Gamma-glutamyl transferase 5 overexpression in cerebrovascular endothelial cells improves brain pathology,cognition,and behavior in APP/PS1 mice

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.

Transformation of marginal zone lymphoma into high-grade B-cell lymphoma expressing terminal deoxynucleotidyl transferase:A case report

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.

Case Report: Carnitine Palmitoyl Transferase II (CPT II) Deficiency

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.

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.

Evaluation of trabecular meshwork-specific promoters in vitro and in vivo using scAAV2 vectors expressing C3 transferase

AIM:To evaluate the potential of two trabecular meshwork(TM)-specific promoters,Chitinase 3-like 1(Ch3L1)and matrix gla protein(MGP),for improving specificity and safety in glaucoma gene therapy based on self-complementary AAV2(scAAV2)vector technologies.METHODS:An scAAV2 vector with C3 transferase(C3)as the reporter gene(scAAV2-C3)was selected.The scAAV2-C3 vectors were driven by Ch3L1(scAAV2-Ch3L1-C3),MGP(scAAV2-MGP-C3),enhanced MGP(scAAV2-eMGP-C3)and cytomegalovirus(scAAV2-CMV-C3),respectively.The cultured primary human TM cells were treated with each vector at different multiplicities of infections.Changes in cell morphology were observed by phase contrast microscopy.Actin stress fibers and Rho GTPases/Rho-associated protein kinase pathway-related molecules were assessed by immunofluorescence staining,real-time quantitative polymerase chain reaction and Western blot.Each vector was injected intracamerally into the one eye of each rat at low and high doses respectively.In vivo green fluorescence was visualized by a Micron III Retinal Imaging Microscope.Intraocular pressure(IOP)was monitored using a rebound tonometer.Ocular responses were evaluated by slit-lamp microscopy.Ocular histopathology analysis was examined by hematoxylin and eosin staining.RESULTS:In TM cell culture studies,the vectormediated C3 expression induced morphologic changes,disruption of actin cytoskeleton and reduction of fibronectin expression in TM cells by inhibiting the Rho GTPases/Rhoassociated protein kinase signaling pathway.At the same dose,these changes were significant in TM cells treated with scAAV2-CMV-C3 or scAAV2-Ch3L1-C3,but not in cells treated with scAAV2-eMGP-C3 or scAAV2-MGP-C3.At lowinjected dose,the IOP was significantly decreased in the scAAV2-Ch3L1-C3-injected eyes but not in scAAV2-MGPC3-injected and scAAV2-eMGP-C3-injected eyes.At highinjected dose,significant IOP reduction was observed in the scAAV2-eMGP-C3-injected eyes but not in scAAV2-MGP-C3-injected eyes.Similar to scAAV2-CMV-C3,scAAV2-Ch3L1-C3 vector showed efficient transduction both in the TM and corneal endothelium.In anterior segment tissues of scAAV2-eMGP-C3-injected eyes,no obvious morphological changes were found except for the TM.Inflammation was absent.CONCLUSION:In scAAV2-transduced TM cells,the promoter-driven efficiency of Ch3L1 is close to that of cytomegalovirus,but obviously higher than that of MGP.In the anterior chamber of rat eye,the transgene expression pattern of scAAV2 vector is presumably affected by MGP promoter,but not by Ch3L1 promoter.These findings would provide a useful reference for improvement of specificity and safety in glaucoma gene therapy using scAAV2 vector.

