center, Kansas City, KS 66160, USA; Zunyi Medical College, Zunyi 563003, China.
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He Y, Li Y, Zhao T, Wang Y, Sun C. Ursolic acid inhibits adipogenesis in 3T3-L1 adipocytes through LKB1/AMPK pathway. PLoS One 2013; 8:e70135. [PMID: 23922935 PMCID: PMC3724828 DOI: 10.1371/journal.pone.0070135] [Citation(s) in RCA: 95] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2013] [Accepted: 06/15/2013] [Indexed: 12/20/2022] Open
Abstract
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.
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Affiliation(s)
- Yonghan He
- Department of Nutrition and Food Hygiene, Public Health College, Harbin Medical University, Harbin, People's Republic of China
- Aquatic and Crop Resource Development, Life Sciences Branch, National Research Council Canada, Charlottetown, Prince Edward Island, Canada
| | - Ying Li
- Department of Nutrition and Food Hygiene, Public Health College, Harbin Medical University, Harbin, People's Republic of China
| | - Tiantian Zhao
- Aquatic and Crop Resource Development, Life Sciences Branch, National Research Council Canada, Charlottetown, Prince Edward Island, Canada
- Department of Psychology, University of Toronto, Toronto, Ontario, Canada
| | - Yanwen Wang
- Aquatic and Crop Resource Development, Life Sciences Branch, National Research Council Canada, Charlottetown, Prince Edward Island, Canada
- Department of Biomedical Sciences, University of Prince Edward Island, Charlottetown, Prince Edward Island, Canada
| | - Changhao Sun
- Department of Nutrition and Food Hygiene, Public Health College, Harbin Medical University, Harbin, People's Republic of China
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Repeated oral administration of oleanolic acid produces cholestatic liver injury in mice. Molecules 2013; 18:3060-71. [PMID: 23470335 PMCID: PMC6270117 DOI: 10.3390/molecules18033060] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2012] [Revised: 02/25/2013] [Accepted: 02/27/2013] [Indexed: 12/13/2022] Open
Abstract
Oleanolic acid (OA) is a triterpenoid and a fantastic molecule with many beneficial effects. However, high-doses and long-term use can produce adverse effects. This study aimed to characterize the hepatotoxic potential of OA. Mice were given OA at doses of 100–3,000 µmol/kg (45–1,350 mg/kg), po for 10 days, and the hepatotoxicity was determined by serum biochemistry, histopathology, and toxicity-related gene expression via real-time RT-PCR. Animal body weight loss was evident at OA doses of 1,000 µmol/kg and above. Serum alanine aminotransferase activities were increased in a dose-dependent manner, indicative of hepatotoxicity. Serum total bilirubin concentrations were increased, indicative of cholestasis. OA administration produced dose-dependent pathological lesions to the liver, including inflammation, hepatocellular apoptosis, necrosis, and feathery degeneration indicative of cholestasis. These lesions were evident at OA doses of 500 µmol/kg and above. Real-time RT-PCR revealed that OA produced dose-dependent increases in acute phase proteins (MT-1, Ho-1, Nrf2 and Nqo1), decreases in bile acid synthesis genes (Cyp7a1 and Cyp8b1), and decreases in liver bile acid transporters (Ntcp, Bsep, Oatp1a1, Oatp1b2, and Ostβ). Thus, the clinical use of OA and OA-type triterpenoids should balance the beneficial effects and toxicity potentials.
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Tang XH, Gao L, Gao J, Fan YM, Xu LZ, Zhao XN, Xu Q. Mechanisms of Hepatoprotection ofTerminalia catappaL. Extract on D-Galactosamine-Induced Liver Damage. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2012; 32:509-19. [PMID: 15481641 DOI: 10.1142/s0192415x04002156] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
The hepatoprotective effects of the extract of Terminalia catappa L. leaves (TCE) against D-Galactosamine (D-GalN)-induced liver injury and the mechanisms underlying its protection were studied. In acute hepatic injury test, it was found that serum ALT activity was remarkably increased (3.35-fold) after injection of D-GalN in mice. But with oral pretreatment of TCE (20, 50 and 100 mg/kg/d) for 7 days, change in serum ALT was notably reversed. In primary cultured hepatocytes from fetal mice, it was found that cell viability was decreased by 45.0% after addition of D-GalN, while incubation with TCE (0.1, 0.5 and 1.0 mg/ml) for 36 hours could prevent the decrease in a dose-dependent manner. Meanwhile, D-GalN-induced both the increase of AST level (1.9-fold) and the decrease of SOD activity (48.0%) in supernatant of primary cultured hepatocytes could also be inhibited by pretreatment with TCE. In order to study the possible mechanisms underlying its hepatoprotective effects, one effective component separated from TCE, 2α, 3β,23-trihydroxyursane-12-en-28-oic acid (DHUA), was used to determine anti-mitochondrial swelling activity and superoxide radicals scavenging activity in vitro. It was found that at the concentration range of 50–500 μmol/L DHUA, Ca2+-induced mitochondrial swelling was dose-dependently inhibited, and superoxide radicals scavenging activity was also shown in a dose-dependent manner. It was concluded that TCE has hepatoprotective activity and the mechanisms underlying its protective effects may be related to the direct mitochondrion protection and strong scavenging activity on reactive oxygen species (ROS).
