Uridine diphosphate glucuronosyltransferase 1A1 prevents the progression of liver injury

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.

陶瓷溶出铁、镍离子与Uridine(脲苷)络合物的性能研究

中药传统熬制一般采用陶瓷器皿,因陶瓷具有强度高、化学惰性、热稳定性好、耐腐蚀等优于金属器皿(金属离子过量则有毒,因此不用金属器皿熬药)的性能,且陶瓷器皿中适当缓慢溶出微量的金属离子,与中药的有效化学成分发生络合作用,从而可能增强药效。采用量子化学中的DFT(密度泛函)法,在B3LYP水平上,使用Gauss09程序包研究陶瓷中所含微量Fe离子和Ni离子分别与中药分子中的有效化学成分Uridine(脲苷)的络合体系,得到相应的优化几何结构、激发态、NBO电荷分布、相互作用能等。结果表明:陶瓷器皿中溶出的Fe离子和Ni离子均能与uridine分子有效络合且相互作用能相近,说明络合物均能稳定存在且稳定性相当,增强了中药中有效化学成分的药效。

Potential role of ecto-5'-nucleotidase in morphine-induced uridine release and neurobehavioral changes

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.

Symptomatic improvement in an acute, non-traumatic spine pain model with a combination of uridine triphosphate, cytidine monophosphate, and hydroxocobalamin

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.

Uridine dynamic administration affects the circadian variation of bile acid metabolism in high-fat-diet-fed mice

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.

Synthesis and Diastereomeric Analysis of Uridine 2’,3’-Cyclic Phosphite

Uridine 2’,3’-cyclic phosphite has been synthesized and the diastereomers were analysed by 2D NMR technique to assign the configuration

An AM1 Study on the Mechanism of Uridine Phospborolysis

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.

Chemically Modified Uridine Molecules Incorporating Acyl Residues to Enhance Antibacterial and Cytotoxic Activities

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.

Uridine alleviates high-carbohydrate diet-induced metabolic syndromes by activating sirt1/AMPK signaling pathway and promoting glycogen synthesis in Nile tilapia(Oreochromis niloticus)

Carbohydrates have a protein sparing effect,but long-term feeding of a high-carbohydrate diet(HCD)leads to metabolic disorders due to the limited utilization efficiency of carbohydrates in fish.How to mitigate the negative effects induced by HCD is crucial for the rapid development of aquaculture.Uridine is a pyrimidine nucleoside that plays a vital role in regulating lipid and glucose metabolism,but whether uridine can alleviate metabolic syndromes induced by HCD remains unknown.In this study,a total of480 Nile tilapia(Oreochromis niloticus)(average initial weight 5.02±0.03 g)were fed with 4 diets,including a control diet(CON),HCD,HCD+500 mg/kg uridine(HCUL)and HCD+5,000 mg/kg uridine(HCUH),for 8 weeks.The results showed that addition of uridine decreased hepatic lipid,serum glucose,triglyceride and cholesterol(P<0.05).Further analysis indicated that higher concentration of uridine activated the sirtuin1(sirt1)/adenosine 5-monophosphate-activated protein kinase(AMPK)signaling pathway to increase lipid catabolism and glycolysis while decreasing lipogenesis(P<0.05).Besides,uridine increased the activity of glycogen synthesis-related enzymes(P<0.05).This study suggested that uridine could alleviate HCD-induced metabolic syndrome by activating the sirt1/AMPK signaling pathway and promoting glycogen synthesis.This finding reveals the function of uridine in fish metabolism and facilitates the development of new additives in aquatic feeds.

Comparative studies on the mechanism of uridine phosphorolysis

We have used quantum mechanical method to study the transition states(TSs) of uridine phosphorolysis reaction. Comparing the four different reaction pathways and the five transition states obtained, we conclude that enzymatic uridine phosphorolysis takes place mainly according to acid-catalyzed S(N)2 mechanism. The proposed reaction pathway is consistent with many experimental results.

