Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 20
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Noncoding RNA Res ; 5(1): 11-21, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31993547

RESUMO

Despite historically known as "junk" DNA, nowadays non-coding RNA transcripts (ncRNAs) are considered as fundamental players in various physiological and pathological conditions. Nonetheless, any alteration in their expression level has been reported to be directly associated with the incidence and aggressiveness of several diseases. MicroRNAs (miRNAs) are the well-studied members of the ncRNAs family. Several reports have highlighted their crucial roles in the post-transcriptional manipulation of several signaling pathways in different pathological conditions. In this review, our main focus is the multifaceted microRNA-486 (miR-486). miR-486-5p and miR-486-3p have been reported to have central roles in several types oncological and non-oncological conditions such as lung, liver, breast cancers and autism, intervertebral disc degeneration and metabolic syndrome, respectively. Moreover, we spotted the light onto the pleiotropic role of miR-486-5p in acting as competing endogenous RNA with other members of ncRNAs family such as long non-coding RNAs.

2.
Drug Discov Ther ; 4(4): 276-84, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22491210

RESUMO

Nitric oxide (NO) appears to play a critical role in modulating gastric mucosal defense. Administration of NO donors has been reported to protect the gastrointestinal mucosa against damage induced by several irritants. However, the possible role of NO in healing existing ulcers must be clarified further. Therefore, the present study was designed to assess the effect of modulation of NO on the healing of an indomethacin-induced peptic ulcer using a NO precursor, L-arginine, and a competitive inhibitor of NO synthase, L-NAME. Results of administering L-arginine were compared to those using nitroglycerin (NTG), an NO donor. Rats were injected with a single oral dose of indomethacin (30 mg/kg) and then treated with L-arginine (200 mg/kg, i.p.), NTG (1 mg/kg, i.p.) or L-NAME (15 mg/kg, i.p.) once daily for 7 d starting 4 h after the indomethacin injection. Gross lesion examination and histological assessment were done. NO, prostaglandin (PGE2), and mucin content in gastric tissue were detected. In addition, oxidative stress markers including glutathione (GSH) and lipid peroxides were measured. L-arginine and NTG almost completely healed indomethacin-induced ulceration as indicated by macroscopic and histological examination, restoration of normal levels of NO and GSH, and a significant attenuation of the increase in PGE2 and lipid peroxides induced by indomethacin. In contrast, L-NAME was found to exacerbate mucosal damage. In conclusion, the present study provides further evidence for the role of NO in gastric ulcer healing and it suggests an alternative path to treating the universal problem of non-steroidal anti-inflammatory-drug-induced gastropathy.


Assuntos
Óxido Nítrico , Úlcera Gástrica , Animais , Inibidores Enzimáticos , Mucosa Gástrica , Ratos Wistar , Úlcera Gástrica/induzido quimicamente
3.
J Biochem Mol Toxicol ; 15(4): 207-14, 2001.
Artigo em Inglês | MEDLINE | ID: mdl-11673849

RESUMO

This work aimed to study the relationship between the accumulation of cadmium (Cd) or aluminum (Al) in certain tissues and the levels of lipid peroxides as well as tissue antioxidants. To carry out such investigations, CdCl2 was given to rats in two dose levels; 0.5 or 2.0 mg/kg i.p for 1 day or daily repeated doses for 2 weeks. Al was given as AlCl3 either in a single dose of 100 mg/kg or daily repeated doses of 20 mg/kg for 2 and 4 weeks. The measured parameters were tissue malondialdehyde (MDA, index of lipid peroxidation) and reduced glutathione (GSH) levels as well as the activities of glutathione peroxidase (GSH-PX), glutathione reductase (GSSG-R), and glucose-6-phosphate dehydrogenase (G-6-PDH) enzymes. Liver and kidney functions were assessed by measuring serum alanine aminotransferase (ALT) and alkaline phosphatase (ALP) activities as well as serum urea and creatinine concentrations. Cd and Al concentrations in the studied tissues were also measured. Results indicated that tissue Cd was significantly increased after administration of either Cd doses. After a single dose of 0.5 or 2.0 mg/kg CdCl2, the increase in tissue Cd levels were accompanied by an increase in MDA and a decrease in GSH levels. On the other hand, after repeated administration of Cd, tissue Cd accumulation was accompanied by increased hepatic and renal GSH levels with decrease in MDA content and a decrease in GSH-PX activity in liver. Liver function was affected at all dose regimens, whereas kidney function was affected only after 2 weeks administration of the higher dose. In Al treated rats, Al concentration was shown to be increased in liver much more than in brain. This was accompanied by a slight decrease in hepatic GSH level after 2 weeks and a decrease in GSH-PX activity after 4 weeks. Liver function was affected only after repeated injection of Al for 2 or 4 weeks. In general, Al administration exhibited safer pattern than Cd.


