RESUMO
Inflammation in the central nervous system (CNS) is a complex process that involves a multitude of molecules and effectors, and it requires the transmigration of blood leukocytes across the blood-brain barrier (BBB) and the activation of resident immune cells. Cannabidiol (CBD), a non-psychotropic cannabinoid constituent of Cannabis sativa, has potent anti-inflammatory and immunosuppressive properties. Yet, how this compound modifies the deleterious effects of inflammation in TMEV-induced demyelinating disease (TMEV-IDD) remains unknown. Using this viral model of multiple sclerosis (MS), we demonstrate that CBD decreases the transmigration of blood leukocytes by downregulating the expression of vascular cell adhesion molecule-1 (VCAM-1), chemokines (CCL2 and CCL5) and the proinflammatory cytokine IL-1ß, as well as by attenuating the activation of microglia. Moreover, CBD administration at the time of viral infection exerts long-lasting effects, ameliorating motor deficits in the chronic phase of the disease in conjunction with reduced microglial activation and pro-inflammatory cytokine production. Adenosine A2A receptors participate in some of the anti-inflammatory effects of CBD, as the A2A antagonist ZM241385 partially blocks the protective effects of CBD in the initial stages of inflammation. Together, our findings highlight the anti-inflammatory effects of CBD in this viral model of MS and demonstrate the significant therapeutic potential of this compound for the treatment of pathologies with an inflammatory component.
Assuntos
Canabidiol/uso terapêutico , Inflamação/tratamento farmacológico , Inflamação/etiologia , Esclerose Múltipla , Receptor A2A de Adenosina/metabolismo , Animais , Encéfalo/citologia , Infecções por Cardiovirus/complicações , Adesão Celular/efeitos dos fármacos , Adesão Celular/fisiologia , Células Cultivadas , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Quimiocina CCL5/genética , Quimiocina CCL5/metabolismo , Modelos Animais de Doenças , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/virologia , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Camundongos , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Esclerose Múltipla/complicações , Esclerose Múltipla/etiologia , Esclerose Múltipla/virologia , Receptor A2A de Adenosina/genética , Triazinas/farmacologia , Triazóis/farmacologia , Molécula 1 de Adesão de Célula Vascular/genética , Molécula 1 de Adesão de Célula Vascular/metabolismoRESUMO
No disponible
Assuntos
Feminino , Adulto , Humanos , Apendicite , Apendicite , Doenças Peritoneais , Doenças Peritoneais , Doenças do Colo , Omento , Anormalidade Torcional , Tomografia Computadorizada por Raios XAssuntos
Veia Axilar , Veia Subclávia , Trombose Venosa/diagnóstico por imagem , Adulto , Humanos , Masculino , Síndrome , UltrassonografiaRESUMO
No disponible
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Masculino , Adulto , Humanos , Veia Axilar , Veia Subclávia , Trombose Venosa , SíndromeRESUMO
INTRODUCTION: Idiopathic hypertrophic cranial pachymeningitis (IHCP) is a rare and little known form of chronic inflammation of the dura mater, the pathogenesis of which remains unclear. CASE REPORT: We report the case of a 77-year-old male who was admitted to hospital after suffering a stroke; following the findings in the MR imaging, the patient was diagnosed as having IHCP. Treatment with corticoids led to an improvement in the patient's condition both clinically and radiologically. CONCLUSIONS: IHCP produces a non-nodular diffuse dural thickening that is hypointense with respect to the brain parenchyma in all the MRI sequences with intravenous contrast enhancement.
