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

Liu, Xiaopei; Chen, Lin; Liu, Mingyi; Zhang, Hong; Huang, Shibo; Xiong, Yan; Xia, Chunhua

doi:10.3389/fphar.2018.00957

“…OATPs are multispecific transport proteins, which can transport cations, anions and neutral compounds in cells, and plays an important role in drug absorption, distribution and excretion in vivo ( Obaidat et al, 2012 ; Liu et al, 2018 ). Shi found that OATP mediates the selective accumulation of the heptamethine dye IR-780 in tumor cells ( Zhang et al, 2010 ).…”

Section: Resultsmentioning

confidence: 99%

ZWZ-3, a Fluorescent Probe Targeting Mitochondria for Melanoma Imaging and Therapy

Liu

¹

,

Wang

²

,

Sun

³

et al. 2022

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The increased drug resistance and metastasis of melanoma resulted in poor prognosis of patients. Here, we designed and synthesized a novel hemicyanine-based fluorescent probe ZWZ-3, and investigated its application for melanoma imaging and treatment both in vitro and in vivo. ZWZ-3 preferentially accumulated in melanoma cells via a process that depended on the organic anion-transporting polypeptide (OATP), which targeted mitochondria on the hemicyanine cationic nitrogen. In addition, we investigated the effect and molecular mechanism of ZWZ-3 in melanoma. In vitro studies showed that ZWZ-3 promoted the generation of reactive oxygen species and induced mitochondrial-mediated cell apoptosis by upregulating Bax and activating caspase-3, caspase-9, and PARP. Importantly, ZWZ-3 also induced autophagy by upregulating LC-3II and Atg5 and downregulating P62. It significantly suppressed tumor growth of A375 xenograft tumor in mice without notable side effects. Histological and immunohistochemical analyses revealed that ZWZ-3 induced apoptosis and inhibited tumor cell proliferation. Thus, ZWZ-3 represents a novel theranostic agent that can be used to effectively targeting, detecting, and treating melanoma. It could also help monitoring disease progression and response to treatment.

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“…Q9NPD5, also known as OATP1B3, is an anion transporter. It has been proven that the hepatic uptake of OPD and OPD′ is mediated by organic anion-transporting polypeptides (OATPs) [ 46 – 48 ]. This report, on the one hand, confirmed the reliability of the molecular modeling results; on the other hand, it pointed out that OPD and OPD′ can affect the transporting activities of OATP1B1 and OATP1B3 in a substrate-dependent manner.…”

Section: Resultsmentioning

confidence: 99%

Differences in the Hemolytic Behavior of Two Isomers in Ophiopogon japonicus In Vitro and In Vivo and Their Risk Warnings

Xu

¹

,

Jiang²,

Sun³

et al. 2020

Oxidative Medicine and Cellular Longevity

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Ophiopogonin D (OPD) and Ophiopogonin D ′ (OPD ′ ) are two bioactive ingredients in Ophiopogon japonicus. Previously published studies have often focused on the therapeutic effects related to OPD’s antioxidant capacity but underestimated the cytotoxicity-related side effects of OPD ′ , which may result in unpredictable risks. In this study, we reported another side effect of OPD ′ , hemolysis, and what was unexpected was that this side effect also appeared with OPD. Although hemolysis effects for saponins are familiar to researchers, the hemolytic behavior of OPD or OPD ′ and the interactions between these two isomers are unique. Therefore, we investigated the effects of OPD and OPD ′ alone or in combination on the hemolytic behavior in vitro and in vivo and adopted chemical compatibility and proteomics methods to explain the potential mechanism. Meanwhile, to explain the drug-drug interactions (DDIs), molecular modeling was applied to explore the possible common targets. In this study, we reported that OPD ′ caused hemolysis both in vitro and in vivo, while OPD only caused hemolysis in vivo. We clarified the differences and DDIs in the hemolytic behavior of the two isomers. An analysis of the underlying mechanism governing this phenomenon showed that hemolysis caused by OPD or OPD ′ was related to the destruction of the redox balance of erythrocytes. In vivo, in addition to the redox imbalance, the proteomics data demonstrated that lipid metabolic disorders and mitochondrial energy metabolism are extensively involved by hemolysis. We provided a comprehensive description of the hemolysis of two isomers in Ophiopogon japonicus, and risk warnings related to hemolysis were presented. Our research also provided a positive reference for the development and further research of such bioactive components.

