BACKGROUND Uridine diphosphate glucuronosyltransferase 1A1(UGT1A1)plays a crucial role in metabolizing and detoxifying endogenous and exogenous substances.However,its contribution to the progression of liver damage re...BACKGROUND Uridine diphosphate glucuronosyltransferase 1A1(UGT1A1)plays a crucial role in metabolizing and detoxifying endogenous and exogenous substances.However,its contribution to the progression of liver damage remains unclear.AIM To determine the role and mechanism of UGT1A1 in liver damage progression.METHODS We investigated the relationship between UGT1A1 expression and liver injury through clinical research.Additionally,the impact and mechanism of UGT1A1 on the progression of liver injury was analyzed through a mouse model study.RESULTS Patients with UGT1A1 gene mutations showed varying degrees of liver damage,while patients with acute-onchronic liver failure(ACLF)exhibited relatively reduced levels of UGT1A1 protein in the liver as compared to patients with chronic hepatitis.This suggests that low UGT1A1 levels may be associated with the progression of liver damage.In mouse models of liver injury induced by carbon tetrachloride(CCl_(4))and concanavalin A(ConA),the hepatic levels of UGT1A1 protein were found to be increased.In mice with lipopolysaccharide or liver steatosis-mediated liver-injury progression,the hepatic protein levels of UGT1A1 were decreased,which is consistent with the observations in patients with ACLF.UGT1A1 knockout exacerbated CCl_(4)-and ConA-induced liver injury,hepatocyte apoptosis and necroptosis in mice,intensified hepatocyte endoplasmic reticulum(ER)stress and oxidative stress,and disrupted lipid metabolism.CONCLUSION UGT1A1 is upregulated as a compensatory response during liver injury,and interference with this upregulation process may worsen liver injury.UGT1A1 reduces ER stress,oxidative stress,and lipid metabolism disorder,thereby mitigating hepatocyte apoptosis and necroptosis.展开更多
OBJECTIVE There is growing evidence that uridine may act as an endogenous neuromodulator with a potential signaling role in the central nervous system in addition to its function in pyrimidine metabolism.We previously...OBJECTIVE There is growing evidence that uridine may act as an endogenous neuromodulator with a potential signaling role in the central nervous system in addition to its function in pyrimidine metabolism.We previously found that acute morphine treatment significantly increased uridine release in the dorsal striatum of mice,while the mechanism involved in morphine-induced uridine release and the role of uridine in morphine-induced neurobehavioral changes have not been understood.METHODS Uridine release in the dorsal striatum of mice was assessed by in vivo microdialysis coupled with high performance liquid chromatography(HPLC) after morphine treatment.Western blotting and immunofluorescence were used to evaluate the expression of uridine-related proteins.Morphine-induced neurobehavioral changes were assessed by locomotor activity,behavioral sensitization and conditioned place preference(CPP)test.The expression of NT5E,an extracellular enzyme involved in formation of nucleosides,including uridine,was specifically knocked down in the dorsal striatum of mice using adeno-associated virus(AAV)-mediated short hairpin RNA(shRNA).RESULTS Both acute and chronic morphine administration significantly increased uridine release in the dorsal striatum,and this was associated with upregulation of NT5E but not other uridine-related proteins.Inhibition of NT5E with APCP or shRNA markedly inhibited morphine-induced uridine release in the dorsal striatum and related neurobehavioral changes,including hyperlocomotor activity,behavioral sensitization and CPP.CONCLUSION The present study increases our understanding of the contribution of NT5E in regulating morphine-induced neurobehavioral changes,at least as related to uridine,and suggests that NT5E may be a novel therapeutic target to manage morphine abuse.展开更多
