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991.
Lladó I Rodríguez-Cuenca S Pujol E Monjo M Estrany ME Roca P Palou A 《Obesity research》2002,10(4):296-305
OBJECTIVE: To investigate the effects of short-term (15 days) cafeteria-diet feeding on the expression of alpha- and beta-adrenergic receptors (AR) and its association with lipolytic stimulation in isolated retroperitoneal white adipocytes. RESEARCH METHODS AND PROCEDURES: Six female and 6 male Wistar rats (4 weeks old) were fed a cafeteria diet plus standard diet for 15 days. The remaining 12 age- and sex-matched rats received a standard diet only. White retroperitoneal adipose tissue was isolated and used for the determination of both alpha(2) and beta-AR expression and for in vitro studies of lipolytic activity. RESULTS: In female control rats, we found higher lipolytic capacities located at the postreceptor level and a lower alpha(2)/beta(3)-AR ratio than male rats. Cafeteria-diet feeding for 15 days decreased lipolytic activity in both male and female rats and altered the alpha(2A)- and beta(3)-AR protein levels with an increase of alpha(2A)-AR in males and a beta(3)-AR decrease in females. DISCUSSION: Our results indicate that a 15-day cafeteria-diet feeding induced an increase in the alpha(2)/beta(3)-AR balance and impaired adipose tissue lipolytic activity, which was higher in males and may contribute to the development of increased fat mass. The higher functionality of alpha(2)-AR, together with the minor role developed by beta(3)-AR and lower lipolytic capacities located at the postreceptor level in cafeteria-diet-fed male rats compared with female rats, may be responsible for the gender-dependent differences observed in this study. 相似文献
992.
Cyclooxygenase-1 derived prostaglandins are involved in the maintenance of renal function in rats with cirrhosis and ascites 总被引:1,自引:0,他引:1
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López-Parra M Clària J Planagumà A Titos E Masferrer JL Woerner BM Koki AT Jiménez W Altuna R Arroyo V Rivera F Rodés J 《British journal of pharmacology》2002,135(4):891-900
1. The maintenance of renal function in decompensated cirrhosis is highly dependent on prostaglandins (PGs). Since PG synthesis is mediated by cyclooxygenase-1 and -2 (COX-1 and COX-2), the present study was designed to examine which COX isoform is involved in this phenomenon. 2. Renal COX-1 and COX-2 protein expression and distribution were analysed by Western blot and immunohistochemistry in nine rats with carbon tetrachloride-induced cirrhosis and ascites and 10 control animals. The effects of placebo and selective COX-1 (SC-560) and COX-2 (celecoxib) inhibitors on urine flow (V), urinary excretion of sodium (U(Na)V) and PGE(2) (U(PGE2)V), glomerular filtration rate (GFR), renal plasma flow (RPF), the diuretic and natriuretic responses to furosemide and renal water metabolism were assessed in 88 rats with cirrhosis and ascites. 3. COX-1 protein levels were found to be unchanged in kidneys from cirrhotic rats. In contrast, these animals showed enhanced renal COX-2 protein expression which was focally increased in the corticomedullary region. Although U(PGE2)V was equally reduced by SC-560 and celecoxib, only SC-560 produced a significant decrease in U(Na)V, GFR and RPF and a pronounced impairment in the diuretic and natriuretic responses to furosemide in rats with cirrhosis and ascites. Neither SC-560 nor celecoxib affected renal water metabolism in cirrhotic rats. 4. These results indicate that despite abundant renal COX-2 protein expression, the maintenance of renal function in cirrhotic rats is mainly dependent on COX-1-derived prostaglandins. 相似文献
993.
