ACTA PHARMACOLOGICA SINICA
·
2021
·Vol. 43
·期 1
·146-156
·
IF 6.15
Yao Xin-peng,Jiao Ting-ying,Jiang Yi-ming,Fan Shi-cheng,Zhao Ying-yuan,Yang Xiao,Gao Yue,Li Fei,Zhou Yan-ying,Chen Pan-pan,Huang Min,Bi Hui-chang
Mifepristone (Mif), an effective synthetic steroidal antiprogesterone drug, is widely used for medical abortion and pregnancy prevention. Due to its anti-glucocorticoid effect, high-dose Mif is also used to treat Cushing’s syndrome. Mif was reported to active pregnane X receptor (PXR) in vitro and PXR can induce hepatomegaly via activation and interaction with yes-associated protein (YAP) pathway. High-dose Mif was reported to induce hepatomegaly in rats and mice, but the underlying mechanism remains unclear. Here, the role of PXR was studied in Mif-induced hepatomegaly in C57BL/6 mice and Pxr -knockout mice. The results demonstrated that high-dose Mif (100 mg · kg −1 · d −1 , i.p .) treatment for 5 days significantly induced hepatomegaly with enlarged hepatocytes and promoted proliferation, but low dose of Mif (5 mg · kg −1 · d −1 , i.p .) cannot induce hepatomegaly. The dual-luciferase reporter gene assays showed that Mif can activate human PXR in a concentration-dependent manner. In addition, Mif could promote nuclear translocation of PXR and YAP, and significantly induced the expression of PXR, YAP, and their target proteins such as CYP3A11, CYP2B10, UGT1A1, ANKRD, and CTGF. However, Mif (100 mg · kg −1 · d −1 , i.p .) failed to induce hepatomegaly in Pxr -knockout mice, as well as hepatocyte enlargement and proliferation, further indicating that Mif-induced hepatomegaly is PXR-dependent. In summary, this study demonstrated that PXR-mediated Mif-induced hepatomegaly in mice probably via activation of YAP pathway. This study provides new insights in Mif-induced hepatomegaly, and provides novel evidence on the crucial function of PXR in liver enlargement and regeneration.
研究领域:
药理学
·
毒理学
·
分子生物学
·
肝病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Nature Communications
·
2025
·Vol. 16
·期 1
·1-19
·
IF 15.7
Wang Xiaojuan,Zhang Guohui,Bian Zhiwei,Chow Vimanda,Grimaldi Marina,Carivenc Coralie,Sirounian Savannah,Li Hao,Sladekova Lucia,Mott Stefano,Luperi Yulia,Gong Yufeng,Costello Cait,Li Linhao,Jachimowicz Matthew,Guo Miao,Hu Shian,Wilson Derek,Balaguer Patrick,Bourguet William,Mani Sridhar,Bonati Laura,Peng Hui,March John,Wang Hongbing,Wang Shengpeng,Krause Henry M.,Liu Jiabao
The literature documenting the value of drug-like molecules found in natural products is vast. Although many dietary and herbal remedies have been found to be effective for treating intestinal inflammation, the identification of their active components has lagged behind. In this study, we find that a major ginger component, furanodienone (FDN), is a selective pregnane X receptor (PXR) ligand with agonistic transcriptional outcomes. We show that FDN binds within a sub-pocket of the PXR ligand binding domain (LBD), with subsequent alterations in LBD structure. Using male mice, we show that orally provided FDN has potent PXR-dependant anti-inflammatory outcomes that are colon-specific. Increased affinity and target gene activation in the presence of synergistically acting agonists indicates further opportunities for augmenting FDN activity, efficacy and safety. Collectively, these results support the translational potential of FDN as a therapeutic agent for the treatment and prevention of colonic diseases.
