Protective effect of aminoguanidine against oxidative stress in an experimental peritoneal adhesion model in rats

Postoperative intraperitoneal adhesion formation is a major cause of intestinal obstruction, pain and infertility. This experimental study was designed to evaluate the degree of adhesion formation and peritoneal tissue levels of malondialdehyde (MDA), reduced glutathione (GSH) and total nitrite and nitrate (NO) and the effect of aminoguanidine (AG) on these metabolite values after postoperative intraperitoneal adhesion formation in rats. A total of 21 adult male Wistar albino rats were randomly divided into three groups. Control rats were untreated; the AG group received AG 200 mg kg(-1) i.p. for 10 consecutive days intraperitoneally after surgery. The sham group was given 0.9% NaCl. The rats were killed on postoperative day 10. The peritoneal tissues were harvested to determine the tissue levels of MDA, GSH, and NO activity. For light microscopic evaluation, the cecum was removed. Adhesion formation scores in the AG group were significantly lower than those of the control and sham groups (p < 0.017, p < 0.026 respectively). In the AG-treated rats, tissue levels of MDA and NO were significantly lower than in the control group (p < 0.017). The levels of GSH in aminoguanidine-treated rats were significantly higher than those of the control group (p < 0.01). The severity of the inflammation was more prominent in the control group compared with the AG-injected rats. The results demonstrate that in this experimental model, intraperitoneal administration of aminoguanidine decreases the incidence and extent of peritoneal adhesions and causes a decrease in MDA and NO and an increase in GSH values.     

Characterization of dopa betaine,tyrosine betaine and N-dimethyltyrosine from Lobaria laetevirens

DOPA betaine, tyrosine betaine and N-dimethyltyrosine were isolated from the lichen Lobaria laetevirens. Their structures were determined by ra     

Protection against acetaminophen-induced hepatotoxicity by L-CySSME and its N-acetyl and ethyl ester derivatives

We have recently observed that S-(2-hydroxyethylmercapto)-L-cysteine (L-CySSME), the mixed disulfide of L-cysteine and 2-mercaptoethanol, prevented cataracts induced in mice by acetaminophen (ACP) by functioning as a prodrug of L-cysteine and protecting the liver. This prompted the evaluation of the more lipophilic N-acetyl (Ac-CySSME) and ethyl ester (Et-CySSME) derivatives of L-CySSME as pro-prodrug forms, as well as the “D” enantiomer, as hepatoprotective agents. Serum ALT levels were measured at 24 hours after a toxic but nonlethal dose of ACP that insured 48 hour survival of the animals. Since the increases in ALT produced were highly variable (even after log transformation) and complicated the statistical analyses, we calculated confidence intervals for the mean ALT levels for each treatment group. This enabled comparisons to be made of the efficacy of L-CySSME as well as Ac-CySSME and Et-CySSME with other representative prodrugs of L-cysteine, namely, 2(RS)-methylthiazolidine-4(R)-carboxylic acid (MTCA), L-2-oxothiazolidine-4-carboxylic acid (OTCA), and N-acetyl-L-cysteine (NAC), in protecting the liver. It was shown that L-CySSME and MTCA administered intraperitoneally at 2.5 mmol/kg were superior to the other cysteine prodrugs at equimolar doses in protecting mice from hepatotoxicity elicited by a 400 mg/kg (2.65 mmol/kg) dose of ACP given i.p. 30 minutes prior to the prodrugs. The “D” form of CySSME was totally without protective effect. Oral doses of the prodrugs even at 2× the i.p. dose were less effective, although MTCA was the most protective. © 1997 John Wiley & Sons, Inc. J Biochem Toxicol 11: 289–295, 1997.     