AIM:To investigate the association of variations in the cyclooxygenase-2 (COX2) and uridine diphosphate glucuronosyltransferase 1A6 (UGTIA6) genes and non-steroidal anti-inflammatory drugs (NSAIDs) use with ris...AIM:To investigate the association of variations in the cyclooxygenase-2 (COX2) and uridine diphosphate glucuronosyltransferase 1A6 (UGTIA6) genes and non-steroidal anti-inflammatory drugs (NSAIDs) use with risk of colon cancer.METHODS: NSAIDs, which are known to reduce the risk of colon cancer, act directly on COX2 and reduce its activity. Epidemiological studies have associated variations in the COX2 gene with colon cancer risk, but others were unable to replicate this finding. Similarly,enzymes in the UGT1A6 gene have been demonstrated to modify the therapeutic effect of NSAIDs on colon adenomas. Polymorphisms in the UGTIA6 gene have been statistically shown to interact with NSAID intake to influence risk of developing colon adenomas, but not colon cancer. Here we examined the association of tagging single nucleotide polymorphisms (SNPs) in the COX2 and UGTIA6 genes, and their interaction with NSAID consumption, on risk of colon cancer in a population of 422 colon cancer cases and 481 population controls.RESULTS: No SNP in either gene was individually statistically significantly associated with colon cancer, nor did they statistically significantly change the protective effect of NSAID consumption in our sample. Like others, we were unable to replicate the association of variants in the COX2 gene with colon cancer risk (P 〉 0.05),and we did not observe that these variants modify the protective effect of NSAIDs (P 〉 0.05). We were able to confirm the lack of association of variants in UGT1A6 with colon cancer risk, although further studies will have to be conducted to confirm the association of these variants with colon adenomas.CONCLUSION: Our study does not support a role of COX2 and UGTIA6 genetic variations in the development of colon cancer.展开更多
Recombinant Escherichia coli pUDP,which overexpressed uridine phosphorylase(UPase),was constructed.0.5 mmol·L 1lactose had a similar induction effect as the commonly used inducer IPTG during 2.5-5.5 h of cell g...Recombinant Escherichia coli pUDP,which overexpressed uridine phosphorylase(UPase),was constructed.0.5 mmol·L 1lactose had a similar induction effect as the commonly used inducer IPTG during 2.5-5.5 h of cell growth.The lactose-induced UPase was stable at 50°C.Wet cells of pUDP was used as catalyst to biosynthesize 5-fluorouridine from 30 mmol·L 1uridine and 5-fluorouracil in phosphate buffer(pH 7.0)catalyzed at 50°C for 1.5 h and the yield of 5-fluorouridine was higher than 68%.Under the optimum reaction conditions for production of 5-fluorouridine,5-methyluridine and azauridine were synthesized from uridine by pUDP,the yield was 61.7%and 47.2%respectively.Deoxynucleosides were also synthesized by pUDP,but the yield was only about 20%.展开更多
Rationale: In a previously published trial on spinal acute non-traumatic pain, peripheral neuro- regenerative combination of UTP, CMP and hydroxocobalamin presented unexpected analgesicproperties. Objective: To corrob...Rationale: In a previously published trial on spinal acute non-traumatic pain, peripheral neuro- regenerative combination of UTP, CMP and hydroxocobalamin presented unexpected analgesicproperties. Objective: To corroborate analgesiceffects of UTP, CMP and hydroxocobalamin combination in a self-paired evolutionary model. Methods: Mean VAS scores from pretreatment, V2 (5th treatment day) and V3 (10th treatment day) were plotted and statistically analyzed (ANOVA) for differences. PFQ scores from pretreatment, V2, and V3 were analyzed using the chisquare test. Results: The difference between V3 and pretreatment mean VAS scores was statistically significant (p < 0.0001). The improvement in PFQ scores throughout the study was found to be statistically significant (p < 0.0001). Conclusion: The combination of UTP, CMP and hydroxocobalamin seems to have analgesic properties in mediumterm use. The complex peripheral neu-roregenerative pharmacodynamics of this combination provides a plausible basis for this finding. Further randomized studies are needed to explore this combination for the indication of neuropathic pain due to spinal structure involvement.展开更多
