RESUMEN
The G-protein-coupled receptor GPR132, also known as G2A, is activated by 9-hydroxyoctadecadienoic acid (9-HODE) and other oxidized fatty acids. Other suggested GPR132 agonists including lysophosphatidylcholine (LPC) have not been readily reproduced. Here, we identify N-acylamides in particular N-acylglycines, as lipid activators of GPR132 with comparable activity to 9-HODE. The order-of-potency is N-palmitoylglycine > 9-HODE ≈ N-linoleoylglycine > linoleamide > N-oleoylglycine ≈ N-stereoylglycine > N-arachidonoylglycine > N-docosehexanoylglycine. Physiological concentrations of N-acylglycines in tissue are sufficient to activate GPR132. N-linoleoylglycine and 9-HODE also activate rat and mouse GPR132, despite limited sequence conservation to human. We describe pharmacological tools for GPR132, identified through drug screening. SKF-95667 is a novel GPR132 agonist. SB-583831 and SB-583355 are peptidomimetic molecules containing core amino acids (glycine and phenylalanine, respectively), and structurally related to previously described ligands. A telmisartan analog, GSK1820795A, antagonizes the actions of N-acylamides at GPR132. The synthetic cannabinoid CP-55 940 also activates GPR132. Molecular docking to a homology model suggested a site for lipid binding, predicting the acyl side-chain to extend into the membrane bilayer between TM4 and TM5 of GPR132. Small-molecule ligands are envisaged to occupy a "classical" site encapsulated in the 7TM bundle. Structure-directed mutagenesis indicates a critical role for arginine at position 203 in transmembrane domain 5 to mediate GPR132 activation by N-acylamides. Our data suggest distinct modes of binding for small-molecule and lipid agonists to the GPR132 receptor. Antagonists, such as those described here, will be vital to understand the physiological role of this long-studied target.
Asunto(s)
Proteínas de Ciclo Celular/agonistas , Glicina/análogos & derivados , Ácidos Palmíticos/farmacología , Peptidomiméticos/farmacología , Receptores Acoplados a Proteínas G/agonistas , Animales , Células CHO , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Cricetulus , Ciclohexanoles/farmacología , Antagonismo de Drogas , Ácidos Grasos Insaturados/farmacología , Glicina/farmacología , Interacciones Hidrofóbicas e Hidrofílicas , Simulación del Acoplamiento Molecular , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Transducción de Señal , Homología Estructural de Proteína , Telmisartán/análogos & derivados , Telmisartán/farmacologíaRESUMEN
Intraosseous epidermal inclusion cysts (IEpC) are benign bone tumors that often present in the phalanges of the fingers, but rarely are seen in the lower extremity. These tumors often present following surgery, and have a similar clinical and radiographic presentation to osteomyelitis. The lack of defining characteristics makes preoperative diagnosis of these tumors very difficult. It is crucial to differentiate these tumors from malignant lesions with similar presentation. This case study presents our treatment of this osseous tumor and reviews the available literature describing this condition. LEVELS OF EVIDENCE: Level V: Case report.
Asunto(s)
Quistes Óseos/cirugía , Quiste Epidérmico/cirugía , Enfermedades del Pie/cirugía , Falanges de los Dedos del Pie/cirugía , Amputación Quirúrgica/métodos , Quistes Óseos/diagnóstico por imagen , Quistes Óseos/patología , Progresión de la Enfermedad , Quiste Epidérmico/diagnóstico por imagen , Quiste Epidérmico/patología , Femenino , Estudios de Seguimiento , Enfermedades del Pie/diagnóstico por imagen , Enfermedades del Pie/patología , Humanos , Imagen por Resonancia Magnética/métodos , Persona de Mediana Edad , Dimensión del Dolor , Índice de Severidad de la Enfermedad , Falanges de los Dedos del Pie/diagnóstico por imagen , Falanges de los Dedos del Pie/patología , Tomografía Computarizada por Rayos X/métodos , Resultado del Tratamiento , Cicatrización de Heridas/fisiologíaRESUMEN
Lateral column lengthening is a common procedure for correction of pes planovalgus. A tricortical bone graft has been a standard among foot and ankle surgeons. The purpose of the present study was to compare the union rates and complications between the 2 forms of fixation for lateral column lengthening. The present study was a retrospective medical record and radiograph review of 52 patients divided into 2 equal groups, allograft (group A) and opening wedge plate (group B). The radiographic analyses compared the preoperative, postoperative and long-term measurements of cuboid abduction and talonavicular angles. The outcome measures included nonunion, hardware removal, and infection. The median follow-up duration for each group was 34.5 (range 6.3 to 89.5) months and 12.6 (range 6.5 to 56.8) months for groups A and B, respectively. Group A had 4 nonunions (15.4%) and group B had 2 nonunions (7.7%). The mean radiographic measurements of cuboid abduction and talonavicular articulation for each group improved significantly. The incidence of hardware removal was greater for group A than for group B (30.8% versus 15.4%), although the difference was not statistically significant. The median time to osseous healing for group A was 12.0 (range 8.0 to 80.0) weeks and for group B was 10.0 (range 6.0 to 36.0) weeks. The interposition plating techniques for lateral column lengthening procedures had a lower nonunion rate and incidence of hardware removal compared with the traditional use of tricortical bone grafting. The findings from the present study will aid surgeons in alternative fixation for lateral column lengthening procedures.