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Deng S, Liu Y, Liu X, Yu J, Chen Y, Huo J. Inhibition of colorectal cancer aggressiveness by Oleanolic acid through Nur77 degradation. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 135:156192. [PMID: 39520953 DOI: 10.1016/j.phymed.2024.156192] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Revised: 10/17/2024] [Accepted: 10/24/2024] [Indexed: 11/16/2024]
Abstract
BACKGROUND Colorectal cancer (CRC) is the second primary malignancy in China with tough treatment challenge. Although Oleanolic acid (OA) protects against various cancers, its mechanisms in CRC are not well defined. Our previously study showed that Nur77 has CRC promoting effect. Thus, we investigated the roles of OA as Nur77 ligand and the regulatory effects on Nur77 degradation in CRC progression. METHODS The proliferative and metastatic phenotypes of OA was examined by CCK-8, EdU, organoid culture, would healing and transwell assays, respectively. Epithelial-mesenchymal transition (EMT) properties were assessed by Western blotting (WB). The interaction between OA and Nur77 was monitored by molecular docking and Molecular Dynamics stimulation (MD). Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene set enrichment analysis (GSEA) were employed to screen the downstream regulatory pathways. The half-time and proteasome degradation of Nur77 were treated with cycloheximide (CHX) and MG132. Co-immunoprecipitation (Co-IP) and ubiquitination assays were employed to detect direct association between Nur77 and PPARγ. Rescued experiments were performed by Nur77 agonist Cytosporone B (Csn-B) treatment. The findings were verified in xenograft and in situ models. RESULTS For the first time, we found the effect of OA on ubiquitination degradation. OA inhibited CRC cell survival and EMT phenotypes by suppressing Nur77. Mechanistically, OA directly bind to Nur77 and facilitated the ubiquitin degradation of Nur77. During this process, PPARγ acted as the ubiquitination activator via interacting with Nur77. Rescued experiments revealed that OA-induced inhibition was recovered by replenishing Nur77. In both subcutaneous and orthotopic CRC models, OA exhibited significant anti-tumor effect together with Nur77 inhibition. CONCLUSION We revealed a new regulatory effect of OA in CRC tumorigenesis via PPARγ-mediated Nur77 ubiquitin degradation.
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Affiliation(s)
- Shan Deng
- The Third Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, 210023, People's Republic of China.
| | - Yuping Liu
- The Third Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, 210023, People's Republic of China
| | - Xiyu Liu
- Division of Sports Medicine and Adult Reconstructive Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, 321 Zhongshan Road, Nanjing, 210008, People's Republic of China
| | - Jialin Yu
- The Third Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, 210023, People's Republic of China
| | - Yan Chen
- The Third Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, 210023, People's Republic of China; Research Center for Multicomponent of Traditional Chinese Medicine and Microecology, Jiangsu Provincial Academy of Chinese Medicine, 100 Shizi Road, Nanjing, Jiangsu, 210028, People's Republic of China.
| | - Jiege Huo
- The Third Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, 210023, People's Republic of China; Department of Oncology, Jiangsu Province Academy of Traditional Chinese Medicine, 100 Shizi Road, Nanjing, Jiangsu, 210028, People's Republic of China.
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Jannus F, Sainz J, Reyes-Zurita FJ. Principal Bioactive Properties of Oleanolic Acid, Its Derivatives, and Analogues. Molecules 2024; 29:3291. [PMID: 39064870 PMCID: PMC11279785 DOI: 10.3390/molecules29143291] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2024] [Revised: 07/10/2024] [Accepted: 07/10/2024] [Indexed: 07/28/2024] Open
Abstract
Natural products have always played an important role in pharmacotherapy, helping to control pathophysiological processes associated with human disease. Thus, natural products such as oleanolic acid (OA), a pentacyclic triterpene that has demonstrated important activities in several disease models, are in high demand. The relevant properties of this compound have motivated re-searchers to search for new analogues and derivatives using the OA as a scaffold to which new functional groups have been added or modifications have been realized. OA and its derivatives have been shown to be effective in the treatment of inflammatory processes, triggered by chronic diseases or bacterial and viral infections. OA and its derivatives have also been found to be effective in diabetic disorders, a group of common endocrine diseases characterized by hyperglycemia that can affect several organs, including the liver and brain. This group of compounds has been reported to exhibit significant bioactivity against cancer processes in vitro and in vivo. In this review, we summarize the bioactive properties of OA and its derivatives as anti-inflammatory, anti-bacterial, antiviral, anti-diabetic, hepatoprotective, neuroprotective, and anticancer agents.
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Affiliation(s)
- Fatin Jannus
- Department of Biochemistry and Molecular Biology I, Faculty of Sciences, University of Granada, Av. Fuentenueva, 18071 Granada, Spain;
| | - Juan Sainz
- Department of Biochemistry and Molecular Biology I, Faculty of Sciences, University of Granada, Av. Fuentenueva, 18071 Granada, Spain;
- Genomic Oncology Area, GENYO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, Av. de la Ilustración, 114, PTS, 18016 Granada, Spain
- Instituto de Investigación Biosanitaria IBs.Granada, 18010 Granada, Spain
- Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), University of Barcelona, 08908 Barcelona, Spain
| | - Fernando J. Reyes-Zurita
- Department of Biochemistry and Molecular Biology I, Faculty of Sciences, University of Granada, Av. Fuentenueva, 18071 Granada, Spain;
- Instituto de Investigación Biosanitaria IBs.Granada, 18010 Granada, Spain
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Yenigün S, Başar Y, İpek Y, Behçet L, Özen T, Demirtaş İ. Determination of antioxidant, DNA protection, enzyme inhibition potential and molecular docking studies of a biomarker ursolic acid in Nepeta species. J Biomol Struct Dyn 2024; 42:5799-5816. [PMID: 37394807 DOI: 10.1080/07391102.2023.2229440] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Accepted: 06/17/2023] [Indexed: 07/04/2023]
Abstract
Ursolic acid (UA), which has many biological properties such as anti-cancer, anti-inflammatory and antioxidant, and regulates some pharmacological processes, has been isolated from the flowers, leaves, berries and fruits of many plant species. In this work, UA was purified from the methanol-chloroform crude extract of Nepeta species (N. aristata, N. baytopii, N. italica, N. trachonitica, N. stenantha) using a silica gel column with chloroform or ethyl acetate solvents via bioactivity-guided isolation. The most active sub-fractions were determined under bioactivities using antioxidant and DNA protection activities and enzyme inhibitions. UA was purified from these fractions and its structure was elucidated by NMR spectroscopy techniques. The highest amount of UA was found in N. stenantha (8.53 mg UA/g), while the lowest amount of UA was found in N. trachonitica (1.92 mg UA/g). The bioactivities of UA were evaluated with antioxidant and DNA protection activities, enzyme inhibitions, kinetics and interactions. The inhibition values (IC50) of α-amylase, α-glucosidase, urease, CA, tyrosinase, lipase, AChE, and BChE were determined between 5.08 and 181.96 µM. In contrast, Ki values of enzyme inhibition kinetics were observed between 0.04 and 0.20 mM. In addition, Ki values of these enzymes for enzyme-UA interactions were calculated as 0.38, 0.86, 0.45, 1.01, 0.23, 0.41, 0.01 and 2.24 µM, respectively. It is supported that UA can be widely used as a good antioxidant against oxidative damage, an effective DNA protector against genetic diseases, and a suitable inhibitor for metabolizing enzymes.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Semiha Yenigün
- Faculty of Science, Department of Chemistry, Ondokuz Mayıs University, Samsun, Turkey
| | - Yunus Başar
- Faculty of Arts and Sciences, Department of Biochemistry, Iğdır University, Iğdır, Turkey
| | - Yaşar İpek
- Faculty of Science, Department of Chemistry, Çankırı Karatekin University, Çankırı, Turkey
| | - Lütfi Behçet
- Faculty of Arts and Sciences, Department of Molecular Biology and Genetics, Bingöl University, Bingöl, Turkey
| | - Tevfik Özen
- Faculty of Science, Department of Chemistry, Ondokuz Mayıs University, Samsun, Turkey
| | - İbrahim Demirtaş
- Faculty of Arts and Sciences, Department of Biochemistry, Iğdır University, Iğdır, Turkey
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ondokuz Mayıs University, Samsun, Turkey
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Wang Y, Liu K. Therapeutic potential of oleanolic acid in liver diseases. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:4537-4554. [PMID: 38294504 DOI: 10.1007/s00210-024-02959-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Accepted: 01/15/2024] [Indexed: 02/01/2024]
Abstract
Liver-associated diseases affect millions of individuals worldwide. In developed countries, the incidence of viral hepatitis is reducing due to advancements in disease prevention, diagnosis, and treatment. However, with improvements in living standards, the prevalence of metabolic liver diseases, such as non-alcoholic fatty liver disease and alcohol-related liver disease, is expected to increase; notably, this rise in the prevalence of metabolic liver disease can lead to the development of more severe liver diseases, including liver failure, cirrhosis, and liver cancer. The growing demand for natural alternative therapies for chronic diseases has highlighted the importance of studying the pharmacology of bioactive compounds in plants. One such compound is oleanolic acid (OA), a pentacyclic triterpenoid known for its antioxidant, anti-inflammatory, anti-ulcer, antibacterial, antiviral, antihypertensive, anti-obesity, anticancer, anti-diabetic, cardioprotective, hepatoprotective, and anti-neurodegenerative properties. Recent studies have demonstrated that OA treatment can reduce the risk of pathological liver damage, ultimately alleviating liver dysregulation and restoring overall liver function. This review aims to explore the latest research on the biological effects of OA and its derivatives. Notably, it explores the mechanisms of action of these compounds in both in vitro and in vivo research models and, ultimately, highlights OA as a promising candidate for alternative therapies in the treatment and management of chronic liver disease.
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Affiliation(s)
- Yongxin Wang
- Department of Hepatobiliary and Pancreatic Surgery II, General Surgery Center, The First Hospital of Jilin University, Changchun, 130021, China
| | - Kai Liu
- Department of Hepatobiliary and Pancreatic Surgery II, General Surgery Center, The First Hospital of Jilin University, Changchun, 130021, China.
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Sun Y, Wei X, Zhao T, Shi H, Hao X, Wang Y, Zhang H, Yao Z, Zheng M, Ma T, Fu T, Lu J, Luo X, Yan Y, Wang H. Oleanolic acid alleviates obesity-induced skeletal muscle atrophy via the PI3K/Akt signaling pathway. FEBS Open Bio 2024; 14:584-597. [PMID: 38366735 PMCID: PMC10988678 DOI: 10.1002/2211-5463.13780] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Revised: 01/08/2024] [Accepted: 02/06/2024] [Indexed: 02/18/2024] Open
Abstract
Oleanolic acid (OA) is a pentacyclic triterpene with reported protective effects against various diseases, including diabetes, hepatitis, and different cancers. However, the effects of OA on obesity-induced muscle atrophy remain largely unknown. This study investigated the effects of OA on skeletal muscle production and proliferation of C2C12 cells. We report that OA significantly increased skeletal muscle mass and improved glucose intolerance and insulin resistance. OA inhibited dexamethasone (Dex)-induced muscle atrophy in C2C12 myoblasts by regulating the PI3K/Akt signaling pathway. In addition, it also inhibited expression of MuRF1 and Atrogin1 genes in skeletal muscle of obese mice suffering from muscle atrophy, and increased the activation of PI3K and Akt, thereby promoting protein synthesis, and eventually alleviating muscle atrophy. Taken together, these findings suggest OA may have potential for the prevention and treatment of muscle atrophy.
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Affiliation(s)
- Yaqin Sun
- College of Veterinary MedicineShanxi Agricultural UniversityJinzhongChina
| | - Xiaofang Wei
- College of Veterinary MedicineShanxi Agricultural UniversityJinzhongChina
| | - Tong Zhao
- College of Veterinary MedicineShanxi Agricultural UniversityJinzhongChina
| | - Hongwei Shi
- College of Veterinary MedicineShanxi Agricultural UniversityJinzhongChina
| | - Xiaojing Hao
- College of Veterinary MedicineShanxi Agricultural UniversityJinzhongChina
| | - Yue Wang
- College of Veterinary MedicineShanxi Agricultural UniversityJinzhongChina
| | - Huiling Zhang
- College of Veterinary MedicineShanxi Agricultural UniversityJinzhongChina
| | - Zhichao Yao
- College of Veterinary MedicineShanxi Agricultural UniversityJinzhongChina
| | - Minxing Zheng
- College of Veterinary MedicineShanxi Agricultural UniversityJinzhongChina
| | - Tianyun Ma
- College of Veterinary MedicineShanxi Agricultural UniversityJinzhongChina
| | - Tingting Fu
- College of Veterinary MedicineShanxi Agricultural UniversityJinzhongChina
| | - Jiayin Lu
- College of Veterinary MedicineShanxi Agricultural UniversityJinzhongChina
| | - Xiaomao Luo
- College of Veterinary MedicineShanxi Agricultural UniversityJinzhongChina
| | - Yi Yan
- College of Veterinary MedicineShanxi Agricultural UniversityJinzhongChina
| | - Haidong Wang
- College of Veterinary MedicineShanxi Agricultural UniversityJinzhongChina
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He K, Meng X, Su J, Jiang S, Chu M, Huang B. Oleanolic acid inhibits the tumor progression by regulating Lactobacillus through the cytokine-cytokine receptor interaction pathway in 4T1-induced mice breast cancer model. Heliyon 2024; 10:e27028. [PMID: 38449659 PMCID: PMC10915379 DOI: 10.1016/j.heliyon.2024.e27028] [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: 11/01/2023] [Revised: 01/26/2024] [Accepted: 02/22/2024] [Indexed: 03/08/2024] Open
Abstract
The therapeutic mechanism of oleanolic acid (OA) in breast cancer has been widely reported, but little has been known about the combined effects of transcriptome and gut microbiome. In this study, the phenotypic effect of oleanolic acid on mice was tested at the end of the administration cycle, and RNA sequencing on murine tumor tissue and 16S-rRNA sequencing on intestinal contents were conducted to analyze gene expression profiles and microbial diversity between the control group and OA treated group using 4T1-induced mice breast cancer model. As a result, it has been confirmed that oleanolic acid would play a significant inhibitory effect on the development of breast tumors in mice. Based on the integrative analysis of the transcriptomic and metagenomic data, it was found that the abundance of Lactobacillus in the intestinal flora of mice significantly increased in the OA group. Moreover, the up-regulation of Il10 had a significant effect on inhibiting the tumor progression, which played a role through cytokine-cytokine receptor interaction pathway.
