Maria Alicia Cortes

SHP-1 in Cell-Cycle Regulation

The reversible phosphorylation of tyrosine residues in proteins, which is governed by the balanced action of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs), is a key element of the signaling pathways that are involved in the control of cell proliferation. Deregulation of either of these key regulators leads to abnormal cell signaling, which is largely associated with human pathologies including cancer. This review focuses on recent studies on the role of the protein tyrosine phosphatase SHP-1 on cell-cycle regulation and its possible roles in tumour onset and progression. SHP-1 is a PTP with two SH2 domains that is expressed in haematopoietic cells and, moderately, in many other cell types, especially malignant epithelial cells. SHP-1 regulates cell proliferation, whether it is by controlling mitogenic pathways activated by receptors with tyrosine kinase activity, or by regulating components of the cell-cycle machinery such as CDK2, p27 and cyclin D1. Since several inhibitors targeting SHP-1 have demonstrated their value in cancer treatment, this phosphatase has been proposed as a therapeutic target for this pathology.

Antitumoral, Antihypertensive, Antimicrobial, and Antioxidant Effects of an Octanuclear Copper(II)-Telmisartan Complex with an Hydrophobic Nanometer Hole

A new Cu(II) complex with the antihypertensive drug telmisartan, [Cu8Tlm16]·24H2O (CuTlm), was synthesized and characterized by elemental analysis and electronic, FTIR, Raman and electron paramagnetic resonance spectroscopy. The crystal structure (at 120 K) was solved by X-ray diffraction methods. The octanuclear complex is a hydrate of but otherwise isostructural to the previously reported [Cu8Tlm16] complex. [Cu8Tlm16]·24H2O crystallizes in the tetragonal P4/ncc space group with a = b = 47.335(1), c = 30.894(3) Å, Z = 4 molecules per unit cell giving a macrocyclic ring with a double helical structure. The Cu(II) ions are in a distorted bipyramidal environment with a somewhat twisted square basis, cis-coordinated at their core N2O2 basis to two carboxylate oxygen and two terminal benzimidazole nitrogen atoms. Cu8Tlm16 has a toroidal-like shape with a hydrophobic nanometer hole, and their crystal packing defines nanochannels that extend along the crystal c-axis. Several biological activities of the complex and the parent ligand were examined in vitro. The antioxidant measurements indicate that the complex behaves as a superoxide dismutase mimic with improved superoxide scavenger power as compared with native sartan. The capacity of telmisartan and its copper complex to expand human mesangial cells (previously contracted by angiotensin II treatment) is similar to each other. The antihypertensive effect of the compounds is attributed to the strongest binding affinity to angiotensin II type 1 receptor and not to the antioxidant effects. The cytotoxic activity of the complex and that of its components was determined against lung cancer cell line A549 and three prostate cancer cell lines (LNCaP, PC-3, and DU 145). The complex displays some inhibitory effect on the A549 line and a high viability decrease on the LNCaP (androgen-sensitive) line. From flow cytometric analysis, an apoptotic mechanism was established for the latter cell line. Telmisartan and CuTlm show antibacterial and antifungal activities in various strains, and CuTlm displays improved activity against the Staphylococcus aureus strain as compared with unbounded copper(II).

A tetradecapeptide somatostatin dicarba-analog: Synthesis, structural impact and biological activity

We described here the first tetradecapeptide somatostatin-analogue where the disulfide bridge has been replaced by a carbon-carbon double bond. This analogue was prepared using microwave assisted ring closing metathesis (RCM) using the 2nd generation Grubbs as catalyst. Under our optimized conditions the cyclization between allylGly 3 and 14 proceeded in moderate yield, excellent cyclic/linear ratio and very high Z-double bond selectivity. NMR studies also demonstrated that the conformational flexibility of this peptide is increased in comparison to that of the natural hormone. Remarkably, this alkene-bridged somatostatin analog is highly selective against somatostatin receptors 1 and 5, suggesting that conformational rigidity is not required for the efficient interaction of somatostatin analogues with these two receptors.

SSTR1- and SSTR3-selective somatostatin analogues.

