RESUMEN
One-step functionalization of alginate with boronic acid groups allowed spontaneous formation of biocompatible hydrogels under basic conditions without additional complementary molecules or crosslinking agents. The dynamic nature of boronate ester bonds formed with vicinal diols present on alginate pyranose rings provided remarkable self-healing, injectable and multi-stimuli responsive properties to the material.
Asunto(s)
Alginatos/química , Ácidos Borónicos/química , Alginatos/síntesis química , Alginatos/toxicidad , Materiales Biocompatibles/síntesis química , Materiales Biocompatibles/química , Materiales Biocompatibles/toxicidad , Ácidos Borónicos/síntesis química , Ácidos Borónicos/toxicidad , Fructosa/química , Células HeLa , Humanos , Hidrogeles , ReologíaRESUMEN
Bortezomib (Velcade®) is a proteasome inhibitor that has been approved for the treatment of multiple myeloma and mantle cell lymphoma. It has been shown to inhibit the expression of cell adhesion molecules, co-stimulatory molecules, and NFκB activation, to deplete alloreactive T lymphocytes, and to decrease Th1 cytokine production. The anti-inflammatory effects of bortezomib were further investigated in this current set of studies. Systemic treatment with bortezomib was efficacious in the thioglycolate-induced MCP-1 production model, and the dinitrofluorobenzene-induced delayed-type hypersensitivity model. Psoriasis is an autoimmune disease that affects about 2% of the world population. Many treatments have been reported with varying degrees of efficacy. A topical bortezomib formulation was developed to minimize systemic exposure. Its tolerability was investigated in a topical imiquimod (IMQ)-induced psoriasis model. Daily application of IMQ on mouse skin induced inflamed scaly skin lesions resembling plaque-type psoriasis. Fatality was observed in the 1-mg/ml dose group. At 0.1 and 0.01 mg/ml, bortezomib potentiated IMQ-induced erythema, scaling, skin thickening, and caused necrotic lesions. Lower doses had no effect on the clinical observations. Histologically, bortezomib dose-dependently increased parakeratosis, hyperkeratosis, acanthosis, and inflammatory cell infiltration. This study demonstrated that topical bortezomib is not suitable for the treatment of psoriasis.
Asunto(s)
Antiinflamatorios/farmacología , Ácidos Borónicos/farmacología , Factores Inmunológicos/farmacología , Pirazinas/farmacología , Adyuvantes Inmunológicos/toxicidad , Aminoquinolinas/toxicidad , Animales , Antiinflamatorios/administración & dosificación , Antiinflamatorios/uso terapéutico , Antiinflamatorios/toxicidad , Ácidos Borónicos/administración & dosificación , Ácidos Borónicos/uso terapéutico , Ácidos Borónicos/toxicidad , Bortezomib , Dinitrofluorobenceno/toxicidad , Modelos Animales de Enfermedad , Composición de Medicamentos , Evaluación Preclínica de Medicamentos , Estabilidad de Medicamentos , Femenino , Hipersensibilidad Tardía/inducido químicamente , Hipersensibilidad Tardía/tratamiento farmacológico , Imiquimod , Factores Inmunológicos/administración & dosificación , Factores Inmunológicos/uso terapéutico , Factores Inmunológicos/toxicidad , Irritantes/toxicidad , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos ICR , Peritonitis/inducido químicamente , Peritonitis/tratamiento farmacológico , Psoriasis/inducido químicamente , Psoriasis/tratamiento farmacológico , Pirazinas/administración & dosificación , Pirazinas/uso terapéutico , Pirazinas/toxicidad , Distribución Aleatoria , Temperatura , Tioglicolatos/toxicidadRESUMEN
OBJECTIVES: Nuclear factor kappa B (NF-kappaB) is a major regulator of pivotal proinflammatory cytokines in the pathogenesis of rheumatoid arthritis (RA). Bortezomib inhibits NF-kappaB activation by blocking the degradation of the NF-kappaB inhibitor, I-kappaB. In this study, the efficacy of bortezomib on murine collagen-induced arthritis (CIA) was investigated. METHODS: Thirty-five male DBA/1 mice were divided into five groups. All mice except controls were injected with type II collagen. Mice in the bortezomib-treated groups were injected intraperitoneally with 0.01, 0.1 and 1 mg/kg bortezomib twice a week for 2 weeks. Controls and mice in the untreated group were also injected intraperitoneally with phosphate-buffered saline in the same manner. Arthritis score and paw thickness were measured and histopathological assessment of joint sections was performed. The expression of proinflammatory cytokines and enzymes was evaluated by immunohistochemical staining. Joint destruction was confirmed using three-dimensional micro-computerised tomography (CT). Blood cells were counted and liver and kidney functions were monitored. RESULTS: Bortezomib significantly attenuated the severity of arthritis and histopathological findings in CIA mice. The expression of tumour necrosis factor alpha, IL-1beta, IL-6, matrix metalloproteinase 3, cyclooxygenase 2 and inducible nitric oxide synthase decreased in bortezomib-treated mice compared with untreated mice. In addition, micro-CT confirmed that bortezomib reduced joint destruction. No adverse effects in blood cells, liver or kidneys were observed with bortezomib treatment. CONCLUSIONS: These data suggest that bortezomib may play an anti-inflammatory role in the pathophysiology of RA and serve as a new therapeutic modality for RA.
Asunto(s)
Antirreumáticos/uso terapéutico , Artritis Experimental/tratamiento farmacológico , Ácidos Borónicos/uso terapéutico , Inhibidores de Proteasas/uso terapéutico , Pirazinas/uso terapéutico , Animales , Antirreumáticos/administración & dosificación , Antirreumáticos/toxicidad , Artritis Experimental/diagnóstico por imagen , Artritis Experimental/patología , Ácidos Borónicos/administración & dosificación , Ácidos Borónicos/toxicidad , Bortezomib , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos/métodos , Mediadores de Inflamación/metabolismo , Masculino , Ratones , Ratones Endogámicos DBA , Inhibidores de Proteasas/administración & dosificación , Inhibidores de Proteasas/toxicidad , Pirazinas/administración & dosificación , Pirazinas/toxicidad , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Microtomografía por Rayos XRESUMEN
Arginase is the endogenous inhibitor of inducible NO synthase (iNOS), because both enzymes use the same substrate, l-arginine (Arg). Importantly, arginase synthesizes ornithine, which is metabolized by the enzyme ornithine decarboxylase (ODC) to produce polyamines. We investigated the role of these enzymes in the Citrobacter rodentium model of colitis. Arginase I, iNOS, and ODC were induced in the colon during the infection, while arginase II was not up-regulated. l-Arg supplementation of wild-type mice or iNOS deletion significantly improved colitis, and l-Arg treatment of iNOS(-/-) mice led to an additive improvement. There was a significant induction of IFN-gamma, IL-1, and TNF-alpha mRNA expression in colitis tissues that was markedly attenuated with l-Arg treatment or iNOS deletion. Treatment with the arginase inhibitor S-(2-boronoethyl)-l-cysteine worsened colitis in both wild-type and iNOS(-/-) mice. Polyamine levels were increased in colitis tissues, and were further increased by l-Arg. In addition, in vivo inhibition of ODC with alpha-difluoromethylornithine also exacerbated the colitis. Taken together, these data indicate that arginase is protective in C. rodentium colitis by enhancing the generation of polyamines in addition to competitive inhibition of iNOS. Modulation of the balance of iNOS and arginase, and of the arginase-ODC metabolic pathway may represent a new strategy for regulating intestinal inflammation.