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Affiliation(s)
- Kan He
- Center for Stem Cell and Translational Medicine, School of Life Sciences, Anhui University, Hefei 230601, Anhui, China
- Traditional Chinese Medicine Research Centre, School of Life Sciences, Anhui University, Hefei 230601, Anhui, China
| | - Xia Meng
- Center for Stem Cell and Translational Medicine, School of Life Sciences, Anhui University, Hefei 230601, Anhui, China
| | - Jinxing Su
- Center for Stem Cell and Translational Medicine, School of Life Sciences, Anhui University, Hefei 230601, Anhui, China
| | - Shangquan Jiang
- Center for Stem Cell and Translational Medicine, School of Life Sciences, Anhui University, Hefei 230601, Anhui, China
- Traditional Chinese Medicine Research Centre, School of Life Sciences, Anhui University, Hefei 230601, Anhui, China
| | - Min Chu
- Center for Stem Cell and Translational Medicine, School of Life Sciences, Anhui University, Hefei 230601, Anhui, China
- Traditional Chinese Medicine Research Centre, School of Life Sciences, Anhui University, Hefei 230601, Anhui, China
| | - Bei Huang
- Center for Stem Cell and Translational Medicine, School of Life Sciences, Anhui University, Hefei 230601, Anhui, China
- Traditional Chinese Medicine Research Centre, School of Life Sciences, Anhui University, Hefei 230601, Anhui, China
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Kong CH, Park K, Kim DY, Kim JY, Kang WC, Jeon M, Min JW, Lee WH, Jung SY, Ryu JH. Effects of oleanolic acid and ursolic acid on depression-like behaviors induced by maternal separation in mice. Eur J Pharmacol 2023; 956:175954. [PMID: 37541369 DOI: 10.1016/j.ejphar.2023.175954] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Revised: 07/11/2023] [Accepted: 08/01/2023] [Indexed: 08/06/2023]
Abstract
Oleanolic acid (OA) and ursolic acid (UA) are structural isomeric triterpenoids. Both triterpenoids have been reported to be able to improve depression. However, no studies have compared their effects in the same system. Whether OA or UA could ameliorate depression-like behaviors in maternal separation (MS)-induced depression-like model was investigated. MS model is a well-accepted mouse model that can reflect the phenotype and pathogenesis of depression. Depression is a mental illness caused by neuroinflammation or changes in neuroplasticity in certain brain regions, such as the prefrontal cortex and hippocampus. Depression-like behaviors were measured using splash test or forced swimming test. In addition, anxiety-like behaviors were also measured using the open field test or elevated plus-maze test. MS-treated female mice showed greater depression-like behaviors than male mice, and that OA improved several depression-like behaviors, whereas UA only relieved anxiety-like behavior of MS-treated mice. Microglial activation, expression levels of TNF-α, and mRNA levels of IDO1 were increased in the hippocampi of MS-treated female mice. However, OA and UA treatments attenuated such increases. In addition, expression levels of synaptophysin and PSD-95 were decreased in the hippocampi of MS-treated female mice. These decreased expression levels of synaptophysin were reversed by both OA and UA treatments, although decreased PSD-95 expression levels were only reversed by OA treatment. Our findings suggest that MS cause depression-like behaviors through female-specific neuroinflammation, changes of tryptophan metabolism, and alterations of synaptic plasticity. Our findings also suggest that OA could reverse MS-induced depression-like behaviors more effectively than UA.
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Affiliation(s)
- Chang Hyeon Kong
- Department of Biomedical and Pharmaceutical Sciences, Kyung Hee University, Seoul, 02447, Republic of Korea
| | - Keontae Park
- Department of Biomedical and Pharmaceutical Sciences, Kyung Hee University, Seoul, 02447, Republic of Korea
| | - Do Yeon Kim
- Department of Biomedical and Pharmaceutical Sciences, Kyung Hee University, Seoul, 02447, Republic of Korea
| | - Jae Youn Kim
- Department of Biomedical and Pharmaceutical Sciences, Kyung Hee University, Seoul, 02447, Republic of Korea
| | - Woo Chang Kang
- Department of Biomedical and Pharmaceutical Sciences, Kyung Hee University, Seoul, 02447, Republic of Korea
| | - Mijin Jeon
- Department of Biomedical and Pharmaceutical Sciences, Kyung Hee University, Seoul, 02447, Republic of Korea
| | - Ji Won Min
- Department of Biomedical and Pharmaceutical Sciences, Kyung Hee University, Seoul, 02447, Republic of Korea
| | - Won Hyung Lee
- Department of Biomedical and Pharmaceutical Sciences, Kyung Hee University, Seoul, 02447, Republic of Korea
| | - Seo Yun Jung
- Department of Biomedical and Pharmaceutical Sciences, Kyung Hee University, Seoul, 02447, Republic of Korea
| | - Jong Hoon Ryu
- Department of Biomedical and Pharmaceutical Sciences, Kyung Hee University, Seoul, 02447, Republic of Korea; Department of Oriental Pharmaceutical Science, Kyung Hee University, Seoul, 02447, Republic of Korea.
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Gutiérrez-Pacheco SL, Peña-Ramos EA, Santes-Palacios R, Valenzuela-Melendres M, Hernández-Mendoza A, Burgos-Hernández A, Robles-Zepeda RE, Espinosa-Aguirre JJ. Inhibition of the CYP Enzymatic System Responsible of Heterocyclic Amines Bioactivation by an Asclepias subulata Extract. PLANTS (BASEL, SWITZERLAND) 2023; 12:2354. [PMID: 37375979 DOI: 10.3390/plants12122354] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Revised: 06/10/2023] [Accepted: 06/15/2023] [Indexed: 06/29/2023]
Abstract
Asclepias subulata plant extract has previously demonstrated antiproliferative activity and antimutagenicity against heterocyclic aromatic amines (HAAs) commonly found in cooked meat. The objective of this work was to evaluate the in vitro ability of an ethanolic extract from the medicinal plant Asclepias subulata extract (ASE), non-heated and heated (180 °C), to inhibit the activity of CYP1A1 and CYP1A2, which are largely responsible for HAAs bioactivation. Ethoxyresorufin and methoxyresorufin O-dealkylation assays were performed in rat liver microsomes exposed to ASE (0.002-960 µg/mL). ASE exerted an inhibitory effect in a dose-dependent manner. The half inhibitory concentration (IC50) for unheated ASE was 353.6 µg/mL and 75.9 µg/mL for heated ASE in EROD assay. An IC40 value of 288.4 ± 5.8 µg/mL was calculated for non-heated ASE in MROD assay. However, after heat treatment, the IC50 value was 232.1 ± 7.4 µg/mL. Molecular docking of corotoxigenin-3-O-glucopyranoside, one of the main components of ASE, with CYP1A1/2 structure, was performed. Results show that the interaction of corotoxigenin-3-O-glucopyranoside with CYP1A1/2s' α-helices, which are related with the active site and the heme cofactor, may explain the plant extract's inhibitory properties. Results showed that ASE inhibits CYP1A enzymatic subfamily and may potentially act as a chemopreventive agent by inhibiting bioactivation of promutagenic dietary HAAs.
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Affiliation(s)
- Samaria Lisdeth Gutiérrez-Pacheco
- Coordinación de Tecnología de Alimentos de Origen Animal, Centro de Investigación en Alimentación y Desarrollo, A.C. Carretera Gustavo Enrique Astiazarán Rosas No. 46, La Victoria, Hermosillo 83304, Mexico
| | - Etna Aida Peña-Ramos
- Coordinación de Tecnología de Alimentos de Origen Animal, Centro de Investigación en Alimentación y Desarrollo, A.C. Carretera Gustavo Enrique Astiazarán Rosas No. 46, La Victoria, Hermosillo 83304, Mexico
| | - Rebeca Santes-Palacios
- Laboratorio de Toxicología Genética, Instituto Nacional de Pediatría, Insurgentes Sur 3700-C, Insurgentes Cuicuilco, Coyoacán, Ciudad de México 04530, Mexico
| | - Martin Valenzuela-Melendres
- Coordinación de Tecnología de Alimentos de Origen Animal, Centro de Investigación en Alimentación y Desarrollo, A.C. Carretera Gustavo Enrique Astiazarán Rosas No. 46, La Victoria, Hermosillo 83304, Mexico
| | - Adrián Hernández-Mendoza
- Coordinación de Tecnología de Alimentos de Origen Animal, Centro de Investigación en Alimentación y Desarrollo, A.C. Carretera Gustavo Enrique Astiazarán Rosas No. 46, La Victoria, Hermosillo 83304, Mexico
| | - Armando Burgos-Hernández
- Departamento de Investigación y Posgrado en Alimentos, Universidad de Sonora, Boulevard Luis Encinas y Rosales SN Centro, Hermosillo 83000, Mexico
| | - Ramón Enrique Robles-Zepeda
- Departamento de Ciencias Químico-Biológicas, Universidad de Sonora, Boulevard Luis Encinas y Rosales SN Centro, Hermosillo 83000, Mexico
| | - Jesús Javier Espinosa-Aguirre
- Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Tercer Circuito Exterior sin Número, Ciudad Universitaria, Ciudad de México 04510, Mexico
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Zafar S, Khan K, Hafeez A, Irfan M, Armaghan M, Rahman AU, Gürer ES, Sharifi-Rad J, Butnariu M, Bagiu IC, Bagiu RV. Ursolic acid: a natural modulator of signaling networks in different cancers. Cancer Cell Int 2022; 22:399. [PMID: 36496432 PMCID: PMC9741527 DOI: 10.1186/s12935-022-02804-7] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 11/24/2022] [Indexed: 12/13/2022] Open
Abstract
Incidence rate of cancer is estimated to increase by 40% in 2030. Furthermore, the development of resistance against currently available treatment strategies has contributed to the cancer-associated mortality. Scientists are now looking for the solutions that could help prevent the disease occurrence and could provide a pain-free treatment alternative for cancers. Therefore, efforts are now put to find a potent natural compound that could sever this purpose. Ursolic acid (UA), a triterpene acid, has potential to inhibit the tumor progression and induce sensitization to conventional treatment drugs has been documented. Though, UA is a hydrophobic compound therefore it is usually chemically modified to increase its bioavailability prior to administration. However, a thorough literature indicating its mechanism of action and limitations for its use at clinical level was not reviewed. Therefore, the current study was designed to highlight the potential mechanism of UA, its anti-cancer properties, and potential applications as therapeutic compound. This endeavour is a valuable contribution in understanding the hurdles preventing the translation of its potential at clinical level and provides foundations to design new studies that could help enhance its bioavailability and anti-cancer potential for various cancers.
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Affiliation(s)
- Sameen Zafar
- grid.412117.00000 0001 2234 2376Department of Healthcare Biotechnology, Atta-Ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad, Punjab Pakistan
| | - Khushbukhat Khan
- grid.412117.00000 0001 2234 2376Department of Healthcare Biotechnology, Atta-Ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad, Punjab Pakistan
| | - Amna Hafeez
- grid.412117.00000 0001 2234 2376Department of Healthcare Biotechnology, Atta-Ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad, Punjab Pakistan
| | - Muhammad Irfan
- grid.412117.00000 0001 2234 2376Department of Healthcare Biotechnology, Atta-Ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad, Punjab Pakistan
| | - Muhammad Armaghan
- grid.412117.00000 0001 2234 2376Department of Healthcare Biotechnology, Atta-Ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad, Punjab Pakistan
| | - Anees ur Rahman
- grid.412117.00000 0001 2234 2376Department of Healthcare Biotechnology, Atta-Ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad, Punjab Pakistan
| | - Eda Sönmez Gürer
- grid.411689.30000 0001 2259 4311Faculty of Pharmacy, Department of Pharmacognosy, Sivas Cumhuriyet University, Sivas, Turkey
| | - Javad Sharifi-Rad
- grid.442126.70000 0001 1945 2902Facultad de Medicina, Universidad del Azuay, Cuenca, Ecuador
| | - Monica Butnariu
- University of Life Sciences “King Mihai I” from Timisoara, 300645 Calea Aradului 119, Timis, Romania
| | - Iulia-Cristina Bagiu
- grid.22248.3e0000 0001 0504 4027Department of Microbiology, Victor Babes University of Medicine and Pharmacy of Timisoara, Timisoara, Romania ,Multidisciplinary Research Center on Antimicrobial Resistance, Timisoara, Romania
| | - Radu Vasile Bagiu
- grid.22248.3e0000 0001 0504 4027Department of Microbiology, Victor Babes University of Medicine and Pharmacy of Timisoara, Timisoara, Romania ,Preventive Medicine Study Center, Timisoara, Romania
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Mall SK, Yadav T, Waziri A, Alam MS. Treatment opportunities with Fernandoa adenophylla and recent novel approaches for natural medicinal phytochemicals as a drug delivery system. EXPLORATION OF MEDICINE 2022. [DOI: 10.37349/emed.2022.00111] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Fernandoa adenophylla (FA, Heterophragma adenophyllum) is a plant, cultivated throughout Africa and Southeast Asia. It contains potent phytochemicals such as novel naphthoquinones, their derivatives (peshwaraquinone, dilapachone, adenophyllone, indadone, and lapachol), and triterpenoids [ursolic acid (UA), β-sitosterol (BS), α-amyrin, and oleanolic acid (OA)] that have been assessed and reported to show potential pharmacological activities. The crude extract obtained from the plant has been investigated for certain pharmacological activities such as antibacterial, antifungal, anti-tubercular (TB), antihypertensive, and leishmanicidal activity. A novel drug delivery systems (NDDS) is the latest technique that combines innovative development, formulations, new technology, and methodologies for the safe delivery of pharmaceutical substances in the body. The present study reports the possible treatment opportunities of FA and recent possible novel drug delivery approaches for the natural medicinal phytochemicals.
