Suppression of D-galactosamine-induced rat liver injury by glycosidic flavonoids-rich fraction from green tea

Tea constituents that had a preventive effect on D-galactosamine-induced liver injury in rats were partially purified by column chromatography from a n-butanol-soluble fraction of green tea. The fraction containing glycosidic flavonoids was found to suppress the D-galactosamine-induced increase of plasma alanine aminotransferase and aspartate aminotransferase activities. These results indicate that glycosidic flavonoids contribute, at least in part, to the liver injury-preventive effect of green tea.     

Glycosidic Flavonoids as Rat-Liver Injury Preventing Compounds from Green Tea

A glycosidic flavonoids-rich fraction from green tea leaves was purified to isolate five glycosidic flavonoids, guided by the detection of a preventive effect on D-galactosamine-induced liver injury in rats. These were identified as a flavone C-glycoside (1) and trisaccharide flavonols (2-5) based on the spectroscopic analyses. These compounds suppressed the D-galactosamine-induced increase of plasma alanine aminotransferase and asparatate aminotransferase activities in rats.     

Effects of dietary protein of proso millet on liver injury induced by D-galactosamine in rats

In this paper, we examined the effects of dietary protein from proso millet on liver injury induced by D-galactosamine or carbon tetrachloride in rats using serum enzyme activities as indices. D-galactosamine-induced elevations of serum activities of aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase were significantly suppressed by feeding the diet containing 20% protein of proso millet for 14 days as compared with those of rats fed a 20% casein diet, but not in the case of carbon tetrachloride. The results showed that proso millet protein is effective at lower dietary protein levels than that of dietary gluten reported previously. Therefore, the findings reported here may suggest that proso millet protein is considered to be another preventive food for liver injury.     

Suppression of D-galactosamine-induced liver injury by mushrooms in rats

Six species of edible mushroom were found to suppress D-galactosamine-induced enhancement of plasma alanine and aspartate aminotransferase activities when powdered mushrooms were added to the diet (5%) and fed to rats for 2 wk. Grifola frondosa exhibited the most potent effect in a dose-dependent manner. A significant effect was observed only from the water-soluble low-molecular-weight fraction of G. frondosa. The results indicate that several mushrooms possess a protective effect against liver injury induced by D-galactosamine.     

Suppression by Hydrangeae Dulcis Folium of D-galactosamine-induced liver injury in vitro and in vivo

Hydrangeae Dulcis Folium, the fermented and dried leaves of Hydrangea macrophylla SER. var. thunbergii MAKINO, suppressed D-galactosamine-induced liver injury by 85.2% when added to the diet at 1% and fed to rats for fifteen days. The hepatoprotective effect is more potent than that of a milk thistle extract and turmeric powder. Some fractionated extracts showed hepatoprotective activity in the D-galactosamine-induced in vitro liver injury model.     

Modification of the hepatotoxicity of D-galactosamine in the rat by cycloheximide.

The effect of cycloheximide (1.5 mg/kg), a potent inhibitor of protein biosynthesis, on D-galastosamine (375 mg/kg)-induced hepatic necrosis and hepatic triglyceride accumulation was studied in rats. Serum transaminase levels, 24 hr after D-galactosamine administration, were significantly reduced in animals treated simultaneously or 4 hr before D-galactosamine with cycloheximide, when compared to animals given D-galactosamine alone. Transaminase levels in rats given cycloheximide 4 hr after D-galactosamine were not reduced. Histological grading of hepatocyte necrosis showed a similar pattern of protection in the pretreated and simultaneously treated groups. Hepatic triglycerides were significantly reduced only in the latter group. Fatality 48 hr after D-galactosamine administration was significantly less common in rats pretreated with cycloheximide when compared to rats given D-galactosamine without cycloheximide, and surviving animals in the cycloheximide pretreated group had a lower serum transaminase level, a lower necrosis score, and a reduced hepatic triglyceride level. These data are consistent with the concept that protein synthesis is important in the pathogenesis of D-galactosamine-induced hepatotoxicity.     

