Fatty acid metabolism and acyl-CoA synthetases in the liver-gut axis

Fatty acids are energy substrates and cell components which participate in regulating signal transduction,transcription factor activity and secretion of bioactive lipid mediators.The acyl-CoA synthetases(ACSs)family containing 26 family members exhibits tissue-specific distribution,distinct fatty acid substrate preferences and diverse biological functions.Increasing evidence indicates that dysregulation of fatty acid metabolism in the liver-gut axis,designated as the bidirectional relationship between the gut,microbiome and liver,is closely associated with a range of human diseases including metabolic disorders,inflammatory disease and carcinoma in the gastrointestinal tract and liver.In this review,we depict the role of ACSs in fatty acid metabolism,possible molecular mechanisms through which they exert functions,and their involvement in hepatocellular and colorectal carcinoma,with particular attention paid to long-chain fatty acids and small-chain fatty acids.Additionally,the liver-gut communication and the liver and gut intersection with the microbiome as well as diseases related to microbiota imbalance in the liver-gut axis are addressed.Moreover,the development of potentially therapeutic small molecules,proteins and compounds targeting ACSs in cancer treatment is summarized.

Mechanism and evolution of multidomain aminoacyl-tRNA synthetases revealed by their inhibition by analogues of a reaction intermediate, and by properties of truncated forms

Many enzymes which catalyze the conversion of large substrates are made of several structural domains belonging to the same polypeptide chain. Transfer RNA (tRNA), one of the substrates of the multidomain aminoacyl-tRNA synthetases (aaRS), is an L-shaped molecule whose size in one dimension is similar to that of its cognate aaRS. Crystallographic structures of aaRS/tRNA complexes show that these enzymes use several of their structural domains to interact with their cognate tRNA. This mini review discusses first some aspects of the evolution and of the flexibility of the pentadomain bacterial glutamyl-tRNA synthetase (GluRS) revealed by kinetic and interaction studies of complementary truncated forms, and then illustrates how stable analogues of aminoacyl-AMP intermediates have been used to probe conformational changes in the active sites of Escherichia coli GluRS and of the nondiscriminating aspartyl-tRNA synthetase (ND-AspRS) of Pseudomonas aeruginosa.

Anti-Aminoacyl tRNA Synthetases Antibodies in Japanese Patients with Interstitial Lung Disease

Objectives: In the present study, we have sought to establish the clinical and immunological characteristics of Japanese patients with interstitial lung disease (ILD). Methods: Serum samples from 35 patients of ILD were screened for autoantibodies using RNA and protein immunoprecipitation assays. Patients with or without serum antibodies to aminoacyl tRNA synthetases (ARS) were assessed clinically and compared. Results: Sera from 12 of 35 (34%) patients with ILD (mean age at onset = 49.7 yrs;range 27 - 65 yrs) were found to contain anti-ARS antibodies (anti-EJ: 3 patients;anti-OJ: 2 patients;anti-PL-12: 3 patients;anti-KS: 4 patients). Nine of the 12 (75%) were female. Six (50%) had Raynaud’s phenomenon, 5 (42%) had arthralgia/arthritis and four (33%) had rheumatoid factor. Lung biopsy specimens of 8 patients with anti-ARS antibodies were examined histologically in detail. The following was determined: Two patients had usual interstitial pneumonia;3 had non-specific interstitial pneumonia;one had organizing pneumonia;one had lymphocyte interstitial pneumonia and the remaining patient had desquamative interstitial pneumonia. Age at disease onset was significantly lower and the frequency of Raynaud’s phenomenon was significantly greater in these patients compared to anti-ARS-negative patients (49.7 yrs vs. 62.6 yrs, p = 0.004;50% vs. 4%, p = 0.003, respectively). Conclusions: These results indicate that the presence of anti-ARS autoantibodies correlates with ILD without definite diagnosis of connective tissue diseases as well as polymyositis/dermatomyositis (PM/DM) with ILD in Japanese patients.