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Affiliation(s)
- Sangeet Kumar Mall
- NIMS Institute of Pharmacy, NIMS University, Rajasthan, Jaipur 303121, India
| | - Tejpal Yadav
- Department of Pharmaceutics, NIMS Institute of Pharmacy, NIMS University, Rajasthan, Jaipur 303121, India
| | - Aafrin Waziri
- Department of Biotechnology, University School of Biotechnology, Guru Gobind Singh Indraprastha University, Delhi 110078, India
| | - Md Sabir Alam
- Department of Pharmaceutics, SGT College of Pharmacy, SGT University Gurugram, Delhi-NCR, Haryana 122505, India
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11
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Bioanalysis by LC-MS/MS and preclinical pharmacokinetic interaction study of ribociclib and oleanolic acid. Bioanalysis 2022; 14:1051-1065. [PMID: 36148926 DOI: 10.4155/bio-2022-0123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Background: Ribociclib (RIBO), approved in 2017 for HR-positive and HER-2-negative metastatic breast cancer treatment is reported to have the potential to induce hepatobiliary toxicity in patients. Oleanolic acid (OLA) has hepatoprotective potential that can be beneficial if coadministered with RIBO. Methodology & results: The primary scope of this study was to develop quantitative bioanalytical methods for RIBO and OLA. Two methods (for +ve electrospray ionization [ESI] and -ve ESI) were developed and validated according to USFDA bioanalytical guidelines. Discussion/conclusion: A single and simple sample preparation method was developed with >75% recovery. The accuracy and precision for RIBO and OLA were within acceptable limits over the calibration range of 5-500 ng/ml. This work reports, for the first time, the drug-drug interaction potential between RIBO and OLA.
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Lee J, Bae Y, Kim NJ, Lim S, Kim YM, Kim J, Chin YW. Anti-rheumatic, and analgesic effects by the parent tuberous roots of Aconitum jaluense in adjuvant induced arthritis rats. JOURNAL OF ETHNOPHARMACOLOGY 2022; 289:114518. [PMID: 34637968 DOI: 10.1016/j.jep.2021.114518] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 08/06/2021] [Accepted: 08/09/2021] [Indexed: 06/13/2023]
Abstract
AIM OF THE STUDY The aim of this study was to test the anti-rheumatic effects of A. jaluense tubers in acute and chronic arthritis rats, and to assign its ingredients through UHPLC-TOF/MS. MATERIALS AND METHODS Subcutaneous injection of carrageenan for acute arthritis and complete Freund's adjuvant (CFA) for chronic arthritis was carried out in the hind paw of SD rats. The paw volume was measured by a plethysmometer thermal hyperalgesia was tested using a thermal plantar tester, and mechanical hyperalgesia was evaluated by ankle flexion evoked vocalizations. The expression of c-Fos in the brain hippocampus was measured with the avidin-biotin-peroxidase technique. The ingredients were assigned by UHPLC-TOF/MS, chromatography was performed by UHPLC system with DAD detector and BEH C18 column, and spectroscopy was conducted by ESI-MS system. RESULTS AND DISCUSSION The 80% ethanoic extract of A. jaluense tubers showed an acute anti-inflammatory effect by suppressing the edema volume in the hind paw of carrageenan-stimulated rats. In addition, A. jaluense tubers exerted an anti-rheumatic activity by reducing the secondary swelling volume from an immunological reaction in the left hind paw of CFA-induced chronic arthritis rats. Additionally, oral treatment with the 80% ethanoic extract -showed potent analgesic effects in the arthritis rats by recovering the paw withdrawal latency stimulated by the thermal hyperalgesia and by reducing the vocalization scores evoked by ankle flexion on both hind paws. Moreover, its treatment also indicated an anti-psychiatric effect by controlling the c-Fos protein expression of the brain hippocampus in CFA-stimulated arthritis rats. These results suggested that these therapeutic effects were exhibited by less toxic mono-esterified diterpenoid alkaloids (MDAs), and nontoxic non-esterified diterpenoid alkaloids (NDAs). CONCLUSION A. jaluense tubers may act as viable therapeutic or preventive candidates for acute and chronic arthritis, particularly, for immune-inflammatory rheumatoid arthritis to suppress the pain and psychiatric condition.
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Affiliation(s)
- JiSuk Lee
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, South Korea.
| | - YoungChul Bae
- Research Group of Pain and Neuroscience, East-West Medical Research Institute, WHO Collaborating Center, Kyung Hee University, Seoul, 02447, South Korea
| | - Nam Jae Kim
- Research Group of Pain and Neuroscience, East-West Medical Research Institute, WHO Collaborating Center, Kyung Hee University, Seoul, 02447, South Korea
| | - Sabina Lim
- Research Group of Pain and Neuroscience, East-West Medical Research Institute, WHO Collaborating Center, Kyung Hee University, Seoul, 02447, South Korea.
| | - Young-Mi Kim
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, South Korea
| | - Jinwoong Kim
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, South Korea.
| | - Young-Won Chin
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, South Korea.
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Pentacyclic triterpene oleanolic acid protects against cardiac aging through regulation of mitophagy and mitochondrial integrity. Biochim Biophys Acta Mol Basis Dis 2022; 1868:166402. [PMID: 35346820 DOI: 10.1016/j.bbadis.2022.166402] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Revised: 03/11/2022] [Accepted: 03/21/2022] [Indexed: 12/15/2022]
Abstract
Advanced aging exhibits altered cardiac geometry and function involving mitochondrial anomaly. Natural compounds display promises in the regulation of cardiac homeostasis via governance of mitochondrial integrity in aging. This study examined the effect of oleanolic acid (OA), a natural pentacyclic triterpenoid with free radical scavenging and P450 cyclooxygenase-regulating properties, on cardiac aging and mechanisms involved with a focus on mitophagy. Young (4-5 month-old) and old (22-24 month-old) mice were treated with OA for 6 weeks prior to assessment of cardiac function, morphology, ultrastructure, mitochondrial integrity, cell death and autophagy. Our data revealed that OA treatment alleviated aging-induced changes in myocardial remodeling (increased heart weight, chamber size, cardiomyocyte area and interstitial fibrosis), contractile function and intracellular Ca2+ handling, apoptosis, necroptosis, inflammation, autophagy and mitophagy (LC3B, p62, TOM20 and FUNDC1 but not BNIP3 and Parkin). OA treatment rescued aging-induced anomalies in mitochondrial ultrastructure (loss of myofilament alignment, swollen mitochondria, increased circularity), mitochondrial biogenesis and O2- production without any notable effect at young age. Interestingly, OA-offered benefit against cardiomyocyte aging was nullified by deletion of the mitophagy receptor FUNDC1 using FUNDC1 knockout mice, denoting an obligatory role for FUNDC1 in OA-elicited preservation of mitophagy. OA reconciled aging-induced changes in E3 ligase MARCH5 but not FBXL2, and failed to affect aging-induced rises in IP3R3. Taken together, our data indicated a beneficial role for OA in attenuating cardiac remodeling and contractile dysfunction in aging through a FUNDC1-mediated mechanism.
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14
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Lee J, Lim S. Anti-inflammatory, and anti-arthritic effects by the twigs of Cinnamomum cassia on complete Freund's adjuvant-induced arthritis in rats. JOURNAL OF ETHNOPHARMACOLOGY 2021; 278:114209. [PMID: 34015366 DOI: 10.1016/j.jep.2021.114209] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Revised: 04/29/2021] [Accepted: 05/12/2021] [Indexed: 06/12/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE The young branches of C. cassia Blume (Cinnamomi Ramulus; Guizhi; ; C. cassia twigs) have long been used as an anti-pyretic, anti-rheumatic, anti-spasmodic and stomachic in traditional medicine. AIM OF THE STUDY The aim of this study was to test the anti-inflammatory, anti-nociceptive, and anti-arthritic effects of Cinnamomum cassia twigs in acute and chronic arthritis rats. MATERIALS AND METHODS Subcutaneous injection of carrageenan for acute inflammation and complete Freund's adjuvant (CFA) for chronic arthritis was carried out in the hind paw of SD rats. The paw volume was measured by a plethysmometer; thermal hyperalgesia was tested using a thermal plantar tester; hyperalgesia was evaluated by ankle flexion evoked vocalizations. The c-Fos expression in the lumbar spinal cord was measured with the avidin-biotin-peroxidase technique. The nitric oxide (NO) generation in lipopolysaccharide (LPS)-induced RAW 264.7 cells was tested by Griess assay. RESULTS AND DISCUSSION An 80% ethanoic extract of the C. cassia twigs exhibited chronic anti-inflammatory and anti-arthritic activities by reducing the edema volume in the paws of CFA-induced chronic arthritis in rats. In addition, it showed analgesic effects through the recovery of the paw withdrawal latency stimulated by thermal hyperalgesia, and suppressing the vocalization scores evoked by ankle flexion in the hind paws of the arthritis rats. It also controlled c-Fos expression in the lumbar spinal cord of the arthritis rats. Moreover, the addition its 80%-ethanoic extract, specifically, its ethyl acetate fraction, powerfully suppressed the paw swelling in carrageenan-stimulated arthritis and the NO production in LPS-induced murine immune cells. CONCLUSION C. cassia twigs may act as a viably sufficient therapeutic or preventive candidate for osteoarthritis and rheumatoid arthritis; additionally, it could prevent gastrointestinal damage with its gastric protection.
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Affiliation(s)
- JiSuk Lee
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, South Korea.
| | - Sabina Lim
- Research Group of Pain and Neuroscience, East-West Medical Research Institute, WHO Collaborating Center, Kyung Hee University, Seoul, 02447, South Korea.
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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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16
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Suroowan S, Abdallah HH, Mahomoodally MF. Herb-drug interactions and toxicity: Underscoring potential mechanisms and forecasting clinically relevant interactions induced by common phytoconstituents via data mining and computational approaches. Food Chem Toxicol 2021; 156:112432. [PMID: 34293424 DOI: 10.1016/j.fct.2021.112432] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 06/28/2021] [Accepted: 07/17/2021] [Indexed: 01/05/2023]
Abstract
Herbals in the form of medicine are employed extensively around the world. Herbal and conventional medicine combination is a potentially dangerous practice mainly in comorbid, hepato insufficient and frail patients leading to perilous herb-drug interactions (HDI) and toxicity. This study features potential HDI of 15 globally famous plant species through data mining and computational methods. Several plant species were found to mimic warfarin. Phytochemicals from M. charantia induced hypoglycemica. M. chamomila and G. biloba possessed anticoagulant activities. S. hispanica reduces postprandial glycemia. R. officinalis has been reported to inhibit the efflux of anticancer substrates while A. sativum can boost the clearance of anticancer agents. P. ginseng can alter blood coagulation. A cross link of the biological and in silico data revealed that a plethora of herbal metabolites such as ursolic and rosmarinic acid among others are possible/probable inhibitors of specific CYP450 enzymes. Consequently, plant species/metabolites with a given pharmacological property/metabolizing enzyme should not be mixed with drugs having the same pharmacological property/metabolizing enzyme. Even if combined with drugs, herbal medicines must be used at low doses for a short period of time and under the supervision of a healthcare professional to avoid potential adverse and toxic effects.
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Affiliation(s)
- Shanoo Suroowan
- Department of Health Sciences, Faculty of Medicine and Health Sciences, University of Mauritius, Réduit, Mauritius
| | - Hassan Hadi Abdallah
- Department of Chemistry, College of Education, Salahaddin University-Erbil, Erbīl, Iraq
| | - Mohamad Fawzi Mahomoodally
- Department of Health Sciences, Faculty of Medicine and Health Sciences, University of Mauritius, Réduit, Mauritius.
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Regioselective Hydroxylation of Oleanolic Acid Catalyzed by Human CYP3A4 to Produce Hederagenenin, a Chiral Metabolite. Catalysts 2021. [DOI: 10.3390/catal11020267] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Oleanolic acid (OA) is a pentacyclic triterpenoid widely found in plants and foods as an aglycone of triterpenoid saponins or as a free acid. OA exhibits beneficial activities for humans, including antitumor, antivirus, and hepatoprotection properties without apparent toxicity. The metabolites produced by the cytochrome P450 (P450) enzymes are critical for the evaluation of the efficacy and safety of drugs. In this study, the potential metabolites of OA were investigated by P450-catalyzed oxidation reactions. Among the various tested human P450s, only human CYP3A4 was active for the hydroxylation of OA. The major metabolite was characterized by a set of analyses using HPLC, LC–MS, and NMR. It was found to be 4-epi-hederagenenin, a chiral product, by regioselective hydroxylation of the methyl group at the C-23 position. These results indicated that CYP3A4 can hydroxylate an OA substrate to make 4-epi-hederagenenin. Possible drug–food interactions are discussed.