We prepared the two enantiomers of 3‐(3′‐quinolyl)‐alanine (Qla, 1) in multigram scale by asymmetric hydrogenation. These amino acids, protected as Fmoc derivatives, were then used in the solid‐phase synthesis of two new somatostatin 14 (SRIF‐14) analogues 8 a and 8 b, tetradecapeptides in which the tryptophan residue (Trp8) is replaced by one of the two enantiomers of 3‐(3′‐quinolyl)‐alanine (Qla8) and therefore lack the NH bond in residue 8. The selectivity of these new analogues for the somatostatin receptors, SSTR1–5, was measured. Substitution with L‐Qla8 yielded peptide 8 a, which was highly selective for SSTR1 and SSTR3, with an affinity similar to that of SRIF‐14. Substitution by D‐Qla gave the relatively selective analogue 8 b, which showed high affinity for SSTR3 and significant affinity for SSTR1, SSTR2 and SSTR5. The biological results demonstrate that bulky and electronically poor aromatic amino acids at position 8 are compatible with strong activity with SSTR1 and SSTR3. Remarkably, these high affinity levels were achieved with peptides in which the conformational mobility was increased with respect to that of SRIF‐14. This observation suggests that conformational rigidity is not required, and might be detrimental to the interaction with receptors SSTR1 and SSTR3. The absence of an indole N proton in Qla8 might also contribute to the increased flexibility observed in these analogues.

Improvement of the antihypertensive capacity of candesartan and trityl candesartan by their SOD mimetic copper(II) complexes

Two new complexes [Cu(Cand)(H2O)4] [1] and [Cu2(TCand)4(H2O)2]·4H2O [2] (Cand = candesartan; TCand = trityl candesartan) have been synthesized and thoroughly characterized. The FTIR, Raman, EPR and diffuse reflectance spectra of the solid compounds show a dimeric complex for [2] with carboxylate bridging of the type found in copper(II) acetate. Both elemental analysis and thermal measurements allow the determination of the total stoichiometries of both complexes. The stability measurements show that the compounds are stable in ethanolic solutions at least for 1h, while the preservation of the overall stochiometry for both species in solution has been determined by spectrophotometric titrations. By metal complexation the absence of antioxidant behavior of both sartans has been improved. Complexes [1] and [2] are strong superoxidedismutase mimetic compounds and complex [2] also behaves as a peroxyl radical scavenger. Furthermore, this higher antioxidant activity works in parallel with the improvement of the expansive activity over the angiotensin II-induced contracted human mesangial cells. These new complexes exhibit even higher efficiency as drugs in comparison with the free non-complexed medication with increased antioxidant ability expressing higher capacity to block the angiotensin II contractile effect. This study provides a new insight into the development of copper(II) complexes as potential drugs.

Insights into Structure-Activity Relationships of Somatostatin Analogs Containing Mesitylalanine

The non-natural amino acid mesitylalanine (2,4,6-trimethyl-L-phenylalanine; Msa) has an electron-richer and a more conformationally restricted side-chain than that of its natural phenylalanine counterpart. Taking these properties into account, we have synthesized ten somatostatin analogs containing Msa residues in different key positions to modify the intrinsic conformational flexibility of the natural hormone. We have measured the binding affinity of these analogs and correlated it with the main conformations they populate in solution. NMR and computational analysis revealed that analogs containing one Msa residue were conformationally more restricted than somatostatin under similar experimental conditions. Furthermore, we were able to characterize the presence of a hairpin at the pharmacophore region and a non-covalent interaction between aromatic residues 6 and 11. In all cases, the inclusion of a D-Trp in the eighth position further stabilized the main conformation. Some of these peptides bound selectively to one or two somatostatin receptors with similar or even higher affinity than the natural hormone. However, we also found that multiple incorporations of Msa residues increased the life span of the peptides in serum but with a loss of conformational rigidity and binding affinity.

Elaboración y empleo de materiales didácticos para la mejora de la enseñanza práctica en la asignatura de Fisiología Humana en el grado de Ciencias de la Actividad Física y del Deporte. Evaluación de resultados

