|
1
|
Shen C, Zhang S, Di H, Wang S, Wang Y, Guan F. The Role of Triterpenoids in Gastric Ulcer: Mechanisms and Therapeutic Potentials. Int J Mol Sci 2025; 26:3237. [PMID: 40244034 PMCID: PMC11990034 DOI: 10.3390/ijms26073237] [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: 03/05/2025] [Revised: 03/25/2025] [Accepted: 03/28/2025] [Indexed: 04/18/2025] Open
Abstract
Gastric ulcer (GU) is a prevalent gastrointestinal disorder impacting millions worldwide, with complex pathogenic mechanisms that may progress to severe illnesses. Conventional therapies relying on anti-secretory agents and antibiotics are constrained by drug abuse and increased bacterial resistance, highlighting the urgent need for safer therapeutic alternatives. Natural medicinal compounds, particularly triterpenoids derived from plants and herbs, have gained significant attention in recent years due to their favorable efficacy and reduced toxicity profiles. Emerging evidence indicates that triterpenoids exhibit potent anti-ulcer properties across various experimental models, modulating key pathways involved in inflammation, oxidative stress, apoptosis, and mucosal protection. Integrating current knowledge of these bioactive compounds facilitates the development of natural triterpenoids, addresses challenges in their clinical translation, deepens mechanistic understanding of GU pathogenesis, and drives innovation of therapeutic strategies for GU. This review comprehensively evaluates the progress of research on triterpenoids in GU treatment since 2000, discussing their biological sources, structural characteristics, pharmacological activities, and mechanisms of action, the animal models employed in the studies, current limitations, and the challenges associated with their clinical application.
Collapse
Affiliation(s)
- Congcong Shen
- School of Pharmacy, Heilongjiang University of Chinese Medicine, Harbin 150040, China; (C.S.); (S.Z.); (H.D.); (S.W.)
| | - Shengyu Zhang
- School of Pharmacy, Heilongjiang University of Chinese Medicine, Harbin 150040, China; (C.S.); (S.Z.); (H.D.); (S.W.)
| | - Han Di
- School of Pharmacy, Heilongjiang University of Chinese Medicine, Harbin 150040, China; (C.S.); (S.Z.); (H.D.); (S.W.)
| | - Shuang Wang
- School of Pharmacy, Heilongjiang University of Chinese Medicine, Harbin 150040, China; (C.S.); (S.Z.); (H.D.); (S.W.)
| | - Yanhong Wang
- School of Pharmacy, Heilongjiang University of Chinese Medicine, Harbin 150040, China; (C.S.); (S.Z.); (H.D.); (S.W.)
- Key Laboratory of Basic and Application Research of Beiyao, Ministry of Education, Heilongjiang University of Chinese Medicine, Harbin 150040, China
| | - Feng Guan
- School of Pharmacy, Heilongjiang University of Chinese Medicine, Harbin 150040, China; (C.S.); (S.Z.); (H.D.); (S.W.)
- Key Laboratory of Basic and Application Research of Beiyao, Ministry of Education, Heilongjiang University of Chinese Medicine, Harbin 150040, China
| |
Collapse
|
|
2
|
Zhao M, Xiang T, Dong Z, Liu G, Wang P, Qi X, Hao Q, Han N, Liu Z, Li S, Yin J, Zhai J. Shenqu xiaoshi oral solution enhances digestive function and stabilizes the gastrointestinal microbiota of juvenile rats with infantile anorexia. JOURNAL OF ETHNOPHARMACOLOGY 2024; 319:117112. [PMID: 37739107 DOI: 10.1016/j.jep.2023.117112] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Revised: 08/26/2023] [Accepted: 08/30/2023] [Indexed: 09/24/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Massa Medicata Fermentata ("Shenqu") has long been applied in the treatment of indigestion in China; in fact, it is the active ingredient in the medicine Shenqu xiaoshi oral solution (SQXSOS). Based on robust clinical evidence, SQXSOS has shown efficacy in treating infantile anorexia (IFA). AIM OF THE STUDY To investigate the underlying mechanisms by which SQXSOS treats IFA. MATERIAL AND METHODS The pharmacodynamic efficacy of SQXSOS was validated through a high-fat diet (HFD)-induced IFA model of juvenile rats, which share physiological similarities to two-year-old humans. Ultra-high-performance liquid chromatography coupled with time-of-flight mass spectrometry (UHPLC-TOF MS) was utilized to analyze the blood-dissolved components of SQXSOS in rats. After identification of the blood-dissolved components, the key components and target genes were predicted through network pharmacology analysis. To further validate the predicted key targets of the blood-dissolved components, RT-PCR and Western blotting were employed to measure the changes in their concentrations. Meanwhile, the efficacy of SQXSOS on the structure of gastrointestinal microbiota (GM) in IFA rats was investigated. RESULTS SQXSOS, when administered to the IFA rats at a dosage equivalent to its clinical dose in humans (3.78 mL/kg/day), induced a significant increase in the gastric emptying rate (+1.9-fold) and small intestine advancement rate (+0.5-fold) compared to the IFA rats. Additionally, SQXSOS reversed the pathological changes observed in the serum levels of digestive functioning biochemicals (-32.4%～+250% compared to the model group, p < 0.05). A total of 40 blood-dissolved components were identified by UHPLC-TOF MS. Berberine, oleanolic acid, ganolucidic acid A, slicyluric acid, and glycyrrhetinic acid were identified as the key components of SQXSOS, while AKT1, STAT3, TP53, JUN, and MAPK1 were identified as the key targets enabling the therapeutic efficacy of SQXSOS in treating IFA. In a target validation study, the mRNA transcript levels of the abovementioned target genes were found to be significantly higher in the gastric antrum of IFA rats. However, SQXSOS administration (3.78 and 7.56 mL/kg/day) reduced the elevated mRNA transcript levels of the abovementioned target genes (41.1-77.3% compared to model group, p < 0.05). GM analysis revealed a significant increase in the Firmicutes/Bacteroidota ratio (F/B ratio, +214.2%) in the IFA fecal samples compared to normal rats, but the high dosage of SQXSOS induced a marked decrease in the F/B ratio (-44.1%) compared to IFA rats. Furthermore, the therapeutic efficacy of SQXSOS against IFA might be attributed to the increase in Muribaculaceae abundance and the decrease in Prevotellaceae_UCG_003 abundance. CONCLUSION Mechanistic investigations indicated that the efficacy of SQXSOS in treating IFA could be manifested by regulating the transcription and expression levels of AKT1, MAPK1, STAT3, and TP53 genes in the gastric antrum as well as modulating the abundance of Muribaculaceae and Prevotellaceae_UCG_003 family. Furthermore, there are still some limitations: the contents of the key biochemicals remained to be determined, similar STAT3 transcription levels were observed in both normal rats and IFA rats, and it is crucial to further validate the potential target GM when transitioning from animal populations to humans.
Collapse
Affiliation(s)
- Meng Zhao
- School of Traditional Chinese Material, Shenyang Pharmaceutical University, Shenyang, 110016, China.
| | - Ting Xiang
- Jiangsu Longfengtang Traditional Chinese Medicine Co. Ltd, Yangtze River Pharmaceutical Group, China.
| | - Zhikui Dong
- Beijing Haiyan Pharmaceutical Co., Ltd, Yangtze River Pharmaceutical Group, China.
| | - Guorui Liu
- Jiangsu Longfengtang Traditional Chinese Medicine Co. Ltd, Yangtze River Pharmaceutical Group, China.
| | - Pengran Wang
- Jiangsu Longfengtang Traditional Chinese Medicine Co. Ltd, Yangtze River Pharmaceutical Group, China.
| | - Xiaoxu Qi
- Jiangsu Longfengtang Traditional Chinese Medicine Co. Ltd, Yangtze River Pharmaceutical Group, China.
| | - Qingqing Hao
- School of Traditional Chinese Material, Shenyang Pharmaceutical University, Shenyang, 110016, China.
| | - Na Han
- School of Traditional Chinese Material, Shenyang Pharmaceutical University, Shenyang, 110016, China.
| | - Zhihui Liu
- School of Traditional Chinese Material, Shenyang Pharmaceutical University, Shenyang, 110016, China.
| | - Sikai Li
- School of Traditional Chinese Material, Shenyang Pharmaceutical University, Shenyang, 110016, China.
| | - Jun Yin
- School of Traditional Chinese Material, Shenyang Pharmaceutical University, Shenyang, 110016, China.
