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
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产品关联
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
✓ 已验证
DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2022
·
IF 6.1
Hangfei Liang,Xiao Yang,Huilin Li,Xinhui Wang,Haiguo Su,Xuan Li,Jianing Tian,Chenghui Cai,Min Huang,Huichang Bi
Previously, we demonstrated that Schisandrol B (SolB) protected against lithocholic acid (LCA)-induced cholestatic liver injury (CLI) through pregnane X receptor (PXR). Additionally, growing evidence has revealed that pyroptosis is involved in CLI. Whether the hepatoprotective effect of SolB driven by PXR activation is related to pyroptosis in CLI remains unclear. First, the hepatoprotective effect of SolB was confirmed, as evidenced by the decreased mortality, morphological and histopathological changes, and biochemical parameters. The upregulated serum lactic dehydrogenase (LDH) level, increased number of TUNEL-positive cells, and formation of hepatocyte membrane pores induced by LCA were significantly alleviated after SolB pretreatment, indicating that SolB attenuated LCA-induced hepatocyte damage. Further analysis revealed that both NOD-like receptor protein 3 (NLRP3) inflammasome-induced canonical pyroptosis and apoptosis protease activating factor-1 (Apaf-1) pyroptosome-induced noncanonical pyroptosis were significantly inhibited after SolB pretreatment, as illustrated by the decreased expression levels of NLRP3, ASC, caspase-1, and GSDMD and the levels of Apaf-1, caspase-11 p20, caspase-3 p20, and GSDME. Furthermore, the activation of the NF-κB and FoxO1 signaling pathways was inhibited after SolB pretreatment. In addition, the activation of PXR via SolB was proven by luciferase reporter gene assays and the upregulation of PXR targets. The results illustrated that SolB could significantly inhibit NLRP3 inflammasome-induced canonical pyroptosis through the PXR/NF-κB/NLRP3 axis and inhibit Apaf-1 pyroptosome-induced noncanonical pyroptosis through the PXR/FoxO1/Apaf-1 axis. Collectively, this study revealed that SolB protected against CLI by inhibiting pyroptosis through PXR, providing new insights for understanding the molecular mechanism of SolB as a promising anti-cholestatic agent.
研究领域:
药理学
·
肝病学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
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.
✓ 已验证
DOI
高影响因子
Chinese Medicine
·
2026
·Vol. 21
·期 1
·116
·
IF 7.4
Yang Xiao,Liang Hangfei,Li Xuan,Tian Jianing,Fan Shicheng,Huang Min,Wan Jianbo,Zuo Zhong,Guo Haibiao,Bi Huichang
Background Mitochondrial biogenesis plays a vital role in various types of hepatocyte injury. Schisandrol B (SolB), a bioactive lignan isolated from Schisandra sphenanthera , exerts a significant hepatoprotective effect against lithocholic acid (LCA)-induced cholestatic liver injury. Whether mitochondrial biogenesis is involved in the anti-cholestasis effect of SolB remains unknown. Methods A mouse model of cholestatic liver injury was induced by intraperitoneal injection of LCA. SolB was administered orally twice a day. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), total bile acids (TBA) and total bilirubin (TBILI), as well as hepatic superoxide dismutase (SOD) activity were measured. Liver pathology was evaluated by toxylin and eosin (H&E) staining. Mitochondrial morphology was examined using electron microscopy. Furthermore, the expression of mitochondrial biogenesis-related genes or proteins was analyzed by RT-qPCR or Western blot. Results We confirmed that SolB pretreatment (200 mg/kg/d) alleviated LCA-induced liver injury as evidenced by histological and biochemical analyses. SolB alleviated LCA-induced mitochondrial dysfunction in mice, as evidenced by increased mitochondrial DNA (mtDNA) content, superoxide dismutase (SOD) levels, and peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α) and mitochondrially encoded cytochrome c oxidase subunit 1 (MTCO1) expression, together with decreased fibroblast growth factor 21 ( Fgf21 ) and growth differentiation factor 15 ( Gdf15 ) gene levels. Transmission electron microscope analysis showed that LCA elicited small, fragmented mitochondria, which were not reversed after SolB pretreatment. However, western blot analysis showed that the expression of mitochondrial dynamics-related proteins, such as dynamin-related protein1 (DRP1), optic atrophy 1 (OPA1), mitofusin 1 (MFN1), and MFN2, was significantly decreased after LCA treatment. Pretreatment with SolB could significantly upregulate DRP1, mitochondrial fission factor (MFF), and fission1 (FIS1) which are crucial to regulate mitochondrial fission. It is worth noting that the protective effect of SolB against LCA-induced liver injury was independent of parkin RBR E3 ubiquitin-protein ligase (PARKIN)-mediated mitophagy as evidenced by decreased PARKIN and microtubule-associated protein light chain 3 (LC3)-II. Conclusion In summary, this study demonstrated that SolB improved mitochondrial function but had no effect on LCA-induced mitochondrial fragmentation, which provides new insights into better understanding hepatoprotective mechanism of SolB against cholestatic liver injury.
