Helicobacter pylori γ-glutamyl transpeptidase:A formidable virulence factor

Helicobacter pylori(H.pylori)produce an enzyme known asγ-glutamyl transpeptidase(HpGGT)that is highly conserved and common to all strains.HpGGT has been gaining increasing attention as an important virulence factor of the bacterium,having been demonstrated to be an important colonization factor in several animal models and has also recently been strongly associated with the development of peptic ulcer disease.From the results of various independent researcher groups,it is clear that HpGGT acts through several pathways to damage gastric epithelial cells including the induction of apoptosis and cell cycle arrest,production of reactive oxygen species leading to DNA damage,promotion of inflammation by increasing cyclooxygenase-2 and interleukin-8 expression,and upregulation of heparin-binding epidermal growth factor-like growth factor resulting in cell survival and proliferation.In addition,the potential role of HpGGT in promoting gastric carcinogenesis will also be discussed in this review.Apart from affecting the gastric epithelium,HpGGT also has immunomodulatory actions on host immune cells where it displays an antiproliferative effect on T cells by inducing cell cycle arrest and also works with other H.pylori virulence factors to skew dendritic cells towards a tolerogenic phenotype,possibly contributing to the persistence of the pathogen in the gastric mucosa.

Helicobacter pylori gamma-glutamyl transpeptidase and its pathogenic role

Helicobacter pylori(H.pylori)gamma-glutamyl transpeptidase(GGT)is a bacterial virulence factor that converts glutamine into glutamate and ammonia,and converts glutathione into glutamate and cysteinylglycine.H.pylori GGT causes glutamine and glutathione consumption in the host cells,ammonia production and reactive oxygen species generation.These products induce cell-cycle arrest,apoptosis,and necrosis in gastric epithelial cells.H.pylori GGT may also inhibit apoptosis and induce gastric epithelial cell proliferation through the induction of cyclooxygenase-2,epidermal growth factor-related peptides,inducible nitric oxide synthase and interleukin-8.H.pylori GGT induces immune tolerance through the inhibition of T cell-mediated immunity and dendritic cell differentiation.The effect of GGT on H.pylori colonization and gastric persistence are also discussed.

Effect of Glutamine Supplementation on Abilities of Antioxidative and y-glutamyl Transpeptidase Activities in Liver and Intestine of Piglets Fed Diets Containing Raw Soybean

Eighteen male piglets weaned at 28 days age were randomly assigned to one of three treatments (1% glutamate. 1% and 2% glutamine supplementation). The basal diet contained 5% raw soybean. The diets were calculated to be isonitrogenous and isoenergetic. The level of plasma glutahione(GSH) increased markedly in piglets fed glutamine, and the response was related to dose. In treatments I and I , the levels of plasma GSH were significantly higher than that in the control at the 35 days age (P<0.05). The level of plasma GSH in treatment I was significantly higher than that in the control at 42 days age (P<0. 05). At 49 days age, there was no significantly difference of the level of GSH in plasma, liver, spleen, intestine and mes-enteric lymph node. The level of superoxide dismutase (SOD) in liver and spleen was higher than that of the control, however, the difference wasn't significant. Dietary glutamine supplementation decreased γ-glutamyl transpeptidase(γ-GT) activities in liver. The activities of γ-GT of liver protein in treatmentⅡ were significantly lower than that in the control (P<0.05). The activities ofγ-GT of duodenum in treatments I and Ⅱwere also significantly lower than that in the control (P<0.05). But there were no significant differences of the activities of γ-GT in jejunum and ileum. The results showed that dietary glutamine supplementation increased the level of plasma GSH, and decreased γ-GT activities.

