RESUMEN
Glomerulonephritis are the result of an inflammatory hit to the glomerulus. They are rare and heterogeneous renal diseases. Each glomerular compartment can be affected. The clinical manifestations present with hematuria, proteinuria and/or impaired renal function, either isolated or combined. Two main clinico-biological syndromes are described: nephrotic syndrome and nephritic syndrome. The latter can present in a more severe form i.e. rapidly progressive glomerulonephritis with the worst prognosis. These different clinical pictures are related to specific glomerular lesions. Thus, podocytic damage is mainly responsible for nephrotic syndromes, mesangial damage is responsible for proteinuria and hematuria and, finally, endothelial damage is responsible for nephritic syndrome and rapidly progressive glomerulonephritis. Therapeutic approaches include non-specific measures, combining both life-style and pharmacological interventions with the aim to reduce risk factors, and specific measures with the use of different immunosuppressive agents.
: Les glomérulonéphrites sont des atteintes inflammatoires du glomérule. Il s'agit de pathologies rénales rares et hétérogènes. Tous les compartiments glomérulaires peuvent être touchés. Les répercussions cliniques sont diverses. Elles se manifestent par une hématurie, une protéinurie et/ou une altération de la fonction rénale, présente chacune de manière isolée ou combinée. Deux principaux syndromes clinico-biologiques sont décrits : le syndrome néphrotique et le syndrome néphritique. Au sein de cette dernière entité, on distingue une forme plus sévère, les glomérulonéphrites rapidement progressives grevées du plus mauvais pronostic. Ces différents tableaux cliniques sont en lien avec des lésions glomérulaires spécifiques. Ainsi, les atteintes podocytaires sont principalement responsables des syndromes néphrotiques, les atteintes mésangiales sont responsables de protéinurie et d'hématurie et les atteintes endothéliales sont responsables de syndromes néphritiques et de glomérulonéphrites rapidement progressives. Les approches thérapeutiques comprennent des mesures non spécifiques, hygiéno-diététiques et pharmacologiques, visant à réduire les différents facteurs de risque, et des mesures spécifiques avec l'utilisation de divers médicaments immunosuppresseurs.
Asunto(s)
Glomerulonefritis , Enfermedades Renales , Síndrome Nefrótico , Glomerulonefritis/diagnóstico , Glomerulonefritis/terapia , Hematuria/etiología , Hematuria/patología , Humanos , Enfermedades Renales/complicaciones , Glomérulos Renales/patología , Síndrome Nefrótico/diagnóstico , Síndrome Nefrótico/etiología , Síndrome Nefrótico/terapia , Proteinuria/etiologíaRESUMEN
Most physicians do not know, or do not remember, the name of phlorizin. Hence this molecule has a major historical importance because it was the precursor of gliflozins, a new class of oral antidiabetic drugs with recent therapeutic perspectives beyond diabetes. This article recalls the history of phlorizin: its discovery in the 19th century by De Koninck and Stas, the demonstration of its ability to induce glucosuria and reduce hyperglycaemia by von Mering, its use to demonstrate the concept of glucose toxicity by the team of DeFronzo and finally the development of selective (phlorizin being not selective) sodium-glucose cotransporter type 2 inhibitors (gliflozins) which block glucose reabsorption in renal tubules. Gliflozins have increasing therapeutic indications, not only in type 2 diabetes, but also in cardiology and nephrology among non-diabetic people with heart failure or renal insufficiency.
La plupart des médecins ne connaissent pas, ou ne se souviennent plus, de la phlorizine. Pourtant, cette molécule a une grande importance historique car elle a été le précurseur des gliflozines, une nouvelle classe d'antidiabétiques oraux ouvrant maintenant de nouvelles perspectives thérapeutiques au-delà du diabète. Cet article retrace l'histoire de la phlorizine : sa découverte au 19ème siècle par De Koninck et Stas, la démonstration de l'induction d'une glucosurie abaissant la glycémie par von Mering, son utilisation pour conceptualiser la notion de glucotoxicité par l'équipe de DeFronzo et, enfin, le développement d'inhibiteurs sélectifs (la phlorizine étant non sélective) des cotransporteurs sodium-glucose de type 2 (SGLT2, gliflozines),dans les tubules rénaux, bloquant la réabsorption du glucose. Les gliflozines ont, maintenant, des indications thérapeutiques de plus en plus larges, non seulement dans le diabète de type 2, mais aussi en cardiologie et en néphrologie chez des personnes non diabétiques avec insuffisance cardiaque ou insuffisance rénale.
