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1
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Meng J, Yang B, Shu C, Jiang S. Saikosaponin-d mediates FOXG1 to reverse docetaxel resistance in prostate cancer through oxidative phosphorylation. Mutat Res 2024; 829:111875. [PMID: 39098234 DOI: 10.1016/j.mrfmmm.2024.111875] [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: 04/19/2024] [Revised: 06/19/2024] [Accepted: 07/22/2024] [Indexed: 08/06/2024]
Abstract
BACKGROUND Prostate cancer (PCa), a prevalent malignancy worldwide, is frequently identified in advanced stages due to the absence of distinctive early symptoms, thereby culminating in the development of chemotherapy-induced drug resistance. Exploring novel resistance mechanisms and identifying new therapeutic agents can facilitate the advancement of more efficacious strategies for PCa treatment. METHODS Bioinformatics analysis was employed to investigate the expression of FOXG1 in PCa tissues. Subsequently, qRT-PCR was utilized to validate FOXG1 mRNA expression levels in corresponding PCa cell lines. FOXG1 knockdown was performed, and cell proliferation was assessed using CCK-8 assays, while cell migration and invasion capabilities were evaluated through wound healing and Transwell assays. Western blot and Seahorse analyzer were used to measure oxidative phosphorylation (OXPHOS) levels. Additionally, to explore potential approaches to alleviate PCa drug resistance, this study assessed the impact of biologically active saikosaponin-d (SSd) on PCa malignant progression and resistance by regulating FOXG1 expression. RESULTS FOXG1 exhibited high expression in PCa tissues and cell lines. Knockdown of FOXG1 inhibited the proliferation, migration, and invasion of PCa cells, while FOXG1 overexpression had the opposite effect and promoted OXPHOS levels. The addition of an OXPHOS inhibitor prevented this outcome. Finally, SSd was shown to suppress FOXG1 expression and reverse docetaxel resistance in PCa cells through the OXPHOS pathway. CONCLUSION This work demonstrated that SSd mediated FOXG1 to reverse malignant progression and docetaxel resistance in PCa through OXPHOS.
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Affiliation(s)
- Jun Meng
- Department of Urology, Wusong Central Hospital, Shanghai 200940, China
| | - Bo Yang
- Department of Urology, Wusong Central Hospital, Shanghai 200940, China
| | - Chang Shu
- Department of Urology, Wusong Central Hospital, Shanghai 200940, China
| | - Shuai Jiang
- Department of Urology, Wusong Central Hospital, Shanghai 200940, China.
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2
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Kim TH. Ginsenosides for the treatment of insulin resistance and diabetes: Therapeutic perspectives and mechanistic insights. J Ginseng Res 2024; 48:276-285. [PMID: 38707641 PMCID: PMC11068994 DOI: 10.1016/j.jgr.2024.03.002] [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: 12/15/2023] [Revised: 01/26/2024] [Accepted: 03/04/2024] [Indexed: 05/07/2024] Open
Abstract
Diabetes mellitus (DM) is a systemic disorder of energy metabolism characterized by a sustained elevation of blood glucose in conjunction with impaired insulin action in multiple peripheral tissues (i.e., insulin resistance). Although extensive research has been conducted to identify therapeutic targets for the treatment of DM, its global prevalence and associated mortailty rates are still increasing, possibly because of challenges related to long-term adherence, limited efficacy, and undesirable side effects of currently available medications, implying an urgent need to develop effective and safe pharmacotherapies for DM. Phytochemicals have recently drawn attention as novel pharmacotherapies for DM based on their clinical relevance, therapeutic efficacy, and safety. Ginsenosides, pharmacologically active ingredients primarily found in ginseng, have long been used as adjuvants to traditional medications in Asian countries and have been reported to exert promising therapeutic efficacy in various metabolic diseases, including hyperglycemia and diabetes. This review summarizes the current pharmacological effects of ginsenosides and their mechanistic insights for the treatment of insulin resistance and DM, providing comprehensive perspectives for the development of novel strategies to treat DM and related metabolic complications.
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Affiliation(s)
- Tae Hyun Kim
- Drug Information Research Institute, Muscle Physiome Research Center, College of Pharmacy, Sookmyung Women's University, Seoul, Republic of Korea
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3
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Yu X, Wang Q, Dai Z. Ginsenosides Inhibit the Proliferation of Lung Cancer Cells and Suppress the Rate of Metastasis by Modulating EGFR/VEGF Signaling Pathways. J Oleo Sci 2024; 73:219-230. [PMID: 38311411 DOI: 10.5650/jos.ess23120] [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] [Indexed: 02/10/2024] Open
Abstract
Ginsenosides Rg3 and Rg5 obtained from Panax (ginseng) have shown significant anticancer activity via the PI3K-Akt signaling pathway. This study evaluated the anticancer and antimetastatic effects of a combination of Rg3 and Rg5 on lung cancer cells. A combination of Rg3 and Rg5 was treated for lung cancer cell line A549 and human lung tumor xenograft mouse model, and anti-metastatic effects on Matrigel plug implantation in mice. The combination of Rg3 and Rg5 showed potent antiproliferative effects on A549 cells with IC50 values of 44.6 and 36.0 μM for Rg3 and Rg5 respectively. The combination of Rg3 and Rg5 (30 µM each) showed 48% cell viability as compared to Rg3 (72% viability) and Rg5 (64% viability) at 30 µM concentrations. The combination of Rg3 and Rg5 induced apoptosis in A549 cells characterized by activation of caspase-9 and caspase-3 and cleavage of PARP, as well as suppression of the autophagic marker LC3A/B. The antitumoral potentials of the combination of Rg3 and Rg5 were ascertained in a lung tumor xenograft mouse model with high efficacy as compared to individual ginsenosides. The metastasislimiting properties of the combination of Rg3 and Rg5 were assessed in Matrigel plug implantation in mice which showed the potent efficacy of the combination as compared to individual ginsenoside. Mechanistically, the combination of Rg3 and Rg5 inhibited the expression of PI3K/Akt/mTOR and EGFR/VEGF signaling pathways in lung cancer cells. Results suggest that the combination of Rg3 and Rg5 suppressed the tumor cell proliferation in lung cancer cells and limited the rate of metastasis which further suggest that the combination has a significant effect as compared to the administration of single ginsenoside.
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Affiliation(s)
- Xuelian Yu
- Department of Pulmonary, Muping Chinese Traditional Medical Hospital
| | - Qihu Wang
- Department of Pulmonary, Muping Chinese Traditional Medical Hospital
| | - Zhaoxin Dai
- Department of Pulmonary, Muping Chinese Traditional Medical Hospital
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4
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Ben-Eltriki M, Shankar G, Tomlinson Guns ES, Deb S. Pharmacokinetics and pharmacodynamics of Rh2 and aPPD ginsenosides in prostate cancer: a drug interaction perspective. Cancer Chemother Pharmacol 2023; 92:419-437. [PMID: 37709921 DOI: 10.1007/s00280-023-04583-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Accepted: 08/14/2023] [Indexed: 09/16/2023]
Abstract
Ginsenoside Rh2 and its aglycon (aPPD) are one of the major metabolites from Panax ginseng. Preclinical studies suggest that Rh2 and aPPD have antitumor effects in prostate cancer (PCa). Our aims in this review are (1) to describe the pharmacokinetic (PK) properties of Rh2 and aPPD ginsenosides; 2) to provide an overview of the preclinical findings on the use of Rh2 and aPPD in the treatment of PCa; and (3) to highlight the mechanisms of its PK and pharmacodynamic (PD) drug interactions. Increasing evidence points to the potential efficacy of Rh2 or aPPD for PCa treatment. Based on the laboratory studies, Rh2 or aPPD combinations revealed an additive or synergistic interaction or enhanced sensitivity of anticancer drugs toward PCa. This review reveals that enhanced anticancer activities were demonstrated in preclinical studies through interactions of Rh2 and/or aPPD with the proteins related to PK (e.g., cytochrome P450 enzymes, transporters) or PD of the other anticancer drugs or PCa signaling pathways. In conclusion, combining Rh2 or aPPD with anti-prostate cancer drugs leads to PK or PD interactions which could facilitate either therapeutically beneficial or toxic effects.
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Affiliation(s)
- Mohamed Ben-Eltriki
- The Vancouver Prostate Centre at Vancouver General Hospital, 2660 Oak Street, Vancouver, BC, V6H 3Z6, Canada.
- Cochrane Hypertension Review Group, Therapeutic Initiative, University of British Columbia, Vancouver, BC, Canada.
- Community Pharmacist, Vancouver Area, BC, Canada.
- Department of Pharmacology and Therapeutics, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB, Canada.
| | - Gehana Shankar
- The Vancouver Prostate Centre at Vancouver General Hospital, 2660 Oak Street, Vancouver, BC, V6H 3Z6, Canada
| | - Emma S Tomlinson Guns
- The Vancouver Prostate Centre at Vancouver General Hospital, 2660 Oak Street, Vancouver, BC, V6H 3Z6, Canada
| | - Subrata Deb
- Department of Pharmaceutical Sciences, College of Pharmacy, Larkin University, Miami, FL, 33169, USA.
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Elmaidomy AH, El Zawily A, Salem AK, Altemani FH, Algehainy NA, Altemani AH, Rateb ME, Abdelmohsen UR, Shady NH. New cytotoxic dammarane type saponins from Ziziphus spina-christi. Sci Rep 2023; 13:20612. [PMID: 37996449 PMCID: PMC10667233 DOI: 10.1038/s41598-023-46841-2] [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: 06/30/2023] [Accepted: 11/06/2023] [Indexed: 11/25/2023] Open
Abstract
Cancer is the world's second-leading cause of death. Drug development efforts frequently focus on medicinal plants since they are a valuable source of anticancer medications. A phytochemical investigation of the edible Ziziphus spina-christi (F. Rhamnaceae) leaf extract afforded two new dammarane type saponins identified as christinin E and F (1, 2), along with the known compound christinin A (3). Different cancer cell lines, such as lung cancer (A549), glioblastoma (U87), breast cancer (MDA-MB-231), and colorectal carcinoma (CT-26) cell lines, were used to investigate the extracted compounds' cytotoxic properties. Our findings showed significant effects on all the tested cell lines at varying concentrations (1, 5, 10, and 20 µg/mL). The three compounds exhibited potent activity at low concentrations (< 10 μg/mL), as evidenced by their low IC50 values. To further investigate the complex relationships between these identified cancer-relevant biological targets and to identify critical targets in the pathogenesis of the disease, we turned to network pharmacology and in silico-based investigations. Following this, in silico-based analysis (e.g., inverse docking, ΔG calculation, and molecular dynamics simulation) was performed on the structures of the isolated compounds to identify additional potential targets for these compounds and their likely interactions with various signalling pathways relevant to this disease. Based on our findings, Z. spina-christi's compounds showed promise as potential anti-cancer therapeutic leads in the future.
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Affiliation(s)
- Abeer H Elmaidomy
- Department of Pharmacognosy, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, 62511, Egypt
| | - Amr El Zawily
- Department of Plant and Microbiology, Faculty of Science, Damanhour University, Damanhour, 22511, Egypt.
- Division of Pharmaceutics and Translational Therapeutics, College of Pharmacy, University of Iowa, Iowa City, IA, 52242, USA.
| | - Aliasger K Salem
- Division of Pharmaceutics and Translational Therapeutics, College of Pharmacy, University of Iowa, Iowa City, IA, 52242, USA
| | - Faisal H Altemani
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, University of Tabuk, 71491, Tabuk, Saudi Arabia
| | - Naseh A Algehainy
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, University of Tabuk, 71491, Tabuk, Saudi Arabia
| | - Abdullah H Altemani
- Department of Family and Community Medicine, Faculty of Medicine, University of Tabuk, 71491, Tabuk, Saudi Arabia
| | - Mostafa E Rateb
- School of Computing, Engineering & Physical Sciences, University of the West of Scotland, Paisley, PA1 2BE, UK
| | - Usama Ramadan Abdelmohsen
- Department of Pharmacognosy, Faculty of Pharmacy, Minia University, Minia, 61519, Egypt.
- Department of Pharmacognosy, Faculty of Pharmacy, Deraya University, Universities Zone, New Minia, 61111, Egypt.
| | - Nourhan Hisham Shady
- Department of Pharmacognosy, Faculty of Pharmacy, Deraya University, Universities Zone, New Minia, 61111, Egypt
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Li Q, Chen Y, Zhao X, Lu B, Qu T, Tang L, Zheng Q. Ginsenoside 24-OH-PD from red ginseng inhibits acute T-lymphocytic leukaemia by activating the mitochondrial pathway. PLoS One 2023; 18:e0285966. [PMID: 37205671 PMCID: PMC10198485 DOI: 10.1371/journal.pone.0285966] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Accepted: 05/04/2023] [Indexed: 05/21/2023] Open
Abstract
Ginsenoside 24-hydroxy-ginsengdiol (24-OH-PD), extracted from red ginseng, is a novel diol-type ginsenoside, strongly inhibits the growth of human T-cell acute lymphoblastic leukaemia (T-ALL) CCRF-CEM cells. Our research aimed at investigating the mechanism underlying this inhibition. Cell viability was determined using the cell counting kit-8 (CCK-8) assay, and NOD/SCID mice bearing CCRF-CEM cells were used to verify the therapeutic effect of 24-OH-PD on T-ALL in vivo. We equally analysed pathways related to 24-OH-PD in CCRF-CEM cells using RNA-Seq analysis. Cell apoptosis, reactive oxygen species (ROS), mitochondrial membrane potential (ΔΨm), and mitochondrial permeability transition pore (mPTP) levels were detected by flow cytometry. The activity of caspase3 and caspase9 was detected by enzyme activity detection kits. The expression levels of apoptosis-related proteins and mRNA were determined through western blotting and quantitative reverse-transcription PCR assays (qRT-PCR). CCK-8 assay and animal xenograft experiments confirmed that 24-OH-PD significantly inhibited T-ALL in a dose-dependent manner, both in vivo and in vitro. RNA-Seq results suggest that mitochondria-mediated apoptosis pathway plays an important role in this process. Furthermore, intracellular ROS levels increased, mPTP opened, and ΔΨm decreased following 24-OH-PD treatment. Pretreatment with the antioxidant, NAC, reversed the effects of 24-OH-PD on apoptosis and ROS generation. Moreover, 24-OH-PD treatment increased the expression of Bax and caspase family members, thereby releasing cytochrome c (Cytc) and inducing apoptosis. Our findings showed that, 24-OH-PD induces apoptosis in CCRF-CEM cells by activating the mitochondrial-dependent apoptosis pathway through ROS accumulation. This inhibitory effect implies that 24-OH-PD could be further developed as treatment of T-ALL.