Enzyme-like effect of metmyoglobin on the thermal cis-trans isomerization of stilbazolium betaine

cis →trans isomerization. A study of the pH and ionic strength dependence of the isomerization reaction rate of the photochrome associated with metmyoglobin was perfomed. A comparative investigation of the reaction carried out in the presence of three proteins, metmyoglobin, apomyoglobin, and human albumin, indicates a specific influence of the heme pocket environment on the reaction. Possible mechanisms of the reaction acceleration are considered. Received: 8 December 1999 / Accepted: 15 February 2000     

Lipid peroxidation, vitamins C, E and reduced glutathione levels in patients with pulmonary tuberculosis

The present study examined the relationship between lipid peroxidation and vitamin C, vitamin E and reduced glutathione levels in plasma, erythrocytes and erythrocyte membranes of pulmonary tuberculosis patients and an equal number of age-and sex-matched healthy subjects. Enhanced plasma, erythrocytes and erythrocyte membrane lipid peroxidation with concomitant decline in vitamin C, vitamin E and reduced glutathione levels were found in pulmonary tuberculosis patients. The elevated lipid peroxidation and decreased vitamin C, vitamin E and reduced glutathione levels indicate the potential of oxidative damage to erythrocytes and erythrocyte membranes of pulmonary tuberculosis patients.     

Protective effect of resveratrol against pembrolizumab-induced hepatotoxicity and neurotoxicity in male rats

The present study investigates the effects of resveratrol (RSV) on brain and liver tissues in rats with pembrolizumab (PEMB)-induced toxicity. Obtained for the study were 28 male Sprague-Dawley rats (3–4 months old) which were divided into four groups: Group 1: Control. Group 2: Administered PEMB at 5 mg/kg/day i.p. for a week. Group 3: Administered RSV orally at the dose of 20 mg/kg/day for 30 days by gavage. Group 4: Administered PEMB and RSV at 20 and 5 mg/kg/day RSV, respectively, for 30 days. The results of this study revealed that PEMB leads to a significant increase in thiobarbituric acid reactive substance (TBARS) levels and a significant decrease in glutathione peroxidase (GPx), catalase (CAT), superoxide dismutase (SOD) activities, and glutathione (GSH) levels in the liver and brain tissues. The decreased SOD, CAT, GPx activities, and GSH levels increased significantly following RSV treatment in Group 4. The PEMB treatment showed histopathological alterations associated with strong positive cysteinyl aspartic acid-protease-3 (caspase-3) immunoreactivity, while RSV treatment reduced both the expression of caspase-3 protein and the histopathological changes. RSV administration prevents the biochemical, immunological, and histological alterations induced by PEMB. It can be suggested that the lower caspase-3 immunoreactivity in the PEMB + RSV group than in the PEMB group led to an inhibition of RSV on apoptosis.     

Understanding nicotinamide dinucleotide cofactor and substrate specificity in class I flavoprotein disulfide oxidoreductases: crystallographic analysis of a glutathione amide reductase

Glutathione reductase (GR) plays a vital role in maintaining the antioxidant levels of the cytoplasm by catalyzing the reduction of glutathione disulfide to reduced glutathione, thereby using NADPH and flavin adenine dinucleotide as cofactors. Chromatiaceae have evolved an unusual homolog that prefers both a modified substrate (glutathione amide disulfide [GASSAG]) and a different cofactor (NADH). Herein, we present the crystal structure of the Chromatium gracile glutathione amide reductase (GAR) both alone and in complex with NAD⁺. An altered charge distribution in the GASSAG binding pocket explains the difference in substrate specificity. The NADH binding pocket of GAR differs from that of wild-type GR as well as that of a low active GR that was engineered to mimic NADH binding. Based on the GAR structure, we propose two attractive rationales for producing an efficient GR enzyme with NADH specificity.     

外源甜菜碱对冬小麦抗旱性生理指标的影响研究

在３种不同土壤水分条件下,研究外源甜菜碱对返青－拔节期小麦叶片光合作用的影响,结果表明：随着土壤水分下降,喷施２５￣５０ｍｇ／ｋｇ外源甜菜碱对提高光合速率、胞间ＣＯ２浓度、叶面积等生理指标越明显,有效地提高了小麦生物学产量。     

Protective effect of diallyl sulfone against acetaminophen-induced hepatotoxicity in mice