Inhibition of Carcinogen Induced Activity of γ-glutamyl Transpeptidase by CertainDietary Constituents in Mouse Skin

Cancer chemoprevention, a desirable and important facet of biomedical research, provides a practical approach to identify potentially useful inhibitors of cancer development, and offers an opporiunity to study the mechanism of carcinogenesis. During the recent Past a number of compounds have been tested for their anticarcinogenic potential specially constituents of our diet. The enzyme γglutamyl transpeptidase (GGT) which catalyses the transfer of glutamyl groups of peptides to other peptides and amino acid and has been proposed as a marker of cell proliferation and neoplasia. It also serves as a tool to evaluate the carcinogenic and cocarcinogenic potential of environmental toxicants. In the present investigations, CGT activity induced by careinogenic polycyclic aromatic hydmiarbons, viz. 7, 12-dimethylbenz(a) anthracene (DMBA) and benzo(a) pyrene (BaP) was significantly inhibited by diallylsulfide (DAS) and indole-3-carbnol (I3C) in mouse skin. DAS and 13C are constituents of garlic and cruciferous vegetables respectively. A significant iIthibition in GGT levels was also observed in a strong mitogen (12-o-tetradecanoyl phorbol-13-acetate) induced activity in mouse skin by pretreatment with DAS/13C. Therefore these dietary constituents seem to be strong modifiers of chemically induced carcinogenesis

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.

Gamma-glutamyl Transpeptidase to Platelet Ratio Predicts Liver Injury in Hepatitis B e Antigen-negative Chronic Hepatitis B Patients With Normal Alanine Aminotransferase

Background and Aims:Chronic hepatitis B virus(HBV)infection is a serious health problem worldwide.Evaluating liver injury in patients with hepatitis B e antigen(HBeAg)-negative chronic hepatitis B(CHB)with detectable HBV DNA and normal alanine aminotransferase(ALT)is crucial to guide their clinical management.We aimed to investigate the stages of liver inflammation and fibrosis as well as the predictive accuracy of gamma-glutamyl transpepti-dase-to-platelet ratio(GPR)in these patients.Methods:A total of 184 treatment-naïve HBeAg-negative CHB pa-tients with detectable HBV DNA and normal ALT were enrolled.The Scheuer scoring system was used to classify liver inflammation and fibrosis.Results:The distribution of patients with different liver inflammation grades were as follows:G0,0(0%);G1,97(52.7%);G2,68(37.0%);G3,12(6.5%);and G4,7(3.8%).The distribution of patients with different liver fibrosis stages were as follows:S0,22(12.0%);S1,72(39.1%);S2,42(22.8%);S3,19(10.3%);and S4,29(15.8%).The areas under the re-ceiver operating characteristic(AUROC)curves of GPR in predicting significant inflammation,severe inflammation,and advanced inflammation were 0.723,0.895,and 0.952,respectively.The accuracy of GPR was significantly superior to that of ALT in predicting liver inflammation.The AUROCs of GPR in predicting significant fibrosis,severe fibrosis,and cirrhosis were 0.691,0.780,and 0.803,respectively.The predictive accuracy of GPR was significantly higher than that of aminotransferase-to-platelet ratio index(APRI)and fibrosis index based on four factors(FIB-4)in identifying advanced fibrosis and cirrhosis,and it was superior to FIB-4 but comparable to APRI in identifying significant fibrosis.Conclusions:Nearly half of the HBeAg-negative CHB patients with detectable HBV DNA and normal ALT levels had significant liver inflammation or fibrosis.GPR can serve as an accurate predictor of liver inflammation and fibrosis in these patients.

The clinical implication of gamma-glutamyl transpeptidase in COVID-19

Background and aim:Coronavirus disease 2019(COVID-19)is a life-threatening disease that predomi-nantly causes respiratory failure.The impact of COVID-19 on other organs remains elusive.Herein,we aimed to investigate the effects of COVID-19 on the hepatobiliary system.Methods:In the current study,we obtained the clinical records and laboratory results from 66 laboratory-confirmed patients with COVID-19 at the Wuhan Tongji Hospital between 10 February 2020 and 28 February 2020.The detailed clinical features and laboratory findings were collected for analysis.Bioinformatics analysis was conducted to evaluate the correlation between gamma-glutamyl transferase(GGT)and severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)entry receptor angiotensin-converting enzyme 2(ACE2).Results:In this cohort,30(51.7%)patients had abnormal liver function on admission,which was asso-ciated with disease severity and enriched in the male and diabetic patients.The elevated levels of direct bilirubin(P¼0.029)and GGT(P¼0.004)were common in patients with severe pneumonia when compared with those with mild pneumonia.In addition,elevated levels of GGT(P¼0.003)and aspartate aminotransferase(AST)(P¼0.007)were positively associated with longer hospital stay.The expression of ACE2 was closely associated with GGT in various human tissues because they shared the common transcriptional regulator hepatic nuclear factor-1 b(HNF1B).Conclusions:Increased GGT levels were common in severe cases and elevated GGT levels were positively associated with prolonged hospital stay and disease severity.Due to the consistent expression with ACE2,GGT is a potent biomarker indicating the susceptibility of SARS-CoV-2 infection.

