Long-term oral administration of Epimedii Folium induced cholestasis in mice by interfering with bile acid transport

Zhao, Jin‐Quan; Zhao, Zhen; Zhang, Cai; Sun, Jia‐Xing; Liu, Fengjie; Yu, Ting; Jiang, Yan; Li, Huijun

doi:10.1016/j.jep.2022.115254

Cited by 5 publications

(2 citation statements)

References 34 publications

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“…Traditional Chinese herbal medicine has been highly valued for a long time because of its abundant sources, low price, stable curative effect and few side effects (Zhao et al., 2023). However, the crude extracts of Chinese herbal medicines are complicated, and a fine exploration is needed to clarify the mechanism of Chinese herbal medicines to better promote their clinical application.…”

Section: Discussionmentioning

confidence: 99%

Icariin alleviates the apoptosis of chondrocytes in osteoarthritis through regulating SIRT‐1‐Nrf2‐HO‐1 signaling

Liu,

Zhong,

Liu

et al. 2024

Chem Biol Drug Des

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Icariin has shown the potential to treat osteoarthritis (OA), but the specific mechanism still needs further exploration. Therefore, this study attempted to reveal the effect and mechanism of icariin on OA based on in vitro and in vivo experiments. In vivo, a mouse model of OA was established by cutting the anterior cruciate ligament, and 10 mg/kg icariin was given to mice orally. Then, the OA injury and pathological changes of cartilage tissue in mice were identified by OA index and hematoxylin and eosin staining. In vitro, the viability of C28/I2 cells incubated with different concentrations of icariin was detected by 3‐(4,5)‐dimethylthiahiazo (‐z‐y1)‐3,5‐di‐ phenytetrazoliumromide assay. Subsequently, C28/I2 cells induced by IL‐1β were used as the cell model of OA, the expression of Sirtuin (SIRT)‐1 in cells was knocked down, and icariin was added for intervention. Next, western blot was used to observe the expression level of sirtuin 1 (SIRT‐1)‐Nrf2‐heme oxygenase 1 (HO‐1) signaling pathway‐related proteins in cells of each group. Besides, cell viability and apoptosis were detected by MTT and apoptosis assay, and DNA damage was observed by comet assay. In vivo experiments, intragastric administration of icariin could effectively reduce the OA index of mice, improve the pathological changes of cartilage tissue, and obviously activated the SIRT‐1‐Nrf2‐HO‐1 signaling pathway. In vitro experiments, icariin did not exhibit toxic effect on C28/I2 cells, but could activate the SIRT‐1‐Nrf2‐HO‐1 signaling pathway, improve the viability, reduce the level of apoptosis and relieve the DNA damage in OA cells; however, these effects were inhibited by si‐ SIRT‐1. Icariin can improve the symptoms of OA by activating the SIRT‐1‐Nrf2‐HO‐1 signaling pathway.

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Section: Discussionmentioning

confidence: 99%

Icariin alleviates the apoptosis of chondrocytes in osteoarthritis through regulating SIRT‐1‐Nrf2‐HO‐1 signaling

Liu,

Zhong,

Liu

et al. 2024

Chem Biol Drug Des

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“…Moreover, EF is also employed as a dietary supplement due to its phytoestrogenic properties. At present, EF and preparations containing EF, including Zhuang-Gu-Guan-Jie pills and Xian-Ling-Gu-Bao capsules, have been reported to be the putative cause of liver injury clinically, mainly featuring jaundice and cholestatic. – Therefore, considering the wide clinical application for EF and its related preparations, research on the material basis and hepatotoxic mechanism is particularly necessary.…”

Section: Introductionmentioning

confidence: 99%

Natural Product Baohuoside I Impairs the Stability and Membrane Location of MRP2 Reciprocally Regulated by SUMOylation and Ubiquitination in Hepatocytes

Zhao,

Du,

Wang

et al. 2024

Chem. Res. Toxicol.

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Epimedii Folium (EF) is a botanical dietary supplement to benefit immunity. Baohuoside I (BI), a prenylated flavonoid derived from EF, has exhibited the cholestatic risk before.Here, the mechanism of BI on the stability and membrane localization of liver MRP2, a bile acid exporter in the canalicular membrane of hepatocytes, was investigated. The fluorescent substrate of MRP2, CMFDA was accumulated in sandwichcultured primary mouse hepatocytes (SCH) under BI stimulation, followed by reduced membrane MRP2 expression. BI triggered MRP2 endocytosis associated with oxidative stress via inhibition of the NRF2 signaling pathway. Meanwhile, BI promoted the degradation of MRP2 by reducing its SUMOylation and enhancing its ubiquitination level. Co-IP and fluorescence colocalization experiments all proved that MRP2 was a substrate protein for SUMOylation for SUMO proteins. CHX assays showed that SUMO1 prolonged the half-life of MRP2 and further increased its membrane expression, which could be reversed by UBC9 knockdown. Correspondingly, MRP2 accumulated in the cytoplasm by GP78 knockdown or under MG132 treatment. Additionally, the SUMOylation sites of MRP2 were predicted by the algorithm, and a conversion of lysines to arginines at positions 940 and 953 of human MRP2 caused its decreased stability and membrane location. K940 was further identified as the essential ubiquitination site for MRP2 by an in vitro ubiquitination assay. Moreover, the decreased ubiquitination of MRP2 enhanced the SUMOylation MRP2 and vice versa, and the crosstalk of these two modifiers could be disrupted by BI. Collectively, our findings indicated the process of MRP2 turnover from the membrane to cytoplasm at the posttranslational level and further elucidated the novel toxicological mechanism of BI.

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Emerging role of the crosstalk between gut microbiota and liver metabolome of subterranean herbivores in response to toxic plants

Tan,

Yao,

Kang

et al. 2024

Ecotoxicology and Environmental Safety

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Long-term oral administration of Epimedii Folium induced cholestasis in mice by interfering with bile acid transport

Cited by 5 publications

References 34 publications

Icariin alleviates the apoptosis of chondrocytes in osteoarthritis through regulating SIRT‐1‐Nrf2‐HO‐1 signaling

Icariin alleviates the apoptosis of chondrocytes in osteoarthritis through regulating SIRT‐1‐Nrf2‐HO‐1 signaling

Natural Product Baohuoside I Impairs the Stability and Membrane Location of MRP2 Reciprocally Regulated by SUMOylation and Ubiquitination in Hepatocytes

Emerging role of the crosstalk between gut microbiota and liver metabolome of subterranean herbivores in response to toxic plants

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