Cystine is the primary source material for the synthesis of glutathione.However,the pharmacokinetics and tissue distribution of cystine are largely unknown.A surrogate analyte D_(4)-cystine was employed to generate ca...Cystine is the primary source material for the synthesis of glutathione.However,the pharmacokinetics and tissue distribution of cystine are largely unknown.A surrogate analyte D_(4)-cystine was employed to generate calibration curves for the determination of levels of D_(4)-cystine and endogenous cystine in mice by liquid chromatography-tandem mass spectrometry(LC-MS/MS).Validation assessments proved the sensitivity,specificity and reproducibility of the method with a lower limit of quantification(LLOQ)of 5 ng/mL over 5e5000 ng/mL in plasma.The pharmacokinetics of D_(4)-cystine were evaluated after administering injections and oral solutions,both of which minimally impacted endogenous cystine levels.The absolute bioavailability of cystine was 18.6%,15.1%and 25.6%at doses of 25,50 and 100 mg/kg,respectively.Intravenously injected D_(4)-cystine resulted in dramatically high plasma levels with reduced levels in the brain and liver.Intragastrically administered D_(4)-cystine resulted in high levels in the plasma and stomach with relatively low levels in the lung,kidney,heart and brain.展开更多
Little is known about the links of disturbed lipid metabolism with hyperuricemia(HUA).We aimed to investigate the asso-ciations of lipidomic profiles with uric acid(UA)/HUA and their modifying factors in middle-aged a...Little is known about the links of disturbed lipid metabolism with hyperuricemia(HUA).We aimed to investigate the asso-ciations of lipidomic profiles with uric acid(UA)/HUA and their modifying factors in middle-aged and elderly Chinese.A total of 350 lipids were quantified in 2247 community-based Chinese aged 50–70 years by high-coverage targeted lipidomics.HUA was defined by plasma UA>420μmol/L in men or>360μmol/L in women.The prevalence of HUA in this population was 10.4%.After multivariable adjustment including BMI and lifestyle,123 lipids were significantly associated with UA,predominantly glycerolipids(GLs)and glycerophospholipids(GPs).Specifically,diacylglycerol[DAG(16:0/22:5),DAG(16:0/22:6),DAG(18:1/20:5),DAG(18:1/22:6)],phosphatidylcholine[PC(16:0/20:5)),and triacylglycerol(TAG(53:0)]were the most significant lipid signatures positively associated with HUA risk,while lysophosphatidylcholine(LPC(20:2))was inversely associated with HUA risk(p<0.05).Network analysis also showed a positive association between TAGs/PCs/DAGs contained module and HUA risk(p<0.01).Notably,HUA-related lipids were associated with de novo lipogenesis fatty acids,especially 16:1n-7(Spearman correlation coefficients=0.32–0.41,p<0.001).Reduced rank regression showed that increased aquatic products intake was correlated to elevated HUA risk and HUA-associated lipids;while high dairy consumption was correlated with low level of HUA-associated lipids(|factor loadings|≥0.2).Moreover,mediation analyses suggested that the lipid-HUA associations were partially mediated by retinol-binding protein 4(RBP4,mediation proportion 5–14%),an adipokine linked with dyslipidemia and insulin resistance.In conclusion,disturbed specific metabolisms of GLs and GPs were associated with high prevalent HUA,partially mediated by RBP4 and/or influenced by certain dietary factors.展开更多
Low dose antibiotics have been used as growth promoters in livestock and fish. The use of antibiotics has been associated with reduced pathogen infections in livestock. In contrast, antibiotic growth promoter has been...Low dose antibiotics have been used as growth promoters in livestock and fish. The use of antibiotics has been associated with reduced pathogen infections in livestock. In contrast, antibiotic growth promoter has been suspected of leading to disease outbreaks in aquaculture. However, this phenomenon is circumstantial and has not been confirmed in experimental conditions. In this study,we showed that antibiotic olaquindox increased the susceptibility of zebrafish to A. hydrophila infection. Olaquindox led to profound alterations in the intestinal microbiota of zebrafish, with a drastic bloom of Enterobacter and diminishing of Cetobacterium. Moreover, the innate immune responses of zebrafish were compromised by olaquindox(P<0.05). Transfer of microbiota to GF zebrafish indicated that while the immuo-suppression effect of olaquindox is a combined effect mediated by both OLA-altered micro biota and direct action of the antibiotic(P<0.05), the increased pathogen susceptibility was driven by the OLA-altered microbiota and was not dependent on direct antibiotic effect. Taken together, these data indicate that low level of OLA induced gut microbiota dysbiosis in zebrafish, which led to increased pathogen susceptibility.展开更多
基金This study was financially supported by the National Natural Science Foundation of the People's Republic of China(Grant Nos.:81773814 and 81530098)the National Key Special Project of Science and Technology for Innovation Drugs of China(Project No.:2017ZX09301013)the National Key Research and Development Program(Grant No.:2018YFC0807403).
