Production of bioactive ginsenosides Rh2 and Rg3 by metabolically engineered yeasts

Wang, Pingping; Wei, Yongjun; Fan, Y.; Liu, Qunfang; Wei, Wei; Yang, Chengshuai; Zhang, Lei; Zhao, Guoping; Yue, Jian‐Min; Yan, Xiaojun; Zhou, Zhihua

doi:10.1016/j.ymben.2015.03.003

Cited by 160 publications

(134 citation statements)

References 29 publications

(45 reference statements)

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“…et al, 2014). Recently, yeast cell factories are created to produce Rh2 or Rg3 from simple sugars (Wang et al, 2015), which may be an alternative approach to replace the traditional method of extracting these rare ginsenosides Rg3 and Rh2 from Panax plants.…”

Section: Discussionmentioning

confidence: 99%

Anti-adipogenic Effects and Mechanisms of Ginsenoside Rg3 in Pre-adipocytes and Obese Mice

Zhang

Wang

et al. 2017

Front. Pharmacol.

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Red or black ginseng has been reported more powerful than white/fresh ginseng in dealing with various diseases/conditions including obesity. The major reason is that heating/steaming, the process of making red or black ginseng, produces large amount of bioactive compounds including ginsenoside Rg3 (Rg3), which are trace in fresh or white ginseng. In the present study, Rg3 was applied both in pre-adipocytes and obese mice to investigate the anti-adipogenic effects and relevant mechanisms. Our results show that Rg3 dose-dependently inhibited cell differentiation both in 3T3-L1 cells (30, 50, and 100 μM) and human primary pre-adipocytes (10, 20, and 30 μM). This inhibitory effect is accompanied by the attenuation of the expressions of adipogenic markers including peroxisome proliferator-activated receptor gamma (PPAR-γ), CCAAT/enhancer binding protein alpha (C/EBP-α), fatty acid synthase (FAS), fatty acid binding protein 4 (FABP4) and perilipin. Although dietary intake of Rg3 (0.1 mg Rg3/kg diet, 8 weeks) did not significantly affect body weight gain, fat pads and food intake as well as of PPAR-γ expression in fat tissues, we found that hepatic PPAR-γ and C/EBP-α protein expressions and hepatic glutathione reductase and glutathione S-transferase, two major antioxidants molecules were significantly reduced by Rg3. These results suggest that ginsenoside Rg3 may be a potential agent in reducing/preventing obesity.

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Section: Discussionmentioning

confidence: 99%

Anti-adipogenic Effects and Mechanisms of Ginsenoside Rg3 in Pre-adipocytes and Obese Mice

Zhang

Wang

et al. 2017

Front. Pharmacol.

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“…Candidate genes responsible for ginsenoside biosynthesis in the Panax genus have been identified in P. ginseng (Han et al, 2011, 2012; Jung et al, 2014; Kim et al, 2014; Jayakodi et al, 2015; Wang P. et al, 2015; Wei et al, 2015), P. notoginseng (Liu et al, 2015; Rai et al, 2016), and P. vietnamensis (Zhang et al, 2015). Transcriptome analysis of P. notoginseng identified several candidate unigenes encoding cytochrome P450 and glycosyltransferase and revealed that these genes were conserved across all Panax species (Rai et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Integrated Transcriptomic and Metabolomic Analysis of Five Panax ginseng Cultivars Reveals the Dynamics of Ginsenoside Biosynthesis

