The action of obestatin in skeletal muscle repair: stem cell expansion, muscle growth, and microenvironment remodeling

The development of therapeutic strategies for skeletal muscle diseases, such as physical injuries and myopathies, depends on the knowledge of regulatory signals that control the myogenic process. The obestatin/GPR39 system operates as an autocrine signal in the regulation of skeletal myogenesis. Using a mouse model of skeletal muscle regeneration after injury and several cellular strategies, we explored the potential use of obestatin as a therapeutic agent for the treatment of trauma-induced muscle injuries. Our results evidenced that the overexpression of the preproghrelin, and thus obestatin, and GPR39 in skeletal muscle increased regeneration after muscle injury. More importantly, the intramuscular injection of obestatin significantly enhanced muscle regeneration by simulating satellite stem cell expansion as well as myofiber hypertrophy through a kinase hierarchy. Added to the myogenic action, the obestatin administration resulted in an increased expression of VEGF/VEGFR2 and the consequent microvascularization, with no effect on collagen deposition in skeletal muscle. Furthermore, the potential inhibition of myostatin during obestatin treatment might contribute to its myogenic action improving muscle growth and regeneration. Taken together, our data demonstrate successful improvement of muscle regeneration, indicating obestatin is a potential therapeutic agent for skeletal muscle injury and would benefit other myopathies related to muscle regeneration

c-Src Regulates Akt Signaling in Response to Ghrelin via β-Arrestin Signaling-Independent and -Dependent Mechanisms

The aim of the present study was to identify the signaling mechanisms to ghrelin-stimulated activation of the serine/threonine kinase Akt. In human embryonic kidney 293 (HEK293) cells transfected with GHS-R1a, ghrelin leads to the activation of Akt through the interplay of distinct signaling mechanisms: an early Gi/o protein-dependent pathway and a late pathway mediated by β-arrestins. The starting point is the Gi/o-protein dependent PI3K activation that leads to the membrane recruitment of Akt, which is phosphorylated at Y by c-Src with the subsequent phosphorylation at A-loop (T308) and HM (S473) by PDK1 and mTORC2, respectively. Once the receptor is activated, a second signaling pathway is mediated by β-arrestins 1 and 2, involving the recruitment of at least β-arrestins, c-Src and Akt. This β-arrestin-scaffolded complex leads to full activation of Akt through PDK1 and mTORC2, which are not associated to the complex. In agreement with these results, assays performed in 3T3-L1 preadipocyte cells indicate that β-arrestins and c-Src are implicated in the activation of Akt in response to ghrelin through the GHS-R1a. In summary this work reveals that c-Src is crucially involved in the ghrelin-mediated Akt activation. Furthermore, the results support the view that β-arrestins act as both scaffolding proteins and signal transducers on Akt activation

Identification of a Novel Risk Locus for Multiple Sclerosis at 13q31.3 by a Pooled Genome-Wide Scan of 500,000 Single Nucleotide Polymorphisms

Multiple sclerosis is a chronic inflammatory demyelinating disease of the central nervous system with an important genetic component and strongest association driven by the HLA genes. We performed a pooling-based genome-wide association study of 500,000 SNPs in order to find new loci associated with the disease. After applying several criteria, 320 SNPs were selected from the microarrays and individually genotyped in a first and independent Spanish Caucasian replication cohort. The 8 most significant SNPs validated in this cohort were also genotyped in a second US Caucasian replication cohort for confirmation. The most significant association was obtained for SNP rs3129934, which neighbors the HLA-DRB/DQA loci and validates our pooling-based strategy. The second strongest association signal was found for SNP rs1327328, which resides in an unannotated region of chromosome 13 but is in linkage disequilibrium with nearby functional elements that may play important roles in disease susceptibility. This region of chromosome 13 has not been previously identified in MS linkage genome screens and represents a novel risk locus for the disease

Headache: What to ask, how to examine, and which scales to use. Recommendationsof the Spanish Society of Neurology’s Headache Study Group