研究领域:
药理学
·
分子生物学
·
天然产物研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2024
·
IF 6.2
Hongyan Li,Yiying Fu,Wangbao Gong,Guangjun Wang,Zhifei Li,Jingjing Tian,Kai Zhang,Ermeng Yu,Yun Xia,Wenping Xie,Jun Xie
The pregnane X receptor (PXR) / nuclear factor-kB (NF-kB) signaling pathway plays a critical role in regulating toxin-induced inflammation and apoptosis in mammals. Whether dietary curcumin (CUR) can prevent copper (Cu)-induced liver injury via this signaling pathway remains to be established in aquatic animals. Juvenile largemouth bass ( Micropterus salmoides ) were exposed to dietary Cu and CUR treatments for 8 weeks. The results showed that chronic Cu exposure induced oxidative stress, causing liver function damage and liver injury. Cu exposure stimulated inflammation by regulating nf-kb and pro-inflammatory genes such as tnfα and il-1β and promoted apoptotic signals in the liver by modulating bcl2 and casp3 mRNA levels. In addition, Pearson correlation analysis verified that inflammatory and apoptotic responses were important indicators of Cu-induced liver injury. CUR attenuated stress responses by enhancing the antioxidant system. Importantly, CUR significantly stimulated PXR mRNA and protein levels in the Cu + CUR group and suppressed NF-κB activation to inhibit the inflammatory and apoptotic signaling cascade. These results suggest that CUR may be an effective activator of PXR in teleost fishes, exerting cytoprotective effects on Cu-induced liver injury via a PXR-mediated NF-κB repression mechanism. In conclusion, this study is the first to demonstrate that CUR may act as a potent PXR ligand that exerts hepatoprotective effects against Cu-induced liver injury. The findings shed light on the specific regulatory role of the PXR/NF-κB signaling pathway in liver pathogenesis and its potential as a therapeutic target in teleost fishes.
研究领域:
水生毒理学
·
分子生物学
·
营养学
✓ 已验证
DOI
高影响因子
PHYTOMEDICINE
·
2021
·
IF 5.34
Ying-yuan Zhao,Xin-peng Yao,Ting-ying Jiao,Jia-ning Tian,Yue Gao,Shi-cheng Fan,Pan-pan Chen,Yi-ming Jiang,Yan-ying Zhou,Yi-xin Chen,Xiao Yang,Min Huang,Hui-chang Bi
Background Schisandrol B (SolB) is one of the bioactive components from a traditional Chinese medicine Schisandra chinensis or Schisandra sphenanthera . It has been demonstrated that SolB exerts hepatoprotective effects against drug-induced liver injury and promotes liver regeneration . It was found that SolB can induce hepatomegaly but the involved mechanisms remain unknown. Purpose This study aimed to explore the mechanisms involved in SolB-induced hepatomegaly. Methods Male C57BL/6 mice were injected intraperitoneally with SolB (100 mg/kg) for 5 days. Serum and liver samples were collected for biochemical and histological analyses. The mechanisms of SolB were investigated by qRT-PCR and western blot analyses, luciferase reporter gene assays and immunofluorescence. Results SolB significantly increased hepatocyte size and proliferation, and then promoted liver enlargement without liver injury and inflammation. SolB transactivated human PXR , activated PXR in mice and upregulated hepatic expression of its downstream proteins, such as CYP3A11 , CYP2B10 and UGT1A1. SolB also significantly enhanced nuclear translocation of PXR and YAP in human cell lines. YAP signal pathway was activated by SolB in mice. Conclusion These findings demonstrated that SolB can significantly induce liver enlargement, which is associated with the activation of PXR and YAP pathways.
研究领域:
药理学
·
分子生物学
·
肝病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Science
·
2024
·
IF 14.3
Yue Feng,Jiakun Shen,Zishen Lin,Zeyi Chen,Min Zhou,Xi Ma
Deoxynivalenol (DON) is a prevalent toxin causing severe liver damage through hepatocellular oxidative stress. However, the underlying mechanisms and effective therapeutic approaches remain unknown. Here, the unique role of the xenobiotic metabolism factor pregnane X receptor (PXR) in mediating DON-induced hepatocellular oxidative stress is investigated. Treatment with the PXR agonist 3-indole-propionic acid (IPA) alleviates DON-induced oxidative stress and liver injury both in vitro and in vivo. Mechanistically, it is discovered for the first time that PXR agonist IPA directly transactivates the m 6 A demethylase FTO expression, leading to site-specific demethylation and decreased abundance of YTHDC1-bound Malat1 lncRNA at single-nucleotide resolution. The diminished m 6 A modification of Malat1 lncRNA reduces its stability and augments antioxidant pathways governed by NRF2, consequently mitigating DON-induced liver injury. Furthermore, Malat1 knockout mice exhibit decreased DON-induced liver injury, emphasizing the role of Malat1 lncRNA in oxidative stress. Collectively, the findings establish that PXR-mediated m 6 A-dependent Malat1 lncRNA expression determines hepatocyte oxidative stress via m 6 A demethylase FTO, providing valuable insights into the potential mechanisms underlying DON-induced liver injury and offers potential therapeutic strategies for its treatment.