A novel therapeutic target for peripheral nerve injury-related diseases: aminoacyl-tRNA synthetases

Aminoacyl-t RNA synthetases（Amino ARSs） are essential enzymes that perform the first step of protein synthesis. Beyond their original roles, Amino ARSs possess non-canonical functions, such as cell cycle regulation and signal transduction. Therefore, Amino ARSs represent a powerful pharmaceutical target if their non-canonical functions can be controlled. Using Amino ARSs-specific primers, we screened m RNA expression in the spinal cord dorsal horn of rats with peripheral nerve injury created by sciatic nerve axotomy. Of 20 Amino ARSs, we found that phenylalanyl-t RNA synthetase beta chain（FARSB）, isoleucyl-t RNA synthetase（IARS） and methionyl-t RNA synthetase（MARS） m RNA expression was increased in spinal dorsal horn neurons on the injured side, but not in glial cells. These findings suggest the possibility that FARSB, IARS and MARS, as a neurotransmitter, may transfer abnormal sensory signals after peripheral nerve damage and become a new target for drug treatment.

Metformin alleviates spinal cord injury by inhibiting nerve cell ferroptosis through upregulation of heme oxygenase-1 expression

Previous studies have reported upregulation of heme oxygenase-1 in different central nervous system injury models.Heme oxygenase-1 plays a critical anti-inflammatory role and is essential for regulating cellular redox homeostasis.Metformin is a classic drug used to treat type 2 diabetes that can inhibit ferroptosis.Previous studies have shown that,when used to treat cardiovascular and digestive system diseases,metformin can also upregulate heme oxygenase-1 expression.Therefore,we hypothesized that heme oxygenase-1 plays a significant role in mediating the beneficial effects of metformin on neuronal ferroptosis after spinal cord injury.To test this,we first performed a bioinformatics analysis based on the GEO database and found that heme oxygenase-1 was upregulated in the lesion of rats with spinal cord injury.Next,we confirmed this finding in a rat model of T9 spinal cord compression injury that exhibited spinal cord nerve cell ferroptosis.Continuous intraperitoneal injection of metformin for 14 days was found to both upregulate heme oxygenase-1 expression and reduce neuronal ferroptosis in rats with spinal cord injury.Subsequently,we used a lentivirus vector to knock down heme oxygenase-1 expression in the spinal cord,and found that this significantly reduced the effect of metformin on ferroptosis after spinal cord injury.Taken together,these findings suggest that metformin inhibits neuronal ferroptosis after spinal cord injury,and that this effect is partially dependent on upregulation of heme oxygenase-1.

MicroRNA (let-7b-5p)-targeted DARS2 regulates lung adenocarcinoma growth by PI3K/AKT signaling pathway

Background:The aberrant intraellular expression of a mitochondrial aspartyl tRNA synthetase 2(DARS2)has been reported in human cancers.Nevertheless its critical role and detailed mechanism in lung adenocarcinoma(LUAD)remain unexplored.Methods:Initially,The Cancer Genome Atlas(TCGA)based Gene Expression Profiling Interactive Analysis(GEPIA)database (http:/gepia.cancer-pku.cn/)was used to analyze the prognostic relevance of DARS2 expression in LUAD.Further,cell counting kit(CCK)8,immunostaining,and transwell invasion assays in LUAD cell lines in vitro,as well as DARS2 silence on LUAD by tumorigenicity experiments in wivo in nude mice,were performed.Besides,we analyzed the expression levels of p-PI3K(phosphorylated Phosphotylinosital3 kinase),PI3K,AKT(Protein Kinase B),p-AKT(phosphorylated Protein Kinase B),PCNA(proliferating cell nudear antigen),cleaved-caspase 3,E cadherin,and N-cadherin proteins using the Westem blot analysis.Results:LUAD tissues showed higher DARS2 expression compared to normal tissues.Upregulation of DARS2 could be related to Tumor-Node-Metastasis(TNM)stage,high lymph node metastasis,and inferior prognosis.DARS2 silence decreased the proliferation,migration,and invasion abilities of LUAD cells.In addition,the DARS2 downregulation decreased the PCNA and N-cadherin expression and increased cleaved:caspase 3 and E cadherin expressions in LUAD cells,coupled with the inactivation of the PI3K/AKT signaling pathway.Moreover,DARS2 silence impaired the tumonigenicity of LUAD in vivo.Interestingly,let:7b-5p could recognize DARS2 through a complementary sequence.Mechanistically,the increased let 7b 5p expression attenuated the promo oncogenic action of DARS2 during LUAD progression,which were inversely correlated to each other in the LUAD tssues Conclusion:In summary,let 7b-5p,downregulated DARS2 expression,regulating the progression of LUAD cells by the PI3K/AKT signaling pathway.

