The present study examined whether or not other cyclic antidepressants, such as the dicyclic drug zimeldine, the tricyclic drug imipramine, and tetracyclic drug maprotiline, and the noncyclic drug nomifensine, inhibit semicarbazide-sensitive amine oxidase (SSAO) activity in dog brain. After treatment with 100 nM clorgyline and 100 nM deprenyl, all four antidepressant drugs inhibit SSAO activity in dog brain. The most potent of inhibition was observed by imipramine, followed by maprotiline, zimeldine and nomifensine. All four drugs are noncompetitive inhibitor of SSAO in dog brain. We found the tricyclic antidepressant drug imipramine to be the most selective inhibitors of SSAO activity in dog brain, as compared with other type of antidepressant drugs.
Septic shock results from a systemic host response to infection, in particular, and is associated with multiorgan dysfunction (MOD). Effective preventive measures against organ failure are essential as it is the cumulative burden of MOD that invariably leads to death. The aim of this study was to determine if a novel compound, 5-ethyl-1-phenyl-2-(1H) pyridone (5-EPP), could decrease the increased serum levels of various biomarkers of MOD in LPS/D-Galactosamine (LPS/D-GalN) and cecal ligation and puncture (CLP) models of septic shock in mice. Treatment with 5-EPP minimized the liver dysfunction as assessed by its ability to decrease the increased serum levels of aminotransferases. It also reduced proinflammatory cytokines such as TNF-alpha, IL-6 and IL-12, and offered complete protection against mortality in LPS/D-GalN model. 5-EPP treatment also offered a significant protection against LPS alone- induced mortality. Pretreatment with 5-EPP minimized the kidney, heart and muscle damage as assessed by its ability to decrease the CLP-induced increases in the serum levels of blood urea nitrogen, creatine kinase, glucose and mortality. Several possible mechanisms for the beneficial effects of 5-EPP in the LPS/D-GalN, LPS alone, and CLP models of septic shock have been discussed. It was concluded from the findings of this study that 5-EPP, a novel pyridone, is a promising candidate for the management of septic shock by offering protection against MOD and mortality clinically seen in septic patients.
Inhibitors of the nuclear enzyme poly-(ADP-ribose) polymerase (PARP) have been demonstrated to attenuate pathophysiological conditions associated with toxicant-induced oxidative stress. This investigation evaluates Nicotinamide (NIC), a non-specific PARP inhibitor, and 6(5)-Phenanthridinone (Phen), a specific PARP-1 inhibitor, for their efficacy in blocking or attenuating bromobenzene (BB) induced hepatocellular toxicity. Male ICR mice were treated with an intraperitoneal injection of bromobenzene, followed by concomitant treatment with NIC or with NIC at 0.5, 1 and 2 hours after BB treatment, or with concomitant treatment of Phen at 10 mg/ml, 20 mg/ml, or 40 mg/ml solution concentration. Mice with only BB treatment displayed substantial hepatotoxicity as evidenced by a 3.5-fold increase in serum alanine transferase (ALT) compared to controls. Mice treated with 3 injections of NIC (at 0.5, 1 and 2 hours) after BB treatment demonstrated a 90% reduction in serum ALT at 24 hours after BB treatment (p < 0.05). Mice with concomitant BB and Phen treatment demonstrated a 75% reduction in ALT at 24 hours after treatment (p < 0.05). Histological evaluations of centrilobular hepatic tissue from treated animals confirm findings of reduced hepatotoxicity as indicated by the ALT results in the NIC and Phen treatment groups. Mortality after 7 days was reduced to levels near controls in the NIC and Phen treatment groups. The PARP-1 inhibitors evaluated in this investigation produce clinically significant attenuation of BB-induced liver injury in male ICR mice.
