β-Hydroxy-β-Methylbutyrate (HMB) Promotes Neurite Outgrowth in Neuro2a Cells

β-Hydroxy-β-methylbutyrate (HMB) has been shown to enhance cell survival, differentiation and protein turnover in muscle, mainly activating phosphoinositide-3-kinase/protein kinase B (PI3K/Akt) and mitogen-activated protein kinases/ extracellular-signal-regulated kinases (MAPK/ERK) signaling pathways. Since these two pathways are related to neuronal survival and differentiation, in this study, we have investigated the neurotrophic effects of HMB in mouse neuroblastoma Neuro2a cells. In Neuro2a cells, HMB promotes differentiation to neurites independent from any effects on proliferation. These effects are mediated by activation of both the PI3K/Akt and the extracellular-signal-regulated kinases (ERK1/2) signaling as demonstrated by the use of specific inhibitors of these two pathways. As myocyte-enhancer factor 2 (MEF2) family of transcription factors are involved in neuronal survival and plasticity, the transcriptional activity and protein levels of MEF2 were also evaluated. HMB promoted MEF2-dependent transcriptional activity mediated by the activation of Akt and ERK1/2 pathways. Furthermore, HMB increases the expression of brain glucose transporters 1 (GLUT1) and 3 (GLUT3), and mTOR phosphorylation, which translates in a higher protein synthesis in Neuro2a cells. Furthermore, Torin1 and rapamycin effects on MEF2 transcriptional activity and HMB-dependent neurite outgrowth support that HMB acts through mTORC2. Together, these findings provide clear evidence to support an important role of HMB in neurite outgrowth.This project has been funded by Abbott Nutrition R&D

β-Hydroxy-β-Methylbutyrate (HMB) Normalizes Dexamethasone-Induced Autophagy-Lysosomal Pathway in Skeletal Muscle

Dexamethasone-induced muscle atrophy is due to an increase in protein breakdown and a decrease in protein synthesis, associated with an over-stimulation of the autophagy-lysosomal pathway. These effects are mediated by alterations in IGF-1 and PI3K/Akt signaling. In this study, we have investigated the effects of β-Hydroxy-β-methylbutyrate (HMB) on the regulation of autophagy and proteosomal systems. Rats were treated during 21 days with dexamethasone as a model of muscle atrophy. Co-administration of HMB attenuated the effects promoted by dexamethasone. HMB ameliorated the loss in body weight, lean mass and the reduction of the muscle fiber cross-sectional area (shrinkage) in gastrocnemius muscle. Consequently, HMB produced an improvement in muscle strength in the dexamethasone-treated rats. To elucidate the molecular mechanisms responsible for these effects, rat L6 myotubes were used. In these cells, HMB significantly attenuated lysosomal proteolysis induced by dexamethasone by normalizing the changes observed in autophagosome formation, LC3 II, p62 and Bnip3 expression after dexamethasone treatment. HMB effects were mediated by an increase in FoxO3a phosphorylation and concomitant decrease in FoxO transcriptional activity. The HMB effect was due to the restoration of Akt signaling diminished by dexamethasone treatment. Moreover, HMB was also involved in the regulation of the activity of ubiquitin and expression of MurF1 and Atrogin-1, components of the proteasome system that are activated or up-regulated by dexamethasone. In conclusion, in vivo and in vitro studies suggest that HMB exerts protective effects against dexamethasone-induced muscle atrophy by normalizing the Akt/FoxO axis that controls autophagy and ubiquitin proteolysis.This project has been funded by Abbott Nutrition R&D

Laparoscopic diagnosis and treatment of nonpalpable testis

INTRODUCTION: Treatment of the cryptorchid testicle is justified due to the increased risk of infertility and malignancy as well as the risk of testicular trauma and psychological stigma on patients and their parents. Approximately 20% of cryptorchid testicles are nonpalpable. In these cases, the videolaparoscopic technique is a useful alternative method for diagnosis and treatment. MATERIALS AND METHODS: We present data concerning 90 patients submitted to diagnostic laparoscopy for impalpable testicles. Forty-six patients (51.1%) had intra-abdominal gonads. In 25 testicles of 19 patients, we performed a two stage laparoscopic Fowler-Stephens orchiopexy. The other 27 patients underwent primary laparoscopic orchiopexy, in a total of 29 testicles. RESULTS: We obtained an overall 88% success rate with the 2 stage Fowler-Stephens approach and only 33% rate success using one stage Fowler-Stephens surgery with primary vascular ligature. There was no intraoperative complication in our group of patients. In the laparoscopic procedures, the cosmetic aspect is remarkably more favorable as compared to open surgeries. Hospital stay and convalescence were brief. CONCLUSIONS: In pediatric age group, the laparoscopic approach is safe and feasible. Furthermore, the laparoscopic orchiopexy presents excellent results in terms of diagnosis and therapy of the impalpable testis, which is why this technique has been routinely incorporated in our Department

Foamy virus infection in primates.

Foamy viruses (FV), the oldest known genus of Retroviridae, are unique among the retroviruses in having no disease association. It is not known why FV are non-pathogenic while infection by their closest relatives can be deadly. This may be related to the estimated 60 million years of coevolution of FV and their primate hosts. We review the current state of knowledge of FV infection, including information about the sites of viral replication and host immune responses, and discuss the role these may play in establishing persistent yet non-pathogenic infections. Whether FV has pathologic consequences in immunosuppressed hosts has not been thoroughly investigated. As most primates in HIV/SIV research are coinfected with FV, investigation into possible interactions between these viruses is of interest. The use of FV as a vector for gene therapy is also discussed