Amelioration of D-galactosamine-induced acute liver injury in rats by dietary supplementation with betaine derived from sugar beet molasses

The effects of betaine supplementation on D-galactosamine-induced liver injury were examined in terms of hepatic and serum enzyme activities and of the levels of glutathione and betaine-derived intermediates. The rats induced with liver injury showed marked increases in serum enzyme activity, but those receiving dietary supplementation of 1% betaine showed enzyme activity levels similar to a control group without liver injury. Administration of betaine also increased both hepatic and serum glutathione levels, even following D-galactosamine injection. The activity of glutathione-related enzymes was markedly decreased following injection of D-galactosamine, but remained comparable to that of the control group in rats receiving 1% betaine. The concentrations of hepatic S-adenosyl methionine and cysteine showed similar trends to that observed for hepatic glutathione levels. These results indicate that 1% betaine has a hepatoprotective effect by increasing hepatic and serum glutathione levels along with glutathione-related enzyme activities in rats.     

Toxicity of polycyclic aromatic hydrocarbons. IV. Effects of diphenaldehyde, a major product of ozonized phenanthrene, in rats

Diphenaldehyde is the major product of phenanthrene ozonized on silica gel. Male Sprague-Dawley rats were treated with a single ip injection of DMSO (3.0 ml/kg) or diphenaldehyde (90 mg/kg) in DMSO. Diphenaldehyde produced significant alterations in levels of serum aspartate aminotransferase, alanine aminotransferase, sorbitol dehydrogenase, gamma-glutamyl transpeptidase, and lactate dehydrogenase relative to DMSO-injected rats 24 hr after injection. These results, as well as gross observations on necropsy, suggest that diphenaldehyde exhibits significant hepatotoxicity.     

Studies designed to increase the stability and antiviral activity (HCMV) of the active benzimidazole nucleoside, TCRB.

The potent activity of 2,5,6-trichloro-1-(beta-D-ribofuranosyl)benzimidazole (TCRB) against Human Cytomegalovirus with the concomitant low cellular toxicity at concentrations that inhibit viral growth prompted considerable interest in this research area. This interest was moderated by the pharmacokinetic studies of TCRB in rats and monkeys that revealed the instability of TCRB in vivo. These studies suggested that the instability was due to a cleavage of the glycosidic bond in vivo which released the heterocycle (2,5,6-trichlorobenzimidazole) into the bloodstream. This prompted us to initiate synthetic studies designed to increase the stability of the glycosidic bond of TCRB and BDCRB. Several synthetic approaches to address this and other problems are presented.     

STAT1 plays an essential role in LPS/D-galactosamine-induced liver apoptosis and injury

Interferon-gamma (IFN-gamma) has been implicated in liver damage in animal models and chronic hepatitis C infection; however, the underlying mechanism is not clear. Here we examined the role of STAT1, a key signaling molecule for IFN-gamma, in a model of murine hepatitis induced by the injection of LPS/D-galactosamine and in human hepatoma Hep3B cells. STAT1 is rapidly activated and highly induced after injection of LPS/D-galactosamine. Both overexpression of STAT1 and hepatocellular damage are located in the same pericentral region. Disruption of the STAT1 gene abolishes LPS/D-galactosamine-induced liver injury. Studies from IFN-gamma-deficient mice indicate that IFN-gamma is the major cytokine responsible for activation and hyperexpression of STAT1 in LPS/D-galactosamine-induced hepatitis. Hep3B cells overexpressing dominant negative STAT1 are resistant to IFN-gamma and IFN-gamma + TNF-alpha-induced cell death, whereas Hep3B cells overexpressing wild-type STAT1 are more susceptible to cell death. Taken together, these findings suggest that STAT1 plays an essential role in LPS/D-galactosamine-induced liver apoptosis and injury.     