Asunto(s)
Diabetes Mellitus Tipo 2 , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Bélgica , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Humanos , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Florizina/farmacología , Florizina/uso terapéutico , Transportador 2 de Sodio-Glucosa/uso terapéutico , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéuticoRESUMEN
Renal allograft rejection involves many mechanisms of innate and adaptive immunity, responsible for parenchymal inflammatory lesions that negatively impact the long-term outcomes of the renal allograft. The heterogeneous presentations of rejections in terms of clinical, biological and histological aspects make them difficult to manage in daily clinical practice. Indeed, current therapeutic strategies are disappointing in term of long-term outcomes, including graft survival. In this article, we will discuss the main effector mechanisms of rejection and their histological classification, as well as the existing treatments and those currently under evaluation.
: Le rejet du greffon rénal fait intervenir de nombreux mécanismes de l'immunité innée et adaptative, responsables de lésions inflammatoires parenchymateuses impactant négativement le devenir au long cours du greffon rénal. La grande hétérogénéité dans la présentation clinique, biologique et histologique des rejets de greffe en fait des entités difficiles à prendre en charge en pratique clinique quotidienne. En effet, les stratégies thérapeutiques actuelles montrent des résultats assez décevants pour le traitement des rejets, ce qui a comme conséquence une diminution significative de la survie des greffons. Nous aborderons dans cet article les principaux mécanismes effecteurs des rejets, leur classification histologique ainsi que les traitements existants et en cours de validation.
Asunto(s)
Rechazo de Injerto , Trasplante de Riñón , Aloinjertos , Rechazo de Injerto/diagnóstico , Rechazo de Injerto/terapia , Supervivencia de Injerto , Humanos , Riñón , Trasplante de Riñón/efectos adversosRESUMEN
PURPOSE: [18F]FDG PET/CT may predict the absence of acute allograft rejection (AR) in kidney transplant recipients (KTRs) with acute kidney injury (AKI). Still, the proposed threshold of 1.6 of the mean of mean standardized uptake values (mSUVmean) in the renal parenchyma needs validation. METHODS: We prospectively performed 86 [18F]FDG PET/CT in 79 adult KTRs who underwent per-cause transplant biopsy for suspected AR. Biopsy-proven polyoma BK nephropathies (n = 7) were excluded. PET/CT was performed 192 ± 18 min after administration of 254.4 ± 30.4 MBq of [18F]FDG. The SUVmean was measured in both upper and lower poles of the renal allograft. One-way analysis of variance (ANOVA) and Tukey's studentized range test were sequentially performed. The receiver operating characteristic (ROC) curve was drawn to discriminate "AR" from non-pathological ("normal" + "borderline") conditions. RESULTS: The median age of the cohort was 55 [43; 63] years, with M/F gender ratio of 47/39. The mean eGFR was 31.9 ± 14.6 ml/min/1.73m2. Biopsies were categorized in 4 groups: "normal" (n = 54), "borderline" (n = 9), "AR" (n = 14), or "others" (n = 2). The median [min; max] mSUVmean reached 1.72 [1.02; 2.07], 1.97 [1.55; 2.11], 2.13 [1.65, 3.12], and 1.84 [1.57; 2.12] in "normal," "borderline," "AR," and "others" groups, respectively. ANOVA demonstrated a significant difference of mSUVmean among groups (F = 13.25, p < 0.0001). The ROC area under the curve was 0.86. Test sensitivity and specificity corresponding to the threshold value of 1.6 were 100% and 30%, respectively. CONCLUSION: [18F]FDG PET/CT may help noninvasively prevent inessential transplant biopsies in KTR with AKI.
Asunto(s)
Fluorodesoxiglucosa F18 , Trasplante de Riñón , Adulto , Aloinjertos , Rechazo de Injerto/diagnóstico por imagen , Humanos , Riñón , Trasplante de Riñón/efectos adversos , Persona de Mediana Edad , Tomografía Computarizada por Tomografía de Emisión de Positrones , RadiofármacosRESUMEN
COVID-19 has been the center of global attention and concern for the last months. Patients undergoing dialysis and especially those treated at the hospital are likely to be infected, due to their mandatory presence at the hospital several times a week and due to their intrinsic fragility in regard of chronic kidney disease, often an older age, and the presence of many associated comorbidities. Thereby, patients with chonic kidney disease treated by haemodialysis have higher odds of a more severe COVID-19 infection with a high mortality rate. Prevention is thus a high priority for these patients.
