Phenolamide(PA)metabolites play important roles in the interaction between plants and pathogens.The putrescine hydroxycinnamoyl transferase genes Os PHT3 and Os PHT4 positively regulate rice cell death and resistance ...Phenolamide(PA)metabolites play important roles in the interaction between plants and pathogens.The putrescine hydroxycinnamoyl transferase genes Os PHT3 and Os PHT4 positively regulate rice cell death and resistance to Magnaporthe oryzae.The b ZIP transcription factor APIP5,a negative regulator of cell death and rice immunity,directly binds to the Os PHT4 promoter to regulate putrescine-derived PAs.Whether other hydroxycinnamoyl transferase(HT)genes also participate in APIP5-mediated immunity remains unclear.Surprisingly,we find that genes encoding agmatine hydroxycinnamoyl transferases Os AHT1 and Os AHT2,tryptamine hydroxycinnamoyl transferases Os TBT1 and Os TBT2,and tyramine hydroxycinnamoyl transferases Os THT1 and Os THT2,responsible for the biosynthesis of polyamine-derived PAs are all up-regulated in APIP5-RNAi transgenic plants compared with segregated wild-type rice.Furthermore,both Os AHT1/2 and Os TBT1/2 are induced during M.oryzae infection,showing expression patterns similar to those previously reported for Os THT1/2 and Os PHT3/4.Transgenic plants overexpressing either Os AHT2-GFP or Os TBT1-GFP show enhanced resistance against M.oryzae and accumulated more PA metabolites and lignin compared with wild-type plants.Interestingly,as demonstrated for Os PHT4,APIP5 directly binds to the promoters of Os AHT1/2,Os TBT1/2,and Os THT1/2,repressing their transcription.Together,these results indicate that the HT genes are common targets of APIP5 and that PAs play critical roles in rice immunity.展开更多
A comparative study was made on the tissue specific expression of glutathione transferases (GST) in brain and testis after exposure of rat to phenobarbitol (PB) and β-methylcholanthrene (MC). Glutathione transferases...A comparative study was made on the tissue specific expression of glutathione transferases (GST) in brain and testis after exposure of rat to phenobarbitol (PB) and β-methylcholanthrene (MC). Glutathione transferases, a family of multifunctional proteins are involved in intracellular transport processes and in detoxication of electrophilic xenobiotics by catalyzing reactions such as conjugation, isomerization, reduction and thiolysis. On purification, the yield of GST proteins by affinity chromatography was 39% in testis and 32% in brain. The affinity purified testis GSTs were resolved by chromatofocusing into six anionic and four cationic isozymes, and in brain glutathione transferases were resolved into four anionic and three cationic isozymes, suggesting the presence of multiple isozymes with Yc, Yb, Yβ and Yδ in both of them. In testis and brain, these isozymes at identical pI values showed variable functions with a battery of substrates and the cationic isozymes of brain and testis showed identical properties in CHP (cumene hydroperoxide) at pH values of above 7.0. Substrate specificity studies and immunoblot analysis of testis and brain proteins revealed that they play a predominant role in the detoxication of phenobarbitol or β-methylcholanthrene. Expression of the isozymes in testis and brain on exposure to PB and MC indicated elevated subunit variation. In both testis and brain, Yδ of π class was expressed on PB treatment and Yc of α class and Yβ of μ class was expressed in MC treated testis and only Yc was predominantly expressed in MC treated brain. Thus these subunits expression is considered as markers for carcinogenesis and specific to chemical toxicity under phenobarbitol and β-methylcholanthrene stress.展开更多
OBJECTIVE:To investigate the influence of Yin-tonification herbal formulas Jaeumganghwa-tang(Ziyin Jianghuo Tang,JEGHT),Ssanghwa-tang(Shuanghe Tang,SHT) and Yukmijihwang-tang(Liuwei Di huang Tang,YMJHT) on the activit...OBJECTIVE:To investigate the influence of Yin-tonification herbal formulas Jaeumganghwa-tang(Ziyin Jianghuo Tang,JEGHT),Ssanghwa-tang(Shuanghe Tang,SHT) and Yukmijihwang-tang(Liuwei Di huang Tang,YMJHT) on the activities of human major cytochrome P450(CYP450 s) and UDP-glucuronosyltransferases isozymes(UGTs) in vitro.METHODS:The activities of CYP450 s(CYP1 A2,CYP3 A4,CYP2 B6,CYP2 C9,CYP2 C19,CYP2 D6 and CYP2 E1) and UGTs(UGT1 A1,UGT1 A4 and UGT2 B7)were assessed using in vitro fluorescence-and luminescence-based enzyme assays,respectively.The effects of herbal formulas on the activities of CYP450 s and UGTs were presented as IC50 values.RESULTS:JEGHT showed the potent inhibition of the CYP2 D6 activity,with weak inhibition on the activities of CYP1 A2,CYP2 B6,CYP2 C9,CYP2 C19,CYP2 E1,CYP3 A4,UGT1 A1,UGT1 A4 and UGT2 B7.SHT inhibited the activities of CYP1 A2 and CYP2 E1,whereas the negligible inhibition of the activities of CYP2 B6,CYP2 C9,CYP2 C19,CYP2 D6,CYP3 A4,UGT1 A1,UGT1 A4 and UGT2 B7 through SHT was observed.YMJHT inhibited CYP2 E1 activity,with a negligible inhibition on the activities of CYP1 A2,CYP2 B6,CYP2 C9,CYP2 C19,CYP2 D6,CYP3 A4,UGT1 A1,UGT1 A4 and UGT2 B7.CONCLUSION:These findings provide information about the potential interactions between three Yin-tonification herbal formulas and conventional drugs.展开更多
AIM: Glutathione S-transferases (GSTs) are involved in the detoxification of many potential carcinogens and appear to play a critical role in the protection from the effects of carcinogens. The contribution of glutath...AIM: Glutathione S-transferases (GSTs) are involved in the detoxification of many potential carcinogens and appear to play a critical role in the protection from the effects of carcinogens. The contribution of glutathione S-transferases M1 and T1 genotypes to susceptibility to the risk of gastric cancer and their interaction with cigarette smoking are still unclear. The aim of this study was to determine whether there was any relationship between genetic polymorphisms of GSTT1 and GSTT1 and gastric cancer. METHODS: A population based case-control study was carried out in a high-risk area, Changle County, Fujian Province, China. The epidemiological data were collected by a standard questionnaire and blood samples were obtained from 95 incidence gastric cancer cases and 94 healthy controls. A polymerase chain reaction method was used to detect the presence or absence of the GSTT1 and GSTT1 genes in genomic DNA. Logistic regression model was employed in the data analysis. RESULTS: An increase in risk for gastric cancer was found among carriers of GSTT1 null genotype. The adjusted odds ratio (OR) was 2.63 95% Confidence Interval (95% CI) 1.17-5.88, after controlling for age, gender, cigarette smoking, alcohol drinking, and fish sauce intake. The frequency of GSTT1 null genotype in cancer cases (43.16%) was not significantly different from that in controls (50.00%). However, the risk for gastric cancer in those with GSTT1 null and GSTT1 non-null genotype was significantly higher than in those with both GSTT1 and GSTT1 non-null genotype (OR = 2.77, 95% CI 1.15-6.77). Compared with those subjects who never smoked and had normal GSTT1 genotype, ORs were 1.60 (95% CI:0.62-4.19) for never smokers with GSTT1 null type, 2.33 (95% CI 0.88-6.28) for smokers with normal GSTT1, and 8.06 (95% CI 2.83-23.67) for smokers with GSTT1 null type. CONCLUSIONS: GSTT1 gene polymorphisms may be associated with genetic susceptibility of stomach cancer and may modulate tobacco-related carcinogenesis of gastric cancer.展开更多
Aim: Purification of glutathione S-transferases (GSTs) from rat testis; separation and identificationunits and their role in eicosanoid biosynthesis. Methods: Purification of mt testicular GSTs by affit?phy, employing...Aim: Purification of glutathione S-transferases (GSTs) from rat testis; separation and identificationunits and their role in eicosanoid biosynthesis. Methods: Purification of mt testicular GSTs by affit?phy, employing S-hexylglutathione-linked epoxy-activated Sepharose 6B column and separation of indiby reverse phase-high pressure liquid chromatography (RP-HPLC). Characterization of affinity purified,um dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and Westem blot analysis. The roGSTs in eicosanoid biosynthesis was determined by incubating GSTs with 5, 6-Leukotriene A_4Me (prostaglandin H_2 (PGH_2) and analyzing the products formed on HPLC/TLC. Results: The present stumajority of rat testicular GSTs are of Y_b size (60%) with molecular weight of 27 kDa. The most preunits, however, are GST Y_(n2) (27% ), followed by GST Y_c (24% ) and GST Y_(nl) (20%). These testiculavery high Leukotriene C_4 (LTC_4) synthase activity with 5, 6-Leukotriene A4Me (LTA_4Me) as theprostaglandin D (PGD) synthase activity with prostaglandin H_2 (PGH_2) as the substrate. Conclusion:testicular GSTs are Y_b sized and are involved in the synthesis of eicosanoids like LTC_4 and PGD_2.(Asian J Androl 2000 Dec; 2: 277-282)展开更多