The need to advance towards a methodology that strengthens self-directed learning and competency development among students has become a key focus of university teaching in recent years. This focus has given rise to new methodological strategies that have been enhanced by the use of information and communication technologies (ICTs). Within the progress of these methodological strategies, the creation of educational resources that help to meet their objectives has become an important part of the work done by university lecturers. Along those lines, a group of lecturers in the Department of Physiology at the University of Alcalá (UAH), Spain, has created a series of educational resources using visual online tools for practical teaching in the Human Physiology subject. These resources were used for the first time in the 2011/12 academic year in the Human Physiology subject, taught in the first year of the bachelor’s degree course in Physical Activity and Sports Sciences. This article presents the resources created and the methodology used. The results obtained from their use are also assessed; these results refer to the students’ satisfaction with the resources, and the contribution that the resources and the methodology made to the students’ learning. A survey was conducted to ascertain the students’ opinions, and a comparative analysis was performed of the grades obtained by the students in the practical part of the subject and their impact on the overall grade, and those obtained in the previous academic year when the resources had not been used. The results show that the students were satisfied with both the educational resources and the methodology used, and that there was a significant improvement in the grades obtained in comparison to the previous academic year.ResumenLa necesidad de caminar hacia una metodología que potencie el aprendizaje autónomo y el desarrollo de las competencias en el alumno se ha convertido en estos últimos años en un elemento clave en la enseñanza universitaria. Esta constante ha impulsado el auge de nuevas estrategias metodológicas que se han visto dinamizadas por el uso de las nuevas tecnologías. Dentro del progreso de estas metodologías, la elaboración de materiales didácticos que favorezcan estos objetivos ha sido y sigue siendo una pieza importante de trabajo entre los docentes universitarios. En esta línea, un grupo de profesores del Departamento de Fisiología de la universidad hemos elaborado una serie de materiales didácticos empleando herramientas visuales y virtuales, para la enseñanza práctica de la asignatura Fisiología Humana. Estos materiales se utilizaron por primera vez durante el curso 2011–12 en la asignatura Fisiología Humana de primer curso del grado de Ciencias de la Actividad Física y del Deporte (CCAFyDE). En este trabajo presentamos los materiales elaborados y la metodología utilizada. También evaluamos el resultado obtenido tras su empleo en cuanto a la satisfacción del alumno y a la contribución que estos materiales y tal metodología han tenido para el aprendizaje de los estudiantes. Para ello se realizó una encuesta entre los alumnos y un análisis comparativo de las calificaciones obtenidas en la parte práctica de la asignatura y de su impacto en el conjunto de la nota total de esta misma, con respecto a las notas obtenidas por los estudiantes del curso anterior, en el que no se utilizaron estos materiales. Los resultados indican una aceptación satisfactoria por parte de los alumnos tanto de los materiales didácticos como de la metodología empleada, así como una mejora significativa en sus calificaciones con respecto al curso anterio

Creating and using educational resources to improve practical teaching in the Human Physiology subject on the bachelor’s degree course in Physical Activity and Sports Sciences. Assessment of results

The need to advance towards a methodology that strengthens self-directed learning and competency development among students has become a key focus of university teaching in recent years. This focus has given rise to new methodological strategies that have been enhanced by the use of information and communication technologies (ICTs). Within the progress of these methodological strategies, the creation of educational resources that help to meet their objectives has become an important part of the work done by university lecturers. Along those lines, a group of lecturers in the Department of Physiology at the University of Alcalá (UAH), Spain, has created a series of educational resources using visual online tools for practical teaching in the Human Physiology subject. These resources were used for the first time in the 2011/12 academic year in the Human Physiology subject, taught in the first year of the bachelor’s degree course in Physical Activity and Sports Sciences. This article presents the resources created and the methodology used. The results obtained from their use are also assessed; these results refer to the students’ satisfaction with the resources, and the contribution that the resources and the methodology made to the students’ learning. A survey was conducted to ascertain the students’ opinions, and a comparative analysis was performed of the grades obtained by the students in the practical part of the subject and their impact on the overall grade, and those obtained in the previous academic year when the resources had not been used. The results show that the students were satisfied with both the educational resources and the methodology used, and that there was a significant improvement in the grades obtained in comparison to the previous academic year.ResumenLa necesidad de caminar hacia una metodología que potencie el aprendizaje autónomo y el desarrollo de las competencias en el alumno se ha convertido en estos últimos años en un elemento clave en la enseñanza universitaria. Esta constante ha impulsado el auge de nuevas estrategias metodológicas que se han visto dinamizadas por el uso de las nuevas tecnologías. Dentro del progreso de estas metodologías, la elaboración de materiales didácticos que favorezcan estos objetivos ha sido y sigue siendo una pieza importante de trabajo entre los docentes universitarios. En esta línea, un grupo de profesores del Departamento de Fisiología de la universidad hemos elaborado una serie de materiales didácticos empleando herramientas visuales y virtuales, para la enseñanza práctica de la asignatura Fisiología Humana. Estos materiales se utilizaron por primera vez durante el curso 2011–12 en la asignatura Fisiología Humana de primer curso del grado de Ciencias de la Actividad Física y del Deporte (CCAFyDE). En este trabajo presentamos los materiales elaborados y la metodología utilizada. También evaluamos el resultado obtenido tras su empleo en cuanto a la satisfacción del alumno y a la contribución que estos materiales y tal metodología han tenido para el aprendizaje de los estudiantes. Para ello se realizó una encuesta entre los alumnos y un análisis comparativo de las calificaciones obtenidas en la parte práctica de la asignatura y de su impacto en el conjunto de la nota total de esta misma, con respecto a las notas obtenidas por los estudiantes del curso anterior, en el que no se utilizaron estos materiales. Los resultados indican una aceptación satisfactoria por parte de los alumnos tanto de los materiales didácticos como de la metodología empleada, así como una mejora significativa en sus calificaciones con respecto al curso anterio