| | - Jianxiu Zhai
- School of Traditional Chinese Material, Shenyang Pharmaceutical University, Shenyang, 110016, China.
| |
Collapse
|
|
3
|
Sun M, Xin Q, Hou K, Qiu J, Wang L, Chao E, Su X, Zhang X, Chen S, Wang C. Production of 11-Oxo-β-Amyrin in Saccharomyces cerevisiae at High Efficiency by Fine-Tuning the Expression Ratio of CYP450:CPR. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2023; 71:3766-3776. [PMID: 36795896 DOI: 10.1021/acs.jafc.2c08261] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/18/2023]
Abstract
The production of glycyrrhetinic acid (GA) and 11-oxo-β-amyrin, the major bioactive components in liquorice, was typically inhibited by P450 oxidation in Saccharomyces cerevisiae. This study focused on optimizing CYP88D6 oxidation by balancing its expression with cytochrome P450 oxidoreductase (CPR) for the efficient production of 11-oxo-β-amyrin in yeast. Results indicated that a high CPR:CYP88D6 expression ratio could decrease both 11-oxo-β-amyrin concentration and turnover ratio of β-amyrin to 11-oxo-β-amyrin, whereas a high CYP88D6:CPR expression ratio is beneficial for improving the catalytic activity of CYP88D6 and 11-oxo-β-amyrin production. Under such a scenario, 91.2% of β-amyrin was converted into 11-oxo-β-amyrin in the resulting S. cerevisiae Y321, and 11-oxo-β-amyrin production was further improved to 810.6 mg/L in fed-batch fermentation. Our study provides new insights into the expression of cytochrome P450 and CPR in maximizing the catalytic activity of P450s, which could guide the construction of cell factories in producing natural products.
Collapse
Affiliation(s)
- Mengchu Sun
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, No. 16, Nanxiaojie, Dongzhimennei, Beijing 100700, P. R. China
| | - Qi Xin
- Institute of Vegetables and Flowers, Chinese Academy of Agricultural Sciences, Beijing 100081, P. R. China
| | - Kangxin Hou
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, No. 16, Nanxiaojie, Dongzhimennei, Beijing 100700, P. R. China
- Department of Food Science, Beijing Key Laboratory of Forestry Food Processing and Safety, College of Biological Sciences and Biotechnology, Beijing Forestry University, Beijing 100083, P. R. China
| | - Jie Qiu
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, No. 16, Nanxiaojie, Dongzhimennei, Beijing 100700, P. R. China
| | - Linmei Wang
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, No. 16, Nanxiaojie, Dongzhimennei, Beijing 100700, P. R. China
| | - Erkun Chao
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, No. 16, Nanxiaojie, Dongzhimennei, Beijing 100700, P. R. China
| | - Xinyao Su
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, No. 16, Nanxiaojie, Dongzhimennei, Beijing 100700, P. R. China
- School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin 301607, P. R. China
| | - Xiuxin Zhang
- Institute of Vegetables and Flowers, Chinese Academy of Agricultural Sciences, Beijing 100081, P. R. China
| | - Shilin Chen
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, No. 16, Nanxiaojie, Dongzhimennei, Beijing 100700, P. R. China
- Innovative Institute of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, Sichuan, P. R. China
| | - Caixia Wang
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, No. 16, Nanxiaojie, Dongzhimennei, Beijing 100700, P. R. China
| |
Collapse
|
|
4
|
Zhou P, Cao Z, Liu Y, Guo T, Yang R, Wang M, Ren X, Wu L, Sun L, Peng C, Wang C, Zhang J. Co-achievement of enhanced absorption and elongated retention of insoluble drug in lungs for inhalation therapy of pulmonary fibrosis. POWDER TECHNOL 2022. [DOI: 10.1016/j.powtec.2022.117679] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
|
|
5
|
Zhou N, Liu D, Bao X. A Validated Liquid Chromatographic Method for Berberine Analysis in Tissue and Application. Int J Anal Chem 2020; 2020:8892696. [PMID: 33061977 PMCID: PMC7545417 DOI: 10.1155/2020/8892696] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2020] [Revised: 08/30/2020] [Accepted: 09/21/2020] [Indexed: 11/17/2022] Open
Abstract
Simple and rapid high-performance liquid chromatography methods were developed for the determination of berberine (BB) in various rat tissues so as to evaluate a P-gp inhibitor, glycyrrhetinic acid (GA), on BB's oral bioavailability. Acetonitrile was used to extract BB from tissues and showed different extraction recoveries in diverse tissues. The intra- and interday precision and accuracy were less than 10%. Long-term stability, pre (post) -preparative stability, and freeze-thaw stability were evaluated, and the results showed it could meet the need of this study. The proposed methods were subsequently applied to investigate the possible drug-drug interaction of GA and BB in vivo from the aspect of tissue distribution. The results showed that no significant difference was found between the group of low dose and high dose at the same time point. The tissue distributions show a saturated model, i.e., the content of BB in tissue tends to be constant while its dose is more than 200 mg/kg. Besides, the contents of BB ranged from high to low according to the order of the liver, kidney, and spleen. The BB content in the liver is especially high as compared to other tissues.
Collapse
Affiliation(s)
- Neng Zhou
- Guangxi Key Laboratory for Agricultural Resources Chemistry and Biotechnology, Yulin 537000, China
- Colleges and Universities Key Laboratory for Efficient Use of Agricultural Resources in the Southeast of Guangxi, Yulin, China
- College of Chemistry and Food Science, Yulin Normal University, Yulin, China
| | - Dangmei Liu
- College of Chemistry and Food Science, Yulin Normal University, Yulin, China
| | - Xiaowang Bao
- College of Chemistry and Food Science, Yulin Normal University, Yulin, China
| |
Collapse
|
|
6
|
Chrzanowski J, Chrzanowska A, Graboń W. Glycyrrhizin: An old weapon against a novel coronavirus. Phytother Res 2020; 35:629-636. [PMID: 32902005 DOI: 10.1002/ptr.6852] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Revised: 07/09/2020] [Accepted: 07/20/2020] [Indexed: 12/15/2022]
Abstract
Currently, over 100 countries are fighting against a common enemy, the severe acute respiratory syndrome coronavirus (SARS-CoV)-2, which causes COVID-19. This has created a demand for a substance whose effectiveness has already been demonstrated in a similar scenario. Glycyrrhizin (GZ) is a promising agent against SARS-CoV-2 as its antiviral activity against SARS-CoV has already been confirmed. It is worthwhile to extrapolate from its proven therapeutic effects as there is a high similarity in the structure and genome of SARS-CoV and SARS-CoV-2. There are many possible mechanisms through which GZ acts against viruses: increasing nitrous oxide production in macrophages, affecting transcription factors and cellular signalling pathways, directly altering the viral lipid-bilayer membrane, and binding to the ACE2 receptor. In this review, we discuss the possible use of GZ in the COVID-19 setting, where topical administration appears to be promising, with the nasal and oral cavity notably being the potent location in terms of viral load. The most recently published papers on the distribution of ACE2 in the human body and documented binding of GZ to this receptor, as well as its antiviral activity, suggest that GZ can be used as a therapeutic for COVID-19 and as a preventive agent against SARS-CoV-2.
Collapse
Affiliation(s)
- Julian Chrzanowski
- Chair and Department of Biochemistry, Medical University of Warsaw, Banacha 1, Warsaw, Poland
| | - Alicja Chrzanowska
- Chair and Department of Biochemistry, Medical University of Warsaw, Banacha 1, Warsaw, Poland
| | - Wojciech Graboń
- Chair and Department of Biochemistry, Medical University of Warsaw, Banacha 1, Warsaw, Poland
| |
Collapse
|
|
7
|
Cai D, Zhang Z, Meng Y, Zhu K, Chen L, Yu C, Yu C, Fu Z, Yang D, Gong Y. Efficient synthesis of piperazinyl amides of 18β-glycyrrhetinic acid. Beilstein J Org Chem 2020; 16:798-808. [PMID: 32395183 PMCID: PMC7188925 DOI: 10.3762/bjoc.16.73] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2019] [Accepted: 04/09/2020] [Indexed: 01/08/2023] Open
Abstract
In the present study, a practical method to prepare piperazinyl amides of 18β-glycyrrhetinic acid was developed. Two main procedures for the construction of important intermediate 8 are discussed. One procedure involves the amidation of 1-Boc-piperazine with 3-acetyl-18β-glycyrrhetinic acid, prepared by the reaction of 18β-glycyrrhetinic acid with acetic anhydride without any solvent at 130 °C. The other procedure to prepare compound 8 involves the amidation of 18β-glycyrrhetinic acid followed by the esterification with acetic anhydride. Finally, compound 8 underwent N-Boc deprotection to prepare product 4. To ascertain the scope of the reaction, another C-3 ester derivative 17 was tested under the optimized reaction conditions. Furthermore, the reasons for the appearance of byproducts were elucidated. Crystallographic data of a selected piperazinyl amide is reported.