Dynamics of glutamine synthetase expression in hepatic ischemiareperfusion injury: Implications for therapeutic interventions

BACKGROUND Hepatic ischemia-reperfusion injury(IRI)poses a great challenge in liver surgery and transplantation because of oxidative stress and inflammatory responses.The changes in glutamine synthetase(GS)expression during hepatic IRI remain unclear.AIM To investigate the dynamic expression of GS during hepatic IRI.METHODS Following hepatic ischemia for 1 h and reperfusion,liver tissue samples were collected at 0.5,6,and 24 hours postreperfusion for fixation,embedding,section-ing.Hematoxylin and eosin staining and GS staining were performed.RESULTS GS expression rapidly decreases in hepatocytes around the central vein after IRI,reaching its lowest point at 6 hours postreperfusion,and then gradually recovers.CONCLUSION GS is highly sensitive to IRI,highlighting its potential role as an indicator of liver injury states and a target for therapeutic intervention.

Molecular Cloning and Bioinformatics Analysis of sucC Gene of Vibrio alginolyticus Strain HY9901

[Objectives]To clone the sucC gene of Vibrio alginolyticus strain HY9901 and conduct the bioinformatics analysis.[Methods]Based on the sucC gene of V.alginolyticus strain HY9901,specific primers were designed to amplify the full length sequence by PCR and make further analysis.[Results]The theoretical molecular weight of SucC protein was about 41528.45 Da,and the full length was 1167 bp,encoding 388 amino acids.It has no signal peptide and transmembrane region,and has a variety of functional sites.It is predicted that it is mainly located in the cytoplasm,and the ubiquitin and lactate modification sites overlap,and it has high gene homology with Vibrio parahaemolyticus.Theα-helix,random coil and extended strand are the main secondary structures.The similarity between the constructed three-level structure model and the template is high.[Conclusions]This study reveals the structural characteristics and functional potential of SucC protein,and provides a theoretical basis for the study of drug resistance mechanism and prevention strategies.

A conservative distribution of tridomain NDP-heptose synthetases in actinobacteria

Heptoses are important structural components of Gram-negative bacterium cell wall and participate in bacterial colonization,infection,and immune recognition.Current knowledge of NDP-heptose originating from D-sedoheptulose 7-phosphate in Grampositive bacterium remains limited.Here,in silico analysis suggested that the special tridomain NDP-heptose synthetases with isomerase,kinase,and nucleotidyltransferase activities are conservatively distributed in Actinobacteria class of Gram-positive bacterium.Enzymatical characterization of the tridomain proteins from different strains showed that they are involved in ADPD-glycero-β-D-manno-heptose biosynthesis despite the unexpected discovery of kinase activities deficient in some proteins.The presence of three types of NDP-heptose synthetases in Gram-positive bacterium suggests that it is also a rich source of heptoses and the heptose moieties may play important roles in vivo.Our work updates the understanding of NDP-heptose biosynthesis in Gram-positive bacterium and lays a solid foundation for further physiological function explorations.

