Evaluation of dichloroacetate treatment in a murine model of hereditary tyrosinemia type 1

Hereditary tyrosinemia type 1 (HT1) is an autosomal recessive disease severely affecting liver and kidney and is caused by a deficiency in fumarylacetoacetate hydrolase (FAH). Administration of 2-(2-nitro-4-trifluoro-methylbenzyol)-1,3 cyclohexanedione (NTBC) improves the HT1 phenotype but some patients do not respond to NTBC therapy. The objective of the present study was to evaluate whether administration of dichloroacetate, an inhibitor of maleyl acetoacetate isomerase (MAAI) to FAH-knockout mice could prevent acute pathological injury caused by NTBC withdrawal. DCA (0.5 and 5g/L) was given in combination with a standard diet or with a tyrosine-restricted diet. With the low-tyrosine diet body weight loss and most of hepatic and renal injuries were prevented regardless the DCA dose. The administration of DCA with a standard diet did not prevent damage nor the oxidative stress response nor the AFP induction seen in FAH-knockout mice. DCA was shown to inhibit hepatic MAAI activity to 86% (0.5g/L) and 94% (5g/L) of untreated wild-type mice. Interestingly, FAH(-/-) mice deprived of NTBC (NTBC-OFF) and NTBC-treated FAH-knockout mice had similar low hepatic MAAI activity levels, corresponding to 10-20% of control. Thus the failure of DCA treatment in FAH(-/-) mice seems to be attributed to the residual MAAI activity, high enough to lead to FAA accumulation and HT1 phenotype.     

Histochemical absence of gamma-glutamyl transpeptidase in chick brain capillary endothelium

It has been proposed that γ-glutamyl transpeptidase (GGTP) is involved in amino acid transport across the blood-brain barrier. A controversy exists, however, about whether or not sufficient GGTP activity is present in chick brain capillaries to be demonstrated histochemically. Under conditions in which GGTP was readily demonstrated in chick kidney, hamster kidney, and hamster brain capillaries, no GGTP activity was present in chick brain capillaries. Therefore, it is unlikely that GGTP activity is present in sufficient quantity in chick brain capillaries to account for all amino acid transport across the blood-brain barrier.     

Gamma-Glutamyl Transpeptidase to Platelet Ratio Is a Novel and Independent Prognostic Marker for Resectable Lung Cancer: A Propensity Score Matching Study

Background: We report this propensity score matching (PSM) analysis to assess prognostic roles of preoperative gamma-glutamyl transpeptidase to platelet ratio (GPR) in video-assisted thoracoscopic (VATS) lobectomy for stage I-II non-small-cell lung cancer (NSCLC).Methods: The PSM-based study conducted on our single-center prospectively collected database from January 2014 to August 2015 provided Kaplan–Meier survival analyses using the log-rank test to discriminate differences in overall survival (OS) and disease-free survival (DFS) between patients stratified by preoperative GPR.Results: Our study includes 379 patients diagnosed with operable primary stage I-II NSCLC. A GPR value at 0.16 was recognized as the optimal cutoff point for prognostic prediction. Both OS and DFS of patients with GPR ≥0.16 were significantly shortened when compared to those of patients with GPR <0.16. Patients with GPR ≥0.16 had significantly lower 5-year rates of OS and DFS than those of patients with GPR <0.16 (P <0.001). Significant associations between GPR and unfavorable survival still are validated in the PSM analysis. Multivariable Cox regression models on both the entire cohort and the PSM cohort consistently demonstrated that an elevated preoperative GPR could be an independent prognostic marker for both OS and DFS of resectable NSCLC.Conclusions: GPR may be an effective and noninvasive prognostic biomarker in VATS lobectomy for surgically resectable NSCLC.     