Assuntos
Alumínio/farmacologia , Antioxidantes/metabolismo , Cádmio/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacos , Alumínio/farmacocinética , Animais , Cádmio/farmacocinética , Rim/efeitos dos fármacos , Rim/fisiologia , Testes de Função Hepática , Masculino , Malondialdeído , Ratos , Ratos Wistar
4.
Pharmacol Toxicol ; 89(3): 140-4, 2001 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-11589785

RESUMO

The major limiting factor in long-term administration of doxorubicin is the development of cumulative dose-dependent cardiomyopathy and congestive heart failure. Although several mechanisms have been suggested to explain the exact cause of doxorubicin-induced cardiomyopathy, the role of the vascular endothelium-derived vasoactive mediators in the pathophysiology of this toxic effect is still unknown. Accordingly, the present study has been initiated to investigate whether the changes in plasma level of endothelin-1 and nitric oxide along with cardiac nitric oxide are associated with the development of doxorubicin-induced cardiomyopathy. Doxorubicin was injected with a single dose of 5 mg/kg and every other day with a dose of 5 mg/kg, intraperitoneally, to have four cumulative doses of, 10, 15, 20 and 25 mg/kg in five separate groups of male rats. An additional group receiving a single dose of 20 mg/kg and one receiving normal saline were also included in the study. Twenty-four hr after the last dose, the animals were sacrificed and the plasma levels of endothelin-1 and nitric oxide in addition to cardiac nitric oxide were determined. The results show that doxorubicin caused a statistically significant increase of 85%, 76% and 97% in plasma endothelin-1 at a cumulative dose levels of 10, 15 and 20 mg/kg, respectively. However, the level of plasma nitric oxide remained unchanged. Furthermore, doxorubicin treatment resulted in a significant dose-dependent increase in serum lactate dehydrogenase and creatine phosphokinase. In contrast, the increase in nitric oxide production in cardiac tissue by doxorubicin was not dose-dependent with the maximum increase (81%) at a cumulative dose of 10 mg/kg. It is worth mentioning that plasma endothelin-1 and cardiac nitric oxide were significantly increased at 24 hr after the single dose of 20 mg/kg doxorubicin. The increase of plasma endothelin-1 and cardiac nitric oxide with the cardiomyopathy enzymatic indices, may point to the conclusion that both endothelin-1 and cardiac nitric oxide are increased during the development of doxorubicin-induced cardiomyopathy.


Assuntos
Cardiomiopatia Dilatada/induzido quimicamente , Doxorrubicina/farmacologia , Endotelina-1/sangue , Miocárdio/metabolismo , Óxido Nítrico/sangue , Animais , Cardiomiopatia Dilatada/metabolismo , Creatina Quinase/sangue , Creatina Quinase/efeitos dos fármacos , L-Lactato Desidrogenase/sangue , L-Lactato Desidrogenase/efeitos dos fármacos , Masculino , Ratos , Ratos Sprague-Dawley , Vasodilatadores
5.
Pharmacol Res ; 44(3): 235-42, 2001 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-11529691

RESUMO

This study has been initiated to investigate, in hypercholesterolaemic rabbits, whether L-carnitine deficiency could be an additional risk factor in atherosclerosis, and if so, whether L-carnitine supplementation could prevent the progression of atherosclerosis. Hypercholesterolaemia was induced by feeding rabbits 2% cholesterol-enriched diet for 28 days, whereas, carnitine deficiency was induced by daily i.p. administration of 250 mg kg(-1) of D-carnitine for 28 days. Histopathological examination of aorta and coronaries from hypercholesterolaemic rabbits revealed severe atherosclerotic lesions, intimal plaques and foam cell formation. Also, hypercholesterolaemic diet resulted in a significant 53 and 43% decrease in reduced glutathion (GSH) levels and a significant (1.87-fold) and (14.1-fold) increase in malonedialdhyde (MDA) levels in aorta and cardiac tissues, respectively. Daily administration of L-carnitine (250 mg kg(-1)) for 28 days, completely prevented the progression of atherosclerotic lesions induced by hpercholesterolaemia in both aorta and coronaries. Conversely, daily administration of D-carnitine (250 mg kg(-1)) for 28 days increased the progression of atherosclerotic lesions with the appearance of foam cells and apparent intimal plaques which are even larger than that seen in hypercholesterolaemic rabbits. Both L-carnitine and D-carnitine produced similar effects on the lipid profile, GSH and MDA which may point to the conclusion that: (1) L-carnitine prevents the progression of atherosclerotic lesions by another mechanism in addition to its antioxidant and lipid-lowering effects; (2) endogenous carnitine depletion and/or carnitine deficiency should be viewed as an additional risk factor in atherogenesis.


Assuntos
Arteriosclerose/patologia , Arteriosclerose/prevenção & controle , Carnitina/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Hipercolesterolemia/patologia , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/patologia , Carnitina/deficiência , Carnitina/farmacologia , Vasos Coronários/efeitos dos fármacos , Vasos Coronários/patologia , Hipercolesterolemia/induzido quimicamente , Masculino , Coelhos , Fatores de Risco
6.
Pharmacol Res ; 43(5): 463-7, 2001 May.
Artigo em Inglês | MEDLINE | ID: mdl-11394938