Induction of insulin resistance by high-sucrose feeding does not raise mean arterial blood pressure but impairs haemodynamic responses to insulin in rats 总被引:4,自引:0,他引:4
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Santuré M Pitre M Marette A Deshaies Y Lemieux C Larivière R Nadeau A Bachelard H 《British journal of pharmacology》2002,137(2):185-196
1. This study was undertaken to further investigate the effects of a sucrose-enriched diet on vascular function and insulin sensitivity in rats. 2. Male Sprague-Dawley rats were randomized to receive a sucrose- or regular rat chow-diet for 4 weeks. A first group of sucrose- and chow-fed rats was instrumented with pulsed Doppler flow probes and intravascular catheters to determine blood pressure, heart rate, regional blood flows and insulin sensitivity in conscious rats. Insulin sensitivity was assessed by the euglycemic hyperinsulinemic clamp technique. Glucose transport activity was examined in isolated muscles by using the glucose analogue [(3)H]-2-deoxy-D-glucose. A second group of sucrose- and chow-fed rats was used to obtain information regarding nitric oxide synthase (NOS) isozymes protein expression in muscles, and determine endothelin content in vascular tissues isolated from both dietary groups. 3. Sucrose feeding was found to induce insulin resistance, but had no effect on resting blood pressure, heart rate, or regional haemodynamics. This insulin resistance was accompanied by alteration in the vascular responses to insulin. Insulin-mediated skeletal muscle vasodilation was impaired, whereas the mesenteric vasoconstrictor response was potentiated in sucrose-fed rats. A reduction in eNOS protein content in muscle and an increase in vascular endothelin peptide were noted in these animals. Moreover, a reduction in insulin-simulated glucose transport activity was also noted in muscles isolated from sucrose-fed rats. 4. Together these data suggest that a cluster of metabolic and haemodynamic abnormalities occur in response to the intake of simple sugars in rats. 相似文献
994.
Effects of levobupivacaine,ropivacaine and bupivacaine on HERG channels: stereoselective bupivacaine block 总被引:2,自引:0,他引:2
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González T Arias C Caballero R Moreno I Delpón E Tamargo J Valenzuela C 《British journal of pharmacology》2002,137(8):1269-1279
1 Levobupivacaine and ropivacaine are the pure S(-) enantiomers of N-butyl- and N-propyl-2',6'-pipecoloxylidide, developed as less cardiotoxic alternatives to bupivacaine. In the present study, we have analysed the effects of levobupivacaine, ropivacaine and bupivacaine on HERG channels stably expressed in CHO cells. 2 The three drugs blocked HERG channels in a concentration-, time- and state-dependent manner. Block measured at the end of 5 s pulses to -10 mV induced by 20 microM bupivacaine (52.7+/-2.0%, n=15) and ropivacaine (55.5+/-2.7%, n=13) was similar (P>0.05) and both lower than that induced by levobupivacaine (67.5+/-4.2%, n=11) (P<0.05). 3 Dextrobupivacaine (20 microM) was less potent (47.2+/-5.2%, n=10) than levobupivacaine (P<0.05), indicating stereoselective HERG channel block. 4. Block induced by the three local anaesthetics exhibited a steep voltage dependence in the range of channel activation. In all cases, block measured at the maximum peak current at a test potential of 0 mV after promoting recovery from inactivation (I-->O) was lower than that observed at the end of 5-s pulses (I+O). 5. Levobupivacaine, ropivacaine and bupivacaine accelerated HERG inactivation kinetics, slowed the recovery from inactivation and shifted the inactivation curve towards more negative membrane potentials. The three local anaesthetics induced a rapid time-dependent decline after using a protocol that quickly activates HERG channels. 6. All these results suggest that: (1) these drugs bind to the open and the inactivated states of HERG channels, (2) they stabilize HERG channels in the inactivated state, and (3) block induced by bupivacaine enantiomers is stereoselective. 相似文献
995.
