JOURNAL OF MEDICINAL CHEMISTRY
·
2026
·
IF 7.3
Xuan Li,Lei Zheng,Xiaowen Jiang,Haiguo Su,Chuoying Mai,Jinyi Li,Yujie Ni,Yonglin He,Wanyu Zheng,Qingqing Yu,Guofang Bi,Hui Ouyang,Shuang Hu,Chenghua Wu,Dan Li,Fengting Liang,Wenhong Zhou,Xiao Yang,Shicheng Fan,Jianhong Fang,Zhongzhen Zhou,Huichang Bi
Abstract Partial hepatectomy (PHx) and liver transplantation are the most effective interventions for end-stage liver diseases, yet druggable targets that promote donor or remnant liver regeneration are critically lacking. Pregnane X receptor (PXR), a key regulator of liver regeneration, is a promising therapeutic target. Previously, we identified the natural product Schisandrol B (SolB) as a PXR agonist to promote liver regeneration. To further improve its PXR activity and selectivity, the present study performed structural simplification of SolB and identified BZZ-034, a ring-opened analogue with an isobutyl amide side chain, as a novel PXR agonist. BZZ-034 exhibited higher PXR binding affinity and stronger transcriptional efficacy than SolB, along with greater selectivity against related nuclear receptors. In vivo, BZZ-034 significantly promoted hepatomegaly and accelerated liver regeneration after PHx in mice. These findings identify BZZ-034 as a promising lead compound and demonstrate that structural simplification is an effective strategy for optimizing complex natural products.
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DOI
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2021
·
IF 4.36
Qiwei Liu,Yunwen Xue,Jingjing Liu,Siqi Ren,Jie Xu,Jinni Yang,Yuanyue Xing,Zunjian Zhang,Rui Song
Ethnopharmacological relevance Radix Bupleuri (RB), traditionally used to treat inflammatory disorders and infectious diseases, represents one of the most successful and widely used herbal drugs in Asia over the past 2000 years. Being realized the role in regulating metabolism and controlling Yin/Yang, RB is not only chosen specifically for treating liver meridian and the corresponding organs, but also believed to have liver meridian guiding property and help potentiate the therapeutic effects of liver. However, the ingredients in RB with liver meridian guiding property and the underly mechanism have not been comprehensively investigated. Aim of study Considering the important role of CYP3A4 in first-pass metabolism and the liver exposure of drugs, the present study aimed to determine whether saikosaponins (SSs) and the corresponding saikogenins (SGs) have a role in inhibiting the catalytic activity of CYP3A4 in human liver microsomes and HepG2 hepatoma cells and whether they could suppress CYP3A4 expression by PXR-mediated pathways in HepG2 hepatoma cells. Materials and methods The effect of SSs and SGs on CYP3A4-mediated midazolam1′-hydroxylation activities in pooled human liver microsomes (HLMs) was first studied. Dose-dependent experiments were performed to obtain the half inhibit concentration (IC 50 ) values. HepG2 cells were used to assay catalytic activity of CYP3A4, reporter function, mRNA levels, and protein expression. The inhibitory effects of SSa and SSd on CYP3A4 activity are negligible, while the corresponding SGs (SGF and SGG) have obvious inhibitory effects on CYP3A4 activity, with IC 50 values of 0.45 and 1.30 μM. The similar results were obtained from testing CYP3A4 catalytic activity in HepG2 cells, which correlated well with the suppression of the mRNA and protein levels of CYP3A4. Time-dependent testing of CYP3A4 mRNA and protein levels, as well as co-transfection experiments using the CYP3A4 promoter luciferase plasmid, further confirmed that SSs and SGs could inhibit the expression of CYP3A4 at the transcription level. Furthermore, PXR protein expression decreased in a concentration- and time-dependent manner after cells were exposed to SSs and SGs. PXR overexpression and RNA interference experiments further showed that SSs and SGs down-regulate the catalytic activity and expression of CYP3A4 in HepG2 may be mainly through PXR-dependent manner. Conclusion SSs and SGs inhibit the catalytic activity and expression of CYP3A4 in a PXR-dependent manner, which may be highly related to the liver meridian guiding property of RB.