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Affiliation(s)
- Xin-Hui Tang
- Institute of Materia Medica, School of Medicine, Nanjing University, Nanjing, P. R. China
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Jin YR, Jin JL, Li CH, Piao XX, Jin NG. Ursolic acid enhances mouse liver regeneration after partial hepatectomy. PHARMACEUTICAL BIOLOGY 2012; 50:523-8. [PMID: 22136205 DOI: 10.3109/13880209.2011.611143] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2023]
Abstract
CONTEXT Ursolic acid is a pentacyclic triterpenoid which has hepatoprotective and antihepatotoxic activities. OBJECTIVE This study investigated whether ursolic acid is able to stimulate liver regeneration in partially hepatectomized mice. MATERIALS AND METHODS Ursolic acid or the vehicle solution was orally administered to the experimental, sham-operated and vehicle-treated group mice for 7 days, positive control animal (mice) was treated with recombinant human hepatocyte growth factor (rhHGF), and then the 70% liver partial hepatectomy was performed. The liver mass recovery rate was estimated by measuring the ratios of mice liver weight to body weight. The liver cells undergoing DNA synthesis were identified by immunohistochemistry analysis using monoclonal anti-BrdU antibodies. The expression levels of cyclin D1, cyclin E and C/EBP proteins (C/EBPα and C/EBPβ) were detected by the Western blotting technique. RESULTS Our results showed administration of ursolic acid significantly increased the ratio of the liver to body weight and BrdU labeling index at 36 and 48 h after partial hepatectomy, and the potency of UA is similar to rhHGF treated positive control mice. In addition, ursolic acid treatment significantly increased cyclin D1, cyclin E and C/EBPβ protein expression levels at 36 h after liver PHx compared with the vehicle-treated control mice. DISCUSSION AND CONCLUSION All these results suggest that ursolic acid stimulates liver proliferation after partial hepatectomy, and this effect may be associated with the stimulation of C/EBPβ expression.
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Affiliation(s)
- Yong-Ri Jin
- Department of Gastroenterology and Hepatology, the Affiliated Hospital of Yanbian University, 119 Juzi Street, Yanji 133000, Jilin Province, China
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Zhong Y, Dai Z, Xu Y, Teng Y, Wu B. Synthesis, stability and pharmacological evaluation of a novel codrug consisting of lamivudine and ursolic acid. Eur J Pharm Sci 2012; 45:110-5. [PMID: 22085635 DOI: 10.1016/j.ejps.2011.10.028] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2011] [Revised: 10/29/2011] [Accepted: 10/29/2011] [Indexed: 10/15/2022]
Abstract
A novel codrug (LMX) was obtained from lamivudine (LMV) and ursolic acid (UA) coupled with ethyl chloroacetate through an amide and ester linkage. The structure of LMX was confirmed by ¹H NMR, ¹³C NMR, IR and HRMS. Herein, the in vitro non-enzymatic and enzymatic hydrolysis and in vivo pharmacological activities of LMX were studied. The kinetics of hydrolysis of LMX was studied in aqueous solution of pH 1-10, 80% buffered human plasma and in the presence of lipase from Porcine pancreas (EC 3.1.1.3) at 37°C. It is found that LMX hydrolysis rate was significantly faster in lipase with half-life of 1.4h compared to pH 7.4 phosphate buffer (t(1/2) 11.2h) and buffered human plasma (t(1/2) 5.4h). The decomposition rates in aqueous solution (pH 1-10) showed a U-shaped curve. LMX was comparatively stable between pH 3 and 6 (half-life >40 h). Pharmacological studies indicated that LMX had the dual action of anti-hepatitis B virus activity and hepatoprotective effects against acute liver injury. These findings suggest that LMX could be a promising candidate agent for the treatment of hepatitis.
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Affiliation(s)
- Yan Zhong
- School of Chemistry and Chemical Engineering, Southeast University, Nanjing 210096, PR China
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Ullevig SL, Zhao Q, Zamora D, Asmis R. Ursolic acid protects diabetic mice against monocyte dysfunction and accelerated atherosclerosis. Atherosclerosis 2011; 219:409-16. [PMID: 21752377 PMCID: PMC3199329 DOI: 10.1016/j.atherosclerosis.2011.06.013] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2011] [Revised: 05/20/2011] [Accepted: 06/06/2011] [Indexed: 02/08/2023]
Abstract
AIMS Accelerated atherosclerosis is a major diabetic complication initiated by the enhanced recruitment of monocytes into the vasculature. In this study, we examined the therapeutic potential of the phytonutrients ursolic acid (UA) and resveratrol (RES) in preventing monocyte recruitment and accelerated atherosclerosis. METHODS AND RESULTS Dietary supplementation with either RES or UA (0.2%) protected against accelerated atherosclerosis induced by streptozotocin in high-fat diet-fed LDL receptor-deficient mice. However, mice that received dietary UA for 11 weeks were significantly better protected and showed a 53% reduction in lesion formation while mice fed a RES-supplemented diet showed only a 31% reduction in lesion size. Importantly, UA was also significantly more effective in preventing the appearance of proinflammatory GR-1(high) monocytes induced by these diabetic conditions and reducing monocyte recruitment into MCP-1-loaded Matrigel plugs implanted into these diabetic mice. Oxidatively stressed THP-1 monocytes mimicked the behavior of blood monocytes in diabetic mice and showed enhanced responsiveness to monocyte chemoattractant protein-1 (MCP-1) without changing MCP-1 receptor (CCR2) surface expression. Pretreatment of THP-1 monocytes with RES or UA (0.3-10μM) for 15h resulted in the dose-dependent inhibition of H(2)O(2)-accelerated chemotaxis in response to MCP-1, but with an IC(50) of 0.4μM, UA was 2.7-fold more potent than RES. CONCLUSION Dietary UA is a potent inhibitor of monocyte dysfunction and accelerated atherosclerosis induced by diabetes. These studies identify ursolic acid as a potential therapeutic agent for the treatment of diabetic complications, including accelerated atherosclerosis, and provide a novel mechanism for the anti-atherogenic properties of ursolic acid.