Influence of chrysin on hepatic marker enzymes and lipid profile against d-galactosamine-induced hepatotoxicity rats

Chrysin is a flavonoid that exists in nature and is the major component of some traditional medicinal herbs. We investigated the hepatoprotective and antihyperlipidaemic potential of chrysin against d-galactosamine (a single intraperitoneal injection 400 mg/kg BW) induced hepatotoxicity in male albino Wistar rats. d-GalN rats exhibited an increased hepato and nephro toxicity marker activities aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase and gamma glutamyl transpeptidase and total bilirubin level while urea, uric acid and creatinine and lipid profile. It also negatively affected the serum total protein, albumin and A/G ratio. Rats treated with chrysin at different concentrations (25, 50 and 100 mg/kg BW) caused a significant improvement in serum protein level, decreased hepato and nephro toxicity markers. It also decreased the levels of very low density lipoprotein cholesterol and low density lipoprotein cholesterol while high density lipoprotein cholesterol significantly increased. It also decreased the levels of total cholesterol, phospholipids, triglycerides, free fatty acids in the plasma and tissues of liver and kidney. The effect of chrysin (25 mg/kg) is comparable with silymarin, a known hepatoprotective drug. Chrysin thus exhibits hepatoprotective and antihyperlipidaemic activity.     

225名处级干部部分生化体检指标检测结果分析

目的 探讨邯郸矿业集团225名矿处级体检干部中,脂肪肝组与非脂肪肝组血液部分生化检测指标间的关系,提醒其关注自身健康.方法 对邯郸矿业集团总医院2010年7～11月体检中心接诊的225名矿处级干部的三酰甘油(TG)、空腹血糖(FPG)、γ-谷氨酰转移酶(γ-GGT)、血尿酸(UA)检测指标进行回顾性调查分析,并按其是否患有脂肪肝将结果分为两组,并进行统计学分析研究.结果 脂肪肝组与非脂肪肝组的TG、FPG、γ-GGT、UA异常检出率分别是59.84%、41.73%、74.02%、15.75%和24.49%、18.37%、18.37%、1.02%,脂肪肝组各项指标异常检出率均明显高于非脂肪肝组,两者差异有统计学意义(P<0.01).并且两组TG、FPG、γ-GGT、UA的平均浓度,脂肪肝组明显高于非脂肪肝组,两者差异具有统计学意义(P<0.01).结论 高血脂、高血糖是诱发脂肪肝的重要因素,脂肪肝患者是发生肝病、痛风和心脑血管病的高发人群,领导干部健康问题不容忽视,应加强锻炼,合理膳食,积极治疗,提高身体健康水平.     

A review of toxicity studies on graphene-based nanomaterials in laboratory animals

We summarized the findings of toxicity studies on graphene-based nanomaterials (GNMs) in laboratory mammals. The inhalation of graphene (GP) and graphene oxide (GO) induced only minimal pulmonary toxicity. Bolus airway exposure to GP and GO caused acute and subacute pulmonary inflammation. Large-sized GO (L-GO) was more toxic than small-sized GO (S-GO). Intratracheally administered GP passed through the air-blood barrier into the blood and intravenous GO distributed mainly in the lungs, liver, and spleen. S-GO and L-GO mainly accumulated in the liver and lungs, respectively. Limited information showed the potential behavioral, reproductive, and developmental toxicity and genotoxicity of GNMs. There are indications that oxidative stress and inflammation may be involved in the toxicity of GNMs. The surface reactivity, size, and dispersion status of GNMs play an important role in the induction of toxicity and biodistribution of GNMs. Although this review paper provides initial information on the potential toxicity of GNMs, data are still very limited, especially when taking into account the many different types of GNMs and their potential modifications. To fill the data gap, further studies should be performed using laboratory mammals exposed using the route and dose anticipated for human exposure scenarios.     