Diallyl sulfone (DASO₂) is a metabolite of diallyl sulfide, a compound derived from garlic. The present study investigated the effect of DASO₂ as a protective agent against acetaminophen (APAP)-induced hepatotoxicity in mice. Oral administration of DASO₂ protected mice against the APAP-induced hepatotoxicity in a dose- and time-dependent manner. When administrated 1 hour prior to, immediately after, or 20 minutes after a toxic dose of APAP, DASO₂ at a dose of 25 mg/kg completely protected mice from development of hepatotoxicity, as indicated by liver histopathology and serum lactate dehydrogenase levels. Protective effect was observed when DASO₂ at a dose as low as 5 mg/kg was given to mice 1 hour prior to APAP administration. Oral administration of DASO₂ to mice 1 hour prior to a toxic dose of APAP significantly inhibited the APAP-induced glutathione depletion in the liver. DASO₂ treatment also decreased the levels of oxidative APAP metabolites in the plasma without affecting the concentrations of nonoxidative APAP metabolites. In liver microsomes, 0.1 mM of DASO₂ caused a 60% decrease in the rate of APAP oxidation to N-acetyl-p-benzoquinone imine, which was determined as glutathione conjugate. This inhibitory effect is mainly due to its inhibition of cytochrome P450 2E1 activity; with an IC₅₀ value equal to 0.11 mM. DASO₂ also slightly inhibited the activities of P450s 3A and 1A, with IC₅₀ values >5 mM. Furthermore, a single oral dose of DASO₂ inactivated P450 2E1- and P450 1A-dependent activities in liver microsomes. The results suggest that the protective effect of DASO₂ against APAP-induced hepatotoxicity is due to its ability to block acetaminophen bioactivation mainly by the inactivation and inhibition of P450 2E1. © 1996 John Wiley & Sons, Inc.     

Studies on hepatotoxicity and toxicokinetics of colchicine

Colchicine (COL) is an alkaloid existing in plants of Liliaceous colchicum. It has widely been used in the treatments of many diseases, such as gout, Familial Mediterranean Fever, and tumor. However, the adverse effects of COL are an obstacle to its safe use. The present studies explored the role of metabolic demethylation in the development of COL‐induced hepatotoxicity. We found that inhibition of CYP3A increased the susceptibility of mice to COL hepatotoxicity, and induction of CYP3A decreased the susceptibility of animals to the hepatotoxicity. The toxicokinetic study demonstrated that pretreatment with ketoconazole caused elevated area under the concentration‐time curve of COL. Three demethylation metabolites of COL were found to be less hepatotoxic than the parent compound. It appears that the formation of electrophilic demethylation metabolites was not involved in the development of COL‐induced liver injury.     

外源甜菜碱对干旱胁迫下小麦幼苗膜脂过氧化作用的影响

用PEG4000溶液对小麦（Triticum aestivum L.heimang)幼苗进行胁迫处理和加入外源甜菜碱（Betaine)作同样处理,6、12、18和24h测定生理变化。结果表明,与对照相比,外源甜菜碱导致小麦幼苗叶片含水量下降,相对膜透性增大,MDA含量升高,SOD和POD活性先降后增,同时脯氨酸大量积累。说明外源甜菜碱对小麦幼苗受伤害程度有明显加深作用。     

Vitamin E and selenium treatment of monocrotaline induced hepatotoxicity in rats

Monocrotaline (MCT) is a hepatotoxic pyrrolizidine alkaloid that is derived from plants; exposure may occur by consumption of contaminated grains, herbal teas and medicines. MCT can cause liver damage. We investigated the antioxidant effects of selenium (Se) and vitamin E against the toxic effects of MCT. Female Wistar albino rats were divided into four groups: a control group, an MCT group, an MCT + Se group, and an MCT + vitamin E group. Liver tissues were harvested, fixed, processed to paraffin and sections were cut. Anti-von Willebrand factor (vWF) immunohistochemistry, terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL), and hematoxylin and eosin staining were performed. Serum and liver tissue glutathione (GSH), catalase (CAT), and glutathione peroxidase (GPx) levels were measured. Histopathological and TUNEL data showed significantly increased liver damage in the MCT group compared to controls. Histopathological and TUNEL staining indicated significant improvements in the MCT + vitamin E and MCT + Se groups compared to the MCT group. MCT significantly reduced the serum GSH level and GPx activity, and liver GPx activity. Biochemical data indicated a significant improvement in serum GSH level in the MCT + vitamin E group compared to the MCT group. We suggest that vitamin E and Se afford limited protection against MCT hepatotoxicity.     