Au cours des derniers mois, la COVID-19 a été au centre des préoccupations et de l'attention de chacun. Les patients dialysés, et surtout ceux hémodialysés en centre, représentent une population particulièrement à risque de contamination vu la nécessité de se rendre à l'hôpital plusieurs fois par semaine et compte tenu de leur fragilité intrinsèque liée au statut de malade rénal chronique, un âge souvent plus avancé, et de nombreuses comorbidités. Ils ont donc un risque de développer une infection grave et potentiellement mortelle. Dès lors, la stratégie de prévention est d'une importance capitale pour ces patients.
Asunto(s)
Infecciones por Coronavirus , Fallo Renal Crónico , Pandemias , Neumonía Viral , Diálisis Renal , Anciano , Betacoronavirus , COVID-19 , Humanos , Fallo Renal Crónico/terapia , SARS-CoV-2RESUMEN
The SARS-CoV-2 virus causes a respiratory distress syndrome, the main symptom of COVID-19 (for "COronaVIrus Disease 2019"). This infectious disease has been causing a major health and socio-economic pandemic since December 2019. The pulmonary alveolus is regarded as the main target of SARS-CoV-2. However, this coronavirus is capable of directly or indirectly affecting other organs, including the kidneys. Here, we summarize the presumed pathophysiology of COVID-19 renal disease. The incidence of acute kidney injury ranges from 0,5 to 22 % of all patients infected with SARS-CoV-2. The need for renal replacement therapy is reported in 5-9 % of patients in intensive care. Histological analysis of renal biopsies mainly shows acute tubular necrosis of varying severity, as well as the congestion of glomerular and peri-tubular capillaries. Endothelitis has been described in few cases. Evidence for a factual inflammation of the glomerulus remains controversial. The medium/long term consequences of COVID-19 nephropathy are unknown and will deserve a tight follow-up.
Le virus SARS-CoV-2 provoque un syndrome de détresse respiratoire aiguë, le symptôme principal de l'infection COVID-19 (pour «COronaVIrus Disease 2019¼). Cette maladie infectieuse provoque une pandémie de gravité sanitaire et socio-économique majeure depuis décembre 2019. La cible principale du SARS-CoV-2 serait l'alvéole pulmonaire. Néanmoins, ce coronavirus est capable d'affecter directement ou indirectement d'autres organes, y compris les reins. Nous résumons ici la physiopathologie présumée de l'atteinte rénale de la COVID-19. L'incidence de l'insuffisance rénale aiguë varie entre 0,5 à 22 % de tous les patients infectés par le SARS-CoV-2. La nécessité d'une épuration extra-rénale est rapportée chez 5-9 % des patients pris en charge aux soins intensifs. L'analyse histologique de biopsies rénales montre, principalement, une nécrose tubulaire aiguë de sévérité variable, ainsi qu'une congestion des capillaires glomérulaires et péri-tubulaires. Une endothélite a parfois été décrite. L'atteinte inflammatoire du glomérule reste débattue. Les conséquences à moyen/long termes de la néphropathie COVID-19 sont inconnues et mériteront un suivi étroit.
Asunto(s)
Lesión Renal Aguda , Betacoronavirus , Infecciones por Coronavirus , Pandemias , Neumonía Viral , Lesión Renal Aguda/complicaciones , COVID-19 , Infecciones por Coronavirus/complicaciones , Infecciones por Coronavirus/epidemiología , Humanos , SARS-CoV-2RESUMEN
Diabetic nephropathy is a complication of diabetes that affects 25-40 % of diabetic patients. This complication is usually associated with other microangiopathic disorders. We describe a case of a patient suffering from type 2 diabetes with proteinuria, and no signs of retinopathy. This case allows us to discuss and review different etiologies of proteinuria in diabetic patients, particularly in patients who don't suffer from retinopathy.