研究领域:
药理学
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民族药理学
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分子生物学
·
中医
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DOI
PubMed
高影响因子
BRITISH JOURNAL OF PHARMACOLOGY
·
2026
·
IF 7.5
Mei Feng,Xin Yang,Kuo Yao,Ke-Fan Yang,Xiang-Yi Zhan,Ming-Sheng Zhou,Hui Jia
Background and Purpose Previous studies have found that activation of the γ-secretase/NICD-PXR/Notch pathway can induce Taxol resistance in triple-negative breast cancer (TNBC) to limit its therapeutic effect. Accordingly, inhibition of the γ-secretase/Notch pathway maybe an effective strategy to enhance Taxol chemosensitivity in TNBC. We have already found that cimigenoside (CG), the active ingredient of Cimicifuga dahurica (Turcz.) Maxim, can inhibit γ-secretase activity. Experimental Approach The dynamic interaction between the natural γ-secretase inhibitor CG and γ-secretase catalytic core presenilin-1 (PSEN-1) was revealed by molecular dynamics simulations and in vitro enzyme activity experiments. The biological characterisation and in vivo role of CG in increasing Taxol sensitivity of TNBC were investigated. The regulatory effect of CG on the γ-secretase/RBPJ-PXR axis was studied through dual luciferase reporter gene assays, nuclear cytoplasmic separation experiments, and western blot assays. Key Results CG stably binds to the PSEN-1 protein cavity to inhibit γ-secretase activity. In vitro studies showed that CG significantly enhanced the inhibition of cell proliferation, migration and invasion, as well as the promotion of apoptosis of MDA-MB-231/Taxol cells by Taxol. CG enhanced the inhibitory effect of Taxol on subcutaneous tumours and lung metastatic TNBC in vivo. Mechanistically, CG inhibited the transcriptional activity of RBPJ by targeting γ-secretase, interfered with the interaction between RBPJ and pregnane X receptor (PXR), down-regulated the expression of PXR-regulated metabolic enzymes and transport proteins, and enhanced the sensitivity of TNBC to Taxol. Conclusions and Implications We show that CG enhances the chemical sensitivity of TNBC by regulating the γ-secretase/RBPJ-PXR axis. Graphical
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PubMed
高影响因子
ARCHIVES OF TOXICOLOGY
·
2026
·
IF 10.9
Huang Fang-Fang,Luo Ying,Chen Hao,Meng Yu-Huan,Li Wei,Liang Hong,Ai Chun-Zhi
Pregnane X receptor (PXR), a nuclear receptor superfamily member, maintains bile acid homeostasis by regulating metabolic enzymes [e.g., cytochrome P450 3A4 (CYP3A4), uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1)] and multidrug resistance protein 1 transporter, and alleviates liver/intestinal inflammation via inhibiting the nuclear factor kappa-B pathway, serving as a critical therapeutic target for cholestatic liver diseases and inflammatory bowel disease. In this study, we established a novel structure-based machine learning strategy to identify PXR agonists from a natural product database. With generated bioactive conformations binding with PXR, we integrated ligand-based and structure-based features to construct a comprehensive machine learning model using light gradient boosting machine. This model illustrated an R 2 of 0.874 for the internal validation set and an R 2 of 0.845 for the external test set, superior to the performance of other machine learning models, e.g. random forest regression, support vector regression, gradient boosting regression, K-nearest neighbors, and extreme gradient boosting. The model was used to predict the PXR agonistic activity of the candidate molecules screened out by the pharmacophore model. Promising candidates were selected out for further assay with HepG2 cell culture combined with a dual-luciferase reporter. Ultimately, natural products like schisantherin A, rhynchophylline, and irigenin were identified as potent PXR agonists, with half-maximal effective concentrations (EC 50 ) of 1.58 μM, 2.57 μM, and 20.67 μM, respectively. These PXR agonists act as potential candidates for targeted therapies against PXR-related diseases. We anticipate that this work will provide support for the design and discovery of PXR modulators.
