RESUMEN
HNF4α is a culprit gene product for a monogenic and dominantly-inherited form of diabetes, referred to as MODY1 (Maturity Onset Diabetes of the Young type 1). Reduced HNF4α activities have been linked to impaired insulin secretion and ß-cell function. Numerous mutations have been identified from the patients and they have been instructive as to the individual residue's role in protein structure-function and dysfunction. As a member of the nuclear receptor (NR) superfamily, HNF4α is made of characteristic modular domains and it functions exclusively as a homodimer despite its sequence homology to RXR, a common heterodimer partner of non-steroidal NRs. Transcription factors commonly dimerize to enhance their molecular functions mainly by facilitating the recognition of double helix target DNAs that display an intrinsic pseudo-2-fold symmetry and the recruitment of the remainder of the main transcriptional machinery. HNF4α is no exception and its dimerization is maintained by the ligand binding domain (LBD) mainly through the leucine-zipper-like interactions at the stalk of two interacting helices. Although many MODY1 mutations have been previously characterized, including DNA binding disruptors, ligand binding disruptors, coactivator binding disruptors, and protein stability disruptors, protein dimerization disruptors have not been formally reported. In this report, we present a set of data for the two MODY1 mutations found right at the dimerization interface (L332 P and L328del mutations) which clearly exhibit the disruptive effects of directly affecting dimerization, protein stability, and transcriptional activities. These data reinforced the fact that MODY mutations are loss-of-function mutations and HNF4α dimerization is essential for its optimal function and normal physiology.
Asunto(s)
Diabetes Mellitus Tipo 2/genética , Factor Nuclear 4 del Hepatocito/genética , Factor Nuclear 4 del Hepatocito/metabolismo , Mutación , Dominios y Motivos de Interacción de Proteínas/genética , Multimerización de Proteína , Dimerización , Células HeLa , Factor Nuclear 4 del Hepatocito/química , Humanos , Mutación con Pérdida de Función/genética , Modelos Moleculares , Mutagénesis Sitio-Dirigida , Unión Proteica , Multimerización de Proteína/genética , Estabilidad Proteica , Estructura Cuaternaria de Proteína/genética , Activación Transcripcional/genéticaRESUMEN
Nanotitanium dioxide particle (nTiO2) inhalation has been reported to induce lung parenchymal injury. After inhalation of nTiO2, we monitored changes in 5-lipoxygenase, endothelial nitric oxide synthase (eNOS), and inducible nitric oxide synthase (iNOS) mRNA in rat lung tissue. Lung function parameters include specific airway resistance (SRaw), peak expiratory flow rate (PEF), functional residual capacity (FRC), and lung compliance (Cchord); blood white blood cell count (WBC), nitric oxide (NO), hydrogen peroxide, and lactic dehydrogenase (LDH); and lung lavage leukotriene C4, interleukin 6 (IL6), tumor necrotic factor α (TNFα), hydroxyl radicals, and NO. Leukotriene receptor antagonist MK571 and 5-lipoxygenase inhibitor MK886 were used for pharmacologic intervention. Compared to control, nTiO2 exposure induced near 5-fold increase in 5-lipoxygenase mRNA expression in lung tissue. iNOS mRNA increased while eNOS mRNA decreased. Lavage leukotriene C4; IL6; TNFα; NO; hydroxyl radicals; and blood WBC, NO, hydrogen peroxide, and LDH levels rose. Obstructive ventilatory insufficiency was observed. MK571 and MK886 both attenuated the systemic inflammation and lung function changes. We conclude that inhaled nTiO2 induces systemic inflammation, cytokine release, and oxidative and nitrosative stress in the lung. The lipoxygenase pathway products, mediated by oxygen radicals and WBC, play a critical role in the obstructive ventilatory insufficiency induced by nTiO2.
Asunto(s)
Resistencia de las Vías Respiratorias/efectos de los fármacos , Lipooxigenasas/metabolismo , Pulmón/fisiopatología , Nanopartículas/toxicidad , Transducción de Señal/efectos de los fármacos , Titanio/toxicidad , Administración por Inhalación , Aerosoles/administración & dosificación , Animales , Líquido del Lavado Bronquioalveolar , Capacidad Residual Funcional , Cinética , Recuento de Leucocitos , Leucotrieno C4/metabolismo , Lipooxigenasas/genética , Pulmón/efectos de los fármacos , Pulmón/enzimología , Pulmón/patología , Masculino , Nanopartículas/administración & dosificación , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo II/genética , Óxido Nítrico Sintasa de Tipo II/metabolismo , Óxido Nítrico Sintasa de Tipo III/genética , Óxido Nítrico Sintasa de Tipo III/metabolismo , Oxígeno/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Titanio/administración & dosificaciónRESUMEN
Upper gastrointestinal (GI) hemorrhage is a common presentation to an emergency department. Often, the diagnosis is peptic ulcer disease in which vague or sharp abdominal pain is associated with bleeding. In contrast, intussusception is a rare cause of abdominal pain and coincident GI bleeding. In this case, we report a 41-year-old woman who had an intussuscepting jejunal obstruction due to a hamartoma of the small bowel. The diagnosis was established by ultrasonography. In review of the literature, abdominal pain and bleeding are two common manifestations of intussusception when the lesion originates in the small bowel. Intussusception is frequently included in the differential diagnosis of pediatric patients with coincident abdominal pain and bleeding. However, it is rarely mentioned as an adult cause of these two findings. Because of the delayed and nonspecific presentations of abdominal discomfort in adult patients with intussusception, the diagnosis is often delayed. This case points out the need for considering intussusception even in middle-aged patients whose initial presentation is concomitant bleeding and pain.