Adjuvant-induced arthritis is an experimental immunopathology in rats that is often used as a model for studying autoimmune chronic inflammation and inflammatory cachexia. In these animals oxidative stress is quite pronounced in the articular inflammation sites. The purpose of this study was to evaluate oxidative stress in the liver of arthritic rats in which morphological and metabolic alterations have been reported to occur. Oxidative injury parameters, levels and production of reactive oxygen species (ROS), and antioxidant parameters were measured in the total liver homogenate and in subcellular fractions, namely cytosol, mitochondria, and peroxisomes. Arthritic rats presented higher levels of ROS than controls in the total homogenate (46% higher) and in all subcellular fractions (51, 38, and 55% higher for mitochondria, peroxisome, and cytosol, respectively). Arthritic rats also presented higher levels of protein carbonyl groups in the total homogenate (75%) and in all subcellular fractions (189, 227, and 260%, respectively, for mitochondria, peroxisomes, and cytosol). The TBARS levels of arthritic rats were more elevated in the total homogenate (36%), mitochondria (20%), and peroxisomes (16%). Arthritic rats also presented higher levels of NO markers in the peroxisomes (112%) and in the cytosol (35%). The catalase activity of all cell compartments was strongly diminished (between 77 and 87%) by arthritis, and glutathione peroxidase activities were diminished in the mitochondria (33.7%) and cytosol (41%). The cytosolic glucose-6-phosphate dehydrogenase activity, on the other hand, was increased (62.9%), the same happening with inducible peroxisomal NO synthase (119.3%). The superoxide dismutase and glutathione reductase activities were not affected. The GSH content was diminished by arthritis in all cellular compartments (50 to 59% diminution). The results reveal that the liver of rats with adjuvant-induced arthritis presents a pronounced oxidative stress and that, in consequence, injury to lipids and proteins is highly significant. The higher ROS content of the liver of arthritic rats seems to be the consequence of both a stimulated pro-oxidant system and a deficient antioxidant defense with a predominance of the latter as indicated by the strongly diminished activities of catalase and glutathione peroxidase.

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The present study investigated the action of copaiba oil (Copaifera reticulata) on the systemic inflammation, oxidative status, and liver cell metabolism of rats with adjuvant-induced arthritis. The later is an experimental autoimmune pathology that shares many features with the human rheumatoid arthritis. Holtzman rats were distributed into the following groups: control (healthy) rats; control rats treated with copaiba oil at the doses of 0.58 and 1.15 g · kg , arthritic rats, and arthritic rats treated with copaiba oil (0.58 and 1.15 g · kg ). The oil was administrated orally once a day during 18 days after arthritis induction. Both doses of copaiba oil improved the paw edema and the dose of 0.58 mg · kg improved the swollen adrenals and lymph nodes besides decreasing the plasmatic myeloperoxidase activity (-30%) of arthritic rats. Copaiba oil (1.15 g · kg ) abolished the increases of protein carbonyl groups and reactive oxygen species in the liver and both doses increased the liver GSH content and the catalase activity in arthritic rats. Copaiba oil (1.15 g · kg ) decreased glycolysis (-65%), glycogenolysis (-58%), and gluconeogenesis (-30%) in the liver of arthritic animals. However, gluconeogenesis was also diminished by the treatment of control rats, which presented lower body weight gain (-45%) and diminished number of hepatocytes per liver area (-20%) associated to higher liver weight (+29%) and increased hepatocyte area (+13%). The results reveal that copaiba oil presented systemic anti-inflammatory and antioxidant actions in arthritic rats. These beneficial effects, however, were counterbalanced by harmful modifications in the liver cell metabolism and morphology of healthy control rats. J. Cell. Biochem. 118: 3409-3423, 2017. © 2017 Wiley Periodicals, Inc.

Adjuvant arthritis in rats, as rheumatoid arthritis in humans, may be of greater or lesser severity, namely polyarthritis and monoarthritis, respectively. The present study was planned to evaluate the oxidative changes in the blood and specifically in the serum albumin of rats with adjuvant-induced mono- and poly-arthritis. Total antioxidant capacity, thiols, carbonyl groups, albumin, uric acid and ascorbic acid were measured in the total serum. The specific oxidative status of albumin was also measured after separation by affinity chromatography. All serum oxidative parameters were close to normal in monoarthritic rats with the exception of the ascorbic acid concentration, which was 23 % lower, and albumin carbonyl groups, which were 64 % higher. Many modifications were found in polyarthritic rats, specially the ascorbic acid concentration (35 % lower) and albumin carbonyl groups (102 % higher). The results revealed that the levels of ascorbic acid in the serum and carbonyl groups in the albumin molecule can be regarded as indicators of the severity of arthritis since they were modified by both monoarthritis and polyarthritis, but to different degrees.