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Affiliation(s)
- Qingmiao Li
- Department of Pharmacy, Shanxi Medical University, Taiyuan, Shanxi, China
| | - Yongfu Chen
- Department of Pharmacy, Shanxi Medical University, Taiyuan, Shanxi, China
| | - Xiaolin Zhao
- Department of Pharmacy, Shanxi Medical University, Taiyuan, Shanxi, China
| | - Bocheng Lu
- Shanxi Traditional Chinese Medicine Hospital, Taiyuan, Shanxi, China
| | - Tingli Qu
- Department of Pharmacy, Shanxi Medical University, Taiyuan, Shanxi, China
| | - Li Tang
- Department of Pharmacy, Shanxi Medical University, Taiyuan, Shanxi, China
| | - Qian Zheng
- Department of Pharmacy, Shanxi Medical University, Taiyuan, Shanxi, China
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7
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Peng Y, Tang R, Ding L, Zheng R, Liu Y, Yin L, Fu Y, Deng T, Li X. Diosgenin inhibits prostate cancer progression by inducing UHRF1 protein degradation. Eur J Pharmacol 2023; 942:175522. [PMID: 36681316 DOI: 10.1016/j.ejphar.2023.175522] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 12/25/2022] [Accepted: 01/18/2023] [Indexed: 01/20/2023]
Abstract
Prostate cancer (PCa) represents the second cause of cancer death in adult men. Aberrant overexpression of UHRF1 has been reported in several cancer types, and is regarded as a novel drug target for cancer therapy. Nevertheless, no UHRF1-targeted small molecule inhibitor has been testing in clinical trials. Traditional Chinese medicine (TCM) prescriptions have a long history for the treatment of PCa in China, and Chinese herbal extracts are important resources for new drug discovery. In the present study, we first screened the potentially effective components from the commonly used TCMs for PCa treatment in clinic by using network pharmacology together with molecular docking. We identified diosgenin (DSG) as a small molecule natural compound specifically targeting UHRF1 protein. Furthermore, we validated the results by using the wet lab experiments. DSG, by directly binding UHRF1 protein, induced UHRF1 protein degradation through the ubiquitin-proteasome pathway. Importantly, DSG induced UHRF1 protein degradation by reducing the protein interaction with a deubiquitinase USP7. DSG reduced the level of genomic DNA methylation, and elevated the expression of such tumor suppressor genes as p21, p16 and LXN, thereby resulting in cell cycle arrest, cellular senescence and the inhibition of xenograft tumor growth. We here presented the first report that DSG specifically induced UHRF1 protein degradation, thereby revealing a novel anticancer mechanism of DSG. Altogether, this present study provided a promising strategy to discover new molecule-targeted drugs from small-molecule natural products.
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Affiliation(s)
- Yuchong Peng
- Key Laboratory of Clinical Precision Pharmacy of Guangdong Higher Education Institutes, The First Affiliated Hospital, Guangdong Pharmaceutical University, Guangzhou, Guangdong, 510699, China; Key Specialty of Clinical Pharmacy, The First Affiliated Hospital, Guangdong Pharmaceutical University, Guangzhou, Guangdong, 510699, China; NMPA Key Laboratory for Technology Research and Evaluation of Pharmacovigilance, Guangdong Pharmaceutical University, Guangzhou, Guangdong, 510006, China
| | - Rong Tang
- Key Laboratory of Clinical Precision Pharmacy of Guangdong Higher Education Institutes, The First Affiliated Hospital, Guangdong Pharmaceutical University, Guangzhou, Guangdong, 510699, China; Key Specialty of Clinical Pharmacy, The First Affiliated Hospital, Guangdong Pharmaceutical University, Guangzhou, Guangdong, 510699, China; NMPA Key Laboratory for Technology Research and Evaluation of Pharmacovigilance, Guangdong Pharmaceutical University, Guangzhou, Guangdong, 510006, China
| | - Liuyang Ding
- Key Laboratory of Clinical Precision Pharmacy of Guangdong Higher Education Institutes, The First Affiliated Hospital, Guangdong Pharmaceutical University, Guangzhou, Guangdong, 510699, China; Key Specialty of Clinical Pharmacy, The First Affiliated Hospital, Guangdong Pharmaceutical University, Guangzhou, Guangdong, 510699, China; NMPA Key Laboratory for Technology Research and Evaluation of Pharmacovigilance, Guangdong Pharmaceutical University, Guangzhou, Guangdong, 510006, China
| | - Rirong Zheng
- Key Laboratory of Clinical Precision Pharmacy of Guangdong Higher Education Institutes, The First Affiliated Hospital, Guangdong Pharmaceutical University, Guangzhou, Guangdong, 510699, China; Key Specialty of Clinical Pharmacy, The First Affiliated Hospital, Guangdong Pharmaceutical University, Guangzhou, Guangdong, 510699, China; NMPA Key Laboratory for Technology Research and Evaluation of Pharmacovigilance, Guangdong Pharmaceutical University, Guangzhou, Guangdong, 510006, China
| | - Youhong Liu
- Department of Oncology, Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China; Hunan Key Laboratory of Molecular Radiation Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
| | - Linglong Yin
- Key Laboratory of Clinical Precision Pharmacy of Guangdong Higher Education Institutes, The First Affiliated Hospital, Guangdong Pharmaceutical University, Guangzhou, Guangdong, 510699, China; Key Specialty of Clinical Pharmacy, The First Affiliated Hospital, Guangdong Pharmaceutical University, Guangzhou, Guangdong, 510699, China; NMPA Key Laboratory for Technology Research and Evaluation of Pharmacovigilance, Guangdong Pharmaceutical University, Guangzhou, Guangdong, 510006, China; School of Clinical Pharmacy, Guangdong Pharmaceutical University, Guangzhou, Guangdong, 510006, China
| | - Yongming Fu
- Key Laboratory of Clinical Precision Pharmacy of Guangdong Higher Education Institutes, The First Affiliated Hospital, Guangdong Pharmaceutical University, Guangzhou, Guangdong, 510699, China; Key Specialty of Clinical Pharmacy, The First Affiliated Hospital, Guangdong Pharmaceutical University, Guangzhou, Guangdong, 510699, China; NMPA Key Laboratory for Technology Research and Evaluation of Pharmacovigilance, Guangdong Pharmaceutical University, Guangzhou, Guangdong, 510006, China
| | - Tanggang Deng
- Key Laboratory of Clinical Precision Pharmacy of Guangdong Higher Education Institutes, The First Affiliated Hospital, Guangdong Pharmaceutical University, Guangzhou, Guangdong, 510699, China; Key Specialty of Clinical Pharmacy, The First Affiliated Hospital, Guangdong Pharmaceutical University, Guangzhou, Guangdong, 510699, China; NMPA Key Laboratory for Technology Research and Evaluation of Pharmacovigilance, Guangdong Pharmaceutical University, Guangzhou, Guangdong, 510006, China
| | - Xiong Li
- Key Laboratory of Clinical Precision Pharmacy of Guangdong Higher Education Institutes, The First Affiliated Hospital, Guangdong Pharmaceutical University, Guangzhou, Guangdong, 510699, China; Key Specialty of Clinical Pharmacy, The First Affiliated Hospital, Guangdong Pharmaceutical University, Guangzhou, Guangdong, 510699, China; NMPA Key Laboratory for Technology Research and Evaluation of Pharmacovigilance, Guangdong Pharmaceutical University, Guangzhou, Guangdong, 510006, China; School of Clinical Pharmacy, Guangdong Pharmaceutical University, Guangzhou, Guangdong, 510006, China.
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8
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Qiu S, Blank LM. Recent Advances in Yeast Recombinant Biosynthesis of the Triterpenoid Protopanaxadiol and Glycosylated Derivatives Thereof. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2023; 71:2197-2210. [PMID: 36696911 DOI: 10.1021/acs.jafc.2c06888] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/17/2023]
Abstract
Plant natural products are a seemingly endless resource for novel chemical structures. However, their extraction often results in high prices, fluctuation in both quantity and quality, and negative environmental impact. The latter might result from the extraction procedure but more often from the high amount of plant biomass required. With the advent of synthetic biology, producing natural plant products in large quantities using yeasts as hosts has become possible. Here, we focus on the recent advances in metabolic engineering of the yeasts species Saccharomyces cerevisiae and Yarrowia lipolytica for the synthesis of ginsenoside triterpenoids, namely, dammarenediol-II, protopanaxadiol, protopanaxatriol, compound K, ginsenoside Rh1, ginsenoside Rh2, ginsenoside Rg3, and ginsenoside F1. A discussion is provided on advanced synthetic biology, bioprocess strategies, and current challenges for the biosynthesis of ginsenoside triterpenoids. Finally, future directions in metabolic and process engineering are summarized and may help reify sustainable ginsenoside production.
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Affiliation(s)
- Shangkun Qiu
- Institute of Applied Microbiology (iAMB), Aachen Biology and Biotechnology (ABBt), RWTH Aachen University, 52074 Aachen, Germany
| | - Lars M Blank
- Institute of Applied Microbiology (iAMB), Aachen Biology and Biotechnology (ABBt), RWTH Aachen University, 52074 Aachen, Germany
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9
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Petitjean M, Isasi JR. Preparation of β-cyclodextrin/polysaccharide foams using saponin. Beilstein J Org Chem 2023; 19:78-88. [PMID: 36761472 PMCID: PMC9887783 DOI: 10.3762/bjoc.19.7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Accepted: 01/10/2023] [Indexed: 01/25/2023] Open
Abstract
Cyclodextrins, cyclic oligosaccharides with a hydrophobic cavity that form inclusion complexes with nonpolar molecules, can be used to functionalize other polysaccharides. Xanthan gum, locust bean gum or chitosan can be crosslinked using citric acid in the presence of β-cyclodextrin to produce insoluble matrices. In this work, polymeric foams based on those polysaccharides and saponin have been prepared using a green synthesis method to increase the porosity of the matrices. The saponin of soapbark (Quillaja saponaria) has been used to obtain foams using different procedures. The influence of the synthesis path on the porosity of the materials and their corresponding sorption capacities in the aqueous phase were evaluated.
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Affiliation(s)
- Max Petitjean
- Department of Chemistry. University of Navarra. 31080 Pamplona, Spain
| | - José Ramón Isasi
- Department of Chemistry. University of Navarra. 31080 Pamplona, Spain
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10
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Abstract
As a steroid skeleton-based saponin, ginsenoside Rh2 (G-Rh2) is one of the major bioactive ginsenosides from the plants of genus Panax L. Many studies have reported the notable pharmacological activities of G-Rh2 such as anticancer, antiinflammatory, antiviral, antiallergic, antidiabetic, and anti-Alzheimer's activities. Numerous preclinical studies have demonstrated the great potential of G-Rh2 in the treatment of a wide range of carcinomatous diseases in vitro and in vivo. G-Rh2 is able to inhibit proliferation, induce apoptosis and cell cycle arrest, retard metastasis, promote differentiation, enhance chemotherapy and reverse multi-drug resistance against multiple tumor cells. The present review mainly summarizes the anticancer effects and related mechanisms of G-Rh2 in various models as well as the recent advances in G-Rh2 delivery systems and structural modification to ameliorate its anticancer activity and pharmacokinetics characteristics.
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11
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Hao Q, Wu Y, Vadgama JV, Wang P. Phytochemicals in Inhibition of Prostate Cancer: Evidence from Molecular Mechanisms Studies. Biomolecules 2022; 12:1306. [PMID: 36139145 PMCID: PMC9496067 DOI: 10.3390/biom12091306] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2022] [Revised: 09/09/2022] [Accepted: 09/12/2022] [Indexed: 11/26/2022] Open
Abstract
Prostate cancer is one of the leading causes of death for men worldwide. The development of resistance, toxicity, and side effects of conventional therapies have made prostate cancer treatment become more intensive and aggressive. Many phytochemicals isolated from plants have shown to be tumor cytotoxic. In vitro laboratory studies have revealed that natural compounds can affect cancer cell proliferation by modulating many crucial cellular signaling pathways frequently dysregulated in prostate cancer. A multitude of natural compounds have been found to induce cell cycle arrest, promote apoptosis, inhibit cancer cell growth, and suppress angiogenesis. In addition, combinatorial use of natural compounds with hormone and/or chemotherapeutic drugs seems to be a promising strategy to enhance the therapeutic effect in a less toxic manner, as suggested by pre-clinical studies. In this context, we systematically reviewed the currently available literature of naturally occurring compounds isolated from vegetables, fruits, teas, and herbs, with their relevant mechanisms of action in prostate cancer. As there is increasing data on how phytochemicals interfere with diverse molecular pathways in prostate cancer, this review discusses and emphasizes the implicated molecular pathways of cell proliferation, cell cycle control, apoptosis, and autophagy as important processes that control tumor angiogenesis, invasion, and metastasis. In conclusion, the elucidation of the natural compounds' chemical structure-based anti-cancer mechanisms will facilitate drug development and the optimization of drug combinations. Phytochemicals, as anti-cancer agents in the treatment of prostate cancer, can have significant health benefits for humans.