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MESH Headings
- Animals
- Aortic Diseases/etiology
- Aortic Diseases/immunology
- Aortic Diseases/prevention & control
- Atherosclerosis/etiology
- Atherosclerosis/immunology
- Atherosclerosis/prevention & control
- Cardiovascular Agents/pharmacology
- Cell Line
- Chemokine CCL2/metabolism
- Chemotaxis, Leukocyte/drug effects
- Diabetes Mellitus, Experimental/complications
- Diabetes Mellitus, Experimental/drug therapy
- Diabetes Mellitus, Experimental/immunology
- Diabetes Mellitus, Experimental/physiopathology
- Diabetic Angiopathies/etiology
- Diabetic Angiopathies/immunology
- Diabetic Angiopathies/prevention & control
- Dose-Response Relationship, Drug
- Female
- Humans
- Hyperlipidemias/complications
- Hyperlipidemias/genetics
- Hyperlipidemias/metabolism
- Kidney/drug effects
- Kidney/physiopathology
- Macrophages/drug effects
- Macrophages/immunology
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Monocytes/drug effects
- Monocytes/immunology
- Oxidative Stress/drug effects
- Receptors, CCR2/metabolism
- Receptors, LDL/deficiency
- Receptors, LDL/genetics
- Resveratrol
- Stilbenes/pharmacology
- Time Factors
- Triterpenes/pharmacology
- Ursolic Acid
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Affiliation(s)
- Sarah L. Ullevig
- Department of Biochemistry, University of Texas Health Science Center at San Antonio
| | - Qingwei Zhao
- Department of Clinical Laboratory Sciences, University of Texas Health Science Center at San Antonio
| | - Debora Zamora
- Department of Clinical Laboratory Sciences, University of Texas Health Science Center at San Antonio
| | - Reto Asmis
- Department of Biochemistry, University of Texas Health Science Center at San Antonio
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Sultana N. Clinically useful anticancer, antitumor, and antiwrinkle agent, ursolic acid and related derivatives as medicinally important natural product. J Enzyme Inhib Med Chem 2011; 26:616-42. [PMID: 21417964 DOI: 10.3109/14756366.2010.546793] [Citation(s) in RCA: 70] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
Medicinal plants are becoming an important research area for novel and bioactive molecules for drug discovery. Novel therapeutic strategies and agents are urgently needed to treat different incurable diseases. Many plant derived active compounds are in human clinical trials. Currently ursolic acid is in human clinical trial for treating cancer, tumor, and skin wrinkles. This review includes the clinical use of ursolic acid in various diseases including anticancer, antitumor, and antiwrinkle chemotherapies, and the isolation and purification of this tritepernoid from various plants to update current knowledge on the rapid analysis of ursolic acid by using analytical methods. In addition, the chemical modifications of ursolic acid to make more effective and water soluble derivatives, previous and current information regarding, its natural and semisynthetic analogs, focusing on its anticancer, cytotoxic, antitumor, antioxidant, anti-inflammatory, anti-HIV, acetyl cholinesterase, α-glucosidase, antimicrobial, and hepatoprotective activities, briefly discussion is attempted here for its research perspectives. This review article contains fourteen medicinally important ursolic acid derivatives and 351 references.
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Affiliation(s)
- Nighat Sultana
- Pharmaceutical Research Center, PCSIR Laboratories Complex, Karachi, Pakistan.
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Freitas FFBP, Fernandes HB, Piauilino CA, Pereira SS, Carvalho KIM, Chaves MH, Soares PMG, Miura LMCV, Leite JRSA, Oliveira RCM, Oliveira FA. Gastroprotective activity of Zanthoxylum rhoifolium Lam. in animal models. JOURNAL OF ETHNOPHARMACOLOGY 2011; 137:700-708. [PMID: 21723384 DOI: 10.1016/j.jep.2011.06.026] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/31/2011] [Revised: 06/14/2011] [Accepted: 06/15/2011] [Indexed: 05/31/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE The stem barks of Zanthoxylum rhoifolium Lam. (Rutaceae), locally known as "mamica de cadela", are popularly used in dyspepsies, stomachic, tonic, antitumoral, antipyretic and are used in treating flatulence and colic. The objective of this study was to evaluate the gastroprotective effect of the ethanolic extract of Zanthoxylum rhoifolium (EEZR) stem barks in acute gastric lesion models, investigating their possible mechanisms. MATERIALS AND METHODS Mice were used for the evaluation of the acute toxicity, and mice and rats to study the gastroprotective activity. The gastroprotective action of EEZR was analyzed in the absolute ethanol, HCl/ethanol and indomethacin-induced gastric lesion models in mice, hypothermic-restraint stress, and ischemia/reperfusion in rats. In the investigation of the gastroprotective mechanisms of EEZR, the participation of the NO-synthase pathway, ATP-sensitive potassium channels (K(ATP)), the levels of the non-protein sulfhydril groups (NP-SH) and the catalase activity using the ethanol-induced gastric mucosa lesion model and the quantification of the gastric mucus and the antisecretory activity through pylorus ligature model in rats were analyzed. RESULTS The animals did not present any signs of acute toxicity for the EEZR (up to the 4 g/kg dose, po), and it was not possible to calculate the DL(50). EEZR (125-500 mg/kg) exhibited a significant gastroprotective effect in absolute ethanol, HCl/ethanol, hypothermic-restraint stress, and ischemia/reperfusion-induced gastric lesion models. EEZR (250 and 500 mg/kg) exhibited still a gastroprotective activity in the indomethacin-induced ulcer model. Gastroprotection of EEZR was significantly decreased in pre-treated mice with l-NAME or glibenclamide, the respective nitric oxide synthase and K(ATP) channels inhibitors. Our studies revealed that EEZR (500 mg/kg) prevented the decrease of the non-protein sulfhydril groups (NP-SH) and increased the catalase levels in ethanol-treated animals. Furthermore, the extract (500 mg/kg) significantly increased the mucus production, however, the gastric secretion parameters (volume, [H(+)], pH) did not show any alteration. CONCLUSIONS Our results indicate that the ethanolic extract of Zanthoxylum rhoifolium exhibits a significant gastroprotection, because it inhibits the formation of gastric lesions using different models. The release of the nitric oxide, the opening of the K(ATP) channels, the participation of the non-protein sulfhydril groups (NP-SH), catalase and the increase of mucous secretion seem to be involved in the gastroprotection activity of the EEZR. Nevertheless, this activity does not seem to be related to antisecretory mechanisms.