BACKGROUND Periodontitis,when exacerbated by diabetes,is characterized by increased M1 macrophage polarization and decreased M2 polarization.O-linkedβ-N-acetylglucosamine(O-GlcNAcylation),catalyzed by O-GlcNAc transf...BACKGROUND Periodontitis,when exacerbated by diabetes,is characterized by increased M1 macrophage polarization and decreased M2 polarization.O-linkedβ-N-acetylglucosamine(O-GlcNAcylation),catalyzed by O-GlcNAc transferase(OGT),promotes inflammatory responses in diabetic periodontitis(DP).Additionally,p38 mitogen-activated protein kinase regulates macrophage polarization.However,the interplay between OGT,macrophage polarization,and p38 signaling in the progression of DP remains unexplored.AIM To investigate the effect of OGT on macrophage polarization in DP and its role in mediating O-GlcNAcylation of p38.METHODS For in vivo experiments,mice were divided into four groups:Control,DP model,model+short hairpin(sh)RNAnegative control,and model+sh-OGT.Diabetes was induced by streptozotocin,followed by ligation and lipopolysaccharide(LPS)administration to induce periodontitis.The impact of OGT was assessed by injecting sh-OGT lentivirus.Maxillary bone destruction was evaluated using micro-computed tomography analysis and tartrateresistant acid phosphatase staining,while macrophage polarization was determined through quantitative real-time polymerase chain reaction(qPCR)and immunohistochemistry.For in vitro experiments,RAW264.7 cells were treated with LPS and high glucose(HG)(25 mmol/L D-glucose)to establish a cell model of DP.OGT was inhibited by OGT inhibitor(OSMI4)treatment and knocked down by sh-OGT transfection.M1/M2 polarization was analyzed using qPCR,immunofluorescence,and flow cytometry.Levels of O-GlcNAcylation were measured using immunoprecipitation and western blotting.RESULTS Our results demonstrated that M1 macrophage polarization led to maxillary bone loss in DP mice,associated with elevated O-GlcNAcylation and OGT levels.Knockdown of OGT promoted the shift from M1 to M2 macrophage polarization in both mouse periodontal tissues and LPS+HG-induced RAW264.7 cells.Furthermore,LPS+HG enhanced the O-GlcNAcylation of p38 in RAW264.7 cells.OGT interacted with p38 to promote its O-GlcNAcylation at residues A28,T241,and T347,as well as its phosphorylation at residue Y221.CONCLUSION Inhibition of OGT-mediated p38 O-GlcNAcylation deactivates the p38 pathway by suppressing its self-phosphorylation,thereby promoting M1 to M2 macrophage polarization and mitigating DP.These findings suggested that modulating macrophage polarization through regulation of O-GlcNAcylation may represent a novel therapeutic strategy for treating DP.展开更多
In patients with Alzheimer’s disease,gamma-glutamyl transferase 5(GGT5)expression has been observed to be downregulated in cerebrovascular endothelial cells.However,the functional role of GGT5 in the development of A...In patients with Alzheimer’s disease,gamma-glutamyl transferase 5(GGT5)expression has been observed to be downregulated in cerebrovascular endothelial cells.However,the functional role of GGT5 in the development of Alzheimer’s disease remains unclear.This study aimed to explore the effect of GGT5 on cognitive function and brain pathology in an APP/PS1 mouse model of Alzheimer’s disease,as well as the underlying mechanism.We observed a significant reduction in GGT5 expression in two in vitro models of Alzheimer’s disease(Aβ_(1-42)-treated hCMEC/D3 and bEnd.3 cells),as well as in the APP/PS1 mouse model.Additionally,injection of APP/PS1 mice with an adeno-associated virus encoding GGT5 enhanced hippocampal synaptic plasticity and mitigated cognitive deficits.Interestingly,increasing GGT5 expression in cerebrovascular endothelial cells reduced levels of both soluble and insoluble amyloid-βin the brains of APP/PS1 mice.This effect may be attributable to inhibition of the expression ofβ-site APP cleaving enzyme 1,which is mediated by nuclear factor-kappa B.Our findings demonstrate that GGT5 expression in cerebrovascular endothelial cells is inversely associated with Alzheimer’s disease pathogenesis,and that GGT5 upregulation mitigates cognitive deficits in APP/PS1 mice.These findings suggest that GGT5 expression in cerebrovascular endothelial cells is a potential therapeutic target and biomarker for Alzheimer’s disease.展开更多
The rapid emergence and spread of colistin-resistant gram-negative bacteria has raised worldwide public health concerns,and phosphoethanolamine(PEtn)transferase modification-mediated colistin resistance has been widel...The rapid emergence and spread of colistin-resistant gram-negative bacteria has raised worldwide public health concerns,and phosphoethanolamine(PEtn)transferase modification-mediated colistin resistance has been widely documented in multiple gram-negative bacterial species.However,whether such a mechanism exists in the zoonotic pathogen Pasteurella multocida is still unknown.Recently,a novel PEtn transferase,PetL,was identified in P.multo-cida,but whether it is associated with colistin resistance remains to be elucidated.In this study,we found that PetL in P.multocida(PetL^(PM))exhibited structural characteristics similar to those of the mobile-colistin-resistant(MCR)protein and the PEtn transferase characterized in Neisseria meningitidis.The transformation of petLPM into E.coli or K.pneumoniae changed the phenotype of several tested strains from colistin sensitive to colistin resistant.Deletion of this gene decreased the colistin minimum inhibitory concentration(MIC)of P.multocida by 64-fold.Our extensive analysis by MALDI-TOF-MS demonstrated that PetLPM participated in the modification of bacterial lipopolysaccharide(LPS)-lipid A.Deletion of petL^(PM) led to an increase in membrane charge but a decrease in cell-surface hydrophobicity and cell permeability in P.multocida.The present study is the first to report the presence of PEtn transferase-mediated colistin resistance in the zoonotic pathogen P.multocida.展开更多
BACKGROUND Gamma-glutamyl transferase(GGT)is a known surrogate marker of hepatic dysfunction and oxidative stress.It has recently been reported to be associated with metabolic diseases,cardiovascular diseases,and mali...BACKGROUND Gamma-glutamyl transferase(GGT)is a known surrogate marker of hepatic dysfunction and oxidative stress.It has recently been reported to be associated with metabolic diseases,cardiovascular diseases,and malignancies including pancreatic cancer.However,data on its association with pancreatic cystic neo-plasm(PCN),is unknown.AIM To investigate the association of GGT with the incidence of PCN.METHODS In this nationwide retrospective cohort study,participants who received general health checkup by National Health Insurance Service in 2009 were included.Newly diagnosed PCNs from one year after the checkup to 2020 were identified.Participants were divided into quartiles based on GGT levels.Multivariable cox proportional hazard models estimated the risk of PCNs according to GGT quartiles(Q1-Q4).Subgroup analyses by age,sex,and comorbidities,and sensitivity analyses varying lag periods and GGT categorizations were performed.RESULTS There were 28940 cases of PCNs among 2655665 eligible participants.The incidence rate was 1.09 cases per 1000 person-years,with a median follow-up of 10.32(interquartile range:10.09-10.58)years.In multivariate regression analysis,adjusted hazard ratios for GGT quartiles using Q1 group as a reference were:1.04[95%confidence interval(CI):1.005-1.075]for Q2,1.065(95%CI:1.03-1.102)for Q3,and 1.109(95%CI:1.07-1.15)for Q4.Subgroup analysis showed consistent results across age,sex,and comorbidities.In sensitivity analyses,the association remained robust even at 3-year and 5-year lag periods.A clear dose-response relationship was also observed when using GGT deciles(All P for trend<0.001).CONCLUSION Higher GGT level is associated with increased risk of PCNs.Therefore,serum GGT levels might have a role as a biomarker for the development of PCNs.展开更多
BACKGROUND The World Health Organization defined long coronavirus disease 2019(COVID-19)as the continuation or development of new symptoms 3 months after the initial severe acute respiratory syndrome coronavirus 2 inf...BACKGROUND The World Health Organization defined long coronavirus disease 2019(COVID-19)as the continuation or development of new symptoms 3 months after the initial severe acute respiratory syndrome coronavirus 2 infection,with these symptoms lasting for at least 2 months with no other explanation.AIM To evaluate the potential laboratory and instrumental findings(short-term and long-term)resulting from COVID-19.METHODS This longitudinal observational COVID-19 cohort study(March 1,2020-March 1,2021)was carried out on patients≥18 years old who were admitted to the University Hospitals of Pisa,Siena and Careggi and the Azienda USL Toscana Nord Ovest,Sud Est and USL Centro Toscana and were subjected to follow-up.Follow-up was conducted between 0 day and 89 days,90 days and 179 days,180 days and 269 days,270 days and 359 days,and more than 360 days after hospitalization.RESULTS Of 2887 patients(58.5%males,average age 66.2 years)hospitalized in the study period(March 1,2020-March 1,2021)carrying out at least one follow-up examination within 12 months of discharge,a total of 1739 patients(705 males,average age 66 years)underwent laboratory tests,of whom 714 patients(470 males,average age 63 years)underwent spirometry.Some laboratory test results remained above the threshold even at follow-up beyond 360 days(C-reactive protein:36%,fibrin degradation fragment:48.8%,gamma-glutamyl transferase:16.8%),while others showed a return to normal range more quickly in almost all patients.Alterations in liver enzymes,hematocrit,hemoglobin,lymphocytes and neutrophils were associated with the risk of requiring oxygen therapy or forced expiratory volume in one second/forced vital capacity alterations at follow-up.CONCLUSION Alterations in liver enzymes,hematocrit or hemoglobin,lymphocytes and neutrophils were associated with risk outcomes(need for oxygen therapy or spirometry alterations).These imbalanced conditions may contribute to pulmonary dysfunction.展开更多