RESUMO

Gastric ulceration was induced in rats by i.p. injection of the non-steroidal anti-inflammatory drug (NSAID), indomethacin (IND) (30 mg kg(-1)). Pyloric ligation was carried out in each animal before injection to enable collection of the gastric juice. Three hours later, the animals were killed and their stomachs were removed. In the gastric juice, the amounts of mucin, pepsin and HCl were assessed. Gastric mucosa were scrapped for the determination of nitric oxide (NO) (as nitrite) after evaluation of the gastric ulcer index. The influence of arginine (ARG) (300 mg kg(-1)), a NO precursor, N(G)-nitro- l -arginine methyl ester (l -NAME) (50 mg kg(-1)), a non-selective constitutive nitric oxide synthase/inducible nitric oxide synthase (cNOS/iNOS) inhibitor, and the selective iNOS inhibitor aminoguanidine (AMG) (50 mg kg(-1)) were studied. Each NO modulator was injected i.p. 30 min before IND administration. Results indicated that IND elevated gastric acidity by 80% of the normal group, decreased non-significantly mucosal nitrite by 22% and exhibited a remarkably high ulcer index (chi = 17). Neither mucin nor pepsin levels were significantly altered. In comparison with the IND group, pretreatment with l -NAME caused a significant decrease in gastric HCl, further decrease in mucosal nitrite (50% of normal) and a two-fold increase in the ulcer index score (chi = 34), despite the decrease in HCl. AMG did not alter gastric acidity, decreased mucosal nitrite by 38% of the normal value and failed to alter significantly the ulcer index of IND. On the other hand, pretreatment with ARG did not alter the gastric acidity and raised mucosal nitrite by 10% above normal. Surprisingly, ARG improved the gastric ulcer score (chi = 1) almost similar to the normal score (chi = zero). Therefore, this study creates a new pathway for the potential treatment of NSAID gastric ulceration through modulation of NO synthesis, regardless of the effect on gastric acidity.


Assuntos
Anti-Inflamatórios não Esteroides/antagonistas & inibidores , Anti-Inflamatórios não Esteroides/toxicidade , Ácido Gástrico/metabolismo , Indometacina/antagonistas & inibidores , Indometacina/toxicidade , Óxido Nítrico/farmacologia , Úlcera Gástrica/prevenção & controle , Proteínas de Transporte Vesicular , Proteínas Adaptadoras de Transporte Vesicular , Animais , Proteínas de Transporte/metabolismo , Inibidores Enzimáticos/farmacologia , Suco Gástrico/efeitos dos fármacos , Suco Gástrico/metabolismo , Mucosa Gástrica/patologia , Masculino , Mucinas/metabolismo , NG-Nitroarginina Metil Éster/farmacologia , Neuropeptídeos/metabolismo , Óxido Nítrico Sintase/antagonistas & inibidores , Ratos , Ratos Wistar , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/patologia
7.
Int J Biochem Cell Biol ; 33(5): 475-82, 2001 May.
Artigo em Inglês | MEDLINE | ID: mdl-11331202

RESUMO

The major goal of this study was to examine the ability of several antioxidants namely, vitamin E, beta-carotene and N-acetylcysteine, to protect the brain from oxidative stress induced by lipopolysaccharide (LPS, endotoxin). LPS, a component of the bacterial wall of gram-negative bacteria, has been recognized as one of the most potent bacterial products in the induction of host inflammatory responses and tissue injury and was used in this study to mimic infections. LPS injection resulted in a significant increase in the stress indices, plasma corticosterone and glucose concentration, a significant alteration of the brain oxidative status observed as elevation of the level of malondialdehyde (MDA, index of lipid peroxidation) and reduction of reduced glutathione (GSH), and a disturbance in the brain energy metabolism presented as a reduction in the ATP/ADP ratio and an increase in the mitochondrial/cytosolic hexokinase ratio. However, the activities of brain superoxide dismutase and Na+, K+-ATPase and contents of cholesterol and phospholipids were not altered. Administration of the aforementioned antioxidants prior to LPS injection ameliorated the oxidative stress by reducing levels of MDA, restoring GSH content and normalizing the mitochondrial/cytosolic hexokinase ratio in the brain in addition to lowering levels of plasma corticosterone and glucose. In conclusion, this study showed the increased free radical generation during infections and LPS-induced stress. It also suggests that brain oxidative status and energy is disturbed.


Assuntos
Acetilcisteína/farmacologia , Encéfalo/metabolismo , Lipopolissacarídeos/farmacologia , Estresse Oxidativo , Vitamina E/farmacologia , beta Caroteno/farmacologia , Trifosfato de Adenosina/metabolismo , Animais , Anti-Inflamatórios/sangue , Antioxidantes/farmacologia , Glicemia/metabolismo , Encéfalo/efeitos dos fármacos , Colesterol/metabolismo , Corticosterona/sangue , Sequestradores de Radicais Livres/farmacologia , Glutationa/metabolismo , Hexoquinase/metabolismo , Lipopolissacarídeos/administração & dosagem , Masculino , Malondialdeído/metabolismo , Fosfolipídeos/metabolismo , Ratos , Ratos Wistar , ATPase Trocadora de Sódio-Potássio/metabolismo , Superóxido Dismutase/metabolismo
8.
Arzneimittelforschung ; 50(5): 449-55, 2000 May.
Artigo em Inglês | MEDLINE | ID: mdl-10858872