This review focuses on multiplicity of monoamine oxidase (MAO) activity in rat hepatic injury. MAO play a major role in the metabolism of biogenic amines. Stress such as immobilization stress (IMMO) or cold stress changes the multiple forms of MAO activity in rat liver. Thyroid hormone-inducible MAO inhibitor may play some role in regulating the MAO activity in rat liver. Carcinogen such as dimethylnitrosamine (DEN) might change the proportions of the forms of MAO activity in tumor cells. This compound is selective to and an irreversible inhibitor of MAO-B. These changes may account for the multiplicity of MAO by hepatic injury.
The present study was examined the effect of the properties of monkey platelet monoamine oxidase (MAO) based on inhibitor sensitivity. Monkey platelet showed a high MAO activity with beta-phenylethylamine (beta-PEA) as substrate and a very low A-form MAO activity with 5 hydroxytryptamine (5-HT) as substrate. Moreover, monkey platelet MAO was sensitive to the drugs deprenyl as B-form MAO inhibitor and less sensitive to clorgyline and harmaline as A form MAO inhibitor with beta-PEA as the B-form MAO substrate. B-form MAO from monkey platelet was more stable against heat treatment at 55 degrees C than B-form MAO in brain. After digestion with trypsin at 37 degrees C for 4 hrs, it was found that MAO from platelet was inhibited about 70% with beta-PEA as substrate with brain. The tricyclic antidepressant imipramine and nortriptyline inhibited B-form MAO activity more potency than B-form MAO in brain. However, when the noncyclic antidepressant nomifensine was used, monkey platelet B-form MAO activities were less potently inhibited. All these reagents were noncompetitive inhibitors of B form MAO in monkey platelet. The present studies demonstrated that monkey platelet MAO is a single of B-form MAO and sensitive to tricyclic antidepressants.
The present study examined whether tamoxifen could suppress antidepressant drug phenelzine can increase an active dopaminergic neurotoxin, 1-methyl-4-phenylpyridinium ion (MPP+)-induced hydroxyl radical (*OH) generation in the extracellular fluid of rat striatum, using in vivo microdialysis system. Rats were anesthetized, and sodium salicylate (0.5 nmol/microl/min) was infused through a microdialysis probe to detect the generation of *OH as reflected by the non-enzymatic formation of 2,3-dihydroxybenzoic acid (DHBA) in the striatum. Infusion of phenelzine (0.1 mM or 0.1 nmol/microl/min) into the striatum drastically increased dopamine (DA) efflux and the *OH formation, trapped as 2,3-DHBA by the possible increased production of MPP+. However, tamoxifen (100 microM) significantly suppressed phenelzine enhanced DA efflux and *OH formation by MPP+. These results in the pressent study is the first demonstration showing the protective effect of tamoxifen on *OH generation induced by phenelzine enhanced MPP+ by suppressing DA efflux.
Our previous study detected 291 and 77 genes showing early embryonic death-associated elevation and reduction of expression, respectively, in the fetal placenta of the cow carrying somatic nuclear transfer-derived cloned embryo. In this study, we mapped the 10 genes showing the elevation and the 10 genes doing the reduction most significantly, using somatic cell hybrid and bovine draft genome sequence. We then compared the mapped positions for these genes with the genomic locations of bovine quantitative trait loci for still-birth and/or abortion. Among the mapped genes, peptidylglycine alpha-amidating monooxygenase (PAM), spectrin, beta, nonerythrocytic 1 (SPTBNI), and an unknown novel gene containing AU277832 expressed sequence tag were intriguing, in that the mapped positions were consistent with the genomic locations of bovine still-birth and/or abortion quantitative trait loci, and thus identified as positional candidates for bovine placental genes responsible for the early embryonic death during the pregnancy attempted by somatic nuclear transfer-derived cloning.