A new N-acetylsulfanilylation series of uridine have been synthesized in good yield using direct acylation method and afforded the 5’-O-N-acetylsulfanilyluridine. In order to obtain newer products, the 5’-O-N-acetyl...A new N-acetylsulfanilylation series of uridine have been synthesized in good yield using direct acylation method and afforded the 5’-O-N-acetylsulfanilyluridine. In order to obtain newer products, the 5’-O-N-acetylsulfanilyluridine derivative was further transformed to a series of 2’,3’-di-O-acyl derivatives containing a wide variety of functionalities in a single molecular framework. The chemical structures of the newly synthesized compounds were confirmed on the basis of their FTIR, 1H-NMR spectroscopy, physicochemical properties and elemental analysis. All the synthesized uridine derivatives were tested for their in vitro antibacterial activity against six human pathogenic bacterial strains and for comparison standard antibiotic Ampicillin was also determined. The study revealed that the selectively acylated deriva-tives 5’-O-N-acetylsulfanilyl-2’,3’-di-O-lauroyluridine and 5’-O-N-acetylsulfanilyl-2’,3’-di-O-pivaloyluridine showed highest inhibition against Staphylococcus aureus and Bacillus cereus, respectively. We also observed that the introduction of hexanoyl, decanoyl, lauroyl, myristoyl and pivaloyl groups, the antibacterial functionality of the compound uridine increases. Another noteworthy observation was that the uridine derivatives were found comparatively more effective against Gram-positive microorganisms than those of Gram-negative microorganisms. In addition, the test chemicals were also tested for cyto-toxicity by brine shrimp lethality bioassay and compounds showed different rate mortality with different concentrations.展开更多
High-fat diet(HFD)is demonstrated to disturb the bile acid metabolism.The rhythm of bile acid metabolism can also be affected by uridine,whose metabolism exhibits a daily rhythm.However,the mechanism of dynamic uridin...High-fat diet(HFD)is demonstrated to disturb the bile acid metabolism.The rhythm of bile acid metabolism can also be affected by uridine,whose metabolism exhibits a daily rhythm.However,the mechanism of dynamic uridine administration affecting bile acid during HFD remains unclear.In this study,C57BL/6J mice were fed HFD(the control group;CON)or HFD with oral administration of uridine in the daytime(DUR)and nighttime(NUR)to investigate the mechanism of the effect of uridine on the bile acid.This study showed that the mRNA expression of uridine transporters and circadian clock genes in the jejunum was affected by zeitgeber time(ZT)(P<0.001).Genes related to the metabolism of pyrimidines in the liver showed a high dependence on daily rhythm(P<0.01),and DUR remarkably up-regulated the expression of ribonucleotide reductase regulatory subunit M2(RRM2)(P<0.05)compared to the CON group.Importantly,the mRNA expression of bile acids nuclear receptors,bile acid synthesis,and transporters in the liver showed significantly rhythmically changed(P<0.05),and the expression of cholesterol 7-alpha-hydroxylase(CYP7A1),fibroblast growth factor receptor 4(FGFR4),Na^(+)/taurocholate co transporting polypeptide(NTCP),and bile salt export pump(BSEP)mRNAs of mice with uridine administration increased significantly(P<0.05).The mRNA expression of the transporters of cholesterol and bile acids in the ileum was also affected by ZT(P<0.01)and significantly dependent on uridine administration(P<0.05).The expression of FXR and SHP was significantly affected by ZT and uridine,respectively.In conclusion,dynamic administration of uridine could regulate the rhythm of gene expression of pyrimidine and bile acid metabolism in the liver and ileum of HFD-fed mice,which contributed to the further study of circadian rhythmic physiological and pathological changes of bile acids.展开更多