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Affiliation(s)
- Qiongyu Hao
- Division of Cancer Research and Training, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, CA 90059, USA
| | - Yanyuan Wu
- Division of Cancer Research and Training, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, CA 90059, USA
- Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, USA
| | - Jaydutt V. Vadgama
- Division of Cancer Research and Training, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, CA 90059, USA
- Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, USA
| | - Piwen Wang
- Division of Cancer Research and Training, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, CA 90059, USA
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Oh HM, Cho CK, Son CG. Experimental Evidence for the Anti-Metastatic Action of Ginsenoside Rg3: A Systematic Review. Int J Mol Sci 2022; 23:9077. [PMID: 36012338 PMCID: PMC9409359 DOI: 10.3390/ijms23169077] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Revised: 08/09/2022] [Accepted: 08/11/2022] [Indexed: 11/26/2022] Open
Abstract
Cancer metastasis is the leading cause of death in cancer patients. Due to the limitations of conventional cancer treatment, such as chemotherapy, there is a need for novel therapeutics to prevent metastasis. Ginsenoside Rg3, a major active component of Panax ginseng C.A. Meyer, inhibits tumor growth and has the potential to prevent tumor metastasis. Herein, we systematically reviewed the anti-metastatic effects of Rg3 from experimental studies. We searched for articles in three research databases, MEDLINE (PubMed), EMBASE, and the Cochrane Central Register of Controlled Trials (CENTRAL) through March 2022. In total, 14 studies (eight animal and six in vitro) provide data on the anti-metastatic effects of Rg3 and the relevant mechanisms. The major anti-metastatic mechanisms of Rg3 involve cancer stemness, epithelial mesenchymal transition (EMT) behavior, and angiogenesis. Taken together, Rg3 would be one of the herbal resources in anti-metastatic drug developments through further well-designed investigations and clinical studies. Our review provides valuable reference data for Rg3-derived studies targeting tumor metastasis.
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Affiliation(s)
- Hyeon-Muk Oh
- College of Korean Medicine, Daejeon University, Daejeon 35235, Korea
| | - Chong-Kwan Cho
- College of Korean Medicine, Daejeon University, Daejeon 35235, Korea
- East-West Cancer Center, Daejeon Korean Medicine Hospital of Daejeon University, Daejeon 35235, Korea
| | - Chang-Gue Son
- College of Korean Medicine, Daejeon University, Daejeon 35235, Korea
- Liver and Immunology Research Center, Daejeon Korean Medicine Hospital of Daejeon University, Daejeon 35235, Korea
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13
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Rg3 and Rh2 ginsenosides suppress embryoid body formation by inhibiting the epithelial-mesenchymal transition. Arch Pharm Res 2022; 45:494-505. [PMID: 35759089 DOI: 10.1007/s12272-022-01395-1] [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: 02/28/2022] [Accepted: 06/21/2022] [Indexed: 11/02/2022]
Abstract
Numerous active compounds derived from ginseng exhibit various pharmacological and therapeutic effects in humans. Despite the benefits of ginsenosides, little is known about their influence on embryonic development, especially in human embryonic models. In this study, we evaluated the effect of two ginsenosides (Rg3 and Rh2) on human embryonic development, using embryoid bodies and three-dimensional (3D) aggregates of pluripotent stem cells. We exposed embryoid bodies to varying concentrations of Rg3 and Rh2 (5, 10, and 25 μg/mL), and their embryotoxicity was evaluated by measuring the size of the embryoid body and the expression of epithelial-mesenchymal transition (EMT) markers. The growth rates of embryoid bodies were reduced upon treatment with a high concentration (25 μg/mL) of Rg3 and Rh2. In addition, Rg3 induced E-cadherin expression while inhibiting N-cadherin and vimentin expression, which implies the inhibition of EMT. Such a change in E-cadherin expression was not observed after Rh2 treatment, but the inhibition of N-cadherin and vimentin expression was observed to be consistent with that observed on treatment with Rg3. Taken together, using the human embryoid model, we found that the two active ginsenosides, Rg3 and Rh2, induce aberrant embryoid body formation and ablate normal EMT.
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14
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Fu L, Zhang W, Zhou X, Fu J, He C. Tumor cell membrane-camouflaged responsive nanoparticles enable MRI-guided immuno-chemodynamic therapy of orthotopic osteosarcoma. Bioact Mater 2022; 17:221-233. [PMID: 35386464 PMCID: PMC8965157 DOI: 10.1016/j.bioactmat.2022.01.035] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Revised: 01/11/2022] [Accepted: 01/19/2022] [Indexed: 02/09/2023] Open
Abstract
Osteosarcoma is a refractory bone disease in young people that needs the updating and development of effective treatment. Although nanotechnology is widely applied in cancer therapy, poor targeting and inadequate efficiency hinder its development. In this study, we prepared alendronate (ALD)/K7M2 cell membranes-coated hollow manganese dioxide (HMnO2) nanoparticles as a nanocarrier to load Ginsenoside Rh2 (Rh2) for Magnetic Resonance imaging (MRI)-guided immuno-chemodynamic combination osteosarcoma therapy. Subsequently, the ALD and K7M2 cell membranes were successively modified on the surface of HMnO2 and loaded with Rh2. The tumor microenvironment (TME)-activated Rh2@HMnO2-AM nanoparticles have good bone tumor-targeting and tumor-homing capabilities, excellent GSH-sensitive drug release profile and MRI capability, and attractive immuno-chemodynamic combined therapeutic efficiency. The Rh2@HMnO2-AM nanoparticles can effectively trigger immunogenic cell death (ICD), activate CD4+/CD8+ T cells in vivo, and upregulate BAX, BCL-2 and Caspase-3 in cellular level. Further results revealed that Rh2@HMnO2-AM enhanced the secretion of IL-6, IFN-γ and TNF-α in serum and inhibited the generation of FOXP3+ T cells (Tregs) in tumors. Moreover, the Rh2@HMnO2-AM treatment significant restricted tumor growth in-situ tumor-bearing mice. Therefore, Rh2@HMnO2-AM may serve as an effective and bio-friendly nanoparticle platform combined with immunotherapy and chemodynamic therapy to provide a novel approach to osteosarcoma therapy.
Ginsenoside Rh2 was loaded in Hollow MnO2 NPs for enhancing its bioavailability. The orthotopic tumor model exhibits a convincing therapeutic effect of nanosystems. Alendronate/cell membranes enhance osteosarcoma targeting and tumor-homing ability. Tumor microenvironment-induced NPs degradation can release immune stimulant and Mn2+. The NPs had excellent immuno-chemodynamic combination osteosarcoma therapy effect.
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Affiliation(s)
- Liwen Fu
- State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai, 201620, China
| | - Weiying Zhang
- Health Management Center, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China
| | - Xiaojun Zhou
- State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai, 201620, China
| | - Jingzhong Fu
- Department of Thoracic Oncology, Jiujiang Cancer Hospital, Jiangxi Province, China
| | - Chuanglong He
- State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai, 201620, China
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15
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Shandilya UK, Lamers K, Zheng Y, Moran N, Karrow NA. Ginsenoside Rb1 selectively improved keratinocyte functions in vitro without affecting tissue regeneration in zebrafish larvae tail regrowth. In Vitro Cell Dev Biol Anim 2022; 58:269-277. [PMID: 35501555 DOI: 10.1007/s11626-022-00664-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Accepted: 02/25/2022] [Indexed: 11/24/2022]
Affiliation(s)
- Umesh K Shandilya
- Department of Animal Biosciences, University of Guelph, Guelph, ON, N1G 2W1, Canada
| | - Kristen Lamers
- Department of Animal Biosciences, University of Guelph, Guelph, ON, N1G 2W1, Canada
| | - Yashi Zheng
- Department of Animal Biosciences, University of Guelph, Guelph, ON, N1G 2W1, Canada
| | - Nicole Moran
- Department of Animal Biosciences, University of Guelph, Guelph, ON, N1G 2W1, Canada
| | - Niel A Karrow
- Department of Animal Biosciences, University of Guelph, Guelph, ON, N1G 2W1, Canada.
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16
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Ancient herbal therapy: A brief history of Panax ginseng. J Ginseng Res 2022; 47:359-365. [DOI: 10.1016/j.jgr.2022.03.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Revised: 03/07/2022] [Accepted: 03/17/2022] [Indexed: 11/17/2022] Open
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17
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Tan MM, Chen MH, Han F, Wang JW, Tu YX. Role of Bioactive Constituents of Panax notoginseng in the Modulation of Tumorigenesis: A Potential Review for the Treatment of Cancer. Front Pharmacol 2021; 12:738914. [PMID: 34776959 PMCID: PMC8578715 DOI: 10.3389/fphar.2021.738914] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Accepted: 09/16/2021] [Indexed: 12/12/2022] Open
Abstract
Cancer is a leading cause of death, affecting people in both developed and developing countries. It is a challenging disease due to its complicated pathophysiological mechanism. Many anti-cancer drugs are used to treat cancer and reduce mortality rates, but their toxicity limits their administration. Drugs made from natural products, which act as multi-targeted therapy, have the ability to target critical signaling proteins in different pathways. Natural compounds possess pharmacological activities such as anti-cancer activity, low toxicity, and minimum side effects. Panax notoginseng is a medicinal plant whose extracts and phytochemicals are used to treat cancer, cardiovascular disorders, blood stasis, easing inflammation, edema, and pain. P. notoginseng's secondary metabolites target cancer's dysregulated pathways, causing cancer cell death. In this review, we focused on several ginsenosides extracted from P. notoginseng that have been evaluated against various cancer cell lines, with the aim of cancer treatment. Furthermore, an in vivo investigation of these ginsenosides should be conducted to gain insight into the dysregulation of several pathways, followed by clinical trials for the potential and effective treatment of cancer.
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Affiliation(s)
- Ming-Ming Tan
- Department of Emergency Medicine, Tiantai People’s Hospital of Zhejiang Province (Tiantai Branch of Zhejiang People’s Hospital), Taizhou, China
| | - Min-Hua Chen
- Department of Critical Care Medicine, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital of Hangzhou Medical College, Hangzhou, China
| | - Fang Han
- Department of Critical Care Medicine, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital of Hangzhou Medical College, Hangzhou, China
| | - Jun-Wei Wang
- Department of Emergency Medicine, Tiantai People’s Hospital of Zhejiang Province (Tiantai Branch of Zhejiang People’s Hospital), Taizhou, China
| | - Yue-Xing Tu
- Department of Critical Care Medicine, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital of Hangzhou Medical College, Hangzhou, China
- Department of Rehabilitation Medicine, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital of Hangzhou Medical College, Hangzhou, China
- Rehabilitation and Sports Medicine Research Institute of Zhejiang Province, Affiliated People’s Hospital of Hangzhou Medical College, Hangzhou, China
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18
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Liu W, Zhang SX, Ai B, Pan HF, Zhang D, Jiang Y, Hu LH, Sun LL, Chen ZS, Lin LZ. Ginsenoside Rg3 Promotes Cell Growth Through Activation of mTORC1. Front Cell Dev Biol 2021; 9:730309. [PMID: 34589493 PMCID: PMC8473834 DOI: 10.3389/fcell.2021.730309] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Accepted: 08/26/2021] [Indexed: 01/15/2023] Open
Abstract
Ginsenoside Rg3 is a steroidal saponin isolated from Panax ginseng. Previous studies have shown that Rg3 treatment downregulates the activity of rapamycin complex 1 (mTORC1) activity and inhibits the growth of cancer cells. However, the inhibitory effect of Rg3 on cancer cells is associated with high concentrations of Rg3 that are difficult to achieve in vivo. The human cervix adenocarcinoma HeLa cells were treated with Rg3. The protein levels of AMP-activated protein kinase alpha (AMPKα), protein kinase B(Akt), ribosomal S6 protein(S6), and Erk were determined by immunoblotting analyses. We used a fluorescent probe to detect reactive oxygen species (ROS) production in living cells. The oxygen consumption rate (OCR) was examined by the Seahorse Extracellular Flux Analyzer. The content of adenosine triphosphate (ATP) was measured by ATPlite kit and Mitotracker was applied to detect the mitochondria. We showed that at lower concentrations, Rg3 activates mTORC1 independent of AKT and AMP-activated protein kinase (AMPK). Rg3 promotes mitochondrial biogenesis and function, increases the oxygen consumption of mitochondria and the content of ATP. This effect is in contrast to that of high concentrations of Rg3, which inhibits cell growth. These findings demonstrate a pro-growth activity of Rg3 that acts through mTORC1 and mitochondrial biogenesis and suggest a dose-dependent effect of Rg3 on tumor cell growth.