Postoperative jaundice related to UGT1A1 and ABCB11 gene mutations:A case report and literature review

BACKGROUND Patients with obstructive jaundice caused by intrahepatic bile duct stones can be effectively managed by surgery.However,some patients may develop postope-rative complications,liver failure,and other life-threatening situations.Here,we report a patient with mutations in the uridine 5’-diphospho-glucuronosyltrans-ferase 1A1(UGT1A1)and bile salt export pump(adenosine triphosphate-binding cassette subfamily B member 11,ABCB11)genes who presented multiple intrahe-patic bile duct stones and cholestasis,and the jaundice of the patient increased after partial hepatectomy.CASE SUMMARY A 52-year-old male patient admitted to the hospital on October 23,2021,with a progressive exacerbation of jaundice,was found to have multiple intrahepatic bile duct stones with the diagnoses of obstructive jaundice and acute cholecystitis.Subsequently,the patient underwent left hepatectomy with biliary exploration,stone extraction,T-tube drainage,and cholecystectomy without developing any intraoperative complications.The patient had a dark urine color with worsening jaundice postoperatively and did not respond well to plasma exchange and other symptomatic and supportive treatments.Since the progressive increase in postoperative bilirubin could not be clinically explained with any potential reason,including,if not at all,viral infection,cholangitis,autoimmune liver disease,and other causes,the patient underwent whole-exon screening for any genetic diseases,which surprisingly identified UGT1A1 and ABCB11 gene mutations related to glucuronidation of indirect bilirubin as well as bile acid transport in hepatocytes,respectively.Thus,we hypothesized that postoperative refractory cholestasis might result from UGT1A1 and ABCB11 gene mutations and further recommended liver transplantation to the patient,who eventually declined it and died from liver failure six months later.CONCLUSION Surgery may aggravate cholestasis in patients with multiple intrahepatic bile duct stones and cholestasis associated with UGT1A1 and ABCB11 gene mutations.A liver transplant may be the best option if active medical treatment fails.

Etiology analysis for term newborns with severe hyperbilirubinemia in eastern Guangdong of China

BACKGROUND Neonatal hyperbilirubinemia is one of the common diseases of newborns that typically presents with yellow staining of skin,resulting in sequelaes such as hearing loss,motor and intellectual development disorders,and even death.The pathogenic factors of neonatal hyperbilirubinemia are complex.Different cases of hyperbilirubinemia may have a single or mixed etiology.AIM To explore the etiological characteristics of severe hyperbilirubinemia in term newborns of eastern Guangdong of China.METHODS Term newborns with severe hyperbilirubinemia in one hospital from January 2012 to December 2021 were retrospectively analyzed.The etiology was determined according to the laboratory results and clinical manifestations.RESULTS Among 1602 term newborns with hyperbilirubinemia in eastern Guangdong of China,32.20%(580/1602)was severe hyperbilirubinemia.Among the causes of severe hyperbilirubinemia,neonatal hemolysis accounted for 15.17%,breast milk jaundice accounted for 12.09%,infection accounted for 10.17%,glucose-6-phosphate dehydrogenase(G6PD)deficiency accounted for 9.14%,and the coexistence of multiple etiologies accounted for 6.55%,unknown etiology accounted for 41.72%.ABO hemolysis and G6PD deficiency were the most common causes in the 20 cases with bilirubin encephalopathy.94 severe hyperbilirubinemia newborns were tested for uridine diphosphate glucuronosyl transferase 1A1(UGT1A1)*6 variant(rs4148323,c.211G>A,p.Arg71Gly),9 cases were 211 G to A homozygous variant,37 cases were 211 G to A heterozygous variant,and 48 cases were wild genotypes.CONCLUSION The main cause for severe hyperbilirubinemia and bilirubin encephalopathy in eastern Guangdong of China were the hemolytic disease of the newborns,G6PD deficiency and infection.UGT1A1 gene variant was also a high-risk factor for neonatal hyperbilirubinemia.Targeted prevention and treatment according to the etiology may reduce the occurrence of bilirubin encephalopathy and kernicterus.