La néphropathie diabétique est une complication qui affecte 25 à 40 % des patients diabétiques. Cette complication est classiquement associée à d'autres atteintes microangiopathiques. Nous rapportons ici l'histoire d'un patient diabétique de type 2 présentant une protéinurie sans signes de rétinopathie. Ce cas permet de discuter des différentes étiologies d'une protéinurie chez les patients diabétiques, en particulier chez les patients sans rétinopathie.
Asunto(s)
Carcinoma de Células Escamosas/diagnóstico , Glomerulonefritis/etiología , Neoplasias Pulmonares/diagnóstico , Anciano , Diabetes Mellitus Tipo 2/complicaciones , Resultado Fatal , Glomerulonefritis/diagnóstico , Humanos , Masculino , Proteinuria/etiologíaRESUMEN
Management of kidney transplant recipients (KTRs) with suspected acute rejection (AR) ultimately relies on kidney biopsy; however, noninvasive tests predicting nonrejection would help avoid unnecessary biopsy. AR involves recruitment of leukocytes avid for fluorodeoxyglucose F(18) ((18) F-FDG), thus (18) F-FDG positron emission tomography (PET) coupled with computed tomography (CT) may noninvasively distinguish nonrejection from AR. From January 2013 to February 2015, we prospectively performed 32 (18) F-FDG PET/CT scans in 31 adult KTRs with suspected AR who underwent transplant biopsy. Biopsies were categorized into four groups: normal (n = 8), borderline (n = 10), AR (n = 8), or other (n = 6, including 3 with polyoma BK nephropathy). Estimated GFR was comparable in all groups. PET/CT was performed 201 ± 18 minutes after administration of 3.2 ± 0.2 MBq/kg of (18) F-FDG, before any immunosuppression change. Mean standard uptake values (SUVs) of both upper and lower renal poles were measured. Mean SUVs reached 1.5 ± 0.2, 1.6 ± 0.3, 2.9 ± 0.8, and 2.2 ± 1.2 for the normal, borderline, AR, and other groups, respectively. One-way analysis of variance demonstrated a significant difference of mean SUVs among groups. A positive correlation between mean SUV and acute composite Banff score was found, with r(2) = 0.49. The area under the receiver operating characteristic curve was 0.93, with 100% sensitivity and 50% specificity using a mean SUV threshold of 1.6. In conclusion, (18) F-FDG PET/CT may help noninvasively prevent avoidable transplant biopsies in KTRs with suspected AR.
Asunto(s)
Fluorodesoxiglucosa F18/administración & dosificación , Rechazo de Injerto/diagnóstico por imagen , Trasplante de Riñón , Imagen Multimodal/métodos , Radiofármacos/administración & dosificación , Enfermedad Aguda , Adolescente , Adulto , Anciano , Femenino , Estudios de Seguimiento , Tasa de Filtración Glomerular , Rechazo de Injerto/patología , Supervivencia de Injerto , Humanos , Fallo Renal Crónico/cirugía , Pruebas de Función Renal , Masculino , Persona de Mediana Edad , Proyectos Piloto , Tomografía de Emisión de Positrones/métodos , Complicaciones Posoperatorias , Pronóstico , Estudios Prospectivos , Curva ROC , Factores de Riesgo , Tomografía Computarizada por Rayos X/métodos , Trasplante Homólogo , Adulto JovenRESUMEN
A successful transplantation implies that immunosuppressive drugs will have to be taken during the whole patient's life. Poor drug compliance is a multifactorial problem, that is particularly dangerous in organ transplantation as it can lead to loss of graft function and return to dialysis treatment. The medical doctor must stimulate the patient's adherence to the strict therapeutic drug protocol. The patient must also be reminded at each medical consultation of the importance of such rigorous drug intake. This bad (or non) compliance is particularly well demonstrated a long time after transplantation. The medical staff, all the health participants, but also the family members must continuously fight against non compliance, which is inherent to any chronic disease.