Assuntos
Meningite , Trombose Venosa/complicações , Idoso , Humanos , Imunossupressores/uso terapêutico , Imageamento por Ressonância Magnética , Masculino , Meningite/diagnóstico , Meningite/tratamento farmacológico , Meningite/etiologia , Meningite/patologia , Trombose Venosa/patologiaRESUMO
Introducción. La paquimeningitis hipertrófica cranealidiopática (PHCI) es una forma rara y poco conocida de inflamacióncrónica de la duramadre, cuya patogenia permanece sin aclarar.Caso clínico. Se trata de un varón de 77 años de edad, ingresadopor un ictus y que, tras los hallazgos de la RM, fue diagnosticadode PHCI. Tras un tratamiento con corticoides mejoró clínica yradiológicamente. Conclusión. La PHCI produce un engrosamientodural difuso no nodular, hipointenso con respecto al parénquimacerebral en todas las secuencias de RM, con captación de contrasteintravenoso
Introduction. Idiopathic hypertrophic cranial pachymeningitis (IHCP) is a rare and little known form of chronicinflammation of the dura mater, the pathogenesis of which remains unclear. Case report. We report the case of a 77-year-oldmale who was admitted to hospital after suffering a stroke; following the findings in the MR imaging, the patient wasdiagnosed as having IHCP. Treatment with corticoids led to an improvement in the patients condition both clinically andradiologically. Conclusions. IHCP produces a non-nodular diffuse dural thickening that is hypointense with respect to thebrain parenchyma in all the MRI sequences with intravenous contrast enhancement
Assuntos
Masculino , Idoso , Humanos , Meningite/diagnóstico , Meningite/tratamento farmacológico , Meningite/etiologia , Meningite/patologia , Trombose Venosa/complicações , Imunossupressores/uso terapêutico , Imageamento por Ressonância MagnéticaRESUMO
No disponible
Assuntos
Transplante de Rim/efeitos adversos , Falência Renal Crônica/etiologia , Rejeição de Enxerto/etiologia , Polimorfismo Genético , Hipertensão/etiologia , Receptores de Citocinas , Fator de Crescimento Transformador beta1/fisiologia , Moléculas de Adesão Celular/fisiologia , Fibrinólise , Trombofilia , Inibidor 1 de Ativador de Plasminogênio , Óxido Nítrico/biossíntese , Fatores de RiscoRESUMO
No disponible
No disponible
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Feminino , Masculino , Criança , Humanos , Adulto , Imageamento por Ressonância Magnética , Tomografia Computadorizada por Raios X , Imageamento por Ressonância Magnética , Meningites Bacterianas , Raquianestesia , HidranencefaliaAssuntos
Biomarcadores , Doenças Cardiovasculares/genética , Predisposição Genética para Doença , Falência Renal Crônica/genética , Transplante de Rim , Polimorfismo Genético , Fatores de Coagulação Sanguínea/genética , Plaquetas , Moléculas de Adesão Celular/genética , Citocinas/genética , Humanos , Fatores de RiscoRESUMO
Epidemiological studies have shown that cigarette smoke, an oxidant agent, is a risk factor for the development of diabetic nephropathy (DN), in which pathogenesis transforming growth factor beta(1) (TGFbeta(1)) plays a key role. In our experimental model we exposed mesangial cell cultures to cigarette smoke concentrate (CSC) to study the effect of smoking on the pathogenesis of DN. Thus, we analyzed the effect of CSC on TGFbeta(1) and lipid peroxidation (8-epi-PGF(2alpha)) in rat mesangial cells. Furthermore, since the protein kinase C (PKC) pathway appears to be a key factor for the enhanced production of TGFbeta(1), we also analyzed the effect of the selective PKCbeta inhibitor LY379196 on TGFbeta(1) response to CSC. CSC induced an increase of both TGFbeta(1) and 8-epi-PGF(2) compared to basal conditions (5 mM glucose). The CSC-induced increase in TGFbeta(1) secretion was significantly suppressed by LY379196. These data suggest that smoking could increase TGFbeta(1) production, probably due to oxidative stress and PKCbeta activation. This finding supports the concept that smoking is a risk factor for DN development.