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Affiliation(s)
- Wei Liu
- Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, China.,Integrative Cancer Centre, The First Affiliated Hospital of Guangzhou, University of Chinese Medicine, Guangzhou, China
| | | | - Bo Ai
- Department of Thoracic Surgery, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hua-Feng Pan
- Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Dan Zhang
- Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yu Jiang
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
| | - Lei-Hao Hu
- Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, China.,Integrative Cancer Centre, The First Affiliated Hospital of Guangzhou, University of Chinese Medicine, Guangzhou, China
| | - Ling-Ling Sun
- Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, China.,Integrative Cancer Centre, The First Affiliated Hospital of Guangzhou, University of Chinese Medicine, Guangzhou, China
| | - Zhe-Sheng Chen
- Institute for Biotechnology, St. John's University, Queens, NY, United States
| | - Li-Zhu Lin
- Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, China.,Integrative Cancer Centre, The First Affiliated Hospital of Guangzhou, University of Chinese Medicine, Guangzhou, China
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19
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He S, Lyu F, Lou L, Liu L, Li S, Jakowitsch J, Ma Y. Anti-tumor activities of Panax quinquefolius saponins and potential biomarkers in prostate cancer. J Ginseng Res 2021; 45:273-286. [PMID: 33841008 PMCID: PMC8020356 DOI: 10.1016/j.jgr.2019.12.007] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2019] [Revised: 10/28/2019] [Accepted: 12/30/2019] [Indexed: 01/15/2023] Open
Abstract
BACKGROUND Prostate carcinoma is the second most common cancer among men worldwide. Developing new therapeutic approaches and diagnostic biomarkers for prostate cancer (PC) is a significant need. The Chinese herbal medicine Panax quinquefolius saponins (PQS) have been reported to show anti-tumor effects. We hypothesized that PQS exhibits anti-cancer activity in human PC cells and we aimed to search for novel biomarkers allowing early diagnosis of PC. METHODS We used the human PC cell line DU145 and the prostate epithelial cell line PNT2 to perform cell viability assays, flow cytometric analysis of the cell cycle, and FACS-based apoptosis assays. Microarray-based gene expression analysis was used to display specific gene expression patterns and to search for novel biomarkers. Western blot and quantitative real-time PCR were performed to demonstrate the expression levels of multiple cancer-related genes. RESULTS Our data showed that PQS inhibited the viability of DU145 cells and induced cell cycle arrest at the G1 phase. A significant decrease in DU145 cell invasion and migration were observed after 24 h treatment by PQS. PQS up-regulated the expression levels of p21, p53, TMEM79, ACOXL, ETV5, and SPINT1 while it down-regulated the expression levels of bcl2, STAT3, FANCD2, DRD2, and TMPRSS2. CONCLUSION PQS promoted cells apoptosis and inhibited the proliferation of DU145 cells, which suggests that PQS may be effective for treating PC. TMEM79 and ACOXL were expressed significantly higher in PNT2 than in DU145 cells and could be novel biomarker candidates for PC diagnosis.
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Key Words
- ACOXL, Acyl-CoA oxidase-like protein
- Chinese medicinal herbs
- DRD2, dopamine receptor D2
- ETV5, ETS variant 5
- FACS, fluorescence-activated cell sorting
- FANCD2, fanconi anemia group D2
- PC, prostate cancer
- PQS, Panax quinquefolius saponins
- Panax quinquefolius
- Potential biomarkers
- Prostate cancer cells
- SPINT1, serine peptidase inhibitor Kunitz type 1
- STAT3, signal transducer and activator of transcription 3
- TCM, Traditional Chinese Medicine
- TMEM79, transmembrane protein 79
- TMPRSS2, transmembrane protease serine 2
- bcl2, B-cell lymphoma 2
- p21, cyclin-dependent kinase inhibitor p21
- p53, tumor suppressor p53
- qRT-PCR, quantitative real-time PCR
- saponins
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Affiliation(s)
- Shan He
- Department of Pathophysiology and Allergy Research, Center of Pathophysiology, Infectiology & Immunology, Vienna General Hospital, Medical University of Vienna, Vienna, Austria
| | - Fangqiao Lyu
- Department of Cell Biology, School of Basic Medicine, Capital Medical University, Beijing, China
| | - Lixia Lou
- The Key Laboratory of Chinese Internal Medicine of Ministry of Education, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Lu Liu
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Songlin Li
- Department of Pharmaceutical Analysis and Metabolomics, Jiangsu Province Academy of Traditional Chinese Medicine and Jiangsu Branch of China Academy of Chinese Medical Sciences, Nanjing, China
| | - Johannes Jakowitsch
- Department of Internal Medicine, Vienna General Hospital, Medical University of Vienna, Vienna, Austria
| | - Yan Ma
- Department of Pathophysiology and Allergy Research, Center of Pathophysiology, Infectiology & Immunology, Vienna General Hospital, Medical University of Vienna, Vienna, Austria
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20
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Biocatalysis for Rare Ginsenoside Rh2 Production in High Level with Co-Immobilized UDP-Glycosyltransferase Bs-YjiC Mutant and Sucrose Synthase AtSuSy. Catalysts 2021. [DOI: 10.3390/catal11010132] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Rare ginsenoside Rh2 exhibits diverse pharmacological effects. UDP-glycosyltransferase (UGT) catalyzed glycosylation of protopanaxadiol (PPD) has been of growing interest in recent years. UDP-glycosyltransferase Bs-YjiC coupling sucrose synthase in one-pot reaction was successfully applied to ginsenoside biosynthesis with UDP-glucose regeneration from sucrose and UDP, which formed a green and sustainable approach. In this study, the his-tagged UDP-glycosyltransferase Bs-YjiC mutant M315F and sucrose synthase AtSuSy were co-immobilized on heterofunctional supports. The affinity adsorption significantly improved the capacity of specific binding of the two recombinant enzymes, and the dual enzyme covalently cross-linked by the acetaldehyde groups significantly promoted the binding stability of the immobilized bienzyme, allowing higher substrate concentration by easing substrate inhibition for the coupled reaction. The dual enzyme amount used for ginsenoside Rh2 biosynthesis is Bs-YjiC-M315F: AtSuSy = 18 mU/mL: 25.2 mU/mL, a yield of 79.2% was achieved. The coimmobilized M315F/AtSuSy had good operational stability of repetitive usage for 10 cycles, and the yield of ginsenoside Rh2 was kept between 77.6% and 81.3%. The high titer of the ginsenoside Rh2 cumulatively reached up to 16.6 mM (10.3 g/L) using fed-batch technology, and the final yield was 83.2%. This study has established a green and sustainable approach for the production of ginsenoside Rh2 in a high level of titer, which provides promising candidates for natural drug research and development.
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21
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Yoon SJ, Kim SK, Lee NY, Choi YR, Kim HS, Gupta H, Youn GS, Sung H, Shin MJ, Suk KT. Effect of Korean Red Ginseng on metabolic syndrome. J Ginseng Res 2020; 45:380-389. [PMID: 34025131 PMCID: PMC8134847 DOI: 10.1016/j.jgr.2020.11.002] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Revised: 09/24/2020] [Accepted: 11/02/2020] [Indexed: 12/27/2022] Open
Abstract
Metabolic syndrome (MS) refers to a clustering of at least three of the following medical conditions: high blood pressure, abdominal obesity, hyperglycemia, low high-density lipoprotein level, and high serum triglycerides. MS is related to a wide range of diseases which includes obesity, diabetes, insulin resistance, cardiovascular disease, dyslipidemia, or non-alcoholic fatty liver disease. There remains an ongoing need for improved treatment strategies for MS. The most important risk factors are dietary pattern, genetics, old age, lack of exercise, disrupted biology, medication usage, and excessive alcohol consumption, but pathophysiology of MS has not been completely identified. Korean Red Ginseng (KRG) refers to steamed/dried ginseng, traditionally associated with beneficial effects such as anti-inflammation, anti-fatigue, anti-obesity, anti-oxidant, and anti-cancer effects. KRG has been often used in traditional medicine to treat multiple metabolic conditions. This paper summarizes the effects of KRG in MS and related diseases such as obesity, cardiovascular disease, insulin resistance, diabetes, dyslipidemia, or non-alcoholic fatty liver disease based on experimental research and clinical studies.
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Key Words
- ACC, Acetyl-Coenzyme A carboxylase
- ADP, adenosine diphosphate
- AG, American ginseng extract
- AGE, advanced glycation end product
- ALT, alanine aminotransferase
- AMPK, AMP-activated protein kinase
- AST, aspartate aminotransferase
- Akt, protein kinase B
- BMI, body mass index
- C/EBPα, CCAAT/enhancer-binding protein alpha
- COX-2, cyclooxygenase-2
- CPT, current perception threshold
- CPT-1, carnitine palmitoyl transferase 1
- CRP, C-reactive protein
- CVD, Cardiovascular disease
- DBP, diastolic blood pressure
- DEN, diethyl nitrosamine
- EAT, epididymis adipose tissue
- EF, ejection fraction
- FABP4, fatty acid binding protein 4
- FAS, Fatty acid synthase
- FFA, free fatty acid
- FR, fine root concentration
- FS, fractional shortening
- GBHT, ginseng-plus-Bai-Hu-Tang
- GLUT, glucose transporter type
- GPx, glutathione peroxidase
- GS, ginsenoside
- GST, glutathione S-transferase
- GST-P, glutathione S-transferase placental form
- GTT, glucose tolerance test
- HCC, hepatocellular carcinoma
- HCEF-RG, hypotensive components-enriched fraction of red ginseng
- HDL, high-density lipoprotein
- HFD, High fat diet
- HOMA-IR, homeostasis model assessment of insulin resistance index
- HbA1c, glycosylated hemoglobin
- I.P., intraperitoneal injection
- IL, interleukin
- IR, insulin resistance
- ITT, insulin tolerance test
- Insulin resistance
- KRG, Korean Red Ginseng
- LDL, low-density lipoprotein
- LPL, lipoprotein lipase
- Lex, lower extremities
- MDA, malondialdehyde
- MMP, Matrix metallopeptidases
- MS, Metabolic syndrome
- Metabolic syndrome
- NAFLD, Non-alcoholic fatty liver disease
- NF-кB, nuclear factor kappa-light-chain-enhancer of activated B cells
- NK cell, Natural killer cell
- NMDA-NR1, N-methyl-D-aspartate NR1
- NO, nitric oxide
- NRF1, Nuclear respiratory factor 1
- Non-alcoholic fatty liver disease
- Nrf2, Nuclear factor erythroid 2-related factor 2
- OLETF rat, Otsuka Long-Evans Tokushima fatty rat
- PCG-1α, PPAR-γ coactivator-1α
- PI3K, phosphoinositide 3-kinase
- PPAR, peroxisome proliferator-activated receptors
- PPD, protopanaxadiol
- PPT, protopanaxatriol
- Panax ginseng
- REKRG, Rg3-enriched KRG
- ROS, Reactive oxygen species
- Rg3-KGE, Rg3-enriched KRG extract
- SBP, systolic blood pressure
- SCD, Stearoyl-Coenzyme A desaturase
- SHR, spontaneously hypertensive rat
- SREBP-1C, Sterol regulatory element-binding protein 1
- STAT5, Signal transducer and activator of transcription 5
- STZ, streptozotocin
- TBARS, thiobarbituric acid reactive substances
- TC, total cholesterol
- TG, triglyceride
- TNF, tumor necrosis factor
- UCP, Mitochondrial uncoupling proteins
- VLDL, very low-density lipoprotein
- iNOS, inducible nitric oxide synthase
- t-BHP, tert-butyl hyperoxide
- tGST, total glutathione
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Affiliation(s)
- Sang Jun Yoon
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon, Republic of Korea
| | - Seul Ki Kim
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon, Republic of Korea
| | - Na Young Lee
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon, Republic of Korea
| | - Ye Rin Choi
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon, Republic of Korea
| | - Hyeong Seob Kim
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon, Republic of Korea
| | - Haripriya Gupta
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon, Republic of Korea
| | - Gi Soo Youn
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon, Republic of Korea
| | - Hotaik Sung
- School of Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Min Jea Shin
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon, Republic of Korea
| | - Ki Tae Suk
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon, Republic of Korea
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22
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Inhibitory effect of ginsenoside Rg3 on cancer stemness and mesenchymal transition in breast cancer via regulation of myeloid-derived suppressor cells. PLoS One 2020; 15:e0240533. [PMID: 33091036 PMCID: PMC7580975 DOI: 10.1371/journal.pone.0240533] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Accepted: 09/28/2020] [Indexed: 01/21/2023] Open
Abstract
Ginsenoside Rg3 (Rg3) has been studied in several cancer models and is suggested to act through various pharmacological effects. We investigated the anticancer properties of Rg3 through myeloid-derived suppressor cell (MDSC) modulation in FM3A mouse mammary carcinoma cells. The effects of Rg3 on MDSCs and consequent changes in cancer stem-like cells (CSCs) and epithelial-mesenchymal transition (EMT) were evaluated by diverse methods. MDSCs promoted cancer by enhancing breast cancer stemness and promoting EMT. Rg3 at a dose without obvious cytotoxicity downregulated MDSCs and repressed MDSC-induced cancer stemness and EMT. Mechanistic investigations suggested that these inhibitory effects of Rg3 on MDSCs and corresponding cancer progression depend upon suppression of the STAT3-dependent pathway, tumor-derived cytokines, and the NOTCH signaling pathway. In a mouse model, MDSCs accelerated tumor progression, and Rg3 delayed tumor growth, which is consistent with the results of in vitro experiments. These results indicated that Rg3 could effectively inhibit the progression of breast cancer. The anticancer effect of Rg3 might be partially due to its downregulation of MDSCs and consequent repression of cancer stemness and EMT in breast cancer. Hence, we suggest the regulation of MDSCs through Rg3 treatment as an effective therapeutic strategy for breast cancer patients.
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23
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Ahmad N, Xu K, Wang JN, Li C. Novel catalytic glycosylation of Glycyrrhetinic acid by UDP-glycosyltransferases from Bacillus subtilis. Biochem Eng J 2020. [DOI: 10.1016/j.bej.2020.107723] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
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Verstraeten SL, Lorent JH, Mingeot-Leclercq MP. Lipid Membranes as Key Targets for the Pharmacological Actions of Ginsenosides. Front Pharmacol 2020; 11:576887. [PMID: 33041822 PMCID: PMC7518029 DOI: 10.3389/fphar.2020.576887] [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: 06/27/2020] [Accepted: 08/18/2020] [Indexed: 12/27/2022] Open
Abstract
In this review, we will focus on the activity of ginsenosides on membranes and their related effects, from physicochemical, biophysical, and pharmacological viewpoints. Ginsenosides are a class of saponins with a large structural diversity and a wide range of pharmacological effects. These effects can at least partly be related to their activity on membranes which results from their amphiphilic character. Some ginsenosides are able to interact with membrane lipids and associate into nanostructures, making them possible adjuvants for vaccines. They are able to modulate membrane biophysical properties such as membrane fluidity, permeability or the formation of lateral domains with some degree of specificity towards certain cell types such as bacteria, fungi, or cancer cells. In addition, they have shown antioxidant properties which protect membranes from lipid oxidation. They further displayed some activity on membrane proteins either through direct or indirect interaction. We investigate the structure activity relationship of ginsenosides on membranes and discuss the implications and potential use as anticancer, antibacterial, and antifungal agents.
