Associations between y-glutamyl transferase, metabolic abnormalities and inflammation in healthy subjects from a population-based cohort: A possible implication for oxidative stress

AIM: To examine the relationships between γ -glutamyltransferase (GGT), alanine-aminotransferase (ALT),aspartate-aminotransferase (AST) and various metabolic parameters, C-reactive protein (CRP) and an oxidative stress marker (nitrotyrosine, NT) in subjects without any metabolic abnormalities from a population-based sample.METHODS: Two hundred and five subjects with normal body mass index (BMI), glucose tolerance, and without any metabolic abnormality were studied out of 1339subjects, without known liver diseases, alcohol abuse or use of hepatotoxic drugs, who are representative of the 45-64 aged population of Asti (north-western Italy).RESULTS: In all patients metabolic parameters and hs-CRP levels linearly increase from the lowest to the highest ALT and GGT tertiles, while in subjects without metabolic abnormalities, there is a significant association between fasting glucose, uric acid, waist circumference,hs-CRP, triglyceride values, and GGT levels. In these subjects, male sex, higher hs-CRP and glucose levels are associated with GGT levels in a multiple regression model, after adjustments for multiple confounders.In the same model, median NT levels are significantly associated with the increasing GGT tertile (β = 1.06;95%CI 0.67-1.45), but not with the AST and ALT tertiles.In a multiple regression model, after adjusting for age,sex, BMI, waist, smoking, and alcohol consumption, both NT (β = 0.05; 95%CI 0.02-0.08) and hs-CRP levels (β =0.09; 95%CI 0.03-0.15) are significantly associated with fasting glycemia.CONCLUSION: GGT, an easy, universally standardized and available measurement, could represent an early marker of sub-clinical inflammation and oxidative stress in otherwise healthy individuals. Prospective studies are needed to establish if GGT could predict future diabetes in these subjects.

Comparing the difference in enhancement of kokumi-tastingγ-glutamyl peptides on basic taste via molecular modeling approaches and sensory evaluation

γ-Glutamyl peptides can enhance basic taste sensations such as saltiness,sweetness,and umaminess,while the molecular mechanism and the difference in taste enhancement remain elusive.Thus,two complex conformations:taste type 1 receptor 1(T1 R1)-MSG and taste type 1 receptor 2(T1 R2)-sucrose were constructed to form binding receptors.These peptides showed affinity for the two receptors,but a higher affi nity scores and more binding amino acid residues for the T1 R1-MSG receptor,implying that they may exhibit a higher umami-enhancing effect.Thereinto,γ-glutamyl alanine(γ-EA)displayed the highest affi nity for the two receptors through mobilizing multiple amino acid residues to form hydrophobic and hydrogen bonds,indicating it had the highest enhancement for umaminess and sweetness among these peptides.Sensory evaluation demonstrated the enhancement ofγ-EA on umaminess was superior to that of sweetness.Generally,γ-glutamyl peptides could enhance basic taste sensation via activating taste receptor,and exhibited a highest umami-enhancing effect.

Prognostic role of plasma levels ofγ-glutamyl transpeptidase in patients with advanced gastric cancer treated with anti-PD-1 immunotherapy