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Affiliation(s)
- F F B P Freitas
- Medicinal Plants Research Center, Federal University of Piauí, Teresina, PI, Brazil
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Wang X, Ikejima K, Kon K, Arai K, Aoyama T, Okumura K, Abe W, Sato N, Watanabe S. Ursolic acid ameliorates hepatic fibrosis in the rat by specific induction of apoptosis in hepatic stellate cells. J Hepatol 2011; 55:379-87. [PMID: 21168456 DOI: 10.1016/j.jhep.2010.10.040] [Citation(s) in RCA: 65] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2010] [Revised: 10/18/2010] [Accepted: 10/28/2010] [Indexed: 01/01/2023]
Abstract
BACKGROUND & AIMS Specific induction of cell death in activated hepatic stellate cells (HSCs) is a promising therapeutic strategy for hepatic fibrosis. In this study, we evaluated the cell-killing effect of ursolic acid (UA), a pentacyclic triterpenoid, in activated HSCs both in vitro and in vivo. METHODS Culture-activated rat HSCs were treated with UA (0-40μM), and the mechanisms of cell death were evaluated. The cell killing effect of UA on activated HSCs in rats chronically treated with thioacetamide (TAA) was detected by dual staining of TdT-mediated dUTP nick-end labeling (TUNEL) and smooth muscle α-actin (αSMA) immunohistochemistry, and resolution of hepatic fibrosis was evaluated. Further, the protective effects of UA on progression of hepatic fibrosis caused by TAA and bile duct ligation (BDL) were evaluated. RESULTS UA induced apoptotic cell death in culture-activated HSCs, but not in isolated hepatocytes and quiescent HSCs. Mitochodrial permeability transition (MPT) preceded the cleavage of caspase-3 and -9 following UA treatment. UA also decreased phosphorylation levels of Akt, and diminished nuclear localization of NFκB in these cells. In rats pretreated with TAA for 6weeks, a single injection of UA induced remarkable increases in TUNEL- and αSMA-dual-positive cells in 24h, and significant regression of hepatic fibrosis within 48h. Moreover, UA ameliorated hepatic fibrogenesis caused by both chronic TAA administration and BDL. CONCLUSIONS UA ameliorated experimental hepatic fibrosis most likely through specific induction of apoptosis in activated HSCs. It is therefore postulated that UA is a potential therapeutic reagent for resolution of hepatic fibrosis.
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Affiliation(s)
- Xu Wang
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
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Bachhav SS, Patil SD, Bhutada MS, Surana SJ. Oleanolic acid prevents glucocorticoid-induced hypertension in rats. Phytother Res 2011; 25:1435-9. [PMID: 21953707 DOI: 10.1002/ptr.3431] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2010] [Revised: 01/05/2011] [Accepted: 01/06/2011] [Indexed: 11/05/2022]
Abstract
The present study was designed to evaluate the antihypertensive activity of oleanolic acid isolated from Viscum articulatum, Burm. (Loranthaceae) in glucocorticoid (dexamethasone)-induced hypertension in rats and to propose a probable mechanism of action for this effect. Male Wistar rats (300-350 g) received dexamethasone (20 μg/kg/day s.c.) or saline (vehicle) for 10 days. In a prevention study, the rats received oleanolic acid (60 mg/kg i.p.) for 5 days, followed by dexamethasone or saline for 10 days. During this period the systolic blood pressure and body weight were evaluated on alternate days. At the end of the experiment, the weight of the thymus gland, plasma nitrate/nitrite (nitric oxide metabolites) concentration and cardiac lipid peroxidation value were determined. Oleanolic acid (60 mg/kg i.p.) significantly prevented a rise in the systolic blood pressure and cardiac lipid peroxidation level after administration of dexamethasone (p < 0.01 and p < 0.05, respectively) without showing any significant effect on the dexamethasone-induced change in body and thymus weights. The decrease in concentration of plasma nitrate/nitrite due to dexamethasone was prevented significantly in the group treated with oleanolic acid (p < 0.05). These findings suggest that oleanolic acid (60 mg/kg i.p.) prevents dexamethasone-induced hypertension in rats, which may be attributed to its antioxidant and nitric oxide releasing action.
