Background and Aims:Voriconazole(VRC),a widely used antifungal drug,often causes hepatotoxicity,which presents a significant clinical challenge.Previous studies demonstrated that Astragalus polysaccharide(APS)can regu...Background and Aims:Voriconazole(VRC),a widely used antifungal drug,often causes hepatotoxicity,which presents a significant clinical challenge.Previous studies demonstrated that Astragalus polysaccharide(APS)can regulate VRC metabolism,thereby potentially mitigating its hepatotoxic effects.In this study,we aimed to explore the mechanism by which APS regulates VRC metabolism.Methods:First,we assessed the association of abnormal VRC metabolism with hepatotoxicity using the Roussel Uclaf Causality Assessment Method scale.Second,we conducted a series of basic experiments to verify the promotive effect of APS on VRC metabolism.Various in vitro and in vivo assays,including cytokine profiling,immunohistochemistry,quantitative polymerase chain reaction,metabolite analysis,and drug concentration measurements,were performed using a lipopolysaccharideinduced rat inflammation model.Finally,experiments such as intestinal biodiversity analysis,intestinal clearance assessments,and Bifidobacterium bifidum replenishment were performed to examine the ability of B.bifidum to regulate the expression of the VRC-metabolizing enzyme CYP2C19 through the gut–liver axis.Results:The results indicated that APS does not have a direct effect on hepatocytes.However,the assessment of gut microbiota function revealed that APS significantly increases the abundance of B.bifidum,which could lead to an anti-inflammatory response in the liver and indirectly enhance VRC metabolism.The dual-luciferase reporter gene assay revealed that APS can hinder the secretion of pro-inflammatory mediators and reduce the inhibitory effect on CYP2C19 transcription through the nuclear factor-κB signaling pathway.Conclusions:The study offers valuable insights into the mechanism by which APS alleviates VRC-induced liver damage,highlighting its immunomodulatory influence on hepatic tissues and its indirect regulatory control of VRC-metabolizing enzymes within hepatocytes.展开更多
Background:As accelerators and products of the progression of chronic kidney disease(CKD),advanced oxidation protein products(AOPPs)affect the function of the liver.Huang Gan granules(HGGs)are commonly used to prevent...Background:As accelerators and products of the progression of chronic kidney disease(CKD),advanced oxidation protein products(AOPPs)affect the function of the liver.Huang Gan granules(HGGs)are commonly used to prevent the progression of CKD,but the pharmacokinetics of aloe-emodin,emodin,rhein,and chrysophanol in HGGs in CKD remain unknown.Objective:To investigate the influence and its molecular mechanism of AOPPs on the in vivo pharmacokinetics of aloe-emodin,emodin,rhein,and chrysophanol in HGGs.Methods:We constructed 5/6 nephrectomised(5/6 nx),adenine-induced(adenine)and AOPP-treated rat models.After oral administration of HGG,the concentrations of aloe-emodin,emodin,rhein,and chrysophanol in the plasma samples were detected by high-performance liquid chromatography(HPLC),and their pharmacokinetics were analysed with the PKSolver software.The plasma concentrations of IL-6 and TNF-αare detected by enzyme linked immunosorbent assay(ELISA).The RT-PCR was performed in the HepG2 cells to explore the effect of TNF-αand IL-6 on the mRNA expression of CYP1A2 and CYP3A4.Result:The results showed that the method was suitable for the quantification of four anthraquinones in plasma and excreta samples with satisfactory linear(R R^(2)>0.9931),precision(<9.4%)and accuracy(±10%).In 5/6 nx,adenine and AOPPs-treated rats,the concentrations of TNF-αand IL-6 were increased.In 5/6 nx and adenine rats,the pharmacokinetic parameters(t_(1/2),MRT_(0-∞)and AUC_(0-∞))of aloe-emodin,emodin,rhein,and chryso-phanol were,respectively,significantly increased and correlated with the concentration of AOPPs.In AOPPs-treated rats,the concentration of AOPPs was significantly increased and the pharmacokinetic parameters of four anthraquinones were also increased.Conclusion:In summary,inflammatory cytokine production may be one of the important causes in AOPPs’regulat-ing the pharmacokinetic of aloe-emodin,emodin,rhein,and chrysophanol in the CKD rats.Studies of aloe-emodin,emodin,rhein,and chrysophanol in CKD facilitate the appropriate prescription of HGGs in the clinical.展开更多
基金supported by the Discipline Construction Project of Guangdong Medical University(No.4SG22009G)the Funds for PhD Researchers of Guangdong Medical University in 2021(No.GDMUB2021021)+7 种基金the Dongguan science and technology commissioner project(20231800500332)the Guangdong province ordinary university characteristic innovation project(2020KTSCX341)the Guangdong Basic and Applied Basic Research Foundation(No.2023A1515111116)the Science and Technology Special Fund Project of Guangdong Province in 2021(No.2021A05199)the Shenzhen Foundation of Science and Technology(Nos.JCYJ20230807151308018 and JCYJ20190814112205770)the Zhanjiang Science and Technology Project(2023B01176)Shenzhen Longhua District Science and Technology Innovation Fund Projects(Nos.2022045,2022051,2022056,2022095,2022123,2021105,2021115 and 2020036)the Research Foundation of Shenzhen Longhua District Central Hospital(No.202203).
