The associations of polycyclic aromatic hydrocarbon(PAH)exposure with serum uric acid(SUA)or hyperuricemia have been rarely assessed.We aimed to investigate the relationships between urinary PAH metabolites and SUA or...The associations of polycyclic aromatic hydrocarbon(PAH)exposure with serum uric acid(SUA)or hyperuricemia have been rarely assessed.We aimed to investigate the relationships between urinary PAH metabolites and SUA or hyperuricemia among US adults and to explore the mediating role of systemic inflammation in the associations.A total of 10,307 US adults were conducted to assess the associations of seven urinary hydroxy–PAH with SUA and hyperuricemia and evaluate the role of C-reactive protein(CRP),a biomarker of systemic inflammation,in such associations.Results showed that each 1-unit increase in ln-transformed 2-hydroxynaphthalene(2-OHNa),1-hydroxyphenanthrene(1-OHPh),2&3-hydroxyphenanthrene(2&3-OHPh)and total hydroxyphenanthrene(OHPh)was associated with a 1.68(95%confidence interval(CI):0.19 to 3.17),2.46(0.78 to 4.13),3.34(1.59 to 5.09),and 2.99(1.23 to 4.75)μmol/L increase in SUA,and a 8%(odds ratio(OR):1.08,1.02 to 1.15),9%(OR:1.09,1.02 to 1.18),13%(OR:1.13,1.05 to 1.22),and 12%(OR:1.12,95%CI:1.03,1.21)increase in hyperuricemia,respectively.Co-exposure of seven PAHs was positively associated with SUA and hyperuricemia,with 2&3-OHPh showing the highest weight(components weights:0.83 and 0.78,respectively).The CRP mediated 11.47%and 10.44%of the associations ofΣOHPh and 2&3-OHPh with SUA and mediated 8.60%and 8.62%in associations ofΣOHPh and 2&3-OHPh with hyperuricemia,respectively.In conclusion,internal levels of PAH metabolites were associated with elevated SUA levels and the increased risk of hyperuricemia among US adults,and CRP played a mediating role in the associations.展开更多
The health effects of traffic-derived pollutants have gathered increasing concerns.Our objectives were to evaluate the associations of traffic-related heavy metal exposure with serum uric acid(SUA)and hyperuricemia an...The health effects of traffic-derived pollutants have gathered increasing concerns.Our objectives were to evaluate the associations of traffic-related heavy metal exposure with serum uric acid(SUA)and hyperuricemia and to explore the underlying mechanism.Traffic-related heavy metals(including zinc,iron,manganese,copper,lead,cadmium,antimony,and barium)and SUA were determined among 3909 community-based adults from the Wuhan-Zhuhai cohort.Various regression methods were applied to assess the association of heavy metals with SUA and hyperuricemia.Furthermore,mediation analyses were employed to evaluate the potential role of systemic inflammation in these associations.In single metal analyses,positive dose-response relationships between urinary zinc,iron,manganese,and antimony and SUA were observed.Furthermore,each 1-unit increase of ln-transformed urinary zinc levels was related to a 37.9%(OR=1.379,95%CI:1.148 to 1.657)increase in the hyperuricemia risk.In multiple metal analyses,both Bayesian kernel machine regression(BKMR)and weighted quantile sum regression(WQS)models showed positive associations of heavy metals mixture with SUA and hyperuricemia risk,and WQS analyses further revealed that zinc was the dominant metal(component weight:0.611 and 0.594,respectively).Additionally,plasma C-reactive protein(CRP)mediated 4.919%and 8.417%of the association of urinary zinc with SUA and hyperuricemia,respectively.In conclusion,exposure to several traffic-related heavy metals or traffic-related heavy metal mixtures were positively associated with SUA and hyperuricemia risk in the general Chinese population,in which zinc played a dominating role.Plasma CRP might partly mediate the association of urinary zinc with SUA and hyperuricemia risk.展开更多
