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Aims How the pathology of type 2 diabetes (T2D), including hyperglycaemia and obesity, affects liver enzymes has not been clinically demonstrated. Thus, we compared time courses of gamma‐glutamyltransferase (GGT) and alanine aminotransferase (ALT) with those of fasting plasma glucose (FPG) and body weight (BW) during treatment with the SGLT2 inhibitor tofogliflozin for T2D. Materials and Methods We post‐hoc analysed preexisting data on 1046 people with T2D administered tofogliflozin or placebo for 24 weeks in four tofogliflozin studies. First, time courses of percent changes in variables during the intervention were analysed using a mixed effect model to explore the similarity of the time courses and to evaluate time‐treatment interactions. Second, clinical factors related to the percent changes in GGT and ALT were clarified using multivariate analyses. Results GGT levels and FPG values rapidly and significantly decreased via tofogliflozin as early as week 4, with decreases maintained until week 24. Conversely, BW and ALT decreased progressively until week 24. Time courses of FPG (p = .365, time‐treatment interaction) and GGT (p = .510) reductions were parallel between tofogliflozin and placebo from weeks 4 to 24, while BW and ALT reductions (p < .001, respectively) were not. Reductions in GGT at week 24 were associated with reductions in FPG and BW at week 24, whereas ALT reductions were only associated with reductions in BW. Conclusions Reductions in GGT and ALT were associated with the anti‐hyperglycaemic and anti‐obesity effects of tofogliflozin, respectively, in people with T2D. Therefore, GGT and ALT may be surrogate markers for hyperglycaemia and obesity in T2D. Reductions in GGT and ALT were associated with the anti‐hyperglycaemic and anti‐obesity effects of tofogliflozin, respectively, in people with T2D. Therefore, GGT and ALT may be surrogate markers for hyperglycaemia and obesity in T2D.

Summary Aims We aimed to quantify and characterise in detail the nature of the dose–response relationship between baseline gamma glutamyltransferase (GGT) level and risk of incident metabolic syndrome (MetS) in the general population and determine the precise estimate of the magnitude of the association. Methods We performed a systematic review and dose–response meta‐analysis of published prospective cohort studies. Relevant studies were identified in a literature search of MEDLINE, EMBASE and Web of Science up to May 2014. A potential nonlinear relationship between GGT levels and MetS was examined using restricted cubic splines. Study‐specific estimates were combined using random‐effects models. Results Of the 323 studies reviewed, we included 10 prospective cohort studies with data on 67,905 participants comprising of 6595 incident MetS cases. In pooled analysis of seven studies with relevant data, baseline GGT level was statistically significantly positively associated with risk of MetS in a nonlinear fashion (p for nonlinearity = 0.003). Comparing individuals in the top vs. bottom thirds of baseline GGT levels, relative risk for MetS in pooled analysis of all 10 eligible studies was 1.88 (95% confidence interval: 1.49–2.38). Evidence was lacking of publication bias among the contributing studies. Conclusion Baseline GGT level is positively and strongly associated with risk of the MetS in a nonlinear dose–response manner.

Backgroundγ-Glutamyltransferase (GGT) is a marker of oxidative stress. Elevated serum GGT is linked to poor survival in various malignancies; however, there are no data on metastatic renal cell carcinoma (mRCC). Additionally, GGT expression in cancer tissues remains largely unknown.ObjectiveThe present study was designed to determine the prognostic role of serum GGT in patients with mRCC and the association between systemic and local GGT levels.Patients and MethodsPretherapeutic serum GGT and other clinicopathological parameters were retrospectively compared with overall survival (OS) in 146 consecutive patients with mRCC receiving tyrosine kinase inhibitor therapy. GGT expression was analyzed in 65 resected specimens using immunohistochemistry.ResultsA total of 82 patients (56%) died during the follow-up period (median 34.9 months). Median OS was 16.0 months and 36.8 months in patients with elevated GGT levels and without elevated GGT, respectively (P < 0.001). On multivariable analysis, elevated serum GGT was an independent adverse prognostic factor (hazard ratio [HR] 4.04, P < 0.001), together with high neutrophils (HR 2.06, P = 0.041), low albumin (HR 2.00, P = 0.006), high lactate dehydrogenase (HR 2.68, P < 0.001), and high De Ritis ratio (HR 1.97, P = 0.004). Preoperative serum GGT levels were 29, 48, and 109 U/l in patients whose renal cancer cells showed negative to weak, moderate, and strong GGT expression, respectively (P = 0.004).ConclusionsElevated serum GGT was an unfavorable prognostic factor in mRCC, and overexpression of GGT in renal cancer cells might be responsible for elevation of serum GGT.