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DOI
PubMed
高影响因子
BRITISH JOURNAL OF PHARMACOLOGY
·
2017
·Vol. 174
·期 8
·672-688
·
IF 5.491
Hang Zeng,Yiming Jiang,Pan Chen,Xiaomei Fan,Dongshun Li,Aiming Liu,Xiaochao Ma,Wen Xie,Peiqing Liu,Frank J Gonzalez,Min Huang,Huichang Bi
Background and Purpose Currently, ursodeoxycholic acid and obeticholic acid are the only two FDA-approved drugs for cholestatic liver diseases. Thus, new therapeutic approaches need to be developed. Here we have evaluated the anti-cholestasis effects of Schisandrol B (SolB), a bioactive compound isolated from Schisandra sphenanthera . Experimental Approach Hepatoprotective effect of SolB against intrahepatic cholestasis, induced by lithocholic acid (LCA), was evaluated in mice. Metabolomic analysis and gene analysis were used to assess involvement of pregnane X receptor (PXR). Molecular docking, cell-based reporter gene analysis and knockout mice were used to demonstrate the critical role of the PXR pathway in the anti-cholestasis effects of SolB. Key Results SolB protected against LCA-induced intrahepatic cholestasis. Furthermore, therapeutic treatment with SolB decreased mortality in cholestatic mice. Metabolomics and gene analysis showed that SolB accelerated metabolism of bile acids, promoted bile acid efflux into the intestine, and induced hepatic expression of the PXR-target genes Cyp3a11, Ugt1a1 , and Oatp2, which are involved in bile acid homeostasis. Mechanistic studies showed that SolB activated human PXR and up-regulated PXR target genes in human cell lines. Additionally, SolB did not protect Pxr -null mice from liver injury induced by intrahepatic cholestasis, thus providing genetic evidence that the effect of SolB was PXR-dependent. Conclusion and Implications These findings provide direct evidence for the hepatoprotective effects of SolB against cholestasis by activating PXR. Therefore, SolB may provide a new and effective approach to the prevention and treatment of cholestatic liver diseases.
研究领域:
肝病学
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药理学
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分子生物学
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DOI
PubMed
高影响因子
AQUATIC TOXICOLOGY
·
2022
·
IF 5.202
Jia Hu,Jingjing Tian,Tongkuo Yuan,Qingqing Yin,Jian Yin
Despite the increasing evidences for adenosine triphosphate-binding cassette (ABC transporters)-mediated efflux of nanoparticles, the universality of these phenomena and the determining factors for the process remained to be clarified. This paper aimed to systemically investigate the role of nanoparticle size in the interactions between adenosine triphosphate-binding cassette (ABC transporters) and gold nanoparticles (AuNPs, 3 nm, 19 nm, and 84 nm, named as Au-3, Au-19, and Au-84) in zebrafish embryos. The results showed that all the three AuNPs induced significant toxicity as reflected by delayed hatching of embryos, decreased glutathione (GSH) contents, and increased reactive oxygen species (ROS) levels. Under the hindrance of embryo chorions, smaller AuNPs could more easily accumulate in the embryos, causing higher toxicity. Addition of transporter inhibitors enhanced the accumulation and toxicity of Au-3 and Au-19, and these nanoparticles induced the expressions of abcc2 and abcb4 , indicating a fact that Au-3 and Au-19 were the potential substrates of ABC transporters, but these phenomena were barely found for Au-84. On the contrary, Au-84 suppressed the gene expressions of various ABC transporters like abcc1, abcg5, and abcg8 . With specific suppressors, transcription factors like nuclear factor-erythroid 2-related factor-2 (Nrf2) and pregnane X receptor (Pxr) were found to be important in the induction of ABC transporters by AuNPs. After all, these results revealed a vital role of nanoparticle sizes in the interactions between ABC transporters and AuNPs in zebrafish embryos, and the critical size could be around 19 nm. Such information would be beneficial in assessing the environmental risk of nanoparticles, as well as their interactions with other chemical toxicants.