Our previous studies have reported the presence of "chain delivery" effects of protein adsorption onto ion exchangers with polymer-grafted ion-exchange groups, such as dextran-grafted and poly(ethylenimine)-...Our previous studies have reported the presence of "chain delivery" effects of protein adsorption onto ion exchangers with polymer-grafted ion-exchange groups, such as dextran-grafted and poly(ethylenimine)-modified Sepharose gels. However, it is unclear if the "chain delivery" occurs on affinity adsorption with specific interactions. This work is designed to address this issue. A dextran-grafted Sepharose gel was prepared, and then the matrix was modified using diethylaminoethyl, a typical ion-exchange group, or octapeptide(FYCHWQDE), an affinity ligand for human immunoglobulin G(h Ig G) to prepare ion-exchange or affinity adsorbents, respectively.Results of h Ig G adsorption showed that the uptake rate represented by the effective diffusivity of h Ig G onto the dextran-grafted ion exchangers was obviously enhanced by the dextran grafting, indicating the presence of"chain delivery" of the bound proteins on the charged groups on the dextran chains. By contrast, the effective diffusivity of h Ig G changed little as ligand density increased on the dextran-grafted FYCHWQDE adsorbents.Their adsorption capacities decreased and effective diffusivities were not accelerated by the dextran grafting.Thus, this work clarified that grafted dextran could not accelerate h Ig G uptake rate on the affinity resins, or in other words, chain delivery did not occur on the specific interaction-based affinity adsorption.展开更多
In our previous work, a series of polyethylenimine(PEI)-derived cation exchangers were synthesized using PEIgrafted resin FF-PEI-L740(ionic capacity, 740 mmol·L^-1) as the basic resin to study lysozyme adsorption...In our previous work, a series of polyethylenimine(PEI)-derived cation exchangers were synthesized using PEIgrafted resin FF-PEI-L740(ionic capacity, 740 mmol·L^-1) as the basic resin to study lysozyme adsorption and chromatographic behavior. It was found that the resin with an ionic capacity of 630 mmol·L^-1(FF-PEI-CR630)possessed high adsorption performance towards lysozyme at 0–100 mmol·L^-1 Na Cl. Therefore, in this work,FF-PEI-CR630 was selected to study the influences of pH and ionic strength(IS) on protein adsorption and chromatographic behavior towards lysozyme. The increase of lysozyme adsorption capacity in the pH range of 6 to 10 was observed. However, the uptake rate decreased in the pH range of 6 to 8 and then remained essentially unchanged from pH 8 to pH 10. Increasing IS led to decreased protein adsorption capacity and increased uptake rate in different pH ranges. Besides, FF-PEI-CR630 maintained dynamic binding capacity as high as over150 mg·ml^-1 at pH 8–10 without NaCl. The research has thus provided insight into the selection of proper pH and IS conditions for protein purification by using FF-PEI-CR630.展开更多
Our previous studies on bovine serum albumin （BSA） adsorption to diethylaminoethyl dextran （DEAE dextran, DexD, grafting-ligand） and DEAE （D, surface-ligand） modified Sepharose FF resins found that all the graft...Our previous studies on bovine serum albumin （BSA） adsorption to diethylaminoethyl dextran （DEAE dextran, DexD, grafting-ligand） and DEAE （D, surface-ligand） modified Sepharose FF resins found that all the grafted resins （FF-DexD and FF-D-DexD） exhibited extremely fast uptake rate （effective diffusivity, De, De/Do 〉 1.4）, which was six times greater than the ungrafted resins （De/Do 〈 0.3）. In this work, the influence of ionic strength （IS） on 6 typical DEAE dextran-grafted resins was investigated. Bath adsorption equilibria and kinetics, breakthrough, and linear gradient elution experiments were conducted. Commercial DEAE Sepharose FF was used for comparison. It is found that protein adsorption capacities on DEAE dextran-FF resins and the commercial resin decreased with increasing IS, but DEAE dextran-FF resins exhibited much higher capacity sensitivity to salt concentration. Besides, steeper decrease of adsorption capacities could be obtained at higher graftingligand or surface-ligand density. It is worth noting that the facilitating role of surface-ligand to the ＂chain delivery＂ effect was weakened after adding salt, leading to the less improvement in uptake rate by increasing surface-ligand density at higher IS. Although the uptake rates of the DEAE dextran-FF resins increased first and then decreased with increasing fS, they kept the extremely high level of De values （De/Do 〉 1.1 ） at the their working/binding IS range. Moreover, the DEAE dextran-FF resin displayed much higher adsorption capacities and De values than commercial ungrafted resin in their working