We applied quantum mechanics/classical mechanics simulations to study excess-electron attachment and ionization of uridine monophosphate anion(d UMP-)in explicit aqueous solutions.We calculated vertical electron affin...We applied quantum mechanics/classical mechanics simulations to study excess-electron attachment and ionization of uridine monophosphate anion(d UMP-)in explicit aqueous solutions.We calculated vertical electron affinities(VEAs),adiabatic electron affinities(AEAs),vertical detachment energies(VDEs),vertical ionization energies(VIEs),and adiabatic ionization energies(AIEs)of the 40 structures obtained from molecular dynamic trajectory.The excess-electron and hole distributions were analyzed in electron attachment and ionization of aqueous d UMP^(-).The converged mean VEA(-0.31 e V)and AEA(2.13 e V)suggest that excess-electron can easily attach to d UMP^(-).The mean vertical(-0.50 e)and adiabatic(-0.62 e)excess-electron on uracil reveal that main excesselectrons are localized on nucleobases at the most snapshots.The distributions at several special snapshots demonstrate the excess-electron delocalization over nucleobases/ribose or ribose/phosphate group after the structural relaxations of d UMP^(2-)dianion.The VDE value(2.78 e V)indicates that d UMP2-dianion could be very stable.Moreover,the mean VIE is 8.13 eV which is in agreement with the previous calculation using solvation model.The hole distributions on uracil suggest that the nucleobases are easily ionized after the irradiation of high-energy rays.In vertical ionizations,the holes would be delocalized over uracil and ribose at several snapshots.Observing the adiabatic hole distributions,it can be found that electrons on phosphate group and holes on nucleobases can be transferred to ribose at the special snapshots in the structural relaxation of neutral species.展开更多
We have cd quantum chemical method tO ho the transition states of uridinephosphorolysis reaction under the neutral condition. Comparing the activation energies ofdifferent reaction modes, we conclude that uridine p...We have cd quantum chemical method tO ho the transition states of uridinephosphorolysis reaction under the neutral condition. Comparing the activation energies ofdifferent reaction modes, we conclude that uridine phosphorolysis takes Place mainlyaccording tO a concerted mechanism. The computational are consistent with somecritical experimental factsss.展开更多
目的:遗传性球形红细胞增多症(hereditary spherocytosis,HS)是最常见的遗传性红细胞膜缺陷病,主要表现为贫血、黄疸、脾大。由于部分患者临床表现不典型、家族史阴性,加上传统的实验室检查敏感性和特异性均较低,常导致漏诊、误诊。目...目的:遗传性球形红细胞增多症(hereditary spherocytosis,HS)是最常见的遗传性红细胞膜缺陷病,主要表现为贫血、黄疸、脾大。由于部分患者临床表现不典型、家族史阴性,加上传统的实验室检查敏感性和特异性均较低,常导致漏诊、误诊。目前已明确ANK1、SPTB、SPTA1、SLC4A1和EPB42基因突变可引起其对应的编码蛋白质缺失,进而导致红细胞膜缺陷。本研究旨在分析HS基因诊断的可行性和临床应用价值。方法:回顾性收集2018年1月至2021年9月中南大学湘雅二医院血液内科收治的26例中国湖南HS患者的资料,分析其临床表现和实验室检测结果。应用二代测序(next-generation sequencing,NGS)结合Sanger测序,检测HS致病基因突变和胆红素代谢调控关键酶尿苷二磷酸葡萄糖醛酸转移酶1家族多肽A1(uridine diphosphate-glucuronosyl transferase 1 family polypeptide A1,UGT1A1)变异。根据美国医学遗传学与基因组学学会(American College of Medical Genetics and Genomics,ACMG)发布的《序列变异解释的标准和指南》进行致病基因变异判读。分析不同基因变异类型患者的临床特征,并对其临床诊断和基因诊断进行对比分析。结果:在26例HS患者中,贫血23例、黄疸25例、脾大24例、胆石症14例;16例有家族史,10例无家族史;25例HS致病基因突变检测结果为阳性,1例阴性。19个家系共检出18个HS致病基因杂合变异,其中14个为致病性变异,1个可能致病性变异,3个意义未明变异。SPTB突变(12个)和ANK1突变(4个)最多。变异类型以无义突变为主(9个)。SPTB突变组与ANK1突变组相比,外周血红细胞参数及溶血指标的差异均无统计学意义(均P>0.05)。ANK1突变组切脾率高于SPTB突变组,差异有统计学意义(χ^(2)=6.970,P=0.014)。不同突变类型(无义突变、移码突变、剪接位点突变及错义突变)组间外周血红细胞参数及溶血指标差异亦均无统计学意义(均P>0.05)。临床确诊的18例患者中,17例与基因诊断一致;临床疑诊患者8例,均经HS致病基因突变检测确诊。24例HS患者行UGT1A1变异检测,5例患者携带UGT1A1变异导致酶活性降低,19例酶活性正常。酶活性降低组较酶活性正常组的总胆红素(total bilirubin,TBIL)水平高,差异具有统计学意义(U=22,P=0.038)。结论:大多数HS患者有贫血、黄疸和脾大,常合并胆石症。中国湖南HS致病基因突变以SPTB和ANK1突变最常见,基因型与临床表型无明显相关性。基因诊断与临床诊断高度一致。UGT1A1酶活性降低可导致HS患者黄疸程度加重。临床联合基因诊断有利于HS的快速、精准诊断;而UGT1A1酶活性相关基因变异检测对HS黄疸评估有重要意义。展开更多
基金the Science and Technology Research Foundations of Guizhou Province,No.QKHJC-ZK(2022)YB642Zunyi Science and Technology Plan Project,No.ZSKHHZ(2022)344,No.ZSKHHZ(2022)360,and No.ZYK160+2 种基金Hubei Province Central Leading Local Science and Technology Development Special Project,No.2022BCE030Changzhou Science and Technology Projects,No.CE20225054Bijie City Science and Planning Bureau,No.BKH(2022)8.