Intermediate filaments are important in building the architecture of liver cells and are proposed to interact with other cellular components. Among intermediate filament associated proteins, plectin is a versatile cytoskeletal linkage protein which has been shown to interact with a variety of cytoskeletal structures. Intermediate filament and plectin might play some roles in tumorigenesis of human hepatocellular carcinoma since cells of hepatocellular carcinoma were morphologically different from normal liver. Plectin exhibited wide distribution spectrum among various tissues, however, it was poorly investigated in human liver and hepatoma tissues. In this paper, we studied the plectin expression in 18 cases of human hepatocellular carcinoma and normal hepatocytes by immunohistochemistry. The results revealed that plectin expression was deficient in human hepatocellular carcinoma and was probably through post-translational modification. Many 0.4 to 0.8 microm-thick keratin bundles were found in intermediate filament extracts of liver and hepatoma tissues. These bundles were greater in diameter about 40 to 80 times of single intermediate filament. We speculated that intermediate filament organized into "filament bundles" to maintain the shape of normal cells. In cancer cells, plectin was deficient and the irregularly loosened filament bundles could cause pleomorphism of cancer cells.
We have recently showed that the pyruvate dehydrogenase (lipoamide) beta (PDHB) gene involved in fatty acid oxidation, the sorbin and SH3 domain containing 1 (SORBS1) gene involved in insulin-stimulated glucose uptake, and the endothelial differentiation, sphingolipid G-protein-coupled receptor, 1 (EDG1) gene involved in blood vessel formation possess expression differences in musculus longissimus muscle between low-marbled and high-marbled steer groups. In the present study, we detected single nucleotide polymorphisms (SNPs) in the promoter regions of the 3 genes between the 2 steer groups. A SNP in the EDG1 exhibited significantly different allelic distribution between animals with extremely high predicted breeding value for marbling and with extremely low one. The EDG1 SNP may be related to changes in gene expression and/or marbling.
Gas chromatography mass/spectrometry quantitative analysis of 11-nor-9-carboxy-delta-9-tetrahydrocannabinol (THCCOOH), the major metabolite of delta-9-tetrahydrocannabinol (THC) found in urine following marijuana use, was performed on serial urine specimens collected from an inpatient adolescent population of marijuana users. Creatinine normalization of THCCOOH was used to compensate for dilute or concentrated urine specimens. The urinary terminal elimination rate constant and terminal half-life was calculated for each subject. The mean urinary elimination rate constant for THCCOOH normalized to creatinine was 0.08433 days(-1) (range 0.05408-0.16544) reflecting a 8.22 day terminal half-life. A half-life of 1.15 days was observed for the initial decline phase of THCCOOH corrected by creatinine suggesting that reuse of marijuana can be detected after this phase ends. The creatinine normalized THCCOOH level was a better indicator for predicting reuse of marijuana than urinary concentrations of THCCOOH. The Mean Residence Time (MRT) of THCCOOH/Cr (5.7 days) correlated well with the length of time a subject will have detectable urinary THCCOOH concentrations (20.8 days).
This study reports the toxicity and metabolism of methacrylonitrile (MeAN) in normal male Sprague-Dawley rats and those pre-treated with caffeine, alcohol or both. Rats were divided into groups often. One group received an oral dose by gavage of 6 % MeAN solution in corn oil (equivalent to 0.5 LD50). Other three groups of rats were pre-treated with alcohol (2 ml of 50% solution in water), caffeine (1 ml of 2% solution in water) or both alcohol and caffeine 12 hr before receiving MeAN dose by gavage. The rats were observed for mortality, cholinomimetic and central nervous system (CNS) effects and urinary dysfunction for 6 hr. The concentrations of cyanide, thiocyanate and glutathione (GSH) were determined in blood, liver, kidney and brain. Alcohol and alcohol + caffeine pre-treatment caused significant increase in cholinomimetic, CNS and urinary dysfunction effects of MeAN and mortality. However, caffeine alone pre-treatment protected rats from these effects. In the rats treated with MeAN alone and those pre-treated with alcohol and alcohol + caffeine the GSH concentrations significantly decreased in liver, brain and kidney. In the rats pre-treated with caffeine alone the concentrations of GSH were not significantly different from controls. In the rats treated with MeAN alone and those pretreated with alcohol and alcohol + caffeine the cyanide and thiocyanate concentrations increased in the blood and other organs up to 2-4 folds whereas in rats pre-treated with caffeine alone the concentrations of cyanide and thiocyanate were not significantly different from controls. Western Blot experiment showed CYP2E1 induction in rats pretreated with alcohol and MeAN. These results suggest that caffeine inhibited and alcohol enhanced toxicity and metabolism of MeAN.