condition. Furthermore, the column results of DEAE dextran-FF resins presented higher dynamic binding capacities than and similar elution ISs with DEAE Sepharose FF to achieve similar （or even higher） recoveries suggest the excellent chromatographic column performance of the DEAE dextran-FF resins. Finally, both high recovery and purity of BSA and γ-globulin could be easily achieved using the typical DEAE dextran-FF column, FF-D60-DexD160, to separate their binary mixtures, by step gradient elution. The research has provided new insights into the practical application of the series of DEAE-dextran grafted resins in protein chromatography and proved their superiority.展开更多
Styrene and ethylbenzene(S/EB)are identified as hazardous air contaminants that raise significant concerns.The association between S/EB exposure and the incidence of type 2 diabetes mellitus(T2DM),and the interaction ...Styrene and ethylbenzene(S/EB)are identified as hazardous air contaminants that raise significant concerns.The association between S/EB exposure and the incidence of type 2 diabetes mellitus(T2DM),and the interaction between genes and environment,remains poorly understood.Our study consisted of 2219 Chinese adults who were part of the Wuhan-Zhuhai cohort.A follow-up assessment was conducted after six years.Exposure to S/EB was quantified by determining the concentrations of urinary biomarkers of exposure to S/EB(UBE-S/EB;urinary phenylglyoxylic acid level plus urinary mandelic acid level).Logistic regression models were constructed to investigate the relations of UBE-S/EB and genetic risk score(GRS)with T2DM prevalence and incidence.The interaction effects of UBE-S/EB and GRS on T2DM were investigated on multiplicative and additive scales.UBE-S/EB was dose-dependently and positively related to T2DM prevalence and incidence.Participants with high levels of UBE-S/EB[relative risk(RR)=1.930,95%confidence interval(CI):1.157-3.309]or GRS(1.943,1.110-3.462)demonstrated the highest risk of incident T2DM,in comparison to those with low levels of UBE-S/EB or GRS.Significant additive interaction between UBE-S/EB and GRS on T2DM incidence was discovered with relative excess risk due to interaction(95%CI)of 0.178(0.065-0.292).The RR(95%CI)of T2DM incidence was 2.602(1.238-6.140)for individuals with high UBE-S/EB and high GRS,compared to those with low UBE-S/EB and low GRS.This study presented the initial evidence that S/EB exposure was significantly related to increased risk of T2DM incidence,and the relationship was interactively aggravated by genetic predisposition.展开更多
Amyloid-β （Aβ） protein aggregation is the main hallmark of Alzheimer＇s disease （AD）. Inhibition of Aft fibrillation is thus a promising therapeutic approach to the prevention and treatment of AD. Recently, we d...Amyloid-β （Aβ） protein aggregation is the main hallmark of Alzheimer＇s disease （AD）. Inhibition of Aft fibrillation is thus a promising therapeutic approach to the prevention and treatment of AD. Recently, we designed a heptapeptide inhibitor, LVFFARK （LK7）. LK7 shows a promising inhibitory capability on Aft fibrillation, but is prone to self-assembling and displays high cytotoxicity, which would hinder its practical application. Herein, we modified LK7 by a head-to-tail cyclization and obtained a cyclic LK7 （cLK7）. cLK7 exhibits a different self-assembly behavior from LK7, and has higher stability against proteolysis than LK7 and little cytotoxicity to SH-SY5Y cells. Thermodynamic analysis revealed that both LK7 and cLK7 could bind to Aβ40 by electrostatic interactions, hydrogen bonding and hydrophobic interactions, but the binding affinity of cLK7 for Afl40 （KD = 4.96 μmol/L） is six times higher than that of LK7 （KD = 32.2 μmol/L）. The strong binding enables cLK7 to stabilize the secondary structure of Aβ40 and potently inhibit its nucleation, fibrillation and cytotoxicity at extensive concentration range, whereas LK7 could only moderately inhibit Aβ40 fibrillation and cytotoxicity at low concentrations. The findings indicate that the peptide cyclization is a promising approach to enhance the performance of peptide-based amyloid inhibitors.展开更多
基金supported by the Key Program of National Natural Science Foundation of China(No.82241088)the Natural Science Foundation of Hubei Province(No.2022CFB813).