文摘BACKGROUND Uridine diphosphate glucuronosyltransferase 1A1(UGT1A1)plays a crucial role in metabolizing and detoxifying endogenous and exogenous substances.However,its contribution to the progression of liver damage remains unclear.AIM To determine the role and mechanism of UGT1A1 in liver damage progression.METHODS We investigated the relationship between UGT1A1 expression and liver injury through clinical research.Additionally,the impact and mechanism of UGT1A1 on the progression of liver injury was analyzed through a mouse model study.RESULTS Patients with UGT1A1 gene mutations showed varying degrees of liver damage,while patients with acute-onchronic liver failure(ACLF)exhibited relatively reduced levels of UGT1A1 protein in the liver as compared to patients with chronic hepatitis.This suggests that low UGT1A1 levels may be associated with the progression of liver damage.In mouse models of liver injury induced by carbon tetrachloride(CCl_(4))and concanavalin A(ConA),the hepatic levels of UGT1A1 protein were found to be increased.In mice with lipopolysaccharide or liver steatosis-mediated liver-injury progression,the hepatic protein levels of UGT1A1 were decreased,which is consistent with the observations in patients with ACLF.UGT1A1 knockout exacerbated CCl_(4)-and ConA-induced liver injury,hepatocyte apoptosis and necroptosis in mice,intensified hepatocyte endoplasmic reticulum(ER)stress and oxidative stress,and disrupted lipid metabolism.CONCLUSION UGT1A1 is upregulated as a compensatory response during liver injury,and interference with this upregulation process may worsen liver injury.UGT1A1 reduces ER stress,oxidative stress,and lipid metabolism disorder,thereby mitigating hepatocyte apoptosis and necroptosis.
基金National Natural Science Foundation of China(81373383).
文摘OBJECTIVE There is growing evidence that uridine may act as an endogenous neuromodulator with a potential signaling role in the central nervous system in addition to its function in pyrimidine metabolism.We previously found that acute morphine treatment significantly increased uridine release in the dorsal striatum of mice,while the mechanism involved in morphine-induced uridine release and the role of uridine in morphine-induced neurobehavioral changes have not been understood.METHODS Uridine release in the dorsal striatum of mice was assessed by in vivo microdialysis coupled with high performance liquid chromatography(HPLC) after morphine treatment.Western blotting and immunofluorescence were used to evaluate the expression of uridine-related proteins.Morphine-induced neurobehavioral changes were assessed by locomotor activity,behavioral sensitization and conditioned place preference(CPP)test.The expression of NT5E,an extracellular enzyme involved in formation of nucleosides,including uridine,was specifically knocked down in the dorsal striatum of mice using adeno-associated virus(AAV)-mediated short hairpin RNA(shRNA).RESULTS Both acute and chronic morphine administration significantly increased uridine release in the dorsal striatum,and this was associated with upregulation of NT5E but not other uridine-related proteins.Inhibition of NT5E with APCP or shRNA markedly inhibited morphine-induced uridine release in the dorsal striatum and related neurobehavioral changes,including hyperlocomotor activity,behavioral sensitization and CPP.CONCLUSION The present study increases our understanding of the contribution of NT5E in regulating morphine-induced neurobehavioral changes,at least as related to uridine,and suggests that NT5E may be a novel therapeutic target to manage morphine abuse.