Objective Antibodies targeting programmed cell death protein 1(PD-1)have become the mainstay of treatment for chemotherapy-refractory gastric cancer,characterized by high levels of programmed cell death ligand-1(PDL-1)expression.However,the routine clinical implementation of PDL-1 testing is currently limited by the lack of robust detection methods.In this regard,the role of plasmaγ-glutamyl transpeptidase(GGT),an N-terminal nucleophilic hydrolase,as an independent predictor of the efficacy of anti-PD-1 therapy remains unknown.In this study,we aimed to assessed the prognostic role of changes in plasma GGT levels(6 weeks vs.baseline)in patients with advanced gastric cancer treated with anti-PD-1 immunotherapy.Methods We retrospectively analyzed data from 57 patients with gastric cancer treated with anti-PD-1 antibodies(camrelizumab,sintilimab,nivolumab,tislelizumab,and toripalimab)at the Union Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan,China,from July 2018 to February 2021.Results We found that after 6 weeks of treatment,there were significant differences between responders and non-responders with respect to plasma GGT levels(P<0.001).Multivariate logistic regression analysis revealed that the continuous value of the 6-week difference in GGT levels(OR=1.437,95%CI=1.116-1.849,P=0.005)and 6-week difference in GGT≥0 or<0(OR=53.675,95%CI=6.379-451.669,P<0.001)were independent predictors of disease control.Survival analysis indicated that a reduction in plasma GGT6 levels during treatment was significantly associated with a favorable progression-free survival(PFS)and overall survival(P<0.001).Consistently,univariate and multivariate Cox regression analyses revealed that a reduction in plasma GGT6 levels during treatment was an independent predictor of PFS(HR=1.033,95%CI=1.013-1.053,P=0.001).Conclusion Alterations in plasma GGT levels during treatment can be used as a predictor of disease progression and survival in patients with advanced gastric cancer undergoing treatment with anti-PD-1 antibodies.

γ-谷氨酰转肽酶在妊娠期肝内胆汁淤积症孕妇产前监测中的意义

目的 探讨妊娠期肝内胆汁淤积症 (ICP)患者血清γ 谷氨酰转肽酶 (γ GT)与围生儿预后的关系。方法 收集 6 3例妊娠晚期ICP患者 ,母血γ GT采用全自动生化仪测定 ,其中 2 5例伴有γ GT升高 ,比较γ GT升高组与γ GT正常组 ,二组围生儿预后及胎盘体视学改变的关系。结果 6 3例ICP患者中 ,γ GT升高者 2 5人 ,其羊水粪染、出生时即刻脐动脉血血气分析pH值 <7.2 0者均高于γ GT正常组 (P <0 .0 5 ) ,γ GT升高组胎盘绒毛间隙亦小于γ GT正常组 (P <0 .0 5 )。结论 ICP患者的血清γ GT在一定程度上反映病情的严重性 。

Association between nonalcoholic fatty liver disease and acute ischemic stroke severity and outcome

AIM:To evaluate the association of nonalcoholic fatty liver disease(NAFLD)with acute ischemic stroke severity and in-hospital outcome.METHODS:We prospectively studied all patients who were admitted in our Department with acute ischemic stroke between September 2010 and August 2012(n=415;39.5%males,mean age 78.8±6.6 years).The severity of stroke was assessed with the National Institutes of Health Stroke Scale(NIHSS)score at admission.NALFD was defined as serum alanine aminotransferase and/or aspartate aminotransferase levels above the upper limit of normal in the absence of other causes of elevated aminotransferases levels[chronic hepatitis B or C,drug toxicity,increased alcohol consumption(】21 and】14 drinks per week in men and women,respectively),cholestatic diseases or rhabdomyolysis].The outcome was assessed with the modified Rankin scale(mRS)score at discharge and in-hospital mortality.Adverse outcome was defined as mRS score at discharge≥2.Dependency at discharge was defined as mRS score between 2 to 5.RESULTS:NAFLD was present in 7.7%of the study population.Patients with NAFLD had lower serum high-density lipoprotein cholesterol and higher triglyceride levels than patients without NAFLD(P【0.05 for both comparisons).Demographic data,the prevalence of other cardiovascular risk factors and the prevalence of established CVD did not differ between the two groups.At admission,the NIHSS score did not differ between patients with and without NAFLD(6.3±6.4and 8.8±9.6,respectively;P=NS).At discharge,the mRS score did not differ between the two groups(1.9±2.2 and 2.6±2.2 in patients with and without NAFLD,respectively;P=NS).Rates of dependency at discharge were also similar in patients with and without NAFLD(36.8%and 55.0%,respectively;P=NS)as were the rates of adverse outcome(42.9%and58.6%,respectively;P=NS).In-hospital mortality rates also did not differ between the 2 groups(8.0%and 7.0%in patients with and without NAFLD,respectively;P=NS).CONCLUSION:The presence of NAFLD in patients admitted for acute ischemic stroke does not appear to be associated with more severe stroke or with worse in-hospital outcome.