Collapse
Affiliation(s)
- Dong Cai
- College of Public Basic Sciences, Jinzhou Medical University, Jinzhou, 121001, China
| | - ZhiHua Zhang
- School of Chemical and Environmental Engineering, Liaoning University of Technology, Jinzhou, 121001, China
| | - Yufan Meng
- College of Pharmacy, Jinzhou Medical University, Jinzhou, 121001, China
| | - KaiLi Zhu
- College of Pharmacy, Jinzhou Medical University, Jinzhou, 121001, China
| | - LiYi Chen
- College of Pharmacy, Jinzhou Medical University, Jinzhou, 121001, China
| | - ChangXiang Yu
- College of Pharmacy, Jinzhou Medical University, Jinzhou, 121001, China
| | - ChangWei Yu
- College of Pharmacy, Jinzhou Medical University, Jinzhou, 121001, China
| | - ZiYi Fu
- College of Pharmacy, Jinzhou Medical University, Jinzhou, 121001, China
| | - DianShen Yang
- College of Public Basic Sciences, Jinzhou Medical University, Jinzhou, 121001, China
| | - YiXia Gong
- College of Public Basic Sciences, Jinzhou Medical University, Jinzhou, 121001, China.,College of Pharmacy, Jiamusi University, Jiamusi, 154007, China
| |
Collapse
|
|
8
|
Zhou N, Zou C, Qin M, Li Y, Huang J. A simple method for evaluation pharmacokinetics of glycyrrhetinic acid and potential drug-drug interaction between herbal ingredients. Sci Rep 2019; 9:11308. [PMID: 31383927 PMCID: PMC6683301 DOI: 10.1038/s41598-019-47880-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Accepted: 06/10/2019] [Indexed: 12/14/2022] Open
Abstract
A simple validated high performance liquid chromatography method was developed for the evaluation of the effect of three kinds of active ingredients in traditional Chinese medicine (TCM) on the pharmacokinetics of glycyrrhetinic acid (GA),a kind of active component from the most commonly used TCM licorice. Our results revealed that all of the calibration curves displayed good linearity. Intra- and inter-day precision for GA ranged from 2.54 to 3.98% and from 4.95 to 7.08%, respectively. The recovery rates for GA were determined to be 96.3–106.4%. All the samples showed satisfactory precision and accuracy in various stability tests. Plasma pharmacokinetic parameters including area under the concentration-time curve (AUC), elimination half-life (t1/2), time to peak concentration(Tmax) and peak concentration Cmax were calculated. No significant difference was found as compared the groups administrating GA with and without other ingredients from TCM.
Collapse
Affiliation(s)
- Neng Zhou
- Guangxi Key Laboratory for Agricultural Resources Chemistry and Biotechnology, Colleges and Universities Key Laboratory for Efficient Use of Agricultural Resources in the Southeast of Guangxi, College of Chemistry and Food Science, Yulin Normal University, Yulin, 53700, China.
| | - Caiyuan Zou
- Guangxi Key Laboratory for Agricultural Resources Chemistry and Biotechnology, Colleges and Universities Key Laboratory for Efficient Use of Agricultural Resources in the Southeast of Guangxi, College of Chemistry and Food Science, Yulin Normal University, Yulin, 53700, China
| | - Menglin Qin
- Guangxi Key Laboratory for Agricultural Resources Chemistry and Biotechnology, Colleges and Universities Key Laboratory for Efficient Use of Agricultural Resources in the Southeast of Guangxi, College of Chemistry and Food Science, Yulin Normal University, Yulin, 53700, China
| | - Yi Li
- Guangxi Key Laboratory for Agricultural Resources Chemistry and Biotechnology, Colleges and Universities Key Laboratory for Efficient Use of Agricultural Resources in the Southeast of Guangxi, College of Chemistry and Food Science, Yulin Normal University, Yulin, 53700, China
| | - Jiayi Huang
- Guangxi Key Laboratory for Agricultural Resources Chemistry and Biotechnology, Colleges and Universities Key Laboratory for Efficient Use of Agricultural Resources in the Southeast of Guangxi, College of Chemistry and Food Science, Yulin Normal University, Yulin, 53700, China
| |
Collapse
|
|
9
|
Yamashita T, Kawada-Matsuo M, Katsumata T, Watanabe A, Oogai Y, Nishitani Y, Miyawaki S, Komatsuzawa H. Antibacterial activity of disodium succinoyl glycyrrhetinate, a derivative of glycyrrhetinic acid against Streptococcus mutans. Microbiol Immunol 2019; 63:251-260. [PMID: 31166029 DOI: 10.1111/1348-0421.12717] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Revised: 05/09/2019] [Accepted: 05/23/2019] [Indexed: 11/28/2022]
Abstract
Streptococcus mutans is a cariogenic bacterium that localizes in the oral cavity. Glycyrrhetinic acid (GRA) is a major component of licorice extract. GRA and several derivatives, including disodium succinoyl glycyrrhetinate (GR-SU), are known to have anti-inflammatory effects in humans. In this study, the antimicrobial effect of GRA and its derivatives against the S. mutans UA159 strain were investigated. Minimum inhibitory concentrations (MICs) of GRA and GR-SU showed antibacterial activity against the S. mutans strain, whereas other tested derivatives did not. Because GR-SU is more soluble than GRA, GR-SU was used for further experiments. The antibacterial activity of GR-SU against 100 S. mutans strains was evaluated and it was found that all strains are susceptible to GR-SU, with MIC values below 256 µg/mL. A cell viability assay showed that GR-SU has a bacteriostatic effect on S. mutans cells. As to growth kinetics, sub-MICs of GR-SU inhibited growth. The effect of GR-SU on S. mutans virulence was then investigated. GR-SU at sub-MICs suppresses biofilm formation. Additionally, GR-SU greatly suppresses the pH drop caused by the addition of glucose and glucose-induced expression of the genes responsible for acid production (ldh and pykF) and tolerance (aguD and atpD). Additionally, expression of enolase, which is responsible for the carbohydrate phosphotransferase system, was not increased in the presence of GR-SU, indicating that GR-SU suppresses incorporation of sugars into S. mutans. In conclusion, GR-SU has antibacterial activity against S. mutans and also decreases S. mutans virulence.
Collapse
Affiliation(s)
- Takahito Yamashita
- Department of Oral Microbiology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Miki Kawada-Matsuo
- Department of Oral Microbiology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Tamaki Katsumata
- Department of Restorative Dentistry and Endodontology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Atsuko Watanabe
- Department of Orthodontics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Yuichi Oogai
- Department of Oral Microbiology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Yoshihiro Nishitani
- Department of Restorative Dentistry and Endodontology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Shouichi Miyawaki
- Department of Orthodontics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Hitoshi Komatsuzawa
- Department of Bacteriology, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan
| |
Collapse
|
|
10
|
Quantitative Analysis and Chromatographic Fingerprinting of WeiChangShu Tablet Using High-Performance Liquid Chromatography Combined with Chemometric Methods. Chromatographia 2018. [DOI: 10.1007/s10337-018-3553-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
|
|
11
|
Shen Z, Qin Q, Liao X, Yang B. Host-guest inclusion system of glycyrrhetic acid with polyamine-β-cyclodextrin: Preparation, characterization, and anticancer activity. J Mol Struct 2017. [DOI: 10.1016/j.molstruc.2017.07.104] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
|
|
12
|
Wang S, Shen Y, Qiu R, Chen Z, Chen Z, Chen W. 18 β-glycyrrhetinic acid exhibits potent antitumor effects against colorectal cancer via inhibition of cell proliferation and migration. Int J Oncol 2017; 51:615-624. [PMID: 28656212 DOI: 10.3892/ijo.2017.4059] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2016] [Accepted: 06/13/2017] [Indexed: 11/06/2022] Open
Abstract
Accumulating evidence shows that 18 β-glycyr-rhetinic acid (GRA) has antitumor activities in breast, ovarian cancer and leukemia, while its role in colorectal cancer remains unknown. In the present study, we investigated the effect of GRA in colorectal cancer cells LoVo, SW480 and SW620 and studied the underlying molecular mechanisms. Results showed that GRA had potent inhibitory effects on colorectal cancer cell proliferation in a dose- and time-dependent manner in vitro and in vivo. Growth inhibition was mediated by pro-apoptosis, as evident from Annexin V-FITC staining, the reduced expression of survivin and the induced expression of cleaved PARP. Furthermore, GRA treatment resulted in marked reduction of cell migration, invasion and wound healing capability, accompanying by the downregulated MMP expression. Moreover, GRA decreased the protein levels of p-PI3K, p-AKT, p-STAT3, p-JNK, p-p38 and p-NF-κB p65, of which the phosphorylation of PI3K and STAT3 decreased as early as 2 h after the GRA treatment. These results suggest that regulation of the apoptosis, invasion and migration of colorectal cancer cells by GRA might be through suppressing PI3K and STAT3 signaling pathways. the present study indicated that GRA could be a potential effective therapy for patients with colorectal cancer.