Red petal spots are beneficial for attracting cotton pollinators and producing hybrid seeds,and the anthocyanin pathway is generally regarded as a metabolic cause of petal coloration.The current study identified an MY...Red petal spots are beneficial for attracting cotton pollinators and producing hybrid seeds,and the anthocyanin pathway is generally regarded as a metabolic cause of petal coloration.The current study identified an MYB-encoding gene(Gar07G09390,Ga MYB)as a candidate gene involved in cotton coloration by map-based cloning,and this MYB could positively regulate a candidate glutathione S transferase gene(Gar07G08900,Ga GST).To unveil potentially involved genes within the Ga MYB-regulating-Ga GST route,color metabolites of both Ga MYB-and Ga GST-virus-induced gene silencing(VIGS)petals were investigated,revealing that they were largely glycosyl-decorated flavonoids.Accordingly,a transcriptomic survey of both VIGS petals identified a glycosyl-transferase gene(Ga GT,Gar02G15390).Notably,this Ga GT is adjacent to one of the genome-wide association study loci concerning petal spots in Gossypium arboreum,and it is also positively regulated by Ga MYB.This new regulatory route including both GST and GT regulated by MYB is conserved among the three cotton species examined in this study(Gossypium arboreum,Gossypium hirsutum,and Gossypium barbadense).Accordingly,comprehensively evaluating the influence of these candidates and their homologs on cotton coloration may provide a more in-depth understanding of cotton coloration,ultimately facilitating the breeding of more colorful cotton.展开更多
Microglial pyroptosis and neuroinflammation have been implicated in the pathogenesis of sepsis-associated encephalopathy(SAE).OGT-mediated O-GlcNAcylation is involved in neurodevelopment and injury.However,its regulat...Microglial pyroptosis and neuroinflammation have been implicated in the pathogenesis of sepsis-associated encephalopathy(SAE).OGT-mediated O-GlcNAcylation is involved in neurodevelopment and injury.However,its regulatory function in microglial pyroptosis and involvement in SAE remains unclear.In this study,we demonstrated that OGT deficiency augmented microglial pyroptosis and exacerbated secondary neuronal injury.Furthermore,OGT inhibition impaired cognitive function in healthy mice and accelerated the progression in SAE mice.Mechanistically,OGT-mediated O-GlcNAcylation of ATF2 at Ser44 inhibited its phosphorylation and nuclear translocation,thereby amplifying NLRP3 inflammasome activation and promoting inflammatory cytokine production in microglia in response to LPS/Nigericin stimulation.In conclusion,this study uncovers the critical role of OGT-mediated O-GlcNAcylation in modulating microglial activity through the regulation of ATF2 and thus protects against SAE progression.展开更多
Effects of Mingzhu Oral Liquid on the Hypothalamic-Pituitary-Adrenal Axis in Rats with Liver-Kidney Yin Deficiency WANG Yi-ting1,ZHAO Yang1,ZHU Fei-ya1,WANG Si-qiong1,ZHU Ling-lei1,LI Tao2,TANG Min-ke1,1.Beijing Unive...Effects of Mingzhu Oral Liquid on the Hypothalamic-Pituitary-Adrenal Axis in Rats with Liver-Kidney Yin Deficiency WANG Yi-ting1,ZHAO Yang1,ZHU Fei-ya1,WANG Si-qiong1,ZHU Ling-lei1,LI Tao2,TANG Min-ke1,1.Beijing University of Chinese Medicine,Beijing,100029,China 2.Guangzhou Yitong Technology Co.,Ltd.,Guangzhou,510653,China【ABSTRACT】Objective:This study aimed to observe the effects of Mingzhu Oral Liquid on the hypothalamic-pituitary-adrenal(HPA)axis in rats with“liver-kidney yin deficiency”,in order to provide scientific research support for its clinical application in treating related disorders.Methods:A“liver-kidney yin deficiency”model was established in male Sprague-Dawley(SD)rats using a combination of chronic restraint stress and a single lipopolysaccharide(LPS)challenge.The rats were randomly divided into four groups:a blank control group,a model group,a low-dose Mingzhu Oral Liquid group,and a high-dose Mingzhu Oral Liquid group.The blank control group and model group were given normal saline by gavage,while the treatment groups received respective doses of Mingzhu Oral Liquid.Gavage administration was performed once daily for 30 consecutive days.During this period,all groups except the blank control group were subjected to restraint stress.Following the final gavage,all groups except the blank control received an intraperitoneal injection of LPS.Samples were collected 24 h post-injection.Serum levels of cyclic adenosine monophosphate(cAMP)and cyclic guanosine monophosphate(cGMP)were measured by enzyme-linked immunosorbent assay(ELISA)to evaluate the model state.The serum concentrations of corticotropin-releasing hormone(CRH),adrenocorticotropic hormone(ACTH),and glucocorticoid(GC)were determined to assess HPA axis activity.Changes in proinflammatory factors[tumor necrosis factor-alpha(TNF-α),interleukin-1 beta(IL-1β)]and the anti-inflammatory factor interleukin-10(IL-10)were also measured.Results:One week into the experiment,the weight gain rate slowed in all stress groups.By the end of the experiment,the body weight of these groups was significantly lower than that of the blank control group.Biochemical and hematological analyses revealed that the model group exhibited a significant decrease in lymphocyte count,an increased cAMP/cGMP ratio,reduced activities of glutathione S-transferase(GST)and glutathione transferase(GLT),elevated levels of blood urea nitrogen(BUN)and serum creatinine(Scr),increased serum contents of TNF-αand IL-1β,and a decreased content of IL-10.These findings confirmed the successful establishment of the rat model.Although the body weight of animals treated with Mingzhu Oral Liquid remained lower than that of the normal group,the treatment improved weight gain compared to the model group.Furthermore,Mingzhu Oral Liquid administration increased lymphocyte count,decreased the cAMP/cGMP ratio,restored GST and GLT activities,reduced BUN and Scr levels,lowered serum TNF-αand IL-1βcontents,and increased IL-10 levels,indicating a significant ameliorative effect on the deficiency symptoms.Additionally,serum levels of CRH,ACTH,and GC were elevated in the model rats,suggesting HPA axis hyperactivity.Treatment with Mingzhu Oral Liquid reduced the serum concentrations of these hormones,significantly alleviating the excited state of the HPA axis in stressed rats.Conclusion:Mingzhu Oral Liquid significantly improves the abnormal overall physical signs,blood biochemical parameters,and systemic inflammation in rats with“liver-kidney yin deficiency.”These therapeutic effects may be associated with the corrective action of Mingzhu Oral Liquid on the dysfunctional HPA axis in this model.展开更多
Gamma glutamyl transferases （GGT） are highly conserved enzymes that occur from bacteria to humans. They remove terminal y-glutamyl residue from peptides and amides. GGTs play an important role in the homeostasis of ...Gamma glutamyl transferases （GGT） are highly conserved enzymes that occur from bacteria to humans. They remove terminal y-glutamyl residue from peptides and amides. GGTs play an important role in the homeostasis of glutathione （a major cellular antioxidant） and in the detoxification of xenobiotics in mammals. They are implicated in diseases like diabetes, inflammation, neurodegenerative diseases and cardiovascular diseases. The physiological role of GGTs in bacteria is still unclear. Nothing is known about the basis for the strong conservation of the enzyme across the living system. The review focuses on the enzyme＇s physiology, chemistry and structural properties of the enzyme with emphasis on the evolutionary relationships. The available data indicate that the members of the GGT family share common structural features but are functionally heterogenous.展开更多