Hemolytic anemia (HA) is a serious health condition resulting from reduced erythrocytes' average life span. Echinochrome (Ech) is a dark-red pigment found in shells and spines of sea urchins. Studying the potential therapeutic effect of Ech on phenylhydrazine (PHZ)-induced HA in rats. Eighteen rats were divided into three groups ( = 6): the control group, the phenylhydrazine-induced HA group and the Ech group, injected intraperitoneally with PHZ and supplemented with oral Ech daily for 6 days. Ech resulted in a considerable increase in RBCs, WBCs, and platelets counts, hemoglobin, reduced glutathione, catalase, and glutathione-S-transferase levels, and a significant decrease in aspartate & alanine aminotransferases, alkaline phosphatase, gamma-glutamyl transferase, bilirubin, creatinine, urea, urate, malondialdehyde & nitric oxide levels in anemic rats. Histopathological examination of liver and kidney tissue samples showed marked improvement. Ech ameliorated phenylhydrazine-induced HA with a hepatorenal protective effect owing to its anti-inflammatory and antioxidant properties.

Helicobacter pylori causes cellular vacuolation in host cells, a cytotoxic event attributed to vacuolating cytotoxin (VacA) and the presence of permeant weak bases such as ammonia. We report here the role of γ-glutamyl transpeptidase (GGT), a constitutively expressed secretory enzyme of H. pylori, in potentiating VacA-dependent vacuolation formation in H. pylori-infected AGS and primary gastric cells. The enhancement is brought about by GGT hydrolysing glutamine present in the extracellular medium, thereby releasing ammonia which accentuates the VacA-induced vacuolation. The events of vacuolation in H. pylori wild type (WT)- and Δggt-infected AGS cells were first captured and visualized by real-time phase-contrast microscopy where WT was observed to induce more vacuoles than Δggt. By using semi-quantitative neutral red uptake assay, we next showed that Δggt induced significantly less vacuolation in AGS and primary gastric epithelial cells as compared to the parental strain (P<0.05) indicating that GGT potentiates the vacuolating effect of VacA. Notably, vacuolation induced by WT was significantly reduced in the absence of GGT substrate, glutamine (P<0.05) or in the presence of a competitive GGT inhibitor, serine-borate complex. Furthermore, the vacuolating ability of Δggt was markedly restored when co-incubated with purified recombinant GGT (rGGT), although rGGT itself did not induce vacuolation independently. Similarly, the addition of exogenous ammonium chloride as a source of ammonia also rescued the ability of Δggt to induce vacuolation. Additionally, we also show that monoclonal antibodies against GGT effectively inhibited GGT activity and successfully suppressed H. pylori-induced vacuolation. Collectively, our results clearly demonstrate that generation of ammonia by GGT through glutamine hydrolysis is responsible for enhancing VacA-dependent vacuolation. Our findings provide a new perspective on GGT as an important virulence factor and a promising target in the management of H. pylori-associated gastric diseases.

Background Several studies have reported the presence of H. pylori in individuals with hepatobiliary diseases, but in vitro and in vivo studies are still needed. Here, we determined the effects of H. pylori γ-glutamyltranspeptidase (GGT) on the induction of apoptosis and IL-8 production in a human cholangiocarcinoma cell line (KKU-100 cells). Methods Cell viability and DNA synthesis were examined by MTT and BrdU assays, respectively. RT-PCR and western blot analysis were performed to assess gene and protein expression, respectively. IL-8 secretion in KKU-100 cells was measured by ELISA. Results Exposure to the H. pylori ggt + strain decreased KKU-100 cell survival and DNA synthesis when compared with cells exposed to the H. pylori ggt mutant strain. Treatment with recombinant H. pylori GGT (rHP-GGT) dramatically decreased cell survival and DNA synthesis, and stimulated apoptosis; these features corresponded to an increased level of iNOS gene expression in KKU-100 cells treated with rHP-GGT. RT-PCR and western blot analyses revealed that rHP-GGT treatment enhanced the expression of pro-apoptotic molecules (Bax, Caspase-9, and Caspase-3) and down-regulated the expression of anti-apoptotic molecules (Bcl-2 and Bcl-xL). The extrinsic-mediated apoptosis molecules, including Fas and activated Caspase-8, were not expressed after treatment with rHP-GGT. Furthermore, rHP-GGT significantly stimulated IL-8 secretion in KKU-100 cells. Conclusion Our data indicate that H. pylori GGT might be involved in the development of cancer in hepatobiliary cells by altering cell kinetics and promoting inflammation.