肝再生剌激因子对小鼠实验性急性肝损伤的保护作用

A hepatic stimulator substance (HSS) was extracted from the liver of male weanling SD rats according to the method of LaBrecque. The mice were injected with carbon tetrachloride or D-galactosamine to induce hepatic injuries and the protective effect of HSS on thus induced hepatic damage was investigated. The results were as follows: (1) HSS could suppresses the elevation of sGPT and sGOT induced by carbon tetrachloride intoxication in a dose-dependent manner. (2) Hepatic histological findings indicated that the degree of CCl4 or D-galactosamine-induced hepatic lesions could be lessened by HSS. (3) CCl4-induced reduction of hepatic mitochondrial succinic dehydrogenase activity could be restored by HSS. (4) Insulin-glucagon enhanced the survival of D-galactosamine intoxicated mice and stimulated hepatocyte proliferation, thus showing less pronounced hepatic damage.     

Glucocorticoid regulation of hepatic cytosolic glucocorticoid receptors in vivo and its relationship to induction of tyrosine aminotransferase

Regulation of rat hepatic cytosolic glucocorticoid receptors was studied using our newly developed exchange assay. Injecting 1 mg of dexamethasone or corticosterone into 150-250 g adrenalectomized rats caused a rapid decline in glucocorticoid receptor binding. Glucocorticoid receptor levels were depressed 80-90% in less than 15 min after hormone treatment, and remained low for about 24-48 h after glucocorticoid administration. 80-90% of glucocorticoid receptor binding was regenerated by 48 h, and complete binding was recovered by 72 h. Regenerated glucocorticoid receptor binding (48-72 h after first hormone injection) could be re-depressed by a second injection of the hormone. Similar results were obtained using normal (intact) rats. Optimum induction of tyrosine aminotransferase activity was obtained within 2 h following the first hormonal injection. Induction of tyrosine aminotransferase activity (measured 2 h after a second injection of the glucocorticoid) correlated with glucocorticoid receptor levels. Thus, 1 mg of dexamethasone or corticosterone greatly enhanced the liver tyrosine aminotransferase activity in the adrenalectomized rats (not previously hormone treated) and in adrenalectomized rats previously injected (48-72 h) with 1 mg of the glucocorticoid hormone. Enhancement of tyrosine aminotransferase activity was lowest 16-24 h after the first hormone injection (when receptor levels were extremely low). These results indicate that the induction of liver tyrosine aminotransferase activity by glucocorticoid hormones is correlated with cytosolic glucocorticoid receptor levels.     

Effects of various levels of dietary Artemisia abyssinica leaves on rats

Artemisia abyssinica leaves, a traditional medicine for the treatment of various disorders, were fed to male Wistar rats at 2% and 10% of the standard diet for 6 weeks. A 2% A. abyssinica leaf diet was not toxic to rats. Depression in growth, hepatopathy and nephropathy were observed in rats fed a diet containing 10% of A. abyssinica leaves. These findings were accompanied by leukopenia, anaemia and alterations of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) and gamma glutamyl transferase (GGT) activities with changes in concentrations of total protein, albumin, cholesterol and urea.     

Studies Designed to Increase the Stability and Antiviral Activity (HCMV) of the Active Benzimidazole Nucleoside,TCRB

Abstract

The potent activity of 2,5,6-trichloro-1-(ß-D-ribofuranosyl)benzimidazole (TCRB) against Human Cytomegalovirus with the concomitant low cellular toxicity at concentrations that inhibit viral growth prompted considerable interest in this research area. This interest was moderated by the pharmacokinetic studies of TCRB in rats and monkeys that revealed the instability of TCRB in vivo. These studies suggested that the instability was due to a cleavage of the glycosidic bond in vivo which released the heterocycle (2,5,6-trichlorobenzimidazole) into the bloodstream. This prompted us to initiate synthetic studies designed to increase the stability of the glycosidic bond of TCRB and BDCRB. Several synthetic approaches to address this and other problems are presented.     