RESUMO

The role of nitric oxide (NO) derived from constitutive (cNOS) and inducible (iNOS) nitric oxide synthases and its relationship to oxygen-derived free radicals and prostaglandins was investigated in two models of inflammation, namely, carrageenan granuloma air pouch (acute model) and Freund's adjuvant-induced arthritis (chronic model) in rats. Inflammation was assessed by measurement of NO and prostaglandin E2 (PGE2) levels and the lysosomal leakage of the enzyme N-acetyl-B-D-glucosaminidase (NAG) into the exudate of the granuloma pouch 4 h after carrageenan injection. Evaluation of paw volume and determination of serum NO, lipid peroxide (LP), and PGE2 levels were used for the assessment of adjuvant-induced arthritis after either 4 days (early phase) or 16 days (late phase) of adjuvant injection. Results of the study showed that the administration of either NG-nitro-L-arginine methyl ester (L-NAME, non-selective cNOS/iNOS inhibitor) or aminoguanidine (AG, selective iNOS inhibitor), prior to carrageenan injection or during development of adjuvant arthritis, caused a significant reduction in NO and PGE2 levels and in the NAG activity of the granuloma inflammatory exudate, whereas decreases in paw volume and in serum NO level were noticed in the adjuvant model as related to untreated rats. Similar treatment with L-arginine failed to elaborate a significant change in the parameters measured. Other observations included: no noticeable differences between the results of early and late phases of adjuvant arthritis; no clear correlation between NO, LP and PGE2 levels in the adjuvant arthritis inflammation and inability of the NOS inhibitors to modify the levels of serum LP that is increased during adjuvant-induced arthritis. The data give further evidence that NO is implicated in the development of both acute and chronic inflammation and that NOS inhibitors have potential antiinflammatory activity. Further studies are required to unravel the mechanisms by which NO interacts with other mediators of inflammation.


Assuntos
Inflamação/metabolismo , Óxido Nítrico/biossíntese , Prostaglandinas/biossíntese , Acetilglucosaminidase/metabolismo , Animais , Artrite Experimental/enzimologia , Artrite Experimental/metabolismo , Artrite Experimental/patologia , Carragenina , Dinoprostona/metabolismo , Inibidores Enzimáticos/farmacologia , Radicais Livres/metabolismo , Granuloma/induzido quimicamente , Granuloma/metabolismo , Granuloma/patologia , Guanidinas/farmacologia , Inflamação/patologia , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/análise , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico Sintase Tipo I , Óxido Nítrico Sintase Tipo II , Óxido Nítrico Sintase Tipo III , Ratos , Ratos Sprague-Dawley
9.
Pharmacol Res ; 39(2): 157-66, 1999 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-10072708

RESUMO

Experimental hypercholesterolemia and its modulation by some natural dietary supplements (pectin, garlic and ginseng) and by the drug gemfibrozil were studied. Experimental hypercholesterolemia was induced by feeding rabbits a 2% cholesterol-enriched diet for 28 days. Hypercholesterolemic rabbits were classified into five groups. One group did not receive treatments and served as a control hypercholesterolemic group. The other four groups were fed the cholesterol-enriched diet in conjunction with either 10% pectin, 2% garlic, 2% ginseng or 135 mg g-1 b.w gemfibrozil in a daily oral dose. A normal group of rabbits fed a plain chow diet was also included in the study. The hypolipidemic effect of the above treatments was examined by estimating serum triglycerides (TG), total-, LDL- and HDL-cholesterol. Post-heparin total and hepatic lipase activities were estimated in post-heparin plasma obtained 10 min after an intravenous injection of heparin (200 IU kg-1 b.w). In order to evaluate the antioxidant status of the rabbits, plasma malondialdehyde (MDA) level and erythrocyte superoxide dismutase (SOD) activity were measured. After killing, aorta from all rabbits were subjected to histopathological examination. Results of the study demonstrated that feeding the cholesterol-enriched diet caused a significant increase in total-, LDL-, and HDL-cholesterol, plasma MDA and post-heparin total and hepatic lipase activities. On the other hand, serum TG and erythrocyte SOD were not changed. Histopathological examination revealed marked alteration in the aortic wall with the appearance of large multiple atheromatous plaques. Both garlic and pectin were successful in a significant reduction of the hypercholesterolemia in a way comparable to gemfibrozil. Garlic was the only treatment that has antilipid peroxidative property. Erythrocyte SOD activity was not affected by hypercholesterolemia or by any of the treatments. Also, none of the treatments were able to modify the significant elevation of post-heparin lipolytic activities associated with the hypercholesterolemia or to significantly affect the serum triglycerides level. Finally, among the hypercholesterolemic groups that received treatments, the least changes in the aortic wall were shown in the animals of the gemfibrozil group. Slight degeneration was observed in the aorta of animals treated with pectin or garlic. Ginseng administration failed to exert any significant protection from the remarkable hypercholesterolemia or atherosclerosis associated with the cholesterol- enriched diet.


