The Causative and Curative Roles of Brain-Derived Neurotrophic Factor in Parkinson’s Disease

Parkinson’s disease (PD) is characterized by the activation of degenerative and inflammatory processes in brain circuits that control movement and, according to the degree of progression of the damage, can cause neuropsychological disorders such as cognitive dysfunction. Changes in gene expression profile or post-translational modifications in secretory proteins such as neurotrophic factors could define the disease progression. Brain-derived neurotrophic factor (BDNF) is relevant, because it not only participates in neuronal survival, neurotransmission, dendritic growth and cellular communication but also in disease progression. In this chapter, considering both experimental evidences and clinical reports, the authors will analyze the contribution of BDNF as one of the causes of neurodegeneration and neuroinflammation; discuss the participation of this neurotrophic factor in the development of cognitive dysfunction, and finally the scope of novel BDNF-based therapies for PD

Production of biologically active human lymphotactin (XCL1) by Lactococcus lactis

Lymphotactin-XCL1 is a chemokine produced mainly by activated CD8? T-cells and directs migration of CD4? and CD8? lymphocytes and natural killer (NK) cells. We expressed human lymphotactin (LTN) by the lactic-acid bacterium Lactococcus lactis. Biological activity of LTN was confirmed by chemo-attraction of human T-cells by chemotaxis demonstrating, for the first time, how this chemokine secreted by a food-grade prokaryote retains biological activity and chemoattracts T lymphocytes. This strain thus represents a feasible well-tolerated vector to deliver active LTN at a mucosal level

Morphological Analysis of Major Segments of Coronary Artery Occlusion: Importance in Myocardial Revascularization Surgery

Revascularization surgery should ensure morphological similarity between the coronary artery and the graft. This is an important factor for its duration and permeability. The aim of this study was to analyze the morphological characteristics and morphometrics of the coronary artery segments with greater occlusion. This was an observational, cross-sectional descriptive study that consisted of two phases. A macroscopic phase in which 11 cadaveric hearts were extracted and coronary dominance and length of the anterior interventricular artery (AIA), the right coronary artery (RCA) and the circumflex artery (CXA) were determined. In the microscopic phase a total of 77 segments of these arteries were obtained and the luminal diameter, wall thickness, and amount of elastic fibers and the presence and size of the atheroma were determined. Right coronary dominance was the most frequent. Total vessel length was 15.65±1.17 cm for the AIA, 12.67±2.02 cm for the RCA and 8.79±2.5 cm for the CXA. Diameters ranged from 2.3 mm in the proximal segments and between 1.1 mm to 1.8 mm in the distal segments. Wall thickness in the proximal segments was between 354 µm and 396 µm and in the distal segments it ranged from 120 µm to 305 µm. The amount of elastic fibers showed that they were muscular arteries. Atheromas were present in 35% in the CXA, and in 32.5% in the AIA and the RCA. The largest ones were found in the proximal segments. This study examined the morphology and morphometry of the segments of the coronary arteries that are more frequently occluded. It provides information on the most significant parameters to be considered for election of the vascular graft in myocardial revascularization surgery

Sex and Age Morphometric Variations in Bony Nasolacrimal Duct and Fossa for Lacrimal Gland in Mexican Population

SUMMARY: Primary acquired nasolacrimal duct obstruction is greater in women over 40 years and has been associated with morphometric variations in the osseous nasolacrimal duct, which varies according to age and sex. The objective is to determine variations regarding sex and age of the nasolacrimal duct and osseous fossa for lacrimal gland. One hundred sixteen dry orbits from Mexican population were analyzed; subdivided into four groups based on age and sex. The length, transverse and anteroposterior diameters of the bone entrance of the nasolacrimal duct, and the length and width of the fossa for lacrimal gland were determined. Statistical tests were applied to determine the significance of the differences found between groups. The nasolacrimal duct in women had shorter length than men in both age groups. The entrance had a wider transverse diameter in women than men independently of age and its anteroposterior diameter was shorter in men under 40 years than over 40 years. The fossa for lacrimal gland was larger in women under 40 years than in men of same age group and women over 40 years old. The lower third of the was wider in women under 40 years than in women over 40 years. Our study confirms significant differences between sex and age groups in some of the morphometric measurements of bony nasolacrimal duct and fossa for lacrimal gland in Mexican population. Comparative studies with and without clinical illness are needed to clarify if the bony characteristics of those structures participate in the etiopathogenesis and distribution differences observed in sex, age and ethnicity of thisillness. KEY WORDS: Nasolacrimal duct; Fossa for lacrimal gland; Morphometry; Primary acquired nasolacrimal duct obstructio

Targeting and retention of HPV16 E7 to the endoplasmic reticulum enhances immune tumour protection

The endoplasmic reticulum (ER) is where the major histocompatibility complex (MHC) class I molecules are loaded with epitopes to cause an immune cellular response. Most of the protein antigens are degraded in the cytoplasm to amino acids and few epitopes reach the ER. Antigen targeting of this organelle by Calreticulin (CRT) fusion avoids this degradation and enhances the immune response. We constructed a recombinant adenovirus to express the E7 antigen with an ER-targeting signal peptide (SP) plus an ER retention signal (KDEL sequence). In cell-culture experiments we demonstrated that this new E7 antigen, SP-E7-KDEL, targeted the ER. Infection of mice with this recombinant adenovirus that expresses SP-E7-KDEL showed interferon induction and tumour-protection response, similar to that provided by an adenovirus expressing the E7 antigen fused to CRT. This work demonstrated that just by adding a SP and the KDEL sequence, antigens can be targeted and retained in the ER with a consequent enhancement of immune response and tumour protection. These results will have significant clinical applications

Caracterización molecular y morfológica de una línea de ratones transgénicos que expresen el gen cre recombinasa.