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“…In another article we submitted, molecular modeling was adopted and screen out a protein called Q9NPD5 which can interact with both OPD and OPD'. This protein belongs to organic anion transporters (OATP) family and it was closely related to cholic acid metabolism [ 28 ], existing studies have confirmed that the down-regulation of OATP1A2 and OATP1B3 in particular leads to abnormal fetal bile acid metabolism between maternal and fetal fetuses [ 29 ]. This may explain from another perspective how OPD and OPD' induce hemolysis.…”

Section: Discussionmentioning

confidence: 99%

Global metabolomic and lipidomic analysis reveals the potential mechanisms of hemolysis effect of Ophiopogonin D and Ophiopogonin D' in vivo

Xu

¹

,

Jiang²,

Huang

³

et al. 2021

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Background OPD and OPD' are the two main active components of Ophiopogon japonicas in Shenmai injection (SMI). Being isomers of each other, they are supposed to have similar pharmacological activities, but the actual situation is complicated. The difference of hemolytic behavior between OPD and OPD' in vivo and in vitro was discovered and reported by our group for the first time. In vitro, only OPD' showed hemolysis reaction, while in vivo, both OPD and OPD' caused hemolysis. In vitro, the primary cause of hemolysis has been confirmed to be related to the difference between physical and chemical properties of OPD and OPD'. In vivo, although there is a possible explanation for this phenomenon, the one is that OPD is bio-transformed into OPD' or its analogues in vivo, the other one is that both OPD and OPD' were metabolized into more activated forms for hemolysis. However, the mechanism of hemolysis in vivo is still unclear, especially the existing literature are still difficult to explain why OPD shows the inconsistent hemolysis behavior in vivo and in vitro. Therefore, the study of hemolysis of OPD and OPD' in vivo is of great practical significance in response to the increase of adverse events of SMI. Methods Aiming at the hemolysis in vivo, this manuscript adopted untargeted metabolomics and lipidomics technology to preliminarily explore the changes of plasma metabolites and lipids of OPD- and OPD'-treated rats. Metabolomics and lipidomics analyses were performed on ultra-high performance liquid chromatography (UPLC) system tandem with different mass spectrometers (MS) and different columns respectively. Multivariate statistical approaches such as principal component analysis (PCA) and orthogonal partial least square-discriminant analysis (OPLS-DA) were applied to screen the differential metabolites and lipids. Results Both OPD and OPD' groups experienced hemolysis, Changes in endogenous differential metabolites and differential lipids, enrichment of differential metabolic pathways, and correlation analysis of differential metabolites and lipids all indicated that the causes of hemolysis by OPD and OPD' were closely related to the interference of phospholipid metabolism. Conclusions This study provided a comprehensive description of metabolomics and lipidomics changes between OPD- and OPD'-treated rats, it would add to the knowledge base of the field, which also provided scientific guidance for the subsequent mechanism research. However, the underlying mechanism require further research.

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

Cited by 16 publications

References 27 publications

ZWZ-3, a Fluorescent Probe Targeting Mitochondria for Melanoma Imaging and Therapy

ZWZ-3, a Fluorescent Probe Targeting Mitochondria for Melanoma Imaging and Therapy

Differences in the Hemolytic Behavior of Two Isomers in Ophiopogon japonicus In Vitro and In Vivo and Their Risk Warnings

Global metabolomic and lipidomic analysis reveals the potential mechanisms of hemolysis effect of Ophiopogonin D and Ophiopogonin D' in vivo

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