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Icariside ?, a main compound in Epimedii Folium, induces idiosyncratic hepatotoxicity by enhancing NLRP3 inflammasome activation.

ABSTRACT: Idiosyncratic drug-induced liver injury (IDILI) is an infrequent but potentially serious disease that develops the main reason for post-marketing safety warnings and withdrawals of drugs. Epimedii Folium (EF), the widely used herbal medicine, has shown to cause idiosyncratic liver injury, but the underlying mechanisms are poorly understood. Increasing evidence has indicated that most cases of IDILI are immune mediated. Here, we report that icariside ? (ICS ?), the major active and metabolic constituent of EF, causes idiosyncratic liver injury by promoting NLRP3 inflammasome activation. ICS ? exacerbates NLRP3 inflammasome activation triggered by adenosine triphosphate (ATP) and nigericin, but not silicon dioxide (SiO2), monosodium urate (MSU) crystal or cytosolic lipopolysaccharide (LPS). Additionally, the activation of NLRC4 and AIM2 inflammasomes is not affected by ICS ?. Mechanistically, synergistic induction of mitochondrial reactive oxygen species (mtROS) is a crucial contributor to the enhancing effect of ICS ? on ATP- or nigericin-induced NLRP3 inflammasome activation. Importantly, in vivo data show that a combination of non-hepatotoxic doses of LPS and ICS ? causes the increase of aminotransferase activity, hepatic inflammation and pyroptosis, which is attenuated by Nlrp3 deficiency or pretreatment with MCC950 (a specific NLRP3 inflammasome inhibitor). In conclusion, these findings demonstrate that ICS ? causes idiosyncratic liver injury through enhancing NLRP3 inflammasome activation and suggest that ICS ? may be a risk factor and responsible for EF-induced liver injury.

SUBMITTER: Wang Z

PROVIDER: S-EPMC7564030 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Icariside Ⅱ, a main compound in Epimedii Folium, induces idiosyncratic hepatotoxicity by enhancing NLRP3 inflammasome activation.

Wang Zhilei Z Xu Guang G Wang Hongbo H Zhan Xiaoyan X Gao Yuan Y Chen Nian N Li Ruisheng R Song Xueai X Guo Yuming Y Yang Ruichuang R Niu Ming M Wang Jiabo J Liu Youping Y Xiao Xiaohe X Bai Zhaofang Z

Acta pharmaceutica Sinica. B 20200409 9

Idiosyncratic drug-induced liver injury (IDILI) is an infrequent but potentially serious disease that develops the main reason for post-marketing safety warnings and withdrawals of drugs. Epimedii Folium (EF), the widely used herbal medicine, has shown to cause idiosyncratic liver injury, but the underlying mechanisms are poorly understood. Increasing evidence has indicated that most cases of IDILI are immune mediated. Here, we report that icariside Ⅱ (ICS Ⅱ), the major active and metabolic cons ...[more]

PMID: 33088683

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Project description:BackgroundEpimedii Folium (EF) is commonly used for treating bone fractures and joint diseases, but the potential hepatotoxicity of EF limits its clinical application. Our previous study confirms that EF could lead to idiosyncratic drug-induced liver injury (IDILI) and hepatocyte apoptosis, but the mechanism remains unknown. Studies have shown that NLRP3 inflammasome plays an important role in the development of various inflammatory diseases such as IDILI. Specific stimulus-induced NLRP3 inflammasome activation may has been a key strategy for lead to liver injury. Therefore, main compounds derived from EF were chosen to test whether the ingredients in EF could activate the NLRP3 inflammasome and to induce IDILI.MethodsBone-marrow-derived macrophages (BMDMs) were treated with Icariside I, and then stimulated with inflammasome stimuli and assayed for the production of caspase-1 and interleukin 1β (IL-1β) and the release of lactate dehydrogenase (LDH). Determination of intracellular potassium, ASC oligomerization as well as reactive oxygen species (ROS) production were used to evaluate the stimulative mechanism of Icariside I on inflammasome activation. Mouse models of NLRP3 diseases were used to test whether Icariside I has hepatocyte apoptosis effects and promoted NLRP3 inflammasome activation in vivo.ResultsIcariside I specifically enhances NLRP3 inflammasome activation triggered by ATP or nigericin but not SiO2, poly(I:C) or cytosolic LPS. Additionally, Icariside I does not alter the activation of NLRC4 and AIM2 inflammasomes. Mechanically, Icariside I alone does not induce mitochondrial reactive oxygen species (mtROS), which is one of the critical upstream events of NLRP3 inflammasome activation; however, Icariside I increases mtROS production induced by ATP or nigericin but not SiO2. Importantly, Icariside I leads to liver injury and NLRP3 inflammasome activation in an LPS-mediated susceptibility mouse model of IDILI, but the effect of Icariside I is absent in the LPS-mediated mouse model pretreated with MCC950, which is used to mimic knockdown of NLRP3 inflammasome activation.ConclusionsOur study reveals that Icariside I specifically facilitates ATP or nigericin-induced NLRP3 inflammasome activation and causes idiosyncratic hepatotoxicity. The findings suggest that Icariside I or EF should be avoided in patients with diseases related to ATP or nigericin-induced NLRP3 inflammasome activation, which may be risk factors for IDILI. Video abstract.