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18
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Zhang J, Chen Z, Zhang L, Zhao X, Liu Z, Zhou W. A systems-based analysis to explore the multiple mechanisms of Shan Zha for treating human diseases. Food Funct 2021; 12:1176-1191. [PMID: 33432314 DOI: 10.1039/d0fo02433c] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Shan Zha has garnered increasing attention in the field of functional foods and medicines due to its widely reported healing effects. However, the potential mechanisms of Shan Zha for human health benefits have not been fully interpreted. Therefore, in the current study, a systems-based method that integrates ADME evaluation, target fishing, gene ontology enrichment analysis, network pharmacology, and pathway analysis is proposed to clarify the underlying pharmacological mechanisms of Shan Zha. As a result, 45 active components of Shan Zha that interacted with 161 protein targets were screened and identified. Moreover, gene ontology enrichment, network and pathway analysis indicated that Shan Zha is beneficial for the treatment of cardiovascular system diseases, digestive system diseases, immune system diseases, inflammatory diseases, cancer, and other diseases through multiple mechanisms. Our study not only proposed an integrated method to comprehensively elucidate the complicated mechanisms of Shan Zha for the treatment of various disorders at the system level, but also provided a reference approach for the mechanistic research of other functional foods.
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Affiliation(s)
- Jingxiao Zhang
- School of Food and Drug, Luoyang Normal University, Luoyang 471934, China.
| | - Ziyi Chen
- Musculoskeletal Research Laboratory, Department of Orthopaedics & Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Shatin 999077, Hong Kong Special Administrative Region
| | - Lilei Zhang
- School of Food and Drug, Luoyang Normal University, Luoyang 471934, China.
| | - Xiaoxiao Zhao
- School of Food and Drug, Luoyang Normal University, Luoyang 471934, China.
| | - Zhigang Liu
- State Key Laboratory of Respiratory Disease for Allergy at Shenzhen University, Shenzhen Key Laboratory of Allergy & Immunology, Shenzhen University School of Medicine, Shenzhen University, Shenzhen, China
| | - Wei Zhou
- School of Food and Drug, Luoyang Normal University, Luoyang 471934, China. and State Key Laboratory of Respiratory Disease for Allergy at Shenzhen University, Shenzhen Key Laboratory of Allergy & Immunology, Shenzhen University School of Medicine, Shenzhen University, Shenzhen, China
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Auxtero MD, Chalante S, Abade MR, Jorge R, Fernandes AI. Potential Herb-Drug Interactions in the Management of Age-Related Cognitive Dysfunction. Pharmaceutics 2021; 13:124. [PMID: 33478035 PMCID: PMC7835864 DOI: 10.3390/pharmaceutics13010124] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 01/14/2021] [Accepted: 01/15/2021] [Indexed: 12/25/2022] Open
Abstract
Late-life mild cognitive impairment and dementia represent a significant burden on healthcare systems and a unique challenge to medicine due to the currently limited treatment options. Plant phytochemicals have been considered in alternative, or complementary, prevention and treatment strategies. Herbals are consumed as such, or as food supplements, whose consumption has recently increased. However, these products are not exempt from adverse effects and pharmacological interactions, presenting a special risk in aged, polymedicated individuals. Understanding pharmacokinetic and pharmacodynamic interactions is warranted to avoid undesirable adverse drug reactions, which may result in unwanted side-effects or therapeutic failure. The present study reviews the potential interactions between selected bioactive compounds (170) used by seniors for cognitive enhancement and representative drugs of 10 pharmacotherapeutic classes commonly prescribed to the middle-aged adults, often multimorbid and polymedicated, to anticipate and prevent risks arising from their co-administration. A literature review was conducted to identify mutual targets affected (inhibition/induction/substrate), the frequency of which was taken as a measure of potential interaction. Although a limited number of drugs were studied, from this work, interaction with other drugs affecting the same targets may be anticipated and prevented, constituting a valuable tool for healthcare professionals in clinical practice.
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Affiliation(s)
- Maria D. Auxtero
- CiiEM, Interdisciplinary Research Centre Egas Moniz, Instituto Universitário Egas Moniz, Quinta da Granja, Monte de Caparica, 2829-511 Caparica, Portugal; (M.D.A.); (S.C.); (M.R.A.); (R.J.)
| | - Susana Chalante
- CiiEM, Interdisciplinary Research Centre Egas Moniz, Instituto Universitário Egas Moniz, Quinta da Granja, Monte de Caparica, 2829-511 Caparica, Portugal; (M.D.A.); (S.C.); (M.R.A.); (R.J.)
| | - Mário R. Abade
- CiiEM, Interdisciplinary Research Centre Egas Moniz, Instituto Universitário Egas Moniz, Quinta da Granja, Monte de Caparica, 2829-511 Caparica, Portugal; (M.D.A.); (S.C.); (M.R.A.); (R.J.)
| | - Rui Jorge
- CiiEM, Interdisciplinary Research Centre Egas Moniz, Instituto Universitário Egas Moniz, Quinta da Granja, Monte de Caparica, 2829-511 Caparica, Portugal; (M.D.A.); (S.C.); (M.R.A.); (R.J.)
- Polytechnic Institute of Santarém, School of Agriculture, Quinta do Galinheiro, 2001-904 Santarém, Portugal
- CIEQV, Life Quality Research Centre, IPSantarém/IPLeiria, Avenida Dr. Mário Soares, 110, 2040-413 Rio Maior, Portugal
| | - Ana I. Fernandes
- CiiEM, Interdisciplinary Research Centre Egas Moniz, Instituto Universitário Egas Moniz, Quinta da Granja, Monte de Caparica, 2829-511 Caparica, Portugal; (M.D.A.); (S.C.); (M.R.A.); (R.J.)
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20
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Chen Z, Liu Q, Zhu Z, Xiang F, Zhang M, Wu R, Kang X. Ursolic Acid Protects Against Proliferation and Inflammatory Response in LPS-Treated Gastric Tumour Model and Cells by Inhibiting NLRP3 Inflammasome Activation. Cancer Manag Res 2020; 12:8413-8424. [PMID: 32982435 PMCID: PMC7494010 DOI: 10.2147/cmar.s264070] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Accepted: 08/26/2020] [Indexed: 12/13/2022] Open
Abstract
Background Inflammation is considered as one of the hallmarks of cancer development and progression. Ursolic acid (UA) showed strong effects as an anti-inflammatory and antioxidant. However, the anti-cancer effects of ursolic acid require further study. Methods This study aimed to investigate the role of ursolic acid in a lipopolysaccharide (LPS)-treated gastric tumour mouse model and in a human gastric carcinoma cell line (BGC-823 cells). This study also aimed to confirm whether ursolic acid can protect against proliferation and the inflammatory response induced by LPS, by inhibiting the activation of the NLRP3 inflammasome via the NF-κB pathway. Results The present study demonstrated that ursolic acid significantly attenuated LPS-treated proliferation in a gastric tumour mouse model and the human gastric carcinoma BGC-823 cell line, reduced the expression of the NLRP3 inflammasome and suppressed the release of pro-inflammatory cytokines. In addition, ursolic acid inhibited the LPS-induced activation of NF-κB. Furthermore, the NF-κB pathway regulated the activation of the NLRP3 inflammasome. Conclusion In conclusion, these results demonstrated that ursolic acid could suppress proliferation and the inflammatory response in an LPS-induced mouse gastric tumour model and human BGC-823 cells by inhibiting the activation of the NLRP3 inflammasome via the NF-κB pathway. This indicates that ursolic acid can be a potential therapeutic agent for the treatment of gastric cancer.
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Affiliation(s)
- Zixi Chen
- Department of Laboratory Medicine, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, People's Republic of China
| | - Qiaoli Liu
- Department of Laboratory Medicine, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, People's Republic of China
| | - Zhaowei Zhu
- Department of Laboratory Medicine, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, People's Republic of China
| | - Fenfen Xiang
- Department of Laboratory Medicine, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, People's Republic of China
| | - Mengzhe Zhang
- Department of Laboratory Medicine, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, People's Republic of China
| | - Rong Wu
- Department of Laboratory Medicine, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, People's Republic of China
| | - Xiangdong Kang
- Department of Laboratory Medicine, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, People's Republic of China
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21
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Jinhua W, Ying Z, Yuhua L. PXR-ABC drug transporters/CYP-mediated ursolic acid transport and metabolism in vitro and vivo. Arch Pharm (Weinheim) 2020; 353:e2000082. [PMID: 32628284 DOI: 10.1002/ardp.202000082] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2020] [Revised: 05/23/2020] [Accepted: 06/05/2020] [Indexed: 12/18/2022]
Abstract
The transporting kinetics and metabolic kinetics of ursolic acid were studied in transgenic cell models. Then, the pharmacokinetics features of ursolic acid and the expression of ATP-binding cassette transporters (ABC transporter) and cytochrome P450 (CYP) enzymes in tissues after pregnane X receptor (PXR) activation by 5-pregnen-3β-ol-20-one-16α-carbonitrile (PCN) were investigated in rats. After silencing of PXR in Caco2-siRNA-PXR cells, there was a decrease in the protein abundance of P-glycoprotein, breast cancer-resistant protein, multidrug resistance-associated protein 2 (MRP2), and CYP2C9. The apparent permeability (PDR) values of 10, 20, and 50 µM ursolic acid in Caco2 cells were 2.19 ± 0.44, 1.40 ± 0.17, and 1.25 ± 0.07, respectively, whereas in Caco2-siRNA-PXR cells, they were 1.85 ± 0.36, 1.24 ± 0.11, and 1.19 ± 0.04, respectively. PXR-RXRα would significantly activate ABC transporter expression in Caco2 cells. Compared with Caco2 cells, when the concentrations of ursolic acid were 10, 20, and 50 µM, the PDR values increased in Caco2-PXR-RXRα cells after PXR activation: 1.60 ± 0.31 versus 1.97 ± 0.21, 1.46 ± 0.08 versus 2.01 ± 0.19, and 1.32 ± 0.26 versus 2.09 ± 0.22, respectively. Simultaneously, PXR-RXRα would activate the expression of CYP2C9; metabolic kinetics of ursolic acid in CYP metabolizing enzyme lysate of Caco2 cells and Caco2-PXR-RXR cells was studied and it was found that the Km values were 81.99 ± 44.32 and 60.05 ± 29.62 µg/ml, and Vmax values were 3.77 ± 0.86 and 3.41 ± 0.96 µg · ml-1 · min-1 , respectively. However, in human CYP metabolizing recombinase, we found that both CYP2C9 and CYP34A were involved in the metabolism of ursolic acid. Vm and Km values for CYP3A4 and CYP2C9 were 3.57 ± 1.12 µg · ml-1 · min-1 and 81.71 ± 18.38 µg/ml, 3.85 ± 1.46 µg · ml-1 · min-1 and 62.18 ± 14.56 µg/ml, respectively. As a strong agonist for mouse pxr, PCN could significantly affect pharmacokinetics of ursolic acid in rats, and it showed discrepant effects on messenger RNA expression of cyp and transporters in tissues.
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Affiliation(s)
- Wen Jinhua
- Department of Pharmacy, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Zhou Ying
- Department of Pharmacy, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Li Yuhua
- Department of Pharmacy, The First Affiliated Hospital of Nanchang University, Nanchang, China
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Gutiérrez-Pacheco SL, Valenzuela-Melendres M, Hernández-Mendoza A, Burgos-Hernández A, Robles-Zepeda RE, Peña-Ramos EA. Antimutagenic effect of an Asclepias subulata extract against heterocyclic aromatic amines commonly found in cooked meat and its heat stability. Food Chem 2020; 322:126725. [PMID: 32283373 DOI: 10.1016/j.foodchem.2020.126725] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2019] [Revised: 03/21/2020] [Accepted: 03/31/2020] [Indexed: 01/15/2023]
Abstract
The antimutagenicity of an extract from the medicinal plant Asclepias subulata (ASE) against heterocyclic aromatic amines (HAAs) commonly found in cooked meat, as well as its stability to heat treatment (HT), was evaluated. HT (180 °C/3 min) had no effect on the content in ASE of the bioactive compound corotoxigenin-3-O-glucopyranoside; conversely, calotropin significantly decreased by 72%. ASE exerted antimutagenicity against PhIP, MelQ, and MelQx in TA98 and TA100 Salmonella strains, and this activity was not affected by heat, with the exception of MelQ (p < 0.05). Since HAAs can induce colorectal cancer, the thermal stability of ASE's antiproliferative effect against colorectal cancer cells was also evaluated. HT decreased (p < 0.05) the antiproliferative activity of ASE; however, the remaining activity was still strong with an IC50 of 16.8 ± 2.03 µg/mL. Therefore, ASE can be used as a food ingredient to reduce the carcinogenic potential of thermally induced HAAs.