✓ 已验证
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2024
·
IF 6.7
Peng Wang,Hui Ouyang,Guofang Bi,Fengting Liang,Shuang Hu,Chenhua Wu,Xiaowen Jiang,Wenhong Zhou,Dan Li,Shuaishuai Zhang,Xiao Yang,Mingliang Zhao,Jian-Hong Fang,Haitao Wang,Wei Jia,Zheng-jiang Zhu,Huichang Bi
Background Depression is a widely recognized neuropsychiatric disorder. Recent studies have shown a potential correlation between bile acid disorders and depression, highlighting the importance of maintaining bile acid balance for effective antidepressant treatment. Schisandrol B (SolB), a primary bioactive compound from Schisandra chinensis(Turcz.)Baill. or Schisandra sphenanthera Rehd.etWils, is pivotal in regulating bile acid homeostasis via pregnane X receptor (PXR) in cholestasis. However, the potential of SolB in alleviating depression-like symptoms, its pharmacological effects, and the underlying mechanisms remain to be fully elucidated. Methods We confirmed the effect of SolB against depression induced by chronic restraint stress (CRS) and chronic unpredictable mild stress (CUMS) in mice. The role of SolB in bile acid homeostasis in depression was analyzed using the metabolomic. Gene analyses and 16S rRNA sequencing were employed to investigate the involvement of PXR. Experiments with Pxr −/− mice were conducted to confirm the essential role of the PXR pathway in SolB's antidepressant effects. Results SolB treatment significantly increased sucrose consumption in the SPT and the locomotor activity in the OFT, while decreasing immobility time in the FST and TST in mice exposed to CRS and CUMS. Additionally, SolB treatment significantly preserved the integrity of the dendritic spine, elevated synaptic protein PSD95 levels, and augmented CREB/BDNF expression. Metabolomic and gene analyses indicated that SolB treatment significantly facilitated bile acid metabolism, promoted intestinal bile acid efflux, decreased hippocampal levels of the secondary bile acids DCA and TLCA, and upregulated expression of the PXR target proteins CYP3A11, SULT2A1, MRP2, and OATP1B1 in the liver, and MRP2 and MDR1 in hippocampus, which are integral to bile acid homeostasis. 16S rRNA sequencing revealed that SolB reduced the abundance of the bile salt hydrolase (BSH)-producing bacteria Lactobacillus johnsonii and Bacteroides fragilis and subsequently decreased the production of TLCA and DCA. Moreover, SolB failed to protect against depression induced by CRS in Pxr -null mice, suggesting that the antidepressant effect of SolB was PXR-dependent. Conclusions These results provide direct evidence of the antidepressant effect of SolB via activation of PXR to regulate bile acid homeostasis in the brain-liver-gut axis, suggesting that SolB may serve as a novel potential target for preventing and treating depression.
研究领域:
神经科学
·
药理学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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