A quantitative trait locus (QTL) responsible for intramuscular fat accumulation in Musculus longissimus of Otsuka Long-Evans Tokushima Fatty (OLETF) rat, Imfm, was previously mapped to the approximately 10-cM genomic region between D1Rat166 and D1Rat90 on chromosome 1 using Imfm congenic strain. In this study, we refined the Imfm region to a approximately 2.3-cM genomic region between D1Rat225 and D1Rat90, using 12 informative recombinants selected from 176 (Imfm congenic x F344) F, x Imfm congenic backcross progenies. Among 46 genes located within the approximately 2.3-cM region, pancreatic lipase gene, Pnlip, that is a possible candidate for obesity QTL, Nidd6/of, was thought to be the most prominent and physiologically relevant positional candidate for the Imfm QTL. It was previously showed that Pnlip possesses an OLETF allele-specific increase of mRNA levels in the pancreas, and that the OLETF allele is longer in variable number of tandem repeat (VNTR) within the 5'-flanking region than normal alleles. We found complete cosegregation of the Imfm QTL with Pnlip VNTR in the 12 informative recombinants, suggesting that Pnlip is also a possible candidate for the Imfm QTL.
A high-sucrose diet induces insulin resistance and dyslipidemia in normal rats. The purpose of the present study was to investigate effects of a high-sucrose diet to glycolipid metabolism in Zucker Diabetic Fatty (ZDF) rat. Male ZDF rats were fed with a high-sucrose (68%) diet from 6 to 18 weeks of age. In biochemical analyses, the glucose levels did not change as compared with those in standard diet-fed rats, but the total cholesterol levels were elevated during the experimental period. In pathological analyses, the relative liver weight increased by about 2-fold as compared with that in standard diet-fed rats, and severe fatty change was observed by high-sucrose feeding. A high-sucrose diet induces fatty liver, but not deterioration of diabetes mellitus in ZDF rats. High sucrose-fed rats are considered to be very useful to determine the relationship between hepatic insulin resistance and diabetes mellitus.
In the present communication some dehydrated dialdol products such as 1, 5 - Diphenyl pent - 1, 4 - diene - 3 - one (A1); 1, 9 - Diphenylnon - 1, 3, 6, 8 - tetraene - 5 - one (A2); 1, 5 - di (2 - hydroxyphenyl) pent - 1, 4 - diene - 3 - one (A3); 1, 5 - difuran pent - 1, 4 - diene - 3 - one (A4); 1, 5 - di [4 - bis (N, Ndimethyl) phenyl] pent - 1, 4 - diene - 3 - one (A5) were screened for their antifungal activity. To reduce their adverse effect on the environment, for the first time, we have attempted to screen the antifungal activity of these synthetic compounds in conjunction with selected natural products. The natural products that were used in our study include Nicotine tobaccum and Neem oil (Azadirachta indica). A set of 15 samples was tested against highly pathogenic and of extensive host range fungi Sclerotium rolfsii, Rhizactonia bataticola, Fusarium udum. The filter paper disc assay to monitor antifungal effect revealed significant and interesting results. We found that the use of the combination of natural and synthetic pesticides is more effective and environmentally healthy compared to just synthetic chemicals and/or less available natural products. These results obtained from the combined use of natural and synthetic chemicals lead us to suggest to a new class of less toxic but more effective pesticides. We call it group as CSYNAP, i. e. Combination of SYnthetic and NAtural products as Pesticides.