基金Supported by A Damon Runyon Cancer Research Foundation Clinical Investigator Award,CI-8An R25 training grant from the National Cancer Institute,R25T CA094186+1 种基金The Case Center for Transdisciplinary Research on Energetics and Cancer,1U54 CA-116867-01A National Cancer Institute K22 Award,1K22 CA120545-01
文摘AIM:To investigate the association of variations in the cyclooxygenase-2 (COX2) and uridine diphosphate glucuronosyltransferase 1A6 (UGTIA6) genes and non-steroidal anti-inflammatory drugs (NSAIDs) use with risk of colon cancer.METHODS: NSAIDs, which are known to reduce the risk of colon cancer, act directly on COX2 and reduce its activity. Epidemiological studies have associated variations in the COX2 gene with colon cancer risk, but others were unable to replicate this finding. Similarly,enzymes in the UGT1A6 gene have been demonstrated to modify the therapeutic effect of NSAIDs on colon adenomas. Polymorphisms in the UGTIA6 gene have been statistically shown to interact with NSAID intake to influence risk of developing colon adenomas, but not colon cancer. Here we examined the association of tagging single nucleotide polymorphisms (SNPs) in the COX2 and UGTIA6 genes, and their interaction with NSAID consumption, on risk of colon cancer in a population of 422 colon cancer cases and 481 population controls.RESULTS: No SNP in either gene was individually statistically significantly associated with colon cancer, nor did they statistically significantly change the protective effect of NSAID consumption in our sample. Like others, we were unable to replicate the association of variants in the COX2 gene with colon cancer risk (P 〉 0.05),and we did not observe that these variants modify the protective effect of NSAIDs (P 〉 0.05). We were able to confirm the lack of association of variants in UGT1A6 with colon cancer risk, although further studies will have to be conducted to confirm the association of these variants with colon adenomas.CONCLUSION: Our study does not support a role of COX2 and UGTIA6 genetic variations in the development of colon cancer.
基金Supported by"Production,Education&Research"item of Shanghai Baoshan(08-H-4)
文摘Recombinant Escherichia coli pUDP,which overexpressed uridine phosphorylase(UPase),was constructed.0.5 mmol·L 1lactose had a similar induction effect as the commonly used inducer IPTG during 2.5-5.5 h of cell growth.The lactose-induced UPase was stable at 50°C.Wet cells of pUDP was used as catalyst to biosynthesize 5-fluorouridine from 30 mmol·L 1uridine and 5-fluorouracil in phosphate buffer(pH 7.0)catalyzed at 50°C for 1.5 h and the yield of 5-fluorouridine was higher than 68%.Under the optimum reaction conditions for production of 5-fluorouridine,5-methyluridine and azauridine were synthesized from uridine by pUDP,the yield was 61.7%and 47.2%respectively.Deoxynucleosides were also synthesized by pUDP,but the yield was only about 20%.
文摘Rationale: In a previously published trial on spinal acute non-traumatic pain, peripheral neuro- regenerative combination of UTP, CMP and hydroxocobalamin presented unexpected analgesicproperties. Objective: To corroborate analgesiceffects of UTP, CMP and hydroxocobalamin combination in a self-paired evolutionary model. Methods: Mean VAS scores from pretreatment, V2 (5th treatment day) and V3 (10th treatment day) were plotted and statistically analyzed (ANOVA) for differences. PFQ scores from pretreatment, V2, and V3 were analyzed using the chisquare test. Results: The difference between V3 and pretreatment mean VAS scores was statistically significant (p < 0.0001). The improvement in PFQ scores throughout the study was found to be statistically significant (p < 0.0001). Conclusion: The combination of UTP, CMP and hydroxocobalamin seems to have analgesic properties in mediumterm use. The complex peripheral neu-roregenerative pharmacodynamics of this combination provides a plausible basis for this finding. Further randomized studies are needed to explore this combination for the indication of neuropathic pain due to spinal structure involvement.