Asunto(s)
Inmunosupresores/uso terapéutico , Trasplante de Riñón , Cumplimiento de la Medicación , Humanos , Cumplimiento de la Medicación/estadística & datos numéricos , Guías de Práctica Clínica como AsuntoRESUMEN
Renal transplantation is the best treatment for end-stage renal disease, but requires efficient immunosuppressive therapy. The latter has evolved over recent years with the development of more powerful drugs and of monoclonal antibodies with very specific target. The first monoclonal antibodies, acting against the interleukin 2 receptor, named basiliximab and daclizumab, have showed an excellent tolerance profile and efficacy to reduce acute graft rejection. However, in spite of these properties, the development of delayed graft function or the graft and patient survivals at 1 year were not modified by the use of such specific treatment. One potential advantage could yet be a decreasing need for corticosteroids and sometimes calcineurin inhibitors which could provide some long term benefits for the renal graft, but also the patient. Alemtuzumab, another monoclonal antibody, aimed at the membrane glycoprotein CD52, can also decrease the incidence of acute rejection and the depth of the required immunosuppressive therapy. Other antibodies are still in development with some interesting preliminary results which however demand confirmation in larger studies.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Antineoplásicos/uso terapéutico , Inmunoglobulina G/uso terapéutico , Inmunosupresores/uso terapéutico , Trasplante de Riñón , Proteínas Recombinantes de Fusión/uso terapéutico , Alemtuzumab , Anticuerpos Monoclonales Humanizados , Basiliximab , Daclizumab , Rechazo de Injerto/prevención & control , HumanosRESUMEN
Methylating carcinogens and cytostatic drugs induce different methylation products in DNA. In cells not expressing the repair protein MGMT or expressing it at a low level, O6-methylguanine is the major genotoxic, recombinogenic, and apoptotic lesion. Genotoxicity and apoptosis triggered by O6-methylguanine require mismatch repair (MMR). In cells expressing O6-methylguanine-DNA methyl transferase (MGMT) at a high level or for agents producing low amounts of O6-methylguanine, N-alkylations become the major genotoxic lesions. N-Alkylations are repaired by base excision repair (BER). In mammalian cells, naturally occurring mutants of BER have not been detected, which points to the importance of BER for viability. In order to ascertain the role of BER in cellular defense, BER was modulated either by transfection or mutational inactivation. It has been shown that overexpression of N-methylpurine-DNA glycosylase (MPG) does not protect, but rather sensitizes cells to SN2 agents. This has been interpreted in terms of an imbalance in BER. Regarding abasic site endonuclease (APE), transient but not stable overexpression of the enzyme was achieved upon transfection in CHO cells, which indicates that unphysiologic APE levels are not tolerated by the cell. Besides the repair function, APE (alias Ref-1) exerts redox capability by which the activity of various transcription factors is modulated. Therefore, it is possible that stable overexpression of mammalian APE impairs transcriptional regulation of genes, whereas transient overexpression may exert some protective effect. DNA polymerase beta (Pol beta) transfection was ineffective in conferring resistance to methylmethane sulfonate (MMS). On the other hand, Pol beta-deficient cells proved to be highly sensitive to methylation-induced chromosomal aberrations and reproductive cell death. The dramatic hypersensitivity in the killing response is largely due to induction of apoptosis. Obviously, nonrepaired BER intermediates are clastogenic and act as a strong trigger of the apoptotic pathway. The elements of this pathway are currently under investigation.
Asunto(s)
Apoptosis/fisiología , ADN Glicosilasas , Reparación del ADN , Guanina/análogos & derivados , Alquilación , Animales , Apoptosis/genética , Disparidad de Par Base , Células CHO , Liasas de Carbono-Oxígeno/fisiología , Cricetinae , Cricetulus , Aductos de ADN/química , Daño del ADN , ADN Polimerasa beta/deficiencia , ADN Polimerasa beta/fisiología , Reparación del ADN/genética , Reparación del ADN/fisiología , ADN-(Sitio Apurínico o Apirimidínico) Liasa , Desoxirribonucleasa IV (Fago T4-Inducido) , Guanina/química , Humanos , Mamíferos , Metilación , Ratones , Ratones Noqueados , Mutagénesis , Mutágenos/toxicidad , N-Glicosil Hidrolasas/fisiología , O(6)-Metilguanina-ADN Metiltransferasa/fisiología , Oxidantes/toxicidad , Oxidación-Reducción , Fosforilación , Procesamiento Proteico-Postraduccional , TransfecciónRESUMEN
Chronic arterial hypotension has been poorly studied. Its mechanisms are not well understood; its treatment (if needed) is disappointing, without any demonstrated improvement of symptoms or prognosis. Thus, a complete medical examination is needed to exclude any organic cause. If none is found, it is important to reassure the patient and to convince him not to use expensive drugs potentially generative of side effects.
