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
·
药理学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2025
·
IF 5.4
Junying Li,Xiaoxiao Shan,Yu Gao,Haizhou Zhu,Hongyan Cheng,Chengjie Xing,Lele Zhou,Wenkang Tao,Yangyang Li,Baoqi Yin,Caiyun Zhang
Ethnopharmacological relevance Kai-Xin-San (KXS) has a significant effect therapeutic on Alzheimer's disease (AD) in clinical practice. According to the compatibility theory of traditional Chinese medicine, Acori Tatarinowii Rhizoma (ATR) serves as the guiding drug in the KXS formulation and is believed to enhance the bioavailability and brain tissue distribution of the other drugs. However, the mechanism underlying the “guiding medicine upwards” effect of ATR in KXS remains unexplored. Aim of the study The aim of this study is to investigate the role of ATR in the efficacy of KXS on amyloid precursor protein/presenilin 1 (APP/PS1) mice, as well as its impact on the brain tissue distribution of other active ingredients in the KXS formula, and to elucidate the mechanism of ATR's “guiding medicine upwards” effect in KXS. Materials and methods The pharmacodynamic effects of ATR in KXS were assessed through behavioral tests, immunohistochemical staining, and Nissl staining. Additionally, the levels of inflammatory factors, as well as the activities of malondialdehyde, superoxide dismutase, and acetylcholinesterase, were measured using enzyme-linked immunosorbent assay kits. Subsequently, the effect of ATR on the ultrastructure of the blood-brain barrier (BBB) in APP/PS1 mice was observed using transmission electron microscopy (TEM), and the pharmacodynamic components of KXS in cerebrospinal fluid were quantified by ultra-high-performance liquid chromatography-triple quadrupole mass spectrometry (UPLC-MS/MS). Furthermore, Western blot (WB) analysis was used to quantitatively assess the expression of tight junction proteins (Claudin-5, Occludin, and ZO-1) and transporters (OCT3, OATP2, P-gp, and MRP1) in the BBB. Finally, bEND.3 cells and astrocyte cells were co-cultured to validate the effect of ATR on KXS. The expressions of OCT3/OATP2 and P-gp/MRP1 in BBB cell model were determined by WB and the content of pharmacodynamic components in the lower chamber of the transwell were also analyzed by UPLC-MS/MS. Results Behavioral test results suggest that KXS significantly improved the learning and memory capacities of APP/PS1 mice compared to the ATR-free KXS group. Furthermore, KXS was more effective in reducing amyloid-β protein deposition in the brain and repairing damaged neurons in the CA1 and CA3 regions than ATR-free KXS. Notably, KXS significantly reversed the pathological biochemical indices compared to the ATR-free KXS group. These results indicate that ATR has a positive effect on the pharmacodynamics of KXS in treating AD. Most importantly, TEM results revealed that KXS repaired the damaged BBB in AD mice, and ATR contributed to the improvement of BBB integrity. Furthermore, KXS and ATR increased the expression levels of Claudin-5, Occludin, and ZO-1 proteins in AD mice. Meanwhile, the levels of ginsenoside Rg1, ginsenoside Rb1, and polygalaxanthone III in the cerebrospinal fluid of the KXS group were 1.47, 1.39, and 2.02 times higher than those in the ATR-free KXS group, respectively. WB results showed that ATR and KXS significantly upregulated the expression of OCT3/OATP2 uptake transporters and downregulated the expression of P-gp/MRP1 efflux transporters compared to ATR-free KXS. Concurrently, in vitro BBB cell experimental results suggest that ATR promoted the transport of ginsenoside Rg1, ginsenoside Rb1, and polygalaxanthone III across BBB cells in KXS, and the regulation of OCT3/OATP2 and P-gp/MRP1 expression was consistent with the in vivo trends observed in AD mice. Conclusions ATR plays a critical role in enhancing the efficacy of KXS in treating AD and facilitates the entry of other pharmacodynamic components into the brain. The mechanism underlying the “guiding medicine upwards” effect of ATR may involve the regulation of OCT3/OATP2 and P-gp/MRP1 transporters.
研究领域:
民族药理学
·
神经科学
·
中药学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）