RESUMEN
Psoriatic arthritis (PsA) is described as a multifactorial autoimmune rheumatic disease although its development is surely linked to some specific HLA genes (especially the HLA-Cw*06:02 allele). To date, its complex immunopathogenetic mechanism is not well clarified. Actually, increasing evidence suggest that qualitative and quantitative interplays between some PsA-susceptibility HLA alleles and other genetic, regulatory and environmental factors, may develop distinct subphenotypes of PsA. We first provide a brief summary of current knowledge about the various PsA conditions. Then, we consider the reasons why further analysis of the clinical course of patients affected by distinct PsA subsets, and who receive different therapeutic treatments, should be carried out in conjunction with deeper investigations about the identification of key genes and immunoregulatory agents by applying the most recent advances in biotechnology. This approach could better explain the molecular mechanisms responsible for both the onset and progression of this multi-faceted pathology with the purpose of significantly improving the management of PsA patients.
Asunto(s)
Artritis Psoriásica/genética , Predisposición Genética a la Enfermedad , Antígenos HLA/genética , Polimorfismo de Nucleótido Simple , Artritis Psoriásica/inmunología , Antígenos HLA-C/genética , HumanosRESUMEN
Recent data from literature report that reactive oxygen species (ROS) seem to play a crucial role in the etiology of both types I and II diabetes. This may render diabetic individuals more prone to oxidative injury when challenged with hypoxic stress. It is in fact well known that many diabetic complications cause ischaemic episodes, with a consequent reduction in oxygen supply to various tissues and organs. To check this hypothesis, in this work we tested type I diabetic individuals' antioxidant capability towards a hypoxic-mediated oxidative challenge. In particular, spontaneously diabetic and age-matched non-diabetic biobreeding (BB) Wistar rats were submitted to chronic normobaric hypoxia, and the response of antioxidant enzymes, as well as redox-sensitive transcription factor NF-kappaB and p53, were monitored. Results show that diabetic subjects present a dramatic enhancement in the major antioxidant enzymes activities, thus supporting the notion of diabetes-related changes in cellular redox status. This allows diabetic individuals to counteract hypoxia-mediated oxidative challenge better than the non-diabetic counterpart. Also the behaviour of both the redox-sensitive nuclear transcription factor NF-kappaB and p53 protein in response to hypoxic stimulation seems to support the hypothesis of a better ROS scavenging efficiency in diabetics under hypoxic conditions. In conclusion, high levels of antioxidant enzymatic defences in diabetic BB rats reflect a positive adaptive response able to assure an efficient protection not only against chronic, diabetes-mediated reactive oxygen species (ROS) overproduction, but also versus further oxidative damage.
Asunto(s)
Antioxidantes/metabolismo , Hipoxia de la Célula , Diabetes Mellitus/enzimología , Diabetes Mellitus/patología , Animales , Caspasa 3/metabolismo , Catalasa/metabolismo , Diabetes Mellitus/metabolismo , Glutatión Peroxidasa/metabolismo , Glutatión Reductasa/metabolismo , Glutatión Transferasa/metabolismo , Lactoilglutatión Liasa/metabolismo , Hígado/enzimología , Pulmón/enzimología , FN-kappa B/metabolismo , Ratas , Ratas Wistar , Superóxido Dismutasa/metabolismo , Superóxido Dismutasa-1 , Tioléster Hidrolasas/metabolismo , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
We present the results of an experiment aimed at comparing the effects of different background radiation environments on metabolism and responses to gamma-rays and cycloheximide of cultured mammalian cells. Chinese hamster V79 cells were maintained in exponential growth in parallel for up to 9 months at the Istituto Superiore di Sanità (ISS) and at the INFN-Gran Sasso underground Laboratory (LNGS) where exposure due to gamma-rays and to radon was reduced by factors of about 70 and 25, respectively. After 9 months the cells grown at the LNGS (cumulative gamma dose about 30 microGy, average radon concentration around 5 Bq/m(3)), compared to the cells grown at the ISS (cumulative gamma-ray dose about 2 mGy, average radon concentration around 120 Bq/m(3)), exhibited i). a significant increase of the cell density at confluence, ii). a significantly higher capacity to scavenge organic and inorganic hydroperoxides but a reduced scavenging capacity towards superoxide anions and iii). an increase in both the basal hprt mutation frequency and sensitivity to the mutagenic effect of gamma-rays. The cells grown at the LNGS also showed a greater apoptotic sensitivity starting at the third month of culture, that was no longer detected after 9 months. Overall, these data suggest a role of background ionizing radiation in determining an adaptive response, although they cannot be considered conclusive.