BackgroundGlutaminase predominates in periportal hepatocytes and it has been proposed that it determines the glutamine-derived nitrogen flow through the urea cycle. Glutamine-derived urea production should, thus, be considerably faster in periportal hepatocytes. This postulate, based on indirect observations, has not yet been unequivocally demonstrated, making a direct investigation of ureogenesis from glutamine highly desirable.MethodsZonation of glutamine metabolism was investigated in the bivascularly perfused rat liver with [U-14C]glutamine infusion (0.6 mM) into the portal vein (antegrade perfusion) or into the hepatic vein (retrograde perfusion).ResultsAmmonia infusion into the hepatic artery in retrograde and antegrade perfusion allowed to promote glutamine metabolism in the periportal region and in the whole liver parenchyma, respectively. The results revealed that the space-normalized glutamine uptake, indicated by 14CO2 production, gluconeogenesis, lactate production and the associated oxygen uptake, predominates in the periportal region. Periportal predominance was especially pronounced for gluconeogenesis. Ureogenesis, however, tended to be uniformly distributed over the whole liver parenchyma at low ammonia concentrations (up to 1.0 mM); periportal predominance was found only at ammonia concentrations above 1 mM. The proportions between the carbon and nitrogen fluxes in periportal cells are not the same along the liver acinus.ConclusionsIn conclusion, the results of the present work indicate that the glutaminase activity in periportal hepatocytes is not the rate-controlling step of the glutamine-derived nitrogen flow through the urea cycle. The findings corroborate recent work indicating that ureogenesis is also an important ammonia-detoxifying mechanism in cells situated downstream to the periportal region.

The current study investigated the action of β-caryophyllene, the major constituent of copaiba oil, on the systemic inflammation, oxidative status, and liver cell metabolism of rats with adjuvant-induced arthritis, a model for rheumatoid arthritis. This study also compared the actions of β-caryophyllene with those previously reported for copaiba oil on arthritic rats. For this purpose, Holtzman healthy and arthritic rats received 215 and 430 mg·kg β-caryophyllene orally once a day during 18 days. Both doses of β-caryophyllene reduced the adjuvant-induced paw edema, swollen of lymph nodes, and number of circulating and articular leukocytes. β-Caryophyllene, at the dose of 430 mg·kg , abolished the increases of protein carbonyl groups and myeloperoxidase activity in the liver and plasma of arthritic rats and, at both doses, it restored the increased levels of reactive oxygen species and reduced glutathione in the arthritic liver. These beneficial actions were of the same extension as those of copaiba oil ( Copaifera reticulata) and, therefore, β-caryophyllene is possibly responsible for the anti-inflammatory and antioxidant actions of the oil. Hepatic gluconeogenesis was 40% lower in arthritic rats, which also presented a reduced number of hepatocytes per liver area (-23%) associated with increased hepatocyte area (+18%) and liver weight (+50%). None of these hepatic alterations were improved by β-caryophyllene, but not even by ibuprofen. However, unlike copaiba oil, β-caryophyllene did not modify the hepatic morphology and metabolism of healthy rats. These results reveal that β-caryophyllene improves the systemic inflammation and oxidative status of arthritic rats and, in addition, it was not associated with hepatotoxicity.

Abstract:The fruit extracts of Citrus aurantium (bitter orange) are traditionally used as weight-loss products and as appetite supressants. An important fruit component is p-synephrine, which is structurally similar to the adrenergic agents. Weight-loss and adrenergic actions are always related to metabolic changes and this work was designed to investigate a possible action of the C. aurantium extract on liver metabolism. The isolated perfused rat liver was used to measure catabolic and anabolic pathways, including oxygen uptake and perfusion pressure. The C. aurantium extract and p-synephrine increased glycogenolysis, glycolysis, oxygen uptake and perfusion pressure. These changes were partly sensitive to -and -adrenergic antagonists. p-Synephrine (200 M) produced an increase in glucose output that was only 15% smaller than the increment caused by the extract containing 196 M p-synephrine. At low concentrations the C. aurantium extract tended to increase gluconeogenesis, but at high concentrations it was inhibitory, opposite to what happened with p-synephrine. The action of the C. aurantium extract on liver metabolism is similar to the well known actions of adrenergic agents and can be partly attributed to its content in p-synephrine. Many of these actions are catabolic and compatible with the weight-loss effects usually attributed to C. aurantium.

The aim of the present study was to compare the in vitro inhibitory effects on the salivary and pancreatic α-amylases and the in vivo hypoglycemic actions of the hydrolysable tannin from Chinese natural gall and the condensed tannin from Acacia mearnsii. The human salivary α-amylase was more strongly inhibited by the hydrolysable than by the condensed tannin, with the concentrations for 50% inhibition (IC50) being 47.0 and 285.4 μM, respectively. The inhibitory capacities of both tannins on the pancreatic α-amylase were also different, with IC50 values being 141.1 μM for the hydrolysable tannin and 248.1 μM for the condensed tannin. The kinetics of the inhibition presented complex patterns in that for both inhibitors more than one molecule can bind simultaneously to either the free enzyme of the substrate-complexed enzyme (parabolic mixed inhibition). Both tannins were able to inhibit the intestinal starch absorption. Inhibition by the hydrolysable tannin was concentration-dependent, with 53% inhibition at the dose of 58.8 μmol/kg and 88% inhibition at the dose of 294 μmol/kg. For the condensed tannin, inhibition was not substantially different for doses between 124.4 μmol/kg (49%) and 620 μmol/kg (57%). It can be concluded that both tannins, but especially the hydrolysable one, could be useful in controlling the postprandial glycemic levels in diabetes.