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Affiliation(s)
- Sandrine L Verstraeten
- Cellular & Molecular Pharmacology Unit (FACM), Louvain Drug Research Institute (LDRI), Université Catholique de Louvain (UCL), Brussels, Belgium
| | - Joseph H Lorent
- Cellular & Molecular Pharmacology Unit (FACM), Louvain Drug Research Institute (LDRI), Université Catholique de Louvain (UCL), Brussels, Belgium.,Membrane Biochemistry & Biophysics, Bijvoet Center for Biomolecular Research, Utrecht University, Utrecht, Netherlands
| | - Marie-Paule Mingeot-Leclercq
- Cellular & Molecular Pharmacology Unit (FACM), Louvain Drug Research Institute (LDRI), Université Catholique de Louvain (UCL), Brussels, Belgium
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Li X, Chu S, Lin M, Gao Y, Liu Y, Yang S, Zhou X, Zhang Y, Hu Y, Wang H, Chen N. Anticancer property of ginsenoside Rh2 from ginseng. Eur J Med Chem 2020; 203:112627. [PMID: 32702586 DOI: 10.1016/j.ejmech.2020.112627] [Citation(s) in RCA: 119] [Impact Index Per Article: 23.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 06/26/2020] [Accepted: 06/26/2020] [Indexed: 12/20/2022]
Abstract
Ginseng has been used as a well-known traditional Chinese medicine since ancient times. Ginsenosides as its main active constituents possess a broad scope of pharmacological properties including stimulating immune function, enhancing cardiovascular health, increasing resistance to stress, improving memory and learning, developing social functioning and mental health in normal persons, and chemotherapy. Ginsenoside Rh2 (Rh2) is one of the major bioactive ginsenosides from Panax ginseng. When applied to cancer treatment, Rh2 not only exhibits the anti-proliferation, anti-invasion, anti-metastasis, induction of cell cycle arrest, promotion of differentiation, and reversal of multi-drug resistance activities against multiple tumor cells, but also alleviates the side effects after chemotherapy or radiotherapy. In the past decades, nearly 200 studies on Rh2 in the treatment of cancer have been published, however no specific reviews have been conducted by now. So the purpose of this review is to provide a systematic summary and analysis of the anticancer effects and the potential mechanisms of Rh2 extracted from Ginseng then give a future prospects about it. In the end of this paper the metabolism and derivatives of Rh2 also have been documented.
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Affiliation(s)
- Xun Li
- College of Pharmacy, Hunan University of Chinese Medicine, Changsha, 410208, PR China; Hunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction Pieces, Changsha, 410208, PR China; Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, PR China
| | - Shifeng Chu
- Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, PR China
| | - Meiyu Lin
- College of Pharmacy, Hunan University of Chinese Medicine, Changsha, 410208, PR China
| | - Yan Gao
- Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, PR China
| | - Yingjiao Liu
- College of Pharmacy, Hunan University of Chinese Medicine, Changsha, 410208, PR China
| | - Songwei Yang
- College of Pharmacy, Hunan University of Chinese Medicine, Changsha, 410208, PR China
| | - Xin Zhou
- Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, PR China
| | - Yani Zhang
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, PR China; Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou, 510405, PR China
| | - Yaomei Hu
- College of Pharmacy, Hunan University of Chinese Medicine, Changsha, 410208, PR China
| | - Huiqin Wang
- College of Pharmacy, Hunan University of Chinese Medicine, Changsha, 410208, PR China
| | - Naihong Chen
- College of Pharmacy, Hunan University of Chinese Medicine, Changsha, 410208, PR China; Hunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction Pieces, Changsha, 410208, PR China; Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, PR China; Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, PR China; Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou, 510405, PR China.
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Kim JH, Oh JM, Chun S, Park HY, Im WT. Enzymatic Biotransformation of Ginsenoside Rb 2 into Rd by Recombinant α-L-Arabinopyranosidase from Blastococcus saxobsidens. J Microbiol Biotechnol 2020; 30:391-397. [PMID: 31893597 PMCID: PMC9728169 DOI: 10.4014/jmb.1910.10065] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
In this study, we used a novel α-L-arabinopyranosidase (AbpBs) obtained from ginsenoside-converting Blastococcus saxobsidens that was cloned and expressed in Escherichia coli BL21 (DE3), and then applied it in the biotransformation of ginsenoside Rb2 into Rd. The gene, termed AbpBs, consisting of 2,406 nucleotides (801 amino acid residues), and with a predicted translated protein molecular mass of 86.4 kDa, was cloned into a pGEX4T-1 vector. A BLAST search using the AbpBs amino acid sequence revealed significant homology with a family 2 glycoside hydrolase (GH2). The over-expressed recombinant AbpBs in Escherichia coli BL21 (DE3) catalyzed the hydrolysis of the arabinopyranose moiety attached to the C-20 position of ginsenoside Rb2 under optimal conditions (pH 7.0 and 40°;C). Kinetic parameters for α-Larabinopyranosidase showed apparent Km and Vmax values of 0.078 ± 0.0002 micrometer and 1.4 ± 0.1 μmol/min/mg of protein against p-nitrophenyl-α-L-arabinopyranoside. Using a purified AbpBs (1 μg/ml), 0.1% of ginsenoside Rb2 was completely converted to ginsenoside Rd within 1 h. The recombinant AbpBs could be useful for high-yield, rapid, and low-cost preparation of ginsenoside Rd from Rb2.
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Affiliation(s)
- Ju-Hyeon Kim
- Department of Biotechnology, Hankyong National University, Anseong 7579, Republic of Korea,HK Ginseng Research Center, Hankyong National University, Anseong 17579, Republic of Korea
| | - Jung-Mi Oh
- Department of Physiology, Chonbuk National University Medical School, Jeonju 54907, Korea
| | - Sungkun Chun
- Department of Physiology, Chonbuk National University Medical School, Jeonju 54907, Korea
| | - Hye Yoon Park
- National Institute of Biological Resources, Incheon 22689, Republic of Korea
| | - Wan Taek Im
- Department of Biotechnology, Hankyong National University, Anseong 7579, Republic of Korea,HK Ginseng Research Center, Hankyong National University, Anseong 17579, Republic of Korea,AceEMzyme Co., Ltd., Anseong 1779, Republic of Korea,Corresponding author Phone: +82-31-6705335 Fax: +82-31-6705339 E-mail:
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Siddiqi MZ, Srinivasan S, Park HY, Im WT. Exploration and Characterization of Novel Glycoside Hydrolases from the Whole Genome of Lactobacillus ginsenosidimutans and Enriched Production of Minor Ginsenoside Rg3( S) by a Recombinant Enzymatic Process. Biomolecules 2020; 10:biom10020288. [PMID: 32059542 PMCID: PMC7072194 DOI: 10.3390/biom10020288] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2019] [Revised: 01/29/2020] [Accepted: 02/07/2020] [Indexed: 12/16/2022] Open
Abstract
Background: Several studies have reported that ginsenoside Rg3(S) is effective in treating metastatic diseases, obesity, and various cancers, however, its presence in white ginseng cannot be estimated, and only a limited amount is present in red ginseng. Therefore, the use of recombinant glycosidases from a Generally Recognized As Safe (GRAS) host strain is a promising approach to enhance production of Rg3(S), which may improve nutritional activity, human health, and quality of life. Method: Lactobacillus ginsenosidimutans EMML 3041T, which was isolated from Korean fermented pickle (kimchi), presents ginsenoside-converting abilities. The strain was used to enrich the production of Rg3(S) by fermenting protopanaxadiol (PPD)-mix-type major ginsenosides (Rb1, Rb2, Rc, and Rd) in four different types of food-grade media (1, MRS; 2, Basel Food-Grade medium; 3, Basel Food-Grade medium-I, and 4, Basel Food-Grade medium-II). Due to its tendency to produce Rg3(S), the presence of glycoside hydrolase in Lactobacillus ginsenosidimutans was proposed, the whole genome was sequenced, and the probable glycoside hydrolase gene for ginsenoside conversion was cloned. Results: The L. ginsenosidimutans EMML 3041T strain was whole genome sequenced to identify the target genes. After genome sequencing, 12 sets of glycoside hydrolases were identified, of which seven sets (α,β-glucosidase and α,β-galactosidase) were cloned in Escherichia coli BL21 (DE3) using the pGEX4T-1 vector system. Among the sets of clones, only one clone (BglL.gin-952) showed ginsenoside-transforming abilities. The recombinant BglL.gin-952 comprised 952 amino acid residues and belonged to glycoside hydrolase family 3. The enzyme exhibited optimal activity at 55 °C and a pH of 7.5 and showed a promising conversion ability of major ginsenoside Rb1→Rd→Rg3(S). The recombinant enzyme (GST-BglL.gin-952) was used to mass produce Rg3(S) from major ginsenoside Rb1. Scale-up of production using 50 g of Rb1 resulted in 30 g of Rg3(S) with 74.3% chromatography purity. Conclusion: Our preliminary data demonstrated that this enzyme would be beneficial in the preparation of pharmacologically active minor ginsenoside Rg3(S) in the functional food and pharmaceutical industries.
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Affiliation(s)
- Muhammad Zubair Siddiqi
- Department of Biotechnology, Hankyong National University, 327 Jungang-ro Anseong-si, Gyeonggi-do 17579, Korea;
- AceEMzyme Co., Ltd., Academic Industry Cooperation, 327 Jungang-ro Anseong-si, Gyeonggi-do Anseong-si, Gyeonggi-do 17579, Korea
| | - Sathiyaraj Srinivasan
- Department of Bio & Environmental Technology, Division of Environmental & Life Science, College of Natural Science, Seoul Women’s University, 623 Hwarangno, Nowon-gu, Seoul 139-774, Korea;
| | - Hye Yoon Park
- National Institute of Biological Resources, Incheon 22689, Korea;
| | - Wan-Taek Im
- Department of Biotechnology, Hankyong National University, 327 Jungang-ro Anseong-si, Gyeonggi-do 17579, Korea;
- AceEMzyme Co., Ltd., Academic Industry Cooperation, 327 Jungang-ro Anseong-si, Gyeonggi-do Anseong-si, Gyeonggi-do 17579, Korea
- Correspondence: ; Tel.: +82-31-6705335; Fax: +82-31-6705339
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A 26-week 20(S)-ginsenoside Rg3 oral toxicity study in Beagle dogs. Regul Toxicol Pharmacol 2020; 110:104522. [DOI: 10.1016/j.yrtph.2019.104522] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Revised: 11/06/2019] [Accepted: 11/08/2019] [Indexed: 11/17/2022]
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Chen H, Yang H, Fan D, Deng J. The Anticancer Activity and Mechanisms of Ginsenosides: An Updated Review. EFOOD 2020. [DOI: 10.2991/efood.k.200512.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
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Zhang J, Li W, Yuan Q, Zhou J, Zhang J, Cao Y, Fu G, Hu W. Transcriptome Analyses of the Anti-Proliferative Effects of 20(S)-Ginsenoside Rh2 on HepG2 Cells. Front Pharmacol 2019; 10:1331. [PMID: 31780945 PMCID: PMC6855211 DOI: 10.3389/fphar.2019.01331] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2019] [Accepted: 10/18/2019] [Indexed: 12/21/2022] Open
Abstract
20(S)-ginsenoside Rh2 (Rh2), a well-known protopanaxadiol-type ginsenoside from Panax ginseng has especially gained attention for its anticancer activities on various types of human cancer cells. However, the molecular mechanism through which Rh2 promotes apoptosis in hepatocellular carcinoma (HePG2) cells is not known at the transcriptome level. Rh2 can specifically inhibit the proliferation of HePG2 in a dose- and time-dependent manner. Moreover, Rh2 can significantly increase the apoptosis which was related with an increase in protein expression levels of caspase-3, caspase-6, and poly (ADP-ribose) polymerase. Comparison of RNA-seq transcriptome profiles from control group and Rh2-treated group yielded a list of 2116 genes whose expression was significantly affected, which includes 971 up-regulated genes and 1145 down-regulated genes. The differentially expressed genes in p53 signaling pathway and DNA replication may have closely relationships to the cells apoptosis caused by Rh2 treatment. The results of qPCR validation showed that dynamic changes in mRNA, such as CDKN1A, CCND2, PMAIP1, GTSE1, and TP73.
