RESUMEN
Liver damage occurred in some patients who took troglitazone (TGZ) for type II diabetes. The 2,4-thiazolidinedione (TZD) ring in TGZ's structure has been implicated in its hepatotoxicity. To further examine the potential role of a TZD ring in toxicity we used HepG2 cells to evaluate two series of compounds containing different cyclic imides. N-phenyl analogues comprised 3-(3,5-dichlorophenyl)-2,4-thiazolidinedione (DCPT); 3-(3,5-dichlorophenyl)-2,4-oxazolidinedione (DCPO) and N-(3,5-dichlorophenyl)succinimide (NDPS). Benzylic compounds, which closely resemble TGZ, included 5-(3,5-dichlorophenylmethyl)-2,4-thiazolidinedione (DCPMT); 5-(4-methoxyphenylmethyl)-2,4-thiazolidinedione (MPMT); 5-(4-methoxyphenylmethylene)-2,4-thiazolidinedione (MPMT-I); 5-(4-methoxyphenylmethyl)-2,4-oxazolidinedione (MPMO); 3-(4-methoxyphenylmethyl)succinimide (MPMS) and 3-(4-methoxyphenylmethylene)succinimide (MPMS-I). Cytotoxicity was assessed using the MTS assay after incubating the compounds (0-250µM) with HepG2 cells for 24h. Only certain TZD derivatives (TGZ, DCPT, DCPMT and MPMT-I) markedly decreased cell viability, whereas MPMT had low toxicity. In contrast, analogues without a TZD ring (DCPO, NDPS, MPMO, MPMS and MPMS-I) were not cytotoxic. These findings suggest that a TZD ring may be an important determinant of toxicity, although different structural features, chemical stability, cellular uptake or metabolism, etc., may also be involved. A simple clustering approach, using chemical fingerprints, assigned each compound to one of three classes (each containing one active compound and close homologues), and provided a framework for rationalizing the activity in terms of structure.
Asunto(s)
Oxazoles/toxicidad , Succinimidas/toxicidad , Tiazolidinedionas/toxicidad , Supervivencia Celular/efectos de los fármacos , Células Hep G2 , Humanos , Oxazoles/química , Relación Estructura-Actividad , Succinimidas/química , Tiazolidinedionas/químicaRESUMEN
Chimpanzees (Pan troglodytes) have been known to exhibit rudimentary abilities in analogical reasoning (Flemming, Beran, Thompson, Kleider, & Washburn, 2008; Gillian, Premack, & Woodruff, 1981; Haun & Call, 2009; Thompson & Oden, 2000; Thompson, Oden, & Boysen, 1997). With a wide array of individual differences, little can be concluded about the species' capacity for analogies, much less their strategies employed for solving such problems. In this study, we examined analogical strategies in 3 chimpanzees using a 3-dimensional search task (e.g., Kennedy & Fragaszy, 2008). Food items were hidden under 1 of 2 or 3 plastic cups of varying sizes. Subsequently, chimpanzees searched for food under the cup of the same relative size in their own set of cups--reasoning by analogy. Two chimpanzees initially appeared to fail the first relational phase of the task. Meta-analyses revealed, however, that they were instead using a secondary strategy not rewarded by the contingencies of the task--choosing on the basis of the same relative position in the sample. Although this was not the intended strategy of the task, it was nonetheless analogical. In subsequent phases of the task, chimpanzees eventually learned to shift their analogical reasoning strategy to match the reward contingencies of the task and successfully choose on the basis of relative size. This evidence not only provides support for the analogical ape hypothesis (Thompson & Oden, 2000), but also exemplifies how foundational conceptually mediated analogical behavior may be for the chimpanzee.
Asunto(s)
Conducta Apetitiva , Aprendizaje por Asociación , Formación de Concepto , Pan troglodytes/psicología , Animales , Conducta de Elección , Señales (Psicología) , Aprendizaje Discriminativo , Reconocimiento Visual de Modelos , Solución de Problemas , Percepción del Tamaño , Especificidad de la Especie , SimbolismoRESUMEN
Theories of spatial navigation hypothesize that animals use vector or topological information to choose routes, often including detours, to move objects or themselves to goals. We assessed adult capuchin monkeys' (Cebus apella) navigation through 192 virtual two-dimensional mazes that incorporated detour problems. Six monkeys initially were significantly less likely to choose the correct paths when detours were required than when not. Three of the six monkeys repeatedly practiced the 192 mazes to asymptotic mastery; the other three did not practice the mazes again. In a subsequent transfer test, each monkey made correct choices equivalently often on familiar and novel mazes, which suggests that they used general planning skills for maze navigation. Of the three monkeys that practiced the 192 maze-set repeatedly, one efficiently detoured and the other two significantly improved detouring compared to their initial performance. Two monkeys, contrary to their performance when completing the 192 maze-set for the first time, made correct choices at the same rate as chimpanzees. Some evidence suggested that two monkeys used topological information, but utilization of vector information was obvious for all monkeys. Our findings suggest that the boundaries of any individual's navigational abilities are not predicted by species, but depend on experience.
