Adverse Effects of Monosodium Glutamate on Liver and Kidney Functions in Adult Rats and Potential Protective Effect of Vitamins C and E

Monosodium glutamate (MSG) was administrated to rats at doses of 0.6 and 1.6 mg/g body weight for 14 days. Body weight and relative liver and kidney weight of rats were significantly increased. On regard to liver functions, the activities of alanine aminotransferase (ALT) and γ glutamyle transferase (GGT) significantly increased in the serum, on MSG administration, meanwhile, serum total protein, albumin and serum total bilirubin significantly decreased. MSG had adverse effects on kidney functions as serum urea and serum creatinine were significantly increased. Vitamin C (0.3 mg/g body weight) and vitamin E (0.2 mg/g body weight) co-adminstrated with MSG, significantly restored the body weight and relative liver and kidney weights to control levels. In the presence of vitamin C and vitamin E the activities of ALT and GGT in the serum were also significantly reduced to become comparable with control trail. Consequently, serum total protein, albumin and serum total bilirubin were significantly increased in the serum, while serum urea and serum creatinine were significantly decreased after administration of each vitamin. The results showed that MSG at doses of 0.6 and 1.6 mg/g of body weight may cause an adverse effect on the hepatic and renal functions which might be due to oxidative stress induced by MSG on the liver and renal tissue. Supplementation of vitamin C and vitamin E was capable of ameliorating MSG-induced oxidative stress on hepatic and renal functions.

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

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How does conserved dopamine neurotrophic factor protect against and rescue neurodegeneration of PC12 cells？

Conserved dopamine neurotrophic factor protects and rescues dopaminergic neurodegeneration induced by 6-hydroxydopamine in vivo,but its potential value in treating Parkinson＇s disease remains controversial.Here,we used the proteasome inhibitors lactacystin and MG132 to induce neurodegeneration of PC12 cells.Afterwards,conserved dopamine neurotrophic factor was administrated as a therapeutic factor,both pretreatment and posttreatment.Our results showed that（1）conserved dopamine neurotrophic factor enhanced lactacystin/MG132-induced cell viability and morphology,and attenuated alpha-synuclein accumulation in differentiated PC12 cells.（2）Enzyme linked immunosorbent assay showed up-regulated 26S proteasomal activity in MG132-induced PC12 cells after pre-and posttreatment with conserved dopamine neurotrophic factor.Similarly,26S proteasome activity was upregulated in lactacystin-induced PC12 cells pretreated with conserved dopamine neurotrophic factor.（3）With regard proteolytic enzymes（specifically,glutamyl peptide hydrolase,chymotrypsin,and trypsin）,glutamyl peptide hydrolase activity was up-regulated in lactacystin/MG132-administered PC12 cells after pre-and posttreatment with conserved dopamine neurotrophic factor.However,upregulation of chymotrypsin activity was only observed in MG132-administered PC12 cells pretreated with conserved dopamine neurotrophic factor.There was no change in trypsin expression.We conclude that conserved dopamine neurotrophic factor develops its neurotrophic effects by modulating proteasomal activities,and thereby protects and rescues PC12 cells against neurodegeneration.

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.

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.

Endotoxins enhance hepatocarcinogenesis induced by oral intake of thioacetamide in rats

AIM To clarify whether endotoxin is of pathogenic importance for hepatocarcinogenesis, or the increased cancer risk results solely from the cirrhotic process. METHODS The rat model of hepatoma was treated by the intake of 0 03% thioacetamide in drinking water for six months. During induction of hepatoma, rats were additionally treated with splenectomy and/or lipopolysaccharide administration. The liver nuclear DNA index and proliferation index were quantitatively analyzed by flow cytometry. Hepatic histology was examined with light and electron microscopes. Plasmic endotoxin concentration and γ glutamyl transpeptidase activity were measured, and hepatoma incidence was recorded. RESULTS Thioacetamide induced cirrhosis and hepatoma in Wistar rats with histology or regenerative nodule, fibrosis and neoplastic foci were quite similar to the pathogenic process of human cirrhosis leading to hepatoma. In comparison with TAA controls (DNA index: 1 15±0 21), exo endotoxin increased the DNA index by 7 8% (1 24±0 25, P <0 02) and hepatoma rate by 16 7. Splenectomy induced enteric endotoxemia increased the DNA index by 25% (1 44±0 15, P <0 01) and hepatoma rate by 33%. A summation of the effects of these two factors increased the DNA index by 36% ( P <0 01)and hepatoma incidence by 50%, moreover, the level of endotoxemia showed a close relation with DNA index ( r =0 96, P <0 01), as well as with the occurrence rate of hepatoma ( r =0 00, P <0 01). Histological findings further verified such alterations. CONCLUSION Lipopolysaccharide administration and/or splenectomy induced enterogenic endotoxemia may enhance rat hepatocarcinogenesis induced by oral intake of thioacetamide.

