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Ginsenoside Rb1 and Rd Remarkably Inhibited the Hepatic Uptake of Ophiopogonin D in Shenmai Injection Mediated by OATPs/oatps.

ABSTRACT: Shenmai injection (SMI) is derived from traditional Chinese herbal prescription Shendong yin and widely used for treating cardiovascular diseases. Ophiopogonin D (OPD) is one of the main active components of SMI. The hepatic uptake of OPD is mediated by organic anion-transporting polypeptides (OATPs/oatps) and inhibited by some other components in SMI. This study aimed to identify the active components of SMI responsible for the inhibitory effects on hepatic uptake of OPD in rats and explore the compatibility mechanisms of complex components in SMI based on OATPs/oatps. The known effective fractions, the known components in Shenmai Formula, and the fractions obtained from SMI by HPLC gradual-separation technology were individually/combinedly tested for their effects on OPD uptake in rat primary hepatocytes and recombinant OATP1B1/OATP1B3-expressing HEK293T cells. The results indicated that the OPD uptake was inhibited by panaxadiol-type ginsenosides (ginsenoside Rb1 and Rd), but slightly influenced by panaxatriol-type ginsenosides in rat primary hepatocytes and recombinant cells. The fractions of SMI-3-1 (0-11 min) and SMI-3-3 (15-20 min) obtained by HPLC gradual-separation technology were proved to be the major effective fractions that influenced the OPD uptake, and subsequently identified as ginsenoside Rb1 and Rd, respectively. The plasma concentrations of OPD in rats given OPD+ginsenoside Rb1+ginsenoside Rd were higher compared to rats given OPD alone at the same dose. In conclusion, ginsenoside Rb1 and Rd are the major effective components in SMI that remarkably inhibited the hepatic OPD uptake mediated by OATPs/oatps. The interaction of complex components by OATPs/oatps may be one of the important compatibility mechanisms in SMI.

SUBMITTER: Liu X

PROVIDER: S-EPMC6113708 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Ginsenoside Rb1 and Rd Remarkably Inhibited the Hepatic Uptake of Ophiopogonin D in Shenmai Injection Mediated by OATPs/oatps.

Liu Xiaopei X Chen Lin L Liu Mingyi M Zhang Hong H Huang Shibo S Xiong Yuqing Y Xia Chunhua C

Frontiers in pharmacology 20180822

Shenmai injection (SMI) is derived from traditional Chinese herbal prescription Shendong yin and widely used for treating cardiovascular diseases. Ophiopogonin D (OPD) is one of the main active components of SMI. The hepatic uptake of OPD is mediated by organic anion-transporting polypeptides (OATPs/oatps) and inhibited by some other components in SMI. This study aimed to identify the active components of SMI responsible for the inhibitory effects on hepatic uptake of OPD in rats and explore the ...[more]

PMID: 30186179

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Project description:Introduction: Shuanghuanglian injection (lyophilized) (SHLI) is commonly used to treat respiratory tract infection. Shenmai injection (SMI) is mainly used to treat cardiovascular diseases. Despite their widespread clinical use, anaphylactoid reactions (ARs) induced by SHLI and SMI have been reported, which have attracted broad attention. However, the impact of ARs on metabolic changes and the underlying mechanisms are still unclear. Methods: ICR mice were used as model animals and were treated with normal saline, C48/80, SHLI and SMI, respectively. The behavior of mice, auricle blue staining and Evans Blue exudation were used as indexes to evaluate the sensitization of SHLI and SMI and determine the optimal sensitization dose. Anaphylactoid mice model was established based on the optimal dose and enzyme-linked immunosorbent assay (ELISA) was used to model verification. Afterwards, plasma samples of administered mice were profiled by LC-MS metabolomics and analyzed to evaluate the changes in metabolites. Results: High doses of both SHLI and SMI can induce severe anaphylactoid reactions while the reaction induced by SMI was weaker. A Partial Least-Squares Discriminant Analysis (PLS-DA) score plot indicated that following administration, significant metabolic changes occurred in mice. 23 distinct metabolites, including deoxycholic acid, histamine, and 5-hydroxytryptophan, were identified in the SHLI groups. 11 distinct metabolites, including androsterone, 17α-hydroxypregnenolone, and 5-hydroxyindoleacetate, were identified in the SMI groups. Meanwhile, different metabolic pathways of SHLI and SMI were predicted by different metabolites. The associated metabolic pathways include steroid hormone biosynthesis, tryptophan metabolism, histidine metabolism, arachidonic acid metabolism, nicotinate and nicotinamide metabolism, and primary bile acid biosynthesis. Conclusion: Study showed that both SHLI and SMI can induce varying degrees of anaphylactoid reactions, a positive correlation between response intensity and dose was observed. Metabolomics showed that SHLI and SMI may promote the simultaneous release of hormones and inflammatory factors by disturbing relevant metabolic pathways, while SMI may also inhibit the release of inflammatory factors in arachidonic acid metabolic pathway, indicating both pro-inflammatory and anti-inflammatory effects. This study will serve as a reference for developing a new approach to evaluate the safety of SHLI and SMI from perspective of susceptible drug varieties. However, ARs mechanism requires further verification.