Asunto(s)
Radiación de Fondo , Fibroblastos/fisiología , Fibroblastos/efectos de la radiación , Rayos gamma , Contaminación del Aire Interior/análisis , Contaminación Radiactiva del Aire/análisis , Animales , Apoptosis/efectos de la radiación , División Celular/efectos de la radiación , Línea Celular , Supervivencia Celular/efectos de la radiación , Cricetinae , Relación Dosis-Respuesta en la Radiación , Pulmón/fisiología , Pulmón/efectos de la radiación , Mutación/efectos de la radiación , Proteínas Proto-Oncogénicas c-myc/metabolismo , Dosis de Radiación , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
Methylglyoxal (2-oxopropanal) is a reactive alpha-oxoaldehyde that can be formed endogenously mainly as a by-product of glycolytic pathway. It is a cytotoxic compound with significant antiproliferative properties as it can bind, under physiological conditions, to nucleic acids and proteins, forming stable adducts. We have recently shown that exogenous methylglyoxal (150-600 microM) is highly toxic for amphibian embryos where it produces, when added to the culture water, inhibition of cell proliferation in the early developmental stages, followed by severe malformations and strongly reduced embryonic viability. In this work we investigate the morphofunctional effect of methylglyoxal on the common toad B. bufo embryo mitochondria in order to verify if its dysmorphogenetic action might be also ascribed to impairment of mitochondrial functions. The mitochondria were isolated from embryos at the developmental stages of morula, neural plate and operculum complete and developing in the presence of 600 microM methylglyoxal. The results show that exogenous methylglyoxal is highly toxic at mitochondrial level, where it produces proliferation, swelling and membrane derangement. As a consequence, mitochondria from treated embryos show decreased oxidative phosphorylation efficiency, as indicated by the significant reduction both of the respiratory control index values and of the embryonic ATP content. On the basis of these data, it is possible that the methylglyoxal-induced embryonic malformations as well as the strongly reduced viability might be also ascribed to energy depletion.
Asunto(s)
Bufo bufo/metabolismo , Respiración de la Célula/efectos de los fármacos , Embrión no Mamífero/citología , Embrión no Mamífero/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Piruvaldehído/toxicidad , Adenosina Difosfato/metabolismo , Adenosina Difosfato/farmacología , Adenosina Trifosfato/metabolismo , Animales , Bufo bufo/embriología , Embrión no Mamífero/enzimología , Embrión no Mamífero/metabolismo , Mitocondrias/enzimología , Mitocondrias/ultraestructura , Consumo de Oxígeno/efectos de los fármacos , Succinato Deshidrogenasa/metabolismoRESUMEN
BACKGROUND: It has been proposed that the anticonvulsant drug phenytoin (PHT) requires bioactivation to reactive intermediate(s) to achieve its recognized teratogenic potential and that embryonal detoxification power may play a fundamental role in the teratogenic response. On this basis, we sought to investigate the potential effects of a teratogenic exposure to PHT on the activities of antioxidant and GSH-related detoxifying enzymes in gestational murine tissues. METHODS: Pregnant Swiss mice were injected intraperitoneally with 0 (vehicle) or 65 mg/kg of PHT on gestation day (GD) 12 (plug day = GD 1). Biochemical determinations, including activities of glutathione transferase, glutathione peroxidase, glutathione reductase, glyoxalase I, glyoxalase II, catalase, and superoxide dismutase, were carried out on maternal and embryonic/fetal livers and in placentas on GD 14 and 19. RESULTS: The major findings of this study show that (1) organogenesis-stage conceptal tissues have detectable levels of all the tested enzymes; (2) most of the embryonic liver and placental enzymes investigated undergo a significant induction within 48 hr (GD 14) after PHT administration; and (3) in the same tissues a down-regulation of enzyme activities is noted near term (GD 19). CONCLUSIONS: Overall, these findings show that teratogenic exposure to PHT is associated with a modulation of reactive-intermediates-scavenging enzyme activities, and provide further support for role of generation of reactive intermediates in PHT-induced teratogenesis.