联合应用纤维蛋白(原)降解产物、D-二聚体及谷氨酰转肽酶对肝硬化的诊断价值

目的探讨纤维蛋白(原)降解产物(FDP)、D-二聚体(D-D)及γ-谷氨酰转肽酶(γ-GT)联合诊断肝硬化的临床价值。方法选择该院2015年1月‐2015年12月收治的80例肝硬化患者为观察组,另选同期健康体检者80例为对照组,分别对所有受检者进行FDP、D-D及γ-GT等检测,判断以上指标对肝硬化的诊断价值。结果观察组FDP、D-D及γ-GT等各项指标水平显著高于对照组,差异有统计学意义(P<0.05);FDP、D-D及γ-GT的单项检测灵敏度分别为62.50%、66.25%和68.75%,特异度分别为72.50%、76.25%和77.50%,联合检测的灵敏度及特异度分别为91.25%、97.50%,差异有统计学意义(P<0.05)。结论 FDP、D-D及γ-GT联合进行肝硬化诊断具有显著价值,可作为临床观察肝硬化病情程度及预后的重要指标。

Serum metabolome profiles characterized by patients with hepatocellular carcinoma associated with hepatitis B and C

AIM: To clarify the characteristics of metabolite profiles in virus-related hepatocellular carcinoma (HCC) patients using serum metabolome analysis.METHODS: The serum levels of low-molecular-weight metabolites in 68 patients with HCC were quantified using capillary electrophoresis chromatography and mass spectrometry. Thirty and 38 of the patients suffered from hepatitis B virus-related HCC (HCC-B) and hepatitis C virus-related HCC (HCC-C), respectively.RESULTS: The main metabolites characteristic of HCC were those associated with glutathione metabolism, notably 13 &#x003b3;-glutamyl peptides, which are by-products of glutathione induction. Two major profiles, i.e., concentration patterns, of metabolites were identified in HCC patients, and these were classified into two groups: an HCC-B group and an HCC-C group including some of the HCC-B cases. The receiver operating characteristic curve for the multiple logistic regression model discriminating HCC-B from HCC-C incorporating the concentrations of glutamic acid, methionine and &#x003b3;-glutamyl-glycine-glycine showed a highly significant area under the curve value of 0.94 (95%CI: 0.89-1.0, P &#x0003c; 0.0001).CONCLUSION: The serum levels of &#x003b3;-glutamyl peptides, as well as their concentration patterns, contribute to the development of potential biomarkers for virus-related HCC. The difference in metabolite profiles between HCC-B and HCC-C may reflect the respective metabolic reactions that underlie the different pathogeneses of these two types of HCC.

Effect of mercuric chloride on membrane-bound enzymes in rat testis

Aim: To study the effect of mercuric chloride on the membrane-bound enzymes. Methods: The effect of mercuric chloride at two different doses, 1 mg/kg (low dose) and 2 mg/kg (high dose), orally for 30 days, was observed on the membrane-bound enzymes in the testis of adult albino rats. Results: Mercuric chloride significantly decreased the body weight and testis weight in the high dose group (P<0.05), but not in the low dose group. The activities of 5' nucleotidase and adenosine triphosphatases were markedly decreased (P<0.01) in the testis of both groups. Alkaline phosphatase and γ-glutamyl transferase activities were significantly increased (P<0.01) in both groups. However, the effect was more pronounced in the high than in the low dose groups. Conclusion: The dose dependent effect of mercuric chloride on these enzymes may affect the membrane characteristics and thereby the fertility of the animal. (Asian J Androl 2002 Dec; 4:309-311)

NIR photosensitizers activated byγ-glutamyl transpeptidase for precise tumor fluorescence imaging and photodynamic therapy