Asunto(s)
Hipotensión , Enfermedad Crónica , Diagnóstico Diferencial , Humanos , Hipotensión/diagnóstico , Hipotensión/etiología , Hipotensión/terapiaRESUMEN
Apurinic endonuclease (APE; also known as Ref-1 protein) is a key enzyme in base excision repair, cleaving apurinic sites that arise spontaneously because of the activity of DNA glycosylases. To address the question of whether APE can be modulated by genotoxic stress affecting cellular protection, we analyzed the expression of APE in Chinese hamster ovary (CHO) cells after treatment with various genotoxic agents. We show that treatment of CHO cells with hydrogen peroxide (H2O2) or sodium hypochlorite (NaOCl) increases the levels of APE mRNA and protein. APE induction was observed 3-9 h after treatment and was accompanied by an increase in APE activity. We also show that the cloned human APE promoter transfected into CHO cells is stimulated by the oxidants, indicating transcriptional activation of the APE gene. When cells were pretreated with NaOCl, inducing APE, and then challenged with H2O2, the clastogenic effect of the challenge dose was significantly reduced, suggesting clastogenic adaptation due to APE induction. To further prove the involvement of APE in adaptation against induced chromosomal breakage, we transfected human APE cDNA driven by an inducible promoter into CHO cells and observed that transient induction of APE reduced the clastogenic effect of H2O2. Overall, the data demonstrate that the APE gene can be activated by oxidative agents, resulting in a transient increase in APE repair activity, which reduces the clastogenic response of cells to an oxidative agent. The protection of cells from chromosomal aberrations seen after prior exposure to oxidants is attributed to an adaptive response to oxidative stress.
Asunto(s)
Liasas de Carbono-Oxígeno/biosíntesis , Transformación Celular Neoplásica , Peróxido de Hidrógeno/farmacología , Proteínas Nucleares/biosíntesis , Estrés Oxidativo/genética , Hipoclorito de Sodio/farmacología , Animales , Células CHO , Liasas de Carbono-Oxígeno/genética , Cricetinae , ADN-(Sitio Apurínico o Apirimidínico) Liasa , Desoxirribonucleasa IV (Fago T4-Inducido) , Inducción Enzimática , Humanos , Cinética , Proteínas Nucleares/genética , Regiones Promotoras Genéticas/efectos de los fármacos , ARN Mensajero/biosíntesis , Proteínas Recombinantes de Fusión/biosíntesis , Factores de Tiempo , Transcripción Genética , TransfecciónRESUMEN
O6-Alkylguanine is the major mutagenic and cytotoxic DNA lesion induced by alkylating agents, including 2-chloroethyl-N-nitrosourea-based antitumor drugs. This lesion is repaired by O6-methylguanine-DNA methyltransferase (MGMT), the expression of which is highly variable in both normal tissues and in tumor cells. The promoter of the human MGMT gene was found to contain two putative activator protein (AP)-1 sites. Here, we show that the level of MGMT mRNA in HeLa S3 cells was increased 3-5-fold by phorbol-12-myristate-13-acetate (TPA) and 1,2-diacyl-sn-glycerol (DAG), which are activators of protein kinase C (PKC), as well as by okadaic acid, an inhibitor of protein phosphatases. The PKC inhibitor 1-(5-isoquinoline sulfonyl)-2-methylpiperazine-HCl eliminated MGMT activation by TPA and DAG but not by OA. Prior down-regulation of PKC abolished subsequent effects of TPA or DAG. The results indicate AP-1 to be involved in regulation of MGMT expression. This hypothesis was supported by showing AP-1 binding to two target sequences of the MGMT promoter and transactivation of the MGMT promoter upon cotransfection with c-fos and c-jun in F9 cells. That TPA-mediated induction of MGMT caused increased cellular resistance to 2-chloroethyl-N-nitrosourea suggests a therapeutic significance for PKC-mediated MGMT modulation.