The Role of Anionic Protein Residues on the Salt Dependence of the Binding of Aminoacyl-tRNA Synthetases to tRNA:A Poisson-Boltzmann Analysis

Long-range electrostatic interactions in proteins/peptides associating to nucleic acids are reflected in the salt-dependence of the binding process.According to the oligocationic binding model,which is based on counterion condensation theory,only the cationic residues of peptides/proteins near the binding interface are assumed to affect the salt dependence in the association of peptides and proteins to nucleic acids.This model has been used to interpret and predict the binding of oligocationic chains-such as oligoarginines/lysines-to nucleic acids,and does an excellent job in these kinds of systems.This simple relationship,which is used to compare or count the number of ionic interactions in protein-nucleic acid complexes,does not hold when acidic residues,i.e.glutamate and aspartate,are incorporated in the protein matrix.Here,we report a combined molecular mechanics(by means of energy-minimization of the structure under the influence of an empirical energy function)and Poisson-Boltzmann(PB)study on the salt-dependence in binding to tRNA of two important enzymes that are involved in the seminal step of peptide formation in the ribosome:Glutamine synthetase(GluRS)and Glutaminyl synthetase(GlnRS)bound to their cognate tRNA.These two proteins are anionic and contain a significant number of acidic residues distributed over the entire protein.Some of these residues are located in the binding interface to tRNA.We computed the salt-dependence in association,SKpred,of these enzyme-tRNA complexes using both the linear and nonlinear solution to the PoissonBoltzmann Equation(PBE).Our findings demonstrate that the SKpred obtained with the nonlinear PBE is in good agreement with the experimental SKobs,while use of the linear PBE resulted in the SKpred being anomalous.We conclude that electrostatic interactions between the binding partners in these systems are less favorable by means of charge-charge repulsion between negatively charged protein residues and phosphateoxygens in the tRNA backbone but also play a significant role in the association process of proteins to tRNA.Some unfavorable electrostatic interactions are probably compensated by hydrogen-bonds between the carboxylate group of the side chain in the interfacial acidic protein residues and the tRNA backbone.We propose that the low experimentally observed SKobs values for both GlnRS-and GluRS-tRNA depend on the distribution and number of anionic residues that exist in these tRNA synthetases.Our computed electrostatic binding free energies were large and unfavorable due to the Coulombic and de-solvation contribution for the GlnRS-tRNA and GluRS-tRNA complexes,respectively.Thus,low SKobs values may not reflect small contributions from the electrostatic contribution in complex-formation,as is often suggested in the literature.When charges are”turned off”in a computer-experiment,our results indicated that”turning off”acidic residues far from a phosphate group significantly influences SKpred.If cationic residues are“turned off”,less impact on SKpred is observed with respect to the distance to the nearest phosphate-group。

Identification and characterization of the chalkiness endosperm gene CHALK-H in rice(Oryza sativa L.)

Chalkiness is one of the most important agronomic traits in rice breeding,which directly affects the quality of rice seed.In this study,we identified a chalkiness endosperm mutant,chalk-h,from N-methyl-N-nitrosourea(MNU)-induced japonica rice cultivar Hwacheong(HC).Compared with wild type(WT)-HC,chalk-h showed severe chalkiness in the endosperm,yellowish green leaves,as well as reduced plant height.Scanning electron microscopy(SEM)analysis showed that starch grains in the chalk-h mutant were irregular in size and loosely arranged,with large gaps between granules,forming ovoid or orbicular shapes.MutMap analysis revealed that the phenotype of chalk-h is controlled by a single recessive gene LOC_Os11g39670 encoding seryl-tRNA synthetase,which is renamed as CHALK-H.A point mutation occurs in chalk-h on the sixth exon(at nucleotide 791)of CHALK-H,in which adenine(A)is replaced by thymidine(T),resulting in an amino acid codon change from glutamine(Glu)to valine(Val).The chalk-h mutant exhibited a heat-sensitive phenotype from the 3-leaf stage,including yellow-green leaves and reduced pigment content.The transcriptional expression of starch synthesis-related genes was down-regulated in the chalk-h mutants compared to WT-HC at different grain-filling stages.With an increase in temperature,the expression of photosynthesis-related genes was down-regulated in the chalk-h mutant compared to WT-HC.Overexpression of CHALK-H rescued the phenotype of chalk-h,with endosperm and leaf color similar to those of WT-HC.Our findings reveal that CHALK-H is a causative gene controlling chalkiness and leaf color of the chalk-h mutant.CHALK-H is the same gene locus as TSCD11,which was reported to be involved in chloroplast development under high temperature.We suggest that CHALK-H/TSCD11 plays important roles not only in chloroplast development,but also in photosynthesis and starch synthesis during rice growth and development,so it has great application potential in rice breeding for high quality and yield.