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Affiliation(s)
- Samaria L Gutiérrez-Pacheco
- Centro de Investigación en Alimentación y Desarrollo, A.C. Coordinación de Tecnología de Alimentos de Origen Animal, Carretera Gustavo Enrique Astiazarán Rosas No. 46, Col. La Victoria, Hermosillo, Sonora C.P. 83304, Mexico
| | - Martin Valenzuela-Melendres
- Centro de Investigación en Alimentación y Desarrollo, A.C. Coordinación de Tecnología de Alimentos de Origen Animal, Carretera Gustavo Enrique Astiazarán Rosas No. 46, Col. La Victoria, Hermosillo, Sonora C.P. 83304, Mexico.
| | - Adrián Hernández-Mendoza
- Centro de Investigación en Alimentación y Desarrollo, A.C. Coordinación de Tecnología de Alimentos de Origen Animal, Carretera Gustavo Enrique Astiazarán Rosas No. 46, Col. La Victoria, Hermosillo, Sonora C.P. 83304, Mexico.
| | - Armando Burgos-Hernández
- Universidad de Sonora, División de Ciencias Biológicas y de la Salud, Blvd. Luis Encinas y Rosales SN, Centro, Hermosillo, Sonora C.P. 83000, Mexico.
| | - Ramón E Robles-Zepeda
- Universidad de Sonora, División de Ciencias Biológicas y de la Salud, Blvd. Luis Encinas y Rosales SN, Centro, Hermosillo, Sonora C.P. 83000, Mexico.
| | - E Aída Peña-Ramos
- Centro de Investigación en Alimentación y Desarrollo, A.C. Coordinación de Tecnología de Alimentos de Origen Animal, Carretera Gustavo Enrique Astiazarán Rosas No. 46, Col. La Victoria, Hermosillo, Sonora C.P. 83304, Mexico.
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Sen A. Prophylactic and therapeutic roles of oleanolic acid and its derivatives in several diseases. World J Clin Cases 2020; 8:1767-1792. [PMID: 32518769 PMCID: PMC7262697 DOI: 10.12998/wjcc.v8.i10.1767] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2020] [Revised: 03/27/2020] [Accepted: 04/30/2020] [Indexed: 02/05/2023] Open
Abstract
Oleanolic acid (OA) and its derivatives are widely found in diverse plants and are naturally effective pentacyclic triterpenoid compounds with broad prophylactic and therapeutic roles in various diseases such as ulcerative colitis, multiple sclerosis, metabolic disorders, diabetes, hepatitis and different cancers. This review assembles and presents the latest in vivo reports on the impacts of OA and OA derivatives from various plant sources and the biological mechanisms of OA activities. Thus, this review presents sufficient data proposing that OA and its derivatives are potential alternative and complementary therapies for the treatment and management of several diseases.
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Affiliation(s)
- Alaattin Sen
- Department of Molecular Biology and Genetics, Faculty of Life and Natural Sciences, Abdullah Gul University, Kayseri 38080, Turkey
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Abstract
The use of traditional Chinese medicine (TCM) has obtained more and more acceptance all over the world due to its multi-target and multi-level function characteristics. Clopidogrel is a major therapeutic option to reduce atherothrombotic events in patients with acute coronary syndrome, recent myocardial infarction, recent stroke or established peripheral arterial disease. These patients probably take TCM. Are there any interactions between clopidogrel and TCM? Whether TCM will affect the efficacy of clopidogrel or increase the adverse reactions of bleeding? Clarifying this information will help physicians make better use of TCM. A literature search was carried out using Web of Science, PubMed and the Cochrane Library to analyze the pharmacokinetic or pharmacodynamic interactions of clopidogrel and TCM. Some herbs can increase the AUC or Cmax of clopidogrel, such as Scutellarin, Danggui, Gegen, Sauchinone and Dengzhan Shengmai capsules. Whereas others can decrease clopidogrel, for example, Ginkgo and Danshen. Furthermore, some herbs can increase the AUC or Cmax of clopidogrel active metabolite, including Ginkgo and Xuesaitong tablet. And others can decrease the clopidogrel active metabolite, such as Scutellarin, Danshen, Fufang Danshen Dripping Pill and Dengzhan Shengmai capsules. Additionally, Schisandra chinensis, Danggui, Gegen and Fufang Danshen Dripping Pill can decrease the AUC or Cmax of the clopidogrel inactive metabolite, while Curcumin on the contrary. The pharmacodynamics of Panax notoginseng, Notoginsenoside Ft1, Hypericum perforatum, Shexiang baoxin pills, Naoxintong capsule increased the antiplatelet activity compared with clopidogrel alone, while Danshen decreased the platelet inhibition. In adverse reactions, Danggui can enhance the adverse effects of clopidogrel on the bleeding time. With more awareness and understanding on potential drug-herb interactions of clopidogrel and TCM, it may be possible to combine clopidogrel with TCM herbs to yield a better therapeutic outcome.
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Affiliation(s)
- Yunzhen Hu
- Department of Pharmacy, The First Affiliated Hosptial, College of Medicine, Zhejiang University, Hangzhou, China.
| | - Jing Wang
- Department of Pharmacy, The First Affiliated Hosptial, College of Medicine, Zhejiang University, Hangzhou, China
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A Systematic Review of Drug Metabolism Studies of Plants With Anticancer Properties: Approaches Applied and Limitations. Eur J Drug Metab Pharmacokinet 2019; 45:173-225. [DOI: 10.1007/s13318-019-00582-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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26
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Yao N, Zeng C, Zhan T, He F, Liu M, Liu F, Zhang H, Xiong Y, Xia C. Oleanolic Acid and Ursolic Acid Induce UGT1A1 Expression in HepG2 Cells by Activating PXR Rather Than CAR. Front Pharmacol 2019; 10:1111. [PMID: 31611795 PMCID: PMC6777376 DOI: 10.3389/fphar.2019.01111] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2019] [Accepted: 08/29/2019] [Indexed: 12/15/2022] Open
Abstract
Background: Oleanolic acid (OA) and its isomer ursolic acid (UA) have recently emerged as research foci based on their biologic activities. We previously demonstrated that UA can inhibit the activities of UGT1A3 and UGT1A4, and OA inhibits UGT1A3 activity in liver microsomes. However, whether OA and UA affect the expression of UGT1As in HepG2 cells and the underlying regulatory mechanism remain unclear. Purpose: The present study aimed to explore the effect of OA and UA on the expression of UGT1As in HepG2 cells and the regulatory mechanisms on UGT1A1 based on the pregnane X receptor (PXR) and constitutive androstane receptor (CAR) signaling pathways. Methods: We analyzed the effect of OA and UA on UGT1A expression and on the PXR/CAR regulatory pathway in HepG2 cells, hPXR-silenced HepG2 cells, and hCAR-silenced HepG2 cells by Q-PCR, Western blotting, and dual-luciferase reporter gene assays. Results: In HepG2 cells, OA and UA both significantly induced the expression of UGT1A1, UGT1A3, UGT1A4, and UGT1A9 and upregulated the expression of PXR. However, OA and UA did not affect CAR expression. A dual-luciferase reporter assay showed that OA and UA could markedly promote PXR-mediated UGT1A1 luciferase activity, whereas OA and UA did not affect CAR-mediated UGT1A1 luciferase activity. In hPXR-silenced HepG2 cells, OA and UA did not elevate UGT1A1 activity compared to the control group. However, the expression of UGT1A1 in hCAR-silenced HepG2 cells was markedly elevated compared to the control group or with non-silenced HepG2 cells treated with OA (10, 20, and 40 μM) or UA (10, 20, and 40 μM). Conclusions: OA and UA significantly induce the expression of UGT1A1, UGT1A3, UGT1A4, and UGT1A9 in HepG2 cells, and their induction on UGT1A1 is mediated by PXR activation, not CAR.
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Affiliation(s)
- Na Yao
- Clinical Pharmacology Institute, Nanchang University, Nanchang, China
| | - Caiwen Zeng
- Laboratory of Translational Medicine and Oncology, Jiangxi Province Cancer Hospital, Nanchang, China
| | - Tao Zhan
- Clinical Pharmacology Institute, Nanchang University, Nanchang, China
| | - Fang He
- Pharmacy Department, Jiangxi Province Cancer Hospital, Nanchang, China
| | - Mingyi Liu
- Clinical Pharmacology Institute, Nanchang University, Nanchang, China
| | - Fanglan Liu
- Clinical Pharmacology Institute, Nanchang University, Nanchang, China
| | - Hong Zhang
- Clinical Pharmacology Institute, Nanchang University, Nanchang, China
| | - Yuqing Xiong
- Clinical Pharmacology Institute, Nanchang University, Nanchang, China
| | - Chunhua Xia
- Clinical Pharmacology Institute, Nanchang University, Nanchang, China
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Oancea IA, van Staden J(KF, Oancea E, Ungureanu EM. Electrochemical detection of ursolic acid from spruce ( Picea abies) essential oils using modified amperometric microsensors. ANAL LETT 2019. [DOI: 10.1080/00032719.2019.1605373] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Affiliation(s)
- Ioana Adina Oancea
- Department of Inorganic Chemistry, Physical Chemistry and Electrochemistry, Politehnica University of Bucharest, Bucharest, Romania
- SC. Dan-Elis. SRL, Cosmetic Product Manufacturing, Topraisar, Romania
- Laboratory of Electrochemistry and PATLAB Bucharest, National Institute of Research for Electrochemistry and Condensed Matter, Bucharest, Romania
| | - Jacobus (Koos) Frederick van Staden
- Laboratory of Electrochemistry and PATLAB Bucharest, National Institute of Research for Electrochemistry and Condensed Matter, Bucharest, Romania
| | - Elena Oancea
- SC. Dan-Elis. SRL, Cosmetic Product Manufacturing, Topraisar, Romania
| | - Eleonora-Mihaela Ungureanu
- Department of Inorganic Chemistry, Physical Chemistry and Electrochemistry, Politehnica University of Bucharest, Bucharest, Romania
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Khan MW, Zhao P, Khan A, Raza F, Raza SM, Sarfraz M, Chen Y, Li M, Yang T, Ma X, Xiang G. Synergism of cisplatin-oleanolic acid co-loaded calcium carbonate nanoparticles on hepatocellular carcinoma cells for enhanced apoptosis and reduced hepatotoxicity. Int J Nanomedicine 2019; 14:3753-3771. [PMID: 31239661 PMCID: PMC6554709 DOI: 10.2147/ijn.s196651] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2018] [Accepted: 03/19/2019] [Indexed: 12/19/2022] Open
Abstract
Background: Cisplatin (CDDP), a widely used chemotherapeutic agent against hepatocellular carcinoma (HCC), faces severe resistance and hepatotoxicity problems which can be alleviated through combination therapy. Purpose: The objective of this study was to develop a pH-dependent calcium carbonate nano-delivery system for the combination therapy of CDDP with oleanolic acid (OA). Methods: A microemulsion method was employed to generate lipid coated cisplatin/oleanolic acid calcium carbonate nanoparticles (CDDP/OA-LCC NPs), and the loading concentration of CDDP and OA was measured by atomic absorption spectroscopy and HPLC respectively.Transmission electron microscopy (TEM) was used to examine the nanoparticles morphology while its pH dependent release characteristics were investigated through in vitro release study. Cellular uptake was examined through a fluorescence microscopy. Apoptotic assays and western blot analysis were conducted to explore the synergistic apoptotic effect of OA on CDDP against HCC cells. The hepatoprotective of OA for CDDP was evaluated through H&E staining. Results: TEM analysis revealed nanoparticles spherical shape with an average particle size of 206±15 nm, and the overall entrapment efficiency was 63.70%±3.9%. In vitro drug release study confirmed the pH-dependent property of the formulation, with the maximum CDDP release of 70%±4.6% at pH 5.5, in contrast to 28%±4.1% CDDP release at pH 7.4. Annexin V-FITC/PI assay and cell cycle analysis confirmed that CDDP and OA synergistically promoted greater HepG2 cells apoptosis for the CDDP/OA-LCC NPs as compared to their individual free drug solutions and NPs-treated groups. Western blot analysis also proved that CDDP/OA-LCC NPs induced the apoptosis by enhancing the proapoptotic protein expressions through downregulating P13K/AKT/mTOR pathway and upregulating p53 proapoptotic pathway. OA helped CDDP to overcome the resistance by downregulating the expression of proteins like XIAP, Bcl-2 via NF-κB pathway. OA also significantly alleviated CDDP-induced hepatotoxicity as evident from the decreased alanine transaminase, aspartate transaminase levels and histochemical evaluation. The possible mechanism may be related to the Nrf-2 induction via its antioxidant mechanism to maintain the redox balance and reduction in CYP2E1 activity which can lead to ROS-mediated oxidative stress. Conclusion: These results suggest that CDDP/OA-LCC NPs have promising applications for co-delivering CDDP and OA to synergize their anti-tumor activity against HCC and to utilize OA’s protective effect against CDDP-induced hepatotoxicity.