Project description:Osteoporosis (OP) is a systemic skeletal disorder, manifesting with a reduction in bone mass and deterioration of the microarchitecture. Mesenchymal stem cells (MSCs) have an innate ability to differentiate into several cell types, including osteoblasts (OB). Ginsenoside Rb1 (GRb1) is an ethanol extract from ginseng and contains a highly concentrated form of ginsenoside. GRb1 shows extensive beneficial health effects such as anti-oxidative and anti-inflammatory functions, modulating the immune system and inhibiting osteoclastogenesis. We hypothesized that GRb1 can promote MSC differentiation into OBs and inhibit bone loss. In the present study, we aimed to address two questions: (1) Will GRb1 have a positive effect on osteogenic differentiation of MSCs? and (2) Will GRb1 halt bone loss in ovariectomized (OVX) rats? We investigated the effects of GRb1 on viability and osteogenic differentiation of rat mesenchymal stem cells (rMSCs). Our results showed that GRb1 at concentrations of 10-8 M and 10-6 M can increase alkaline phosphatase activity, mineralization and the expression of osteogenic related proteins, such as osteopontin and osteoprotegerin, while incubating rMSCs with osteogenic induction medium and GRb1. Adding GRb1 into the medium can prevent rMSCs from Oxidative damage at the concentration of 25?M H2O2. Furthermore, 40 4-month-old rats were assigned to 5 groups(8 rats per group): the basal group, the sham group, the OVX group, the high dose of GRb1 group (6 mg/kg/day) and the low dose of GRb1 group (3 mg/kg/day). Rats recrived treatment 3days after surgery and last for 14 weeks. Examinations included serum analysis, mechanical testing, Masson-Goldner trichrome staining and bone histomorphometry analysis. The results showed that OVX can lead to dyslipidemia and excessive oxidative stress, whereas GRb1 cannot significantly halt dyslipidemia and excessive oxidative stress in OVX rats. In addition, the bone density of the lumbar vertebra and femur were decreased significantly in the OVX rats, and GRb1 could not inhibit bone loss. Bone histomorphometry analysis showed that the number and width of bone trabecula of the tibia were reduced in OVX rats, and GRb1 could not prevent their occurrence. A bone biomechanics assay showed that GRb1 cannot improve the ability of bone structure to resist fracture of the femur in OVX rats. The current study demonstrated that GRb1 has an obvious effect on osteogenic differentiation in rMSCs but no obvious effect on bone loss in OVX rats. These findings indicate GRb1 has a positive effect on rMSCs but does not have an effect on bone loss in OVX rats at the concentration we used.

Dataset Information

Ginsenoside Rb1 and Rd Remarkably Inhibited the Hepatic Uptake of Ophiopogonin D in Shenmai Injection Mediated by OATPs/oatps.

Publications

Ginsenoside Rb1 and Rd Remarkably Inhibited the Hepatic Uptake of Ophiopogonin D in Shenmai Injection Mediated by OATPs/oatps.

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