The acetylcholinesterase inhibitory activity of 89 organic extracts from marine organisms was evaluated through a TLC bioautography methodology. Extracts from soft corals (Eunicea and Plexaura) were the most active compared with extracts from sponges. The bioguided chemical study of the most active extract, obtained from Pseudoplexaura porosa, led to the isolation of a diterpene with spectroscopic properties consistent to those published to the cembrane Steylolide. However, further analysis by X-ray diffraction indicated that the compound was the 14-acetoxycrassine (1), correcting the structure reported to the Styelolide. Additionally, the acetylcholinesterase inhibitory activity of fourteen cembranoids (2-15) isolated from soft corals Eunicea knighti and Pseudoplexaura flagellosa was evaluated. Cembranoids 2, 3 and 4 were the most active compounds in the TLC bioassay. Then, the most promising cembranoids, 14-acetoxycrassine (1) and asperdiol (2), were tested quantitatively and they exhibited IC values of 1.40 ± 0.113 and 0.358 ± 0.130 μM, respectively.
The desensitization of the GH-induced Janus kinase 2 (JAK2) and signal transducer and activator of transcription 5 (STAT5) signaling pathway plays a crucial role in GH regulation of hepatic genes. Previous studies have demonstrated that the inactivation of the GH-induced JAK2/STAT5 pathway is regulated by protein translation and suppressors of cytokine signaling (SOCS). In this study we sought to explore the relationships between endoplasmic reticulum stress, GH-induced JAK2/STAT5 activity and SOCS expression. 1,2-bis(o-Aminophenoxy)ethane-N,N,N,N-tetraacetic acid (acetoxymethyl)ester (BAPTA-AM), used to provoke endoplasmic reticulum stress, caused a drastic inhibition of protein translation that correlated with the phosphorylation of the eukaryotic translation initiation factor 2alpha. Both GH and BAPTA-AM caused a rapid induction of the transcription factor C/EBP homology protein (CHOP) and an additive effect was observed with combined treatment, which suggests a regulatory role of GH on endoplasmic reticulum stress. Endoplasmic reticulum stress did not interfere with the rapid GH activation of STAT5 DNA binding activity. However, BAPTA-AM prolonged the DNA binding activity of STAT5 without affecting STAT5 or JAK2 protein levels. GH-induced phosphorylation of JAK2 and STAT5 DNA binding activity were prolonged in the presence of BAPTA-AM, suggesting that endoplasmic reticulum stress prevents the inactivation of STAT5 DNA binding activity by modulating the rate of JAK2/STAT5 dephosphorylation. Like BAPTA-AM, the endoplasmic reticulum stressors dithiothreitol and A23187 also prolonged the GH-induced STAT5 DNA binding activity. We were not able to correlate BAPTA-AM effects to the GH-dependent expression of SOCS proteins or SOCS mRNA, suggesting that endoplasmic reticulum stress modulates the rate of JAK2/STAT5 dephosphorylation through mechanisms other than inhibition of SOCS expression. This study indicates that cellular stress may modulate transcription through the JAK/STAT pathway.
La nutrición es un regulador importante de las acciones de la hormona de crecimiento (GH). Se ha demostrado que el déficit de nutrientes induce un estado de resistencia a la hormona, en el cual están involucrados, entre otros factores, alteraciones post-receptor en la vía de señalización, pero se desconocen los mecanismos responsables. En este trabajo se investigó la participación de algunos miembros de la familia de proteínas supresoras de la señalización por citocinas (SOCS) en la resistencia causada por malnutrición, que inhibe la activación de la señalización a través de Janus cinasa 2/transductor de señal y activador de la transcripción 5 (JK2/STAT5). Se estudiaron los cambios en la expresión génica del receptor de GH (RGH), IGF-I y SOCS3 en el hígado de ratas alimentadas con una dieta baja en proteína (8%) y estimuladas con GH. La restricción en el consumo de proteína disminuyó significativamente (p<0,05) los contenidos de ARNm del RGH al igual que el número de sitios receptores, pero elevó significativamente (p<0,05) la transcripción del gen SOCS3. La administración de hormona de crecimiento humana recombinante (rhGH) a ratas restringidas en proteína incrementó los niveles del mensajero del RGH y del IGF-I, pero sólo para el primero se lograron restablecer valores comparables a los de animales alimentados con una dieta alta en proteína (20%). La transcripción de SOCS3 en el grupo malnutrido se incrementó aún más como resultado de la administración de GH. En resumen, los resultados obtenidos sugieren que la reducción en la sensibilidad del tejido hepático a la GH que acompaña la malnutrición puede deberse en parte a una sobreexpresión de la proteína SOCS3. Además, la distribución ubicua de SOCS3 y CIS plantea un papel más amplio de las proteínas SOCS como reguladoras de la sensibilidad de los tejidos a las citocinas.Palabras clave: hormona de crecimiento, SOCS, malnutrición, hormonas. Role of suppressor of cytokine signaling proteins in growth hormone resistance induced by malnutritionNutrition is an important regulator of growth hormone (GH) action. Nutritional deprivation causes a GH resistance involving post-receptor alterations in the signaling pathway, but the responsible mechanisms remain unknown. Herein, suppressors of cytokine signaling proteins (SOCS) were investigated as potential agents in GH-resistance induced by malnutrition which inhibits activation of Janus kinase 2/signal transductor and activator of transcription 5 (JAK2/STAT5) pathway. Growth hormone receptor (GHR), IGF-I and SOCS3 mRNA expression was meassured in the liver of rats fed with a low protein diet and with GH stimulation. Protein diet restriction significantly diminished GHR mRNA and receptor binding sites (p<0.05), but caused a highly increased SOCS3 gene expression. In diet-restricted rats, GH administration increased GHR and IGF-I mRNA; however, GHR reached basal levels observed in animals feeding with a high protein diet. The malnourished group increased SOCS3 gene transcription in response to GH administration. These resu...
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