Elaboració i ocupació de materials didàctics per a millorar l'ensenyament pràctic en l'assignatura de Fisiologia Humana en el grau de Ciències de l'Activitat Física i de l'Esport. Avaluació de resultats

The need to advance towards a methodology that strengthens self-directed learning and competency development among students has become a key focus of university teaching in recent years. This focus has given rise to new methodological strategies that have been enhanced by the use of information and communication technologies (ICTs). Within the progress of these methodological strategies, the creation of educational resources that help to meet their objectives has become an important part of the work done by university lecturers. Along those lines, a group of lecturers in the Department of Physiology at the University of Alcalá (UAH), Spain, has created a series of educational resources using visual online tools for practical teaching in the Human Physiology subject. These resources were used for the first time in the 2011/12 academic year in the Human Physiology subject, taught in the first year of the bachelor’s degree course in Physical Activity and Sports Sciences. This article presents the resources created and the methodology used. The results obtained from their use are also assessed; these results refer to the students’ satisfaction with the resources, and the contribution that the resources and the methodology made to the students’ learning. A survey was conducted to ascertain the students’ opinions, and a comparative analysis was performed of the grades obtained by the students in the practical part of the subject and their impact on the overall grade, and those obtained in the previous academic year when the resources had not been used. The results show that the students were satisfied with both the educational resources and the methodology used, and that there was a significant improvement in the grades obtained in comparison to the previous academic year.ResumenLa necesidad de caminar hacia una metodología que potencie el aprendizaje autónomo y el desarrollo de las competencias en el alumno se ha convertido en estos últimos años en un elemento clave en la enseñanza universitaria. Esta constante ha impulsado el auge de nuevas estrategias metodológicas que se han visto dinamizadas por el uso de las nuevas tecnologías. Dentro del progreso de estas metodologías, la elaboración de materiales didácticos que favorezcan estos objetivos ha sido y sigue siendo una pieza importante de trabajo entre los docentes universitarios. En esta línea, un grupo de profesores del Departamento de Fisiología de la universidad hemos elaborado una serie de materiales didácticos empleando herramientas visuales y virtuales, para la enseñanza práctica de la asignatura Fisiología Humana. Estos materiales se utilizaron por primera vez durante el curso 2011–12 en la asignatura Fisiología Humana de primer curso del grado de Ciencias de la Actividad Física y del Deporte (CCAFyDE). En este trabajo presentamos los materiales elaborados y la metodología utilizada. También evaluamos el resultado obtenido tras su empleo en cuanto a la satisfacción del alumno y a la contribución que estos materiales y tal metodología han tenido para el aprendizaje de los estudiantes. Para ello se realizó una encuesta entre los alumnos y un análisis comparativo de las calificaciones obtenidas en la parte práctica de la asignatura y de su impacto en el conjunto de la nota total de esta misma, con respecto a las notas obtenidas por los estudiantes del curso anterior, en el que no se utilizaron estos materiales. Los resultados indican una aceptación satisfactoria por parte de los alumnos tanto de los materiales didácticos como de la metodología empleada, así como una mejora significativa en sus calificaciones con respecto al curso anterio