Collapse
Affiliation(s)
- Saisai Wang
- Department of Colorectal Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, P.R. China
| | - Yong Shen
- Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, The Second Affiliated Hospital, Cancer Institute, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, P.R. China
| | - Runfeng Qiu
- Department of Colorectal Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, P.R. China
| | - Zhiliang Chen
- Department of Colorectal Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, P.R. China
| | - Zhehang Chen
- Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, P.R. China
| | - Wenbin Chen
- Department of Colorectal Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, P.R. China
| |
Collapse
|
|
13
|
Sidova V, Zoufaly P, Pokorny J, Dzubak P, Hajduch M, Popa I, Urban M. Cytotoxic conjugates of betulinic acid and substituted triazoles prepared by Huisgen Cycloaddition from 30-azidoderivatives. PLoS One 2017; 12:e0171621. [PMID: 28158265 PMCID: PMC5291411 DOI: 10.1371/journal.pone.0171621] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2016] [Accepted: 01/23/2017] [Indexed: 11/18/2022] Open
Abstract
In this work, we describe synthesis of conjugates of betulinic acid with substituted triazoles prepared via Huisgen 1,3-cycloaddition. All compounds contain free 28-COOH group. Allylic bromination of protected betulinic acid by NBS gave corresponding 30-bromoderivatives, their substitution with sodium azides produced 30-azidoderivatives and these azides were subjected to CuI catalysed Huisgen 1,3-cycloaddition to give the final conjugates. Reactions had moderate to high yields. All new compounds were tested for their in vitro cytotoxic activities on eight cancer and two non-cancer cell lines. The most active compounds were conjugates of 3β-O-acetylbetulinic acid and among them, conjugate with triazole substituted by benzaldehyde 9b was the best with IC50 of 3.3 μM and therapeutic index of 9.1. Five compounds in this study had IC50 below 10 μM and inhibited DNA and RNA synthesis and caused block in G0/G1 cell cycle phase which is highly similar to actinomycin D. It is unusual that here prepared 3β-O-acetates were more active than compounds with the free 3-OH group and this suggests that this set may have common mechanism of action that is different from the mechanism of action of previously known 3β-O-acetoxybetulinic acid derivatives. Benzaldehyde type conjugate 9b is the best candidate for further drug development.
Collapse
Affiliation(s)
- Veronika Sidova
- Department of Organic Chemistry, Faculty of Science, Palacky University, Olomouc, Czech Republic
| | - Pavel Zoufaly
- Department of Organic Chemistry, Faculty of Science, Palacky University, Olomouc, Czech Republic
| | - Jan Pokorny
- Department of Organic Chemistry, Faculty of Science, Palacky University, Olomouc, Czech Republic
| | - Petr Dzubak
- Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic
| | - Marian Hajduch
- Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic
| | - Igor Popa
- Department of Organic Chemistry, Faculty of Science, Palacky University, Olomouc, Czech Republic
- Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic
| | - Milan Urban
- Department of Organic Chemistry, Faculty of Science, Palacky University, Olomouc, Czech Republic
- Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic
| |
Collapse
|
|
14
|
Oyama K, Kawada-Matsuo M, Oogai Y, Hayashi T, Nakamura N, Komatsuzawa H. Antibacterial Effects of Glycyrrhetinic Acid and Its Derivatives on Staphylococcus aureus. PLoS One 2016; 11:e0165831. [PMID: 27820854 PMCID: PMC5098735 DOI: 10.1371/journal.pone.0165831] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2016] [Accepted: 10/18/2016] [Indexed: 01/16/2023] Open
Abstract
Staphylococcus aureus is a major pathogen in humans and causes serious problems due to antibiotic resistance. We investigated the antimicrobial effect of glycyrrhetinic acid (GRA) and its derivatives against 50 clinical S. aureus strains, including 18 methicillin-resistant strains. The minimum inhibitory concentrations (MICs) of GRA, dipotassium glycyrrhizate, disodium succinoyl glycyrrhetinate (GR-SU), stearyl glycyrrhetinate and glycyrrhetinyl stearate were evaluated against various S. aureus strains. Additionally, we investigated the bactericidal effects of GRA and GR-SU against two specific S. aureus strains. DNA microarray analysis was also performed to clarify the mechanism underlying the antibacterial activity of GR-SU. We detected the antimicrobial activities of five agents against S. aureus strains. GRA and GR-SU showed strong antibacterial activities compared to the other three agents tested. At a higher concentration (above 2x MIC), GRA and GR-SU showed bactericidal activity, whereas at a concentration of 1x MIC, they showed a bacteriostatic effect. Additionally, GRA and GR-SU exhibited a synergistic effect with gentamicin. The expression of a large number of genes (including transporters) and metabolic factors (carbohydrates and amino acids) was altered by the addition of GR-SU, suggesting that the inhibition of these metabolic processes may influence the degree of the requirement for carbohydrates or amino acids. In fact, the requirement for carbohydrates or amino acids was increased in the presence of either GRA or GR-SU. GRA and GR-SU exhibited strong antibacterial activity against several S. aureus strains, including MRSA. This activity may be partly due to the inhibition of several pathways involved in carbohydrate and amino acid metabolism.
Collapse
Affiliation(s)
- Kentaro Oyama
- Department of Oral Microbiology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
- Department of Oral maxillofacial Surgery, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Miki Kawada-Matsuo
- Department of Oral Microbiology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Yuichi Oogai
- Department of Oral Microbiology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Tetsuya Hayashi
- Department of Bacteriology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Norifumi Nakamura
- Department of Oral maxillofacial Surgery, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Hitoshi Komatsuzawa
- Department of Oral Microbiology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
- * E-mail:
| |
Collapse
|
|
15
|
Lupane and 18α-oleanane derivatives substituted in the position 2, their cytotoxicity and influence on cancer cells. Eur J Med Chem 2016; 121:120-131. [DOI: 10.1016/j.ejmech.2016.05.029] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2016] [Revised: 05/11/2016] [Accepted: 05/13/2016] [Indexed: 12/25/2022]
|
|
16
|
|
|
17
|
Soural M, Hodon J, Dickinson NJ, Sidova V, Gurska S, Dzubak P, Hajduch M, Sarek J, Urban M. Preparation of Conjugates of Cytotoxic Lupane Triterpenes with Biotin. Bioconjug Chem 2015; 26:2563-70. [DOI: 10.1021/acs.bioconjchem.5b00567] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Affiliation(s)
- Miroslav Soural
- Department
of Organic Chemistry, Faculty of Science, Palacky University in Olomouc, 17. listopadu 1192/12, 771 46 Olomouc, Czech Republic
- Institute
of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University in Olomouc, Hnevotinska 5, 779
00 Olomouc, Czech Republic
| | - Jiri Hodon
- Department
of Organic Chemistry, Faculty of Science, Palacky University in Olomouc, 17. listopadu 1192/12, 771 46 Olomouc, Czech Republic
- Institute
of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University in Olomouc, Hnevotinska 5, 779
00 Olomouc, Czech Republic
| | - Niall J. Dickinson
- Department
of Organic Chemistry, Faculty of Science, Palacky University in Olomouc, 17. listopadu 1192/12, 771 46 Olomouc, Czech Republic
| | - Veronika Sidova
- Department
of Organic Chemistry, Faculty of Science, Palacky University in Olomouc, 17. listopadu 1192/12, 771 46 Olomouc, Czech Republic
| | - Sona Gurska
- Institute
of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University in Olomouc, Hnevotinska 5, 779
00 Olomouc, Czech Republic
| | - Petr Dzubak
- Institute
of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University in Olomouc, Hnevotinska 5, 779
00 Olomouc, Czech Republic
| | - Marian Hajduch
- Institute
of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University in Olomouc, Hnevotinska 5, 779
00 Olomouc, Czech Republic
| | - Jan Sarek
- Institute
of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University in Olomouc, Hnevotinska 5, 779
00 Olomouc, Czech Republic
| | - Milan Urban
- Department
of Organic Chemistry, Faculty of Science, Palacky University in Olomouc, 17. listopadu 1192/12, 771 46 Olomouc, Czech Republic
- Institute
of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University in Olomouc, Hnevotinska 5, 779
00 Olomouc, Czech Republic
| |
Collapse
|
|
18
|
Effect of glycyrrhetinic acid on lipid raft model at the air/water interface. BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES 2014; 1848:434-43. [PMID: 25445675 DOI: 10.1016/j.bbamem.2014.11.014] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/18/2014] [Revised: 10/24/2014] [Accepted: 11/13/2014] [Indexed: 01/02/2023]
Abstract
To investigate an interfacial behavior of the aglycon of glycyrrhizin (GC), glycyrrhetinic acid (GA), with a lipid raft model consisting of equimolar ternary mixtures of N-palmitoyl sphingomyelin (PSM), dioleoylphosphatidylcholine (DOPC), and cholesterol (CHOL), Langmuir monolayer techniques were systematically conducted. Surface pressure (π)-molecular area (A) and surface potential (ΔV)-A isotherms showed that the adsorbed GA at the air/water interface was desorbed into the bulk upon compression of the lipid monolayer. In situ morphological analysis by Brewster angle microscopy and fluorescence microscopy revealed that the raft domains became smaller as the concentrations of GA in the subphase (CGA) increased, suggesting that GA promotes the formation of fluid networks related to various cellular processes via lipid rafts. In addition, ex situ morphological analysis by atomic force microscopy revealed that GA interacts with lipid raft by lying down at the surface. Interestingly, the distinctive striped regions were formed at CGA=5.0 μM. This phenomenon was observed to be induced by the interaction of CHOL with adsorbed GA and is involved in the membrane-disrupting activity of saponin and its aglycon. A quantitative comparison of GA with GC (Sakamoto et al., 2013) revealed that GA interacts more strongly with the raft model than GC in the monolayer state. Various biological activities of GA are known to be stronger than those of GC. This fact allows us to hypothesize that differences in the interactions of GA/GC with the model monolayer correlate to their degree of exertion for numerous activities.