研究领域:
毒理学
·
分子生物学
·
药理学
·
基因组学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
TOXICOLOGY LETTERS
·
2024
·
IF 2.9
Yifei Zhang,Jie Yang,Shicheng Fan,Yue Gao,Chenghui Cai,Huilin Li,Xuan Li,Xiao Yang,Yunhui Xing,Min Huang,Huichang Bi
The activation of pregnane X receptor (PXR) or peroxisome proliferator-activated receptor α (PPARα) can induce liver enlargement. Recently, we reported that PXR or PPARα activation-induced hepatomegaly depends on yes-associated protein (YAP) signaling and is characterized by hepatocyte hypertrophy around the central vein area and hepatocyte proliferation around the portal vein area. However, it remains unclear whether PXR or PPARα activation-induced hepatomegaly can be reversed after the withdrawal of their agonists. In this study, we investigated the regression of enlarged liver to normal size following the withdrawal of PCN or WY-14643 (typical agonists of mouse PXR or PPARα) in C57BL/6 mice. The immunohistochemistry analysis of CTNNB1 and KI67 showed a reversal of hepatocyte size and a decrease in hepatocyte proliferation after the withdrawal of agonists. In details, the expression of PXR or PPARα downstream proteins (CYP3A11, CYP2B10, ACOX1, and CYP4A) and the expression of proliferation-related proteins (CCNA1, CCND1, and PCNA) returned to the normal levels. Furthermore, YAP and its downstream proteins (CTGF, CYR61, and ANKRD1) also restored to the normal states, which was consistent with the change in liver size. These findings demonstrate the reversibility of PXR or PPARα activation-induced hepatomegaly and provide new data for the safety of PXR and PPARα as drug targets.
研究领域:
药理学
·
肝病学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
FOOD CHEMISTRY
·
2014
·
IF 3.259
Junyan Wang,Minmin Huang,Haihong Hu,Lushan Yu,Su Zeng
The induction of drug-metabolising enzymes is being increasingly recognised for its clinical importance in drug research and development. In the present study, we used a pregnane X receptor (PXR)-mediated reporter gene assay to evaluate the activating effects of various food, herb, and horticultural plant constituents on the PXR and a UGT1A1 reporter gene DNA construct. The results showed that of 102 naturally occurring constituents tested, 50 activated the PXR signaling pathway and induced expression of the UGT1A1 -reporter gene DNA construct. Eleven constituents strongly induced gene expression (a response of >70% compared to that associated with rifampicin), and were further evaluated in in vitro experiments to confirm the induction of UGT1A1 mRNA and protein expression. The results suggest that foods and herbs containing these constituents should be consumed with caution to avoid undesirable drug–drug interactions with co-administered drugs that are substrates for UGT1A1.
研究领域:
药理学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CHEMICO-BIOLOGICAL INTERACTIONS
·
2024
·
IF 4.7
Shaofei Song,Hong Peng,Yuan Li,Tingting Zhao,Renjie Cao,Lei Zheng,Min Huang,Yiming Jiang
Liver regeneration after liver tumor resection or liver transplantation is crucial, the remaining liver frequently fails to regenerate in some patients. Oleanolic acid (OA), a pentacyclic triterpenoid compound which has been shown to protect against various liver diseases. However, the effect of OA on liver regeneration after partial hepatectomy (PHx) is still unclear. In this study, the results showed that OA (50 mg/kg, twice daily) treatment induced liver mass restoration and increased the liver-to-body weight ratio of mice following PHx. Meanwhile, OA promoted hepatocyte proliferation and increased the number of BrdU-, Ki67-and PCNA-positive cells. Furthermore, OA increased the nuclear accumulation of PXR and induced the expression of PXR downstream proteins such as CYP3A11, UGT1A1 and GSTM2 in mice, as well as in AML12 and HepRG cells. Luciferase reporter assay and nuclear localization of PXR further demonstrated the effect of OA on PXR activation in vitro . Molecular docking simulation showed that OA could interact with the PXR active sites. Moreover, OA inhibited the expression of FOXO1, RBL2 and CDKN1B, and increased the expression of PCNA, CCND1 and CCNE1 in vivo and in vitro . Silencing of Pxr further confirmed that OA-mediated upregulation of proliferation-related proteins depended on PXR. The current study illustrated that OA exhibited a significant promoting effect on liver regeneration following PHx, potentially through regulation of the PXR signaling pathway to accelerate liver recovery.