Alterations of oxidative-antioxidative status in human cutaneous leishmaniasis

Enhanced lipid peroxidation and decreased antioxidant defences have been defined in several diseases. In the present study, we aimed to evaluate the oxidative-antioxidative status of patients with cutaneous leishmaniasis (CL). Concentrations of erythrocyte lipid peroxidation (LPO), as an indicator for the oxidative status, reduced glutathione (GSH), glutathione peroxidase (GSH-Px) and serum vitamin C levels, as indicators for the antioxidative status, were measured. Seventy patients aged between 15 and 50 years (38 patients had active CL and 32 patients had healed CL) and 40 healthy controls aged between 19 and 50 years were included in the study. LPO and GSH of the patients with active CL were significantly higher (p < 0.001), whereas erythrocyte GSH-Px and serum vitamin C levels were lower (p < 0.001, p < 0.01 respectively) than those of healthy controls. There was a significant inverse correlation between LPO and serum vitamin C level (r=-0.32, p < 0.05) in active CL. No significant correlation of LPO, GSH, GSH-Px and serum vitamin C levels in control groups or in the group with healed CL was detected. In the light of our findings it is possible to conclude that patients having CL are affected by oxidative stress, which most likely induces the endogenous antioxidant system. An imbalance between the oxidant and antioxidant systems occurs and the suppressed antioxidants and increased lipid peroxidation may contribute to the progression of the disease.     

Cisplatin induced nephrotoxicity and the modulating effect of glutathione ester

The objective of this study was to assess the therapeutic advantage of glutathione ester along with cisplatin. Comparisons were made with renal reduced glutathione, enzymatic antioxidants, and lipid peroxidation levels. Cisplatin caused differential toxic effects on renal antioxidants and lipid peroxidation. However administration of glutathione ester modulates the toxic effects of cisplatin observed in renal antioxidants and lipid peroxidation. The finding that glutathione ester co-administration along with cisplatin is more effective and advantageous in protecting against the nephrotoxicity of cisplatin when it was given alone.     

The protective mechanisms of defibrotide on liver ischaemia-reperfusion injury

During some surgical interventions, temporary occlusion of the hepatic blood supply may cause ischaemia-reperfusion (I/R) injury and hepatic dysfunction. In this study the protective effect of defibrotide (DEF) was evaluated in a rat model of liver I/R injury. Four groups of rats were subjected to the following protocols: saline infusion without ischaemia, DEF infusion without ischaemia, DEF infusion with hepatic I/R, and saline infusion with hepatic I/R. After a midline laporatomy, liver ischaemia was induced by 45 min of portal occlusion. DEF 175 mg/kg(-1) was infused before ischaemia in 10 ml of saline. The same volume of saline was infused into the control animals. At the end of the 45-min reperfusion interval, the animals were sacrified. Superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) enzyme activities were determined in haemolysates, and malondialdehyde (MDA) level in the liver tissue was measured. Tissue MDA levels were significantly higher in the I/R plus saline group compared to the sham operation control groups (p < 0.01 and p < 0.05, respectively). Tissue MDA levels decreased in the DEF plus I/R group compared to the I/R plus saline group (p < 0.05), but DEF could not reduce tissue lipid peroxidation to the levels of the control sham operation groups. SOD and GSH-Px enzyme activities were significantly higher in DEF-treated animals than in the other groups (p < 0.05). These results suggest that DEF protects liver against I/R injury by increasing the antioxidant enzyme levels.     

Glycine betaine and polar lipid composition in halophilic archaebacteria in response to growth in different salt concentrations

Abstract Examples of halophilic archaebacteria contain low levels of between 1 and 20 mM trimethyl glycine (glycine betaine). In disrupted cell preparations, the glycine betaine is associated with the membrane fraction and is not detectable in cell supernatants. Cells of Natronococcus occultus grown in different salt concentrations show an increase in cell-associated glycine betaine along with an increase in the ratio of phosphatidyl glycerophosphate (PG) to phosphatidyl glycerol (PG) in the cell membrane.     