Systematic analyses of glutamine and glutamate metabolisms across different cancer types

Background: Glutamine and glutamate are known to play important roles in cancer biology. However, no detailed information is available in terms of their levels of involvement in various biological processes across different cancer types, whereas such knowledge could be critical for understanding the distinct characteristics of different cancer types. Our computational study aimed to examine the functional roles of glutamine and glutamate across different cancer types.Methods: We conducted a comparative analysis of gene expression data of cancer tissues versus normal control tissues of 11 cancer types to understand glutamine and glutamate metabolisms in cancer. Specifically, we developed a linear regression model to assess differential contributions by glutamine and/or glutamate to each of seven biological processes in cancer versus control tissues.Results: While our computational predictions were consistent with some of the previous observations, multiple novel predictions were made:(1) glutamine is generally not involved in purine synthesis in cancer except for breast cancer, and is similarly not involved in pyridine synthesis except for kidney cancer;(2) glutamine is generally not involved in ATP production in cancer;(3) glutamine's contribution to nucleotide synthesis is minimal if any in cancer;(4) glutamine is not involved in asparagine synthesis in cancer except for bladder and lung cancers; and(5) glutamate does not contribute to serine synthesis except for bladder cancer.Conclusions: We comprehensively predicted the roles of glutamine and glutamate metabolisms in selected metabolic pathways in cancer tissues versus control tissues, which may lead to novel approaches to therapeutic development targeted at glutamine and/or glutamate metabolism. However, our predictions need further functional validation.

Correlation between UGT1A1 Polymorphism and Neonatal Hyperbilirubinemia of Neonates in Wuhan

This study attempts to discuss the correlation between UGT1A1＊28 as uridine diphosphate glucuronosyltransferase gene promoter and coding region Gly71 Arg gene polymorphism with neonatal hyperbilirubinemia of neonates in Wuhan. A total of 168 neonates were divided into the hyperbilirubinemia group（case group, n=108） and healthy neonates group（control group, n=60）. Their DNA was obtained through blood extraction. The gene exon mutation of UGT1A1 was detected by Sanger sequencing, which revealed the relationship between UGT1A1＊28 and Gly71 Arg polymorphism with neonatal hyperbilirubinemia of neonates. The results showed that：（1） The frequency of UGT1A1＊28 allele mutation in the case group and the control group was 9.3% and 10% respectively, with the difference being not significant between the two groups（P〉0.05）.（2） The frequency of Gly71 Arg allele mutation in the case group and the control group was 35.1% and 21.7% respectively, with the difference being significant between the two groups（P〈0.01）.（3） The serum bilirubin level of Gly71 Arg mutant homozygous and heterozygous subgroups（n=66） in the case group was 302.7±31.4 μmol/L, which was significantly higher than 267.3±28.5 μmol/L of the wild subgroup（n=42）（P〈0.01）. It was suggested that the occurrence of neonatal hyperbilirubinemia of neonates in Wuhan was not associated with UGT1A1＊28 gene polymorphism, but closely with the Gly71 Arg gene polymorphism. Meanwhile, the Arg allele mutation was related to the degree of jaundice.

Pharmacogenetics of irinotecan:An ethnicity-based prediction of irinotecan adverse events

Irinotecan is now regarded as the most active drug for the treatment of colorectal cancer.However,one of the most difficult issues oncologists face is deciding the optimal dose for an individual patient,as each individual shows different outcomes even at the same dose with regard to treatment related adverse events,ranging from no toxicity to a lethal event.Inherited genetic polymorphism of a single gene or multiple genes(haplotype or linkage disequilibrium) involved in SN-38 glucuronidation,a predominant route of irinotecan detoxification,is now recognized as a significant factor that can alter the incidence of side effects.Attempts to explore such inherited genetic variability have been focused on elucidating interindividual as well as interethnic differences.Genotyping studies in relation to adverse events in an individual or in a group of similar ethnicity should contribute to establishing individualoriented or ethnicity-oriented irinotecan treatment regimens.This review highlights current single-or multi-tired approaches for the elucidation of genetic predispositions of patients to severe toxicities,especially among Asians.The purpose of this is to contribute to minimizing toxicity by dose modifications,with the consequent aim of maximizing dose intensity and efficacy,an ultimate goal of irinotecan-individualized therapy.

羧基和咪唑基团在柚柠檬苦素类化合物糖基转移酶催化反应中的作用(英文)

Limonoid bitterness is a serious problem in the citrus industry worldwide. Limonoid glucosyltransferase is an enzyme that catalyzes the conversion of bitter limonoid into non-bitter limonoid glucoside while retaining the health benefit of limonoids in the juice. The immobilization of this enzyme in a column can solve the juice bitterness problem. More information about the catalytic residues of the enzyme is needed in this immobilization process. Glutamate/aspartate,histidine,lysine,tryptophan,serine,and cysteine residues were chemi-cally modified to investigate their roles in the catalytic function of limonoid glucosyltransferase. Inactivation of the enzyme following modi-fication of carboxyl and imidazole moieties was a consequence of a loss in substrate binding and catalysis in the glucosyltransfer reaction. The modification of a single histidine residue completely destroyed the ability of limonoid glucosyltransferase to transfer the D-glucopyranosyl unit. Tryptophan seemed to have some role in maintaining the active conformation of the catalytic site. Lysine also seemed to have some direct or indirect role in this catalysis but the modification of serine and cysteine did not have any effect on catalysis. Therefore,we conclude that the carboxyl and imidazole groups containing amino acids are responsible for the catalytic action of the enzyme.