研究领域:
药理学
·
肝脏病学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Science China-Life Sciences
·
2025
·
IF 9.5
Feng Yue,Lin Zishen,Wang Haoran,Men Zhaoyue,Shen Jiakun,Ma Xi
Deoxynivalenol (DON) is a prevalent mycotoxin in animal feed that particularly impacts weaned piglets, causing liver damage, growth retardation, and posing significant public health risks. However, the precise mechanisms underlying DON-induced liver damage and optimal treatment approaches remain unclear. The pregnane X receptor (PXR) holds a pivotal position in hepatic xenobiotic elimination and drug metabolism. This research aimed to explore the involvement of PXR in DON-induced liver injury and evaluate the potential of the PXR agonist, 3-indolepropionic acid (IPA), to alleviate liver damage and associated diarrhea in weaned piglets under practical farming conditions. The results demonstrated that DON initiates p53-mediated hepatocyte apoptosis in weaned piglets. RNA-seq and hepatocyte-specific PXR knockout (PXR-HKO) mice revealed PXR’s regulatory role in DON-induced hepatocyte apoptosis. IPA reduces DON-induced hepatocyte apoptosis in piglets, mice, and hepatocyte cell lines by enhancing PXR expression and facilitating nuclear translocation. Furthermore, AlphaFold3 predictions and Co-IP assays demonstrate that DON diminishes PXR-p53 binding, thereby amplifying p53-mediated apoptotic transactivation. In conclusion, this study elucidates a novel mechanism by which PXR decreases its binding to p53 upon DON exposure, thereby promoting hepatocyte apoptosis. Additionally, it validates the positive impact of IPA in mitigating liver damage and diarrhea caused by DON in weaned piglets.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Acta Pharmaceutica Sinica B
·
2021
·
IF 11.614
Peihua Liu,Ling Jiang,Weimin Kong,Qiushi Xie,Ping Li,Xiaonan Liu,Jiayi Zhang,Ming Liu,Zhongjian Wang,Liang Zhu,Hanyu Yang,Ying Zhou,Jianjun Zou,Xiaodong Liu,Li Liu
Drug-induced hyperglycemia/diabetes is a global issue. Some drugs induce hyperglycemia by activating the pregnane X receptor (PXR), but the mechanism is unclear. Here, we report that PXR activation induces hyperglycemia by impairing hepatic glucose metabolism due to inhibition of the hepatocyte nuclear factor 4-alpha (HNF4 α )‒glucose transporter 2 (GLUT2) pathway. The PXR agonists atorvastatin and rifampicin significantly downregulated GLUT2 and HNF4 α expression, and impaired glucose uptake and utilization in HepG2 cells. Overexpression of PXR downregulated GLUT2 and HNF4 α expression, while silencing PXR upregulated HNF4 α and GLUT2 expression. Silencing HNF4α decreased GLUT2 expression, while overexpressing HNF4 α increased GLUT2 expression and glucose uptake. Silencing PXR or overexpressing HNF4 α reversed the atorvastatin-induced decrease in GLUT2 expression and glucose uptake. In human primary hepatocytes, atorvastatin downregulated GLUT2 and HNF4α mRNA expression, which could be attenuated by silencing PXR . Silencing HNF4α downregulated GLUT2 mRNA expression. These findings were reproduced with mouse primary hepatocytes. Hnf4α plasmid increased Slc2a2 promoter activity. Hnf4α silencing or pregnenolone-16 α -carbonitrile (PCN) suppressed the Slc2a2 promoter activity by decreasing HNF4 α recruitment to the Slc2a2 promoter. Liver-specific Hnf4α deletion and PCN impaired glucose tolerance and hepatic glucose uptake, and decreased the expression of hepatic HNF4 α and GLUT2. In conclusion, PXR activation impaired hepatic glucose metabolism partly by inhibiting the HNF4 α ‒GLUT2 pathway. These results highlight the molecular mechanisms by which PXR activators induce hyperglycemia/diabetes.