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Affiliation(s)
- Sagar S Bachhav
- Department of Pharmacology, R C Patel Institute of Pharmaceutical Education and Research, Shirpur, District Dhule, Maharashtra, India
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Li Y, Kang Z, Li S, Kong T, Liu X, Sun C. Ursolic acid stimulates lipolysis in primary-cultured rat adipocytes. Mol Nutr Food Res 2010; 54:1609-17. [PMID: 20521271 DOI: 10.1002/mnfr.200900564] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Ursolic acid (UA) is a pentacyclic triterpenic acid with many biological functions naturally existing in many kinds of food. To investigate whether UA can accelerate lipolysis, primary-cultured rat adipocytes were treated with UA, and glycerol release in the culture medium was measured. UA stimulated lipolysis significantly. Furthermore, the lipolytic effect of UA was inhibited by the protein kinase A (PKA) specific inhibitor H89, suggesting that UA exerted its lipolytic function through the cAMP-dependent PKA pathway. Downstream targets of the PKA pathway, hormone-sensitive lipase (HSL) and perilipin A were checked, UA enhanced lipolysis by promoting the translocation of HSL from the cytosol to the lipid droplets and inhibiting the expression of perilipin A. Additionally, adipose triglyceride lipase (ATGL), a novel rate-limiting lipase in the lipolytic catabolism, was upregulated by UA. UA-induced expression of ATGL could not be blocked by H89, suggesting that ATGL upregulation is not regulated by the PKA pathway. These findings suggest that UA significantly stimulates lipolysis by translocating HSL, decreasing perilipin A expression by the PKA pathway, and up-regulating ATGL in primary cultured adipocytes. Thus, UA is a promising candidate for the treatment of obesity.
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Affiliation(s)
- Ying Li
- Department of Nutrition and Food Hygiene, Public Health College, Harbin Medical University, Harbin, PR China
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Klaassen CD, Reisman SA. Nrf2 the rescue: effects of the antioxidative/electrophilic response on the liver. Toxicol Appl Pharmacol 2010; 244:57-65. [PMID: 20122946 DOI: 10.1016/j.taap.2010.01.013] [Citation(s) in RCA: 303] [Impact Index Per Article: 20.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2009] [Revised: 12/23/2009] [Accepted: 01/26/2010] [Indexed: 02/06/2023]
Abstract
Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that positively regulates the basal and inducible expression of a large battery of cytoprotective genes. These gene products include proteins that catalyze reduction reactions (NAD(P)H:quinone oxidoreductase 1, Nqo1), conjugation reactions (glutathione-S-transferases, Gsts and UDP-glucuronosyltransferases, Ugts), as well as the efflux of potentially toxic xenobiotics and xenobiotic conjugates (multidrug resistance-associated proteins, Mrps). The significance of Nrf2 in the liver has been established, as livers of Nrf2-null mice are more susceptible to various oxidative/electrophilic stress-induced pathologies than wild-type mice. In contrast, both pharmacological and genetic models of hepatic Nrf2 activation are protective against oxidative/electrophilic stress. Furthermore, because certain Nrf2-target genes in the liver could affect the distribution, metabolism, and excretion of xenobiotics, the effects of Nrf2 on the kinetics of drugs and other xenobiotics should also be considered, with a special emphasis on metabolism and excretion. Therefore, this review highlights the research that has contributed to the understanding of the importance of Nrf2 in toxicodynamics and toxicokinetics, especially that which pertains to the liver.
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Affiliation(s)
- Curtis D Klaassen
- Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160-7417, USA.
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Zhou XF, Zhang P, Pi HF, Zhang YH, Ruan HL, Wang H, Wu JZ. Triterpenoids from the roots of Actinidia chinensis. Chem Biodivers 2009; 6:1202-7. [PMID: 19697338 DOI: 10.1002/cbdv.200800214] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Two new triterpenoids, 1 and 2, were isolated from the hepatoprotective AcOEt fraction of the roots of Actinidia chinensis, together with eight known 12-en-28-oic acids of oleanane or ursane type, 3-10. The two new compounds were elucidated as 2alpha,3beta-dihydroxyurs-12-en-28,30-olide (1) and 2alpha,3beta,24-trihydroxyurs-12-en-28,30-olide (2), on the basis of spectroscopic (IR, NMR, and MS) analyses. The chemotaxonomic significances of some triterpenoids were also discussed.
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Affiliation(s)
- Xue-Feng Zhou
- Key Laboratory of Marine Bio-resources Sustainable Utilization, South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou, PR China
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Lee MK, Kim SH, Yang H, Lim DY, Ryu JH, Lee ES, Jew SS, Park HG, Sung SH, Kim YC. Asiatic Acid Derivatives Protect Primary Cultures of Rat Hepatocytes against Carbon Tetrachloride-Induced Injury via the Cellular Antioxidant System. Nat Prod Commun 2009. [DOI: 10.1177/1934578x0900400605] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
We attempted to elucidate the hepatoprotective mechanism of two asiatic acid (AS) derivatives, 3β,23-dihydroxyurs-2-oxo-12-ene-28-oic acid (AS-10) and 3β,23-dihydroxyurs-12-ene-28-oic acid (AS-14), which exhibited significant protective activity against carbon tetrachloride (CCl4)-induced hepatotoxicity in primary cultures of rat hepatocytes. Our findings showed that AS-10 and AS-14 preserved the level of glutathione and the activities of antioxidant enzymes such as glutathione reductase, glutathione peroxidase, superoxide dismutase and catalase. In addition, these compounds ameliorated lipid peroxidation, as demonstrated by a reduction in the production of malondialdehyde. Furthermore, AS-10 and AS-14 did not restore the reduced total GSH level by BSO, indicating that the hepatoprotective activities of these compounds may be involved, in part, by regulating GSH synthesis. From these results, we suggest that both AS-10 and AS-14 exerted their hepatoprotective activities against CCl4-induced injury by preserving the cellular antioxidative defense system.
