RESUMEN
Iodine is a significant micronutrient. Iodine deficiency (ID)-induced hypothyroxinemia and hypothyroidism during developmental period can cause cerebellar dysfunction. However, mechanisms are still unclear. Therefore, the present research aims to study effects of developmental hypothyroxinemia caused by mild ID and hypothyroidism caused by severe ID or methimazole (MMZ) on parallel fiber-Purkinje cell (PF-PC) synapses in filial cerebellum. Maternal hypothyroxinemia and hypothyroidism models were established in Wistar rats using ID diet and deionized water supplemented with different concentrations of potassium iodide or MMZ water. Birth weight and cerebellum weight were measured. We also examined PF-PC synapses using immunofluorescence, and western blot analysis was conducted to investigate the activity of Neurexin1/cerebellin1 (Cbln1)/glutamate receptor d2 (GluD2) tripartite complex. Our results showed that hypothyroxinemia and hypothyroidism decreased birth weight and cerebellum weight and reduced the PF-PC synapses on postnatal day (PN) 14 and PN21. Accordingly, the mean intensity of vesicular glutamate transporter (VGluT1) and Calbindin immunofluorescence was reduced in mild ID, severe ID, and MMZ groups. Moreover, maternal hypothyroxinemia and hypothyroidism reduced expression of Neurexin1/Cbln1/GluD2 tripartite complex. Our study supports the hypothesis that developmental hypothyroxinemia and hypothyroidism reduce PF-PC synapses, which may be attributed to the downregulation of Neurexin1/Cbln1/GluD2 tripartite complex.
Asunto(s)
Regulación hacia Abajo , Glutamato Deshidrogenasa/biosíntesis , Hipotiroidismo/metabolismo , Yodo/deficiencia , Complejos Multiproteicos/biosíntesis , Proteínas del Tejido Nervioso/biosíntesis , Precursores de Proteínas/biosíntesis , Células de Purkinje/metabolismo , Receptores de Superficie Celular/biosíntesis , Sinapsis/metabolismo , Animales , Animales Recién Nacidos , Femenino , Hipotiroidismo/patología , Células de Purkinje/patología , Ratas , Ratas Wistar , Sinapsis/patologíaRESUMEN
IL-23 has been well studied in the context of T cell differentiation; however, its role in the differentiation of myeloid progenitors is less clear. In this paper, we describe a novel role of IL-23 in myeloid cell differentiation. Specifically, we have identified that in human PBMCs, IL-23 induces the expression of MDL-1, a PU.1 transcriptional target during myeloid differentiation, which orchestrates osteoclast differentiation through activation of DNAX activating protein of 12 kDa and its ITAMs. The molecular events that lead to the differentiation of human macrophages to terminally differentiated osteoclasts are dependent on spleen tyrosine kinase and phospholipase Cγ2 phosphorylation for the induction of intracellular calcium flux and the subsequent activation of master regulator osteoclast transcription factor NFATc1. IL-23-elicited osteoclastogenesis is independent of the receptor activator of NF-κB ligand pathway and uses a unique myeloid DNAX activating protein of 12 kDa-associated lectin-1(+)/DNAX activating protein of 12 kDa(+) cell subset. Our data define a novel pathway that is used by IL-23 in myeloid cells and identify a major mechanism for the stimulation of osteoclastogenesis in inflammatory arthritis.
Asunto(s)
Artritis/inmunología , Interleucina-23/metabolismo , Macrófagos/citología , Células Progenitoras Mieloides/citología , Osteoclastos/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Artritis/metabolismo , Calcio/metabolismo , Diferenciación Celular , Células Cultivadas , Activación Enzimática , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Lectinas Tipo C/biosíntesis , Activación de Macrófagos/inmunología , Macrófagos/inmunología , Proteínas de la Membrana/metabolismo , Complejos Multiproteicos/biosíntesis , Factores de Transcripción NFATC/biosíntesis , Factores de Transcripción NFATC/metabolismo , Osteoclastos/citología , Fosfolipasa C gamma/metabolismo , Fosforilación , Estructura Cuaternaria de Proteína , Proteínas Tirosina Quinasas/metabolismo , Ligando RANK/metabolismo , Receptores de Superficie Celular/biosíntesis , Receptores de Interleucina/metabolismo , Transducción de Señal , Quinasa SykRESUMEN
Preclinical studies revealed that curcumin, the yellow curry pigment, emodin, a compound derived from grapes, and taurolidine, derived from a biogenic amino acid, and some of their structural homologs possess anti-angiogenic and cancer chemopreventive properties. Whereas curcumin and emodin can act via inhibition of COP9 signalosome-associated kinases, taurolidine blocks protein biosynthesis.