文摘Cystine is the primary source material for the synthesis of glutathione.However,the pharmacokinetics and tissue distribution of cystine are largely unknown.A surrogate analyte D_(4)-cystine was employed to generate calibration curves for the determination of levels of D_(4)-cystine and endogenous cystine in mice by liquid chromatography-tandem mass spectrometry(LC-MS/MS).Validation assessments proved the sensitivity,specificity and reproducibility of the method with a lower limit of quantification(LLOQ)of 5 ng/mL over 5e5000 ng/mL in plasma.The pharmacokinetics of D_(4)-cystine were evaluated after administering injections and oral solutions,both of which minimally impacted endogenous cystine levels.The absolute bioavailability of cystine was 18.6%,15.1%and 25.6%at doses of 25,50 and 100 mg/kg,respectively.Intravenously injected D_(4)-cystine resulted in dramatically high plasma levels with reduced levels in the brain and liver.Intragastrically administered D_(4)-cystine resulted in high levels in the plasma and stomach with relatively low levels in the lung,kidney,heart and brain.
基金supported by the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB38010300,XDB38020000)Shanghai Municipal Science and Technology Major Project(2017SHZDZX01)+2 种基金the Ministry of Science and Technology of China(2017YFC0909701,2023YFC2506702,and 2023YFC2506704)the National Natural Science Foundation of China(81970684,81700700,and 81561128018)the Chinese Academy of Sciences(KSCX2-EW-R-10).
文摘Little is known about the links of disturbed lipid metabolism with hyperuricemia(HUA).We aimed to investigate the asso-ciations of lipidomic profiles with uric acid(UA)/HUA and their modifying factors in middle-aged and elderly Chinese.A total of 350 lipids were quantified in 2247 community-based Chinese aged 50–70 years by high-coverage targeted lipidomics.HUA was defined by plasma UA>420μmol/L in men or>360μmol/L in women.The prevalence of HUA in this population was 10.4%.After multivariable adjustment including BMI and lifestyle,123 lipids were significantly associated with UA,predominantly glycerolipids(GLs)and glycerophospholipids(GPs).Specifically,diacylglycerol[DAG(16:0/22:5),DAG(16:0/22:6),DAG(18:1/20:5),DAG(18:1/22:6)],phosphatidylcholine[PC(16:0/20:5)),and triacylglycerol(TAG(53:0)]were the most significant lipid signatures positively associated with HUA risk,while lysophosphatidylcholine(LPC(20:2))was inversely associated with HUA risk(p<0.05).Network analysis also showed a positive association between TAGs/PCs/DAGs contained module and HUA risk(p<0.01).Notably,HUA-related lipids were associated with de novo lipogenesis fatty acids,especially 16:1n-7(Spearman correlation coefficients=0.32–0.41,p<0.001).Reduced rank regression showed that increased aquatic products intake was correlated to elevated HUA risk and HUA-associated lipids;while high dairy consumption was correlated with low level of HUA-associated lipids(|factor loadings|≥0.2).Moreover,mediation analyses suggested that the lipid-HUA associations were partially mediated by retinol-binding protein 4(RBP4,mediation proportion 5–14%),an adipokine linked with dyslipidemia and insulin resistance.In conclusion,disturbed specific metabolisms of GLs and GPs were associated with high prevalent HUA,partially mediated by RBP4 and/or influenced by certain dietary factors.
基金supported by the National Basic Research Program of China (2015CB150605)the National Natural Science Foundation of China (31272672, 31572633)+1 种基金the Beijing Earmarked Fund for Modern Agro-industry Technology Research System (SCGWZJ 20161104-4)the Fundamental Research Funds for the Central Public Welfare Research Institute (1610382016013)
文摘Low dose antibiotics have been used as growth promoters in livestock and fish. The use of antibiotics has been associated with reduced pathogen infections in livestock. In contrast, antibiotic growth promoter has been suspected of leading to disease outbreaks in aquaculture. However, this phenomenon is circumstantial and has not been confirmed in experimental conditions. In this study,we showed that antibiotic olaquindox increased the susceptibility of zebrafish to A. hydrophila infection. Olaquindox led to profound alterations in the intestinal microbiota of zebrafish, with a drastic bloom of Enterobacter and diminishing of Cetobacterium. Moreover, the innate immune responses of zebrafish were compromised by olaquindox(P<0.05). Transfer of microbiota to GF zebrafish indicated that while the immuo-suppression effect of olaquindox is a combined effect mediated by both OLA-altered micro biota and direct action of the antibiotic(P<0.05), the increased pathogen susceptibility was driven by the OLA-altered microbiota and was not dependent on direct antibiotic effect. Taken together, these data indicate that low level of OLA induced gut microbiota dysbiosis in zebrafish, which led to increased pathogen susceptibility.