Assuntos
Dinoprosta/metabolismo , Inibidores Enzimáticos/toxicidade , Mesângio Glomerular/efeitos dos fármacos , Fumaça , Alcatrões/toxicidade , Fator de Crescimento Transformador beta/metabolismo , Animais , Células Cultivadas , Cromatografia Líquida de Alta Pressão , Dinoprosta/análogos & derivados , Relação Dose-Resposta a Droga , Mesângio Glomerular/metabolismo , Mesângio Glomerular/patologia , Mesilatos/farmacologia , Proteína Quinase C/antagonistas & inibidores , Pirróis/farmacologia , Ratos , Ratos Sprague-Dawley , Nicotiana , Fator de Crescimento Transformador beta1RESUMO
BACKGROUND: Chronic allograft nephropathy (CAN) is the main cause of graft loss after the first year of transplantation, and renal biopsies show a predominance of fibrotic lesions. Human transforming growth factor beta-1 (TGF-beta 1) is the principal profibrogenetic cytokine which has been recently implicated in the development of CAN. Seven TGF-beta 1 gene polymorphisms have been recently described and some of them have been related to the development of several diseases. AIM: To analyse the relationship between TGF-beta 1 gene polymorphisms and the development of CAN in a group of renal transplant patients with a long-term follow-up. METHODS: A restriction enzyme-based method for TGF-beta 1 genotyping was used to detect four TGF-beta 1 gene polymorphisms in codon 10, 25 and 5'-flanking region (-800 and -509 positions). A retrospective case-control study were performed on sixty renal transplant recipients with 8 years of post-transplant, 22 of them with CAN (cases) and 38 with normal graft function (controls). We studied 73 subjects to analyse the distribution of the genotypes in the area. RESULTS: The genotype frequencies were similar in the study and control group. The presence of chronic allograft nephropathy was statistically associated with the combination Pro/Pro10 TT509 polymorphism in the TGF-beta 1 gene, and these patients develop chronic rejection more quickly than the rest of the patients. Chronic allograft nephropathy was also associated with delta age recipient-donor, with older donors being a significant risk factor for chronic nephropathy. The logistic regression analysis confirmed the independent role of TT509 Pro/Pro10 TGF-beta 1 polymorphism with a Odd Ratio of 5.8 (1.14-29.7) in chronic nephropathy being the delta age recipient-donor a confounder factor but not an effect modifier. The rest of the TGF-beta 1 gene polymorphisms and the classic risk factors were not associated with the development of chronic allograft nephropathy. CONCLUSIONS: These data suggest a leading role for TGF-beta 1 gene polymorphisms (TT509 Pro/Pro10) in the development of chronic allograft nephropathy. The identification of this genetic predisposition to chronic allograft rejection could play a decisive role in the prevention of this common pathology.
Assuntos
Doença Enxerto-Hospedeiro/genética , Nefropatias/genética , Transplante de Rim/efeitos adversos , Polimorfismo Genético , Fator de Crescimento Transformador beta/genética , Adolescente , Adulto , Idoso , Criança , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/fisiopatologia , Humanos , Nefropatias/etiologia , Nefropatias/fisiopatologia , Transplante de Rim/imunologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fator de Crescimento Transformador beta1 , Transplante HomólogoAssuntos
Encéfalo/patologia , Eclampsia/diagnóstico , Eclampsia/patologia , Adulto , Cesárea , Feminino , Humanos , Imageamento por Ressonância Magnética , GravidezRESUMO
No disponible
No disponible
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Gravidez , Adulto , Feminino , Humanos , Cesárea , Imageamento por Ressonância Magnética , Eclampsia , TelencéfaloRESUMO
No disponible
No disponible
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Pessoa de Meia-Idade , Masculino , Humanos , Adenocarcinoma , Imageamento por Ressonância Magnética , Encefalite , Neoplasias Encefálicas , Neoplasias PulmonaresRESUMO