研究领域:
环境科学
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毒理学
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分子生物学
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纳米技术
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产品关联
DOI
PubMed
高影响因子
ACTA PHARMACOLOGICA SINICA
·
2021
·Vol. 43
·期 8
·2139-2146
·
IF 6.15
Huang Dong,Zhao Ying-yuan,Wang Rui-min,Li Wei,Yuan Fang-yu,Yan Xue-long,Yang Xiao,Tang Gui-hua,Yin Sheng,Bi Hui-chang
Cholestasis is a major cause of a series of bile flow malfunction-related liver diseases. Pregnane X receptor (PXR) is a key regulator in endo- and xeno-biotics metabolism, which has been considered as a promising therapeutic target for cholestasis. In this study we conducted human PXR (hPXR) agonistic screening using dual-luciferase reporter gene assays, which led to discovering a series of potent hPXR agonists from a small Euphorbiaceae diterpenoid library, containing 35 structurally diverse diterpenoids with eight different skeleton types. The most active compound 6 , a lathyrane diterpenoid (5/11/3 ring system), dose-dependently activated hPXR with a high selectivity, and significantly upregulated the expression of hPXR downstream genes CYP3A4 and UGT1A1 . In LCA-induced cholestasis mouse model, administration of compound 6 (50 mg· kg −1 . d −1 , ip) for 7 days significantly suppressed liver necrosis and decreased serum levels of AST, ALT, Tbili, ALP, and TBA, ameliorating LCA-induced cholestatic liver injury. We further revealed that compound 6 exerted its anti-cholestatic efficacy via activation of PXR pathway, accelerating the detoxification of toxic BAs and promoting liver regeneration. These results suggest that lathyrane diterpenoids may serve as a promising scaffold for future development of anti-cholestasis drugs.
研究领域:
药理学
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肝病学
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分子生物学
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DOI
PubMed
高影响因子
DRUG METABOLISM AND DISPOSITION
·
2020
·Vol. 48
·期 9
·830-839
·
IF 3.231
Tingying Jiao,Xinpeng Yao,Yingyuan Zhao,Yanying Zhou,Yue Gao,Shicheng Fan,Panpan Chen,Xuan Li,Yiming Jiang,Xiao Yang,Frank J. Gonzalez,Min Huang,Huichang Bi
Dexamethasone (Dex), a widely prescribed anti-inflammatory drug, was reported to induce liver enlargement (hepatomegaly) in clinical practice and in animal models. However, the underlying mechanisms are not elucidated. Dex is a known activator of pregnane X receptor (PXR). Yes-associated protein (YAP) has been implicated in chemically induced liver enlargement. Here, the roles of PXR and YAP pathways were investigated in Dex-induced hepatomegaly. Upregulation of PXR downstream proteins, including cytochrome P450 (CYP) 3A11, 2B10, and organic anion transporter polypeptide 2 (OATP2) (also known as SLCO1A4 and SLC21A5 in mouse), indicated PXR signaling was activated after high dose of Dex (50 mg/kg, i.p.), and Dex at 100 μM activated PXR in the dual-luciferase reporter gene assay. Dex also increased the expression of total YAP, nuclear YAP, and YAP downstream proteins, including connective tissue growth factor and cysteine-rich angiogenic inducer 61, indicating activation of the YAP pathway. Furthermore, nuclear translocation of YAP was promoted by activation of PXR. However, hepatocyte proliferation was inhibited with significant decrease in the expression of proliferation-related proteins cyclin D1 and proliferating cell nuclear antigen as well as other regulatory factors, such as forkhead box protein M1, c-MYC, and epidermal growth factor receptor. The inhibitory effect of Dex on hepatocyte proliferation was likely due to its anti-inflammation effect of suppression of inflammation factors. β-catenin staining revealed enlarged hepatocytes, which were mostly attributable to the accumulation of lipids, such as triglycerides. In summary, high-dose Dex increased liver size accompanied by enlarged hepatocytes, and this was due to the activation of PXR/YAP and their effects on lipid accumulation but not hepatocyte proliferation. These findings provide new insights for understanding the mechanism of Dex-induced hepatomegaly.