Assuntos
Alho/química , Hipercolesterolemia/tratamento farmacológico , Hipolipemiantes/farmacologia , Panax/química , Pectinas/farmacologia , Plantas Medicinais , Animais , Aorta/patologia , Colesterol/sangue , Colesterol na Dieta/administração & dosagem , Genfibrozila/farmacologia , Hipercolesterolemia/sangue , Hipercolesterolemia/patologia , Masculino , Fotomicrografia , Coelhos , Superóxido Dismutase/sangue , Triglicerídeos/sangue
10.
J Nutr ; 127(2): 218-24, 1997 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-9039821

RESUMO

The cellular distribution of enzymes that esterify retinol and hydrolyze retinyl esters (RE) was studied in liver of vitamin A-sufficient, -deficient, and deficient rats treated with retinoic acid or N-(4-hydroxyphenyl)-retinamide. Livers were perfused and cell fractions enriched in hepatocytes, and nonparenchymal cells were obtained for assays of RE and enzyme activity. The specific activity of lecithin:retinol acyltransferase (LRAT) was approximately 10-fold greater in the nonparenchymal cell than the hepatocyte fraction from both vitamin A-sufficient and retinoid-treated rats. Total RE mass, newly synthesized [3H]RE and LRAT activity were positively correlated in liver and isolated cells of both normal (P < 0.0001) and retinoid-treated rats (P < 0.0002). In nonparenchymal cells, these three constituents were nearly equally enriched as evaluated by their relative specific activity values (RSA, defined as the percentage of recovered activity divided by the percentage of recovered protein), which were each significantly greater than 1.0, with values of 4.3 for total RE mass (P < 0.05), 3.6 for newly synthesized [3H]RE (P < 0.01) and 3.8 for LRAT activity (P < 0.01). In contrast, the specific activities of neutral and acid bile salt-independent retinyl ester hydrolases (REH) did not vary with vitamin A status, and their RSA values were close to 1.0 in both hepatocytes and nonparenchymal cells. These data show that LRAT and REH are differentially regulated by retinoids and that these enzymes also differ in their spacial distribution between liver parenchymal and nonparenchymal cells.


Assuntos
Aciltransferases/metabolismo , Hidrolases de Éster Carboxílico/metabolismo , Fenretinida/farmacologia , Fígado/enzimologia , Tretinoína/farmacologia , Animais , Feminino , Fígado/citologia , Masculino , Ratos , Ratos Endogâmicos Lew , Tretinoína/fisiologia , Vitamina A/administração & dosagem , Deficiência de Vitamina A/enzimologia
11.
Dis Markers ; 13(1): 19-29, 1996 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-8875115

RESUMO

Serum lactate dehydrogenase (LDH) isoenzyme and amino acid (a.a) patterns were evaluated in comparison to several other biochemical parameters for liver and renal function with the objective of clarifying the differential diagnosis of hepatic disorders and predicting the outcome of schistosomal infection in Egyptian patients. Patients examined included those with complicated hepatic disorders and others with different stages of schistosomal infestation, hepatoma or bladder cancer, in addition to a normal control group. Several biochemical parameters appeared to be useful in establishing consistent differences or similarities between the studied groups. Examples are; elevated serum AST/ALT ratio and methionine content in chronic schistosomiasis, elevated serum urea/creatinine ratio and leucine content in all schistosomal patients and extremely high levels of N-acetyl-beta-D-glucosaminidase (NAG) in the urine of non-schistosomal bladder cancer patients. In addition, characteristic LDH isoenzyme profiles distinguish between the studied groups, in particular separating chronic schistosomiasis from schistosomal bladder cancer and hepatoma from other hepatic disorders.


Assuntos
Aminoácidos/sangue , L-Lactato Desidrogenase/sangue , Esquistossomose/sangue , Acetilglucosaminidase/urina , Alanina Transaminase/sangue , Aspartato Aminotransferases/sangue , Humanos , Isoenzimas , Rim/fisiopatologia , Fígado/fisiopatologia , Esquistossomose/fisiopatologia
12.
Experientia ; 52(4): 336-9, 1996 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-8620936

RESUMO

The level of malondialdehyde (MDA), an index of lipid peroxidation, and the antioxidants superoxide dismutase (SOD) and glutathione (GSH), as well as the activity of Na+, K(+)-ATPase, were assessed in whole rat brain after immobilization, anemic hypoxia (NaNO2) and 72 h starvation. The effect of these stressors on plasma glucose and corticosterone levels was also observed. Hypoxia and starvation stimulated the lipid peroxide formation in brain as indicated by an increase in the level of MDA, being higher after starvation than hypoxia. Brain SOD activity was also increased in response to hypoxia and starvation while GSH content was only diminished in hypoxia. However, neither MDA nor antioxidants were affected by immobilization. On the other hand, the activity of brain Na+, K(+)-ATPase was significantly increased by immobilization and hypoxia but decreased in starvation. A similar pattern of change was also observed in plasma glucose and corticosterone levels in response to these stressors. These results elucidate differences in the biochemical response of animals towards various types of stress, with increased lipid peroxide formation in hypoxia and starvation.


Assuntos
Antioxidantes/metabolismo , Encéfalo/metabolismo , Peroxidação de Lipídeos , ATPase Trocadora de Sódio-Potássio/metabolismo , Estresse Fisiológico/metabolismo , Animais , Glicemia/metabolismo , Corticosterona/sangue , Glutationa/metabolismo , Hipóxia , Masculino , Malondialdeído/metabolismo , Ratos , Ratos Wistar , Restrição Física , Inanição/metabolismo , Superóxido Dismutase/metabolismo
13.
Arzneimittelforschung ; 45(12): 1324-8, 1995 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-8595093

