RESUMEN
In chronic kidney disease (CKD) patients, cardiovascular (CV) morbidity and mortality rate is higher than in the general population, because of frequently concomitant hypertension, peripheral vascular disease, heart failure, vascular calcification (VC), diabetes and mineral bone disease. Recently, another important factor associated to CV risk in CKD has been deeply investigated: vitamin D deficiency. Vitamin D Receptors (VDRs) are present in several systems and tissues and VDR activation is associated to positive effects, resulting in better blood pressure control and prevention of diabetic nephropathy. Unfortunately, the natural, non-selective vitamin D receptor activator (VDRA), calcitriol, is associated to higher serum calcium and phosphate levels, thus worsening CV risk in CKD. Recent data showed that the selective VDRA paricalcitol might have ameliorative CV effects. The potential positive impact of the use of paricalcitol on diabetic nephropathy, cardiac disease, hypertension, and VC may open new paths in the fight against CV disease in CKD patients.
RESUMEN
In chronic kidney disease (CKD) patients, cardiovascular (CV) morbidity and mortality rate is higher than in the general population, because of frequently concomitant hypertension, peripheral vascular disease, heart failure, vascular calcification (VC), diabetes and mineral bone disease. Recently, another important factor associated to CV risk in CKD has been deeply investigated: vitamin D deficiency. Vitamin D Receptors (VDRs) are present in several systems and tissues and VDR activation is associated to positive effects, resulting in better blood pressure control and prevention of diabetic nephropathy. Unfortunately, the natural, non-selective vitamin D receptor activator (VDRA), calcitriol, is associated to higher serum calcium and phosphate levels, thus worsening CV risk in CKD. Recent data showed that the selective VDRA paricalcitol might have ameliorative CV effects. The potential positive impact of the use of paricalcitol on diabetic nephropathy, cardiac disease, hypertension, and VC may open new paths in the fight against CV disease in CKD patients.
Asunto(s)
Envejecimiento/efectos de los fármacos , Receptores de Calcitriol/metabolismo , Presión Sanguínea/efectos de los fármacos , Calcitriol/farmacología , Calcio/sangre , Enfermedades Cardiovasculares/complicaciones , Enfermedades Cardiovasculares/tratamiento farmacológico , Ergocalciferoles/farmacología , Humanos , Hipertensión/complicaciones , Hipertensión/tratamiento farmacológico , Fallo Renal Crónico/complicaciones , Fallo Renal Crónico/tratamiento farmacológico , Fosfatos/sangre , Receptores de Calcitriol/efectos de los fármacos , Calcificación Vascular/complicaciones , Calcificación Vascular/tratamiento farmacológicoRESUMEN
Deficiencies in vitamin D and vitamin D receptor (VDR) activation adversely affect cardiovascular health in the general population and in people at high risk of cardiovascular disease, as well as contributing to secondary hyperparathyroidism in patients with chronic kidney disease (CKD). Furthermore, epidemiological and observational data indicate that there is a close interrelationship between progressive renal dysfunction in CKD, cardiovascular disease, and mortality. The causes of death in patients even with only moderate kidney dysfunction are commonly associated with cardiovascular events. Modulation of vitamin D levels results in correlative regulatory effects on mineral homeostasis, hypertension, vascular disease, and calcification, as well as a number of other endpoints in cardiac and renal disease. The use of VDR activators to treat these and other parameters outside of cardiovascular and renal disease not only results in enhanced patient health but significantly lowers the risk of mortality in CKD and non-CKD patients with low systemic activity of vitamin D. The cardiovascular and renal systems continue to demonstrate their interrelated effects on each other, particularly when vitamin D and VDR signaling are considered.