Three novel alleles of OsGS1 developed by base-editing-mediated artificial evolution confer glufosinate tolerance in rice

Only few glufosinate-tolerant genes,such as phosphinothricin acetyltransferase(PAT)and bialaphos resistance(bar)identified from Streptomyces,are currently available for developing genetically modified rice in agricultural application.Following the rapid development of genome editing technology,generation of novel glufosinate-tolerant gene resources through artificial evolution of endogenous genes is more promising and highly desirable in rice molecular breeding program.In this study,the endogenous Glutamine synthetase1(OsGS1)was artificially evolved by base-editing-mediated gene evolution(BEMGE)in rice cells to create novel alleles conferring glufosinate tolerance in rice germplasms.Two novel glufosinate-tolerant OsGS1 alleles(OsGS1-AVPS and OsGS1-+AF)and one reported tolerant allele(OsGS1-SGTA)were successfully identified from approximately 4200 independent hygromycin-tolerant calli.Germination assays and spray tests revealed that these three OsGS1 alleles confer glufosinate tolerance in rice.Furthermore,OsGS1-AVPS and OsGS1-SGTA were quickly deployed into the elite rice cultivar Nangeng 46 through precise base editing.Overall,our results demonstrate the feasibility of developing glufosinate-tolerant rice by editing an endogenous rice gene in molecular breeding programs.

Effects of Rare Earth Lanthanum and Cerium on Key Enzyme Activi-ties of Soybean Nitrogen Metabolism

In this study,the typical northeast soybean varieties Dongnong 42(high protein),Dongnong 47(high fat)and Dongnong 52(mixed-use)were used as experimental materials and planted in pots.Foliar spraying 100,150 and 200 mg•L^(-1)LaCl_(3)solution,30,60 and 90 mg•L^(-1)CeCl_(3)solution and 40,60 and 70 mg•L^(-1)LaCl_(3)+CeCl_(3)mixed solution.To study the effects of different types and concentrations of rare earth on nitrate reductase activity,glutamine synthetase activity of soybean leaves and protein content of soybean grains.The results showed that spraying appropriate concentration of rare earth solution on the leaves could increase the activities of nitrate reductase and glutamine synthase in soybean functional leaves and the protein content of soybean grains.The protein content of the three types of soybean grains was significantly positively correlated with the activity of nitrate reductase and glutamine synthetase in the leaves.

Comparative Study of Immunological Properties on Glutamine Synthetase Isozymes in Rice Plants

In rice (Oryza sativa L.) roots two glutamine synthetase (GS) isozymes, GSra and GSrb, were identified recently in the author's experiments, but the homology of both GSra and GSrb as well as their localization in the rice roots are unclear. In the present study, the purified GSra and GSrb from rice roots were used to immunize rabbits to obtain the respective antibodies. The immunodiffusion and immunoblotting experiments showed that the antibody against GSra or GSrb was specific for GS and its isozymes. The immunoprecipitation test indicated that the antibody of GSra or GSrb not only recognized its respective antigen, but also well recognized each other's antigen. GSra or GSrb antibody recognized also better cytosolic GS1 of rice leaves, but the recognization for chloroplast GS2 from rice or spinach (Spinacia oleracea Mill.) leaves was weaker. Our results indicate that GSra and GSrb from rice roots are quite similar in antigenicity and are extremely similar proteins and that both GSra and GSrb may also be a form of cytosolic GS just as the cytosolic GS1 of rice leaves.