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Affiliation(s)
- Muhammad Waseem Khan
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, People's Republic of China
| | - Pengxuan Zhao
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, People's Republic of China
| | - Asifullah Khan
- State Key Laboratory of Natural Medicines and Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, People's Republic of China
| | - Faisal Raza
- State Key Laboratory of Natural Medicines and Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, People's Republic of China
| | - Shahid Masood Raza
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, People's Republic of China
| | - Muhammad Sarfraz
- School of Basic Medical Sciences, Henan University, Kaifeng, Henan 475001/475004, People's Republic of China
| | - Yan Chen
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, People's Republic of China
| | - Minsi Li
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, People's Republic of China
| | - Tan Yang
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, People's Republic of China
| | - Xiang Ma
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, People's Republic of China
| | - Guangya Xiang
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, People's Republic of China
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Mochizuki M, Uozumi T, Hisaka S, Osawa T. Ursolic Acid and Derivatives Exhibit Anti-atherosclerotic Activity by Inhibiting the Expression of Cell Adhesion Molecules Induced by TNF-alpha. FOOD SCIENCE AND TECHNOLOGY RESEARCH 2019. [DOI: 10.3136/fstr.25.405] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Affiliation(s)
- Mika Mochizuki
- Department of Health and Nutrition Faculty of Psychological and Physical Science, Aichi Gakuin University
| | - Taichi Uozumi
- Laboratory of Food and Biodynamics, Nagoya University Graduate School of Bioagricultural Sciences
| | | | - Toshihiko Osawa
- Department of Health and Nutrition Faculty of Psychological and Physical Science, Aichi Gakuin University
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30
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Karlik W, Chłopecka M, Bamburowicz-Klimkowska M, Mendel M. Modulations of bovine hepatic microsomal metabolism of benzimidazoles by secondary plant metabolites. J Vet Pharmacol Ther 2018; 42:222-229. [PMID: 30474118 DOI: 10.1111/jvp.12727] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2018] [Revised: 09/11/2018] [Accepted: 09/21/2018] [Indexed: 10/27/2022]
Abstract
The study was aimed to estimate the effect of plant secondary metabolites present in ruminants diet and phytogenic feed additives on liver microsomal metabolism of albendazole and fenbendazole. The selected phytocompounds comprised of flavonoids (apigenin, quercetin) and saponins (hederagenin, medicagenic acid). The experiments were performed on liver microsomal fraction obtained from routinely slaughtered cows. The intensity of albendazole and fenbendazole metabolism in the presence of flavonoids and saponins was analyzed in equimolar concentration (100 μM). The obtained results revealed that both flavonoids and saponins intensify the metabolism of albendazole and fenbendazole in bovine microsomes. In the case of albendazole, apigenin and quercetin doubled the amount of degraded drug and the amount of produced albendazole sulfoxide. Additionally, both flavonoids increased the amount of produced albendazole sulfone. Saponins, hederagenin, and medicagenic acid intensified the degradation of albendazole (1.8-fold) and the production of albendazole sulfoxide (twofold). Medicagenic acid inhibited the production of albendazole sulfone. In the case of fenbendazole, the degradation of the drug and the production of oxfendazole were increased four and five times in the presence of saponins and flavonoids, respectively. The enhancement of benzimidazoles' metabolism caused by the studied plant metabolites could change pharmacokinetics and the efficacy of benzimidazoles' treatment in cattle.
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Affiliation(s)
- Wojciech Karlik
- Division of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Warsaw University of Life Sciences, Warsaw, Poland
| | - Magdalena Chłopecka
- Division of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Warsaw University of Life Sciences, Warsaw, Poland
| | | | - Marta Mendel
- Division of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Warsaw University of Life Sciences, Warsaw, Poland
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31
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Bacanlı M, Aydın S, Anlar HG, Çal T, Arı N, Ündeğer Bucurgat Ü, Başaran AA, Başaran N. Can ursolic acid be beneficial against diabetes in rats? ACTA ACUST UNITED AC 2018. [DOI: 10.1515/tjb-2017-0289] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Abstract
Objective:
Diabetes mellitus, a heteregenous metabolic and chronic disease, is a growing health problem especially in developing countries. It is claimed that diabetes associated with increased formation of free radicals and decrease in antioxidant potential and also alterations in lipid profile and enzyme levels. Ursolic acid is commonly used in traditional Chinese medicine due to its beneficial effects. The aim of this study was to investigate the effects of ursolic acid on streptozotocin-induced diabetes in Wistar albino rats.
Methods:
DNA damage was evaluated in the blood and liver cells of rats by alkaline comet assay. The activities of antioxidant enzymes, oxidative stress parameters, biochemical parameters, hepatic enzyme levels and lipid profile parameters were also evaluated.
Results:
The results of this study demonstrate that diabetes caused genotoxic damage, changes in hepatic enzyme and lipid profile, biochemical and antioxidant enzyme activities and oxidative stress parameters in rats. Ursolic acid was found to be protective against diabetes induced effects in blood and liver samples of rats.
Conclusions:
According to our results, it seems that ursolic acid may be beneficial against diabetes and its adverse effects in rats.
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Thakur R, Sharma A, Lingaraju MC, Begum J, Kumar D, Mathesh K, Kumar P, Singh TU, Kumar D. Ameliorative effect of ursolic acid on renal fibrosis in adenine-induced chronic kidney disease in rats. Biomed Pharmacother 2018; 101:972-980. [PMID: 29635907 DOI: 10.1016/j.biopha.2018.02.143] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2017] [Revised: 02/27/2018] [Accepted: 02/27/2018] [Indexed: 12/18/2022] Open
Abstract
Ursolic acid (UA), an ursane-type pentacyclic triterpenoid commonly found in apple peels and holy basil has been shown to possess many beneficial effects. Renal fibrosis is a complication of kidney injury and associated with increased risk of morbidity and mortality. In our previous investigation, a lupane-type pentacyclic triterpenoid, betulinic acid (BA) was found to have protective effect on chronic kidney disease (CKD) and renal fibrosis. This prompted us to explore the therapeutic value of UA, a chemically related compound to BA in CKD. CKD was induced by feeding adenine with the feed at a concentration of 0.75% for 28 days. UA at the dose rate of 30 mg/kg in 0.5% carboxy methyl cellulose (CMC) was administered by oral route, simultaneously with adenine feeding for 28 days. Adenine feeding increased the kidney weight to body weight index, decreased the kidney function due to injury as indicated by increased markers like serum urea, uric acid, creatinine, cystatin C and neutrophil gelatinase-associated lipocalin (NGAL) and initiated the fibrotic response in kidney by increasing the profibrotic proteins viz. transforming growth factor-beta (TGF-β), connective tissue growth factor (CTGF), fibronectin and collagen. However, treatment with UA reversed the damage induced by adenine as shown by reduced kidney injury and fibrosis markers which was further clearly evident in histological picture indicating the suitability of UA for use in CKD.
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Affiliation(s)
- Richa Thakur
- Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar, 243 122, UP, India
| | - Anshuk Sharma
- Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar, 243 122, UP, India
| | - Madhu C Lingaraju
- Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar, 243 122, UP, India.
| | - Jubeda Begum
- Department of Veterinary Microbiology, College of Veterinary & Animal Sciences, G. B. Pant University of Agriculture and Technology, Pantnagar, 263153, UK, India
| | - Dhirendra Kumar
- Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar, 243 122, UP, India
| | - Karikalan Mathesh
- Centre for Wildlife Conservation Management and Disease Surveillance, Indian Veterinary Research Institute, Izatnagar, 243 122, UP, India
| | - Pawan Kumar
- Division of Pathology, Indian Veterinary Research Institute, Izatnagar, 243 122, UP, India
| | - Thakur Uttam Singh
- Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar, 243 122, UP, India
| | - Dinesh Kumar
- Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar, 243 122, UP, India
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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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Inhibition of Cytochrome P450 Activities by Extracts of Hyptis verticillata Jacq.: Assessment for Potential HERB-Drug Interactions. Molecules 2018; 23:molecules23020430. [PMID: 29462868 PMCID: PMC6017200 DOI: 10.3390/molecules23020430] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2017] [Revised: 02/06/2018] [Accepted: 02/13/2018] [Indexed: 11/21/2022] Open
Abstract
Understanding the potential for adverse drug reactions (ADRs), from herb-drug interactions, is a key aspect of medicinal plant safety, with particular relevance for public health in countries where medicinal plant use is highly prevalent. We undertook an in-depth assessment of extracts of Hyptis verticillata Jacq., via its impact on activities of key cytochrome P450 (CYP) enzymes (CYPs 1A1, 1A2, 1B1, 3A4 and 2D6), its antioxidant properties (determined by DPPH assays) and chemical characterisation (using LC-MS). The dried plant aqueous extract demonstrated potent inhibition of the activities of CYPs 1A1 (7.6 µg/mL), 1A2 (1.9 µg/mL), 1B1 (9.4 µg/mL) and 3A4 (6.8 µg/mL). Further analysis of other crude extracts demonstrated potent inhibition of CYP1A2 activity for a dried plant ethanol extract (1.5 µg/mL), fresh plant ethanol extract (3.9 µg/mL), and moderate activity for a fresh plant aqueous extract (27.8 µg/mL). All four extracts demonstrated strong antioxidant activity, compared to the positive control (ascorbic acid, 1.3 µg/mL), with the dried plant ethanol extract being the most potent (1.6 µg/mL). Analysis of the dried plant aqueous extract confirmed the identity of seven phytochemicals, five lignans and two triterpenes. Individual screening of these phytochemicals against the activity of CYP1A2 identified yatein as a moderate inhibitor (71.9 μM), likely to contribute to the plant extract’s potent bioactivity. Further analysis on the impact of this plant on key drug metabolizing enzymes in vivo appears warranted for likely ADRs, as well as furthering development as a potential chemopreventive agent.
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Zou Y, Yan C, Liu JC, Huang ZJ, Xu JY, Zhou JP, Zhang HB, Zhang YH. Synthesis and anti-hepatocellular carcinoma activity of novel O 2-vinyl diazeniumdiolate-based nitric oxide-releasing derivatives of oleanolic acid. Chin J Nat Med 2018; 15:928-937. [PMID: 29329650 DOI: 10.1016/s1875-5364(18)30009-8] [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: 01/10/2017] [Indexed: 11/19/2022]
Abstract
Considering that high levels of nitric oxide (NO) exert anti-cancer effect and the derivatives of oleanolic acid (OA) have shown potent anti-cancer activity, new O2-vinyl diazeniumdiolate-based NO releasing derivatives (5a-l, 11a-l) of OA were designed, synthesized, and biologically evaluated in the present study. These derivatives could release different amounts of NO in liver cells. Among them, 5d, 5i, 5j, 11g, 11h, and 11j released more NO in SMMC-7721 cells and displayed stronger proliferative inhibition against SMMC-7721 and HepG2 cells than OA and other tested compounds. The most active compound 5j showed almost 20-fold better solubility than OA in aqueous solution, released larger amounts of NO in liver cancer cells than that in normal ones, and exhibited potent anti-hepatocellular carcinoma activity but little effect on the normal liver cells. The inhibitory activity against the cancer cells was significantly diminished upon addition of an NO scavenger, suggesting that NO may contribute, at least in part, to the activity of 5j.
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Affiliation(s)
- Yu Zou
- State Key Laboratory of National Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing 210009, China
| | - Chang Yan
- State Key Laboratory of National Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing 210009, China
| | - Jing-Chao Liu
- State Key Laboratory of National Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing 210009, China
| | - Zhang-Jian Huang
- State Key Laboratory of National Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing 210009, China.
| | - Jin-Yi Xu
- State Key Laboratory of National Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing 210009, China
| | - Jin-Pei Zhou
- State Key Laboratory of National Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing 210009, China
| | - Hui-Bin Zhang
- State Key Laboratory of National Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing 210009, China.
| | - Yi-Hua Zhang
- State Key Laboratory of National Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing 210009, China.
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Ramos-Hryb AB, Cunha MP, Kaster MP, Rodrigues ALS. Natural Polyphenols and Terpenoids for Depression Treatment: Current Status. ACTA ACUST UNITED AC 2018. [DOI: 10.1016/b978-0-444-64068-0.00006-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/09/2023]
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Chang HY, Chen CJ, Ma WC, Cheng WK, Lin YN, Lee YR, Chen JJ, Lim YP. Modulation of pregnane X receptor (PXR) and constitutive androstane receptor (CAR) activation by ursolic acid (UA) attenuates rifampin-isoniazid cytotoxicity. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2017; 36:37-49. [PMID: 29157826 DOI: 10.1016/j.phymed.2017.09.016] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/18/2017] [Revised: 06/30/2017] [Accepted: 09/24/2017] [Indexed: 06/07/2023]
Abstract
BACKGROUND Interactions between transcriptional inducers of cytochrome P450 (CYP450) enzymes and therapeutic drugs may be prevented by antagonizing the activation of a nuclear receptor (NR), pregnane X receptor (PXR, NR1I2), thus improving therapeutic efficacy. PURPOSE In the present study, we aim to identify that ursolic acid (UA), a widely distributed pentacyclic triterpene, may act as an effective antagonist of PXR and its sister NR receptor, constitutive androstane receptor (CAR, NR1I3). METHODS The hepatocellular carcinoma cell line, HepG2, was used to evaluate the promoter activity of PXR and CAR target genes, CYP3A4 and CYP2B6, respectively. Catalytic activities, mRNA, and protein expression of CYP3A4 and CYP2B6 were evaluated in a differentiated HepaRG cell line. Coregulation of PXR with coregulators on CYP3A4 promoter response elements was also been characterized. RESULTS Transient transfection assays showed that UA effectively attenuated CYP3A4 and CYP2B6 promoter activities mediated by rifampin (RIF, human PXR agonist) and CITCO (human CAR agonist). These inhibitory effects were well correlated with the expression and catalytic activities of CYP3A4 and CYP2B6. Furthermore, the interaction of co-regulators with PXR and the transcriptional complexes in the CYP3A4 promoter activity and CYP3A4 promoter xenobiotic response element (everted repeat 6, ER6), respectively, were disrupted in the presence of UA. UA showed an antagonistic effect against PXR, and reversed the cytotoxic effects of isoniazid (INH) induced by RIF. Taken together, these results show that UA inhibits the transactivation effects of PXR and CAR, and reduces the expression and function of CYP3A4 and CYP2B6. CONCLUSION The present study suggests that UA could be a powerful agent for reducing potentially dangerous interactions between transcriptional inducers of CYP enzymes and therapeutic drugs.