Introducción: La cefalea es el motivo de consulta neurológico más prevalente en los distintos niveles asistenciales, donde la anamnesis y exploración son primordiales para realizar un diagnóstico y tratamiento adecuados. Con la intención de unificar la atención de esta patología, el Grupo de Estudio de Cefalea de la Sociedad Española de Neurología (GECSEN) ha decidido elaborar unas recomendaciones consensuadas para mejorar y garantizar una adecuada asistencia en atención primaria, urgencias y neurología. Metodología: El documento es práctico, sigue el orden de la dinámica de actuación durante una consulta: anamnesis, escalas que cuantifican el impacto y la discapacidad y exploración. Además, finaliza con pautas para realizar un seguimiento adecuado y un manejo de las expectativas del paciente con el tratamiento pautado.Conclusiones: Esperamos ofrecer una herramienta que mejore la atención al paciente con cefalea para garantizar una asistencia adecuada y homogénea a nivel nacional.Introduction: Headache is the most common neurological complaint at the different levelsof the healthcare system, and clinical history and physical examination are essential in thediagnosis and treatment of these patients. With the objective of unifying the care given topatients with headache, the Spanish Society of Neurology’s Headache Study Group (GECSEN)has decided to establish a series of consensus recommendations to improve and guaranteeadequate care in primary care, emergency services, and neurology departments.Methods: With the aim of creating a practical document, the recommendations follow thedynamics of a medical consultation: clinical history, physical examination, and scales quantif-ying headache impact and disability. In addition, we provide recommendations for follow-upand managing patients’ expectations of the treatment.Conclusions: With this tool, we aim to improve the care given to patients with headache inorder to guarantee adequate, homogeneous care across Spain

The metabolic versatility of PAOs as an opportunity to obtain a highly P-enriched stream for further P-recovery

The effects of two sequencing batch reactor operation strategies for phosphorus stream enrichment over the biological phosphorus removal performance have been studied. The objective of both strategies is of performing an extraction cycle in order to obtain a new stream highly enriched with phosphorus. In the 1st strategy the amount of influent volatile fatty acids (VFAs) is the same in each cycle; while in the 2nd strategy the influent VFAs concentration is increased during phosphorus extraction experiments. Despite the strong decrease of the stored poly-P inside the cells in both strategies after the recovery cycles, the ability of the systems to remove phosphorus was not affected. The P-release/HAcuptake ratio (changing from 0.73 to 0.21 mmol P mmol C-1) together with FISH analyses (around 85% of Accumulibacter through the experimental period) confirmed that a shift from PAM to GAM occurred after phosphorus enrichment in the 2nd strategy experiments. These results suggest that energy required for VFA uptake by polyphosphate-accumulating organisms (PAO5) was not only derived from polyphosphates degradation, but also from glycogen degradation. FISH also revealed that Type II Accumulibacter species are responsible of the metabolic shift. The strategy based on increasing influent VFAs concentration during phosphorus extraction experiments showed a higher extraction efficiency (from 46% to 76%), as higher phosphorus concentration within supernatant can be achieved (from 113.9 to 198.7 mg Pl(-1)). Following this strategy, it is possible to concentrate up to 81% of the incoming phosphorus in a single enriched stream. This suggests that, despite the extra addition of carbon source needed (9%), this strategy is more appropriate if phosphorus recovery for reuse purposes is required. (C) 2015 Elsevier BM. All rights reserved.This research work has been supported by the Generalitat Valenciana (GVPRE/2008/044) and the Polytechnic University of Valencia (PAID-06-08-3227), which are gratefully acknowledged. Special acknowledgements to Consejo Nacional de la Ciencia y la Tecnologia de Mexico (CONACYT) No. 207966.Acevedo Juárez, B.; Camiña, C.; Corona, JE.; Borrás Falomir, L.; Barat Baviera, R. (2015). The metabolic versatility of PAOs as an opportunity to obtain a highly P-enriched stream for further P-recovery. Chemical Engineering Journal. 270:459-467. doi:10.1016/j.cej.2015.02.063S45946727