Propósito y Método de estudio: El gen Nurr1 es importante para la diferenciación y mantenimiento de neuronas dopaminérgicas mesencefálicas. Su inactivación es letal, los ratones Knockout (KO)mueren al nacer y presentan pérdida de las neuronas dopaminérgicas mesencefálicas. Aún se desconoce cuál de las regiones donde se expresa Nurr1es la responsable de la letalidad. Una estrategia para dilucidar la función del gen Nurr1 en las diferentes regiones donde se expresa, es mediante la generación de un ratón Knockout condicional. Para esto se necesita de un ratón con el gen Nurr1 flanqueado por sitios loxP y que a la vez exprese la enzima Cre recombinasa bajo un promotor específico de tejido y de esta manera al recombinar los sitios loxP se inactivaría el gen Nurr1. Previamente se generó una línea de ratones transgénicos que expresan cre-recombinasa bajo la regulación de una región promotora de 4.2 kb del gen Pitx3. En el presente trabajo se obtuvo la caracterización a nivel molecular y a nivel morfológico de esta línea de ratones transgénicos llamada Pitx3-Cre. Se realizaron cruzas de la línea Pitx3-Cre para obtener la frecuencia del transgén a través de las generaciones. Mediante PCR se obtuvieron tanto el genotipo como la caracterización molecular de la integridad del transgén Pitx3-Cre recombinasa. Para la caracterización morfológica los ratones Pitx3-Cre se aparearon con ratones Rosa26R, un modelo para medir la actividad de Crerecombinasa in vivo, que se basa en la expresión de lacZ dependiente de recombinación de sitios loxP, y que se observa por medio de una tinción para LacZ. Contribuciones y conclusiones: Se logró establecer que la inserción del transgén ocurrió en un solo locus en base a la frecuencia observada de su transmisión a la descendencia. Además se confirmó la integridad del transgén, tanto de la secuencia promotora y codificante. En esta línea de ratones la expresión del transgén Pitx3-Cre se observó en base a la tinción positiva de lacZ en el epitelio olfativo, en la hipófisis, glándula salival submaxilar y músculo esquelético. El transgén no se expresa en el bulbo olfatorio, la tinción lacZ observada en esta estructura, es debido a la presencia de los axones del epitelio olfativo, cuyas neuronas si expresan el transgén. Esta expresión es dependiente del locus de integración del transgén y no de la especificidad de la secuencia reguladora 4.2 kb del gen Pitx3. Esta línea de ratones puede utilizarse para la inactivación condicional de genes en las regiones mencionadas y en particular para estudiar la importancia de la expresión de Nurr1 en la hipófisis

Potenciación de la respuesta antitumoral mediante el envío y retención de antígenos en retículo endoplásmico

En el retículo endoplásmico, las moléculas del MHC de clase I se asocian con los epítopes para inducir la respuesta inmune celular. La mayoría de los antígenos se degradan en el citoplasma, y tan sólo unos cuantos epítopes llegan al RE. En este trabajo demostramos que fusionando el antígeno E7 al péptido señal y a la señal de retención en RE, KDEL, los antígenos son enviados y retenidos en el RE, con la consecuente mejora en la respuesta inmune antitumoral. Estos resultados pueden aplicarse en clínicas importantes

Plasmid DNA for Therapeutic Applications in Cancer

Recently, the interest in using nucleic acids for therapeutic applications has been increasing. DNA molecules can be manipulated to express a gene of interest for gene therapy applications or vaccine development. Plasmid DNA can be developed to treat different diseases, such as infections and cancer. In most cancers, the immune system is limited or suppressed, allowing cancer cells to grow. DNA vaccination has demonstrated its capacity to stimulate the immune system to fight against cancer cells. Furthermore, plasmids for cancer gene therapy can direct the expression of proteins with different functions, such as enzymes, toxins, and cytotoxic or proapoptotic proteins, to directly kill cancer cells. The progress and promising results reported in animal models in recent years have led to interesting clinical results. These DNA strategies are expected to be approved for cancer treatment in the near future. This review discusses the main strategies, challenges, and future perspectives of using plasmid DNA for cancer treatment

Production of biologically active human lymphotactin (XCL1) by Lactococcus lactis

Abstract Lymphotactin-XCL1 is a chemokine produced mainly by activated CD8? T-cells and directs migration of CD4? and CD8? lymphocytes and natural killer (NK) cells. We expressed human lymphotactin (LTN) by the lactic-acid bacterium Lactococcus lactis. Biological activity of LTN was confirmed by chemo-attraction of human T-cells by chemotaxis demonstrating, for the first time, how this chemokine secreted by a food-grade prokaryote retains biological activity and chemoattracts T lymphocytes. This strain thus represents a feasible well-tolerated vector to deliver active LTN at a mucosal level