Asunto(s)
Anticonvulsivantes/toxicidad , Antioxidantes/metabolismo , Glutatión/metabolismo , Fenitoína/toxicidad , Teratógenos , Aborto Veterinario/inducido químicamente , Animales , Catalasa/metabolismo , Fisura del Paladar/inducido químicamente , Citosol/enzimología , Regulación hacia Abajo , Femenino , Glutatión Peroxidasa/metabolismo , Glutatión Reductasa/metabolismo , Glutatión Transferasa/metabolismo , Lactoilglutatión Liasa/metabolismo , Hígado/efectos de los fármacos , Hígado/embriología , Hígado/enzimología , Ratones , Placenta/efectos de los fármacos , Placenta/enzimología , Embarazo , Superóxido Dismutasa/metabolismo , Tioléster Hidrolasas/metabolismo , Factores de TiempoRESUMEN
This paper reports the effect of the tyrosinase (monophenol o-diphenol:oxygen oxidoreductase; EC 1.14.18.1) inhibitors diethyldithiocarbamate (DETC), L-tropolone, kojic acid, phenylthiourea (PTU) and L-mimosine on the in vitro growth of Tuber borchii (a white truffle) mycelium. A significant inhibitory effect on mycelium growth was observed for DETC, PTU and L-tropolone (0% growth compared to control at 100 microg ml(-1) DETC, PTU and L-tropolone and at 10 microg ml(-1) DETC and L-tropolone). As a comparison the action of the same inhibitors was also tested on the growth and pigmentation of the mould Cladosporium sphaerospermum. In the presence of CuSO(4) 10(-6) M T. borchii mycelium acquired pigmentation (as rounded aggregates compared to control revealed by SEM microscopy). Tyrosinase activity in the extract from T. borchii mycelium (18-day culture) was detected spectrophotometrically.
Asunto(s)
Ascomicetos/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Monofenol Monooxigenasa/antagonistas & inhibidores , Ascomicetos/crecimiento & desarrollo , Cladosporium/crecimiento & desarrollo , Sulfato de Cobre , Medios de Cultivo/química , Ditiocarba/farmacología , Microscopía Electrónica de Rastreo , Mimosina/farmacología , Monofenol Monooxigenasa/metabolismo , Micotoxinas/farmacología , Feniltiourea/farmacología , Pigmentos Biológicos , Pironas/farmacología , Tropolona/farmacologíaRESUMEN
This work deals with the antioxidant enzymatic response and the ultrastructural aspects of the skeletal muscle of young and aged rats kept under hypoxic or hyperoxic normobaric conditions. It is in fact well known that the supply of oxygen at concentrations higher or lower than those occurring under normal conditions can promote oxidative processes that can cause tissue damage. The enzymes investigated were both those directly involved in reactive oxygen species (ROS) scavenging (superoxide dismutase, catalase and selenium-dependent glutathione peroxidase), and those challenged with the detoxication of cytotoxic compounds produced by the action of ROS on biological molecules (glutathione transferase, glyoxalase I, glutathione reductase), in order to obtain a comparative view of the defence strategies used with respect to aging. Our results support the hypothesis that one of the major contributors to the aging process is the oxidative damage produced at least in part by an impairment of the antioxidant enzymatic system. This makes the aged organism particularly susceptible to oxidative stress injury and to the related degenerative diseases, especially in those tissues with high demand for oxidative metabolism.