et al. 2017

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Panax ginseng C.A. Meyer is a traditional medicinal herb that produces bioactive compounds such as ginsenosides. Here, we investigated the diversity of ginsenosides and related genes among five genetically fixed inbred ginseng cultivars (Chunpoong [CP], Cheongsun [CS], Gopoong [GO], Sunhyang [SH], and Sunun [SU]). To focus on the genetic diversity related to ginsenoside biosynthesis, we utilized in vitro cultured adventitious roots from the five cultivars grown under controlled environmental conditions. PCA loading plots based on secondary metabolite composition classified the five cultivars into three groups. We selected three cultivars (CS, SH, and SU) to represent the three groups and conducted further transcriptome and gas chromatographymass spectrometry analyses to identify genes and intermediates corresponding to the variation in ginsenosides among cultivars. We quantified ginsenoside contents from the three cultivars. SH had more than 12 times the total ginsenoside content of CS, with especially large differences in the levels of panaxadiol-type ginsenosides. The expression levels of genes encoding squalene epoxidase (SQE) and dammarenediol synthase (DDS) were also significantly lower in CS than SH and SU, which is consistent with the low levels of ginsenoside produced in this cultivar. Methyl jasmonate (MeJA) treatment increased the levels of panaxadiol-type ginsenosides up to 4-, 13-, and 31-fold in SH, SU, and CS, respectively. MeJA treatment also greatly increased the quantity of major intermediates and the expression of the underlying genes in the ginsenoside biosynthesis pathway; these intermediates included squalene, 2,3-oxidosqualene, and dammarenediol II, especially in CS, which had the lowest ginsenoside content under normal culture conditions. We conclude that SQE and DDS are the most important genetic factors for ginsenoside biosynthesis with diversity among ginseng cultivars.

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“…Ginsenosides (ginseng saponins), the primary active components of Panax ginseng , have been demonstrated to have anticancer activities, particularly ginsenoside Rh2 (GRh2) and ginsenoside Rg3 (GRg3) (2,3). GRh2 and GRg3 are protopanaxadiol (PPD)-type ginsenosides, which have one and two glucose moieties at the C3 hydroxyl of PPD, respectively (4). Previously, it has been reported that GRh2 and GRg3 may inhibit growth (5), induce apoptosis (6) and restrict tumor invasion and metastasis (7,8) in mammalian tumor cells.…”

Section: Introductionmentioning

confidence: 99%

Ginsenoside Rh2 and Rg3 inhibit cell proliferation and induce apoptosis by increasing mitochondrial reactive oxygen species in human leukemia Jurkat cells

Xia

Wang

Zhou

et al. 2017

Molecular Medicine Reports

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Ginsenoside Rh2 (GRh2) and ginsenoside Rg3 (GRg3) are primary bioactive components in Panax ginseng. The present study aimed to investigate the underlying mechanisms of apoptotic cell-death induced by GRh2 and GRg3 in human leukemia Jurkat cells. The Cell Counting kit-8 assay was used to determine cell proliferation. Apoptosis was detected by nuclear morphologic observation by Hoechst 33342 staining and Annexin V-allophycocyanin and 7-amino-actinomycin D assay. mitoTEMPO, a mitochondrial reactive oxygen species (ROS) scavenger, was used to examine the effects of mitochondrial ROS on cell viability and mitochondrial membrane potential (MMP). Finally, the expression levels of numerous mitochondrial-associated apoptosis proteins were assessed by western blot analysis. These results demonstrated that GRh2 and GRg3 inhibited cell growth and induced apoptosis, and that GRh2 had greater cytotoxicity than GRg3. GRh2 induced generation of more mitochondrial ROS compared with GRg3 in Jurkat cells; however, this effect was ameliorated by subsequent treatment with mitoTEMPO. Furthermore, excess mitochondrial ROS induced by GRh2 was more potent than GRg3 in inhibiting cell proliferation and reducing MMP. In addition, expression levels of apoptosis-associated proteins were significantly increased in Jurkat cells treated with GRh2 than GRg3. In conclusion, these findings suggested that GRh2 and GRg3 induce mitochondrial-associated apoptosis by increasing mitochondrial ROS in human leukemia Jurkat cells. GRh2 may more effectively inhibit cell growth and accelerate apoptosis than GRg3. This study provides a potential novel strategy for the treatment of acute lymphoblastic leukemia.

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Production of bioactive ginsenosides Rh2 and Rg3 by metabolically engineered yeasts

Cited by 160 publications

References 29 publications

Anti-adipogenic Effects and Mechanisms of Ginsenoside Rg3 in Pre-adipocytes and Obese Mice

Anti-adipogenic Effects and Mechanisms of Ginsenoside Rg3 in Pre-adipocytes and Obese Mice

Integrated Transcriptomic and Metabolomic Analysis of Five Panax ginseng Cultivars Reveals the Dynamics of Ginsenoside Biosynthesis

Ginsenoside Rh2 and Rg3 inhibit cell proliferation and induce apoptosis by increasing mitochondrial reactive oxygen species in human leukemia Jurkat cells

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