Choline and betaine ameliorate liver lipid accumulation induced by vitamin B6 deficiency in rats

We investigated the efficacy of supplementing the diet with choline or betaine in ameliorating lipid accumulation induced by vitamin B₆ (B₆) deficiency in rat liver. Male Wistar rats were fed a control, B₆-deficient, choline-supplemented (2, 4, or 6 g choline bitartrate/kg diet) B₆-deficient diet or betaine-supplemented (1, 2, or 4 g betaine anhydrous/kg diet) B₆-deficient diet for 35 d; all diets contained 9 g L-methionine (Met)/kg diet. Choline or betaine supplementation attenuated liver lipid deposition and restored plasma lipid profiles to control levels. These treatments restored the disruptions in Met metabolism and the phosphatidylcholine (PC)/phosphatidylethanolamine (PE) ratio induced by B₆ deficiency in liver microsomes. These results suggest that choline and betaine ameliorated liver lipid accumulation induced by B₆ deficiency via recovery of Met metabolism and very low-density lipoprotein secretion by restoring the supply of PC derived from PE.     

Protein and m-RNA expression of farnesyl-transferases,RhoA and RhoB in rat liver hepatocytes: action of perillyl alcohol and vitamin A <Emphasis Type="BoldItalic">in vivo</Emphasis>.

Summary We analysed the action, in rats in vivo, of the protein isoprenylation inhibitor perillyl alcohol (POH) and that of vitamin A, alone or in association, on m-RNA and protein expression of farnesyltransferases (FTases α and β subunits) and their protein substrates RhoA and RhoB, in isolated hepatocytes. Combined administration of POH and vitamin A induced a sharp decrease in FTase α protein after 96 h, suggesting an involvement not only of farnesyltransferases but also of geranylgeranyltransferases, which share the FTase α protein. FTase β protein did not decrease. POH plus vitamin A, in contrast with POH or vitamin A alone, induced a decrease in RhoB protein, probably because of different cleavages. No modification was observed in RhoA protein. Vitamin A alone increased RhoB m-RNA and protein expression. As one of the functions of RhoB is cell polarisation, these data support our previous hypothesis of a polarised transport of vitamin A from hepatocytes to hepatic stellate cells. As the behaviours of m-RNAs and proteins in this study were often different, cytoplasmic metabolic pathways must be considered for the parameters studied. The behaviour of Rho B, which is thought to have an antioncogene function, is discussed in view of its isoprenylated forms in the membranes. These preliminary findings stress the need, when studying the association of two isoprenoids in cancer therapy, to consider normal as well as tumour-bearing animals.     

Effect of Ketoconazole,a Cytochrome P450 Inhibitor,on the Efficacy of Quinine and Halofantrine against Schistosoma mansoni in Mice

The fear that schistosomes will become resistant to praziquantel (PZQ) motivates the search for alternatives to treat schistosomiasis. The antimalarials quinine (QN) and halofantrine (HF) possess moderate antischistosomal properties. The major metabolic pathway of QN and HF is through cytochrome P450 (CYP) 3A4. Accordingly, this study investigates the effects of CYP3A4 inhibitor, ketoconazole (KTZ), on the antischistosomal potential of these quinolines against Schistosoma mansoni infection by evaluating parasitological, histopathological, and biochemical parameters. Mice were classified into 7 groups: uninfected untreated (I), infected untreated (II), infected treated orally with PZQ (1,000 mg/kg) (III), QN (400 mg/kg) (IV), KTZ (10 mg/kg)+QN as group IV (V), HF (400 mg/kg) (VI), and KTZ (as group V)+HF (as group VI) (VII). KTZ plus QN or HF produced more inhibition (P<0.05) in hepatic CYP450 (85.7% and 83.8%) and CYT b5 (75.5% and 73.5%) activities, respectively, than in groups treated with QN or HF alone. This was accompanied with more reduction in female (89.0% and 79.3%), total worms (81.4% and 70.3%), and eggs burden (hepatic; 83.8%, 66.0% and intestinal; 68%, 64.5%), respectively, and encountering the granulomatous reaction to parasite eggs trapped in the liver. QN and HF significantly (P<0.05) elevated malondialdehyde levels when used alone or with KTZ. Meanwhile, KTZ plus QN or HF restored serum levels of ALT, albumin, and reduced hepatic glutathione (KTZ+HF) to their control values. KTZ enhanced the therapeutic antischistosomal potential of QN and HF over each drug alone. Moreover, the effect of KTZ+QN was more evident than KTZ+HF.