Asunto(s)
Envejecimiento/metabolismo , Hiperoxia/enzimología , Hipoxia/enzimología , Músculo Esquelético/enzimología , Envejecimiento/patología , Animales , Catalasa/análisis , Glutatión Peroxidasa/análisis , Glutatión Transferasa/análisis , Hiperoxia/patología , Hipoxia/patología , Lactoilglutatión Liasa/análisis , Masculino , Músculo Esquelético/ultraestructura , Ratas , Ratas Wistar , Superóxido Dismutasa/análisisRESUMEN
Methylglyoxal (2-oxopropanal) is a cytotoxic compound that can be formed endogenously as a by-product of glycolytic pathway; so its concentration is expected to increase when glycolysis activity increases such as during embryo development. In this work we study the effect of exogenous methylglyoxal on development and embryo viability during Bufo Bufo development and on the enzymes and cofactors involved in its detoxication process (glyoxalase I and II, reduced glutathione and glyceraldehyde 3-phosphate dehydrogenase). The results show that exogenous methylglyoxal does not affect the enzymatic pattern until stage 20, while it induces a significant activity decrease of the tested enzymes at stage 25. On the contrary methylglyoxal positively influences the reduced glutathione concentration at all the considered stages. At morphological and histological levels methylglyoxal causes a strong retardation of cell division in the early stages, that results in various abnormalities in the late development. In conclusion, methylglyoxal enters the embryo and is antiproliferative and teratogenic: the data further supports the hypothesis of the importance of the glyoxalase system in the process of cell growth and division.
Asunto(s)
Piruvaldehído/farmacología , Animales , Bufo bufo , Diferenciación Celular/efectos de los fármacos , División Celular/efectos de los fármacos , Citosol/efectos de los fármacos , Citosol/metabolismo , Embrión no Mamífero/efectos de los fármacos , Embrión no Mamífero/enzimología , Embrión no Mamífero/metabolismo , Desarrollo Embrionario , Glutatión/metabolismo , Gliceraldehído-3-Fosfato Deshidrogenasas/metabolismo , Indicadores y Reactivos , Proteínas/metabolismoRESUMEN
In this work we have investigated the expression of glyoxalase I (GLO I) and glyoxalase II (GLO II) activities during Bufo bufo embryo development and in some tissues of both male and female adult animals, in order to study how they correlate with cell proliferation and differentiation. The results show that both the activities are expressed at significant levels from the earliest developmental stages, reaching the highest values at the end of embryonic development (stage 25). The GLO I/GLO II ratio is very high at the beginning of the development and then gradually decreases as the development goes on. These data emphasize the importance of GLO I activity in the phases in which elevated cell division is taking place. In the differentiated tissues, a peculiar sexual dimorphism in both GLO I and GLO II activities, with higher values in female than in male, was found. GLO I embryonic activity levels are comparable to those found in female differentiated tissues, but significantly higher than those detected in male differentiated tissues. On the contrary, the GLO II activities found in the adult tissues were always higher than those found in embryos. These results further support the idea that high GLO I/GLO II ratios are a characteristic of the proliferative status, which assures a good scavenging action against the potentially cytotoxic and cytostatic effect of methylglyoxal.
Asunto(s)
Lactoilglutatión Liasa/metabolismo , Tioléster Hidrolasas/metabolismo , Animales , Bufo bufo , Embrión no Mamífero/enzimología , Desarrollo Embrionario , Femenino , MasculinoRESUMEN
At 9 mM glucose, experimental results show that mitochondrial phosphate depletion (induced by glucose phosphorylation, catalyzed by mitochondrial hexokinase) reduces the activities of the respiratory chain, oxidative phosphorylation, and glutaminase. Consequently, the 14C-lactate oxidation to 14CO2 is lowered in the presence of glucose. The fall of ATP level triggers a high aerobic glycolysis by deinhibiting fructose-6-P kinase. NADH, generated by enhanced glyceraldehyde-3-P dehydrogenase activity, increases the reducing power. Moreover, the lactate dehydrogenase (LDH) system is shifted toward lactate formation, while NAD+ is regenerated and the oligomycin-inhibited ATP production is replaced by the iodoacetate-inhibited ATP production. From 14CO2 production and lactate accumulation it is calculated that about 60% of 14C-glucose which disappears is channelled into extraglycolytic reactions. On the contrary, 82% of glucose below l mM is metabolized through non-glycolytic reactions. The pyruvate kinase-M2 (PK-M2) inhibition does not limit the glycolytic flow from 9 mM glucose, but it may cause sustained gluconeogenesis.