Expression and alterations of different molecular form γ-glutamyl transferase and total RNA concentration during the carcinogenesis of rat hepatoma

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Serum Gamma-glutamyl Transferase Levels Predict Functional Outcomes after Aneurysmal Subarachnoid Hemorrhage

Objective We aim to explore the potential association between serum gamma-glutamyl transferase levels and functional outcome after aneurysmal subarachnoid hemorrhage in a Chinese population. Methods A total of 386 aneurysmal subarachnoid hemorrhage patients were included in the study from September 2007 to February 2015. Baseline serum gamma-glutamyl transferase levels and 6-month follow-up functional outcomes were determined. A poor outcome was defined as a modified ranking scale score of ≥ 3. The multivariable logistic model was used to analyze the relationship between serum gamma-glutamyl transferase and clinical outcomes after aneurysmal subarachnoid hemorrhage. Results The adjusted poor outcome rates of patients with gamma-glutamyl transferase levels of 〈 30 U/L, 30-50 U/L and ≥ 50 U/L were 16.7%, 19.6%, and 34.4%, respectively （P 〈 0.01）. The age-sex and multivariable adjusted odds ratios （95% confidence intervals） of poor prognosis comparing the top group （≥ 50 U/L） with the lowest group （〈 30 U/L） were 5.76 （2.74-12.13）, 6.64 （2.05-21.52）, and 6.36 （1.92-21.02）. A significant linear trend existed between gamma-glutamyl transferase level and aneurysmal subarachnoid hemorrhage prognosis. This association was also observed among nondrinkers. Conclusion Patients with higher gamma-glutamyl transferase levels were more likely to have a poor prognosis. Serum gamma-glutamyl transferase can be considered to be an independent predictor of functional outcomes after aneurysmal subarachnoid hemorrhage.

Association of serum gamma-glutamyl transferase with treatment outcome in chronic hepatitis B patients

AIM:To investigate the association of serum gammaglutamyl transferase(GGT) levels with chronic hepatitis B infection and hepatitis B e antigen(HBe Ag) seroconversion.METHODS:A retrospective study was performed on clinical data collected from patients who had been positive for hepatitis B surface antigen for > 6 mo and who were antiviral-treatment na?ve(n = 215) attending the Hepatitis Clinic at Nanjing Drum Tower Hospital between August 2010 and December 2013. Healthy individuals without liver disease(n = 83) were included as controls. Patients were categorized into four groups based on disease status as recommended by the European Association for the Study of the Liver:immune tolerance(IT; n = 47),HBe Ag-positive hepatitis(EPH; n = 93),HBe Ag-negative hepatitis(ENH;n = 20),and inactive carrier(IC; n = 55). Prediction of complete response(CR) based on serum GGT was also examined in EPH patients(n = 33) treated for 48 wk with nucleos(t)ide analogue(NA) therapy,including lamivudine plus adefovir combination therapy(n = 20) or entecavir monotherapy(n = 13). CR was defined as a serum hepatitis B virus DNA level < 500 copies/m L and HBe Ag seroconversion by 48 wk of treatment. RESULTS:Serum GGT levels were significantly increased in EPH and ENH patients relative to the IT,IC,and healthy control groups(P < 0.01 for all). However,no significant difference in serum GGT levels was found between the EPH and ENH groups. Baseline serum GGT levels were significantly higher in patients who achieved CR(7/33; 21.2%) compared to patients in the non-CR group(26/33; 78.8%; P = 0.011). In addition,the decline in serum GGT was greater in CR patients compared to non-CR patients after 24 wk and 48 wk of treatment(P = 0.012 and P = 0.008,respectively). The receiver operating characteristic curve yielded a sensitivity of 85.71% and a specificity of 61.54% at a threshold value of 0.89 times the upper limit of normal for baseline serum GGT in the prediction of CR following NA therapy. CONCLUSION:Serum GGT is significantly elevated in EPH and ENH patients and is a potential biomarker for the prediction of HBe Ag seroconversion following NA therapy.