研究领域:
药理学
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肝病学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
BRITISH JOURNAL OF PHARMACOLOGY
·
2024
·
IF 6.8
Qian-Wen Zhang,Meng-Jiao Yang,Chun-Yu Liao,Reham Taha,Qing-Yu Li,Mohammed Ismail Abdelmotalab,Si-Yu Zhao,Yan Xu,Zhen-Zhou Jiang,Cheng-Han Chu,Xin Huang,Chun-Hua Jiao,Li-Xin Sun
Background and Purpose Ulcerative colitis (UC) is an idiopathic inflammatory bowel disease, and the range of current clinical treatments is not ideal. We previously found that polysaccharide of Atractylodes macrocephala Koidz (PAMK) is beneficial in DSS-induced colitis, and we aimed to investigate the underlying mechanisms in this study. Experimental Approach PAMK was used to treat DSS-induced colitis in mice, 16S rRNA sequencing analysis was used to detect changes in the intestinal microbiota, targeted metabolomics analysis was used to determine the content of tryptophan-metabolizing bacteria, and western blotting was used to determine aryl hydrocarbon receptor (AhR) and pregnane X receptor (PXR) levels. Furthermore, antibiotic-mediated depletion of gut microbiota and faecal microbiota transplantation were performed to assess the role of the gut microbiota in PAMK alleviation of colitis. Key Results PAMK treatment relieved intestinal microbiota dysbiosis in mice with colitis, contributed to the proliferation of tryptophan-metabolizing bacteria, and increased the levels of tryptophan metabolites, resulting in a significant increase in the nuclear translocation of PXR and expression of PXR and its target genes, but not AhR. The gut microbiota is important in PAMK treatment of colitis, including in the alleviation of symptoms, inhibition of inflammation, maintenance of the integrity of the intestinal barrier, and the regulation of the Th17/Treg cell balance. Conclusion and Implications Based on our findings, we elucidate a novel mechanism by which PAMK alleviates DSS-induced colitis and thus provides evidence to support the potential development of PAMK as a new clinical drug against UC.
研究领域:
免疫学
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微生物学
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药理学
·
胃肠病学
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DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2024
·
IF 6.7
Jia-Yi Dou,Mei-Jie Zhou,Mei-Yan Xuan,Jia Guo,Sai-Hu Liu,Li-Hua Lian,Zhen-Yu Cui,Ji-Xing Nan,Yan-Ling Wu
Background Astilbin (ATB), a natural dihydroflavonol compound, exists in many plants, processed and functional foods. ATB has multiple pharmacological effects, such as antioxidant, lipid-lowering, and hepatoprotective. However, its anti-hepatic fibrosis and mechanisms remain unclearly elucidated. Purpose This study explored the effect of ATB against the hepatic fibrosis and its regulation of hepatic microenvironment by regulating hepatic stellate cells-macrophage crosstalk. Method Thioacetamide (TAA) was intraperitoneal injected to establish hepatic fibrosis mice, and treated with ATB or curcumin by gavage, respectively. Hepatic stellate cells (HSCs) were stimulated with TGF-β or conditioned medium (CM) from LPS-induced THP-1, then cultured with ATB, PXR agonist or antagonist. Results In TAA-induced mice, ATB improved histopathological changes, serum transaminases increase; alleviated extracellular matrix (ECM) deposition, epithelial-mesenchymal transformation (EMT), inflammatory infiltration, PTEN induced kinase 1 (PINK1)/Parkin-mediated mitophagy and activated pregnane X receptor (PXR) expression. In vitro , ATB significantly reduced ECM, inflammatory cytokines release, mitophagy, EMT, and activated PXR expression. ATB could increase PXR and decrease PINK1/Parkin, functioning as a PXR agonist. PXR deficiency in LX-2 could degrade the regulation of ATB on ECM, inflammation, EMT, and mitophagy. CM from LPS-induced THP-1 activated LX-2 and resulted in PXR decreasing, while ATB could regulate the crosstalk between HSCs and macrophages. Deficiency of PXR, whether in LX-2 or in macrophages, all weakened the inhibitory effect of ATB on α-SMA, EMT, inflammatory cytokines, and PINK1/Parkin signaling. Conclusion ATB ameliorated hepatic fibrosis by inhibiting HSCs activation, inflammation and EMT through PXR-mediated PINK1/Parkin signaling. Especially, ATB targeted the hepatic microenvironment between hepatic stellate cells and macrophages, which might be a promising strategy for the treatment of hepatic fibrosis.