Kinases,representing almost 500 proteins in the human genome,are responsible for catalyzing the phosphorylation reaction of amino acid residues at their targets.As the largest family of kinases,the protein tyrosine ki...Kinases,representing almost 500 proteins in the human genome,are responsible for catalyzing the phosphorylation reaction of amino acid residues at their targets.As the largest family of kinases,the protein tyrosine kinases(PTKs)have roles in controlling the essential cellular activities,and their deregulation is generally related to pathologic conditions.The recent efforts on identifying their signal transducer or mediator role in cellular signaling revealed the interaction of PTKs with numerous enzymes of different classes,such as Ser/Thr kinases(STKs),glutathione transferases(GSTs),and receptor tyrosine kinases(RTKs).In either regulation or enhancing the signaling,PTKs are determined in close interaction with these enzymes,under specific cellular conditions,such as oxidative stress and inflammation.In this concept,intensive research on thiol metabolizing enzymes recently showed their involvement in the physiologic functions in cellular signaling besides their well known traditional role in antioxidant defense.The shared signaling components between PTK and GST family enzymes will be discussed in depth in this research review to evaluate the results of recent studies important in drug targeting for therapeutic intervention,such as cell viability,migration,differentiation and proliferation.展开更多
Poly(lactate-co-3-hydroxybutyrate)[P(LA-co-3HB)]is a high-molecular-weight biomaterial with excellent biocompatibility and biodegradability.In this study,the properties of P(LA-co-3HB)were examined and found to be aff...Poly(lactate-co-3-hydroxybutyrate)[P(LA-co-3HB)]is a high-molecular-weight biomaterial with excellent biocompatibility and biodegradability.In this study,the properties of P(LA-co-3HB)were examined and found to be affected by its lactate fraction.The efficiency of lactyl-CoA biosynthesis from intracellular lactate significantly affected the microbial synthesis of P(LA-co-3HB).Two CoA transferases from Anaerotignum lactatifermentans and Bacillota bacterium were selected for use in copolymer biosynthesis from 11 candidates.We found that cotAl enhanced the lactate fraction by 31.56%compared to that of the frequently used modified form of propionyl-CoA transferase from Anaerotignum propionicum.In addition,utilizing xylose as a favorable carbon source and blocking the lactate degradation pathway further enhanced the lactate fraction to 30.42 mol%and 52.84 mol%,respectively.Furthermore,when a 5 L bioreactor was used for fermentation utilizing xylose as a carbon source,the engineered strain produced 60.60 wt%P(46.40 mol%LA-co-3HB),which was similar to the results of our flask experiments.Our results indicate that the application of new CoA transferases has great potential for the biosynthesis of other lactate-based copolymers.展开更多
Currently,there is a lack of effective medicines capable of halting or reve rsing the progression of neurodegenerative disorde rs,including amyotrophic lateral sclerosis,Parkinson s disease,multiple sclerosis,or Alzhe...Currently,there is a lack of effective medicines capable of halting or reve rsing the progression of neurodegenerative disorde rs,including amyotrophic lateral sclerosis,Parkinson s disease,multiple sclerosis,or Alzheimer s disease.Given the unmet medical need,it is necessary to reevaluate the existing para digms of how to to rget these diseases.When considering neurodegenerative diseases from a systemic neurometabolic perspective,it becomes possible to explain the shared pathological features.This innovative approach presented in this paper draws upon exte nsive research conducted by the authors and researchers worldwide.In this review,we highlight the importance of metabolic mitochondrial dysfunction in the context of neurodegenerative diseases.We provide an overview of the risk factors associated with developing neurodegenerative disorders,including genetic,epigenetic,and environmental fa ctors.Additionally,we examine pathological mechanisms implicated in these diseases such as oxidative stress,accumulation of misfolded proteins,inflammation,demyelination,death of neurons,insulin resistance,dysbiosis,and neurotransmitter disturbances.Finally,we outline a proposal for the restoration of mitochondrial metabolism,a crucial aspect that may hold the key to facilitating curative therapeutic interventions for neurodegenerative disorders in forthcoming advancements.展开更多
The positive effect of levodopa in the treatment of Parkinson’s disease,although it is limited in time and has severe side effects,has encouraged the scientific community to look for new drugs that can stop the neuro...The positive effect of levodopa in the treatment of Parkinson’s disease,although it is limited in time and has severe side effects,has encouraged the scientific community to look for new drugs that can stop the neurodegenerative process or even regenerate the neuromelanin-containing dopaminergic nigrostriatal neurons.Successful preclinical studies with coenzyme Q10,mitoquinone,isradipine,nilotinib,TCH346,neurturin,zonisamide,deferiprone,prasinezumab,and cinpanemab prompted clinical trials.However,these failed and after more than 50 years levodopa continues to be the key drug in the treatment of the disease,despite its severe side effects after 4–6 years of chronic treatment.The lack of translated successful results obtained in preclinical investigations based on the use of neurotoxins that do not exist in the human body as new drugs for Parkinson’s disease treatment is a big problem.In our opinion,the cause of these failures lies in the experimental animal models involving neurotoxins that do not exist in the human body,such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and 6-hydroxydopamine,that induce a very fast,massive and expansive neurodegenerative process,which contrasts with the extremely slow one of neuromelanin-containing dopaminergic neurons.The exceedingly slow progress of the neurodegenerative process of the nigrostriatal neurons in idiopathic Parkinson’s patients is due to(i)a degenerative model in which the neurotoxic effect of an endogenous neurotoxin affects a single neuron,(ii)a neurotoxic event that is not expansive and(iii)the fact that the neurotoxin that triggers the neurodegenerative process is produced inside the neuromelanin-containing dopaminergic neurons.The endogenous neurotoxin that fits this degenerative model involving one single neuron at a time is aminochrome,since it(i)is generated within neuromelanin-containing dopaminergic neurons,(ii)does not cause an expansive neurotoxic effect and(iii)triggers all the mechanisms involved in the neurodegenerative process of the nigrostriatal neurons in idiopathic Parkinson’s disease.In conclusion,based on the hypothesis that the neurodegenerative process of idiopathic Parkinson’s disease corresponds to a single-neuron neurodegeneration model,we must search for molecules that increase the expression of the neuroprotective enzymes DT-diaphorase and glutathione transferase M2-2.It has been observed that the activation of the Kelch-like ECH-associated protein 1/nuclear factor(erythroid-derived 2)-like 2 pathway is associated with the transcriptional activation of the DT-diaphorase and glutathione transferase genes.展开更多
BACKGROUND High-grade B-cell lymphoma(HGBL)is an unusual malignancy that includes myelocytomatosis viral oncogene(MYC),B-cell lymphoma-2(BCL-2),and/or BCL-6 rearrangements,termed double-hit or triple-hit lymphomas,and...BACKGROUND High-grade B-cell lymphoma(HGBL)is an unusual malignancy that includes myelocytomatosis viral oncogene(MYC),B-cell lymphoma-2(BCL-2),and/or BCL-6 rearrangements,termed double-hit or triple-hit lymphomas,and HGBL-not otherwise specific(HGBL-NOS),which are morphologically characteristic of HGBL but lack MYC,BCL-2,or BCL-6 rearrangements.HGBL is partially transformed by follicular lymphoma and other indolent lymphoma,with few cases of marginal zone lymphoma(MZL)transformation.HGBL often has a poor prognosis and intensive therapy is currently mainly advocated,but there is no good treatment for these patients who cannot tolerate chemotherapy.CASE SUMMARY We reported a case of MZL transformed into HGBL-NOS with TP53 mutation and terminal deoxynucleotidyl transferase expression.Gene analysis revealed the gene expression profile was identical in the pre-and post-transformed tissues,suggesting that the two diseases are homologous,not secondary tumors.The chemotherapy was ineffective and the side effect was severe,so we tried combination therapy including venetoclax and obinutuzumab.The patient tolerated treatment well,and reached partial response.The patient had recurrence of hepatocellular carcinoma and died of multifunctional organ failure.He survived for 12 months after diagnosis.CONCLUSION Venetoclax combined with obinutuzumab might improve the survival in some HGBL patients,who are unsuitable for chemotherapy.展开更多
