Abstract. An increase in the perfusate glucose concentration from near zero to about 11 mM increased glycogen synthesis in the perfused, isolated rat liver from zero to a value about half the maximum seen in the intact animal. Increased synthesis appeared to be due not only to provision of substrate but also to conversion of glycogen synthetase to the active form and of glycogen phosphorylase to the inactive form. These glucose effects, which are apparently independent of changes in levels of hormones or adenosine 3':5'-cyclic phosphate, may be physiologically significant for control of the blood glucose level.The liver plays a central role in the regulation of blood glucose.1' 2 Control appears to be due in part to changes in the tissue level of adenosine 3': 5'-cyclic phosphate (cyclic AMP) resulting from alterations in the activity of the sympathetic nervous system and in the secretion of glucagon and insulin.3 In addition, the liver possesses intrinsic control systems2' 4 which help stabilize the blood glucose. One of these is described in this report.There are several possibilities regarding the nature of these nonhormonal controls. A negative feedback system in which a rise in blood glucose suppresses gluconeogenesis has been proposed by Ruderman and Herrera5 but these workers could show only a small suppression (25%) of gluconeogenesis from alanine by 17 mM glucose in the isolated, perfused liver, and Exton and Park6 could not show any inhibition of gluconeogenesis from lactate by 19 mM glucose in a similar system. A quantitatively significant regulation of glucose utilization through adjustments in the rate of hepatic glycolysis also seems unlikely since the intrinsic rate of this process is very low under aerobic conditions.6 Another possibility, which we have examined in this study, is that glycogen metabolism is affected by the glucose concentration. In this connection, DeWulf and Hers7 found that intravenous injection of glucose into the mouse led to a rapid activation of hepatic glycogen synthetase and suggested that this effect was independent of changes in insulin or glucocorticoid secretion. Holmes and Mansour8 reported that glucose inactivated glycogen phosphorylase in the isolated rat diaphragm in vitro.In the present study, we have found that elevation of the glucose concentration in the medium perfusing the isolated rat liver promotes net synthesis of glycogen by conversion of glycogen synthetase to the active form9 and transformation of glycogen phosphorylase to the inactive form. These effects of glucose appear to be independent of changes in the tissue level of cyclic AMP. 383
Abstract:We tested trifluralin against Trypanosoma cruzi in a model of chronic Chagas disease in mice. CF1 mice (nΩ 148) were intraperitoneally infected with 10 5 trypomastigotes of T. cruzi, H510C8C3 clone. One hundred mice were partially treated with benznidazole. Mortality was 100% at day 41 in the control group (nΩ48). At day 90 of the chronic disease (74% survival) mice were divided into three groups and treated orally with trifluralin (50 mg/kg/day, nΩ26), benznidazole (50 mg/kg/day, nΩ25) and vehicle (peanut oil; control group, nΩ23) for 60 days. Electrocardiography (under pentobarbital anaesthesia, 30 mg/kg/dose), serologic immunofluorescence and microstrout were performed at the beginning and at the end of the treatment. Mice were sacrificed at day 10 after treatment; cardiac tissue was studied histopathologically and polymerase chain reaction (PCR) was performed. Spontaneous mortality was 30.43%, 3.85% and 4% in the control, trifluralin and benznidazole groups, respectively (significant survival, PΩ0.03). Microstrouts were negative in all three groups. Negative immunofluorescence titers were 0%, 16% (PΩ0.05) and 29% (PϽ0.02) in the control, trifluralin and benznidazole groups, respectively. The prevailing electrocardiographic disorder was prolongation of the PR interval in the control group, which was not significantly altered in trifluralin-and benznidazole-treated mice, suggesting that trifluralin and benznidazole improve or even stop the damage caused by the disease on the conduction system. Trifluralinand benznidazole-treated animals showed similar histologic patterns of myocarditis. PCR results were negative for benznidazole and trifluralin (100% and 70.8%, respectively). These results show the therapeutic potential of trifluralin in the treatment of chronic Chagas disease.
This study examines the anti-ulcerogenic activity of a chloroform extract of Tanacetum vulgare and purified parthenolide, the major sesquiterpene lactone found in the extract. Gastric ulcers induced by oral administration of absolute ethanol to rats were reduced dose-dependently by oral pretreatment of animals with the chloroform extract (2.5-80 mg kg(-1)) or parthenolide (5-40 mg kg(-1)). When administered 30 min before challenge with the alcohol the protection ranged between 34 and 100% for the extract and 27 and 100% for parthenolide. When the products were administered orally 24 h before treatment with ethanol, 40 mg kg(-1) of the extract and of the lactone reduced the mean ulcer index from 4.8+/-0.3 for control animals to 1.4+/-0.2 and 0.5+/-0.1, respectively. The products also prevented alcohol-induced reduction of the number of sulphydryl groups within the gastric mucosa (50.6+/-2.3 microg (mgprotein)(-1) for normal animals compared with 17.7+/-3.0 microg (mg protein)(-1) for alcohol-treated animals). Administration of the extract (80 mg kg(-1)) or parthenolide (40 mg kg(-1)) 24 h before ethanol treatment restored the numbers of mucosal -SH groups to values near those found for normal animals. These results suggest that the products assayed, in particular parthenolide, might find therapeutic application, although further work is required to establish their profit/risk ratio.
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