Carbon tetrachloride (CCl4) is a compound associated with free radical mediated hepatotoxicity in humans and laboratory animals. Previous research indicates that the cytotoxicity caused by CCl4 may be mediated by the rapid induction of PARP-1, a nuclear repair enzyme, which results in celluar depletion of NAD+ and ATP. Animal models indicate that the inhibition of PARP-1 after CCl4 exposure will attenuate cytotoxicity in mouse hepatocytes. In this investigation, the potential hepatoprotective effects of the PARP-1 inhibitor 6,(5H)-phenanthridinone against CCl4-induced hepatotoxicity was tested in human cells from the HepG2 primary hepatoma cell line. Cytotoxicity assay results indicate significant reductions in cell death with treatment of 20uM and 40uM solutions of 6,(5H)-phenanthridinone. PARP-1 activity assay results confirm that these protective effects correspond to the inhibition of PARP-1 by 6,(5H)-phenanthridinone. The findings in this study indicate that the effect of PARP-1 inhibition on cytotoxicity in human hepatocytes after CCl4 insult is consistent with the effect of PARP-1 inhibition on cytotoxicity found in animal models.
Valproate is a widely used anticonvulsant drug. Valproate is linked to hepatotoxicity which is rare but potentially lethal. The pathomechanism is not yet completely understood. Previous studies have shown a protective effect of glycine on this toxicity in rat hepatocytes (Vance et al., 1994). In the present study we investigated the hepatoxicity of 1-4 mM valproate in combination with glycine through absorption of neutral red from human hepatoma cells (Hep G2) in monolayer cell culture. Cell toxicity was measured by enzyme release with standard photometric test kits. In addition, a histomorphological evaluation was performed. A significant increase in the IC50 value of valproate cytotoxicity after addition of 12 mmol/l glycine was found. The average release of mitochondrial glutamate dehydrogenase as indicator of cell membrane damage decreased after addition of glycine. Cells treated with valproate in combination with 12 mmol/l glycine showed less histomorphological deformation of the nucleus and improved cell adherence. In conclusion a hepatoprotective effect of glycine on valproate-induced toxicity is also given in human hepatocytes. A nonspecific hepatoprotective effect of glycine can be assumed at least in vitro.
We have recently showed that the 7 expressed sequence tags (ESTs), c2-11#2, c3-3, c20-29, c22-3, c26-18#1, c26-42, and g5-10, possess expression differences in musculus longissimus muscle between low-marbled and high-marbled steer groups. In the present study, we detected single nucleotide polymorphisms (SNPs) in the 5' flanking regions of the 7 EST sequences between the 2 steer groups. A SNP for the c2-11#2 EST exhibited significantly different allelic distribution between animals with extremely high predicted breeding value for marbling and with extremely low one. The SNP in the ribosomal protein L27a (RPL27A) gene containing the c2-11#2 EST sequence may be related to changes in gene expression and/or marbling.
Monascus purpureus-fermented rice (MR), a preparation which has been shown to be hypolipidemic and antiatherogenic in rabbits and hamsters was fed to quail maintained on a high fat diet to determine if it could influence lipidemia and hepatic steatosis. MR was fed at two levels (0.8 or 1.6 g/kg/d), and compared with a lipoptropic preparation (dongbaogantai 0.6 g/kg/d) and an established hypolipidemic compound (lovastatin 6 mg/kg/d). All the test compounds lowered serum lipids and liver cholesterol levels. Dongbaogantai inhibited hepatic steatosis to the greatest extent (78%), lovastatin inhibited steatosis by 29% and the low and high doses of MR by 25 and 43%, respectively. These serum cholesterol lowering agents have been shown to reduce hepatic steatosis induced by dietary means.
Sivelestat sodium hydrate (sivelestat) is a selective inhibitor of polymorphonuclear leukocyte elastase (PMN-E). We administered sivelestat to patients with septic acute lung injury (ALI) to examine its usefulness. The primary endpoints in the study were the duration of artificial ventilation and pulmonary oxygenation ability, and the secondary endpoints were mortality and the concentrations of PMN-E, SP-D, TNF-alpha and IL-8 in blood. In the sivelestat group, the duration of artificial ventilation, pulmonary oxygenation ability, and the blood PMN-E, SP-D, TNF-alpha and IL-8 concentrations decreased significantly. Administration of sivelestat was found to reduce alveolar dysfunction and improve respiratory function, and it was suggested that early administration might be useful.