Carnitine Palmitoyl Transferase II (CPTII) is a very important enzyme that helps with the oxidation of long-chain fatty acid to produce energy. Deficiency in CPTII will lead to energy deficiency in the case of fasting...Carnitine Palmitoyl Transferase II (CPTII) is a very important enzyme that helps with the oxidation of long-chain fatty acid to produce energy. Deficiency in CPTII will lead to energy deficiency in the case of fasting and the accumulation of the long chain fatty in the body. There are three types of CPT II deficiency, the myopathic form, the severe infantile hepatocardiomuscular form and the lethal neonatal form. They are all inherited as an autosomal recessive. Diagnosis of the CPTII are 1) tandem mass spectrometry (MS/MS) in adult form and 2) CPTII polymorphism (F352C), which is linked to reducing the activity of CPTII in infantile form [1]. Glucose is the primary management and medium-chain fatty acid is an alternative due to the bypass of the CPTII enzyme in the pathway. For the prevention of CPTII deficiency are to avoid long chain fatty acid (C12-fatty acid), fasting, prolonged exercise, known triggers, and certain medications such as anti-epileptics and general anesthesia. During the rhabdomyolysis and myoglobinuria attack, it is very important to maintain hydration to avoid acute renal failure. If, however, renal failure occurs, dialysis is recommended. We present a case of a 27-year-old African American woman with the significant past medical history of CPT II deficiency leading to recurrent rhabdomyolysis and myoglobinuria. Together with all the research studies from diagnosis to treatment of CPTII deficiency will help in clinical management of patients. And this case report will add to the existing case reports of patients who have CPTII deficiency in terms of how we diagnose, how we treat, and how we prevent symptoms from re-occurring.展开更多
基金supported by grants from the National Natural Science Foundation of China (32161143009, 31822041 and 31972225) to Y.N.the National Natural Science Foundation of China (U20A2021) to R.W.the National Natural Science Foundation of China (31801692) to F.Z
文摘Phenolamide(PA)metabolites play important roles in the interaction between plants and pathogens.The putrescine hydroxycinnamoyl transferase genes Os PHT3 and Os PHT4 positively regulate rice cell death and resistance to Magnaporthe oryzae.The b ZIP transcription factor APIP5,a negative regulator of cell death and rice immunity,directly binds to the Os PHT4 promoter to regulate putrescine-derived PAs.Whether other hydroxycinnamoyl transferase(HT)genes also participate in APIP5-mediated immunity remains unclear.Surprisingly,we find that genes encoding agmatine hydroxycinnamoyl transferases Os AHT1 and Os AHT2,tryptamine hydroxycinnamoyl transferases Os TBT1 and Os TBT2,and tyramine hydroxycinnamoyl transferases Os THT1 and Os THT2,responsible for the biosynthesis of polyamine-derived PAs are all up-regulated in APIP5-RNAi transgenic plants compared with segregated wild-type rice.Furthermore,both Os AHT1/2 and Os TBT1/2 are induced during M.oryzae infection,showing expression patterns similar to those previously reported for Os THT1/2 and Os PHT3/4.Transgenic plants overexpressing either Os AHT2-GFP or Os TBT1-GFP show enhanced resistance against M.oryzae and accumulated more PA metabolites and lignin compared with wild-type plants.Interestingly,as demonstrated for Os PHT4,APIP5 directly binds to the promoters of Os AHT1/2,Os TBT1/2,and Os THT1/2,repressing their transcription.Together,these results indicate that the HT genes are common targets of APIP5 and that PAs play critical roles in rice immunity.
基金Project supported by Department of Science and Technology and Council for Scientific and Industrial Research, New Delhi
文摘A comparative study was made on the tissue specific expression of glutathione transferases (GST) in brain and testis after exposure of rat to phenobarbitol (PB) and β-methylcholanthrene (MC). Glutathione transferases, a family of multifunctional proteins are involved in intracellular transport processes and in detoxication of electrophilic xenobiotics by catalyzing reactions such as conjugation, isomerization, reduction and thiolysis. On purification, the yield of GST proteins by affinity chromatography was 39% in testis and 32% in brain. The affinity purified testis GSTs were resolved by chromatofocusing into six anionic and four cationic isozymes, and in brain glutathione transferases were resolved into four anionic and three cationic isozymes, suggesting the presence of multiple isozymes with Yc, Yb, Yβ and Yδ in both of them. In testis and brain, these isozymes at identical pI values showed variable functions with a battery of substrates and the cationic isozymes of brain and testis showed identical properties in CHP (cumene hydroperoxide) at pH values of above 7.0. Substrate specificity studies and immunoblot analysis of testis and brain proteins revealed that they play a predominant role in the detoxication of phenobarbitol or β-methylcholanthrene. Expression of the isozymes in testis and brain on exposure to PB and MC indicated elevated subunit variation. In both testis and brain, Yδ of π class was expressed on PB treatment and Yc of α class and Yβ of μ class was expressed in MC treated testis and only Yc was predominantly expressed in MC treated brain. Thus these subunits expression is considered as markers for carcinogenesis and specific to chemical toxicity under phenobarbitol and β-methylcholanthrene stress.
基金the Construction of Scientific Evidences for Herbal Medicine Formulas(K16251) and Evaluation of Herb-Drug Interactions(No.K16252) grant from the Korea Institute of Oriental Medicine(KIOM)
文摘OBJECTIVE:To investigate the influence of Yin-tonification herbal formulas Jaeumganghwa-tang(Ziyin Jianghuo Tang,JEGHT),Ssanghwa-tang(Shuanghe Tang,SHT) and Yukmijihwang-tang(Liuwei Di huang Tang,YMJHT) on the activities of human major cytochrome P450(CYP450 s) and UDP-glucuronosyltransferases isozymes(UGTs) in vitro.METHODS:The activities of CYP450 s(CYP1 A2,CYP3 A4,CYP2 B6,CYP2 C9,CYP2 C19,CYP2 D6 and CYP2 E1) and UGTs(UGT1 A1,UGT1 A4 and UGT2 B7)were assessed using in vitro fluorescence-and luminescence-based enzyme assays,respectively.The effects of herbal formulas on the activities of CYP450 s and UGTs were presented as IC50 values.RESULTS:JEGHT showed the potent inhibition of the CYP2 D6 activity,with weak inhibition on the activities of CYP1 A2,CYP2 B6,CYP2 C9,CYP2 C19,CYP2 E1,CYP3 A4,UGT1 A1,UGT1 A4 and UGT2 B7.SHT inhibited the activities of CYP1 A2 and CYP2 E1,whereas the negligible inhibition of the activities of CYP2 B6,CYP2 C9,CYP2 C19,CYP2 D6,CYP3 A4,UGT1 A1,UGT1 A4 and UGT2 B7 through SHT was observed.YMJHT inhibited CYP2 E1 activity,with a negligible inhibition on the activities of CYP1 A2,CYP2 B6,CYP2 C9,CYP2 C19,CYP2 D6,CYP3 A4,UGT1 A1,UGT1 A4 and UGT2 B7.CONCLUSION:These findings provide information about the potential interactions between three Yin-tonification herbal formulas and conventional drugs.
基金Natural Science Foundation of Fujian Province,China,No.C001009
文摘AIM: Glutathione S-transferases (GSTs) are involved in the detoxification of many potential carcinogens and appear to play a critical role in the protection from the effects of carcinogens. The contribution of glutathione S-transferases M1 and T1 genotypes to susceptibility to the risk of gastric cancer and their interaction with cigarette smoking are still unclear. The aim of this study was to determine whether there was any relationship between genetic polymorphisms of GSTT1 and GSTT1 and gastric cancer. METHODS: A population based case-control study was carried out in a high-risk area, Changle County, Fujian Province, China. The epidemiological data were collected by a standard questionnaire and blood samples were obtained from 95 incidence gastric cancer cases and 94 healthy controls. A polymerase chain reaction method was used to detect the presence or absence of the GSTT1 and GSTT1 genes in genomic DNA. Logistic regression model was employed in the data analysis. RESULTS: An increase in risk for gastric cancer was found among carriers of GSTT1 null genotype. The adjusted odds ratio (OR) was 2.63 95% Confidence Interval (95% CI) 1.17-5.88, after controlling for age, gender, cigarette smoking, alcohol drinking, and fish sauce intake. The frequency of GSTT1 null genotype in cancer cases (43.16%) was not significantly different from that in controls (50.00%). However, the risk for gastric cancer in those with GSTT1 null and GSTT1 non-null genotype was significantly higher than in those with both GSTT1 and GSTT1 non-null genotype (OR = 2.77, 95% CI 1.15-6.77). Compared with those subjects who never smoked and had normal GSTT1 genotype, ORs were 1.60 (95% CI:0.62-4.19) for never smokers with GSTT1 null type, 2.33 (95% CI 0.88-6.28) for smokers with normal GSTT1, and 8.06 (95% CI 2.83-23.67) for smokers with GSTT1 null type. CONCLUSIONS: GSTT1 gene polymorphisms may be associated with genetic susceptibility of stomach cancer and may modulate tobacco-related carcinogenesis of gastric cancer.