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Affiliation(s)
- Hsiao-Yun Chang
- Department of Biotechnology, Asia University, Taichung, Taiwan
| | - Chao-Jung Chen
- School of Chinese Medicine, China Medical University, Taichung, Taiwan; Proteomics Core Laboratory, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan
| | - Wei-Chih Ma
- Department of Pharmacy, College of Pharmacy, China Medical University, Taichung, Taiwan
| | - Wai-Kok Cheng
- Department of Pharmacy, College of Pharmacy, China Medical University, Taichung, Taiwan
| | - Yen-Ning Lin
- Department of Pharmacy, College of Pharmacy, China Medical University, Taichung, Taiwan
| | - Ying-Ray Lee
- Translational Medicine Research Center, Chia-Yi Christian Hospital, Chiayi, Taiwan
| | - Jih-Jung Chen
- Faculty of Pharmacy, School of Pharmaceutical Sciences, National Yang Ming University, Taipei, Taiwan
| | - Yun-Ping Lim
- Department of Pharmacy, College of Pharmacy, China Medical University, Taichung, Taiwan; Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan; Department of Medical Research, China Medical University Hospital, Taichung, Taiwan.
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Cancer chemoprevention revisited: Cytochrome P450 family 1B1 as a target in the tumor and the microenvironment. Cancer Treat Rev 2017; 63:1-18. [PMID: 29197745 DOI: 10.1016/j.ctrv.2017.10.013] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2017] [Revised: 10/30/2017] [Accepted: 10/31/2017] [Indexed: 02/08/2023]
Abstract
Cancer chemoprevention is the use of synthetic, natural or biological agents to prevent or delay the development or progression of malignancies. Intriguingly, many phytochemicals with anti-inflammatory and anti-angiogenic effects, recently proposed as chemoprevention strategies, are inhibitors of Cytochrome P450 family 1B1 (CYP1B1), an enzyme overexpressed in a wide variety of tumors and associated with angiogenesis. In turn, pro-inflammatory cytokines were reported to boost CYP1B1 expression, suggesting a key role of CYP1B1 in a positive loop of inflammatory angiogenesis. Other well-known pro-tumorigenic activities of CYP1B1 rely on metabolic bioactivation of xenobiotics and steroid hormones into their carcinogenic derivatives. In contrast to initial in vitro observations, in vivo studies demonstrated a protecting role against cancer for the other CYP1 family members (CYP1A1 and CYP1A2), suggesting that the specificity of CYP1 family inhibitors should be carefully taken into account for developing potential chemoprevention strategies. Recent studies also proposed a role of CYP1B1 in multiple cell types found within the tumor microenvironment, including fibroblasts, endothelial and immune cells. Overall, our review of the current literature suggests a positive loop between inflammatory cytokines and CYP1B1, which in turn may play a key role in cancer angiogenesis, acting on both cancer cells and the tumor microenvironment. Strategies aiming at specific CYP1B1 inhibition in multiple cell types may translate into clinical chemoprevention and angioprevention approaches.
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Vaghela M, Sahu N, Kharkar P, Pandita N. In vivo pharmacokinetic interaction by ethanolic extract of Gymnema sylvestre with CYP2C9 (Tolbutamide), CYP3A4 (Amlodipine) and CYP1A2 (Phenacetin) in rats. Chem Biol Interact 2017; 278:141-151. [PMID: 29042257 DOI: 10.1016/j.cbi.2017.10.015] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2017] [Revised: 10/04/2017] [Accepted: 10/13/2017] [Indexed: 02/05/2023]
Abstract
Gymnema sylvestre (GS) is a medicinal herb used for diabetes mellitus (DM). Herbs are gaining popularity as medicines in DM for its safety purpose. The aim of the present study was to evaluate in vivo pharmacokinetic (PK) interaction between allopathic drugs tolbutamide (TOLBU), amlodipine (AMLO), and phenacetin (PHENA) at low (L) and high (H) doses with ethanolic extract (EL) from GS. EL was extracted and subjected to TLC, total triterpenoid content (19.76 ± 0.02 W/W) and sterol content (0.1837 ± 0.0046 W/W) estimation followed by identification of phytoconstituents using HRLC-MS and GC-MS. PK interaction study with CYP2C9, CYP3A4 and CYP1A2 enzymes were assessed using TOLBU, AMLO and PHENA respectively to index cytochrome (CYP) mediated interaction in rats after concomitant administration of EL extract (400 mg/kg) from GS for 7 days. The rats were divided into four groups for each PK study where, group I and II were positive control for low and high dose of test drugs (CYP substrates) while group II and IV were orally administered EL. The PK study result of PHENA indicated that area under the plasma concentration-time curve (AUC0-24) was significantly (P < 0.0001) increased by 1.4 (L) and 1.3-fold (H), plasma concentration (Cmax) was significantly (P < 0.001) increased by 1.6 (L) and 1.4-fold (H). Whereas for TOLBU; clearance rate (CL) was significantly (P < 0.0001) decreased by 2.4 (L) and 2.3-fold (H), Cmax, was significantly (P < 0.001) decreased by 26.5% (L) and 50.4% (H) and AUC0-24 was significantly (P < 0.0001) decreased by 59.8% (L) and 57.5% (H). Thus, EL is seen to be interacting with CYP1A2 by inhibiting its metabolic activity. HRLC-MS and GC-MS helped identify the presence of gymnemic acid (GA), triterpenoids and steroids in EL which could be the reason for PK interaction of CYP1A2 and CYP2C9. Also, in silico structure based site of metabolism study showed Fe accessibility and intrinsic activity for GA-IV, GA-VI, GA-VII and GA-X with CYP2C9. PK parameters of AMLO were not significantly affected by pre-treatment of EL. Thereby our findings indicate that co-administration of GS with drugs that are metabolized by CYP2C9 and CYP1A2 could lead to potential HDI.
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Affiliation(s)
- Madhuri Vaghela
- Department of Chemistry, Sunandan Divatia School of Science, SVKM's NMIMS University, Mumbai 400056, Maharashtra, India.
| | - Niteshkumar Sahu
- Department of Pharmaceutical Chemistry, SPP-School of Pharmacy and Technology Management, SVKM's NMIMS University, Mumbai 400056, Maharashtra, India
| | - Prashant Kharkar
- Department of Pharmaceutical Chemistry, SPP-School of Pharmacy and Technology Management, SVKM's NMIMS University, Mumbai 400056, Maharashtra, India
| | - Nancy Pandita
- Department of Chemistry, Sunandan Divatia School of Science, SVKM's NMIMS University, Mumbai 400056, Maharashtra, India.
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Zhang W, Liang C, Liu H, Li Z, Chen R, Zhou M, Li D, Ye Q, Luo C, Sun J. Polymeric nanoparticles developed by vitamin E-modified aliphatic polycarbonate polymer to promote oral absorption of oleanolic acid. Asian J Pharm Sci 2017; 12:586-593. [PMID: 32104372 PMCID: PMC7032188 DOI: 10.1016/j.ajps.2017.08.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2017] [Revised: 07/31/2017] [Accepted: 08/09/2017] [Indexed: 11/28/2022] Open
Abstract
Oleanolic acid (OA) exhibited good pharmacological activities in the clinical treatment of hypoglycemia, immune regulation, acute jaundice and chronic toxic hepatitis. However, the oral delivery of OA is greatly limited by its inferior water solubility and poor intestinal mucosa permeability. Herein, we developed a novel polymeric nanoparticle (NP) delivery system based on vitamin E modified aliphatic polycarbonate (mPEG-PCC-VE) to facilitate oral absorption of OA. OA encapsulated mPEG-PCC-VE NPs (OA/mPEG-PCC-VE NPs) showed uniform particle size of about 170 nm with high drug loading capability (8.9%). Furthermore, the polymeric mPEG-PCC-VE NPs, with good colloidal stability and pH-sensitive drug release characteristics, significantly enhanced the in vitro dissolution of OA in the alkaline medium. The in situ single pass intestinal perfusion (SPIP) studies performed on rats demonstrated that the OA/mPEG-PCC-VE NPs showed significantly improved permeability in the whole intestinal tract when compared to OA solution, especially for duodenum and colon. As a result, the in vivo pharmacokinetics study indicated that the bioavailability of OA/mPEG-PCC-VE NPs showed 1.5-fold higher than commercially available OA tablets. These results suggest that mPEG-PCC-VE NPs are a promising platform to facilitate the oral delivery of OA.
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Affiliation(s)
- Wenjuan Zhang
- School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang 110016, China
| | - Chufan Liang
- HAISCO (Shenyang) Pharmaceutical Co. Ltd., Shenyang, China
| | - Hao Liu
- School of Pharmacy, BioMolecular Sciences Department, The University of Mississippi, Oxford, MS 38677, USA
| | - Zhenbao Li
- School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang 110016, China
| | - Rui Chen
- School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang 110016, China
| | - Mei Zhou
- School of Continuing Education, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang 110016, China
| | - Dan Li
- School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang 110016, China
| | - Qing Ye
- School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang 110016, China
| | - Cong Luo
- School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang 110016, China
| | - Jin Sun
- School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang 110016, China.,Municipal Key Laboratory of Biopharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang 110016, China
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Lin YN, Chen CJ, Chang HY, Cheng WK, Lee YR, Chen JJ, Lim YP. Oleanolic Acid-Mediated Inhibition of Pregnane X Receptor and Constitutive Androstane Receptor Attenuates Rifampin-Isoniazid Cytotoxicity. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2017; 65:8606-8616. [PMID: 28945086 DOI: 10.1021/acs.jafc.7b02696] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Abstract
Interactions between transcriptional inducers of cytochrome P450 (CYP450) and pharmacological agents might decrease drug efficacy and induce side effects. Such interactions could be prevented using an antagonist of the pregnane X receptor (PXR) and constitutive androstane receptor (CAR). Here, we aimed to determine the antagonistic effect of oleanolic acid (OA) on PXR and CAR. OA attenuated the promoter activities, expressions, and enzyme catalytic activities of CYP3A4 and CYP2B6 mediated by rifampin (RIF) and CITCO. Moreover, OA displayed species specificity for rodent PXR. Interaction of coregulators with PXR and transcriptional complexes on the CYP3A4 promoter was disrupted by OA. Additionally, OA reversed the cytotoxic effects of isoniazid induced by RIF. These data demonstrate that OA inhibited the transactivation of PXR and CAR, reduced the expression and function of CYP3A4 and CYP2B6, and may therefore serve as an effective agent for reducing probability adverse interactions between transcriptional inducers of CYP450 and therapeutic drugs.
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Affiliation(s)
- Yen-Ning Lin
- Department of Pharmacy, College of Pharmacy, China Medical University , Taichung 40402, Taiwan
| | - Chao-Jung Chen
- Proteomics Core Laboratory, Department of Medical Research, China Medical University Hospital , Taichung 40402, Taiwan
- School of Chinese Medicine, China Medical University , Taichung 40402, Taiwan
| | - Hsiao-Yun Chang
- Department of Biotechnology, Asia University , Taichung 41354, Taiwan
| | - Wai-Kok Cheng
- Department of Pharmacy, College of Pharmacy, China Medical University , Taichung 40402, Taiwan
| | - Ying-Ray Lee
- Translational Medicine Research Center, Chia-Yi Christian Hospital , Chiayi 60002, Taiwan
| | - Jih-Jung Chen
- Faculty of Pharmacy, School of Pharmaceutical Sciences, National Yang Ming University , Taipei, Taiwan
| | - Yun-Ping Lim
- Department of Pharmacy, College of Pharmacy, China Medical University , Taichung 40402, Taiwan
- Department of Internal Medicine, China Medical University Hospital , Taichung 40402, Taiwan
- Department of Medical Research, China Medical University Hospital , Taichung 40402, Taiwan
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Mendel M, Chłopecka M, Dziekan N, Karlik W. Interactions between erythromycin, flunixin meglumine, levamisole and plant secondary metabolites towards bovine gastrointestinal motility-in vitro study. J Vet Pharmacol Ther 2017; 41:281-291. [PMID: 28913883 DOI: 10.1111/jvp.12455] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2017] [Accepted: 08/14/2017] [Indexed: 11/30/2022]
Abstract
Continued ingestion of plant secondary metabolites by ruminants can provoke pharmacological interactions with pharmaceutical agents used in animals. As some drugs and phytocompounds affect smooth muscle activity, the aim of this study was to verify the possible interaction between selected pharmaceutical agents and plant secondary metabolites towards bovine gastrointestinal motility. The interactions between phytocompounds-apigenin, quercetin, hederagenin, medicagenic acid-and medicines-erythromycin, flunixin meglumine and levamisole-were evaluated on bovine isolated abomasal and duodenal specimens obtained from routinely slaughtered cows. The obtained results confirmed the contractile effect of all three drugs used solely. Hederagenin and medicagenic acid (0.001 μM) enhanced the contractile effect of levamisole. Hederagenin additionally increased the impact of erythromycin. Both saponins (100 μM) showed synergistic effects with all tested pharmaceuticals. Apigenin and quercetin (0.001 μM) intensified the contractile response induced by erythromycin and levamisole. Moreover, both flavonoids (100 μM) showed an antagonistic interaction with all tested drugs which in that situation were devoid of the prokinetic effect. To conclude, plant metabolic metabolites such as saponins and flavonoids are potent modifiers of the effect of drugs towards gut motility. The synergy observed between phytocompounds and selected medicines can be beneficial in the treatment of cows with hypomotility disorders.