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Affiliation(s)
- Mi Kyeong Lee
- College of Pharmacy and Research Institute of Pharmaceutical Science, Seoul National University, 599 Gwanak-Ro, Gwanak-Gu, Seoul 151-742, Republic of Korea
| | - Seung Hyun Kim
- College of Pharmacy and Research Institute of Pharmaceutical Science, Seoul National University, 599 Gwanak-Ro, Gwanak-Gu, Seoul 151-742, Republic of Korea
| | - Hyekyung Yang
- College of Pharmacy and Research Institute of Pharmaceutical Science, Seoul National University, 599 Gwanak-Ro, Gwanak-Gu, Seoul 151-742, Republic of Korea
| | - Doo-Yeon Lim
- College of Pharmacy and Research Institute of Pharmaceutical Science, Seoul National University, 599 Gwanak-Ro, Gwanak-Gu, Seoul 151-742, Republic of Korea
| | - Je-Ho Ryu
- College of Pharmacy and Research Institute of Pharmaceutical Science, Seoul National University, 599 Gwanak-Ro, Gwanak-Gu, Seoul 151-742, Republic of Korea
| | - Eung Seok Lee
- College of Pharmacy, Yeungnam University, 214-1 Dae-Dong, Gyeongsan 712-749, Republic of Korea
| | - Sang-Sup Jew
- College of Pharmacy and Research Institute of Pharmaceutical Science, Seoul National University, 599 Gwanak-Ro, Gwanak-Gu, Seoul 151-742, Republic of Korea
| | - Hyeung-Guen Park
- College of Pharmacy and Research Institute of Pharmaceutical Science, Seoul National University, 599 Gwanak-Ro, Gwanak-Gu, Seoul 151-742, Republic of Korea
| | - Sang Hyun Sung
- College of Pharmacy and Research Institute of Pharmaceutical Science, Seoul National University, 599 Gwanak-Ro, Gwanak-Gu, Seoul 151-742, Republic of Korea
| | - Young Choong Kim
- College of Pharmacy and Research Institute of Pharmaceutical Science, Seoul National University, 599 Gwanak-Ro, Gwanak-Gu, Seoul 151-742, Republic of Korea
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Mukherjee PK, Sahoo AK, Narayanan N, Kumar NS, Ponnusankar S. Lead finding from medicinal plants with hepatoprotective potentials. Expert Opin Drug Discov 2009; 4:545-76. [DOI: 10.1517/17460440902911433] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
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Reisman SA, Aleksunes LM, Klaassen CD. Oleanolic acid activates Nrf2 and protects from acetaminophen hepatotoxicity via Nrf2-dependent and Nrf2-independent processes. Biochem Pharmacol 2009; 77:1273-82. [PMID: 19283895 DOI: 10.1016/j.bcp.2008.12.028] [Citation(s) in RCA: 144] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Oleanolic acid is a plant-derived triterpenoid, which protects against various hepatotoxicants in rodents. In order to determine whether oleanolic acid activates nuclear factor erythroid 2-related factor 2 (Nrf2), a transcription factor known to induce various antioxidant and cytoprotective genes, wild-type and Nrf2-null mice were treated with oleanolic acid (90 mg/kg, i.p.) once daily for 3 days. Oleanolic acid increased nuclear accumulation of Nrf2 in wild-type but not Nrf2-null mice, as determined by Western blot and immunofluorescence. Oleanolic acid-treated wild-type mice had increased hepatic mRNA expression of the Nrf2 target genes NAD(P)H:quinone oxidoreductase 1 (Nqo1); glutamate-cysteine ligase, catalytic subunit (Gclc); heme oxygenase-1 (Ho-1); as well as Nrf2 itself. In addition, oleanolic acid increased protein expression and enzyme activity of the prototypical Nrf2 target gene, Nqo1, in wild-type, but not in Nrf2-null mice. Oleanolic acid protected against acetaminophen hepatotoxicity in wild-type mice but to a lesser extent in Nrf2-null mice. Oleanolic acid-mediated Nrf2-independent protection from acetaminophen is, in part, due to induction of Nrf2-independent cytoprotective genes, such as metallothionein. Collectively, the present study demonstrates that oleanolic acid facilitates Nrf2 nuclear accumulation, causing induction of Nrf2-dependent genes, which contributes to protection from acetaminophen hepatotoxicity.