文摘Aim: Purification of glutathione S-transferases (GSTs) from rat testis; separation and identificationunits and their role in eicosanoid biosynthesis. Methods: Purification of mt testicular GSTs by affit?phy, employing S-hexylglutathione-linked epoxy-activated Sepharose 6B column and separation of indiby reverse phase-high pressure liquid chromatography (RP-HPLC). Characterization of affinity purified,um dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and Westem blot analysis. The roGSTs in eicosanoid biosynthesis was determined by incubating GSTs with 5, 6-Leukotriene A_4Me (prostaglandin H_2 (PGH_2) and analyzing the products formed on HPLC/TLC. Results: The present stumajority of rat testicular GSTs are of Y_b size (60%) with molecular weight of 27 kDa. The most preunits, however, are GST Y_(n2) (27% ), followed by GST Y_c (24% ) and GST Y_(nl) (20%). These testiculavery high Leukotriene C_4 (LTC_4) synthase activity with 5, 6-Leukotriene A4Me (LTA_4Me) as theprostaglandin D (PGD) synthase activity with prostaglandin H_2 (PGH_2) as the substrate. Conclusion:testicular GSTs are Y_b sized and are involved in the synthesis of eicosanoids like LTC_4 and PGD_2.(Asian J Androl 2000 Dec; 2: 277-282)
基金Supported by the National Natural Science Foundation of China,No.81973684Natural Science Foundation of Sichuan Province,No.2023NSFSC1760Youth Talent Fund of Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital,No.2021QN09。
文摘BACKGROUND Periodontitis,when exacerbated by diabetes,is characterized by increased M1 macrophage polarization and decreased M2 polarization.O-linkedβ-N-acetylglucosamine(O-GlcNAcylation),catalyzed by O-GlcNAc transferase(OGT),promotes inflammatory responses in diabetic periodontitis(DP).Additionally,p38 mitogen-activated protein kinase regulates macrophage polarization.However,the interplay between OGT,macrophage polarization,and p38 signaling in the progression of DP remains unexplored.AIM To investigate the effect of OGT on macrophage polarization in DP and its role in mediating O-GlcNAcylation of p38.METHODS For in vivo experiments,mice were divided into four groups:Control,DP model,model+short hairpin(sh)RNAnegative control,and model+sh-OGT.Diabetes was induced by streptozotocin,followed by ligation and lipopolysaccharide(LPS)administration to induce periodontitis.The impact of OGT was assessed by injecting sh-OGT lentivirus.Maxillary bone destruction was evaluated using micro-computed tomography analysis and tartrateresistant acid phosphatase staining,while macrophage polarization was determined through quantitative real-time polymerase chain reaction(qPCR)and immunohistochemistry.For in vitro experiments,RAW264.7 cells were treated with LPS and high glucose(HG)(25 mmol/L D-glucose)to establish a cell model of DP.OGT was inhibited by OGT inhibitor(OSMI4)treatment and knocked down by sh-OGT transfection.M1/M2 polarization was analyzed using qPCR,immunofluorescence,and flow cytometry.Levels of O-GlcNAcylation were measured using immunoprecipitation and western blotting.RESULTS Our results demonstrated that M1 macrophage polarization led to maxillary bone loss in DP mice,associated with elevated O-GlcNAcylation and OGT levels.Knockdown of OGT promoted the shift from M1 to M2 macrophage polarization in both mouse periodontal tissues and LPS+HG-induced RAW264.7 cells.Furthermore,LPS+HG enhanced the O-GlcNAcylation of p38 in RAW264.7 cells.OGT interacted with p38 to promote its O-GlcNAcylation at residues A28,T241,and T347,as well as its phosphorylation at residue Y221.CONCLUSION Inhibition of OGT-mediated p38 O-GlcNAcylation deactivates the p38 pathway by suppressing its self-phosphorylation,thereby promoting M1 to M2 macrophage polarization and mitigating DP.These findings suggested that modulating macrophage polarization through regulation of O-GlcNAcylation may represent a novel therapeutic strategy for treating DP.
基金supported by STI2030-Major Projects,No.2021ZD 0201801(to JG)Shanxi Province Basic Research Program,No.20210302123429(to QS).
文摘In patients with Alzheimer’s disease,gamma-glutamyl transferase 5(GGT5)expression has been observed to be downregulated in cerebrovascular endothelial cells.However,the functional role of GGT5 in the development of Alzheimer’s disease remains unclear.This study aimed to explore the effect of GGT5 on cognitive function and brain pathology in an APP/PS1 mouse model of Alzheimer’s disease,as well as the underlying mechanism.We observed a significant reduction in GGT5 expression in two in vitro models of Alzheimer’s disease(Aβ_(1-42)-treated hCMEC/D3 and bEnd.3 cells),as well as in the APP/PS1 mouse model.Additionally,injection of APP/PS1 mice with an adeno-associated virus encoding GGT5 enhanced hippocampal synaptic plasticity and mitigated cognitive deficits.Interestingly,increasing GGT5 expression in cerebrovascular endothelial cells reduced levels of both soluble and insoluble amyloid-βin the brains of APP/PS1 mice.This effect may be attributable to inhibition of the expression ofβ-site APP cleaving enzyme 1,which is mediated by nuclear factor-kappa B.Our findings demonstrate that GGT5 expression in cerebrovascular endothelial cells is inversely associated with Alzheimer’s disease pathogenesis,and that GGT5 upregulation mitigates cognitive deficits in APP/PS1 mice.These findings suggest that GGT5 expression in cerebrovascular endothelial cells is a potential therapeutic target and biomarker for Alzheimer’s disease.
基金supported in part by the Hubei Provincial Natural Science Foundation of China(grant no.2023AFA094)the Yingzi Tech&Huazhong Agricultural University Intelligent Research Institute of Food Health(No.IRIFH202209)+1 种基金Fundamental Research Funds for the Central Universities(Project 2662023PY005)the Hubei Hongshan Laboratory&Huazhong Agricultural University Start-up Fund.
文摘The rapid emergence and spread of colistin-resistant gram-negative bacteria has raised worldwide public health concerns,and phosphoethanolamine(PEtn)transferase modification-mediated colistin resistance has been widely documented in multiple gram-negative bacterial species.However,whether such a mechanism exists in the zoonotic pathogen Pasteurella multocida is still unknown.Recently,a novel PEtn transferase,PetL,was identified in P.multo-cida,but whether it is associated with colistin resistance remains to be elucidated.In this study,we found that PetL in P.multocida(PetL^(PM))exhibited structural characteristics similar to those of the mobile-colistin-resistant(MCR)protein and the PEtn transferase characterized in Neisseria meningitidis.The transformation of petLPM into E.coli or K.pneumoniae changed the phenotype of several tested strains from colistin sensitive to colistin resistant.Deletion of this gene decreased the colistin minimum inhibitory concentration(MIC)of P.multocida by 64-fold.Our extensive analysis by MALDI-TOF-MS demonstrated that PetLPM participated in the modification of bacterial lipopolysaccharide(LPS)-lipid A.Deletion of petL^(PM) led to an increase in membrane charge but a decrease in cell-surface hydrophobicity and cell permeability in P.multocida.The present study is the first to report the presence of PEtn transferase-mediated colistin resistance in the zoonotic pathogen P.multocida.
文摘BACKGROUND Gamma-glutamyl transferase(GGT)is a known surrogate marker of hepatic dysfunction and oxidative stress.It has recently been reported to be associated with metabolic diseases,cardiovascular diseases,and malignancies including pancreatic cancer.However,data on its association with pancreatic cystic neo-plasm(PCN),is unknown.AIM To investigate the association of GGT with the incidence of PCN.METHODS In this nationwide retrospective cohort study,participants who received general health checkup by National Health Insurance Service in 2009 were included.Newly diagnosed PCNs from one year after the checkup to 2020 were identified.Participants were divided into quartiles based on GGT levels.Multivariable cox proportional hazard models estimated the risk of PCNs according to GGT quartiles(Q1-Q4).Subgroup analyses by age,sex,and comorbidities,and sensitivity analyses varying lag periods and GGT categorizations were performed.RESULTS There were 28940 cases of PCNs among 2655665 eligible participants.The incidence rate was 1.09 cases per 1000 person-years,with a median follow-up of 10.32(interquartile range:10.09-10.58)years.In multivariate regression analysis,adjusted hazard ratios for GGT quartiles using Q1 group as a reference were:1.04[95%confidence interval(CI):1.005-1.075]for Q2,1.065(95%CI:1.03-1.102)for Q3,and 1.109(95%CI:1.07-1.15)for Q4.Subgroup analysis showed consistent results across age,sex,and comorbidities.In sensitivity analyses,the association remained robust even at 3-year and 5-year lag periods.A clear dose-response relationship was also observed when using GGT deciles(All P for trend<0.001).CONCLUSION Higher GGT level is associated with increased risk of PCNs.Therefore,serum GGT levels might have a role as a biomarker for the development of PCNs.
基金Supported by Regione Toscana,No.D55H20000210002.