研究领域:
药理学
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肝病学
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细胞生物学
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免疫学
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产品关联
DOI
PubMed
高影响因子
ACTA PHARMACOLOGICA SINICA
·
2022
·Vol. 44
·期 1
·169-177
·
IF 7.169
Zhang Yi-fei,Gao Yue,Yang Jie,Jiang Yi-ming,Huang Min,Fan Shi-cheng,Bi Hui-chang
Pregnane X receptor (PXR) is highly expressed in the liver and plays a pivotal role in xenobiotic and endobiotic metabolism. We previously reported that PXR activation by its specific mouse agonist pregnenolone 16α-carbonitrile (PCN) significantly induces liver enlargement and lipid accumulation. However, the effect of long-term PCN treatment on PXR and mouse liver is still unknown. This study aimed to explore the influence of long-term administration of PCN on mouse liver and hepatic lipid homeostasis. Male C57BL/6 mice were injected intraperitoneally with PCN (100 mg/kg once a week) for 42 weeks. Serum and liver samples were collected for biochemical and histological analysis. PXR activation was investigated by Western blot. Ultra-high-performance liquid chromatography coupled with electrospray ionization high-resolution mass spectrometry (UHPLC-ESI-HRMS)-based lipidomics analysis was performed to explore the change in different lipid categories. The results showed that long-term treatment with PCN significantly promoted hepatomegaly without hepatocyte proliferation and enlargement. Long-term treatment with PCN did not upregulate PXR target proteins in mice, and there was no significant upregulation of CYP3A11, CYP2B10, UGT1A1, MRP2, or MRP4. Lipidomics analysis showed obvious hepatic lipid accumulation in the PCN-treated mice, and the most significant change was found in triglycerides (TGs). Additionally, long-term treatment with PCN had no risk for carcinogenesis. These findings demonstrated that long-term PCN treatment induces hepatomegaly and lipid accumulation without hepatocyte proliferation or enlargement.
研究领域:
药理学
·
毒理学
·
肝病学
·
脂质代谢
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产品关联
DOI
PubMed
高影响因子
ACS Chemical Neuroscience
·
2022
·
IF 5.78
Qianlei Zhao,Tingting Chen,Chao Ni,Yingying Hu,Yan Nan,Wei Lin,Yanli Liu,Feixia Zheng,Xulai Shi,Zhongdong Lin,Jianghu Zhu,Zhenlang Lin
The blood–brain barrier (BBB) is an important physiological barrier of the human body contributing to maintaining brain homeostasis and normal function. Hypoxic-ischemic (HI)-related brain injury is one of the main causes of neonatal acute morbidity and chronic disability. The previous research of our group confirmed that there was serious BBB destruction during HI brain injury. However, at present, the protection strategy of BBB is very limited, and further research on the protection mechanism is warranted. Indole-3-propionic acid (IPA) is a bacterial metabolism with anti-inflammatory and antioxidant properties, having neuroprotective effects and protective effects on the mucosal barrier. However, the role of IPA in BBB is not clear. In this research, we demonstrated the protective effect of IPA on BBB disruption from HI brain injury and hypothesized that it involves the amelioration of inflammation, oxidative stress, and MMP activation, thereby inhibiting apoptosis of rat brain microvascular endothelial cells (rBMECs). We demonstrated that expression levels of several inflammatory markers, including iNOS, TNF-α, IL-6, and IL-1β, were significantly increased from HI damage or OGD injury. However, IPA treatment inhibited the increase significantly. Moreover, we demonstrated that IPA reduced intracellular ROS levels and MMP activation in rBMECs from OGD injury. Further research on the underlying detailed molecular mechanisms suggested that IPA attenuates inflammation by inhibiting NF-κB signaling. Finally, we investigated the mechanism of the relationship between PXR activation and NF-κB inhibition. The results suggested overexpression of PXR in rBMECs could significantly counteract the decrease of junction proteins and downregulate the increased p-IκB-α and p-NF-κB from OGD injury. However, the protective effects of IPA were reversed by antagonists of the PXR. Taken together, IPA might mitigate HI-induced damage of the BBB and the protective effect may be exerted through modulating the PXR signaling pathway.
研究领域:
神经科学
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药理学
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细胞生物学
·
分子生物学
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DOI
PubMed
高影响因子
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