Asunto(s)
Conservadores de la Densidad Ósea/uso terapéutico , Calcitriol/uso terapéutico , Agonistas de los Canales de Calcio/uso terapéutico , Enfermedades Cardiovasculares/prevención & control , Hiperparatiroidismo Secundario/prevención & control , Enfermedades Renales/tratamiento farmacológico , Receptores de Calcitriol/efectos de los fármacos , Enfermedades Cardiovasculares/tratamiento farmacológico , Enfermedades Cardiovasculares/etiología , Enfermedad Crónica , Cinacalcet , Progresión de la Enfermedad , Quimioterapia Combinada , Medicina Basada en la Evidencia , Humanos , Hiperparatiroidismo Secundario/tratamiento farmacológico , Hiperparatiroidismo Secundario/etiología , Enfermedades Renales/complicaciones , Enfermedades Renales/diagnóstico , Enfermedades Renales/mortalidad , Naftalenos/uso terapéutico , Diálisis Renal/métodos , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
Increased vascular calcification is a major cause of cardiovascular events in patients with chronic kidney disease (CKD). It is the result of an active ossification process counteracted by ''bone'' proteins such as osteopontin, alkaline phosphatase, osteoprotegerin, and osteocalcin. Chronic kidney disease - mineral and bone disorder (CKD-MBD) is a systemic disorder of mineral and bone metabolism that occurs in CKD. In addition to abnormalities in the serum calcium and phosphate profile, CKD-MBD is characterized by abnormalities of bone turnover, mineralization, volume and growth as well as vascular calcification. Considering that the presence and extent of vascular calcification in CKD portend a poor prognosis, many efforts have been made to shed light on this complicated phenomenon to prevent vascular calcium deposition and its progression. Indeed, careful control of calcium load, serum phosphate and parathyroid hormone along with the use of calcium-free phosphate binders and vitamin D receptor activators represent a new therapeutic armamentarium to improve quality of life and reduce mortality in CKD.
Asunto(s)
Calcinosis/tratamiento farmacológico , Calcinosis/metabolismo , Enfermedades Renales/complicaciones , Enfermedades Renales/metabolismo , Enfermedades Vasculares/tratamiento farmacológico , Enfermedades Vasculares/metabolismo , Biomarcadores/sangre , Calcinosis/sangre , Calcinosis/patología , Calcio/sangre , Quelantes/uso terapéutico , Enfermedad Crónica , Enfermedad de la Arteria Coronaria/metabolismo , Progresión de la Enfermedad , Quimioterapia Combinada , Medicina Basada en la Evidencia , Humanos , Enfermedades Renales/sangre , Enfermedades Renales/tratamiento farmacológico , Enfermedades Renales/patología , Hormona Paratiroidea/sangre , Fosfatos/sangre , Guías de Práctica Clínica como Asunto , Pronóstico , Calidad de Vida , Insuficiencia Renal Crónica/metabolismo , Enfermedades Vasculares/sangre , Enfermedades Vasculares/patología , Vitamina D/uso terapéuticoRESUMEN
1. The aim of this work was to evaluate the role of leukotrienes in brain damage in vivo in a model of focal cerebral ischaemia in the rat, obtained by permanent occlusion of middle cerebral artery. 2. A significant (P < 0.01) elevation of LTC(4), LTD(4) and LTE(4) (cysteinyl-leukotrienes) levels occurred 4 h after ischaemia induction in the ipsilateral cortices of ischaemic compared to sham-operated animals (3998 +/- 475 and 897 +/- 170 fmol g(-1) tissue, respectively, P < 0.01). 3. The NMDA receptor antagonist MK-801 and the adenosine A(2A) receptor antagonist SCH 58261 were administered in vivo at doses known to reduce infarct size and compared with the leukotriene biosynthesis inhibitor MK-886. 4. MK-886 (0.3 and 2 mg kg(-1) i.v.) and MK-801 (3 mg kg(-1) i.p.) decreased cysteinyl-leukotriene levels (-78%, P < 0.05; -100%, P < 0.01; -92%, P < 0.01, respectively) 4 h after permanent occlusion of the middle cerebral artery, whereas SCH 58261 (0.01 mg kg(-1) i.v.) had no significant effects. 5. MK-886 (2 mg kg(-1) i.v.) was also able to significantly reduce the cortical infarct size by 30% (P < 0.05). 6. We conclude that cysteinyl-leukotriene formation is associated with NMDA receptor activation, and that it represents a neurotoxic event, the inhibition of which is able to reduce brain infarct area in a focal ischaemic event.