La nefropatía crónica del injerto renal (NCIR) es la principal causa de pérdida del injerto después del primer año post-trasplante y en la biopsia renal encontramos un predominio de las lesiones fibróticas. El transforming growth factor beta-1 (TGF-β1) es la principal citoquina profibrogenética y ha sido implicada en el mecanismo de producción de la NCIR. Se han descrito varios polimorfismos del gen del TGF-β1, algunos de ellos se han relacionado con el desarrollo de enfermedades. El objetivo de este estudio es analizar la posible relación entre estos polimorfismos y el desarrollo de NCIR en un grupo de pacientes trasplantados renales con largo tiempo de seguimiento. Mediante enzimas de restricción identificamos cuatro polimorfismos del gen del TGF-β en el codon 10, 25 y en -800 y -509 (en el promotor). Realizamos un estudio retrospectivo de casos y controles donde se estudiaron 60 pacientes trasplantados renales con 8 años de seguimiento post-trasplante, 22 de ellos con NCIR (casos) y 38 con normofunción (controles), analizamos también población general para el estudio de la distribución genotípica en el área geográfica (grupo control externo, n = 73). Las frecuencias genotípicas fueron similares en el grupo control y de estudio. La presencia de NCIR se asoció de forma significativa con la combinación de los polimorfismos Pro/Pro10 TT-509 del gen del TGF-β1 y estos pacientes además desarrollaron NCIR de forma más precoz que el resto. La NCIR se asoció también con la diferencia de edad entre el receptor y el donante (Δ edad r-d), siendo los donantes mayores que el receptor un factor de riesgo para el desarrollo de NCIR. El análisis mediante regresión logística confirmó el papel independiente del polimorfismo TT509 Pro/Pro10 en la NCIR, con un Odd Ratio de 5,8 (1,14-29,7), siendo la edad Δ r-d un parámetro que no modifica el proceso de formas más determinante que el polimorfismo, pero pudiendo añadir al efecto de éste un carácter más marcado. Estos datos sugieren un papel importante de los polimorfismos del gen del TGF-β1 en el desarrollo de NCIR (TT509Pro/Pro10). La identificación de esta predisposición genética para el desarrollo de NCIR podría jugar un papel decisivo en la prevención de esta frecuente patología
Background: Chronic allograft nephropathy (CAN) is the main cause of graft loss after the first year of transplantation, and renal biopsies show a predominance of fibrotic lesions. Human transforming growth factor beta-1 (TGF-β1) is the principal profibrogenetic cytokine which has been recently implicated in the development of CAN. Seven TGF-β1 gene polymorphisms have been recently described and some of them have been related to the development of several diseases. Aim: to analyse the relationship between TGF-β1 gene polymorphisms and the development of CAN in a group of renal transplant patients with a long-term follow- up. Methods: a restriction enzyme-based method for TGF-β1 genotyping was used to detect four TGF-β1 gene polymorphisms in codon 10, 25 and 5-flanking region (-800 and -509 positions). A retrospective case-control study were performed on sixty renal transplant recipients with 8 years of post-transplant, 22 of them with CAN (cases) and 38 with normal graft function (controls). We studied 73 subjects to analyse the distribution of the genotypes in the area. Results: the genotype frequencies were similar in the study and control group. The presence of chronic allograft nephropathy was statistically associated with the combination Pro/Pro10 TT509 polymorphism in the TGF-β1 gene, and these patients develop chronic rejection more quickly than the rest of the patients. Chronic allograft nephropathy was also associated with Δ age recipient-donor, with older donors being a significant risk factor for chronic nephropathy. The logistic regression analysis confirmed the independent role of TT509 Pro/Pro10 TGF-β1 polymorphism with a Odd Ratio of 5.8 (1.14-29.7) in chronic nephropathy being the Δ age recipient-donor a confounder fator but not an effect modifier. The rest of the TGF-β1 gene polymorphisms and the classic risk factors were not associated with the development of chronic allograft nephropathy. Conclusions: these data suggest a leading role for TGF-β1 gene polymorphisms (TT509Pro/Pro10) in the development of chronic allograft nephropathy. The identification of this genetic predisposition to chronic allograft rejection could play a decisive role in the prevention of this common pathology
Assuntos
Masculino , Feminino , Criança , Adulto , Idoso , Pessoa de Meia-Idade , Humanos , Doença Enxerto-Hospedeiro/genética , Nefropatias/genética , Transplante de Rim/efeitos adversos , Fator de Crescimento Transformador beta/genética , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/fisiopatologia , Nefropatias/etiologia , Nefropatias/fisiopatologia , Transplante de Rim/imunologia , Estudos Retrospectivos , Transplante HomólogoRESUMO