Sterling J Herzig Y Goren T Finkelstein N Lerner D Goldenberg W Miskolczi I Molnar S Rantal F Tamas T Toth G Zagyva A Zekany A Finberg J Lavian G Gross A Friedman R Razin M Huang W Krais B Chorev M Youdim MB Weinstock M 《Journal of medicinal chemistry》2002,45(24):5260-5279
Carbamate derivatives of N-propargylaminoindans (Series I) and N-propargylphenethylamines (Series II) were synthesized via multistep procedures from the corresponding hydroxy precursors. The respective rasagiline- and selegiline-related series were designed to combine inhibitory activities of both acetylcholine esterase (AChE) and monoamine oxidase (MAO) by virtue of their carbamoyl and propargylamine pharmacophores. Each compound was tested for these activities in vitro in order to find molecules with similar potencies against each enzyme. Compounds with such dual AChE and MAO inhibitory activities are expected to have potential for the treatment of Alzheimer's disease. The observed SAR also offers insight into the requirements of the active sites on these enzymes. A carbamate moiety was found to be essential for AChE inhibition, which was absent in the corresponding hydroxy precursors. The propargyl group caused 2-70-fold decrease in AChE inhibitory activity (depending on the position of the carbamoyl group) of Series I, but had little or no effect in Series II. Thus, the 6- and 7-carbamyloxyphenyls in Series I were either equipotent to, or slightly (2- to 5-fold) less active as AChE inhibitors than, the corresponding compounds in Series II, while the 4-carbamyloxyphenyls were more potent. The presence of the carbamate moiety in 6- and 7-carbamyloxyphenyls of Series I, considerably decreased MAO-A and -B inhibitory activity, compared to that of the parent hydroxy analogues, while the opposite was true for Series II. Thus, the 6- and 7-carbamyloxyphenyls in Series I were 2-3 orders of magnitude weaker MAO inhibitors while the 4- carbamyloxyphenyls were equipotent with the corresponding compounds in Series II. In both series, N-methylation of the propargylamine enhanced the MAO (A and B equally) inhibitory activities and decreased the AChE inhibitory activity. Two candidates belonging to the indan and tetralin ring systems (24c, 27b) and one phenethylamine (53d) were identified as possible leads for further development based on the following criteria: (a) comparable AChE and MAO-B inhibitory activities, (b) good to moderate AChE inhibitory activity, and (c) lack of strong MAO-A selectivity. However, it is likely that these compounds will be metabolized to the corresponding phenols, with inhibitory activities against AChE and/or MAO-A or -B, different from those of the parent carbamates. Thus, the apparent enzyme inhibition will be a result of the combined inhibition of all of these individual metabolites. The results of our ongoing in vivo screening programs will be published elsewhere. 相似文献
996.
Local anesthetics inhibit the ion channel activity of nicotinic acetylcholine receptors in a noncompetitive fashion. This inhibitory action is ascribed to two possible inhibitory mechanisms: an open-channel-blocking mechanism and/or an allosteric process where the drug binds either to the closed channel or to other nonluminal sites, respectively. 相似文献
997.
Cioffi G D'Auria M Braca A Mendez J Castillo A Morelli I De Simone F De Tommasi N 《Journal of natural products》2002,65(11):1526-1529
Two new myricetin glycosides, myricetin 7-O-beta-D-glucopyranosyl-(1-->6)-beta-D-glucopyranoside (1) and myricetin 7-O-alpha-L-rhamnopyranosyl-(1-->6)-beta-D-glucopyranoside (2), together with the known compounds quercetin 3-O-beta-D-glucopyranoside (3), quercetin 3-O-alpha-L-rhamnopyranoside (4), quercetin 3-O-beta-D-galactopyranoside (5), methyl gallate (6), isovanillin (7), 4-hydroxymethylbenzoate (8), 3,4-dihydroxymethylbenzoate (9), and caffeoyl aldehyde (10) were isolated from the leaves of Tachigalia paniculata. The structures of these compounds were determined by spectroscopic methods. Their antioxidant activity was determined by measuring free-radical scavenging effects using three different assays, namely, the Trolox Equivalent Antioxidant Capacity (TEAC) assay, the coupled oxidation of beta-carotene and linoleic acid (autoxidation assay), and the inhibition of xanthine oxidase activity. Compounds 1, 2, and 6 showed activity in the TEAC test, compounds 5-7 and 10 were moderately active in the autoxidation assay, while compounds 1 and 2 were the most potent of the isolates in the xanthine oxidase test. 相似文献
998.