RESUMO

Three antischistosomal drugs, praziquantel (CAS 55268-74-1, EMBAY 8440, Prz), oxamniquine (CAS 21738-42-1, Oxa) and oltipraz (CAS 64224-21-1, Olt) were examined for their ability to reverse the disturbances in carbohydrate metabolism induced by Schistosoma mansoni (S. mansoni) infection. The infected mice were screened every 2 weeks for 16 weeks for their body and liver weights in addition to assessment of the activities of liver pyruvate kinase (PK), phosphofructokinase (PFK) (glycolysis), citrate synthase (CS) (Krebs' cycle) glycogen phosphorylase (GP) (glycogenolysis), glucose-6-phosphate dehydrogenase (G6PDH) and 6-phosphogluconate dehydrogenase (6PGDH) (hexose monophosphate shunt). Results of the study showed that infection with S. mansoni caused the following changes in mice livers: 1. significant increase in liver weights from the 6th week of infection, which coincided with schistosomal egg deposition, whereas body weights were reduced, 2. remarkable increase in the activities of PK and PFK from the 4th week of infection, 3. marked reduction in CS, GP, G6PDH and 6PGDH. These results lead to the conclusion that glycolysis is largely stimulated in the livers of infected mice on the expense of other metabolic pathways of glucose utilization. Administration of Prz to infected mice caused normalization of all measured enzyme activities almost from the 2nd week of infection, whereas liver and body weights were improved from the 10th week. Oxa was less effective in these regards while Olt was the least. These data support the selection of Prz as a drug of choice for S. mansoni infection.


Assuntos
Glucose/metabolismo , Fígado/enzimologia , Esquistossomose mansoni/enzimologia , Esquistossomicidas/uso terapêutico , Animais , Peso Corporal/efeitos dos fármacos , Ciclo do Ácido Cítrico/efeitos dos fármacos , Feminino , Glicólise/efeitos dos fármacos , Fígado/efeitos dos fármacos , Glicogênio Hepático/metabolismo , Masculino , Camundongos , Tamanho do Órgão/efeitos dos fármacos , Oxamniquine/uso terapêutico , Oxamniquine/toxicidade , Via de Pentose Fosfato/efeitos dos fármacos , Praziquantel/uso terapêutico , Praziquantel/toxicidade , Pirazinas/uso terapêutico , Pirazinas/toxicidade , Esquistossomose mansoni/tratamento farmacológico , Esquistossomicidas/toxicidade , Tionas , Tiofenos
14.
Pharmacol Res ; 32(5): 279-85, 1995 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-8868057

RESUMO

In the present study, the potential involvement of lipid peroxidation and disruption of lysosomal integrity in the pathogenesis of different experimental models of inflammation was examined. The chosen models were carrageenan-induced paw oedema, carrageenan granuloma pouch (acute phase) and Freund's adjuvant-induced arthritis in rats. The pharmacological and biochemical effects of naftazone, a lysosomal membrane stabilizer and indomethacin, a standard anti-inflammatory agent were evaluated with regard to paw oedema volume, serum and exudate activities of the lysosomal enzyme N-acetyl-beta-D-glucosaminidase (NAG), in addition to serum and liver lipid peroxide (LP) levels. Intraperitoneal administration of the test drugs, in rats subjected to inflammation, produced: (1) a significant inhibition of carrageenan-induced paw oedema, (2) a marked reduction of the paw oedema of the Freund's adjuvant arthritis animals, (3) a remarkable decrease of lysosomal leakage of NAG into the exudate of carrageenan granuloma pouch, (4) a slight, but significant, reduction of NAG activity in the serum of rats subjected to carrageenan inflammation, and (5) a reduction of the serum level of LP that was elevated in adjuvant-induced arthritic rats. The level of liver LP was altered by either drugs in an opposite manner; while naftazone lowered hepatic LP, indomethacin markedly elevated its level. The results of the present investigation revealed that lipid peroxidation and disruption of lysosomal integrity are implicated in the pathogenesis of inflammatory processes, and the protection against these deleterious effects imparted both drugs significant anti-inflammatory activity.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Indometacina/farmacologia , Inflamação/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Lisossomos/efeitos dos fármacos , Naftoquinonas/farmacologia , Acetilglucosaminidase/metabolismo , Animais , Artrite Experimental/metabolismo , Artrite Experimental/patologia , Carragenina , Edema/induzido quimicamente , Edema/patologia , Pé/patologia , Adjuvante de Freund , Granuloma/metabolismo , Inflamação/patologia , Lisossomos/ultraestrutura , Masculino , Ratos , Ratos Sprague-Dawley
15.
J Lipid Res ; 36(7): 1498-506, 1995 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-7595074

RESUMO

Previous studies have indicated the presence of both neutral and acid, bile salt-independent retinyl ester hydrolases associated with plasma membrane and endosome fractions of rat liver homogenates. In the present studies, chylomicrons containing tritium-labeled retinyl esters were injected intravenously into rats in order to study the initial metabolism of retinyl esters during and after uptake into the liver. At various times after chylomicron injection, plasma was obtained and the liver was homogenized and subjected to analytical subcellular fractionation. Labeled retinyl esters were rapidly cleared from plasma (half-time approximately 10 min) and appeared in the liver. Within the liver, label first appeared in plasma membrane/endosomal fractions that were also enriched in both neutral and acid, bile salt-independent retinyl ester hydrolase activities. At no time were the labeled esters significantly associated with fractions enriched in lysosomes. Rather, it appeared that the labeled esters were hydrolyzed and/or transferred to fractions enriched in endoplasmic reticulum. These studies demonstrate the co-localization of newly delivered retinyl esters and bile salt-independent retinyl ester hydrolase enzyme activities and thus, suggest a probable role for these enzymes in the initial hepatic metabolism of chylomicron retinyl esters. This conclusion was further supported by the observation that plasma membrane/endosomal fractions were active in catalyzing the hydrolysis of chylomicron remnant retinyl esters in vitro.