Mammalian γ-glutamyltranspeptidase (GGT) has been identified as a bone-resorbing factor. Since GGT of Bacillus subtilis exhibits similarity in their primary structure and enzymatic characteristics with mammalian GGTs, the bone-resorbing activity of bacterial GGT was examined in this study. Osteoclastogenesis was performed in a co-culture system of mouse calvaria-derived osteoblasts and bone marrow cells. A conditioned medium from GGT-overproducing B. subtilis culture showed significantly higher activity of osteoclast formation than a conditioned medium from wild-type B. subtilis culture. Recombinant GGT (rGGT) of wild-type B. subtilis and an enzymatic activity-defected rGGT of B. subtilis 2288 mutant were expressed in Escherichia coli and purified using His tag. Both purified rGGTs induced similar levels of osteoclastogenesis, suggesting that B. subtilis GGT possesses virulent bone-resorbing activity and its activity is probably independent of its enzymatic activity. Furthermore, a recombinant protein of B. subtilis GGT heavy subunit (Bs rGGT/H) showed strong activity of osteoclastogenesis while the light subunit failed to show strong activity, suggesting that the bone-resorbing activity is mainly located at the heavy subunit. More importantly, the GGT enzymatic activity may not be required for this virulence activity since the light subunit contains the catalytic pocket. In addition, B. subtilis rGGT stimulated mRNA expressions of receptor activator of nuclear factor kappa-B ligand (RANKL) and cyclooxygenase-2 (COX-2), while an osteoprotegerin inhibited the osteoclast formation induced by Bs rGGT/H. This is the first demonstration that bacterial GGT itself is sufficient to act as a bone-resorbing virulence factor via RANKL-dependent pathway. Therefore, it can be hypothesized that GGT of periodontopathic bacteria may play an important role as a virulence factor in bone destruction.

In our previous study, we showed that Helicobacter pylori γ-glutamyltranspeptidase (GGT) is associated with H. pylori-induced apoptosis through a mitochondrial pathway. To better understand the role of GGT in apoptosis, we examined the effect of GGT on cell cycle regulation in AGS cells. To determine the effect of recombinant GGT (rGGT) on cell cycle distribution and apoptosis, rGGT-treated and untreated AGS cells were analyzed in parallel by flow cytometry using propidium iodide (PI). We found that rGGT inhibited the growth of AGS cells in a time-dependent manner, and that the pre-exposure of cells to a caspase-3 inhibitor (z-DEVD-fmk) effectively blocked GGT-induced apoptosis. Cell cycle analysis showed G1 phase arrest and apoptosis in AGS cells following rGGT treatment. The rGGT-mediated G1 phase arrest was found to be associated with down-regulation of cyclin E, cyclin A, Cdk 4, and Cdk 6, and the up-regulation of the cyclindependent kinase (Cdk) inhibitors p27 and p21. Our results suggest that H. pylori GGT induces cell cycle arrest at the G1-S phase transition.

The gamma-glutamyltranspeptidase (GGT) of Helicobacter pylori (HpGT) is a newly found virulence factor. In an approach to gain insight into the gene function, the four domains of the HpGT were cloned and expressed in baculovirus expression system. The results of a functional assay showed that the HpGT products acted as GGT, even when the N-terminal 380 amino acids were deleted. However, only the full length open reading frame (ORF) of the HpGT gene was apparently effective on cell growth. This result indicated that the products of the full length ORF might have an important role in gastric carcinogenesis. In this paper, we are the first to report that changes of mitochondrial membrane potential can be detected using 5, 5', 6, 6'-tetrachloro-1, 1', 3, 3'-tetraethylbenzimidazole carbocyanine iodide (JC-1) staining in insect cells.

To determine whether gamma-glutamyl transpeptidase (gamma-GT) is involved in the maintenance of elevated cysteine levels in cervical carcinoma. Four cervical carcinoma cell lines were tested in vitro for cysteine accumulation and gamma-GT levels. The highest and lowest gamma-GT-expressing cell lines were used in in vivo experiments to determine the effect of gamma-GT inhibition on cysteine levels. Treatment of a series of cervical carcinoma cell lines with acivicin decreased intracellular cysteine concentrations. Cysteine depletion was evident in Me180 cells which had the greatest levels of gamma-GT activity, and had a more pronounced cysteine decrease in medium with glutathione and cysteine concentrations simulating the in vivo situation. Also investigated were the effects of inhibition of gamma-GT activity on intracellular cysteine levels in xenografts grown in severe combined immunodeficient (SCID) mice. With the use of 35 mg/kg of acivicin, gamma-GT activity decreased to basal levels of detection in both tumour types and significant decreases in cysteine levels were seen in the high gamma-GT-expressing tumours (Me180). Thus, inhibition of gamma-GT activity may have therapeutic potential in high-expressing cancers. In tumours and cell lines with elevated levels of gamma-GT activity, inhibition of this enzyme led to decreases of cysteine levels.