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Affiliation(s)
- Scott A Reisman
- Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, 66160-7417, USA
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43
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Conklin DR, Cowan KS, Aschner M. Detection of Metallothionein (MT) Proteins with Radiolabeled [14C]Iodoacetamide. ACTA ACUST UNITED AC 2008. [DOI: 10.3109/15376519609068460] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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Abstract
There is growing interest in the elucidation of the biological functions of triterpenoids, ubiquitously distributed throughout the plant kingdom, some of which are used as anticancer and anti-inflammatory agents in Asian countries. Ursolic acid (UA), a natural pentacyclic triterpenoid carboxylic acid, is the major component of some traditional medicine herbs and is well known to possess a wide range of biological functions, such as antioxidative, anti-inflammation, and anticancer activities, that are able to counteract endogenous and exogenous biological stimuli. In contrast to these beneficial properties, some laboratory studies have recently revealed that the effects of UA on normal cells and tissues are occasionally pro-inflammatory. Thus, UA may be designated as a double-edged sword with both positive and negative effects, and further evaluations of the effects of UA on the biological status of target cells or tissues are necessary. This review summarizes previous and current information regarding UA, and provides new insights into the underlying molecular mechanisms of its activities.
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Affiliation(s)
- Yasutaka Ikeda
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto, Japan
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Lee JR, Park SJ, Lee HS, Jee SY, Seo J, Kwon YK, Kwon TK, Kim SC. Hepatoprotective Activity of Licorice Water Extract against Cadmium-induced Toxicity in Rats. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2007; 6:195-201. [PMID: 18955229 PMCID: PMC2686628 DOI: 10.1093/ecam/nem078] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Licorice is commonly used as a cure for digestive disorders and as a detoxification agent in East Asia. This study investigated the protective effect of licorice water extract against cadmium (CdCl2, Cd)-induced liver toxicity in rats. To induce acute toxicity, Cd (4 mg/kg body weight) was dissolved in normal saline and intravenously (i.v.) injected into rats. The rats then received either a vehicle or licorice water extract (50, 100 mg/kg/day) for 3 days, and were subsequently exposed to a single injection of Cd 24 h after the last licorice/vehicle treatment. Alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) were significantly increased by Cd treatment. In contrast, pretreatment with licorice reduced ALT, AST and LDH. In histopathological analysis, licorice decreased the central necrosis around central veins, the peripheral hemorrhage around portal triads, the percentage of degenerative hepatic regions (%/mm2 hepatic parenchyma) and the number of degenerative hepatic cells (N/100 hepatic cells). Licorice also inhibited the increment of Bad (a BH3 domain-containing protein) translocation by Cd in liver cells. These results demonstrate that licorice could have a hepatoprotective effect by inhibiting the translocation of Bad to the mitochondria in Cd-intoxificated rats.
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Affiliation(s)
- Jong Rok Lee
- College of Oriental Medicine, Daegu Haany University, 165 Sang-dong, Suseong-gu, Daegu 706-828, Republic of Korea.
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Sudhahar V, Kumar SA, Varalakshmi P, Sundarapandiyan R. Mitigating role of lupeol and lupeol linoleate on hepatic lipemic-oxidative injury and lipoprotein peroxidation in experimental hypercholesterolemia. Mol Cell Biochem 2006; 295:189-98. [PMID: 16933029 DOI: 10.1007/s11010-006-9288-2] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2006] [Accepted: 07/24/2006] [Indexed: 11/26/2022]
Abstract
In the present study, the role of pentacyclic triterpenes, lupeol and its ester lupeol linoleate, was studied in relation to hepatic oxidative abnormalities and lipoprotein peroxidation in hypercholesterolemic rats. Hypercholesterolemia was induced in male Wistar rats by feeding them with high cholesterol diet (4% cholesterol + 1% cholic acid; HCD) for 30 days. Pentacyclic triterpenes, lupeol and lupeol linoleate were supplemented (50 mg/kg body wt/day) during the last 15 days. After the experimental period, there was a significant depression in hepatic activities of antioxidant enzymes, SOD (38.39%), CAT (25.03%) and GPx (30.26%) along with a marked fall in the levels of non-enzymic antioxidant molecules GSH (31.39%), vitamin C (46.07%) and vitamin E (42.28%), with a concomitant increase (p<0.001) in lipid peroxidation and in the activities of serum alkaline phosphatase, lactate dehydrogenase and aminotransferases when compared to controls. Treatment with triterpenes decreased lipid peroxidation and reverted the activities of antioxidants (p<0.001 and p<0.01) and marker enzymes to near control. Histopathological findings further confirmed the hepatoprotective nature of triterpenes by showing the normal architecture in treated rats, as against the fatty cellular changes in HCD fed rats. Further, the susceptibility of apo-B containing lipoprotein to oxidation by copper and Fenton's reagent was increased in in vitro condition in HCD fed rats, whereas the lipoproteins were less susceptible to oxidation in triterpenes treated animals. Therefore, it may be concluded that lupeol and its ester afford protection against the hepatic abnormalities and lipoprotein peroxidation in hypercholesterolemic rats.
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Affiliation(s)
- V Sudhahar
- Department of Medical Biochemistry, Dr. ALM. Postgraduate Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai, 600 113, India
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Abdel-Wahhab MA, Ahmed HH, Hagazi MM. Prevention of aflatoxin B1-initiated hepatotoxicity in rat by marine algae extracts. J Appl Toxicol 2006; 26:229-38. [PMID: 16389658 DOI: 10.1002/jat.1127] [Citation(s) in RCA: 73] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Chemoprevention by extracts of Laurencia obtusa (E1) and Caulerpa prolifera (E2) collected from the Egyptian coast of the Red Sea against aflatoxin B(1) (AFB(1))-initiated hepatotoxicity in female Sprague-Dawley rats has been studied. Animals were fed aflatoxin-contaminated diet (3 mg kg(-1) diet) for 6 days then treated orally with pure aflatoxin B(1) (AFB(1)) (200 microg kg(-1) b.w.) for 4 days either in combination with or before E1 or E2 administration (50 mg kg(-1) b.w.). AFB(1) resulted in a signicant increase in serum alpha fetoprotein, carcinoembryonic antigen, tumor necrosis factor alpha, nitric oxide, interleukin-1alpha, procollagen III and lipid peroxidation level in the liver. It caused a signicant decrease in food intake, body weight, serum leptin, the activities of glutathione peroxidase, superoxide dismutase and DNA and RNA concentrations in the liver. Cotreatment with AFB(1) and E1 or E2 resulted in an obvious improvement in all tested parameters. Noteworthy, E2 was more effective than E1 in the protection against AFB(1)-induced hepatotoxicity.