文摘A new N-acetylsulfanilylation series of uridine have been synthesized in good yield using direct acylation method and afforded the 5’-O-N-acetylsulfanilyluridine. In order to obtain newer products, the 5’-O-N-acetylsulfanilyluridine derivative was further transformed to a series of 2’,3’-di-O-acyl derivatives containing a wide variety of functionalities in a single molecular framework. The chemical structures of the newly synthesized compounds were confirmed on the basis of their FTIR, 1H-NMR spectroscopy, physicochemical properties and elemental analysis. All the synthesized uridine derivatives were tested for their in vitro antibacterial activity against six human pathogenic bacterial strains and for comparison standard antibiotic Ampicillin was also determined. The study revealed that the selectively acylated deriva-tives 5’-O-N-acetylsulfanilyl-2’,3’-di-O-lauroyluridine and 5’-O-N-acetylsulfanilyl-2’,3’-di-O-pivaloyluridine showed highest inhibition against Staphylococcus aureus and Bacillus cereus, respectively. We also observed that the introduction of hexanoyl, decanoyl, lauroyl, myristoyl and pivaloyl groups, the antibacterial functionality of the compound uridine increases. Another noteworthy observation was that the uridine derivatives were found comparatively more effective against Gram-positive microorganisms than those of Gram-negative microorganisms. In addition, the test chemicals were also tested for cyto-toxicity by brine shrimp lethality bioassay and compounds showed different rate mortality with different concentrations.
基金This paper was jointly supported by grants from the Science and Technology Projects of Hunan Province(2019RS3020,2019RS3021),Jiangxi Provincial Innovation and Entrepreneurship Projects.
文摘High-fat diet(HFD)is demonstrated to disturb the bile acid metabolism.The rhythm of bile acid metabolism can also be affected by uridine,whose metabolism exhibits a daily rhythm.However,the mechanism of dynamic uridine administration affecting bile acid during HFD remains unclear.In this study,C57BL/6J mice were fed HFD(the control group;CON)or HFD with oral administration of uridine in the daytime(DUR)and nighttime(NUR)to investigate the mechanism of the effect of uridine on the bile acid.This study showed that the mRNA expression of uridine transporters and circadian clock genes in the jejunum was affected by zeitgeber time(ZT)(P<0.001).Genes related to the metabolism of pyrimidines in the liver showed a high dependence on daily rhythm(P<0.01),and DUR remarkably up-regulated the expression of ribonucleotide reductase regulatory subunit M2(RRM2)(P<0.05)compared to the CON group.Importantly,the mRNA expression of bile acids nuclear receptors,bile acid synthesis,and transporters in the liver showed significantly rhythmically changed(P<0.05),and the expression of cholesterol 7-alpha-hydroxylase(CYP7A1),fibroblast growth factor receptor 4(FGFR4),Na^(+)/taurocholate co transporting polypeptide(NTCP),and bile salt export pump(BSEP)mRNAs of mice with uridine administration increased significantly(P<0.05).The mRNA expression of the transporters of cholesterol and bile acids in the ileum was also affected by ZT(P<0.01)and significantly dependent on uridine administration(P<0.05).The expression of FXR and SHP was significantly affected by ZT and uridine,respectively.In conclusion,dynamic administration of uridine could regulate the rhythm of gene expression of pyrimidine and bile acid metabolism in the liver and ileum of HFD-fed mice,which contributed to the further study of circadian rhythmic physiological and pathological changes of bile acids.
基金supported by the National Natural Science Foundation of China(No.22173014,No.21773226,and No.21873100)Open Fund of the State Key Laboratory of Molecular Reaction Dynamics in Dalian Institute of Chemical Physics,Chinese Academy of Sciences。
文摘We applied quantum mechanics/classical mechanics simulations to study excess-electron attachment and ionization of uridine monophosphate anion(d UMP-)in explicit aqueous solutions.We calculated vertical electron affinities(VEAs),adiabatic electron affinities(AEAs),vertical detachment energies(VDEs),vertical ionization energies(VIEs),and adiabatic ionization energies(AIEs)of the 40 structures obtained from molecular dynamic trajectory.The excess-electron and hole distributions were analyzed in electron attachment and ionization of aqueous d UMP^(-).The converged mean VEA(-0.31 e V)and AEA(2.13 e V)suggest that excess-electron can easily attach to d UMP^(-).The mean vertical(-0.50 e)and adiabatic(-0.62 e)excess-electron on uracil reveal that main excesselectrons are localized on nucleobases at the most snapshots.The distributions at several special snapshots demonstrate the excess-electron delocalization over nucleobases/ribose or ribose/phosphate group after the structural relaxations of d UMP^(2-)dianion.The VDE value(2.78 e V)indicates that d UMP2-dianion could be very stable.Moreover,the mean VIE is 8.13 eV which is in agreement with the previous calculation using solvation model.The hole distributions on uracil suggest that the nucleobases are easily ionized after the irradiation of high-energy rays.In vertical ionizations,the holes would be delocalized over uracil and ribose at several snapshots.Observing the adiabatic hole distributions,it can be found that electrons on phosphate group and holes on nucleobases can be transferred to ribose at the special snapshots in the structural relaxation of neutral species.