Cardioprotective and antihypertensive effects of Enicostemma littorale Blume extract in fructose-fed rats

We investigated the protective effects of Enicostemma littorale Blume (EL) extract on hypertension and insulin resistance along with its associated cardiovascular complications in high fructose (HF) fed rats. For this, rats were divided among 4 groups: (i) control, fed laboratory chow; (ii) fed with a high level of fructose; (iii) fed with a high level of fructose plus E. littorale extract; and (iv) fed with a high level of fructose plus rosiglitazone (Rg). EL and Rg treatments were given simultaneously with HF diet. The results show that untreated HF-fed rats showed altered oral glucose tolerance, increased fasting insulin, and increased fasting glucose. These rats also exhibited hypertriglyceridemia, moderate hypertension, platelet hyperaggregability, decreased prothrombin time, activated partial thromboplastin time, altered vascular reactivity, and increased serum levels of enzymes (creatine kinase, type muscle-brain (CK-MB), aspartate aminotransferase (SGOT), lactate dehydrogenase (LDH), and alanine aminotransferase (SGPT). This is the first demonstration of platelet hyperaggregation and prothrombotic alteration in HF-fed rats. HF-fed rats treated with EL showed improved insulin resistance, along with reduced hypertriglyceridemia, hypertension, platelet aggregability, blood coagulation, serum enzymes (CK-MB, SGOT, LDH and SGPT), and vascular reactivity. These effects of EL in HF-induced hypertensive rats might be associated with the suppression of hyperinsulinemia and hypertriglyceridemia, along with its antiatherogenic and antithrombogenic potential. These data indicate that the aqueous extract of EL has great therapeutic potential for the prevention and (or) management of insulin resistance and the associated hypertension.     

Effects of feeding and lighting stimuli on the synthesis of ornithine aminotransferase and serine dehydratase in rat liver

In a previous study we showed that rats fed ad libitum and maintained on a 12-h light/ 12-h dark cycle demonstrated out-of-phase circadian oscillations in the rates of ornithine aminotransferase and serine dehydratase synthesis. As part of an investigation of the factors regulating both the generation of these cycles and their dissimilarity, this paper ompares the circadian fluctuations in the rates of ornithine aminotransferase and serine dehydratase synthesis measured immunochemically in rats given a single 2-h daily feeding in conjunction with exposure to constant light or a 12-h light/12-h dark cycle. When the 2-hr feeding was administered to rats under constant light, reciprocal circadian oscillations in ornithine aminotransferase and serine dehydratase synthesis were observed regardless of the temporal location of the feeding interval. Ornithine aminotransferase synthesis began to increase after the feeding interval and reached a maximum 12 h later while serine dehydratase showed the opposite response. In rats maintained on both the restricted feeding regimen and a 12-h light/12-h dark cycle, however, retention of synthesis oscillations depended on the temporal location of the restricted feeding interval within the light-dark cycle. Rats fed for 2 h at the beginning of the dark phase exhibited circadian oscillations in serine dehydratase synthesis and a high nonoscillating level of ornithine aminotransferase synthesis, whereas rats fed for 2 h at the beginning of the light phase exhibited circadian oscillations in ornithine aminotransferase synthesis and a low nonoscillating level of serine dehydratase synthesis. These responses suggest the existence of meal-responsive and light-responsive regulators of ornithine aminotransferase and serine dehydratase synthesis.     

Epidermal growth factor as a new regulator of induction of tyrosine aminotransferase and tryptophan oxygenase by glucocorticoids

Epidermal growth factor (EGF) dose-dependently enhanced the induction of tyrosine aminotransferase and tryptophan oxygenase by glucocorticoids in primary cultures of adult rat hepatocytes without itself having any effect on these enzymes in the absence of glucocorticoids. The amplifications were observed even with dexamethasone at high concentrations (10(-6) M-10(-5) M) that had a maximal effect. EGF had no effect on induction of tyrosine aminotransferase by glucagon or Bt2cAMP. The effect of EGF was also observed in adrenal-ectomized and submaxillary gland-ectomized rats. These results suggest that EGF is an endogenous amplifier of the action of glucocorticoids.     