Rapid recovery from T lymphopenia by CD28 superagonist therapy 总被引:3,自引:3,他引:0
Slow recovery of T-cell numbers and function contributes to the high incidence of life-threatening infections after cytotoxic cancer therapies. We have tested the therapeutic potential of a novel class of superagonistic CD28-specific antibodies that induce polyclonal T-cell proliferation without T-cell receptor engagement in an experimental rat model of T lymphopenia. We show that in lethally irradiated, bone marrow-reconstituted hosts, CD28 superagonist is able to dramatically accelerate repopulation by a small inoculum of mature, allotype-marked T cells. CD28-driven recovery of CD4 cells was superior to that of CD8 T cells. CD28 superagonist- expanded CD4 T cells had maintained repertoire diversity and were functional both in vitro and in vivo, suggesting that treatment with a human CD28-specific superagonist will protect T-lymphopenic patients from opportunistic infections. 相似文献
999.
Extracorporeal photochemotherapy for paediatric patients with graft-versus-host disease after haematopoietic stem cell transplantation 总被引:3,自引:0,他引:3
Messina C Locatelli F Lanino E Uderzo C Zacchello G Cesaro S Pillon M Perotti C Del Fante C Faraci M Rivabella L Calore E De Stefano P Zecca M Giorgiani G Brugiolo A Balduzzi A Dini G Zanesco L Dall'Amico R 《British journal of haematology》2003,122(1):118-127
This study aimed to ascertain whether extracorporeal photochemotherapy (ECP) is an effective treatment for paediatric patients with refractory graft-versus-host disease (GVHD). From January 1992 to December 2000, 77 children (median age 8.6 years) with either acute (n = 33) or chronic (n = 44) GVHD, resistant to conventional immunosuppressive therapy, were treated with ECP in four Italian paediatric hospitals. After ECP, acute GVHD involving skin, liver and gut responded completely in 76%, 60% and 75% of patients respectively. The 5-year overall survival was 69% for responding patients vs 12% for non-responders (P = 0.001). Among the 44 children with chronic GVHD, 15 (44%) showed a complete response and 10 (29%) a significant improvement after ECP. The 5-year overall survival was 96% for responders vs 58% for non-responders (P = 0.04). Our results suggest that ECP is an effective treatment that may be useful in paediatric patients with either acute or chronic GVHD who have failed to respond to standard immunosuppressive therapy. 相似文献
1000.
Pola R Gaetani E Flex A Aprahamian T Proia AS Bosch-Marcé M Smith RC Pola P 《Experimental neurology》2003,184(1):264-273
Apolipoprotein E-knockout (apoE KO) mice have peripheral sensory nerve defects, reduced and delayed response to noxious thermal stimuli, abnormal morphology of unmyelinated fibers, and impaired blood-nerve and blood-brain barriers. In this study, we show that, compared to wild-type mice, peripheral nerves of apoE KO mice have impaired ability to respond to ischemia, as demonstrated by measurement of motor and sensory conduction velocity. In addition, mice lacking apoE exhibit a deficit of reinnervation of ischemic epidermis, evaluated by immunofluorescent staining for the pan-neuronal marker PGP 9.5. Also regional nerve blood flow, measured by laser Doppler, and intraneural angiogenesis after ischemia are significantly compromised in apoE-deficient mice. Finally, upregulation of the angiogenic cytokine vascular endothelial growth factor (VEGF), which physiologically occurs after ischemia in the peripheral nerve of wild-type mice, is severely impaired in apoE KO mice. Among the several neural defects that have already been described in mice lacking apoE, this is the first demonstration that functional recovery to ischemia is impaired in the peripheral nerves of these animals. This deficit is mirrored by the inability of upregulating VEGF and mounting an appropriate intraneural angiogenic response following injury. These findings provide new evidence of possible interdependent relationships between VEGF, angiogenesis, and nerve function and regeneration and may provide new important information on the role of apoE in the nervous system. 相似文献