文摘The associations of polycyclic aromatic hydrocarbon(PAH)exposure with serum uric acid(SUA)or hyperuricemia have been rarely assessed.We aimed to investigate the relationships between urinary PAH metabolites and SUA or hyperuricemia among US adults and to explore the mediating role of systemic inflammation in the associations.A total of 10,307 US adults were conducted to assess the associations of seven urinary hydroxy–PAH with SUA and hyperuricemia and evaluate the role of C-reactive protein(CRP),a biomarker of systemic inflammation,in such associations.Results showed that each 1-unit increase in ln-transformed 2-hydroxynaphthalene(2-OHNa),1-hydroxyphenanthrene(1-OHPh),2&3-hydroxyphenanthrene(2&3-OHPh)and total hydroxyphenanthrene(OHPh)was associated with a 1.68(95%confidence interval(CI):0.19 to 3.17),2.46(0.78 to 4.13),3.34(1.59 to 5.09),and 2.99(1.23 to 4.75)μmol/L increase in SUA,and a 8%(odds ratio(OR):1.08,1.02 to 1.15),9%(OR:1.09,1.02 to 1.18),13%(OR:1.13,1.05 to 1.22),and 12%(OR:1.12,95%CI:1.03,1.21)increase in hyperuricemia,respectively.Co-exposure of seven PAHs was positively associated with SUA and hyperuricemia,with 2&3-OHPh showing the highest weight(components weights:0.83 and 0.78,respectively).The CRP mediated 11.47%and 10.44%of the associations ofΣOHPh and 2&3-OHPh with SUA and mediated 8.60%and 8.62%in associations ofΣOHPh and 2&3-OHPh with hyperuricemia,respectively.In conclusion,internal levels of PAH metabolites were associated with elevated SUA levels and the increased risk of hyperuricemia among US adults,and CRP played a mediating role in the associations.
基金supported by the Key Program of the National Natural Science Foundation of China(No.82241088).
文摘The health effects of traffic-derived pollutants have gathered increasing concerns.Our objectives were to evaluate the associations of traffic-related heavy metal exposure with serum uric acid(SUA)and hyperuricemia and to explore the underlying mechanism.Traffic-related heavy metals(including zinc,iron,manganese,copper,lead,cadmium,antimony,and barium)and SUA were determined among 3909 community-based adults from the Wuhan-Zhuhai cohort.Various regression methods were applied to assess the association of heavy metals with SUA and hyperuricemia.Furthermore,mediation analyses were employed to evaluate the potential role of systemic inflammation in these associations.In single metal analyses,positive dose-response relationships between urinary zinc,iron,manganese,and antimony and SUA were observed.Furthermore,each 1-unit increase of ln-transformed urinary zinc levels was related to a 37.9%(OR=1.379,95%CI:1.148 to 1.657)increase in the hyperuricemia risk.In multiple metal analyses,both Bayesian kernel machine regression(BKMR)and weighted quantile sum regression(WQS)models showed positive associations of heavy metals mixture with SUA and hyperuricemia risk,and WQS analyses further revealed that zinc was the dominant metal(component weight:0.611 and 0.594,respectively).Additionally,plasma C-reactive protein(CRP)mediated 4.919%and 8.417%of the association of urinary zinc with SUA and hyperuricemia,respectively.In conclusion,exposure to several traffic-related heavy metals or traffic-related heavy metal mixtures were positively associated with SUA and hyperuricemia risk in the general Chinese population,in which zinc played a dominating role.Plasma CRP might partly mediate the association of urinary zinc with SUA and hyperuricemia risk.