研究领域:
药理学
·
分子生物学
·
内分泌学
·
糖尿病研究
✓ 已验证
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2025
·
IF 4.7
Qiqi Yang,Yuan Yao,Junping Wang,Mengdi Pang,Jinyan Wu,Fusheng Yin,Jun He,Yanyan Wang,Weidong Chen
Non-small cell lung cancer (NSCLC) is characterized by a complex pathogenesis and high mortality. Targeted drug therapy represents a precise method of treatment. However, Improving sensitivity to targeted agents is currently a major challenge in clinical tumor therapy. Neogambogic acid (NGA), a bioactive compound isolated from the Traditional Chinese Medicine (TCM) Gamboge, has shown potential in NSCLC treatment. Nonetheless, the mechanism by which NGA enhances the sensitivity of NSCLC to the targeted drug Almonertinib remains unclear. This study aimed to elucidate the mechanisms underlying the ability of NGA to enhance the sensitivity of NSCLC to Almonertinib, revealing the synergistic effect exerted by the combination therapy. We established a subcutaneous grafted tumor model of mouse lung cancer by injecting Lewis cells, and evaluated the therapeutic efficacy in vivo . The study demonstrated that NGA combined with Almonertinib effectively suppressed NSCLC tumor growth by promoting cancer cell apoptosis and reducing serum tumor marker levels. In vitro experiments revealed that this combination synergistically inhibited lung cancer cell proliferation and induced apoptosis. Mechanistically, NGA demonstrated the ability to bind to Pregnane X receptor (PXR), regulating the expression of drug-metabolizing enzymes and transporters. We further validated this effect using PXR agonists and inhibitors in A549 cells. Additionally, the combination of NGA with Almonertinib significantly inhibited aberrant EGFR activation and downstream PI3K/AKT signaling, leading to enhanced apoptosis. This study demonstrated that the combination of NGA and Almonertinib inhibited the expression of CYP3A4, P-gp, and BCRP via PXR modulation. Meanwhile, it inhibited the EGFR/PI3K/AKT pathway and enhanced the sensitivity of NSCLC to Almonertinib, exerting synergistic anti-tumor effects. Our findings suggest a promising strategy for integrating active TCM components with targeted therapy in NSCLC management.
研究领域:
肿瘤学
·
药理学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INFLAMMATION
·
2020
·Vol. 44
·期 2
·645-658
·
IF 3.212
Shao Yun-yun,Guo Yao,Feng Xiao-juan,Liu Jun-jin,Chang Zhuang-peng,Deng Gui-feng,Xu Ding,Gao Jian-ping,Hou Rui-gang
To investigate the beneficial effects of oridonin, a diterpenoid compound isolated from Rabdosia rubescens, on the inflammatory response in TNBS-induced post-inflammatory irritable bowel syndrome (PI-IBS) model and the underlying mechanism. Using the PI-IBS rat model and Caco-2 cell lines, we found that intestinal barrier function reflected by lactulose/mannitol (L/M) ratio and tight junction protein level was significantly ameliorated by oridonin. We also demonstrated that oridonin abrogated inflammation through inhibiting the phosphorylation of NF-κBp65 as well as its downstream gene (iNOS, COX-2, IL-1β, and IL-6) level. Molecular docking studies confirmed the good binding activity between oridonin and PXR. In Caco-2 cell lines, oridonin markedly inhibited LPS-induced NF-κB activation in a PXR-dependent manner. Meanwhile, PXR and its target genes CYP3A4 and P-gp were induced by oridonin, which was associated with the decreased expression of NF-κB and the recovery of intestinal barrier. This study indicated that the therapeutic effect of oridonin on experimental PI-IBS through repairing intestinal barrier function may be closely associated with the regulatory role of PXR/NF-κB signaling pathway. Oridonin may serve as a PXR ligand for the development of drugs in the therapy for PI-IBS.
研究领域:
药理学
·
胃肠病学
·
分子生物学
·
细胞生物学
✓ 已验证
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）