Role of lysosomotrophic reagents in glucocorticoid hormone action

Administration of (10 mg/200 g) methylamine or chloroquine to adrenalectomized rats for 2 days followed by a single injection of either cortisol (2.5 mg/200 g) or dexamethasone (0.5 mg/200 g) resulted in a significant enhancement of the tyrosine aminotransferase enzymatic activity in rat liver versus rats given a single injection only of either steroid. Lysosomotrophic reagents were unable to induce tyrosine aminotransferase when administered alone. Cytosols from rat liver treated with lysosomotrophic reagents in vivo had approx. 20-30% more specific binding to [3H]dexamethasone as compared to the control, untreated rats. This enhanced binding was due to an increase in the concentration of the receptor rather than a change in the affinity of the hormone for the receptor. Rat livers perfused with and homogenized in 10 mM Tris-HCI/0.25 M sucrose buffer (pH 7.5) containing about 5 mM lysosomotrophic reagents showed optimum stabilization of the steroid unbound glucocorticoid receptor in vitro at both 4 degrees C and 25 degrees C. These reagents had no effect on in vitro transformation of [3H]dexamethasone-receptor complex or on the binding of the thermally transformed receptor to the nuclei. It is concluded from these studies that lysosomotrophic reagents enhance tyrosine aminotransferase induction by glucocorticoids and stabilize unbound glucocorticoid receptor both in vivo and in vitro without any effect on in vitro transformation of the steroid-receptor complex.     

Effects of Ballota nigra on blood biochemical parameters and insulin in albino rats

Ingestion of aqueous 70% ethanol extract of Ballota nigra (400 mg/kg body weight for 7 days) by albino rats (n=10) was investigated to study its effects on glucose, total cholesterol, triglycerides, aspartate aminotransferase (AST), alanine aminotransferase (ALT), troponin I (TnI), serum creatine kinase (CK), total protein, total bilirubin and blood urea. Ballota nigra extract caused a significant decrease in blood glucose, total serum cholesterol and CK levels. Blood levels of TnI, AST, ALT, triglycerides, total bilirubin, total protein and blood urea were unchanged. The hypoglycemic effect of Ballota nigra extract on albino rats was further investigated by conducting a glucose tolerance test intraperitoneally (IPGTT). Healthy rats that were fasting for 18 hours followed by administration of a dose of 400 mg/kg body weight of the crude extract of Ballota nigra, orally. A significant decrease in blood glucose levels (after 15, 30, and 45 minutes) with a significant increase in serum insulin level (after 15 and 30 minute) was noted. These results suggest that, the crude extract of Ballota nigra have hypoglycemic, insulin-releasing and cholesterol lowering effects in rats.     

Dietary freshwater clam (Corbicula fluminea) extract suppresses accumulation of hepatic lipids and increases in serum cholesterol and aminotransferase activities induced by dietary chloretone in rats

We investigated the ameliorative effect of freshwater clam extract (FCE) on fatty liver, hypercholesterolemia, and liver injury in rats exposed to chloretone. Furthermore, we examined the effects of major FCE components (fat and protein fractions) to determine the active components in FCE. Chloretone increased serum aminotransferase activities and led to hepatic lipid accumulation. Serum aminotransferase activities and hepatic lipid content were lower in rats fed total FCE or fat/protein fractions of FCE. Expression of fatty acid synthase and fatty acid desaturase genes was upregulated by chloretone. Total FCE and fat/protein fractions of FCE suppressed the increase in gene expression involved in fatty acid synthesis. Serum cholesterol levels increased twofold upon chloretone exposure. Total FCE or fat/protein fractions of FCE showed hypocholesterolemic effects in rats with hypercholesterolemia induced by chloretone. These suggest that FCE contains at least two active components against fatty liver, hypercholesterolemia, and liver injury in rats exposed to chloretone.