文摘BACKGROUND The World Health Organization defined long coronavirus disease 2019(COVID-19)as the continuation or development of new symptoms 3 months after the initial severe acute respiratory syndrome coronavirus 2 infection,with these symptoms lasting for at least 2 months with no other explanation.AIM To evaluate the potential laboratory and instrumental findings(short-term and long-term)resulting from COVID-19.METHODS This longitudinal observational COVID-19 cohort study(March 1,2020-March 1,2021)was carried out on patients≥18 years old who were admitted to the University Hospitals of Pisa,Siena and Careggi and the Azienda USL Toscana Nord Ovest,Sud Est and USL Centro Toscana and were subjected to follow-up.Follow-up was conducted between 0 day and 89 days,90 days and 179 days,180 days and 269 days,270 days and 359 days,and more than 360 days after hospitalization.RESULTS Of 2887 patients(58.5%males,average age 66.2 years)hospitalized in the study period(March 1,2020-March 1,2021)carrying out at least one follow-up examination within 12 months of discharge,a total of 1739 patients(705 males,average age 66 years)underwent laboratory tests,of whom 714 patients(470 males,average age 63 years)underwent spirometry.Some laboratory test results remained above the threshold even at follow-up beyond 360 days(C-reactive protein:36%,fibrin degradation fragment:48.8%,gamma-glutamyl transferase:16.8%),while others showed a return to normal range more quickly in almost all patients.Alterations in liver enzymes,hematocrit,hemoglobin,lymphocytes and neutrophils were associated with the risk of requiring oxygen therapy or forced expiratory volume in one second/forced vital capacity alterations at follow-up.CONCLUSION Alterations in liver enzymes,hematocrit or hemoglobin,lymphocytes and neutrophils were associated with risk outcomes(need for oxygen therapy or spirometry alterations).These imbalanced conditions may contribute to pulmonary dysfunction.
基金supported by Major Projects in Agricultural Biological Breeding(2023ZD0403902)the HAAFS Science and Technology Innovation Special Project(2022KJCXZX-MHS-1)。
文摘Red petal spots are beneficial for attracting cotton pollinators and producing hybrid seeds,and the anthocyanin pathway is generally regarded as a metabolic cause of petal coloration.The current study identified an MYB-encoding gene(Gar07G09390,Ga MYB)as a candidate gene involved in cotton coloration by map-based cloning,and this MYB could positively regulate a candidate glutathione S transferase gene(Gar07G08900,Ga GST).To unveil potentially involved genes within the Ga MYB-regulating-Ga GST route,color metabolites of both Ga MYB-and Ga GST-virus-induced gene silencing(VIGS)petals were investigated,revealing that they were largely glycosyl-decorated flavonoids.Accordingly,a transcriptomic survey of both VIGS petals identified a glycosyl-transferase gene(Ga GT,Gar02G15390).Notably,this Ga GT is adjacent to one of the genome-wide association study loci concerning petal spots in Gossypium arboreum,and it is also positively regulated by Ga MYB.This new regulatory route including both GST and GT regulated by MYB is conserved among the three cotton species examined in this study(Gossypium arboreum,Gossypium hirsutum,and Gossypium barbadense).Accordingly,comprehensively evaluating the influence of these candidates and their homologs on cotton coloration may provide a more in-depth understanding of cotton coloration,ultimately facilitating the breeding of more colorful cotton.
基金supported by the Jiangsu Provincial Medical Key Discipline(Laboratory)Cultivation Unit(JSDW202249)the Natural Science Foundation of Jiangsu Province(BK20211108)+4 种基金a Scientific Research Project of the Health Commission of Nantong(MS2023035)Nantong Natural Science Foundation(JC2023114)the Scientific Research Innovation Team of Kangda College of Nanjing Medical University(KD2022KYCXTD005)Nantong University Clinical Medicine Special Project(2022JY005)the Postgraduate Research&Practice Innovation Program of Jiangsu province(KYCX23_3416).
文摘Microglial pyroptosis and neuroinflammation have been implicated in the pathogenesis of sepsis-associated encephalopathy(SAE).OGT-mediated O-GlcNAcylation is involved in neurodevelopment and injury.However,its regulatory function in microglial pyroptosis and involvement in SAE remains unclear.In this study,we demonstrated that OGT deficiency augmented microglial pyroptosis and exacerbated secondary neuronal injury.Furthermore,OGT inhibition impaired cognitive function in healthy mice and accelerated the progression in SAE mice.Mechanistically,OGT-mediated O-GlcNAcylation of ATF2 at Ser44 inhibited its phosphorylation and nuclear translocation,thereby amplifying NLRP3 inflammasome activation and promoting inflammatory cytokine production in microglia in response to LPS/Nigericin stimulation.In conclusion,this study uncovers the critical role of OGT-mediated O-GlcNAcylation in modulating microglial activity through the regulation of ATF2 and thus protects against SAE progression.
文摘Effects of Mingzhu Oral Liquid on the Hypothalamic-Pituitary-Adrenal Axis in Rats with Liver-Kidney Yin Deficiency WANG Yi-ting1,ZHAO Yang1,ZHU Fei-ya1,WANG Si-qiong1,ZHU Ling-lei1,LI Tao2,TANG Min-ke1,1.Beijing University of Chinese Medicine,Beijing,100029,China 2.Guangzhou Yitong Technology Co.,Ltd.,Guangzhou,510653,China【ABSTRACT】Objective:This study aimed to observe the effects of Mingzhu Oral Liquid on the hypothalamic-pituitary-adrenal(HPA)axis in rats with“liver-kidney yin deficiency”,in order to provide scientific research support for its clinical application in treating related disorders.Methods:A“liver-kidney yin deficiency”model was established in male Sprague-Dawley(SD)rats using a combination of chronic restraint stress and a single lipopolysaccharide(LPS)challenge.The rats were randomly divided into four groups:a blank control group,a model group,a low-dose Mingzhu Oral Liquid group,and a high-dose Mingzhu Oral Liquid group.The blank control group and model group were given normal saline by gavage,while the treatment groups received respective doses of Mingzhu Oral Liquid.Gavage administration was performed once daily for 30 consecutive days.During this period,all groups except the blank control group were subjected to restraint stress.Following the final gavage,all groups except the blank control received an intraperitoneal injection of LPS.Samples were collected 24 h post-injection.Serum levels of cyclic adenosine monophosphate(cAMP)and cyclic guanosine monophosphate(cGMP)were measured by enzyme-linked immunosorbent assay(ELISA)to evaluate the model state.The serum concentrations of corticotropin-releasing hormone(CRH),adrenocorticotropic hormone(ACTH),and glucocorticoid(GC)were determined to assess HPA axis activity.Changes in proinflammatory factors[tumor necrosis factor-alpha(TNF-α),interleukin-1 beta(IL-1β)]and the anti-inflammatory factor interleukin-10(IL-10)were also measured.Results:One week into the experiment,the weight gain rate slowed in all stress groups.By the end of the experiment,the body weight of these groups was significantly lower than that of the blank control group.Biochemical and hematological analyses revealed that the model group exhibited a significant decrease in lymphocyte count,an increased cAMP/cGMP ratio,reduced activities of glutathione S-transferase(GST)and glutathione transferase(GLT),elevated levels of blood urea nitrogen(BUN)and serum creatinine(Scr),increased serum contents of TNF-αand IL-1β,and a decreased content of IL-10.These findings confirmed the successful establishment of the rat model.Although the body weight of animals treated with Mingzhu Oral Liquid remained lower than that of the normal group,the treatment improved weight gain compared to the model group.Furthermore,Mingzhu Oral Liquid administration increased lymphocyte count,decreased the cAMP/cGMP ratio,restored GST and GLT activities,reduced BUN and Scr levels,lowered serum TNF-αand IL-1βcontents,and increased IL-10 levels,indicating a significant ameliorative effect on the deficiency symptoms.Additionally,serum levels of CRH,ACTH,and GC were elevated in the model rats,suggesting HPA axis hyperactivity.Treatment with Mingzhu Oral Liquid reduced the serum concentrations of these hormones,significantly alleviating the excited state of the HPA axis in stressed rats.Conclusion:Mingzhu Oral Liquid significantly improves the abnormal overall physical signs,blood biochemical parameters,and systemic inflammation in rats with“liver-kidney yin deficiency.”These therapeutic effects may be associated with the corrective action of Mingzhu Oral Liquid on the dysfunctional HPA axis in this model.
文摘Gamma glutamyl transferases （GGT） are highly conserved enzymes that occur from bacteria to humans. They remove terminal y-glutamyl residue from peptides and amides. GGTs play an important role in the homeostasis of glutathione （a major cellular antioxidant） and in the detoxification of xenobiotics in mammals. They are implicated in diseases like diabetes, inflammation, neurodegenerative diseases and cardiovascular diseases. The physiological role of GGTs in bacteria is still unclear. Nothing is known about the basis for the strong conservation of the enzyme across the living system. The review focuses on the enzyme＇s physiology, chemistry and structural properties of the enzyme with emphasis on the evolutionary relationships. The available data indicate that the members of the GGT family share common structural features but are functionally heterogenous.