Asunto(s)
Isquemia Encefálica/metabolismo , Isquemia Encefálica/patología , Cisteína/metabolismo , Leucotrienos/metabolismo , Animales , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Maleato de Dizocilpina/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Indoles/farmacología , Inhibidores de la Lipooxigenasa/farmacología , Masculino , Fármacos Neuroprotectores/farmacología , Antagonistas de Receptores Purinérgicos P1 , Pirimidinas/farmacología , Ratas , Ratas Sprague-Dawley , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores Purinérgicos P1/metabolismo , Triazoles/farmacologíaRESUMEN
We used the increase in cytosolic Ca2+ levels, [Ca2+]i, as a way to characterize PAF (platelet-activating factor, 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) receptors in human platelets and rat and human macrophages. [Ca2+] was measured by means of the fluorescent probe fura-2/acetoxymethylester. PAF recognized heterogeneous receptors in human macrophages only (curve slope <1). The PAF antagonist SCH 37370 (1-acetyl-4(8-chloro-5,6-dihydro-11H-benzo[5.6]cyclohepta[1,2-b]pyridine -11-ylidine)piperidine) abolished [Ca2+]i elevation in human platelets, while in rat and human macrophages the maximal inhibition was 76% and 85%, respectively. On the contrary, the antagonist WEB 2086 (3-[4-(2-chlorophenyl)-9-methyl-6Hthieno[3,2-f] [1,2,4]triazolo-[4,3-a] [1,4]-diazepin-2-yl]-1-(4-morpholiny)-1-propanon, apafant) totally inhibited the effect of PAF in both platelets and macrophages. The WEB 2086 concentration-response curves had a slope <1 in the three cell types, indicating interaction with heterogeneous receptors. Accordingly, 3H-WEB 2086 bound to two different classes of sites. Both phases of [Ca2+]i elevation (influx or release) were equally affected by the antagonists. These data support the notions that: 1) PAF receptors are heterogeneous; 2) the two antagonists have a different selectivity toward the receptor subtypes: WEB 2086 recognizes two different receptors both in platelets and in macrophages, while SCH 37370 does not discriminate between receptor subtypes in platelets, and only interacts with one subtype in macrophages; and 3) both SCH 37370 and WEB 2086 display different potencies in rat and human macrophages.
Asunto(s)
Plaquetas/metabolismo , Calcio/sangre , Macrófagos/metabolismo , Glicoproteínas de Membrana Plaquetaria/metabolismo , Receptores de Superficie Celular , Receptores Acoplados a Proteínas G , Animales , Azepinas/farmacología , Citosol/metabolismo , Humanos , Loratadina/análogos & derivados , Masculino , Piperidinas/farmacología , Glicoproteínas de Membrana Plaquetaria/antagonistas & inhibidores , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Triazoles/farmacologíaRESUMEN
The paper reports a case of teratoma of the urachus in a 53-year-old patient. The difficulties of diagnosing this pathology are underlined, in particular in relation to the rarity of the site of which no other examples have been reported in the literature.
Asunto(s)
Teratoma , Uraco , Diagnóstico Diferencial , Femenino , Humanos , Persona de Mediana Edad , Teratoma/diagnóstico , Teratoma/cirugía , Tomografía Computarizada por Rayos XRESUMEN
The expression of the various members of the zein multigene family in maize endosperm is controlled by different regulatory loci. One of these loci, Opaque-2, coding for a bZIP transcriptional factor, controls the expression of a subset of zein genes. Analysis of genomic DNA from plants carrying wild-type (O2) or mutant o2 alleles shows specific DNA restriction patterns that correlate with transcript types and their various gene products. Northern and western analyses show the presence in different wild types of a 1.7 kb transcript coding for different sizes of normal O2 proteins that migrate as doublets in the 68-72 kDa range. Among the various o2 mutants analysed we showed the occurrence of various null-transcript alleles, the presence of alleles with a normal size transcript which, however, produce a different-sized o2 protein, and a mutant producing both a normal size transcript and a longer transcript, but generating only a single o2 product migrating around 40 kDa. Analysis of other mutations (o7, fl2) known to affect zein polypeptide synthesis shows no interference of these mutations in the expression of the O2 gene products. The overall results indicate the occurrence of micro heterogeneity in the O2 wild-type genes and a broad spectrum of o2 mutations, both producing different sizes of O2 or o2 proteins. A nomenclature of the O2 and o2 genes based on the RFLP, transcripts and products of the various alleles is presented.