Assuntos
Hidrolases de Éster Carboxílico/metabolismo , Membrana Celular/enzimologia , Quilomícrons/metabolismo , Endossomos/enzimologia , Fígado/enzimologia , Retinoides/metabolismo , Animais , Assialoglicoproteínas , Fracionamento Celular , Esterificação , Fetuínas , Cinética , Fígado/ultraestrutura , Masculino , Microssomos Hepáticos/enzimologia , Microssomos Hepáticos/ultraestrutura , Ratos , Ratos Sprague-Dawley , Trítio , Vitamina A/metabolismo , alfa-Fetoproteínas
16.
Pharmacol Res ; 31(1): 73-9, 1995 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-7784309

RESUMO

Pumpkin-seed oil (PSO), a natural supplement rich with antioxidant ingredients, was given to rats in which arthritis was induced using Freund's complete adjuvant. Its effect was compared with that of indomethacin, as a classical anti-inflammatory agent. Two experimental patterns were studied, an acute phase that was applied only with PSO and a chronic phase applied for both PSO and indomethacin. Compared to normal untreated rats, it was shown that the induction of arthritis caused a decrease in serum sulphhydryl groups, with an increase in serum ceruloplasmin in both phases. Blood glutathione was first elevated in the acute phase, then its level was reduced in the chronic phase. Serum N-acetyl-beta-D-glucosaminidase activity was elevated only at the acute phase, while plasma total proteins and albumin were reduced at the chronic phase. Liver glucose-6-phosphate dehydrogenase activity was markedly increased, while no changes were observed in the levels of liver lipid peroxides and glutathione. These changes in the studied parameters were attributed to the superoxides and free radicals during arthritic inflammation. Administration of PSO succeeded in modulating most of the altered parameters affected during arthritis, especially at the chronic phase. Also, a remarkable inhibition of paw oedema was observed. A similar pattern was obtained upon treatment with indomethacin except that indomethacin markedly elevated liver lipid peroxides levels. Concurrent administration of PSO with indomethacin caused no changes in the parameters studied compared to that induced by treatment with indomethacin alone.


Assuntos
Artrite Experimental/tratamento farmacológico , Sequestradores de Radicais Livres , Óleos/farmacologia , Sementes/química , Animais , Artrite Experimental/induzido quimicamente , Modelos Animais de Doenças , Glutationa/sangue , Indometacina/farmacologia , Fígado/efeitos dos fármacos , Masculino , Ratos , Ratos Sprague-Dawley , Fatores de Tempo
17.
Biochem Pharmacol ; 48(1): 139-44, 1994 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-8043015

RESUMO

Non-specific carboxylesterases (carboxylesterases) and glutathione S-transferases (GSTs) are two groups of drug metabolizing enzymes responsible for hydrolysis and glutathione conjugation of xenobiotics. This study was conducted to determine the following: (1) the distribution of carboxylesterase and GST activities in different rat liver cells, (2) the effects of vitamin A deficiency (A-) on the absolute activities and on the distribution of carboxylesterases and GSTs in rat liver. Rat livers were fractionated into parenchymal and non-parenchymal cells by means of collagenase perfusion and differential centrifugation. Non-parenchymal cells were further fractionated by means of Percoll density gradient centrifugation into a layer of Kupffer cells and another layer containing stellate and endothelial cells. Carboxylesterase and GST activities were determined in these fractions. show that: (1) both carboxylesterases and GSTs were mainly localized in the parenchymal fraction, (2) there was no significant difference between male and female rats with regard total activity or distribution of carboxylesterases and GSTs in rat liver cells, (3) A- caused a highly significant reduction in carboxylesterase and GST activities in total liver homogenates and parenchymal cells. This reduction was not ameliorated by administration of retinoic acid 18 hr before sacrifice of animals. These results open up a new era of investigations about the potential role of vitamin A in the regulation of detoxification enzymes.


Assuntos
Hidrolases de Éster Carboxílico/metabolismo , Glutationa Transferase/metabolismo , Fígado/enzimologia , Deficiência de Vitamina A/enzimologia , Animais , Feminino , Masculino , Gravidez , Ratos , Ratos Sprague-Dawley , Fatores Sexuais , Vitamina A/metabolismo
18.
J Biol Chem ; 268(24): 17867-70, 1993 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-8349671

RESUMO

Radiation inactivation by high energy electrons, a method for determining the size of a protein without prior purification, was used to study the acid and neutral cholesteryl ester hydrolase (CEH) activities of rat liver microsomes. The same preparations were also assayed for the microsomal, "nonspecific" carboxylesterases using o-nitrophenyl acetate as substrate. Non-specific esterase activity surviving radiation could be fit to a single exponential function, the slope of which yielded a target size of 47 +/- 5 kDa (mean +/- S.D., n = 7). Surviving CEH activity assayed at pH 5 could also be fit to a single exponential that yielded a target size of 71 +/- 14 kDa (n = 5). In contrast, the surviving CEH activity assayed at pH 7 was more complex. The data from six experiments were described as the sum of two exponentials, indicating that most of the activity is due to an entity that is three to four times larger and a minor amount to one that is half the size of the pH 5 enzyme. The results are consistent with the suggestion that the acid and neutral microsomal CEH activities are due to distinct enzymes, which are not the "nonspecific" carboxylesterases. Their sizes also differ from those previously determined for lysosomal acid lipase and other lipases in the liver.