基金Supported by the National Natural Science Foundation of China(21236005,21621004)
文摘Our previous studies have reported the presence of "chain delivery" effects of protein adsorption onto ion exchangers with polymer-grafted ion-exchange groups, such as dextran-grafted and poly(ethylenimine)-modified Sepharose gels. However, it is unclear if the "chain delivery" occurs on affinity adsorption with specific interactions. This work is designed to address this issue. A dextran-grafted Sepharose gel was prepared, and then the matrix was modified using diethylaminoethyl, a typical ion-exchange group, or octapeptide(FYCHWQDE), an affinity ligand for human immunoglobulin G(h Ig G) to prepare ion-exchange or affinity adsorbents, respectively.Results of h Ig G adsorption showed that the uptake rate represented by the effective diffusivity of h Ig G onto the dextran-grafted ion exchangers was obviously enhanced by the dextran grafting, indicating the presence of"chain delivery" of the bound proteins on the charged groups on the dextran chains. By contrast, the effective diffusivity of h Ig G changed little as ligand density increased on the dextran-grafted FYCHWQDE adsorbents.Their adsorption capacities decreased and effective diffusivities were not accelerated by the dextran grafting.Thus, this work clarified that grafted dextran could not accelerate h Ig G uptake rate on the affinity resins, or in other words, chain delivery did not occur on the specific interaction-based affinity adsorption.
基金supported by the National Natural Science Foundation of China (Nos. 21878222 and 21621004).
文摘In our previous work, a series of polyethylenimine(PEI)-derived cation exchangers were synthesized using PEIgrafted resin FF-PEI-L740(ionic capacity, 740 mmol·L^-1) as the basic resin to study lysozyme adsorption and chromatographic behavior. It was found that the resin with an ionic capacity of 630 mmol·L^-1(FF-PEI-CR630)possessed high adsorption performance towards lysozyme at 0–100 mmol·L^-1 Na Cl. Therefore, in this work,FF-PEI-CR630 was selected to study the influences of pH and ionic strength(IS) on protein adsorption and chromatographic behavior towards lysozyme. The increase of lysozyme adsorption capacity in the pH range of 6 to 10 was observed. However, the uptake rate decreased in the pH range of 6 to 8 and then remained essentially unchanged from pH 8 to pH 10. Increasing IS led to decreased protein adsorption capacity and increased uptake rate in different pH ranges. Besides, FF-PEI-CR630 maintained dynamic binding capacity as high as over150 mg·ml^-1 at pH 8–10 without NaCl. The research has thus provided insight into the selection of proper pH and IS conditions for protein purification by using FF-PEI-CR630.
基金Supported by the National Natural Science Foundation of China(21406160,21621004)
文摘Our previous studies on bovine serum albumin （BSA） adsorption to diethylaminoethyl dextran （DEAE dextran, DexD, grafting-ligand） and DEAE （D, surface-ligand） modified Sepharose FF resins found that all the grafted resins （FF-DexD and FF-D-DexD） exhibited extremely fast uptake rate （effective diffusivity, De, De/Do 〉 1.4）, which was six times greater than the ungrafted resins （De/Do 〈 0.3）. In this work, the influence of ionic strength （IS） on 6 typical DEAE dextran-grafted resins was investigated. Bath adsorption equilibria and kinetics, breakthrough, and linear gradient elution experiments were conducted. Commercial DEAE Sepharose FF was used for comparison. It is found that protein adsorption capacities on DEAE dextran-FF resins and the commercial resin decreased with increasing IS, but DEAE dextran-FF resins exhibited much higher capacity sensitivity to salt concentration. Besides, steeper decrease of adsorption capacities could be obtained at higher graftingligand or surface-ligand density. It is worth noting that the facilitating role of surface-ligand to the ＂chain delivery＂ effect was weakened after adding salt, leading to the less improvement in uptake rate by increasing surface-ligand density at higher IS. Although the uptake rates of the DEAE dextran-FF resins increased first and then decreased with increasing fS, they kept the extremely high level of De values （De/Do 〉 1.1 ） at the their working/binding IS range. Moreover, the DEAE dextran-FF resin displayed much higher adsorption capacities and De values than commercial ungrafted resin in their working condition. Furthermore, the column results of DEAE dextran-FF resins presented higher dynamic binding capacities than and similar elution ISs with DEAE Sepharose FF to achieve similar （or even higher） recoveries suggest the excellent chromatographic column performance of the DEAE dextran-FF resins. Finally, both high recovery and purity of BSA and γ-globulin could be easily achieved using the typical DEAE dextran-FF column, FF-D60-DexD160, to separate their binary mixtures, by step gradient elution. The research has provided new insights into the practical application of the series of DEAE-dextran grafted resins in protein chromatography and proved their superiority.