Collapse
|
|
19
|
Evaluation on the Pharmacological Effect of Traditional Chinese Medicine SiJunZiTang on Stress-Induced Peptic Ulcers. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2013; 2013:186076. [PMID: 23840247 PMCID: PMC3694386 DOI: 10.1155/2013/186076] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/18/2013] [Revised: 05/09/2013] [Accepted: 05/20/2013] [Indexed: 11/17/2022]
Abstract
Purpose. To explore the effects of SiJunZiTang (SJZT) on central neurotransmitters and the inhibition of HCl hypersecretion, along with the role of the vagus nerve. From this, the effects of SJZT and its constituent ingredients on inhibiting stress-induced peptic ulcers will be determined. Methods. Methods used to determine SJZT's effectiveness included (1) measuring the antipeptic ulcer effects of varying combinations of the constituents of SJZT; (2) evaluations of monoamine (MA) level in the brain; and (3) measuring the effects of longer-term SJZT treatment. Results. Comparing the control and experimental groups where the rats' vagus nerves were not cut after taking SJZT orally (500 mg/kg and 1000 mg/kg), the volume of enterogastric juice, free HCl and total acidity all reduce dose-dependently. The group administered SJZT at 1000 mg/kg showed significant reductions (P < 0.05). For the experimental groups where the vagus nerves were cut, a comparison with the control group suggests that the group receiving SJZT (500 mg/kg) orally for 21 days demonstrated a cure rate of 34.53%. Conclusion. The results display a correlation between the therapeutic effects of SJZT on stress-induced peptic ulcers and central neurotransmitter levels. Further to this, SJZT can inhibit the hypersecretion of HCl in the stomach, thus inhibiting stress-induced peptic ulcers.
Collapse
|
|
20
|
The effect of glycyrrhetinic acid on pharmacokinetics of cortisone and its metabolite cortisol in rats. J Biomed Biotechnol 2012; 2012:856324. [PMID: 23258958 PMCID: PMC3509542 DOI: 10.1155/2012/856324] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2012] [Revised: 10/01/2012] [Accepted: 10/02/2012] [Indexed: 11/17/2022] Open
Abstract
The purpose of this paper is to study pharmacokinetics of cortisone (E) and its metabolite cortisol (F) in rats after administration of glycyrrhetinic acid (GA) and cortisone. Healthy male SD rats were randomized to be given 20 mg/kg E or E combined with 10 mg/kg GA. Blood samples were collected at 5, 10, 20, 40, 60, 90, 120, 150, 180, and 240 min after administration. The serum concentrations of E and F were determined by HLPC and pharmacokinetic parameters were calculated using DASver2.0 software. The parameters of AUC(0−t), AUC(0−∞), and Cmax for E in the group of E + GA were significantly higher than those in the group of E (P < 0.01); the half-time (t1/2β) was extended compared to E (P < 0.05) and CL/F was dropped obviously (P < 0.01). The rise in AUC(0−t), AUC(0−∞), and Cmax for cortisol in the group of E + GA was significantly compared to the group of E (P < 0.01). CL/F was lower than E (P < 0.01) and the half-time (t1/2β) was slightly extended. In this study, we find that GA restrains the metabolism of E and F and thus increases AUC, t1/2β, and Cmax of E and F, which may be related to its inhibition effect on 11β-hydroxysteroid dehydrogenase (11β-HSD).
Collapse
|
|
21
|
Harwansh RK, Patra KC, Pareta SK, Singh J, Rahman MA. Nanoemulsions as vehicles for transdermal delivery of glycyrrhizin. BRAZ J PHARM SCI 2011. [DOI: 10.1590/s1984-82502011000400014] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
The present investigation aims to evaluate an isotropic and thermodynamically stable nanoemulsion formulation for transdermal delivery of glycyrrhizin (GZ), with minimum surfactant and cosurfactant (Smix) concentrations that could improve its solubility, permeation enhancement, and stability. Pseudo-ternary phase diagrams were developed and various nanoemulsion formulations were prepared using soyabean oil as oil, Span 80, Brij 35 as a surfactant and isopropyl alcohol as a cosurfactant. Nanoemulsion formulations that passed the thermodynamic stability tests were characterized for pH, viscosity and droplet size using a transmission electron microscopy. The transdermal ability of glycyrrhizin through human cadaver skin was determined using Franz diffusion cells. The in vitro skin permeation profile of the optimized nanoemulsion formulation (NE2) was compared to that of conventional gel. A significant increase in permeability parameters such as steady-state flux (Jss) and permeability coefficient (Kp) was observed in the optimized nanoemulsion formulation (NE2), which consisted of 1% wt/wt of mono ammonium glycyrrhizinate (MAG), 32.4% Span 80, 3.7% Brij 35, 10% isopropyl alcohol, 46.5% soyabean oil and 6.4% distilled water. No obvious skin irritation was observed for the studied nanoemulsion formulation (NE2) or the gel. The results indicated that nanoemulsions are promising vehicles for transdermal delivery of glycyrrhizin through human cadaver skin, without the use of additional permeation enhancers, because excipients of nanoemulsions act as permeation enhancers themselves.
Collapse
|
|
22
|
Abstract
Objectives Radix Bupleuri represents one of the most successful and widely used herbal drugs in Asia for treatment of many diseases over the past 2000 years. Thorough studies have been carried out on many species of this genus and have generated immense data about the chemical composition and corresponding biological activity of extracts and isolated secondary metabolites. In this work, we review the chemistry and pharmacology of the genus Bupleurum and explore the relationships between the pharmacological effects and the chemical composition of these drugs. Key findings Early studies on the genus Bupleurum had focused only on the traditional uses of the plants in the treatment of inflammatory disorders and infectious diseases. After chemical profiling, several groups of secondary metabolites were characterized with relevant biological activity: triterpene saponins (saikosaponins), lignans, essential oils and polysaccharides. As a result, present interest is now focused on the bioactivity of the isolated triterpene saponins acting as immunomodulatory, anti‐inflammatory and antiviral agents, as well as on the observed ant‐iulcer activity of the polysaccharides and anti‐proliferative activity of different lignans. Many saikosaponins exhibited very potent anti‐inflammatory, hepatoprotective and immunomodulatory activities both in vivo and in vitro. Conclusions Further investigations and screenings are required to explore other Bupleurum species, to evaluate the clinical safety and possible interactions with other drugs or herbs. Standardization of Bupleuri extracts is crucial for them being integrated into conventional medicine due to large chemical and biological variations between different species and varieties.