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.

Silymarin in non alcoholic fatty liver disease

AIM: This study was undertaken to evaluate the hepatic effects of silybum marianum on non alcoholic fatty liver disease (NAFLD). METHODS: In 72 patients affected by NAFLD, main metabolic, hepatic and anti-inflammatory parameters were assayed after 3 mo of a restricted diet and before silymarin treatment (twice a day orally). The brightness of liver echography texture (hepatorenal ratio brightness) was also defined at same time. These evaluations were repeated after 6 mo of treatment. RESULTS: Serum levels of some metabolic and anti-inflammatory data nonsignificantly lowered after 6 mo of silymarin. On the contrary, Steato test, alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma-glutamyl transpeptidase were significantly (P < 0.001) reduced. Instead, the AST/ALT ratio unchanged. Finally, the hepatorenal brightness ratio, as an index of hepatic steatosis, significantly (P < 0.05) dropped. CONCLUSION: The obtained results indicate that silymarin appears to be effective to reduce the biochemical, inflammatory and ultrasonic indices of hepatic steatosis. Some parameters indicative of early stage of atherosclerosis were also lowered.

在孟加拉国的不含酒精的脂肪肝疾病病人的不含酒精的 steatohepatitis

AIM: To explore the prevalence and risk factors for nonalcoholic steatohepatitis (NASH) in nonalcoholic fatty liver disease (NAFLD) patients. METHODS: We have included 493 patients with sonographic evidence of a fatty change, and 177 of these individuals were evaluated and confirmed after liver biopsy. The exclusion criteria consisted of significant alcohol abuse (【 20 g daily), evidence of hepatitis B and C, evidence of drug-induced fatty liver disease and other specific liver diseases such as hemochromatosis, Wilson’s disease or autoimmune liver disease. The patients were assessed for metabolic syndrome, and biochemical, anthropometric and histopathological evaluations were carried out. The degree of disease activity in the NAFLD patients was evaluated using the NAFLD Activity Score. The data were analyzed by SPSS, version 16.0. RESULTS: Females predominated among the study participants (250, 57.0%), and the mean age was 40.8 ± 10.2 years. The numbers of overweight, obeseⅠ and obese Ⅱ patients were 58 (13.2%), 237 (53.9%) and 93 (21.2%), respectively. However, there were 422 (96.2%) centrally obese patients. NASH was absent in 10 (5.6%) cases, borderline in 92 (52.6%) cases and present in 75 (42.4%) cases. The presence of diabetes could significantly (P = 0.001) differentiate NASH from simple steatosis. The following parameters did not influence the development of NASH: age, sex, basal metabolic index, waist circumference, serum high-density lipoprotein, triglyceride, insulin resistance index, hypertension and metabolic syndrome. The serum gammaglutamyl transpeptidase (GGT) level was significantly higher (P = 0.05, 51.7 ± 32.8 and 40.4 ± 22.6 U/L) in the NASH patients, with a sensitivity of 45% and a specificity of only 68%. The serum alanine aminotransferase and aspartate aminotransferase levels were not able to predict NASH. CONCLUSION: Females were the predominant sufferers of NAFLD in Bangladesh. The prevalence of NASH was high. Diabetes was found to be the main culprit in developing NASH. GGT was the only biochemical marker of NASH. We recommend liver biopsy in NAFLD patients who have diabetes and elevated GGT.