The Beneficial Effects of Oral Cotrimoxazole upon Likely Biomarkers of Oxidative Stress in Advanced Fibrotic Lung Disease

Introduction: In cases of idiopathic pulmonary fibrosis, we have observed an elevation in mean red cell volume, serum gamma glutamyl transferase and peripheral monocyte counts, initially in a pilot study but also in new incident cases. These changes could not be explained by drug therapy, vitamin deficiency or other diseases. Method: We compared the peripheral blood abnormalities in 149 patients with lung fibrosis to 448 age and sex matched controls. We also examined the effect of cotrimoxazole treatment for 12 weeks on these abnormalities. From the pilot study of cotrimoxazole in lung fibrosis patients, the relationship of the peripheral blood monocyte count and serum cytokine transforming growth factor beta-1 was examined. Epstein Barr viral status was examined in a selection of patients in case it explained our observations. Results: The findings confirm the elevation in mean red cell volume, gamma glutamyl transferase and peripheral monocyte counts in patients compared with matched controls. Oral cotrimoxazole ameliorated these 3 blood abnormalities. Serological evidence of Epstein Barr viral infection was present in tested patients but active viral replication was absent. The monocyte count had a linear relationship with the serum transforming growth factor beta-1 levels, which increased by 600 pg/ml for every of 0.1 × 109/l increase in the monocyte count. Conclusion: These observations may reflect oxidative stress which was reduced by cotrimoxazole. A related sulphonamide “dapsone” is known to reduce oxidative stress through direct effects on neutrophil and monocyte function;similar effects may explain these findings and require a formal study.

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

Chiral Polyamides Having L-Glutamyl Residue as a Component

Polyamides with chiral environment were obtained from aromatic diamine, 1,3-phenylenediamine (1,3-PDA) or 1,4- phenylenediamine (1,4-PDA), and N-α-benzoyl-L-glutamic acid (Benzoyl-L-Glu). The optical rotation ([α]D) for 1,3- PDA-Benzoyl-L-Glu was determined to be 3.7 deg cm2 g–1, while that for 1,4-PDA-Benzoyl-L-Glu to be 9.7 deg cm2 g–1. 1,3-PDA-Benzoyl-L-Glu showed adsorption selectivity toward D-Glu and its adsorption selectivity was determined to be 1.68. Contrary to this, 1,4-PDA-Benzoyl-L-Glu showed adsorption selectivity toward L-Glu and the adsorption selectivity toward L-Glu was determined to be 1.33. From those results, those two types of chiral polyamide are expected to applicable to chiral separation or chiral recognition.

Evaluation of Acute and Repeated Dose Toxicity of the Polyherbal Formulation Linkus Syrup in Experimental Animals

The objective of the present study was to evaluate the pre-clinical efficacy and toxicity of polyherbal cough syrup Linkus. Method: Animals (healthy Wistar albino rats;(150 - 250 g) of either sex) were housed under standard environmental conditions;i.e. 25°C ± 1°C and 12 h dark/light cycle. Food and water were available at libitum. The rats were treated orally with the recommended doses of the test drug (Linkus). After 15 minutes, they were individually placed in a closed Plexiglas chamber (20 × 10 × 10 cm) and exposed to citric acid (0.1 g/ml) inhalation for 7 minutes. The cough reflexes were produced and counted for the last 5 minutes and compared with those of the control animals. The following studies were conducted to evaluate the toxicity of the test drug in healthy Wistar albino rats: lethal dose50 (LD50);rats of either sex (n = 10/sex) were treated orally with doses (1 or 5 g/kg) of the test drug. Mortality and behavioral changes were observed for 1 week. Repeated dose toxicity on the healthy Wistar albino rats of both sexes (n = 5/dose/sex) was treated orally with doses of 20 mg/kg (adult human dose = ~1400 mg), 500 mg/kg (adult human dose = ~35,000 mg) and 1000 mg/kg (adult human dose = ~70,000 mg) of test drug (Linkus) for 14 days. Additionally, the control animals were treated orally with water for 14 days. Results: In female rats, the test drug (Linkus) at the dose of 300 mg/kg caused significant (p < 0.01) reduction in the cough reflexes as compared to the control. However, in male rats, a significant reduction was observed at the tested dose of 200 mg/kg (p < 0.05) and 300 mg/kg (p < 0.01). The test product did not cause mortality in rats at the given doses of 1 or 5 g/kg. Other signs of toxicity like hair loss and weight reduction were not observed. In female and male rats, the test drug (Linkus) at different doses did not show any abnormal effects on complete blood count profile of rats. Serum enzyme markers, i.e. alanine aminotransferase (ALT), alakaline phosphatase, gamma glutamyle transferase (GGT), direct bilirubin, creatinine, and proteins were also observed and found that the test drug at a higher dose did not cause any of the abnormality and had shown significant p value as compared to the control. Conclusion: The test drug (Linkus) could be an effective and safe cough syrup because it did not show any of the side effects or toxicity on experimental animals.

Gamma-glutamyl transferases： A structural, mechanistic and physiological perspective

Gamma glutamyl transferases （GGT） are highly conserved enzymes that occur from bacteria to humans. They remove terminal y-glutamyl residue from peptides and amides. GGTs play an important role in the homeostasis of glutathione （a major cellular antioxidant） and in the detoxification of xenobiotics in mammals. They are implicated in diseases like diabetes, inflammation, neurodegenerative diseases and cardiovascular diseases. The physiological role of GGTs in bacteria is still unclear. Nothing is known about the basis for the strong conservation of the enzyme across the living system. The review focuses on the enzyme＇s physiology, chemistry and structural properties of the enzyme with emphasis on the evolutionary relationships. The available data indicate that the members of the GGT family share common structural features but are functionally heterogenous.