Photodynamic therapy(PDT),a light triggered therapeutic mode,has been recognized as an attractive treatment for oncotherapy.The phototoxicity to normal tissues during treatment limited the development of PDT owing to the always“on”properties of photosensitizers.Activatable photosensitizers are of great importance for improving the selectivity of PDT.Herein,we regarded the overexpressed GGT(γ-Glutamyl transpeptidase)enzyme in tumor cells as a biomarker and developed an activatable photosensitizer Cy-GGT by decorating a specific recognition moiety of GGT,L-glutamic acid,to a hemicyanine dye based on photosensitizer Cy-NH_(2).Cy-GGT was in the“off”state with negligible fluorescence and suppressed singlet oxygen generation,but it could be specifically hydrolyzed to Cy-NH_(2) in the presence of GGT,accompanied with significant fluorescence recovery and singlet oxygen generation increase under light irradiation.The in vitro and in vivo studies indicated that Cy-GGT was suitable for precise tumor imaging and could work as an efficient photosensitizer for inhibiting tumor growth.

Enzyme-activatable disk-shaped nanocarriers augment tumor permeability for breast cancer combination therapy

Unique physiopathological characteristics of tumor tissues impose obstacles to the sufficient penetration of traditional nanomedicines,resulting in undesirable drug delivery efficacy and therapeutic outcomes.Here,we constructed TRAIL-[NDHCPT]^(GAC),a synergistic hydroxycamptothecin(HCPT)and tumor necrosis factor-related apoptosis-inducing ligand(TRAIL)protein co-loaded disk-shaped nanocarrier withγ-glutamyl transpeptidase responsiveness.When the novel nanodisks extravasated into the tumor interstitium,theγ-glutamyl transpeptidase overexpressed on the tumor cell membranes cleaved theγ-glutamyl portions of the nanodisk surface to produce positively charged amino groups.As a result,the cationic nanodisks possessed stronger tumor infiltration ability through transcytosis than anionic nanodisks.HCPT and TRAIL exerted synergistic antitumor effects with better overall therapeutic efficacy.This TRAIL-[ND-HCPT]^(GAC)system performed significantly better than free HCPT and remarkably prolonged the survival of breast tumor-bearing mice with no significant toxicity.

健脾消食法对非酒精性脂肪性肝病患者ALT、AST、GGT的影响

目的:观察健脾消食法对非酒精性脂肪性肝病患者谷丙转氨酶(alanine aminotransferase,ALT)、谷草转氨酶(aspartate transaminase,AST)及谷氨酰转肽酶(gamma-glutamyl transpetidase,GGT)和血脂的影响。方法:将110例患者随机分为治疗组和对照组,每组55例。治疗组采用健脾消食汤治疗,水煎分两次服,每次1剂。对照组给予复方蛋氨酸胆碱片,每次3片,每日3次,2个月为1个疗程。观察两组患者治疗2个月后肝功ALT、AST、GGT以及血脂指标。结果:对照组肝功能AST、ALT及GGT指标治疗4周内下降趋势明显优于治疗组,差异有统计学意义(P<0.05);对照组治疗4周后肝功AST、ALT及GGT指标逐渐升高,而治疗组治疗期间肝功AST、ALT及GGT指标逐步稳定下降,未出现升高状态,两组患者在治疗8周的变化比较,治疗组肝功AST、ALT及GGT改善明显优于对照组,差异有显著统计学意义(P<0.01);治疗组治疗后改善血脂指标效果优于对照组,差异有统计学意义(P<0.05)。结论:健脾消食法能改善非酒精性脂肪性肝炎患者肝功能(AST、ALT、GGT)和血脂指标。

Identification of isopeptidase activity in the midgut of insects： Purification, properties and nutritional ecology of a Hofmannophila pseudospretella （Lepidoptera： Oecophoridae） larval enzyme

A γ-glutamyl transpeptidase （isopeptidase） has been purified 580-fold to homogeneity from the midgut of keratinophagous larvae of Hofmannophila pseudospretella. The enzyme is a single polypeptide of molecular mass 80 kDa. The enzyme was identified by its hydrolytic activity against the synthetic substrate, γ-glutamyl-AMC, its molecular mass and inhibition profile compared to other γ-glutamyl transpeptidases. The enzyme is low or absent from most other insect digestive systems apart from other keratinophagous lepidopteran larvae and predatory carabids. While isopepfide bonds are present in high levels of the proteins in the diet of keratinophages, their presence in the diet of predatory beetles has not been established.