Asunto(s)
Proteínas de Unión al ADN/genética , Genes de Plantas , Proteínas de Plantas/genética , Factores de Transcripción/genética , Zea mays/genética , Alelos , Northern Blotting , Proteínas de Unión al ADN/química , Mutación , Proteínas de Plantas/química , Factores de Transcripción/química , Transcripción Genética , Zea mays/química , Zeína/genéticaRESUMEN
Zeins constitute 60-70% of maize endosperm protein. Zein genes are specifically transcribed in the endosperm, and a correlation has been established between tissue-specific expression and demethylation. Three inbred lines and their reciprocal crosses were analysed to assess for allele-specific differences in methylation, transcription and translation. DNAs from endosperm, embryo and seedling tissues analysed by cleavage with methylation-sensitive restriction enzymes and Southern blot hybridization with zein cDNA and genomic sequences show that specific demethylation of zein sequences occurs only in endosperm and is restricted to the maternal complements. Steady-state transcript accumulation of zein mRNA assessed by RNase protection assay reveals qualitative and quantitative differences among endosperm RNAs of the inbreds and of their reciprocal hybrids. Moreover, two-dimensional gel electrophoresis of zein proteins identified polypeptides that are maternally imprinted in reciprocal crosses. These results indicate that endosperm-specific expression of specific zein alleles may occur via parental imprinting and disclose a possible role of methylation in regulating the expression of genes differently contributed in the endosperm by the maternal and paternal genomes.
Asunto(s)
ADN de Plantas/metabolismo , Regulación de la Expresión Génica de las Plantas , Genes de Plantas , Zea mays/genética , Zea mays/metabolismo , Zeína/biosíntesis , Zeína/genética , Alelos , Cruzamientos Genéticos , Sondas de ADN , ADN de Plantas/aislamiento & purificación , Metilación , ARN Mensajero/biosíntesis , ARN de Planta/biosíntesis , Mapeo Restrictivo , Semillas , Zea mays/crecimiento & desarrollo , Zeína/aislamiento & purificaciónRESUMEN
The maize (Zea mays L.) Opaque2 (O2) protein is an endosperm-specific transcriptional activator whose DNA-binding activity is regulated diurnally by a phosphorylation/dephosphorylation mechanism. We show that the O2 transcript undergoes pronounced oscillations during the day-night cycle. The highest level of the O2 message is present at midday and the lowest level at midnight. The level of O2 transcript follows a diurnal rhythm that appears controlled by the circadian clock. Two different endosperm-expressed DNA-binding proteins, PBF (prolamin box-binding factor) and OHP1 (O2-heterodimerizing protein 1), were also analyzed. While the PBF message levels oscillate diurnally, the steady-state levels of OHP1 transcript were constant through the day and night. We present data showing that the seed is not directly involved in the perception of the light signal, but presumably responds to diurnal fluxes of nutrients into the endosperm. Moreover, we show that the O2 protein is not involved in the regulation of its own transcript levels. These data indicate that O2 activity is down-regulated at night by both a reduction in O2 transcript and by hyperphosphorylation of residual O2 protein, and suggest that regulatory gene activity during endosperm development may be acutely sensitive to a diurnal signal(s) emanating from the plant and passing into the developing seeds.