Assuntos
Microssomos Hepáticos/enzimologia , Esterol Esterase/antagonistas & inibidores , Esterol Esterase/efeitos da radiação , Animais , Hidrolases de Éster Carboxílico/metabolismo , Hidrolases de Éster Carboxílico/efeitos da radiação , Relação Dose-Resposta à Radiação , Elétrons , Cinética , Masculino , Peso Molecular , Ratos , Ratos Sprague-Dawley
19.
J Lipid Res ; 32(4): 685-93, 1991 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-1856611

RESUMO

We recently reported the presence of a neutral, bile salt-independent retinyl ester hydrolase (REH) activity in rat liver microsomes and showed that it was distinct from the previously studied bile salt-dependent REH and from nonspecific carboxylesterases (Harrison, E. H., and M. Z. Gad. 1989. J. Biol. Chem. 264: 17142-17147). We have now further characterized the hydrolysis of retinyl esters by liver microsomes and have compared the observed activities with those catalyzing the hydrolysis of cholesteryl esters. Microsomes and microsomal subfractions enriched in plasma membranes and endosomes catalyze the hydrolysis of retinyl esters at both neutral and acid pH. The acid and neutral REH enzyme activities can be distinguished from one another on the basis of selective inhibition by metal ions and by irreversible, active site-directed serine esterase inhibitors. The same preparations also catalyze the hydrolysis of cholesteryl esters at both acid and neutral pH. However, the enzyme(s) responsible for the neutral REH activity can be clearly responsible for the neutral REH activity can be clearly differentiated from the neutral cholesteryl ester hydrolase(s) on the basis of differential stability, sensitivity to proteolysis, and sensitivity to active site-directed reagents. These results suggest that the neutral, bile salt-independent REH is relatively specific for the hydrolysis of retinyl esters and thus may play an important physiological role in hepatic vitamin A metabolism. In contrast to the neutral hydrolases, the activities responsible for hydrolysis of retinyl esters and cholesterol esters at acid pH are similar in their responses to the treatments mentioned above. Thus, a single microsomal acid hydrolase may catalyze the hydrolysis of both types of ester.(ABSTRACT TRUNCATED AT 250 WORDS)


Assuntos
Hidrolases de Éster Carboxílico/metabolismo , Microssomos Hepáticos/enzimologia , Esterol Esterase/metabolismo , Animais , Ácidos e Sais Biliares/farmacologia , Ésteres do Colesterol/metabolismo , Estabilidade Enzimática , Esterases/antagonistas & inibidores , Concentração de Íons de Hidrogênio , Hidrólise , Masculino , Metais/farmacologia , Microssomos Hepáticos/efeitos dos fármacos , Ratos , Ratos Endogâmicos , Frações Subcelulares/fisiologia , Vitamina A/análogos & derivados , Vitamina A/metabolismo
20.
J Biol Chem ; 264(29): 17142-7, 1989 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-2793848

RESUMO

Previous studies have demonstrated that homogenates of the livers of rats contain a neutral retinyl ester hydrolase activity that requires millimolar concentrations of bile salts for maximal in vitro activity. The enzymatic properties of this neutral, bile salt-dependent retinyl ester hydrolase activity in liver homogenates are nearly identical to those observed in the present report for the in vitro hydrolysis of retinyl palmitate by purified rat pancreatic cholesteryl ester hydrolase (EC 3.1.1.13). Moreover, anti-rat pancreatic cholesteryl ester hydrolase IgG completely inhibits the bile salt-dependent retinyl ester hydrolase activity of rat liver homogenates whereas normal rabbit IgG does not. We also show that liver homogenates contain a neutral, bile salt-independent retinyl ester hydrolase activity that differs from the bile salt-dependent activity in that 1) its absolute activity does not vary markedly among individual rats, 2) it is not inhibited by antibodies to pancreatic cholesteryl ester hydrolase, and 3) it is localized in the microsomal fraction of liver homogenates. Subfractionation of microsomes demonstrates that the neutral, bile salt-independent retinyl ester hydrolase activity is associated with liver cell plasma membranes and thus may play a role in the hydrolysis of retinyl esters delivered to the liver by chylomicron remnants.


Assuntos
Ácidos e Sais Biliares/farmacologia , Hidrolases de Éster Carboxílico/metabolismo , Fígado/enzimologia , Pâncreas/enzimologia , Vitamina A/análogos & derivados , Animais , Membrana Celular/enzimologia , Citosol/enzimologia , Diterpenos , Hidrólise , Imunoglobulina G , Masculino , Microssomos Hepáticos/enzimologia , Ratos , Ratos Endogâmicos , Ésteres de Retinil , Esterol Esterase/imunologia , Esterol Esterase/metabolismo , Vitamina A/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...