Gamma-glutamyl transferase and cardiovascular risk in nonalcoholic fatty liver disease:The Gut and Obesity Asia initiative

BACKGROUND Gamma-glutamyl transferase(GGT)is associated with the risk of cardiovascular disease(CVD)in the general population.AIM To identify the association of baseline GGT level and QRISK2 score among patients with biopsy-proven nonalcoholic fatty liver disease(NAFLD).METHODS This was a retrospective study involving 1535 biopsy-proven NAFLD patients from 10 Asian centers in 8 countries using data collected by the Gut and Obesity in Asia(referred to as“GO ASIA”)workgroup.All patients with available baseline GGT levels and all 16 variables for the QRISK2 calculation(QRISK2-2017;developed by researchers at the United Kingdom National Health Service;https://qrisk.org/2017/;10-year cardiovascular risk estimation)were included and compared to healthy controls with the same age,sex,and ethnicity.Relative risk was reported.QRISK2 score>10%was defined as the high-CVD-risk group.Fibrosis stages 3 and 4(F3 and F4)were considered advanced fibrosis.RESULTS A total of 1122 patients(73%)had complete data and were included in the final analysis;314(28%)had advanced fibrosis.The median age(interquartile range[IQR])of the study population was 53(44-60)years,532(47.4%)were females,and 492(43.9%)were of Chinese ethnicity.The median 10-year CVD risk(IQR)was 5.9%(2.6-10.9),and the median relative risk of CVD over 10 years(IQR)was 1.65(1.13-2.2)compared to healthy individuals with the same age,sex,and ethnicity.The high-CVD-risk group was significantly older than the low-risk group(median[IQR]:63[59-67]vs 49[41-55]years;P<0.001).Higher fibrosis stages in biopsy-proven NAFLD patients brought a significantly higher CVD risk(P<0.001).Median GGT level was not different between the two groups(GGT[U/L]:Median[IQR],high risk 60[37-113]vs low risk 66[38-103],P=0.56).There was no correlation between baseline GGT level and 10-year CVD risk based on the QRISK2 score(r=0.02).CONCLUSION The CVD risk of NAFLD patients is higher than that of healthy individuals.Baseline GGT level cannot predict CVD risk in NAFLD patients.However,advanced fibrosis is a predictor of a high CVD risk.

The Micro-determination of Serum Gamma-Glutamyl Transferase

The method of serum gamma-glutamyl transferase colorimeter assay was modified by changing the wave length from 420 nm to 400 nm, the incubated temperature from 37℃ to 50℃, the sample amount from 30 μl to 6μl. The modified method was proved to be more sensitive, with CV of intra-group being 2. 06% and accuracy 97. 4%. The method is suitable for clinical application with small-amount blood samples collected frorri earlobe or finger tip.

Effect of <i>Lactobacillus brevis</i>SBC8803 on Gamma-Glutamyl Transferase in Japanese Habitual Drinkers: A Double-Blind, Placebo-Controlled Study

A randomized, double-blind, placebo-controlled clinical trial in Japanese habitual drinkers was conducted to evaluate the efficacy of Lactobacillus brevis SBC8803 to alleviate adverse effect of alcohol. Subjects who drank habitually and had moderately higher levels of gamma-glutamyl transferase (GGT) (50 - 100 IU/L) were enrolled. The levels of transaminases in these subjects were almost within normal levels (aspartate transaminase (AST) <30 IU/L and alanine transaminase (ALT) <40 IU/L). Either the capsules containing placebo (n = 23) or 130 mg (4.0 × 1010 colony-forming units) of live L. brevis SBC8803 (n = 22) per day were administered for the continuous eight weeks (56 days). During the period, the subjects both in test group and placebo groups have kept each drinking behavior as usual. Regarding lipid metabolism, triacylglycerol (TG) levels in the male test group significantly decreased at week 4 as compared with week 0. Biomarkers of hepatocytes-damage;AST and ALT levels showed no significant differences between the pla- cebo and test groups at both weeks 4 and 8. Oxidative stress marker;GGT at weeks 4 was significantly lower in the test group than that in the placebo group (p = 0.017), but not at weeks 8. However, taking a reduced rate of GGT at weeks 8 comparing with that at week 0, that in the test group showed larger value comparing with that in the placebo group. These data about TG and GGT suggest that, although efficacy of L. brevis SBC8803 is limited in this study, intake of the probiotic may alleviate alcoholic influence in lipid metabolism and oxidative stress.