Collapse
Affiliation(s)
- Mohamed L Ashour
- Institute of Pharmacy and Molecular Biotechnology, University Heidelberg, Im Neuenheimer Feld 364, Heidelberg, Germany
| | | |
Collapse
|
|
23
|
Peng WB, Sun WZ, Jiang T, Li GQ, Dai SJ. In vitro and in vivo pharmacokinetics of two novel 1,3-cyclic propanyl phosphate ester prodrugs of 18β-glycyrrhetic acid in rats. JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH 2010; 12:879-893. [PMID: 20924902 DOI: 10.1080/10286020.2010.508283] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/30/2023]
Abstract
The in vitro metabolism of two novel phosphate prodrugs of glycyrrhetic acid (GA) was studied by the method of incubation in the rat liver microsome and the in vivo plasma pharmacokinetics after injecting intravenously (i.v.) into six rats was investigated, respectively. The prodrugs diminished gradually with time and most of the parent drugs were released in 30 min in vitro. In this paper, the in vivo plasma concentration data were analyzed by compartmental modeling. Both the prodrugs and the corresponding released parent drugs could be described by a two-compartment model, which existed for 48 h in rats. The t(1/2) increases remarkably after i.v. administration to rats when compared with injecting the parent drugs directly.
Collapse
Affiliation(s)
- Wei-Bing Peng
- Key Laboratory of Marine Drugs, Ministry of Education & Marine Drug and Food Institute, Ocean University of China, Qingdao, China
| | | | | | | | | |
Collapse
|
|
24
|
Kaliora AC, Stathopoulou MG, Triantafillidis JK, Dedoussis GVZ, Andrikopoulos NK. Chios mastic treatment of patients with active Crohn’s disease. World J Gastroenterol 2007; 13:748-53. [PMID: 17278198 PMCID: PMC4066008 DOI: 10.3748/wjg.v13.i5.748] [Citation(s) in RCA: 65] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the effectiveness of mastic administration on the clinical course and plasma inflammatory mediators of patients with active Crohn’s disease (CD).
METHODS: This pilot study was conducted in patients with established mild to moderately active CD, attending the outpatient clinics of the hospital, and in healthy controls. Ten patients and 8 controls were recruited for a 4-wk treatment with mastic caps (6 caps/d, 0.37 g/cap). All patients successfully completed the protocol. CD Activity Index (CDAI), Nutritional Risk Index (NRI), C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), monocyte chemotactic protein-1 (MCP-1), and total antioxidant potential (TAP) were evaluated in the plasma at baseline and at the end of the treatment period. Results were expressed as mean values ± SE and P < 0.05 was considered to indicate statistical significance.
RESULTS: Patients exhibited significant reduction of CDAI (222.9 ± 18.7 vs 136.3 ± 12.3, P = 0.05) as compared to pretreament values. Plasma IL-6 was significantly decreased (21.2 ± 9.3 pg/mL vs 7.2 ± 2.8 pg/ mL, P = 0.027), and so did CRP (40.3 ± 13.1 mg/mL vs 19.7 ± 5.5, P = 0.028). TAP was significantly increased (0.15 ± 0.09 vs 0.57 ± 0.15 mmol/L uric acid, P = 0.036). No patient or control exhibited any kind of side effects.
CONCLUSION: The results suggest that mastic significantly decreased the activity index and the plasma levels of IL-6 and CRP in patients with mildly to moderately active CD. Further double-blind, placebo-controlled studies in a larger number of patients are required to clarify the role of this natural product in the treatment of patients with CD.
Collapse
Affiliation(s)
- Andriana C Kaliora
- Department of Science of Dietetics-Nutrition, Harokopio University of Athens, 70 El. Venizelou ave., Kallithea 17671, Athens, Greece.
| | | | | | | | | |
Collapse
|
|
25
|
Feng S, Li C, Xu X, Wang X. Screening strains for directed biosynthesis of β-d-mono-glucuronide-glycyrrhizin and kinetics of enzyme production. ACTA ACUST UNITED AC 2006. [DOI: 10.1016/j.molcatb.2006.06.016] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
|
|
26
|
Synthesis and pharmacological activity of benzofurylhydroxyureas and benzofurylhydroxamic acids. Pharm Chem J 2006. [DOI: 10.1007/s11094-006-0186-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
|
|
27
|
Rahman S, Sultana S. Chemopreventive activity of glycyrrhizin on lead acetate mediated hepatic oxidative stress and its hyperproliferative activity in Wistar rats. Chem Biol Interact 2006; 160:61-9. [PMID: 16426592 DOI: 10.1016/j.cbi.2005.12.003] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2005] [Revised: 12/03/2005] [Accepted: 12/06/2005] [Indexed: 11/19/2022]
Abstract
Lead is a pervasive environmental pollutant with no beneficial biological role and its toxicity continues to be a major health problem due to its interference with natural environment. In the present study we have evaluated the chemopreventive effect of glycyrrhizin on lead acetate mediated hepatic oxidative stress, toxicity and tumor promotion related alterations in rats. Lead acetate (100mg/kg bwt., i.p.) enhanced lipid peroxidation with concomitant reduction in glutathione, glutathione reductase, glutathione-S-transferase and glutathione peroxidase activities. There was an increase in the levels of transaminase enzymes and LDH. Lead acetate treatment also enhanced ornithine decarboxylase (ODC) activity and [(3)H] thymidine incorporation into hepatic DNA. Pretreatment of rats orally with glycyrrhizin (150 and 300 mg/kg bwt., orally) resulted in a significant decrease in hepatic microsomal lipid peroxidation (P<0.001) and increase in the level of GSH content (P<0.001) and its dependent enzyme. There was significant reduction in the levels of SGPT, SGOT and LDH (P<0.001). A significant inhibition in ODC activity and DNA synthesis (P<0.001) was also observed. On the basis of the above results it can be hypothesized that glycyrrhizin is a potent chemopreventive compound against lead acetate mediated hepatic oxidative stress, toxicity and tumor promotion related responses in rats.
Collapse
Affiliation(s)
- Sahar Rahman
- Section of Chemoprevention and Nutrition Toxicology, Department of Medical Elementology and Toxicology, Faculty of Science, Jamia Hamdard (Hamdard University), Hamdard Nagar, New Delhi 110062, India
| | | |
Collapse
|
|
28
|
Tsukahara M, Nishino T, Furuhashi I, Inoue H, Sato T, Matsumoto H. Synthesis and inhibitory effect of novel glycyrrhetinic acid derivatives on IL-1 beta-induced prostaglandin E(2) production in normal human dermal fibroblasts. Chem Pharm Bull (Tokyo) 2005; 53:1103-10. [PMID: 16141576 DOI: 10.1248/cpb.53.1103] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Olean-11,13(18)-dien-3beta,30-diol dihemiphthalate (3), which was derived from glycyrrhetinic acid (GA), has been reported to produce a potent of anti-inflammatory effect in in vivo assays. Using 3 as a lead compound, we attempted to synthesize some modified compounds which varied in the following; i) the position of a carboxyl group in the phthalate moiety, ii) the number of carboxyls attached to the benzoyl group, iii) conversion of benzene ring to another ring system, iv) the linkage form between the benzene ring and oleanene skeleton at position 3 and/or 30. These were screened for their inhibitory activity against interleukin-1 beta (IL-1 beta)-induced prostaglandin E(2) (PGE(2)) production in normal human dermal fibroblasts (NHDF). Although conversion of the ortho-carboxyl group of 3 into the meta-position or the para-position led to an increase in inhibitory activity, the elimination or increase of the carboxyl group resulted in loss of the inhibitory activity. Conversion of the ester bond to the amide bond at position 3 and/or 30 of 3 did not contribute to a significant increase in inhibitory activity. On the other hand, among the derivatives possessing an anthranilic acid moiety at position 30 of 3beta-O-acetyl-olean-11,13(18)-dien-30-oic acid (20), 3beta-hydroxy-30-nor-olean-11,13(18)-dien-20 beta-[N-(2-carboxyphenyl)]carboxamide (30) showed the most potent inhibitory activity (IC(50) 1.0 microM) in this series.