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Affiliation(s)
- Mosaad A Abdel-Wahhab
- Food Toxicology and Contaminants Department, National Research Center, Dokki, Cairo, Egypt.
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48
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Oh SH, Choi JE, Lim SC. Protection of betulin against cadmium-induced apoptosis in hepatoma cells. Toxicology 2006; 220:1-12. [PMID: 16436312 DOI: 10.1016/j.tox.2005.08.025] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2005] [Revised: 08/12/2005] [Accepted: 08/26/2005] [Indexed: 02/07/2023]
Abstract
The protective effects of betulin (BT) against cadmium (Cd)-induced cytotoxicity have been previously reported. However, the mechanisms responsible for these protective effects are unclear. Therefore, this study investigated the mechanisms responsible for the protection of BT against Cd-induced cytotoxicity in human hepatoma cell lines. The protection of BT against Cd cytotoxicity was more effective in the HepG2 than in the Hep3B cells. The protection of BT on Cd-induced cytotoxicity in the HepG2 cells appeared to be related to the inhibition of apoptosis, as determined by PI staining and DNA fragmentation analysis. The anti-apoptosis exerted by BT involved the blocking of Cd-induced reactive oxygen species (ROS) generation, the abrogation of the Cd-induced Fas upregulation, the blocking of caspase-8-dependent Bid activation, and subsequent inhibition of mitochondrial pathway. The BT pretreatment did not affect the p21 and p53 expression levels, when compared with those of the treated cells with Cd alone. BT induced the transient S phase arrest at an early stage and the G0/G1 arrest at a relatively late stage, but it did not observe the sub-G1 apoptotic peak. In the Hep3B cells, Cd did not induce ROS generation. The BT pretreatment partially inhibited the Cd-induced apoptosis, which was related with the incomplete blockage in caspase-9 or -3 activation, as well as in Bax activation. Taken together, it was found that Cd can induce apoptosis via the Fas-dependent and -independent apoptosis pathways. However, the observed protective effects of BT were clearly more sensitive to Fas-expressing HepG2 cells than to Fas-deficient Hep3B cells.
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Affiliation(s)
- Seon-Hee Oh
- Research Center for Resistant Cells, College of Medicine, Chosun University, Dong-gu, Gwangju 501-759, Republic of Korea
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Tian Z, Lin G, Zheng RX, Huang F, Yang MS, Xiao PG. Anti-hepatoma activity and mechanism of ursolic acid and its derivatives isolated from Aralia decaisneana. World J Gastroenterol 2006; 12:874-9. [PMID: 16521214 PMCID: PMC4066151 DOI: 10.3748/wjg.v12.i6.874] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2005] [Revised: 07/23/2005] [Accepted: 07/29/2005] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the anti-tumor activity of ursolic acid (UA) and its derivatives isolated from Aralia decaisneana on hepatocellular carcinoma both in vitro and in vivo. METHODS In vivo cytotoxicity was first screened by 3-[4,5-dimethylthiazol-2-yl]-2, 5-diphenyltetrazolium bromide (MTT) assay. Morphological observation, DNA ladder, flow cytometry analysis, Western blot and real time PCR were employed to elucidate the cytotoxic mechanism of UA. Implanted mouse hepatoma H22 was used to evaluate the growth inhibitory effect of UA in vivo. RESULTS UA could significantly inhibit the proliferation of HepG2 and its drug-resistance strain, R-HepG2 cells, but had no inhibitory effect on primarily cultured normal mouse hepatocytes whereas all the six derivatives of UA could not inhibit the growth of all tested cell lines. Further study on mechanism demonstrated that apoptosis and G0/G1 arrest were involved in the cytotoxicity and cleavage of poly-(ADP-ribose)-polymerase (PARP). Downregulation of cyclooxygenase-2 (COX-2) protein and upregulation of heat shock protein (HSP) 105 mRNA correlated to the apoptosis of HepG2 cells treated with UA. In addition, UA also could inhibit the growth of H22 hepatoma in vivo. CONCLUSION UA is a promising anti-tumor agent, but further work needs to be done to improve its solubility.
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Affiliation(s)
- Ze Tian
- Department of Pharmacology, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100094, China.
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50
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Dzubak P, Hajduch M, Vydra D, Hustova A, Kvasnica M, Biedermann D, Markova L, Urban M, Sarek J. Pharmacological activities of natural triterpenoids and their therapeutic implications. Nat Prod Rep 2006; 23:394-411. [PMID: 16741586 DOI: 10.1039/b515312n] [Citation(s) in RCA: 466] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Affiliation(s)
- Petr Dzubak
- Laboratory of Experimental Medicine, Department of Pediatrics, Faculty of Medicine, Palacky University and Faculty Hospital in Olomouc, Czech Republic
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