文摘We have cd quantum chemical method tO ho the transition states of uridinephosphorolysis reaction under the neutral condition. Comparing the activation energies ofdifferent reaction modes, we conclude that uridine phosphorolysis takes Place mainlyaccording tO a concerted mechanism. The computational are consistent with somecritical experimental factsss.
文摘目的:遗传性球形红细胞增多症(hereditary spherocytosis,HS)是最常见的遗传性红细胞膜缺陷病,主要表现为贫血、黄疸、脾大。由于部分患者临床表现不典型、家族史阴性,加上传统的实验室检查敏感性和特异性均较低,常导致漏诊、误诊。目前已明确ANK1、SPTB、SPTA1、SLC4A1和EPB42基因突变可引起其对应的编码蛋白质缺失,进而导致红细胞膜缺陷。本研究旨在分析HS基因诊断的可行性和临床应用价值。方法:回顾性收集2018年1月至2021年9月中南大学湘雅二医院血液内科收治的26例中国湖南HS患者的资料,分析其临床表现和实验室检测结果。应用二代测序(next-generation sequencing,NGS)结合Sanger测序,检测HS致病基因突变和胆红素代谢调控关键酶尿苷二磷酸葡萄糖醛酸转移酶1家族多肽A1(uridine diphosphate-glucuronosyl transferase 1 family polypeptide A1,UGT1A1)变异。根据美国医学遗传学与基因组学学会(American College of Medical Genetics and Genomics,ACMG)发布的《序列变异解释的标准和指南》进行致病基因变异判读。分析不同基因变异类型患者的临床特征,并对其临床诊断和基因诊断进行对比分析。结果:在26例HS患者中,贫血23例、黄疸25例、脾大24例、胆石症14例;16例有家族史,10例无家族史;25例HS致病基因突变检测结果为阳性,1例阴性。19个家系共检出18个HS致病基因杂合变异,其中14个为致病性变异,1个可能致病性变异,3个意义未明变异。SPTB突变(12个)和ANK1突变(4个)最多。变异类型以无义突变为主(9个)。SPTB突变组与ANK1突变组相比,外周血红细胞参数及溶血指标的差异均无统计学意义(均P>0.05)。ANK1突变组切脾率高于SPTB突变组,差异有统计学意义(χ^(2)=6.970,P=0.014)。不同突变类型(无义突变、移码突变、剪接位点突变及错义突变)组间外周血红细胞参数及溶血指标差异亦均无统计学意义(均P>0.05)。临床确诊的18例患者中,17例与基因诊断一致;临床疑诊患者8例,均经HS致病基因突变检测确诊。24例HS患者行UGT1A1变异检测,5例患者携带UGT1A1变异导致酶活性降低,19例酶活性正常。酶活性降低组较酶活性正常组的总胆红素(total bilirubin,TBIL)水平高,差异具有统计学意义(U=22,P=0.038)。结论:大多数HS患者有贫血、黄疸和脾大,常合并胆石症。中国湖南HS致病基因突变以SPTB和ANK1突变最常见,基因型与临床表型无明显相关性。基因诊断与临床诊断高度一致。UGT1A1酶活性降低可导致HS患者黄疸程度加重。临床联合基因诊断有利于HS的快速、精准诊断;而UGT1A1酶活性相关基因变异检测对HS黄疸评估有重要意义。