Collapse
Affiliation(s)
- Michiko Tsukahara
- Research Laboratory, Minophagen Pharmaceutical Co., Ltd.; 2-2-3 Komatsubara, Zama, Kanagawa 228-0002, Japan.
| | | | | | | | | | | |
Collapse
|
|
29
|
Ohtake N, Nakai Y, Yamamoto M, Sakakibara I, Takeda S, Amagaya S, Aburada M. Separation and isolation methods for analysis of the active principles of Sho-saiko-to (SST) oriental medicine. J Chromatogr B Analyt Technol Biomed Life Sci 2005. [PMID: 15556493 DOI: 10.1016/s1570-0232(04)00547-1] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Sho-saiko-to (SST) was introduced into Japan as an oriental classical medicine from China approximately 1500 years ago, and it is currently the most representative Kampo medicine (traditional Japanese medicine). SST is manufactured in Japan as an ethical drug on a modern industrial scale in which the quality of ingredients is standardized with Good Manufacturing Practices (GMP) regulation. SST is widely used for the treatment of chronic hepatitis. Experimental and clinical studies including multi-center, placebo-controlled, double-blind studies have demonstrated the various pharmacological effects of SST. SST is prepared from the hot water extraction of seven raw materials, therefore many kinds of constituents are included. Three-dimensional (3D) HPLC analysis is useful for obtaining many kinds of constituents, especially low molecular ultraviolet (UV) quenching compounds, contained in SST as well as its fractions. Fingerprint pattern provided by 3D HPLC analysis makes possible to identify the overall-viewing of SST. Databases of UV spectra of the components of medicinal herbs obtained by reversed-phase (RP) HPLC using a photodiode array (PDA) and fingerprint patterns of crude drugs made by 3D HPLC analysis facilitate the identification, analysis and quality of herbal drugs. Studies using both PDA HPLC and an amino acid analysis with a fluorometric detector have found that SST contains fifteen major low molecular compounds (i.e. baicalin, wogonin-7-O-glucuronide, liquiritin, their three aglycons, liquiritin apioside, glycyrrhizin, saikosaponin b1, saikosaponin b2, ginsenoside Rg1, ginsenoside Rb1, (6)-gingerol, (6)-shogaol and arginine). These compounds have various pharmacological actions, and are assumed to be responsible, at least partly, for the pharmacological effects of SST. Although there have only been a few investigations on high molecular compounds with pharmacological actions contained in SST, several kinds of polysaccharides have been isolated from constituent herbs of SST. This review paper summarizes analytical methods of separation, isolation and identification of compounds with biological activities from SST, which is a mixture drug of medicinal herbs. Accordingly, this paper would not focus on methods of separation, isolation and analysis of particular compounds from each constituent herb of SST.
Collapse
Affiliation(s)
- Nobuhiro Ohtake
- Medicinal Evaluation Laboratories, Tsumura Research Institute, Tsumura & Co., 3586 Yoshiwara, Ami-machi, Inashiki-gun, Ibaraki 300-1192, Japan.
| | | | | | | | | | | | | |
Collapse
|
|
30
|
Ohtake N, Nakai Y, Yamamoto M, Sakakibara I, Takeda S, Amagaya S, Aburada M. Separation and isolation methods for analysis of the active principles of Sho-saiko-to (SST) oriental medicine. J Chromatogr B Analyt Technol Biomed Life Sci 2004; 812:135-48. [PMID: 15556493 PMCID: PMC7105231 DOI: 10.1016/j.jchromb.2004.06.051] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2004] [Accepted: 06/29/2004] [Indexed: 12/16/2022]
Abstract
Sho-saiko-to (SST) was introduced into Japan as an oriental classical medicine from China approximately 1500 years ago, and it is currently the most representative Kampo medicine (traditional Japanese medicine). SST is manufactured in Japan as an ethical drug on a modern industrial scale in which the quality of ingredients is standardized with Good Manufacturing Practices (GMP) regulation. SST is widely used for the treatment of chronic hepatitis. Experimental and clinical studies including multi-center, placebo-controlled, double-blind studies have demonstrated the various pharmacological effects of SST. SST is prepared from the hot water extraction of seven raw materials, therefore many kinds of constituents are included. Three-dimensional (3D) HPLC analysis is useful for obtaining many kinds of constituents, especially low molecular ultraviolet (UV) quenching compounds, contained in SST as well as its fractions. Fingerprint pattern provided by 3D HPLC analysis makes possible to identify the overall-viewing of SST. Databases of UV spectra of the components of medicinal herbs obtained by reversed-phase (RP) HPLC using a photodiode array (PDA) and fingerprint patterns of crude drugs made by 3D HPLC analysis facilitate the identification, analysis and quality of herbal drugs. Studies using both PDA HPLC and an amino acid analysis with a fluorometric detector have found that SST contains fifteen major low molecular compounds (i.e. baicalin, wogonin-7-O-glucuronide, liquiritin, their three aglycons, liquiritin apioside, glycyrrhizin, saikosaponin b1, saikosaponin b2, ginsenoside Rg1, ginsenoside Rb1, (6)-gingerol, (6)-shogaol and arginine). These compounds have various pharmacological actions, and are assumed to be responsible, at least partly, for the pharmacological effects of SST. Although there have only been a few investigations on high molecular compounds with pharmacological actions contained in SST, several kinds of polysaccharides have been isolated from constituent herbs of SST. This review paper summarizes analytical methods of separation, isolation and identification of compounds with biological activities from SST, which is a mixture drug of medicinal herbs. Accordingly, this paper would not focus on methods of separation, isolation and analysis of particular compounds from each constituent herb of SST.
Collapse
Affiliation(s)
- Nobuhiro Ohtake
- Medicinal Evaluation Laboratories, Tsumura Research Institute, Tsumura & Co., 3586 Yoshiwara, Ami-machi, Inashiki-gun, Ibaraki 300-1192, Japan.
| | | | | | | | | | | | | |
Collapse
|
|
31
|
Hsiang CY, Lai IL, Chao DC, Ho TY. Differential regulation of activator protein 1 activity by glycyrrhizin. Life Sci 2002; 70:1643-56. [PMID: 11991252 DOI: 10.1016/s0024-3205(01)01556-9] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Glycyrrhizin, a major component of Glycyrrhiza uralensis (licorice) root, is a saponin and exhibits a number of pharmacological effects, including anti-inflammation, anti-ulcer, anti-allergy, and anticarcinogenesis. Activator protein I (AP-1), a nuclear transcription factor, consists of Jun/Fos heterodimers or Jun/Jun homodimers, and blocking of tumor promoter-induced AP-1 activity could inhibit induced cellular transformation. In order to elucidate the molecular mechanism of glycyrrhizin-induced anticarcinogenesis, effect of glycyrrhizin on the AP-1 activity in untreated and tumor promoter-12-O-tetradecanoylphorbol-13-acetate (TPA)-treated conditions was analyzed in this study. Glycyrrhizin induced the AP-1/TATA reporter activity in a dose-dependent fashion, which was judged by chloramphenicol acetyltransferase assay and electrophoretic mobility-shift assay. Similar results were observed in HepG2 and Vero cells, suggested that glycyrrhizin effect was cell type-independent. In addition, the cis element responsible for glycyrrhizin activity was AP-1 responsive element. Further analysis indicated that glycyrrhizin exhibited a different regulation on the AP-1 activity in untreated and TPA-treated cells. Glycyrrhizin induced the AP-1 activity in untreated cells, while it inhibited the TPA-induced AP-1 activation in TPA-treated cells. These results provide insight into the biological actions of glycyrrhizin and the molecular basis for the development of new chemoprotective agents for cancer.