Expression of Presenilin-2 and Glutathione S Transferase π and Their Clinical Significance in Breast Infiltrating Ductal Carcinoma

To investigate the expressions of presenilin-2 (PS2) and glutathione Stransferase π (GSTπ) and their roles in prognosis and therapy of breast infiltrating ductalcarcinoma. Methods: The paraffin-embedded specimens of 210 patients with breast infiltrating ductalcarcinoma were examined by using LSAB immunohistochemistry for the expression of PS2 and GSTπ.Results: The expression rate of PS2 and GSTπ was 49.5% (104/210) and 48.1% (101/210) respectively.The 5-year and 10-year postoperative survival rates in 4 groups, from high to low, were group 1 (PS2positive expression/GSTπ negative expression), group 2 (PS2 positive expression/GSTπ positiveexpression), group 3 (PS2 negative expression/GSTπ negative expression) and group 4 (PS2 negativeexpression/GSTπ positive expression) in turn. Conclusion: The prognosis of the group 1 was thebest, followed by the group 2, group 3 and group 4 in turn. These results suggested that thereasonable use of endocrinotherapy and chemotherapy for patients with breast infiltrating ductalcarcinoma is necessary.

Glutathione S-transferases M1,T1 genotypes and the risk of gastric cancer:A case-control study

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.

Purification and characterization of rat testicular glutathione S-transferases:role in the synthesis of eicosanoids

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)

STUDY OF THE DELETION MUTATION OF GLUTATHIONE S TRANSFERASE M1 GENE AND ITS ROLE IN SUSCEPTIBILITYTO HEPATOCELLULAR CARCINOMA

Objection: To investigate the glutathione S transferase M1 (GSTM1) gene inherent deletion and its relation to prevalence of hepatocellular carcinoma (HCC) in Guangxi, China. Methods: The GSTM1 gene polymorphism of 120 HCC patients and 100 healthy subjects both from the same high aflatoxin B1 (AFB1) contaminated area were detected using PCR technique with special primers. Another 40 patients from AFB1 low risk area were also tested. Results: In HCC high risk area, it was found that the frequencies of GSTM1 null genotype in HCC patients and healthy subjects were 59% and 51% respectively, with no significant difference. However, the frequency of GSTM1-null genotype in control group from AFB1 low risk area was lower than those from high risk area (P<0.01). Conclusion: Populations in this HCC endemic region show a higher rate of GSTM1-null genotype, which may be partially responsible for the susceptibility to AFB1 induced HCC. But the detoxification effect of GSTM1 alone is not sufficient to resist the genetic toxicity of AFB1, especially in those people who expose to excess AFB1. The GSTM1 gene deletion would not be suitable as an independent predictor of susceptibility to HCC.

Oxidative stress-elevated high gamma glutamyl transferase levels, and aging, intake of tropical food plants, migration and visual disability in Central Africans

·AIM:To investigate the independent pathogenic role of high serum gamma-glutamyl transferase (GGT) levels, sociodemographic data, dietary and environmental risk factors for visual disability (VD). ·METHODS:This was a case-control study, run in 200 black Congolese patients managed in Saint Joseph Hospital Ophthalmology Division from Kinshasa town. Logistic regression model was used to identify determinants of VD (n = 58) among sex, age, cigarette smoking, alcohol abuse, rural-urban migration, education levels, aging ≥60 years, intake of red Beans, Safou fruit and Taro leaves, lipid profile, residence, socioeconomic status, and GGT. ·RESULTS:After adjusting for confounding factors, we identified migration (OR=3.7 95% CI:1.2-11.3; P =0.023), low education level (OR=3.1 95% CI 1.1-8.5; P =0.026), no intake of Safou fruit (OR=34.2 95% CI 11.5-102; P < 0.0001), age ≥60 years (OR=2.5 95% CI 1.01-6.5; P = 0.049), and serum GGT ≥10U/L (OR=3.6 95% CI 1.3-9.6; P = 0.012) as the significant and independent determinants of VD. ·CONCLUSION:VD appears as a major public health problem in Central Africa to be prevented or delayed by control of migration, lifestyle changes, antioxidant supplements, appropriate diet, nutrition education, and blocking of oxidative stress.