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Affiliation(s)
- Ji Zhang
- Jiangsu Collaborative Innovation Center of Regional Modern Agriculture & Environmental Protection/Jiangsu Key Laboratory for Eco-Agricultural Biotechnology around Hongze Lake, School of Life Sciences, Huaiyin Normal University, Huaian, China
| | - Weibo Li
- Jiangsu Collaborative Innovation Center of Regional Modern Agriculture & Environmental Protection/Jiangsu Key Laboratory for Eco-Agricultural Biotechnology around Hongze Lake, School of Life Sciences, Huaiyin Normal University, Huaian, China
| | - Qiaoyun Yuan
- Jiangsu Collaborative Innovation Center of Regional Modern Agriculture & Environmental Protection/Jiangsu Key Laboratory for Eco-Agricultural Biotechnology around Hongze Lake, School of Life Sciences, Huaiyin Normal University, Huaian, China
| | - Jing Zhou
- Jiangsu Collaborative Innovation Center of Regional Modern Agriculture & Environmental Protection/Jiangsu Key Laboratory for Eco-Agricultural Biotechnology around Hongze Lake, School of Life Sciences, Huaiyin Normal University, Huaian, China
| | - Jianmei Zhang
- Jiangsu Collaborative Innovation Center of Regional Modern Agriculture & Environmental Protection/Jiangsu Key Laboratory for Eco-Agricultural Biotechnology around Hongze Lake, School of Life Sciences, Huaiyin Normal University, Huaian, China
| | - Yufeng Cao
- Jiangsu Collaborative Innovation Center of Regional Modern Agriculture & Environmental Protection/Jiangsu Key Laboratory for Eco-Agricultural Biotechnology around Hongze Lake, School of Life Sciences, Huaiyin Normal University, Huaian, China
| | - Guangbo Fu
- Department of Urology, The Affiliated Huaian No. 1 People's Hospital of Nanjing Medical University, Huaian, China
| | - Weicheng Hu
- Jiangsu Collaborative Innovation Center of Regional Modern Agriculture & Environmental Protection/Jiangsu Key Laboratory for Eco-Agricultural Biotechnology around Hongze Lake, School of Life Sciences, Huaiyin Normal University, Huaian, China
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Shi X, Xu J, Lu C, Wang Z, Xiao W, Zhao L. Immobilization of high temperature-resistant GH3 β-glucosidase on a magnetic particle Fe3O4-SiO2-NH2-Cellu-ZIF8/zeolitic imidazolate framework. Enzyme Microb Technol 2019; 129:109347. [DOI: 10.1016/j.enzmictec.2019.05.004] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Revised: 05/08/2019] [Accepted: 05/13/2019] [Indexed: 02/06/2023]
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Song YN, Hong HG, Son JS, Kwon YO, Lee HH, Kim HJ, Park JH, Son MJ, Oh JG, Yoon MH. Investigation of Ginsenosides and Antioxidant Activities in the Roots, Leaves, and Stems of Hydroponic-Cultured Ginseng ( Panax ginseng Meyer). Prev Nutr Food Sci 2019; 24:283-292. [PMID: 31608253 PMCID: PMC6779092 DOI: 10.3746/pnf.2019.24.3.283] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Accepted: 08/20/2019] [Indexed: 11/06/2022] Open
Abstract
There has been very little reported on ginsenoside composition and antioxidant activity of hydroponic-cultured ginseng roots (HCR), leaves (HCL), and stems (HCS). We profiled 6 ginsenoside compounds in HCR, HCL, and HCS using high-performance liquid chromatography. Antioxidative activity of HCR, HCL, and HCS were evaluated using total phenolic content (TPC) and total flavonoid content (TFC), 2,2-diphenyl-1-picrylhydrazyl (DPPH) free-radical-scavenging activity assays, and ferric reducing antioxidant power (FRAP) assays. Total ginsenoside contents of HCL and HCS were significantly higher than that of HCR (P<0.05). Rb1 was detected in HCR (23.02 mg/g) but was detected at very low levels in HCL and HCS (2.07~7.30 mg/g). Rg1 was the most abundant ingredient in HCL, followed by Rd; this was different than for HCR and HCS. The TPC and TFC ranged from 52.82~155.31 mg gallic acid equivalent/100 g and 194.71~256.52 mg quercetin equivalent/100 g, respectively, of which HCL contained the highest levels. Moreover, HCL was the most effective in both DPPH and FRAP activities. In this study, we also evaluated the inhibitory effect of HCR, HCL, and HCS on the activities of mushroom tyrosinase through whitening activity test. The inhibitory effect of HCL on tyrosinase activity was higher than that of HCR and HCS. This study provides information about ginsenoside contents and the antioxidative activity of hydroponic-cultured ginseng, and suggests that the whole ginseng plant (including roots, leaves, and stems) may be a beneficial functional vegetables.
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Affiliation(s)
- Yu-Na Song
- Food Analysis Team in North Branch, Gyeonggi-do Institute of Health & Environment, Gyeonggi 11780, Korea
| | - Hae-Geun Hong
- Food Analysis Team in North Branch, Gyeonggi-do Institute of Health & Environment, Gyeonggi 11780, Korea
| | - Jong Seong Son
- Food Analysis Team in North Branch, Gyeonggi-do Institute of Health & Environment, Gyeonggi 11780, Korea
| | - Yeon Ok Kwon
- Food Analysis Team in North Branch, Gyeonggi-do Institute of Health & Environment, Gyeonggi 11780, Korea
| | - Hyun Ho Lee
- Food Analysis Team in North Branch, Gyeonggi-do Institute of Health & Environment, Gyeonggi 11780, Korea
| | - Hyeon Ji Kim
- Food Analysis Team in North Branch, Gyeonggi-do Institute of Health & Environment, Gyeonggi 11780, Korea
| | - Jeong Hwa Park
- Food Analysis Team in North Branch, Gyeonggi-do Institute of Health & Environment, Gyeonggi 11780, Korea
| | - Myeong Jin Son
- Food Analysis Team in North Branch, Gyeonggi-do Institute of Health & Environment, Gyeonggi 11780, Korea
| | - Jo-Gyo Oh
- Food Analysis Team in North Branch, Gyeonggi-do Institute of Health & Environment, Gyeonggi 11780, Korea
| | - Mi-Hye Yoon
- Food Analysis Team in North Branch, Gyeonggi-do Institute of Health & Environment, Gyeonggi 11780, Korea
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Mechesso AF, Quah Y, Park SC. Ginsenoside Rg3 reduces the adhesion, invasion, and intracellular survival of Salmonella enterica serovar Typhimurium. J Ginseng Res 2019; 45:75-85. [PMID: 33437159 PMCID: PMC7790883 DOI: 10.1016/j.jgr.2019.09.002] [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: 06/10/2019] [Revised: 09/08/2019] [Accepted: 09/17/2019] [Indexed: 11/28/2022] Open
Abstract
Background Invasive infections due to foodborne pathogens, including Salmonella enterica serovar Typhimurium, are prevalent and life-threatening. This study aimed to evaluate the effects of ginsenoside Rg3 (Rg3) on the adhesion, invasion, and intracellular survival of S. Typhimurium. Methods The impacts of Rg3 on bacterial growth and host cell viability were determined using the time kill and the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assays, respectively. Gentamicin assay and confocal microscopic examination were undertaken to determine the effects of Rg3 on the adhesive and invasive abilities of S. Typhimurium to Caco-2 and RAW 264.7 cells. Quantitative reverse transcription polymerase chain reaction was performed to assess the expression of genes correlated with the adhesion, invasion, and virulence of S. Typhimurium. Results Subinhibitory concentrations of Rg3 significantly reduced (p < 0.05) the adhesion, invasion, and intracellular survival of S. Typhimurium. Rg3 considerably reduced (p < 0.05) the bacterial motility as well as the release of nitrite from infected macrophages in a concentration-dependent manner. The expression of genes related to the adhesion, invasion, quorum sensing, and virulence of S. Typhimurium including cheY, hilA, OmpD, PrgK, rsgE, SdiA, and SipB was significantly reduced after Rg3 treatment. Besides, the compound downregulated rac-1 and Cdc-42 that are essential for actin remodeling and membrane ruffling, thereby facilitating Salmonella entry into host cells. This report is the first to describe the effects of Rg3 on "trigger" entry mechanism and intracellular survival S. Typhimurium. Conclusion Rg3 could be considered as a supplement agent to prevent S. Typhimurium infection.
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Affiliation(s)
- Abraham F Mechesso
- Laboratory of Veterinary Pharmacokinetics and Pharmacodynamics, College of Veterinary Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Yixian Quah
- Laboratory of Veterinary Pharmacokinetics and Pharmacodynamics, College of Veterinary Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Seung-Chun Park
- Laboratory of Veterinary Pharmacokinetics and Pharmacodynamics, College of Veterinary Medicine, Kyungpook National University, Daegu, Republic of Korea
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Lv L, Lu J, Zhang H, Wang X, Su G, Piao H, Zhao Y. Acylation of 25-hydroxyprotopanaxatriol with aromatic acids increases cytotoxicity. Fitoterapia 2019; 137:104279. [DOI: 10.1016/j.fitote.2019.104279] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Revised: 07/26/2019] [Accepted: 07/26/2019] [Indexed: 01/27/2023]
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Yan H, Jin H, Fu Y, Yin Z, Yin C. Production of Rare Ginsenosides Rg3 and Rh2 by Endophytic Bacteria from Panax ginseng. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2019; 67:8493-8499. [PMID: 31310523 DOI: 10.1021/acs.jafc.9b03159] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/20/2023]
Abstract
The ginsenosides Rh2 and Rg3 induce tumor cell apoptosis, inhibit tumor cell proliferation, and restrain tumor invasion and metastasis. Despite Rh2 and Rg3 having versatile pharmacological activities, contents of them in natural ginseng are extremely low. To produce ginsenosides Rh2 and Rg3, the saponin-producing capacity of endophytic bacteria isolated from Panax ginseng was investigated. In this work, 81 endophytic bacteria isolates were taken from ginseng roots by tissue separation methods. Among them, strain PDA-2 showed the highest capacity to produce the rare ginsenosides; the concentrations of rare ginsenosides Rg3 and Rh2 reached 62.20 and 18.60 mg/L, respectively. On the basis of phylogenetic analysis, it was found that strain PDA-2 belongs to the genus Agrobacterium and was very close to Agrobacterium rhizogenes.
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Affiliation(s)
- Huayu Yan
- Department of Chemistry , Yanbian University , Yanji , Jilin 133002 , People's Republic of China
| | - Huding Jin
- Graduate School of Convergence Science and Technology , Seoul National University , Seoul 151-742 , South Korea
| | - Yu Fu
- Department of Chemistry , Yanbian University , Yanji , Jilin 133002 , People's Republic of China
- College of Chemistry and Life Science , Anshan Normal University , Anshan , Liaoning 114007 , People's Republic of China
| | - Zhenxing Yin
- Department of Chemistry , Yanbian University , Yanji , Jilin 133002 , People's Republic of China
| | - Chengri Yin
- Department of Chemistry , Yanbian University , Yanji , Jilin 133002 , People's Republic of China
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Metwaly AM, Lianlian Z, Luqi H, Deqiang D. Black Ginseng and Its Saponins: Preparation, Phytochemistry and Pharmacological Effects. Molecules 2019; 24:E1856. [PMID: 31091790 PMCID: PMC6572638 DOI: 10.3390/molecules24101856] [Citation(s) in RCA: 81] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2019] [Revised: 05/12/2019] [Accepted: 05/13/2019] [Indexed: 01/19/2023] Open
Abstract
Black ginseng is a type of processed ginseng that is prepared from white or red ginseng by steaming and drying several times. This process causes extensive changes in types and amounts of secondary metabolites. The chief secondary metabolites in ginseng are ginsenosides (dammarane-type triterpene saponins), which transform into less polar ginsenosides in black ginseng by steaming. In addition, apparent changes happen to other secondary metabolites such as the increase in the contents of phenolic compounds, reducing sugars and acidic polysaccharides in addition to the decrease in concentrations of free amino acids and total polysaccharides. Furthermore, the presence of some Maillard reaction products like maltol was also engaged. These obvious chemical changes were associated with a noticeable superiority for black ginseng over white and red ginseng in most of the comparative biological studies. This review article is an attempt to illustrate different methods of preparation of black ginseng, major chemical changes of saponins and other constituents after steaming as well as the reported biological activities of black ginseng, its major saponins and other metabolites.
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Affiliation(s)
- Ahmed M Metwaly
- Liaoning University of Traditional Chinese Medicine, 77 Life one Road, DD port, Dalian Economic and Technical Development Zone, Dalian 116600, China.
- Department of Pharmacognosy, Faculty of Pharmacy, Al-Azhar University, Cairo 11884, Egypt.
| | - Zhu Lianlian
- Liaoning University of Traditional Chinese Medicine, 77 Life one Road, DD port, Dalian Economic and Technical Development Zone, Dalian 116600, China.
| | - Huang Luqi
- National Resource Center for Chinese Materia Medica, China Academy of Chinese Medical Sciences, 16 Mennei South street, Dong-Cheng District, Beijing 100700, China.
| | - Dou Deqiang
- Liaoning University of Traditional Chinese Medicine, 77 Life one Road, DD port, Dalian Economic and Technical Development Zone, Dalian 116600, China.
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Zhang S, Xie J, Zhao L, Pei J, Su E, Xiao W, Wang Z. Cloning, overexpression and characterization of a thermostable β-xylosidase from Thermotoga petrophila and cooperated transformation of ginsenoside extract to ginsenoside 20(S)-Rg3 with a β-glucosidase. Bioorg Chem 2019; 85:159-167. [DOI: 10.1016/j.bioorg.2018.12.026] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Revised: 12/17/2018] [Accepted: 12/19/2018] [Indexed: 11/26/2022]
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Hou JG, Jeon BM, Yun YJ, Cui CH, Kim SC. Ginsenoside Rh2 Ameliorates Doxorubicin-Induced Senescence Bystander Effect in Breast Carcinoma Cell MDA-MB-231 and Normal Epithelial Cell MCF-10A. Int J Mol Sci 2019; 20:ijms20051244. [PMID: 30871042 PMCID: PMC6429443 DOI: 10.3390/ijms20051244] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Revised: 03/07/2019] [Accepted: 03/09/2019] [Indexed: 12/12/2022] Open
Abstract
The anthracycline antibiotic doxorubicin is commonly used antineoplastic drug in breast cancer treatment. Like most chemotherapy, doxorubicin does not selectively target tumorigenic cells with high proliferation rate and often causes serve side effects. In the present study, we demonstrated the cellular senescence and senescence associated secretory phenotype (SASP) of both breast tumor cell MDA-MB-231 and normal epithelial cell MCF-10A induced by clinical dose of doxorubicin (100 nM). Senescence was confirmed by flattened morphology, increased level of beta galactose, accumulating contents of lysosome and mitochondrial, and elevated expression of p16 and p21 proteins. Similarly, SASP was identified by highly secreted proteins IL-6, IL-8, GRO, GM-CSF, MCP-1, and MMP1 by antibody array assay. Reciprocal experiments, determined by cell proliferation and apoptosis assays and cell migration and cell invasion, indicated that SASP of MDA-MB-231 cell induces growth arrest of MCF-10A, whereas SASP of MCF-10A significantly stimulates the proliferation of MDA-MB-231. Interestingly, SASP from both cells powerfully promotes the cell migration and cell invasion of MDA-MB-231 cells. Treatment with the natural product ginsenoside Rh2 does not prevent cellular senescence or exert senolytic. However, SASP from senescent cells treated with Rh2 greatly attenuated the above-mentioned bystander effect. Altogether, Rh2 is a potential candidate to ameliorate this unwanted chemotherapy-induced senescence bystander effect.