Project description:Background: Endothelial dysfunction is commonly accompanied by a reduced capacity for nitric oxide (NO) production and decreased NO sensitivity, playing a central role in numerous vascular diseases. Saturated free fatty acids are known to reduce NO production and then induce endothelial dysfunction. Alternative splicing participates in the regulation of cellular and tissular homeostasis and is highly regulated by serine-arginine protein kinase (SRPK1). The role of SRPK1 in the biology of endothelial cells remains elusive. Icariside Ⅱ (ICA Ⅱ) has been reported to have protective effects on endothelial function. However, the specific molecular mechanisms are still unknown. The purpose of this study is to explore the role of SRPK1 in the biology of endothelial cells and the underlying mechanism of ICA Ⅱ on palmitic acid (PA) induced endothelial dysfunction. Methods: Endothelial dysfunction was induced using PA in human umbilical vein endothelial cells (HUVECs). The expression and phosphorylation of related proteins in the SRPK1-Akt-eNOS signaling pathway were detected by Western Blot. Cell Counting Kit-8 assay and Ki-67 immunofluorescence were used to estimate cell viability. Endothelial cell function was assessed by detecting NO production using DAF-FM DA. Interaction between ICA Ⅱ and SRPK1 was demonstrated by a biotinylated protein interaction pull-down assay. Results: The expressions of eNOS, Akt, and SRPK1 were down-regulated in the endothelial dysfunction stimulated by PA. SRPK1 inhibitor SPHINX31 restrained endothelial cell viability in a dose-dependent manner. Moreover, inhibition of SRPK1 using SPHINX31 and knockdown of SRPK1 by shRNA also showed a down-regulation of the proteins associated with the SRPK1-Akt-eNOS signaling pathway. Biotinylated protein interaction pull-down assay revealed that ICA Ⅱ could be directly bound with SRPK1. On the other hand, ICA Ⅱ could attenuate the PA-induced endothelial dysfunction and restore cell viability through the SRPK1-Akt-eNOS pathway. Conclusions: ICA Ⅱ, bound with SRPK1, could attenuate the endothelial dysfunction induced by the PA in HUVECs via the SRPK1-Akt-eNOS signaling pathway.

Project description:Background: Doxorubicin (DOX) has been widely used in cancer treatment. However, DOX can cause a range of significant side effects, of which hepatotoxicity is a common one, and therefore limits its clinical use. Pterostilbene (PTS) has been shown to exhibit anti-oxidant and anti-inflammatory effects in the treatment of liver diseases but whether PTS could protect against hepatotoxicity in DOX-treated mice is unknown. Methods: In our study, we use C57/BL6J mice and the HepG2 cell line. We divided the mice in 4 groups: the control, the PTS treatment, the DOX treatment, and the DOX + PTS treatment group. Liver histopathology was judged by performing hematoxylin-eosin and Masson staining. Immunohistochemistry was used to perform the expression of NLRP3. The levels of serum alanine transaminase (ALT) and aspartate transaminase (AST) were evaluated. Levels of malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH), and DCFH-DA staining were used to evaluate the oxidative injury. Western blot and real-time PCR were applied to evaluate the expressions of proteins and mRNA. MTT was used to evaluate DOX-induced cell injury and the protective effects of PTS. Recombinant Trx-1 was used to analyze the mechanism of PTS. A TUNEL assay was used to detect apoptosis in DOX-induced HepG2 cells and the protective effects of PTS. Results: PTS ameliorated DOX-induced liver pathological changes and the levels of AST and ALT. PTS also decreased the level of MDA, increased the level of SOD, GSH, and the expression of Trx-1 in DOX-treated mice. PTS decreased the levels of NLRP3 and IL-1β mRNA and the expressions of their proteins in DOX-treated mice. In addition, PTS also decreased the expression of Cleaved Caspase-3 and BAX and increased the expression of BCL-2. In vitro, after treatment with recombinant Trx-1, ROS and NLRP3 inflammasome were both decreased. Treatment with PTS could rescue the downregulation of Trx-1, decreased the ROS level and the NLRP3 inflammasome, and protected HepG2 cells against DOX-induced apoptosis. Conclusion: The results show that PTS exhibits protective effects against DOX-induced liver injuries via suppression of oxidative stress, fibrosis, NLRP3 inflammasome stimulation, and cell apoptosis which might lead to a new approach of preventing DOX-induced hepatotoxicity.

Dataset Information

Icariside ?, a main compound in Epimedii Folium, induces idiosyncratic hepatotoxicity by enhancing NLRP3 inflammasome activation.

Publications

Icariside Ⅱ, a main compound in Epimedii Folium, induces idiosyncratic hepatotoxicity by enhancing NLRP3 inflammasome activation.

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