OAS蛋白结构与抗病毒机制关系的研究进展

2＇-5＇寡聚腺苷酸合成酶（2＇-5＇oligoadenylate synthetase,OAS）是由Ian Kerr等最先在人体细胞中发现的,之后在小鼠、猪、牛、犬和低等生物如海绵动物体内也陆续发现了OAS[1-2]。

Effect of Low Temperature Stress on Sweet Potato S-Adenosyl Methionine Synthetase Gene Expression

[Objective] The mRNA expression level changes of S-adenosylmethionine synthetase （SAMS） under low temperature stress was studied. [Method] Total RNA were extracted from leaves, stem and earthnut of sweet potato 0,12,24,48 and 72 h after low temperature treatement, mRNA expression level was analyzed by reverse expression and Real-time PCR technique. [Result] The expression quality of the gene extracted from leaves, stem and earthnut increased and the expression quality reached the peak point 24,72 and 72 h after low temperature treatment respectively. The expression change of earthnut was the biggest. [Conclusion] Low temperature was good for increasing mRNA expression of relevart genes.

Development of Alfalfa (Medicago sativa L.) Regeneration System and Agrobacterium-Mediated Genetic Transformation

The regeneration ability of four alfalfa （Medicago sativa L.） cultivars, Xinjiang Daye, Longdong, Gannong 1 and Gannong 3, was studied, and the effects of various cultivars, explant sources and medium recipes on regeneration were compared. The better callus forming frequency obtained from hypocotyls of Xinjiang Daye is 88.5% and regeneration frequency is 9.8% in our initial experiments. To further optimize regeneration system for genetic transformation, we therefore changed concentrations of plant growth regulators and supplemented with glutamine into callus-induction and shoot-regeneration media. Callus forming frequency and shoot differentiation frequency were increased to 100%. The time taken to generate transgenic plants （16 weeks） was shorter than that for previouse procedure （25 weeks） and regeneration frequency was promoted to 15.1%. The results show that addition of glutamine is particularly important for shortening period of regeneration and promoting regeneration frequency. For study of genetic transformation of alfalfa, Agrobacterium tumefaciens-mediated transformation of Xinjiang Daye was developed based on this optimized regeneration system. The plant expression vector carrying two glutamine synthetases （GS 1 and GS2） and △1-pyrroline-5-carboxylate synthetase （P5CS） gene was used for alfalfa in vitro transformation. Six transgenic alfalfa plantlets with resistance to PPT were obtained. The introduction of foreign genes into plants was assessed in the transformants by PCR analysis and Southern hybridizations.

Modulating effects of acyl-CoA synthetase 5-derived mitochondrial Wnt2B palmitoylation on intestinal Wnt activity

AIM: To investigate the role of acyl-CoA synthetase 5 (ACSL5) activity in Wnt signaling in intestinal surface epithelia.

UGT1A1 predicts outcome in colorectal cancer treated with irinotecan and fluorouracil