基金supported by National Natural Science Foundation of China (82241088,82203996).
文摘Styrene and ethylbenzene(S/EB)are identified as hazardous air contaminants that raise significant concerns.The association between S/EB exposure and the incidence of type 2 diabetes mellitus(T2DM),and the interaction between genes and environment,remains poorly understood.Our study consisted of 2219 Chinese adults who were part of the Wuhan-Zhuhai cohort.A follow-up assessment was conducted after six years.Exposure to S/EB was quantified by determining the concentrations of urinary biomarkers of exposure to S/EB(UBE-S/EB;urinary phenylglyoxylic acid level plus urinary mandelic acid level).Logistic regression models were constructed to investigate the relations of UBE-S/EB and genetic risk score(GRS)with T2DM prevalence and incidence.The interaction effects of UBE-S/EB and GRS on T2DM were investigated on multiplicative and additive scales.UBE-S/EB was dose-dependently and positively related to T2DM prevalence and incidence.Participants with high levels of UBE-S/EB[relative risk(RR)=1.930,95%confidence interval(CI):1.157-3.309]or GRS(1.943,1.110-3.462)demonstrated the highest risk of incident T2DM,in comparison to those with low levels of UBE-S/EB or GRS.Significant additive interaction between UBE-S/EB and GRS on T2DM incidence was discovered with relative excess risk due to interaction(95%CI)of 0.178(0.065-0.292).The RR(95%CI)of T2DM incidence was 2.602(1.238-6.140)for individuals with high UBE-S/EB and high GRS,compared to those with low UBE-S/EB and low GRS.This study presented the initial evidence that S/EB exposure was significantly related to increased risk of T2DM incidence,and the relationship was interactively aggravated by genetic predisposition.
文摘Amyloid-β （Aβ） protein aggregation is the main hallmark of Alzheimer＇s disease （AD）. Inhibition of Aft fibrillation is thus a promising therapeutic approach to the prevention and treatment of AD. Recently, we designed a heptapeptide inhibitor, LVFFARK （LK7）. LK7 shows a promising inhibitory capability on Aft fibrillation, but is prone to self-assembling and displays high cytotoxicity, which would hinder its practical application. Herein, we modified LK7 by a head-to-tail cyclization and obtained a cyclic LK7 （cLK7）. cLK7 exhibits a different self-assembly behavior from LK7, and has higher stability against proteolysis than LK7 and little cytotoxicity to SH-SY5Y cells. Thermodynamic analysis revealed that both LK7 and cLK7 could bind to Aβ40 by electrostatic interactions, hydrogen bonding and hydrophobic interactions, but the binding affinity of cLK7 for Afl40 （KD = 4.96 μmol/L） is six times higher than that of LK7 （KD = 32.2 μmol/L）. The strong binding enables cLK7 to stabilize the secondary structure of Aβ40 and potently inhibit its nucleation, fibrillation and cytotoxicity at extensive concentration range, whereas LK7 could only moderately inhibit Aβ40 fibrillation and cytotoxicity at low concentrations. The findings indicate that the peptide cyclization is a promising approach to enhance the performance of peptide-based amyloid inhibitors.