Interaction between N-Phospho-Amino Acids and Nucleoside in Aqueous Medium

Nucleosides were phosphorylated with different N- (O, O-diisopropyl) phosphoryl amino acids to give nucleoside mono phosphates in aqueous solution. 2', 3', and 5'-isomers had been confirmed by comparison with authentic samples on the basis of HPLC analysis. The conversion percentage of nucleoside indicated that N- (O, O-diisopropyl) phosphoryl aspartic acid reacted with adenosine and guanosine at a much higher rate than other kinds of N- phosphoryl amino acids. while phosphorylation of cytidine and uridine was relatively easy by using N- (O, O-diisopropyl) phosphoryl threonine. The result could give some clue to the prebiotic code origin of nucleic acid and protein.

Genetic analysison the association between polymorphisms of UGT1A1and GST and neonatal hyperbilirubinemia

Objective:To investigate whether polymorphisms of uridine diphosphoglucuronate-glucuronosyltransferase 1A1(UGT1A1)c.211G>A and glutathione S transferases(GST)gene(GSTT1and GSTM1)are associated with neonatal hyperbilirubinemia.Methods:A case-control study was performed.A multiplex polymerase chain reaction(PCR)was used to detect the GSTT1and GSTM1polymorphisms.Single nucleotide polymorphism of UGT1A1c.211G>A was identified by PCR combined with DNA sequencing.The effects and co-expression of UGT1A1c.211G>A,GSTT1and GSTM1gene polymorphisms on the development of neonatal hyperbilirubinemia were estimated.Results:A allele frequency of c.211G>A polymorphism of UGT1A1gene was 0.186in case group and 0.086in control group,respectively.A allele frequency of the polymorphism of UGT1A1gene in the case group was higher than that of the control group(χ2=5.968,P=0.022).The frequencies of GSTT1and GSTM1in the case group were similar to that of the control groups.Logistic regression analysis showed that UGT1A1c.211G>A variant and UGT1A1+GSTM1 mutation affected neonatal hyperbilirubinemia.Conclusion:UGT1A1c.211G>A gene polymorphism may be one risk factor involved in the development of neonatal hyperbilirubinemia,and GST gene polymorphism may not be associated with the development of neonatal hyperbilirubinemia in our study.The co-expression of UGT1A1c.211G>A and GSTM1polymorphisms may reduce the risk for neonatal hyperbilirubinemia development.

Tobacco smoking and its drug interactions with comedications involving CYP and UGT enzymes and nicotine

Tobacco smoking is a global public health threat causing several illnesses including cardiovascular disease(Myocardial infarction), cerebrovascular disease(Stroke), peripheral vascular disease(Claudication), chronic obstructive pulmonary disease, asthma, reduced female infertility, sexual dysfunction in men, different types of cancer and many other diseases. It has been estimated in 2015 that approximately 1.3 billion people smoke, around the globe. Use of medications among smokers is more common, nowadays. This review is aimed to identify the medications affected by smoking, involving Cytochrome P450(CYP)and uridine diphosphate-glucuronosyltransferases(UGTs) enzymes and Nicotine. Polycyclic aromatic hydrocarbons(PAHs) of tobacco smoke have been associated with the induction of CYP enzymes such as CYP1A1, CYP1A2 and possibly CYP2E1 and UGT enzymes. The drugs metabolized by CYP1A1,CYP1A2, CYP2E1 and UGT enzymes might be affected by tobacco smoking and the smokers taking medications metabolized by those enzymes, may need higher doses due to decreased plasma concentrations through enhanced induction by PAHs of tobacco smoke. The prescribers and the pharmacists are required to be aware of medications affected by tobacco smoking to prevent the toxicityassociated complications during smoking cessation.