Asunto(s)
Ritmo Circadiano/fisiología , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Regulación de la Expresión Génica de las Plantas/fisiología , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Zea mays/fisiología , Oscuridad , Luz , Fosforilación , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Transactivadores/genética , Transcripción Genética , Zea mays/genéticaRESUMEN
The transcript levels of heavy-chain zein genes (zH1 and zH2) and the occurrence of the zH polypeptides in different opaque-2 (o2) lines were investigated by RNA-blot analyses and by sodium dodecylsulfate-polyacrylamide gel electrophoresis or two-dimensional gel electrophoresis protein fractionations. Four mutant alleles o2R, o2T, o2It, and o2-676 introgressed into different genetic backgrounds (GBs) were considered. The mono-dimensional gel electrophoresis zein pattern can be either conserved or different among the various GBs carrying the same o2 allele. Likewise, in the identical GB carrying different o2 alleles, the zein pattern can be either conserved or differentially affected by the different mutant allele. Zein protein analysis of reciprocal crosses between lines with different o2 alleles or the same o2 showed in some case a more than additive zH pattern in respect to the o2 parent lines. Electrophoretic mobility shift assay approaches, with O2-binding oligonucleotide and endosperm extracts from the above o2 lines, failed to reveal o2-specific retarded band in any of the o2 extracts. The results suggest that the promoter of some zH1 and zH2 contains motif(s) that can respond to factors other than O2.
Asunto(s)
Proteínas de Unión al ADN/genética , Proteínas de Plantas , Semillas/genética , Factores de Transcripción/genética , Zea mays/genética , Zeína/genética , Alelos , Northern Blotting , Cruzamientos Genéticos , Proteínas de Unión al ADN/metabolismo , Electroforesis en Gel Bidimensional , Electroforesis en Gel de Poliacrilamida , Genotipo , Semillas/metabolismo , Factores de Transcripción/metabolismo , Transcripción Genética , Zea mays/metabolismo , Zeína/metabolismoRESUMEN
In the maize endosperm, the Opaque2 (O2) basic leucine zipper transcriptional activator regulates the expression of a subset of the zein seed storage protein gene family. Immunodetection of wild-type or mutant O2 polypeptides fractionated by SDS-PAGE resolved a closely spaced doublet migrating in the 68- to 72-kD range, whereas by using isoelectric focusing, seven to nine isoforms were detected for each allele. Phosphatase treatment simplified the protein patterns to a single band corresponding to the nonphosphorylated component. In vivo and in vitro labeling confirmed that O2 can be phosphorylated. In protein gel blots probed with DNA, only the nonphosphorylated and hypophosphorylated O2 polypeptides were able to bind an oligonucleotide containing the O2 binding sequence. Upon in situ dephosphorylation of the focused isoforms by phosphatase treatment of the isoelectric focusing filter, the hyperphosphorylated forms acquired DNA binding activity. The ratio among the various isoforms remained constant throughout the developmental stages of endosperm growth but changed from daytime to nighttime, with a significant increase of the hyperphosphorylated forms during the night period. These results indicate that O2 exists in vivo as a pool of differently phosphorylated polypeptides and demonstrate that O2 DNA binding activity is modulated by a phosphorylation/dephosphorylation mechanism that appears to be influenced by environmental conditions.
Asunto(s)
ADN de Plantas/metabolismo , Proteínas de Unión al ADN/metabolismo , Proteínas de Plantas/metabolismo , Factores de Transcripción/metabolismo , Zea mays/metabolismo , Ritmo Circadiano , Proteínas de Unión al ADN/química , Proteínas de Unión al ADN/genética , Regulación de la Expresión Génica de las Plantas , Genes de Plantas , Leucina Zippers/genética , Leucina Zippers/fisiología , Mutación , Fosforilación , Proteínas de Plantas/química , Proteínas de Plantas/genética , Factores de Transcripción/química , Factores de Transcripción/genética , Zea mays/genéticaRESUMEN
The degree to which the eudicot-based ABC model of flower organ identity applies to the other major subclass of angrosperms, the monocots, has yet to be fully explored. We cloned silky1 (si1), a male sterile mutant of Zea mays that has homeotic conversions of stamens into carpels and lodicules into palea/lemma-like structures. Our studies indicate that si1 is a monocot B function MADS box gene. Moreover, the si1 zag1 double mutant produces a striking spikelet phenotype where normal glumes enclose reiterated palea/lemma-like organs. These studies indicate that B function gene activity is conserved among monocots as well as eudicots. In addition, they provide compelling developmental evidence for recognizing lodicules as modified petals and, possibly, palea and lemma as modified sepals.