Factors related to the spontaneous passage of common bile duct stones through the papilla: a single-center retrospective cohort study

ObjectiveCommon bile duct (CBD) stones can spontaneously pass through the papilla. This study explored factors associated with stone passage by comparing differences in the clinical features of stones retained in the CBD and excreted stones.MethodsData were retrospectively collected for all patients who were hospitalized in our center between March 2016 and May 2021 with clinical, laboratory, or imaging evidence of CBD stones. All patients underwent endoscopic retrograde cholangiopancreatography (ERCP) and were classified into two groups: group A (stones extracted by ERCP, n = 86) and group B (stones discharged before ERCP, n = 15). Demographic data, biochemical and radiological findings were compared between the groups.ResultsStone size (0.82 vs. 0.33 cm), and levels of total bilirubin (58.2 vs. 28.8 μmol/L), gamma-glutamyl transpeptidase (416.7 vs. 193.9 U/L), alkaline phosphatase (191.9 vs. 123.1 U/L), carbohydrate antigen 19-9 (603.7 vs. 37.2 U/mL), and α-L-fucosidase (37.4 vs. 22.6 U/L) were significantly higher in group A than in group B. Logistic regression analyses showed that stone size was the only factor significantly associated with spontaneous passage of CBD stones.ConclusionsCBD stones less than 0.33 cm in size may be self-expelled through the papilla.     

γ-Glutamyl transpeptidase-dependent mutagenicity and cytotoxicity of γ-glutamyl derivatives: A model for biochemical targeting of chemotherapeutic agents

Many carcinomas in humans are rich in γ-glutamyl transpeptidase (GGT), a plasma membrane enzyme that reacts with extracellular substrates. Thus, biochemical targeting of chemotherapeutic agents may be achieved by converting anticancer drugs into their γ-glutamyl derivatives. Chemical conversion of phenylhydrazine (PH) and biochemical modification of daunomycin (DM) into their γ-glutamyl derivatives γ-glutamyl phenylhydrazine (GGPH) and γ-glutamyl DM (GGDM) resulted in the abolishment of their mutagenicity and cytotoxicity, as judged by decreased viability and increased mutant yields in cultures of several Salmonella Ames strains. Commercial γ-glutamyl-p-nitroanilide (GGPNA) was not toxic or mutagenic. Mutagenicity and/or cytotoxicity of these γ-glutamyl derivatives were restored upon reaction with GGT, with concomitant release of PH, and p-nitroaniline (PNA). The GGT-dependent release of DM from GGDM was demonstrated by thin layer chromatography (TLC), spectral analysis, and specific mutagenicity. Mutagenicity and/or cytotoxicity of γ-glutamyl derivatives increased in the presence of glycylglycine, a GGT activator, and decreased in the presence of serine-borate, a GGT inhibitor. GGDM retained considerable DNA binding capacity. Its inability to kill and mutagenize was due to altered transport properties. The results are compatible with the notion that γ-glutamylation is a feasible method for biochemical targeting of drugs containing a primary amino group to GGT-rich tumors. Environ. Mol. Mutagen. 32:377–386, 1998 © 1998 Wiley-Liss, Inc.     

Promotion of glutathione-γ-glutamyl transpeptidase-dependent lipid peroxidation by copper and ceruloplasmin: The requirement for iron and the effects of antioxidants and antioxidant enzymes

Oxidative damage (lipid peroxidation, LPO) induced in a completely defined system containing glutathione (GSH), purified γ-glutamyl transpeptidase (GGT), and EDTA- and ADP-chelated ferric iron was enhanced by catalytic amounts of cupric ions and by ceruloplasmin (CP). The enhancement depended on GSH concentration, GGT activity, the presence of iron, and the chelation of copper by ophenanthroline. High concentrations of CP inhibited LPO. Cu- and CP-enhanced, GSH-GGT-driven LPO was inhibited by the chain-breaking radical scavengers butylated hydroxyanisol, α-tocopherol, and Trolox C (a synthetic analog of α-tocopherol) but not by the hydroxyl scavenger mannitol. Ascorbic acid increased LPO in the presence of Cu or CP. Cu-enhanced LPO was partially sensitive to superoxide dismutase but not to catalase or horseradish peroxidase. The results indicate that Cu and CP enhance thiol-driven LPO and promote thiol-dependent mutagenesis by a very similar, if not the same, mechanism and are in agreement with the idea that this enhancement is due to redox reactions of chelated Cu and Fe, rather than to the reactivity of Cu in the Fenton reaction. Environ. Mol. Mutagen. 29:73–80, 1997 © 1997 Wiley-Liss, Inc.