Asunto(s)
Cebus/fisiología , Aprendizaje por Laberinto/fisiología , Animales , Cognición/fisiología , Interpretación Estadística de Datos , Objetivos , Modelos Logísticos , Masculino , Memoria/fisiología , Procesos Mentales , Orientación/fisiología , Desempeño Psicomotor/fisiología , Grabación de Cinta de VideoRESUMEN
We examined whether navigation is impacted by experience in two species of nonhuman primates. Five chimpanzees (Pan troglodytes) and seven capuchin monkeys (Cebus apella) navigated a cursor, using a joystick, through two-dimensional mazes presented on a computer monitor. Subjects completed 192 mazes, each one time. Each maze contained one to five choices, and in up to three of these choices, the correct path required moving the cursor away from the Euclidean direction toward the goal. Some subjects completed these mazes in a random order (Random group); others in a fixed order by ascending number of choices and ascending number of turns away from goal (Ordered group). Chimpanzees in both groups performed equivalently, demonstrated fewer errors and a higher rate of self-correcting errors with increasing experience at solving the mazes, and made significantly fewer errors than capuchin monkeys. Capuchins were more sensitive to the mode of presentation than chimpanzees; monkeys in the Ordered group made fewer errors than monkeys in the Random group. However, capuchins' performance across testing changed little, and they remained particularly susceptible to making errors when the correct path required moving away from the goal. Thus, these two species responded differently to the same spatial challenges and same learning contexts. The findings indicate that chimpanzees have a strong advantage in this task compared to capuchins, no matter how the task is presented. We suggest that differences between the species in the dynamic organization of attention and motor processes contribute to their differences in performance on this task, and predict similar differences in other tasks requiring, as this one does, sustained attention to a dynamic visual display and self-produced movements variably towards and away from a goal.
Asunto(s)
Cebus/psicología , Aprendizaje por Laberinto , Orientación , Pan troglodytes/psicología , Práctica Psicológica , Animales , Atención , Femenino , Masculino , Desempeño Psicomotor , Conducta Espacial , Especificidad de la EspecieRESUMEN
Previous evidence has suggested that analogical reasoning (recognizing similarities among object relations when the objects themselves are dissimilar) is limited to humans and apes. This study investigated whether capuchin monkeys (Cebus apella) can use analogical reasoning to solve a 3-dimensional search task. The task involved hiding a food item under 1 of 2 or 3 plastic cups of different sizes and then allowing subjects to search for food hidden under the cup of analogous size in their own set of cups. Four monkeys were exposed to a series of relational matching tasks. If subjects reached criterion on these tasks, they were exposed to relational transfer tasks involving novel stimuli. Three of the monkeys failed to reach criterion on the basic relational matching tasks and therefore were not tested further. One monkey, however, revealed above-chance performance on a series of transfer tasks with 3 novel stimuli. This evidence suggests that contrary to previous arguments, a member of a New World monkey species can solve an analogical problem.
Asunto(s)
Conducta Apetitiva , Aprendizaje por Asociación , Cebus/psicología , Formación de Concepto , Aprendizaje Discriminativo , Percepción de Forma , Solución de Problemas , Percepción del Tamaño , Animales , Atención , Conducta de Elección , Percepción de Color , Generalización del Estimulo , Conducta Imitativa , Masculino , Aprendizaje por Probabilidad , Transferencia de Experiencia en PsicologíaRESUMEN
Nephrotoxicity of the agricultural fungicide N-(3,5-dichlorophenyl)succinimide (NDPS) in rats is believed to involve metabolism on the succinimide ring. To further investigate this hypothesis, we synthesized and tested the following NDPS analogues, which contain other cyclic imide rings and may therefore be metabolized differently than NDPS: 3-(3,5-dichlorophenyl)-2,4-oxazolidinedione (DCPO), 3-(3,5-dichlorophenyl)-2,4-imidazolidinedione (DCPI), 3-(3,5-dichlorophenyl)-1-methyl-2,4-imidazolidinedione (DCPM) and 3-(3,5-dichlorophenyl)-2,4-thiazolidinedione (DCPT). Male Fischer 344 rats were administered DCPO, DCPI, DCPM, DCPT (0.6 or 1.0 mmol/kg, i.p. in corn oil), NDPS (0.6 mmol/kg, i.p. in corn oil) or corn oil (4 ml/kg). As evidenced by diuresis, proteinuria, elevated blood urea nitrogen levels, increased kidney weights and proximal tubular damage, NDPS produced severe nephrotoxicity in the rats. In contrast, DCPO, DCPI, DCPM and DCPT were mild nephrotoxicants. None of the compounds elevated serum alanine transferase activity or liver weights in the rats, however DCPT produced centrilobular necrosis. These experiments confirm that NDPS-induced nephrotoxicity is critically dependent on the presence of the succinimide ring. Furthermore, replacement of the succinimide ring with a thiazolidinedione ring produced a more pronounced effect on the liver than on the kidney. Liver damage has been reported in type II diabetic patients taking troglitazone, rosiglitazone and pioglitazone. Since these compounds also contain a thiazolidinedione ring, DCPT may be useful for investigating the role of this structural feature in hepatotoxicity.