BACKGROUND: The aim of the present study was to determine the effect of losartan on transforming growth factor-beta1 (TGF-beta1) plasma levels and urinary albumin excretion (UAE) in patients with type 2 diabetes mellitus, mild hypertension and microalbuminuria. METHODS: Fourteen patients (eight males, aged 55+/-6 years) with type 2 diabetes mellitus, mild arterial hypertension and microalbuminuria, participating in an open, uncontrolled, pilot study were included. Patients were treated for 8 weeks with losartan. TGF-beta1 plasma levels, UAE and 24-h blood pressure monitoring were determined at baseline and at 4 and 8 weeks. RESULTS: At 4 and 8 weeks of treatment, a reduction was observed in TGF-beta1 plasma levels (5.5+/-4.5 vs 2.0+/-0.6 and 2.6+/-1.0 ng/ml, P<0.005), UAE (96+/-65 vs 59+/-59 and 64+/-47 microg/min, P<0.01), 24-h systolic blood pressure (136+/-9 vs 129+/-9 and 130+/-10 mmHg, P<0.01) and 24-h diastolic blood pressure (77+/-9 vs 74+/-8 and 74+/-7 mmHg, P<0.03). Stratifying the patients by baseline TGF-beta1, seven had TGF-beta1 plasma values higher than normal controls. At 4 and 8 weeks, they showed a marked reduction in TGF-beta1 values (9.0+/-3.9 to 2.1+/-0.7 and 2.5+/-0.7 ng/ml, P<0.01) and UAE (106+/-83 to 49+/-42 and 38+/-26 microg/min, P<0.05), with good correlation between the percentage reduction of both parameters (r=0.83, P<0.01). The remaining seven patients, with normal baseline TGF-beta1 plasma levels, showed no change in TGF-beta1 plasma levels and UAE after treatment. CONCLUSION: Treatment with losartan decreases TGF-beta1 plasma values and UAE in type 2 diabetes mellitus patients with high baseline TGF-beta1 levels, suggesting that TGF-beta1 may be a marker to detect patients who may particularly benefit from renin-angiotensin system blockade.
Assuntos
Albuminúria , Anti-Hipertensivos/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipertensão/tratamento farmacológico , Losartan/uso terapêutico , Fator de Crescimento Transformador beta/sangue , Pressão Sanguínea/efeitos dos fármacos , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/urina , Angiopatias Diabéticas/sangue , Angiopatias Diabéticas/tratamento farmacológico , Angiopatias Diabéticas/urina , Diástole/efeitos dos fármacos , Feminino , Humanos , Hipertensão/sangue , Hipertensão/urina , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Sístole/efeitos dos fármacosRESUMO
Chronic allograft nephropathy is the principal cause of late graft loss after the first year of renal transplantation. Transforming growth factor-beta1 (TGF-beta1) is a key fibrogenetic cytokine involved in the fibrosis of a number of chronic diseases of the kidney and other organs, and recently evidence has shown that TGF-beta1 is involved in the pathogenesis of chronic renal allograft dysfunction. Production of TGF-beta1 in these circumstances may be modulated by the intrarenal renin-angiotensin system (angiotensin II induces TGF-beta1 production and secretion by the mesangial cells) and by a direct effect of cyclosporin A, which stimulates the synthesis and expression of TGF-beta1. In a prospective study of 14 renal transplant patients exhibiting chronic graft nephropathy, we demonstrated that treatment with losartan significantly decreased plasma levels of TGF-beta1 by >50%. There was a significant correlation (P=0.04) between the increase in circulating angiotensin II after 2 weeks and the decrease in plasma TGF-beta(1) at the end of the study period, suggesting that the degree of angiotensin II receptor blockade plays a decisive role in the synthesis of TGF-beta1. A significant decrease in circulating endothelin-1 (ET-1) levels also occurred during treatment with losartan, together with a decrease in proteinuria. In a randomized 2x2 crossover study, the effects of losartan and amlodipine on renal haemodynamics and on profibrogenetic cytokines were analysed. Whereas amlodipine increased the glomerular filtration rate (GFR) through an increase in the FF and P(G), losartan slightly decreased the GFR, but with a significant decrease in FF and P(G). With respect to the profibrogenetic cytokines, losartan decreased the plasma levels of TGF-beta1 and ET-1, while amlodipine did not significantly change TGF-beta1 and slightly increased ET-1.