Relationship between alcohol consumption and clinical manifestation of patients with fatty liver:a single-center study

BACKGROUND:Fatty liver is a common chronic liver disease worldwide.It is associated with an increasing morbidity in China in recent years.The aim of this study was to analyze the effect of drinking alcohol on the hemoglobin and biochemical values of patients with fatty liver.METHODS:We investigated the clinical and laboratory data of 669 patients with fatty liver.Of the 669 patients,166 consumed alcohol more than 60 g per week for at least 2 years,and 503 did not have a history of long-term alcohol consumption.We further analyzed the relationship between alcohol consumption and clinical characteristics of these patients.RESULTS:The values of aspartate transaminase (AST),gammaglutamyl transpeptidase (GGT),and hemoglobin in the long-term consumption group were significantly higher than those in the non long-term consumption group (P<0.05).In the patients without long-term alcohol consumption,the values of GGT and hemoglobin in patients with light alcohol consumption were significantly higher than those in non alcohol consumers (P<0.05).CONCLUSION:Alcohol consumption is associated with significantly increased values of AST,GGT,and hemoglobin in patients with fatty liver,suggesting their potential roles in hepatic steatosis.

在不含酒精的脂肪肝疾病和尖锐 ischemic 击严厉和结果之间的协会

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.

Liver transplant for large hepatocellular carcinoma in Malatya: Therole of gamma glutamyl transferase and alpha-fetoprotein, aretrospective cohort study

BACKGROUND There is increasing interest in transplanting patients with hepatocellularcarcinoma (HCC) with tumors greater than 5 cm (Milan criteria).AIM To investigate possible prognostically-useful factors for liver transplantation inHCC patients with large tumors.METHODS In this clinical study, 50 patients with HCC who were transplanted at our LiverTransplant Center between April 2006 and August 2019 and had tumors greaterthan 6 cm maximum diameter were retrospectively analyzed. Their survival andfull clinical characteristics were examined, with respect to serum alphafetoprotein(AFP) and gamma glutamyl transpeptidase (GGT) levels. Kaplan-Meier survival estimates were used to determine overall survival and disease-freesurvival in these patients. The inclusion criterion was evidence of HCC. Exclusioncriteria were the presence of macroscopic portal vein thrombosis or metastasisand a follow-up period of less than 90 d.RESULTS Using receiver operating characteristic curve (ROC) analysis, cutoff values of AFP200 ng/mL and GGT 104 IU/L were identified and used in this study.Significantly longer overall survival (OS) and disease-free-survival (DFS) were found in patients who had lower values of either parameter, compared withhigher values. Even greater differences in survival were found when the 2parameters were combined. Two tumor size bands were identified, in searchingfor the limits of this approach with larger tumors, namely 6-10 cm and > 10 cm.Combination parameters in the 6-10 cm band reflected 5-year OS of 76.2% inpatients with low AFP plus low GGT vs 0% for all other groups. Patients withtumors greater than 10 cm, did not have low AFP plus low GGT. The mostconsistent clinical correlates for longer survival were degree of tumordifferentiation and absence of microscopic portal venous invasion.CONCLUSION Serum levels of AFP and GGT, both alone and combined, represent a simpleprognostic identifier in patients with large HCCs undergoing liver transplantation.

Transient elevation of hepatic enzymes in volunteers after intake of alcohol

BACKGROUND: In the organs that mediate alcohol effects on the human body and its health, the liver plays a particular important role. This study was designed to detect the changes of hepatic enzymes after alcohol intake and evaluate the corresponding damage to the human body. METHODS: Fifteen volunteers were included according to the criteria. After the intake of 80g ethanol containing beverage, alcohol levels were detected and blood samples were collected at 0.5-to 3-hour interval to detect the levels of hepatic enzymes simultaneously. RESULTS: After the intake of 80g ethanol, various symptoms occurred in volunteers while the concentration of blood alcohol peaked at 1 hour and normalized within 24 hours. The ratio of alanine aminotransferase (ALT) to aspartate aminotransferase (AST) increased significantly when the venous alcoholic concentration increased from 0g/L to 1.2g/L and the levels of alkaline phosphatase (ALP) and gamma-glutamyl transpeptidase(γ-GT) were elevated when the alcoholic concentration reached 0.4g/L. No significant changes were noticed in ALT, AST or cholinesterase (CHE). CONCLUSION: Acute alcohol intoxication may cause the changes of hepatic enzymes and prove the existence of reversible hepatic injury.

Endotoxins enhance hepatocarcinogenesis induced by oral intake of thioacetamide in rats

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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.

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.