AIM:To evaluate effects of UDP-glucuronosyltransferase1A1(UGT1A1) and thymidylate synthetase(TS) gene polymorphisms on irinotecan in metastatic colorectal cancer(mCRC).METHODS:Two irinotecan-and fluorouracil-based regimens,FOLFIRI and IFL,were selected as second-line therapy for 138 Chinese mCRC patients.Genomic DNA was extracted from peripheral blood samples before treatment.UGT1A1 and TS gene polymorphisms were determined by direct sequencing and restriction fragment length polymorphism,respectively.Gene polymorphisms of UGT1A1*28,UGT1A1*6 and promoter enhancer region of TS were analyzed.The relationship between genetic polymorphisms and clinical outcome,that is,response,toxicity and survival were assessed.Pharmacokinetic analyses were performed in a subgroup patients based on different UGT1A1 genotypes.Plasma concentration of irinotecan and its active metabolite SN-38 and inactive metabolite SN-38G were determined by high performance liquid chromatography.Differences in irinotecan and its metabolites between UGT1A1 gene variants were compared.RESULTS:One hundred and eight patients received the FOLFIRI regimen,29 the IFL regimen,and one irinotecan monotherapy.One hundred and thirty patients were eligible for toxicity and 111 for efficacy evaluation.One hundred and thirty-six patients were tested for UGT1A1*28 and *6 genotypes and 125 for promoter enhancer region of TS.Patients showed a higher frequency of wild-type UGT1A1*28(TA6/6) compared with a Caucasian population(69.9% vs 45.2%).No significant difference was found between response rates and UGT1A1 genotype,although wild-type showed lower response rates compared with other variants(17.9% vs 24.2% for UGT1A1*28,15.7% vs 26.8% for UGT1A1*6).When TS was considered,the subgroup with homozygous UGT1A1*28(TA7/7) and non-3RG genotypes showed the highest response rate(33.3%),while wild-type UGT1A1*28(TA6/6) with non-3RG only had a 13.6% response rate,but no significant difference was found.Logistic regression showed treatment duration was closely linked to clinical response.In toxicity comparison,UGT1A1*28 TA6/6 was associated with lower incidence of grade 2-4 diarrhea(27.8% vs 100%),and significantly reduced the risk of grade 4 neutropenia compared with TA7/7(7.8% vs 37.5%).Wild-type UGT1A1*6(G/G) tended to have a lower incidence of grade 3/4 diarrhea vs homozygous mutant(A/A) genotype(13.0% vs 40.0%).Taking UGT1A1 and TS genotypes together,lower incidence of grade 2-4 diarrhea was found in patients with non-3RG TS genotypes,when TA6/6 was compared with TA7/7(35.3% vs 100.0%).No significant association with time to progression(TTP) and overall survival(OS) was observed with either UGT1A1 or TS gene polymorphisms,although slightly longer TTP and OS were found with UGT1A1*28(TA6/6).Irinotecan PK was investigated in 34 patients,which showed high area under concentration curve(AUC) of irinotecan and SN-38,but low AUC ratio(SN-38G /SN-38) in those patients with UGT1A1*28 TA7/7.CONCLUSION:A distinct distribution pattern of UGT1A1 genotypes in Chinese patients might contribute to relatively low toxicity associated with irinotecan and 5-fluorouracil in mCRC patients.

Long-chain acyl-CoA synthetase in fatty acid metabolism involved in liver and other diseases:An update

Long-chain acyl-Co A synthetase(ACSL) family members include five different ACSL isoforms, each encoded by a separate gene and have multiple spliced variants. ACSLs on endoplasmic reticulum and mitochondrial outer membrance catalyze fatty acids with chain lengths from 12 to 20 carbon atoms to form acyl-Co As, which are lipid metabolic intermediates and involved in fatty acid metabolism, membrane modifications and various physiological processes. Gain- or lossof-function studies have shown that the expression of individual ACSL isoforms can alter the distribution and amount of intracellular fatty acids. Changes in the types and amounts of fatty acids, in turn, can alter the expression of intracellular ACSLs. ACSL family members affect not only the proliferation of normal cells, but the proliferation of malignant tumor cells. They also regulate cell apoptosis through different signaling pathways and molecular mechanisms. ACSL members have individual functions in fatty acid metabolism in different types of cells depending on substrate preferences, subcellular location and tissue specificity, thus contributing to liver diseases and metabolic diseases, such as fatty liver disease, obesity, atherosclerosis and diabetes. They are also linked to neurological disorders and other diseases. However, the mechanisms are unclear. This review addresses new findings in the classification and properties of ACSLs and the fatty acid metabolismassociated effects of ACSLs in diseases.