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Affiliation(s)
- Jin-Gang Hou
- Intelligent Synthetic Biology Center, Daejeon 34141, Korea.
| | - Byeong-Min Jeon
- Department of Biological Sciences, KAIST, Daejeon 34141, Korea.
| | - Yee-Jin Yun
- Department of Biological Sciences, KAIST, Daejeon 34141, Korea.
| | - Chang-Hao Cui
- Intelligent Synthetic Biology Center, Daejeon 34141, Korea.
| | - Sun-Chang Kim
- Intelligent Synthetic Biology Center, Daejeon 34141, Korea.
- Department of Biological Sciences, KAIST, Daejeon 34141, Korea.
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Ginsenoside Rg3: Potential Molecular Targets and Therapeutic Indication in Metastatic Breast Cancer. MEDICINES 2019; 6:medicines6010017. [PMID: 30678106 PMCID: PMC6473622 DOI: 10.3390/medicines6010017] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Revised: 01/21/2019] [Accepted: 01/23/2019] [Indexed: 01/28/2023]
Abstract
Breast cancer is still one of the most prevalent cancers and a leading cause of cancer death worldwide. The key challenge with cancer treatment is the choice of the best therapeutic agents with the least possible toxicities on the patient. Recently, attention has been drawn to herbal compounds, in particular ginsenosides, extracted from the root of the Ginseng plant. In various studies, significant anti-cancer properties of ginsenosides have been reported in different cancers. The mode of action of ginsenoside Rg3 (Rg3) in in vitro and in vivo breast cancer models and its value as an anti-cancer treatment for breast cancer will be reviewed.
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40
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Wang P, Wei W, Ye W, Li X, Zhao W, Yang C, Li C, Yan X, Zhou Z. Synthesizing ginsenoside Rh2 in Saccharomyces cerevisiae cell factory at high-efficiency. Cell Discov 2019; 5:5. [PMID: 30652026 PMCID: PMC6331602 DOI: 10.1038/s41421-018-0075-5] [Citation(s) in RCA: 112] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2018] [Revised: 10/19/2018] [Accepted: 11/02/2018] [Indexed: 12/13/2022] Open
Abstract
Synthetic biology approach has been frequently applied to produce plant rare bioactive compounds in microbial cell factories by fermentation. However, to reach an ideal manufactural efficiency, it is necessary to optimize the microbial cell factories systemically by boosting sufficient carbon flux to the precursor synthesis and tuning the expression level and efficiency of key bioparts related to the synthetic pathway. We previously developed a yeast cell factory to produce ginsenoside Rh2 from glucose. However, the ginsenoside Rh2 yield was too low for commercialization due to the low supply of the ginsenoside aglycone protopanaxadiol (PPD) and poor performance of the key UDP-glycosyltransferase (UGT) (biopart UGTPg45) in the final step of the biosynthetic pathway. In the present study, we constructed a PPD-producing chassis via modular engineering of the mevalonic acid pathway and optimization of P450 expression levels. The new yeast chassis could produce 529.0 mg/L of PPD in shake flasks and 11.02 g/L in 10 L fed-batch fermentation. Based on this high PPD-producing chassis, we established a series of cell factories to produce ginsenoside Rh2, which we optimized by improving the C3–OH glycosylation efficiency. We increased the copy number of UGTPg45, and engineered its promoter to increase expression levels. In addition, we screened for more efficient and compatible UGT bioparts from other plant species and mutants originating from the direct evolution of UGTPg45. Combining all engineered strategies, we built a yeast cell factory with the greatest ginsenoside Rh2 production reported to date, 179.3 mg/L in shake flasks and 2.25 g/L in 10 L fed-batch fermentation. The results set up a successful example for improving yeast cell factories to produce plant rare natural products, especially the glycosylated ones.
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Affiliation(s)
- Pingping Wang
- 1CAS-Key Laboratory of Synthetic Biology, CAS Center for Excellence in Molecular Plant Sciences, Institute of Plant Physiology and Ecology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 300 Fenglin Rd, Shanghai, 200032 China
| | - Wei Wei
- 1CAS-Key Laboratory of Synthetic Biology, CAS Center for Excellence in Molecular Plant Sciences, Institute of Plant Physiology and Ecology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 300 Fenglin Rd, Shanghai, 200032 China
| | - Wei Ye
- 2University of Chinese Academy of Sciences, Beijing, 100049 China.,Bio-Med Big Data Center, CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, Shanghai, 200031 China
| | - Xiaodong Li
- 1CAS-Key Laboratory of Synthetic Biology, CAS Center for Excellence in Molecular Plant Sciences, Institute of Plant Physiology and Ecology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 300 Fenglin Rd, Shanghai, 200032 China.,2University of Chinese Academy of Sciences, Beijing, 100049 China
| | - Wenfang Zhao
- 1CAS-Key Laboratory of Synthetic Biology, CAS Center for Excellence in Molecular Plant Sciences, Institute of Plant Physiology and Ecology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 300 Fenglin Rd, Shanghai, 200032 China
| | - Chengshuai Yang
- 1CAS-Key Laboratory of Synthetic Biology, CAS Center for Excellence in Molecular Plant Sciences, Institute of Plant Physiology and Ecology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 300 Fenglin Rd, Shanghai, 200032 China.,2University of Chinese Academy of Sciences, Beijing, 100049 China
| | - Chaojing Li
- 1CAS-Key Laboratory of Synthetic Biology, CAS Center for Excellence in Molecular Plant Sciences, Institute of Plant Physiology and Ecology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 300 Fenglin Rd, Shanghai, 200032 China.,2University of Chinese Academy of Sciences, Beijing, 100049 China
| | - Xing Yan
- 1CAS-Key Laboratory of Synthetic Biology, CAS Center for Excellence in Molecular Plant Sciences, Institute of Plant Physiology and Ecology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 300 Fenglin Rd, Shanghai, 200032 China
| | - Zhihua Zhou
- 1CAS-Key Laboratory of Synthetic Biology, CAS Center for Excellence in Molecular Plant Sciences, Institute of Plant Physiology and Ecology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 300 Fenglin Rd, Shanghai, 200032 China
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Fu Y. Biotransformation of ginsenoside Rb1 to Gyp-XVII and minor ginsenoside Rg3 by endophytic bacterium Flavobacterium
sp. GE 32 isolated from Panax ginseng. Lett Appl Microbiol 2019; 68:134-141. [DOI: 10.1111/lam.13090] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2018] [Revised: 10/11/2018] [Accepted: 10/12/2018] [Indexed: 12/26/2022]
Affiliation(s)
- Y. Fu
- College of Chemistry and Life Science; Anshan Normal University; Anshan China
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Ren G, Shi Z, Teng C, Yao Y. Antiproliferative Activity of Combined Biochanin A and Ginsenoside Rh₂ on MDA-MB-231 and MCF-7 Human Breast Cancer Cells. Molecules 2018; 23:molecules23112908. [PMID: 30413008 PMCID: PMC6278524 DOI: 10.3390/molecules23112908] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2018] [Revised: 10/25/2018] [Accepted: 11/03/2018] [Indexed: 12/01/2022] Open
Abstract
Breast cancer is the most frequently diagnosed cancer in women worldwide. The antiproliferative activities of biochanin A (BA) and ginsenoside Rh2 were determined by evaluating their inhibitory effect on MDA-MB-231 human breast cancer cell proliferation. The combination of BA with Rh2 was also assessed. In MDA cells, combination treatment led to a decrease in the EC50 values of BA and Rh2 to 25.20 μM and 22.75 μM, respectively. In MCF-7 cells, the EC50 values of combined BA and Rh2 decreased to 27.68 μM and 25.41 μM, respectively. BA combined with Rh2 also improved the inhibition of MDA-MB-231 and MCF-7 cell migration and invasion compared to the individual compounds. Western blot analysis demonstrated upregulation in p-p53, p-p38, and p-ASK1 proteins while levels of TRAF2 were downregulated. These results suggest that BA combined with Rh2 exhibits synergistic effects against MDA-MB-231 and MCF-7 cell proliferation.
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Affiliation(s)
- Guixing Ren
- College of Pharmacy and Biological Engineering, Chengdu University, No.1 Shilling Road, Chenglo Avenue, Longquan District, Chengdu 610106, China.
| | - Zhenxing Shi
- Laboratory of Biomass and Green Technologies, University of Liege-Gembloux Agro-Bio Tech, Passage des Déportés 2, B-5030 Gembloux, Belgium.
| | - Cong Teng
- Institute of Crop Science, Chinese Academy of Agricultural Sciences, No.80 South Xueyuan Road, Haidian District, Beijing 100081, China.
| | - Yang Yao
- Institute of Crop Science, Chinese Academy of Agricultural Sciences, No.80 South Xueyuan Road, Haidian District, Beijing 100081, China.
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43
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Li C, Wang Z, Li G, Wang Z, Yang J, Li Y, Wang H, Jin H, Qiao J, Wang H, Tian J, Lee AW, Gao Y. Acute and repeated dose 26-week oral toxicity study of 20(S)-ginsenoside Rg3 in Kunming mice and Sprague-Dawley rats. J Ginseng Res 2018; 44:222-228. [PMID: 32148403 PMCID: PMC7031733 DOI: 10.1016/j.jgr.2018.10.001] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2018] [Revised: 10/10/2018] [Accepted: 10/11/2018] [Indexed: 12/14/2022] Open
Abstract
Background 20(S)-ginsenoside-Rg3 (C42H72O13), a natural triterpenoid saponin, is extracted from red ginseng. The increasing use of 20(S)-ginsenoside Rg3 has raised product safety concerns. Methods In acute toxicity, 20(S)-ginsenoside Rg3 was singly and orally administrated to Kunming mice and Sprague–Dawley (SD) rats at the maximum doses of 1600 mg/kg and 800 mg/kg, respectively. In the 26-week toxicity study, we used repeated oral administration of 20(S)-ginsenoside Rg3 in SD rats over 26 weeks at doses of 0, 20, 60, or 180 mg/kg. Moreover, a 4-week recovery period was scheduled to observe the persistence, delayed occurrence, and reversibility of toxic effects. Results The result of acute toxicity shows that oral administration of 20(S)-ginsenoside Rg3 to mice and rats did not induce mortality or toxicity up to 1600 and 800 mg/kg, respectively. During a 26-week administration period and a 4-week withdrawal period (recovery period), there were no significant differences in clinical signs, body weight, food consumption, urinalysis parameters, biochemical and hematological values, or histopathological findings. Conclusion The mean oral lethal dose (LD50) of 20(S)-ginsenoside Rg3, in acute toxicity, is above 1600 mg/kg and 800 mg/kg in mice and rats, respectively. In a repeated-dose 26-week oral toxicity study, the no-observed-adverse-effect level for female and male SD rats was 180 mg/kg.
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Affiliation(s)
- Chunmei Li
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, China
| | - Zhezhe Wang
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, China
| | - Guisheng Li
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, China
| | - Zhenhua Wang
- School of Life Science, Center for Mitochondria and Healthy Aging, Yantai University, Yantai, China
| | - Jianrong Yang
- School of Life Science, Center for Mitochondria and Healthy Aging, Yantai University, Yantai, China
| | - Yanshen Li
- School of Life Science, Center for Mitochondria and Healthy Aging, Yantai University, Yantai, China
| | - Hongtao Wang
- School of Life Science, Center for Mitochondria and Healthy Aging, Yantai University, Yantai, China
| | - Haizhu Jin
- Department of Food and Biological Engineering, Wenjing College of Yantai University, Yantai, China
| | - Junhua Qiao
- Yantai University Hospital, Yantai University, Yantai, China
| | - Hongbo Wang
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, China
| | - Jingwei Tian
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, China
| | | | - Yonglin Gao
- School of Life Science, Center for Mitochondria and Healthy Aging, Yantai University, Yantai, China
- Corresponding author. School of Life Science, Yantai University, 30, Qingquan RD, Laishan District, Yantai, 264005, China.
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Shin KO, Choe SJ, Uchida Y, Kim I, Jeong Y, Park K. Ginsenoside Rb1 Enhances Keratinocyte Migration by a Sphingosine-1-Phosphate-Dependent Mechanism. J Med Food 2018; 21:1129-1136. [PMID: 30148701 DOI: 10.1089/jmf.2018.4246] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
The cutaneous wound healing process is tightly regulated by a range of cellular responses, including migration. Sphingosine-1-phosphate (S1P) is a signaling lipid produced in keratinocytes (KC) and it is known to stimulate skin wound repair through increased KC migration. Of the multifunctional triterpene ginsenosides, Rb1 enhances cutaneous wound healing process by increasing KC migration, but cellular mechanisms responsible for the Rb1-mediated increase in KC migration are largely unknown. Therefore, we hypothesized that, and assessed whether, Rb1 could stimulate KC migration through S1P-dependent mechanisms. Rb1 significantly increases S1P production by regulating the activity of metabolic conversion enzymes associated with S1P generation and degradation, sphingosine kinase 1 (SPHK1) and S1P lyase, respectively, in parallel with enhanced KC migration. However, blockade of ceramide to S1P metabolic conversion using a specific inhibitor of SPHK1 attenuated the expected Rb1-mediated increase in KC migration. Furthermore, a pan-S1P receptor inhibitor pertussis toxin significantly attenuated Rb1-induced stimulation of KC migration. Moreover, the Rb1-induced increases in KC migration required S1P receptor(s)-mediated activation of ERK1/2 and NF-κB, leading to production of key cutaneous migrating proteins, matrix metalloproteinase (MMP)-2 and MMP-9. Taken together, the results show that Rb1 stimulates KC migration through an S1P→S1P receptor(s)→ERK1/2→NF-κB→MMP-2/-9 pathway. This research revealed a previously unidentified cellular mechanism for Rb1 in enhancing KC migration and pointing to a new therapeutic approach to stimulate the cutaneous wound healing process.