Collapse
Affiliation(s)
- Chien-Yun Hsiang
- Department of Microbiology, China Medical College, Taichun, Taiwan
| | | | | | | |
Collapse
|
|
32
|
|
|
33
|
Farina C, Pinza M, Pifferi G. Synthesis and anti-ulcer activity of new derivatives of glycyrrhetic, oleanolic and ursolic acids. FARMACO (SOCIETA CHIMICA ITALIANA : 1989) 1998; 53:22-32. [PMID: 9543723 DOI: 10.1016/s0014-827x(97)00013-x] [Citation(s) in RCA: 78] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
A review is made of the literature describing the structural changes to glycyrrhetic, oleanolic and ursolic acids and their influence on anti-ulcer activity. For the glycyrrhetic acid derivatives some analogues were prepared in which the ketonic group in position 11 was removed and the carboxylic function at position 30 was either intact, reduced to alcohol or transformed into ketone. This first series of compounds suggests the possibility of obtaining compounds devoid of the conjugated ketonic group, maintaining anti-ulcer activity but with reduced or lacking mineralocorticoid activity. Based on these findings, a series of carbenoxolone analogues in the beta-amyrin series of glycyrrhetic and oleanolic acid was prepared. In particular, the delta 9,11 unsaturated compounds 14b and 23b and the 11-methylene derivative 18 present advantages in terms of acute toxicity and mineralocorticoid activity as compared to the reference compound. The derivative 14b in the volunteer showed an increase of gastric PGE2 levels with minor pseudoaldosteronic effect. Among the ursolic acid derivatives, the dihemisuccinate sodium salt 35b demonstrated a good separation between anti-ulcer and mineralocorticoid activities. Nevertheless, kidney and liver toxicity was observed in the monkey thus jeopardizing its further development. Better results were obtained with the uvaol dihemiphthalate sodium salt and the diene analogue 39b. In particular, 38b and 39b showed a potent anti-ulcer activity, 3- to 25-fold higher than carbenoxolone. Furthermore, compound 38b does not show signs of liver toxicity in the monkey.
Collapse
Affiliation(s)
- C Farina
- SmithKline Beecham SpA, Baranzate, Milan, Italy
| | | | | |
Collapse
|
|
34
|
Inoue H, Nagata N, Shibata S, Koshihara Y. Inhibitory effect of glycyrrhetinic acid derivatives on capsaicin-induced ear edema in mice. JAPANESE JOURNAL OF PHARMACOLOGY 1996; 71:281-9. [PMID: 8886925 DOI: 10.1254/jjp.71.281] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
We examined the effect of glycyrrhetinic acid (Ia) and its derivatives on ear edema induced by topical application of capsaicin in mice. Three dihemiphthalate compounds: di-sodium salt of 18 beta-olean-12-ene-3 beta,30-diol (deoxoglycyrrhetol, IIa) di-O-hemiphthalate (IIb); 18 beta-olean-9(11),12-diene-3 beta, 30-diol di-O-hemiphthalate (IIIa); and olean-11,13(18)-diene-3 beta,30-diol di-O-hemiphthalate (IVa) inhibited capsaicin-induced edema with ED50 values of 52.6, 41.0 and 51.8 mg/kg (p.o.), respectively. However, glycyrrhetinic acid and deoxoglycyrrhetol at a dose of 200 mg/kg (p.o.) had no effect. Compound IIIa (100 mg/kg, p.o.) also inhibited the edema response to capsaicin in mast cell-deficient mice. Furthermore, compounds IIb, IIIa and IVa (25-100 mg/kg, p.o.) prevented ear edema in response to intradermal injection of substance P (SP) and compound 48/80. In addition, these compounds at a high dose of 100 mg/kg (p.o.) produced a significant inhibition of the plasma extravasation in ear skin induced by i.v. administration of SP. The above results suggest that the effect of these compounds on capsaicin-induced ear edema is due at least in part to an inhibition of the increase of vascular permeability induced by vasoactive agents released from mast cells. Moreover, it seems likely that these compounds at a high dose can suppress vasodilatation and plasma extravasation induced by SP involved in capsaicin-induced edema.
Collapse
Affiliation(s)
- H Inoue
- Research Laboratory, Minophagen Pharmaceutical Co., Kanagawa, Japan
| | | | | | | |
Collapse
|
|
35
|
Saito S, Furumoto T, Ochiai M, Hosono A, Hoshino H, Haraguchi U, Ikeda R, Shimada N. Synthetic studies on the relationship between anti-HIV activities and micelle forming abilities of various alkylated glycyrrhetinate diglycoside sodium sulfates and related compounds. Eur J Med Chem 1996. [DOI: 10.1016/0223-5234(96)89163-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
|
|
36
|
|
|
37
|
Dehpour A, Zolfaghari M, Samadian T, Kobarfard F, Faizi M, Assari M. Antiulcer activities of liquorice and its derivatives in experimental gastric lesion induced by ibuprofen in rats. Int J Pharm 1995. [DOI: 10.1016/0378-5173(94)00377-h] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
|
|
38
|
Studies on synthesis and structure-activity relationships against cytoprotective activity of triterpenoidal diglycosides with an acid saccharide, d-glucopyranosuronic acid. Eur J Med Chem 1994. [DOI: 10.1016/0223-5234(94)90073-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
|
|
39
|
Inoue H, Inoue K, Takeuchi T, Nagata N, Shibata S. Inhibition of rat acute inflammatory paw oedema by dihemiphthalate of glycyrrhetinic acid derivatives: comparison with glycyrrhetinic acid. J Pharm Pharmacol 1993; 45:1067-71. [PMID: 8158525 DOI: 10.1111/j.2042-7158.1993.tb07182.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
The anti-inflammatory profile of dihemiphthalate compounds of glycyrrhetinic acid derivatives in acute rat paw oedema induced by various vasoactive agents was compared with the parent compound. Three dihemiphthalate compounds (the di-sodium salt of 18 beta-olean-12-ene- 3 beta,30-diol di-O-hemiphthalate, 18 beta-olean-9(11),12-dione-3 beta,30-diol di-O-hemiphthalate and olean-11,13(18)-diene-3 beta,30-diol di-O-hemiphthalate), significantly inhibited development of carrageenan-induced rat paw oedema during the first 3 h (ED50 70, 90, and 108 mg kg-1 respectively, p.o.), while glycyrrhetinic acid (ED50, 200 mg kg-1) showed a significant inhibition of paw oedema 3 h after carrageenan treatment. The dihemiphthalate compounds also suppressed mouse paw oedema induced by histamine, bradykinin, and PAF acether at doses of less than 100 mg kg-1. However, these compounds failed to inhibit 5-HT-induced mouse paw oedema. Glycyrrhetinic acid had little effect on mouse paw inflammation induced by the above irritants. The three compounds at 10(-7)-10(-4) M, inhibited histamine-induced contraction of guinea-pig isolated ileum. However, concentration-response curves to 5-HT and bradykinin were not affected by the same compounds. These results suggest that the dihemiphthalate compounds modulate vascular permeability caused by endogenous vasoactive agents as one of the anti-inflammatory mechanisms. This action is quite different from that of glycyrrhetinic acid.
Collapse
Affiliation(s)
- H Inoue
- Research Laboratory, Minophagen Pharmaceutical Co., Kanagawa, Japan
| | | | | | | | | |
Collapse
|
|
40
|
Gomez-Sanchez EP, Gomez-Sanchez CE. Central hypertensinogenic effects of glycyrrhizic acid and carbenoxolone. Exp Biol Med (Maywood) 1993; 234:263-77. [PMID: 1476186 DOI: 10.3181/0805-rm-178] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
The apparent mineralocorticoid excess syndrome of patients ingesting large amounts of licorice or its derivatives is thought to be caused by the antagonism by these compounds of the enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD). 11 beta-HSD inactivates cortisol and corticosterone, allowing the more abundantly produced glucocorticoids access to the mineralocorticoid receptor (MR) in the kidney, where they act as mineralocorticoids. We have found that the infusion of both glycyrrhizic acid, an active principle of licorice, and carbenoxolone, a synthetic analogue, into a lateral ventricle of the brain [intracerebroventricular (icv)] of a rat, at a dose less than that which has an effect when infused subcutaneously, produces hypertension. Furthermore, the hypertension produced by the oral administration of carbenoxolone or glycyrrhizic acid is blocked by the icv administration of RU 28318, an MR antagonist, at a dose below that which has an effect on blood pressure when infused subcutaneously. While the oral administration caused saline polydipsia and polyuria typical of chronic systemic mineralocorticoid excess, the icv licorice derivatives produced hypertension without affecting saline appetite. Sensitizing the rats to mineralocorticoid hypertension by renal mass reduction and increasing salt consumption was not necessary for the production of hypertension. These findings provide additional evidence for a central role in blood pressure control by mineralocorticoids that is distinct from their renal effects. They also suggest that more is involved in licorice-induced hypertension than only inhibition of 11 beta-HSD.
Collapse
|
|
41
|
Schleimer RP, Kato M. Regulation of lung inflammation by local glucocorticoid metabolism: an hypothesis. J Asthma 1992; 29:303-17. [PMID: 1522051 DOI: 10.3109/02770909209044790] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Affiliation(s)
- R P Schleimer
- Johns Hopkins Asthma and Allergy Center, Department of Medicine, Baltimore, Maryland 21224
| | | |
Collapse
|