Asunto(s)
Regulación Enzimológica de la Expresión Génica , O(6)-Metilguanina-ADN Metiltransferasa/genética , Proteína Quinasa C/fisiología , Alquilantes/farmacología , Reparación del ADN , Resistencia a Antineoplásicos , Células HeLa , Humanos , O(6)-Metilguanina-ADN Metiltransferasa/biosíntesis , Ácido Ocadaico/farmacología , Regiones Promotoras Genéticas , ARN Mensajero/análisis , Acetato de Tetradecanoilforbol/farmacología , Factor de Transcripción AP-1/metabolismoRESUMEN
The regular use of various nonsteroidal anti-inflammatory drugs (NSAIDs) was shown to decrease the incidence of colorectal cancer. This effect is thought to be caused predominantly by inhibition of cyclooxygenase-2 (COX-2) and, subsequently, prostaglandin synthesis. However, recent studies have suggested that COX-independent pathways may contribute considerably to these antiproliferative effects. To evaluate the involvement of COX-dependent and COX-independent mechanisms further, we assessed the effects of celecoxib (selective COX-2 inhibitor) and SC560 (selective COX-1 inhibitor) on cell survival, cell cycle distribution, and apoptosis in three colon cancer cell lines, which differ in their expression of COX-2. Both drugs induced a G0/G1 phase block and reduced cell survival independent of whether or not the cells expressed COX-2. Celecoxib was more potent than SC560. The G0/G1 block caused by celecoxib could be attributed to a decreased expression of cyclin A, cyclin B1, and cyclin-dependent kinase-1 and an increased expression of the cell cycle inhibitory proteins p21Waf1 and p27Kip1. In addition, celecoxib, but not SC560, induced apoptosis, which was also independent of the COX-2 expression of the cells. In vivo, celecoxib as well as SC560 reduced the proliferation of HCT-15 (COX-2 deficient) colon cancer xenografts in nude mice, but both substances had no significant effect on HT-29 tumors, which express COX-2 constitutively. Thus, our in vitro and in vivo data indicate that the antitumor effects of celecoxib probably are mediated through COX-2 independent mechanisms and are not restricted to COX-2 over-expressing tumors.
Asunto(s)
Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Neoplasias del Colon/tratamiento farmacológico , Inhibidores de la Ciclooxigenasa/farmacología , Isoenzimas/antagonistas & inhibidores , Sulfonamidas/farmacología , Animales , Western Blotting , Células CACO-2 , Celecoxib , Ciclo Celular/fisiología , Proteínas de Ciclo Celular/efectos de los fármacos , Proteínas de Ciclo Celular/metabolismo , División Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Inhibidor p21 de las Quinasas Dependientes de la Ciclina , Inhibidor p27 de las Quinasas Dependientes de la Ciclina , Ciclinas/efectos de los fármacos , Ciclinas/metabolismo , Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa 2 , Relación Dosis-Respuesta a Droga , Células HT29 , Humanos , Isoenzimas/metabolismo , Proteínas de la Membrana , Ratones , Ratones Desnudos , Prostaglandina-Endoperóxido Sintasas/metabolismo , Pirazoles/farmacología , Células Tumorales Cultivadas , Proteínas Supresoras de Tumor/efectos de los fármacos , Proteínas Supresoras de Tumor/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Two genetic screening methods, the fluorescence resonance energy transfer (FRET) technique on the LightCycler and the real-time pyrophosphate detection technique on the Pyrosequencer have been compared with regard to their usefulness as screening methods for subject recruitment in clinical studies in pharmacology units. Two SNPs of possible clinical relevance were selected, namely the 118A>G SNP of the OPRM1 gene and the 3435C>T SNP of the ABCB1 gene. Genotypes diagnosed using conventional sequencing served as control. The allelic frequency of the mutated 118G allele of the OPRM1 gene was 12.7% and that of the mutated 3435T allele of the ABCB1 gene was 50.7%. All results obtained with the Pyrosequencer were in accord with those obtained using conventional sequencing. With the LightCycler, an incorrect genotype was assigned to 1 of the 130 DNA samples corresponding to an error rate of 0.8%. Although both methods were found suitable for rapid SNP detection, Pyrosequencing was the preferred method since it provides the nucleotide sequence directly thus facilitating interpretation.