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Affiliation(s)
- M Mendel
- Division of Pharmacology and Toxicology, Department of Preclinical Sciences, Faculty of Veterinary Medicine, Warsaw University of Life Sciences, Warsaw, Poland
| | - M Chłopecka
- Division of Pharmacology and Toxicology, Department of Preclinical Sciences, Faculty of Veterinary Medicine, Warsaw University of Life Sciences, Warsaw, Poland
| | - N Dziekan
- Division of Pharmacology and Toxicology, Department of Preclinical Sciences, Faculty of Veterinary Medicine, Warsaw University of Life Sciences, Warsaw, Poland
| | - W Karlik
- Division of Pharmacology and Toxicology, Department of Preclinical Sciences, Faculty of Veterinary Medicine, Warsaw University of Life Sciences, Warsaw, Poland
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Xie H, Wu J, Liu D, Liu M, Zhang H, Huang S, Xiong Y, Xia C. In vitro inhibition of UGT1A3, UGT1A4 by ursolic acid and oleanolic acid and drug-drug interaction risk prediction. Xenobiotica 2017; 47:785-792. [PMID: 27600106 DOI: 10.1080/00498254.2016.1234087] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2016] [Revised: 09/05/2016] [Accepted: 09/05/2016] [Indexed: 12/13/2022]
Abstract
1. Ursolic acid (UA) and oleanolic acid (OA) may have important activity relevant to health and disease prevention. Thus, we studied the activity of UA and OA on UDP-glucuronosyltransferases (UGTs) and used trifluoperazine as a probe substrate to test UGT1A4 activity. Recombinant UGT-catalyzed 4-methylumbelliferone (4-MU) glucuronidation was used as a probe reaction for other UGT isoforms. 2. UA and OA inhibited UGT1A3 and UGT1A4 activity but did not inhibit other tested UGT isoforms. 3. UA-mediated inhibition of UGT1A3 catalyzed 4-MU-β-d-glucuronidation was via competitive inhibition (IC50 0.391 ± 0.013 μM; Ki 0.185 ± 0.015 μM). UA also competitively inhibited UGT1A4-mediated trifluoperazine-N-glucuronidation (IC50 2.651 ± 0.201 μM; Ki 1.334 ± 0.146 μM). 4. OA offered mixed inhibition of UGT1A3-mediated 4-MU-β-d-glucuronidation (IC50 0.336 ± 0.013 μM; Ki 0.176 ± 0.007 μM) and competitively inhibited UGT1A4-mediated trifluoperazine-N-glucuronidation (IC50 5.468 ± 0.697 μM; Ki 6.298 ± 0.891 μM). 5. Co-administering OA or UA with drugs or products that are substrates of UGT1A3 or UGT1A4 may produce drug-mediated side effects.
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Affiliation(s)
- Hongbo Xie
- a Clinical Pharmacology Institute, Nanchang University , Nanchang , P.R. China
| | - Jie Wu
- a Clinical Pharmacology Institute, Nanchang University , Nanchang , P.R. China
| | - Dan Liu
- a Clinical Pharmacology Institute, Nanchang University , Nanchang , P.R. China
| | - Mingyi Liu
- a Clinical Pharmacology Institute, Nanchang University , Nanchang , P.R. China
| | - Hong Zhang
- a Clinical Pharmacology Institute, Nanchang University , Nanchang , P.R. China
| | - Shibo Huang
- a Clinical Pharmacology Institute, Nanchang University , Nanchang , P.R. China
| | - Yuqing Xiong
- a Clinical Pharmacology Institute, Nanchang University , Nanchang , P.R. China
| | - Chunhua Xia
- a Clinical Pharmacology Institute, Nanchang University , Nanchang , P.R. China
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Jiang K, Chi T, Li T, Zheng G, Fan L, Liu Y, Chen X, Chen S, Jia L, Shao J. A smart pH-responsive nano-carrier as a drug delivery system for the targeted delivery of ursolic acid: suppresses cancer growth and metastasis by modulating P53/MMP-9/PTEN/CD44 mediated multiple signaling pathways. NANOSCALE 2017; 9:9428-9439. [PMID: 28660943 DOI: 10.1039/c7nr01677h] [Citation(s) in RCA: 64] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Abstract
Ursolic acid (UA) has been recently used as a promising anti-tumor and cancer metastatic chemo-preventive agent due to its low toxicity and liver-protecting property. However, the low bioavailability and nonspecific tumor targeting restrict its further clinical application. To address the problem, a silica-based mesoporous nanosphere (MSN) controlled-release drug delivery system (denoted UA@M-CS-FA) was designed and successfully synthesized, and was functionalized with folic acid (FA) and pH-sensitive chitosan (CS) for the targeted delivery of UA to folate receptor (FR) positive tumor cells. UA@M-CS-FA were spherical with mean diameter below 150 nm, and showed about -20 mV potential. Meanwhile, UA@M-CS-FA exhibited a pH-sensitive release manner and high cellular uptake in FR over-expressing HeLa cancer cells. Also, in vitro cellular assays suggested that UA@M-CS-FA inhibited cancer cell growth, invasion and migration. Mechanistically, UA@M-CS-FA induced cancer cell apoptosis and inhibited migration via cell cycle arrest in the G0/G1 stage, regulating the PARP/Bcl-2/MMP-9/CD44/PTEN/P53. Importantly, in vivo experiments further confirmed that UA@M-CS-FA significantly suppressed the tumor progression and lung metastasis in tumor-bearing nude mice. Immunohistochemical analysis revealed that UA@M-CS-FA treatment regulated CD44, a biomarker of cancer metastasis. Overall, our data demonstrated that a CS and FA modified MSN controlled-release drug delivery system could help broaden the usage of UA and reflect the great application potential of the UA as an anticancer or cancer metastatic chemopreventive agent.
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Affiliation(s)
- Kai Jiang
- Cancer Metastasis Alert and Prevention Center, Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, Fuzhou University, Fuzhou 350002, China.
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Bacanlı M, Başaran AA, Başaran N. The antioxidant, cytotoxic, and antigenotoxic effects of galangin, puerarin, and ursolic acid in mammalian cells. Drug Chem Toxicol 2017; 40:256-262. [PMID: 27461151 DOI: 10.1080/01480545.2016.1209680] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Phenolic compounds not only contribute to the sensory qualities of fruits and vegetables but also exhibit several health protective properties. Galangin, puerarin, and ursolic acid are commonly used plant phenolics in folk medicine. In this study, the antioxidant capacities of galangin, puerarin, and ursolic acid by the trolox equivalent antioxidant capacity (TEAC) assay and the cytotoxic effects by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in V79 cells were investigated. The genotoxic potentials of galangin, puerarin, and ursolic acid were evaluated by micronucleus (MN) and alkaline COMET assays in human lymphocytes and in V79 cells. Galangin, puerarin, and ursolic acid (10, 100, 500, 1000, 2000, 5000, 10 000, and 20 000 μM) were found to have antioxidant activities at the studied concentrations. IC50 values of galangin, puerarin, and ursolic acid in V79 cells were found to be 275.48 μM, 2503.712 μM, and 224.85 μM, respectively. Galangin, puerarin, and ursolic acid, at the all concentrations, have not exerted genotoxic effects and galangin, puerarin, and ursolic acid revealed a reduction in the frequency of MN and DNA damage induced by H2O2.
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Affiliation(s)
- Merve Bacanlı
- a Department of Pharmaceutical Toxicology , Faculty of Pharmacy, Hacettepe University , Ankara , Turkey and
| | - A Ahmet Başaran
- b Department of Pharmacognosy , Faculty of Pharmacy, Hacettepe University , Ankara , Turkey
| | - Nurşen Başaran
- a Department of Pharmaceutical Toxicology , Faculty of Pharmacy, Hacettepe University , Ankara , Turkey and
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β-Amyrin, a pentacyclic triterpene, exhibits anti-fibrotic, anti-inflammatory, and anti-apoptotic effects on dimethyl nitrosamine–induced hepatic fibrosis in male rats. Hum Exp Toxicol 2016; 36:113-122. [DOI: 10.1177/0960327116638727] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Hepatic fibrosis is a leading cause of morbidity and mortality worldwide. Attenuation of fibrogenic process can significantly lower the mortality rate. However, pharmaceutical intervention at fibrogenesis stage remains a major task in medicine. So there is a need for a natural compound to treat hepatic fibrosis. This study was outlined to investigate the anti-fibrotic effect of β-amyrin in dimethylnitrosamine (DMN)-induced hepatic fibrosis male rats. Serum liver function markers (aspartate transaminase, alanine transaminase, alkaline phosphatase and lactate dehydrogenase), oxidative stress markers (malondialdehyde, superoxide dismutase, catalase, glutathione peroxidase, glutathione reduced content and vitamin C), tissue inflammatory marker (tumor necrosis factor α (TNF-α)), apoptosis marker (caspase 3) and fibrolytic marker (tissue inhibitor of metalloproteinase 1 (TIMP-1)) were evaluated before and after β-amyrin treatment in DMN-induced rat. β-Amyrin treatment attenuated the altered levels of the serum enzyme markers produced by DMN and caused a subsequent recovery toward normalization. Oxidative stress markers and TNF-α levels were reduced significantly ( p < 0.001) as well as proteins’ (caspase-3 and TIMP-1) expression was reduced in β-amyrin –treated DMN rats. By virtue of β-amyrin properties of inhibiting oxidative stress, apoptosis, inflammation, and fibrogenesis, it might act as an ideal anti-inflammatory and anti-fibrogenic agent to halt the progression of liver fibrosis to chronicity.
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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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Liu D, Li S, Qi JQ, Meng DL, Cao YF. The inhibitory effects of nor-oleanane triterpenoid saponins from Stauntonia brachyanthera towards UDP-glucuronosyltransferases. Fitoterapia 2016; 112:56-64. [PMID: 27223851 DOI: 10.1016/j.fitote.2016.05.007] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2016] [Revised: 05/12/2016] [Accepted: 05/16/2016] [Indexed: 12/25/2022]
Abstract
The inhibition of UDP-glucuronosyltransferases (UGTs) by herbal components might be an important reason for clinical herb-drug interaction (HDI). The inhibitory effects on UGTs via nor-oleanane triterpenoid saponins, which were the bioactive ingredients from Stauntonia brachyanthera, a traditional Chinese folk medicines with highly biological values, were evaluated comprehensively with recombinant UGT isoforms as enzyme source and a nonspecific substrate 4-methylumbelliferone (4-MU) as substrate. The results showed that there are seven compounds, 2, 3, 4, 8, 9, 13 and 14, respectively, exhibited potential inhibitions towards UGT1A1, UGT1A3 and UGT1A10 among all 23 compounds isolated from the plants. The IC50 values were 17.1μM, 13.5μM, 9.5μM, 15.7μM, 16.3μM, 1.1μM, and 0.3μM, respectively. Data fitting using Dixon and Lineweaver-Burk plots demonstrated that the inhibition of UGT1A10, UGT1A1 and UGT1A3 was best fit to noncompetitive type and competitive, respectively. The inhibition kinetic parameter (Ki) was calculated to be 39μM, 17μM, 3.3μM, 10μM, 9.3μM, 0.19μM, and 0.016μM, respectively. All these experimental data suggested that HDI might occur when compounds containing herbs were co-administered with drugs which mainly undergo UGTs-mediated metabolism.
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Affiliation(s)
- Dan Liu
- Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Shuang Li
- Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Jia-Qi Qi
- Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Da-Li Meng
- Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, China.
| | - Yun-Feng Cao
- Key Laboratory of Contraceptives and Devices Research (NPFPC), Shanghai Engineer and Technology Research Center of Reproductive Health Drug and Devices, 200000, China; Translational Medicine Center, The First Affiliated Hospital of Liaoning Medical University, Jing Zhou, China
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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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Jamal M, Imam SS, Aqil M, Amir M, Mir SR, Mujeeb M. Transdermal potential and anti-arthritic efficacy of ursolic acid from niosomal gel systems. Int Immunopharmacol 2015; 29:361-369. [PMID: 26545446 DOI: 10.1016/j.intimp.2015.10.029] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2015] [Revised: 10/21/2015] [Accepted: 10/22/2015] [Indexed: 01/31/2023]
Abstract
The aim of the present study was to optimize niosomes by experimental design for enhanced transdermal delivery of ursolic acid for the effective treatment of arthritis. The experimental design (3 factor 3 levels, Box-Behnken design) was used to study individual and combined effects of different formulation variables. The variables cholesterol (X1), span 60 (X2) and phospholipid (X3) were taken as independent factors and their effect was observed on size (Y1) entrapment efficiency (Y2), and transflux (Y3). The formulation composition with span 60 (85mg), cholesterol (12.3mg), and phospholipid (65mg) was found to fulfil requisites of optimized ursolic acid niosome formulation (URNF). URNF had shown vesicle size of 665.45nm, entrapment efficiency of 92.74% with transflux of 17.25μg/cm(2)/h. The in vivo bioactivity showed that the prepared URNF-gel was able to provide good anti-arthritic activity due to enhanced permeation of UA through the skin and results were found to be comparable to standard gel (Omni gel). The radiographical image confirmed that, the developed URNF-gel was found to be effective to treat arthritis. Thus niosomal gel of ursolic acid would be a promising alternative to conventional therapy for safe and efficient treatment of arthritis and musculoskeletal disorders.
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Affiliation(s)
- Mahvish Jamal
- Faculty of Pharmacy, Jamia Hamdard University, New Delhi, India
| | - Syed Sarim Imam
- Glocal School of Pharmacy, Glocal University, Saharanpur, Uttar Pradesh, India
| | - Mohd Aqil
- Faculty of Pharmacy, Jamia Hamdard University, New Delhi, India.
| | - Mohd Amir
- Faculty of Pharmacy, Jamia Hamdard University, New Delhi, India
| | - Shaukat R Mir
- Faculty of Pharmacy, Jamia Hamdard University, New Delhi, India
| | - Mohd Mujeeb
- Faculty of Pharmacy, Jamia Hamdard University, New Delhi, India.
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