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Affiliation(s)
- Kyong-Oh Shin
- 1 Department of Food Science and Nutrition, and Convergence Program of Material Science for Medicine and Pharmaceutics, Hallym University , Chuncheon, Korea
| | - Sung Jay Choe
- 2 Department of Dermatology, Yonsei University Wonju College of Medicine , Wonju, Korea
| | - Yoshikazu Uchida
- 3 Department of Dermatology, School of Medicine, University of California , San Francisco, San Francisco, California, USA
- 4 Northern California Institute for Research and Education , Veterans Affairs Medical Center, San Francisco, California, USA
| | - Inyong Kim
- 5 Research Center for Industrialization of Natural Nutraceuticals, Dankook University , Cheonan, Korea
| | - Yoonhwa Jeong
- 5 Research Center for Industrialization of Natural Nutraceuticals, Dankook University , Cheonan, Korea
- 6 Department of Food Science and Nutrition, Dankook University , Cheonan, Korea
| | - Kyungho Park
- 1 Department of Food Science and Nutrition, and Convergence Program of Material Science for Medicine and Pharmaceutics, Hallym University , Chuncheon, Korea
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Singh H, Du J, Singh P, Mavlonov GT, Yi TH. Development of superparamagnetic iron oxide nanoparticles via direct conjugation with ginsenosides and its in-vitro study. JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY B-BIOLOGY 2018; 185:100-110. [DOI: 10.1016/j.jphotobiol.2018.05.030] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/07/2018] [Revised: 05/03/2018] [Accepted: 05/29/2018] [Indexed: 12/21/2022]
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Chen T, Li B, Qiu Y, Qiu Z, Qu P. Functional mechanism of Ginsenosides on tumor growth and metastasis. Saudi J Biol Sci 2018; 25:917-922. [PMID: 30108441 PMCID: PMC6087812 DOI: 10.1016/j.sjbs.2018.01.012] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2018] [Accepted: 01/18/2018] [Indexed: 01/09/2023] Open
Abstract
Ginsengs, has long been used as one medicinal herb in China for more than two thousand years. Many studies have shown that ginsengs have preventive and therapeutic roles for cancer, and play a good complementary role in cancer treatment. Ginsenosides, as most important constituents of ginseng, have been extensively investigated and emphasized in cancer chemoprevention and therapeutics. However, the functional mechanism of Ginsenosides on cancer is not well known. This review will focus on introducing the functional mechanisms of ginsenosides and their metabolites, which regulate signaling pathways related with tumor growth and metastasis. Ginsenosides inhibit tumor growth via upregulating tumor apoptosis, inducing tumor cell differentiation and targeting cancer stem cells. In addition, Ginsenosides regulate tumor microenvironment via suppressing tumor angiogenesis-related proteins and pathways. Structural modification of ginsenosides and their administration alone or combinations with other Chinese medicines or chemical medicines have recently been developed to be a new therapeutic strategy for cancer.
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Affiliation(s)
- Tianli Chen
- Department of Pharmacy, Changchun University of Chinese Medicine, Changchun, Jilin, PR China
| | - Bowen Li
- Department of Pharmacy, Changchun University of Chinese Medicine, Changchun, Jilin, PR China
| | - Ye Qiu
- Department of Pharmacy, Changchun University of Chinese Medicine, Changchun, Jilin, PR China
| | - Zhidong Qiu
- Department of Pharmacy, Changchun University of Chinese Medicine, Changchun, Jilin, PR China
| | - Peng Qu
- National Cancer Institute, National Institutes of Health, Frederick, MD, USA
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47
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Duan Z, Deng J, Dong Y, Zhu C, Li W, Fan D. Anticancer effects of ginsenoside Rk3 on non-small cell lung cancer cells: in vitro and in vivo. Food Funct 2018; 8:3723-3736. [PMID: 28949353 DOI: 10.1039/c7fo00385d] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Ginsenoside Rk3 (Rk3) is present in the roots of processed Panax notoginseng herbs and it exerts anti-platelet aggregation, pro-immunogenic and cardioprotective effects. However, little is known regarding the anticancer activities of this compound, especially in lung cancer. This study was designed to investigate the anticancer effects of Rk3 on non-small cell lung cancer (NSCLC) cells and in an H460 xenograft tumor model. Our results showed that Rk3 reduced cell viability, inhibited both cell proliferation and colony formation, and induced G1 phase cell cycle arrest by downregulating the expression of cyclin D1 and CDK4 and upregulating the expression of P21. Rk3 also induced apoptosis in a concentration-dependent manner in H460 and A549 cells by Annexin V/PI staining, TUNEL assay and JC-1 staining, resulting in a change in the nuclear morphology. Moreover, Rk3 induced the activation of caspase-8, -9, and -3, promoted changes in mitochondrial membrane potential, decreased the expression of Bcl-2, increased the expression of Bax, and caused the release of cytochrome c, which indicated that the apoptosis-inducing effects of Rk3 were triggered via death receptor-mediated mitochondria-dependent pathways. Furthermore, Rk3 significantly inhibited the growth of H460 xenograft tumors without an obvious effect on the body weight of the treated mice. Histological analysis indicated that Rk3 inhibited tumor growth by altering the proliferation and morphology of tumor cells. In addition, we confirmed that Rk3 inhibited angiogenesis via CD34 staining and chick embryo chorioallantoic membrane (CAM) assay in vivo. Taken together, our findings revealed not only the anticancer effect of Rk3 on NSCLC cells but also a new promising therapeutic agent for human NSCLC.
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Affiliation(s)
- Zhiguang Duan
- Shaanxi Key Laboratory of Degradable Biomedical Materials, School of Chemical Engineering, Northwest University, 229 North Taibai Road, Xi'an, Shaanxi 710069, China.
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Leem DG, Shin JS, Kim KT, Choi SY, Lee MH, Lee KT. Dammarane-type triterpene ginsenoside-Rg18 inhibits human non-small cell lung cancer A549 cell proliferation via G 1 phase arrest. Oncol Lett 2018; 15:6043-6049. [PMID: 29556318 DOI: 10.3892/ol.2018.8057] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2016] [Accepted: 01/17/2018] [Indexed: 12/16/2022] Open
Abstract
A previous study reported that a novel dammarane-type triterpene saponin, ginsenoside-Rg18, derived from the root of Panax ginseng, displayed hydroxyl radical scavenging, anti-bacterial and cytotoxic activities. However, the underlying molecular mechanisms of its anti-proliferative effect on non-small cell lung cancer (NSCLC) A549 cells remains unclear. In the present study, it was determined that Rg18 inhibited the proliferation of A549 cells with a half-maximal inhibitory concentration of 150 µM. Flow cytometry analysis indicated that cell cycle progression was blocked by Rg18 at G1 phase in A549 cells, which was accompanied by downregulation of cyclin-dependent kinase 2 (CDK2), CDK4, CDK6, cyclin D1, cyclin D2, cyclin E and phosphorylated retinoblastoma protein expression at the protein level. In addition, the CDK inhibitors (CDKNs), CDKN1A and CDKN1B, were upregulated following Rg18 treatment. Furthermore, Rg18 treatment resulted in the intracellular accumulation of reactive oxygen species (ROS), and a dose-dependent inhibition of p38 mitogen activated protein kinase (p38), c-Jun N-terminal kinase (JNK) and nuclear factor-κB (NF-κB)/p65 phosphorylation. Taken together, Rg18-mediated G1 phase arrest was closely associated with the generation of intracellular ROS, and p38, JNK and NF-κB/p65 inhibition in A549 human NSCLC cells.
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Affiliation(s)
- Dong-Gyu Leem
- Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea.,Department of Life and Nanopharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Ji-Sun Shin
- Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Kyung-Tack Kim
- Traditional Food Research Center, Korea Food Research Institute, Seongnam 13539, Republic of Korea
| | - Sang Yoon Choi
- Traditional Food Research Center, Korea Food Research Institute, Seongnam 13539, Republic of Korea
| | - Myung-Hee Lee
- Traditional Food Research Center, Korea Food Research Institute, Seongnam 13539, Republic of Korea
| | - Kyung-Tae Lee
- Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea.,Department of Life and Nanopharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea
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Yuxian X, Feng T, Ren L, Zhengcai L. Tanshinone II-A Inhibits Invasion and Metastasis of Human Hepatocellular Carcinoma Cells in Vitro and in Vivo. TUMORI JOURNAL 2018; 95:789-95. [DOI: 10.1177/030089160909500623] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Aims and Background Tanshinone II-A is an alcohol extract of the root of the traditional Chinese medicinal plant Salvia miltiorrhiza Bunge, whose effects and mechanism in tumor metastasis are still unclear. The aim of this study was to investigate the effects of tanshinone II-A on tumor invasion and metastasis in human hepatocellular carcinoma (HCC) and its possible mechanism of action. Methods and Study Design The HCC cell lines HepG2 and SMMC-7721 were treated with tanshinone II-A at different doses. Invasion and metastasis of tumor cells were examined by in vitro and in vivo assays. The molecular mechanisms of tanshinone II-A for inhibiting invasion and metastasis of HCC cells were investigated by Western blot and gelatin zymography. Results Treatment with tanshinone II-A had inhibitory effects on the migration and invasion of HCC cells. Increasing doses resulted in enhanced inhibitory effects. At 0.5 mg/L, the inhibitory effect was noticeable. At 1 mg/L, the inhibitory rate was 53.15%. The inhibitory effect became stronger with time; among 24, 48, 72 and 96 hours of treatment, the most significant effects were observed at 72 hours. Tanshinone II-A also significantly inhibited in vivo metastasis of HepG2 cells. Tanshinone II-A inhibited in vitro and in vivo invasion and metastasis of HCC cells by reducing the expression of the metalloproteinases MMP2 and MMP9 and by blocking NF-kappa B activation. Conclusions Tanshinone II-A effectively inhibited invasion and metastasis of HCC cells in vitro and in vivo, partly by inhibiting the activity of MMP2 and MMP9, and partly via the NF-kappa B signal transduction pathway.
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Affiliation(s)
- Xu Yuxian
- Department of Epidemiology, Faculty of Preventive Medicine, Fourth Military Medical University, Xi'an
| | - Tian Feng
- Department of Urology, Chinese PLA 210th Hospital, Dalian, Liaoning Province
| | - Li Ren
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Liu Zhengcai
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China
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Lee DY, Kim HG, Lee YG, Kim JH, Lee JW, Choi BR, Jang IB, Kim GS, Baek NI. Isolation and Quantification of Ginsenoside Rh23, a New Anti-Melanogenic Compound from the Leaves of Panax ginseng. Molecules 2018; 23:molecules23020267. [PMID: 29382138 PMCID: PMC6017343 DOI: 10.3390/molecules23020267] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2017] [Revised: 01/23/2018] [Accepted: 01/26/2018] [Indexed: 11/22/2022] Open
Abstract
A new ginsenoside, named ginsenoside Rh23 (1), and 20-O-β-d-glucopyranosyl-3β,6α,12β,20β,25-pentahydroxydammar-23-ene (2) were isolated from the leaves of hydroponic Panax ginseng. Compounds were isolated by various column chromatography and their structures were determined based on spectroscopic methods, including high resolution quadrupole/time of flight mass spectrometry (HR-QTOF/MS), nuclear magnetic resonance (NMR) spectroscopy, and infrared (IR) spectroscopy. To determine anti-melanogenic activity, the change in the melanin content in melan-a cells treated with identified compounds was tested. Additionally, we investigated the melanin inhibitory effects of ginsenoside Rh23 on pigmentation in a zebrafish in vivo model. Compound 1 inhibited potent melanogenesis in melan-a cells with 37.0% melanogenesis inhibition at 80 µM and also presented inhibition on the body pigmentation in zebrafish model. Although compound 2 showed slightly lower inhibitory activity than compound 1, it also showed significantly decreased melanogenesis in melan-a cell and in zebrafish model. These results indicated that compounds isolated from hydroponic P. ginseng may be used as new skin whitening compound through the in vitro and in vivo systems. Furthermore, this study demonstrated the utility of MS-based compound 1 for the quantitative analysis. Ginsenoside Rh23 (1) was found at a level of 0.31 mg/g in leaves of hydroponic P. ginseng.
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Affiliation(s)
- Dae Young Lee
- Department of Herbal Crop Research, National Institute of Horticultural and Herbal Science, RDA, Eumseong 27709, Korea.
| | - Hyoung-Geun Kim
- Department of Oriental Medicine Biotechnology, Kyung Hee University, Yongin 17104, Korea.
| | - Yeong-Geun Lee
- Department of Oriental Medicine Biotechnology, Kyung Hee University, Yongin 17104, Korea.
| | - Jin Hee Kim
- College of Herbal Bio-industry, Daegu Haany University, Gyeongsan 38610, Korea.
| | - Jae Won Lee
- Department of Herbal Crop Research, National Institute of Horticultural and Herbal Science, RDA, Eumseong 27709, Korea.
| | - Bo-Ram Choi
- Department of Herbal Crop Research, National Institute of Horticultural and Herbal Science, RDA, Eumseong 27709, Korea.
| | - In-Bae Jang
- Department of Herbal Crop Research, National Institute of Horticultural and Herbal Science, RDA, Eumseong 27709, Korea.
| | - Geum-Soog Kim
- Department of Herbal Crop Research, National Institute of Horticultural and Herbal Science, RDA, Eumseong 27709, Korea.
| | - Nam-In Baek
- Department of Oriental Medicine Biotechnology, Kyung Hee University, Yongin 17104, Korea.
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