文摘Background and Aims:Voriconazole(VRC),a widely used antifungal drug,often causes hepatotoxicity,which presents a significant clinical challenge.Previous studies demonstrated that Astragalus polysaccharide(APS)can regulate VRC metabolism,thereby potentially mitigating its hepatotoxic effects.In this study,we aimed to explore the mechanism by which APS regulates VRC metabolism.Methods:First,we assessed the association of abnormal VRC metabolism with hepatotoxicity using the Roussel Uclaf Causality Assessment Method scale.Second,we conducted a series of basic experiments to verify the promotive effect of APS on VRC metabolism.Various in vitro and in vivo assays,including cytokine profiling,immunohistochemistry,quantitative polymerase chain reaction,metabolite analysis,and drug concentration measurements,were performed using a lipopolysaccharideinduced rat inflammation model.Finally,experiments such as intestinal biodiversity analysis,intestinal clearance assessments,and Bifidobacterium bifidum replenishment were performed to examine the ability of B.bifidum to regulate the expression of the VRC-metabolizing enzyme CYP2C19 through the gut–liver axis.Results:The results indicated that APS does not have a direct effect on hepatocytes.However,the assessment of gut microbiota function revealed that APS significantly increases the abundance of B.bifidum,which could lead to an anti-inflammatory response in the liver and indirectly enhance VRC metabolism.The dual-luciferase reporter gene assay revealed that APS can hinder the secretion of pro-inflammatory mediators and reduce the inhibitory effect on CYP2C19 transcription through the nuclear factor-κB signaling pathway.Conclusions:The study offers valuable insights into the mechanism by which APS alleviates VRC-induced liver damage,highlighting its immunomodulatory influence on hepatic tissues and its indirect regulatory control of VRC-metabolizing enzymes within hepatocytes.
基金supported by Guangdong Science and Technology Program(No.2015B020211006)the Technology Project of Guangzhou City in China(No.201604020137)+2 种基金Shenzhen Foundation of Science and Technology(No.JCYJ20190814112205770)Research Foundation of Shenzhen Hospital of Southern Medical University(No.PY2021YM03)the Project of Traditional Chinese Medicine Bureau of Guangdong Province(No.20221273).
文摘Background:As accelerators and products of the progression of chronic kidney disease(CKD),advanced oxidation protein products(AOPPs)affect the function of the liver.Huang Gan granules(HGGs)are commonly used to prevent the progression of CKD,but the pharmacokinetics of aloe-emodin,emodin,rhein,and chrysophanol in HGGs in CKD remain unknown.Objective:To investigate the influence and its molecular mechanism of AOPPs on the in vivo pharmacokinetics of aloe-emodin,emodin,rhein,and chrysophanol in HGGs.Methods:We constructed 5/6 nephrectomised(5/6 nx),adenine-induced(adenine)and AOPP-treated rat models.After oral administration of HGG,the concentrations of aloe-emodin,emodin,rhein,and chrysophanol in the plasma samples were detected by high-performance liquid chromatography(HPLC),and their pharmacokinetics were analysed with the PKSolver software.The plasma concentrations of IL-6 and TNF-αare detected by enzyme linked immunosorbent assay(ELISA).The RT-PCR was performed in the HepG2 cells to explore the effect of TNF-αand IL-6 on the mRNA expression of CYP1A2 and CYP3A4.Result:The results showed that the method was suitable for the quantification of four anthraquinones in plasma and excreta samples with satisfactory linear(R R^(2)>0.9931),precision(<9.4%)and accuracy(±10%).In 5/6 nx,adenine and AOPPs-treated rats,the concentrations of TNF-αand IL-6 were increased.In 5/6 nx and adenine rats,the pharmacokinetic parameters(t_(1/2),MRT_(0-∞)and AUC_(0-∞))of aloe-emodin,emodin,rhein,and chryso-phanol were,respectively,significantly increased and correlated with the concentration of AOPPs.In AOPPs-treated rats,the concentration of AOPPs was significantly increased and the pharmacokinetic parameters of four anthraquinones were also increased.Conclusion:In summary,inflammatory cytokine production may be one of the important causes in AOPPs’regulat-ing the pharmacokinetic of aloe-emodin,emodin,rhein,and chrysophanol in the CKD rats.Studies of aloe-emodin,emodin,rhein,and chrysophanol in CKD facilitate the appropriate prescription of HGGs in the clinical.