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Transferencia Resonante de Energía de Fluorescencia/métodos , Pruebas Genéticas , Selección de Paciente , Transportadoras de Casetes de Unión a ATP/genética , Ensayos Clínicos como Asunto , ADN/análisis , Transferencia Resonante de Energía de Fluorescencia/normas , Pruebas Genéticas/métodos , Genotipo , Humanos , Farmacología , Fosfatos/análisis , Polimorfismo de Nucleótido Simple , Receptores Opioides mu/genética , Sensibilidad y Especificidad , Análisis de Secuencia de ADNRESUMEN
Blood pressure variability is a physiological phenomenon influenced by many internal and external factors. This variability could be also influenced by pathological conditions such as arterial hypertension. Two forms must be mainly distinguished: the blood pressure variability at long but also short-term. The latter could only be studied by continuous recordings. From the initial invasive intraarterial approach, it can nowadays be explored by a non invasive system of beat to beat recordings using the infrared photo plethysmography (the FINAPRES system). In this paper, some important questions will be treated such as the interest of measuring blood pressure variability, its cardiovascular prognosis and how therapeutic tools can be applied when it is increased?
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Hipertensión/fisiopatología , Monitoreo Fisiológico , Animales , Antihipertensivos/farmacología , Determinación de la Presión Sanguínea , Enfermedades Cardiovasculares/fisiopatología , Humanos , Hipertensión/tratamiento farmacológico , Hipertensión/etiologíaRESUMEN
AIM: To provide a sensitive genetic screening method for rapid identification of all known length polymorphisms in the promoter region of the uridine 5'-diphosphoglucose glucuronosyltransferase (UGT) 1A1 gene comprising (TA)5, (TA)7 and (TA)8 repeats as opposed to the non-mutated (TA)6 allele. METHODS: The UGT1A1 promoter genotype was assessed in 115 subjects by means of a newly developed pyrosequencing method. PCR-generated DNA templates of heterozygous (TA)5 and (TA)7 carriers were cloned into a TOPO TA vector and verified by sequencing. In addition, a (TA)8 segment was produced by cloning to demonstrate the ability of the method to detect this mutation. RESULTS: All length polymorphisms of the UGT1A1 promoter described in the literature were clearly identified. Fifteen subjects had Gilbert's syndrome with elevated serum bilirubin associated with a homozygous (TA)7TAA/(TA)7TAA genotype. Two subjects with the rare genotypes (TA)5TAA/(TA)6TAA and (TA)5TAA/(TA)7TAA were found, where only the latter one displayed elevated serum bilirubin levels. Allelic frequencies were 0.9%, 66.1% and 33% for the (TA)5TAA, (TA)6TAA and (TA)7TAA allele, respectively. CONCLUSION: Our method enables reliable genetic single-step screening for all known length polymorphisms in the UGT1A1 gene promoter that cause Gilbert's syndrome. This facilitates pharmacogenetic-guided dosing of drugs with known toxicity metabolized by UGT1A1.
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Pruebas Genéticas/métodos , Enfermedad de Gilbert/genética , Glucuronosiltransferasa/genética , Farmacogenética , Genotipo , Glucuronosiltransferasa/aislamiento & purificación , Humanos , Reacción en Cadena de la Polimerasa , Polimorfismo Genético , Regiones Promotoras GenéticasAsunto(s)
Cromosomas Humanos X , Enfermedades de la Córnea/diagnóstico , Opacidad de la Córnea/diagnóstico , Sustancia Propia/patología , Lámina Limitante Posterior/patología , Genes Recesivos , Ictiosis Ligada al Cromosoma X/diagnóstico , Adulto , Enfermedades de la Córnea/patología , Opacidad de la Córnea/genética , Opacidad de la Córnea/patología , Diagnóstico Diferencial , Humanos , Ictiosis Ligada al Cromosoma X/genética , Ictiosis Ligada al Cromosoma X/patología , Masculino , RecurrenciaRESUMEN
Receptor tyrosine kinases play essential roles in cell proliferation and differentiation. We have recently shown that peptides corresponding to the transmembrane domains of the epidermal growth factor (EGF) and ErbB2 receptors inhibit their corresponding receptor activation in cancer cell lines. We extend this observation to cells transfected with chimeric insulin receptors where the transmembrane domain has been replaced by that of the EGF receptor or a mutated Erb2 domain. Peptides corresponding to the transmembrane domains of the EGF receptor and ErbB2 are able to inhibit specifically the autophosphorylation of insulin receptors with the corresponding domain. This inhibitory effect is correlated with the propensity of the different transmembrane domains to self-associate in a genetic reporter assay. Thus, our data strengthen the notion that transmembrane domains are involved in erbB receptor activation, and that these receptors can be modulated by inhibiting protein-protein interactions within the membrane.