Mitochondrial carnitine palmitoyl transferase-Ⅱ inactivity aggravates lipid accumulation in rat hepatocarcinogenesis

AIM To investigate the dynamic alteration of mitochondrial carnitine palmitoyl transferase Ⅱ(CPT-Ⅱ) expression during malignant transformation of rat hepatocytes.METHODS Sprague-Dawley male rats were fed with normal, high fat(HF), and HF containing 2-fluorenylacetamide(2-FAA) diet, respectively. According to the Hematoxylin and Eosin staining of livers, rats were divided into control, fatty liver, degeneration, pre-cancerous, and cancerous groups. Liver lipids were dyed with Oil Red O, CPT-Ⅱ alterations were analyzed by immunohistochemistry, and compared with CPT-Ⅱ specific concentration(μg/mg protein). Levels of total cholesterol(Tch), triglyceride(TG), and aminotransferases [alanine aminotransferase(ALT), aspartate aminotransferase(AST)] were determined by the routine methods.RESULTS After intake of HF and/or HF+2-FAA diets, the rat livers showed mass lipid accumulation. The lipid level in the control group was significantly lower than that in other groups. The changes of serum TG and Tch levels were abnormally increasing, 2-3 times more than those in the controls(P < 0.05). During the rat liver morphological changes from normal to cancer development process with hepatocyte injury, serum AST and ALT levels were significantly higher(4-8 times, P < 0.05) than those in the control group. The specific concentration of CPT-Ⅱ in liver tissues progressively decreased during hepatocyte malignant transformation, with the lowest CPT-Ⅱ levels in the cancer group than in any of the other groups(P < 0.05).CONCLUSION Low CPT-Ⅱ expression might lead to abnormal hepatic lipid accumulation, which should promote the malignant transformation of hepatocytes.

STUDY ON ANTITUMOR DRUG-INDUCED APOPTOSIS IN HUMAN CANCER CELLS BY TERMINAL DEOXYNU-CLEOTIDYL TRANSFERASE ASSAY

Objective: Considerable evidence has showed that apoptosis is involved in both cancer development and inhibition. A new assay (terminal deoxynucleotidyl tansferase, TdT) was recently reported to have advan tages in the detection of apoptosis. In this study, this assay was used to investigate antitumor drug induced apoptosis in human cancer cells. Methods: TdT assay, DNA gel electrophoresis, electron and light microscopy were used to observe apoptosis. Results: Our results showed that cisplatin induced apoptosis in both HL 60 and SV40T transformed human bronchial epithelial cells was detected with a good dosage and time response. The occurrence of the apoptosis was preceded by the decrease of bcl 2 mRNA expression. With the TdT assay, apoptotic cells were observed in ovarian tumor of patients treated with carboplatin. Conclusion: TdT assay may be applicable to monitor apoptosis in human cancers induced by chemotherapy, and to evaluate tumor cell response during treatment.

Theoretical Study on GSH Activation Mechanism of a New Type of Glutathione Transferase Gtt2

Glutathione transferases（GSTs） play an important role in the detoxification of xenobiotic/endobiotic toxic compounds. The α-, π-, and/l-classes of cytosolic GSTs have been studied extensively, while Gtt2 from Saccharo- myces cerevisiae, a novel atypical GST, is still poorly understood. In the present study, we investigated the gluta- thione（GSH） activation mechanism of Gtt2 using the density functional theory（DFT） with the hybrid functional B3LYP. The computational results show that a water molecule could assist a proton transfer between the GSH thiol and the N atom of His133. The energy barrier of proton transfer is 46.0 kJ/mol. The GSH activation mechanism and the characteristics of active site are different from those of classic cytosolic GSTs.