文摘Kinases,representing almost 500 proteins in the human genome,are responsible for catalyzing the phosphorylation reaction of amino acid residues at their targets.As the largest family of kinases,the protein tyrosine kinases(PTKs)have roles in controlling the essential cellular activities,and their deregulation is generally related to pathologic conditions.The recent efforts on identifying their signal transducer or mediator role in cellular signaling revealed the interaction of PTKs with numerous enzymes of different classes,such as Ser/Thr kinases(STKs),glutathione transferases(GSTs),and receptor tyrosine kinases(RTKs).In either regulation or enhancing the signaling,PTKs are determined in close interaction with these enzymes,under specific cellular conditions,such as oxidative stress and inflammation.In this concept,intensive research on thiol metabolizing enzymes recently showed their involvement in the physiologic functions in cellular signaling besides their well known traditional role in antioxidant defense.The shared signaling components between PTK and GST family enzymes will be discussed in depth in this research review to evaluate the results of recent studies important in drug targeting for therapeutic intervention,such as cell viability,migration,differentiation and proliferation.
基金supported by the National Natural Science Foundation of China(22278137)the National Key R&D Program of China(2021YFC2103500)Partially supported by Open Funding Project of the State Key Laboratory of Bioreactor Engineering.
文摘Poly(lactate-co-3-hydroxybutyrate)[P(LA-co-3HB)]is a high-molecular-weight biomaterial with excellent biocompatibility and biodegradability.In this study,the properties of P(LA-co-3HB)were examined and found to be affected by its lactate fraction.The efficiency of lactyl-CoA biosynthesis from intracellular lactate significantly affected the microbial synthesis of P(LA-co-3HB).Two CoA transferases from Anaerotignum lactatifermentans and Bacillota bacterium were selected for use in copolymer biosynthesis from 11 candidates.We found that cotAl enhanced the lactate fraction by 31.56%compared to that of the frequently used modified form of propionyl-CoA transferase from Anaerotignum propionicum.In addition,utilizing xylose as a favorable carbon source and blocking the lactate degradation pathway further enhanced the lactate fraction to 30.42 mol%and 52.84 mol%,respectively.Furthermore,when a 5 L bioreactor was used for fermentation utilizing xylose as a carbon source,the engineered strain produced 60.60 wt%P(46.40 mol%LA-co-3HB),which was similar to the results of our flask experiments.Our results indicate that the application of new CoA transferases has great potential for the biosynthesis of other lactate-based copolymers.
文摘Currently,there is a lack of effective medicines capable of halting or reve rsing the progression of neurodegenerative disorde rs,including amyotrophic lateral sclerosis,Parkinson s disease,multiple sclerosis,or Alzheimer s disease.Given the unmet medical need,it is necessary to reevaluate the existing para digms of how to to rget these diseases.When considering neurodegenerative diseases from a systemic neurometabolic perspective,it becomes possible to explain the shared pathological features.This innovative approach presented in this paper draws upon exte nsive research conducted by the authors and researchers worldwide.In this review,we highlight the importance of metabolic mitochondrial dysfunction in the context of neurodegenerative diseases.We provide an overview of the risk factors associated with developing neurodegenerative disorders,including genetic,epigenetic,and environmental fa ctors.Additionally,we examine pathological mechanisms implicated in these diseases such as oxidative stress,accumulation of misfolded proteins,inflammation,demyelination,death of neurons,insulin resistance,dysbiosis,and neurotransmitter disturbances.Finally,we outline a proposal for the restoration of mitochondrial metabolism,a crucial aspect that may hold the key to facilitating curative therapeutic interventions for neurodegenerative disorders in forthcoming advancements.
文摘The positive effect of levodopa in the treatment of Parkinson’s disease,although it is limited in time and has severe side effects,has encouraged the scientific community to look for new drugs that can stop the neurodegenerative process or even regenerate the neuromelanin-containing dopaminergic nigrostriatal neurons.Successful preclinical studies with coenzyme Q10,mitoquinone,isradipine,nilotinib,TCH346,neurturin,zonisamide,deferiprone,prasinezumab,and cinpanemab prompted clinical trials.However,these failed and after more than 50 years levodopa continues to be the key drug in the treatment of the disease,despite its severe side effects after 4–6 years of chronic treatment.The lack of translated successful results obtained in preclinical investigations based on the use of neurotoxins that do not exist in the human body as new drugs for Parkinson’s disease treatment is a big problem.In our opinion,the cause of these failures lies in the experimental animal models involving neurotoxins that do not exist in the human body,such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and 6-hydroxydopamine,that induce a very fast,massive and expansive neurodegenerative process,which contrasts with the extremely slow one of neuromelanin-containing dopaminergic neurons.The exceedingly slow progress of the neurodegenerative process of the nigrostriatal neurons in idiopathic Parkinson’s patients is due to(i)a degenerative model in which the neurotoxic effect of an endogenous neurotoxin affects a single neuron,(ii)a neurotoxic event that is not expansive and(iii)the fact that the neurotoxin that triggers the neurodegenerative process is produced inside the neuromelanin-containing dopaminergic neurons.The endogenous neurotoxin that fits this degenerative model involving one single neuron at a time is aminochrome,since it(i)is generated within neuromelanin-containing dopaminergic neurons,(ii)does not cause an expansive neurotoxic effect and(iii)triggers all the mechanisms involved in the neurodegenerative process of the nigrostriatal neurons in idiopathic Parkinson’s disease.In conclusion,based on the hypothesis that the neurodegenerative process of idiopathic Parkinson’s disease corresponds to a single-neuron neurodegeneration model,we must search for molecules that increase the expression of the neuroprotective enzymes DT-diaphorase and glutathione transferase M2-2.It has been observed that the activation of the Kelch-like ECH-associated protein 1/nuclear factor(erythroid-derived 2)-like 2 pathway is associated with the transcriptional activation of the DT-diaphorase and glutathione transferase genes.
基金Supported by The Lishui Science and Technology Planing Projects,No.2020SJZC048.
文摘BACKGROUND High-grade B-cell lymphoma(HGBL)is an unusual malignancy that includes myelocytomatosis viral oncogene(MYC),B-cell lymphoma-2(BCL-2),and/or BCL-6 rearrangements,termed double-hit or triple-hit lymphomas,and HGBL-not otherwise specific(HGBL-NOS),which are morphologically characteristic of HGBL but lack MYC,BCL-2,or BCL-6 rearrangements.HGBL is partially transformed by follicular lymphoma and other indolent lymphoma,with few cases of marginal zone lymphoma(MZL)transformation.HGBL often has a poor prognosis and intensive therapy is currently mainly advocated,but there is no good treatment for these patients who cannot tolerate chemotherapy.CASE SUMMARY We reported a case of MZL transformed into HGBL-NOS with TP53 mutation and terminal deoxynucleotidyl transferase expression.Gene analysis revealed the gene expression profile was identical in the pre-and post-transformed tissues,suggesting that the two diseases are homologous,not secondary tumors.The chemotherapy was ineffective and the side effect was severe,so we tried combination therapy including venetoclax and obinutuzumab.The patient tolerated treatment well,and reached partial response.The patient had recurrence of hepatocellular carcinoma and died of multifunctional organ failure.He survived for 12 months after diagnosis.CONCLUSION Venetoclax combined with obinutuzumab might improve the survival in some HGBL patients,who are unsuitable for chemotherapy.
文摘Carnitine Palmitoyl Transferase II (CPTII) is a very important enzyme that helps with the oxidation of long-chain fatty acid to produce energy. Deficiency in CPTII will lead to energy deficiency in the case of fasting and the accumulation of the long chain fatty in the body. There are three types of CPT II deficiency, the myopathic form, the severe infantile hepatocardiomuscular form and the lethal neonatal form. They are all inherited as an autosomal recessive. Diagnosis of the CPTII are 1) tandem mass spectrometry (MS/MS) in adult form and 2) CPTII polymorphism (F352C), which is linked to reducing the activity of CPTII in infantile form [1]. Glucose is the primary management and medium-chain fatty acid is an alternative due to the bypass of the CPTII enzyme in the pathway. For the prevention of CPTII deficiency are to avoid long chain fatty acid (C12-fatty acid), fasting, prolonged exercise, known triggers, and certain medications such as anti-epileptics and general anesthesia. During the rhabdomyolysis and myoglobinuria attack, it is very important to maintain hydration to avoid acute renal failure. If, however, renal failure occurs, dialysis is recommended. We present a case of a 27-year-old African American woman with the significant past medical history of CPT II deficiency leading to recurrent rhabdomyolysis and myoglobinuria. Together with all the research studies from diagnosis to treatment of CPTII deficiency will help in clinical management of patients. And this case report will add to the existing case reports of patients who have CPTII deficiency in terms of how we diagnose, how we treat, and how we prevent symptoms from re-occurring.
