The HGR motif is the antiangiogenic determinant of vasoinhibin : implications for a therapeutic orally active oligopeptide

The hormone prolactin acquires antiangiogenic and antivasopermeability properties after undergoing proteolytic cleavage to vasoinhibin, an endogenous prolactin fragment of 123 or more amino acids that inhibits the action of multiple proangiogenic factors. Preclinical and clinical evidence supports the therapeutic potential of vasoinhibin against angiogenesis-related diseases including diabetic retinopathy, peripartum cardiomyopathy, rheumatoid arthritis, and cancer. However, the use of vasoinhibin in the clinic has been limited by difficulties in its production. Here, we removed this barrier to using vasoinhibin as a therapeutic agent by showing that a short linear motif of just three residues (His46-Gly47-Arg48) (HGR) is the functional determinant of vasoinhibin. The HGR motif is conserved throughout evolution, its mutation led to vasoinhibin loss of function, and oligopeptides containing this sequence inhibited angiogenesis and vasopermeability with the same potency as whole vasoinhibin. Furthermore, the oral administration of an optimized cyclic retro-inverse vasoinhibin heptapeptide containing HGR inhibited melanoma tumor growth and vascularization in mice and exhibited equal or higher antiangiogenic potency than other antiangiogenic molecules currently used as anti-cancer drugs in the clinic. Finally, by unveiling the mechanism that obscures the HGR motif in prolactin, we anticipate the development of vasoinhibin-specific antibodies to solve the on-going challenge of measuring endogenous vasoinhibin levels for diagnostic and interventional purposes, the design of vasoinhibin antagonists for managing insufficient angiogenesis, and the identification of putative therapeutic proteins containing HGR.“Consejo Nacional de Ciencia y Tecnología” (CONACYT) and UNAM grant.http://link.springer.com/journal/10456ImmunologyNeurolog

Pharmacological blockade of the P2X7 receptor reverses retinal damage in a rat model of type 1 diabetes

Aims: Retinopathy is a leading cause of vision impairment in diabetes. Its pathogenesis involves inflammation, pathological angiogenesis, neuronal and glial dysfunction. The purinergic P2X7 receptor (P2X7R) has a leading role in inflammation and angiogenesis. Potent and selective P2X7R blockers have been synthesized and tested in Phase I/II clinical studies. We hypothesize that P2X7R blockade will ameliorate diabetes-related pathological retinal changes. Methods: Streptozotocin (STZ)-treated rats were intraperitoneally inoculated with either of two small molecule P2X7R receptor inhibitors, A740003 and AZ10606120, and after blood glucose levels increased to above 400 mg/dL, retinae were analyzed for P2X7R expression, vascular permeability, VEGF, and IL-6 expression. Results: STZ administration caused a near fourfold increase in blood glucose, a large increase in retinal microvasculature permeability, as well as in retinal P2X7R, VEGF, and IL-6 expression. P2X7R blockade fully reversed retinal vascular permeability increase, VEGF accumulation, and IL-6 expression, with no effect on blood glucose. Conclusion: P2X7R blockade might be promising strategy for the treatment of microvascular changes observed in the early phases of diabetic retinopathy

Lack of Delta-Sarcoglycan (Sgcd) Results in Retinal Degeneration

Age-related macular degeneration (AMD) is the leading cause of central vision loss and severe blindness among the elderly population. Recently, we reported on the association of the SGCD gene (encoding for δ-sarcoglycan) polymorphisms with AMD. However, the functional consequence of Sgcd alterations in retinal degeneration is not known. Herein, we characterized changes in the retina of the Sgcd knocked-out mouse (KO, Sgcd−/−). At baseline, we analyzed the retina structure of three-month-old wild-type (WT, Sgcd+/+) and Sgcd−/− mice by hematoxylin and eosin (H&E) staining, assessed the Sgcd–protein complex (α-, β-, γ-, and ε-sarcoglycan, and sarcospan) by immunofluorescence (IF) and Western blot (WB), and performed electroretinography. Compared to the WT, Sgcd−/− mice are five times more likely to have retinal ruptures. Additionally, all the retinal layers are significantly thinner, more so in the inner plexiform layer (IPL). In addition, the number of nuclei in the KO versus the WT is ever so slightly increased. WT mice express Sgcd-protein partners in specific retinal layers, and as expected, KO mice have decreased or no protein expression, with a significant increase in the α subunit. At three months of age, there were no significant differences in the scotopic electroretinographic responses, regarding both a- and b-waves. According to our data, Sgcd−/− has a phenotype that is compatible with retinal degeneration

Seminario de Investigación Académica II (Ing) - IN397 - 202100

Seminario de Investigación Académica II es un curso de especialidad en la carrera de Ingeniería Industrial, el objetivo es desarrollar el proyecto de tesis enfocado en resolver problemas del contexto de la realidad del sector. El curso se desarrolla en cinco unidades de aprendizaje, con sesiones teóricas que van desde las etapas básicas del proceso de investigación científica, la propuesta inicial del tema de investigación, la identificación y diagnóstico del problema, la construcción del estado del arte que sustenta el informe final con el tema de tesis. El proceso es sistemático, continuo, enriquecedor en función a las variantes que se presentan durante el tiempo de búsqueda, selección y análisis de la información que sustenta el tema de tesis, en este proceso, es permanente el acompañamiento basado en recomendaciones, técnicas y estrategias por parte del equipo de docentes conformado por el asesor metodológico y el asesor temático. Propósito: El propósito de este curso es que el estudiante inicie el plan de tesis en el que se evidencia la aplicación práctica de su carrera, mediante la gestión de información académica, relevante para su tesis y, a partir de ella, plantear un problema de investigación susceptible a una posible solución. En el curso se contribuye al desarrollo de las competencias generales: comunicación oral, comunicación escrita y manejo de información todas a nivel 2. Por otro lado, también se busca el desarrollo de las competencias específicas de ABET (7): Capacidad de adquirir y aplicar nuevos conocimientos según sea necesario, utilizando estrategias de aprendizaje apropiadas, a nivel 2. Tiene como requisito el nivel 5 de inglés y haber alcanzado los 120 créditos