Somos como dos pelusas que se juntan en el camino y como vamos avanzando hacemos una gran
bola de bendiciones... Asi nos describe ISIS BREITER..
Esa es mi amiga ISIS ahora correra China, ultramaratonista entrenada por Nahila Hernandez también quienes han corrido y ganado los ultramaratones de los 4 desiertos.
TE AMAMOS CAMPEONA
Dianostico no es Destino
Fundación Verónica Ruiz
Enfermedades Neurodegenerativas y Enfermedad de Hunyington México
A 2016 study led by Kazantsev identified a compound, which the investigators named MIND4, that appeared to protect against HD-associated neurodegeneration in two ways - by activating the NRF2-mediated pathway and by inhibiting the regulatory enzyme SIRT2, a strategy also being investigated to treat Parkinson's disease. A related compound, called MIND4-17, was found to only activate the NRF2 pathway but to do so more powerfully than did MIND4. The current investigation's overall goal was to examine whether the NRF2 activation responses observed in that study were also present in human cells, indicating their potential for therapeutic development.
An initial series of experiments in cellular and animal models replicated the previous finding of powerful activation of the NRF2 pathway by MIND4-17 and also showed increased expression of antioxidant proteins further down the pathway. The investigators then found that MIND4-17 acts by mimicking the same process that activates the NRF2 pathway in response to oxidative stress. In stress-free conditions NRF2 is bound into a complex by two other proteins, one of which mediates a process leading to the breakdown of NRF2. MIND4-17 binds to and modifies the mediating protein in way that changes the shape and arrests formation of the protein complex, thereby allowing newly synthesized NRF2 to escape degradation and move to the nucleus where it can activate protective antioxidant genes.
NRF2 activation also induced anti-inflammatory effects in microglia and macrophages, immune cells known to infiltrate the brain in late-stage HD; and treatment with MIND4, which crosses the blood-brain barrier, reduced levels of a key inflammatory protein in a mouse model of HD. MIND4-17 treatment of monocytes - the precursors to macrophages - from patients with HD reduced their production of inflammatory cytokines.
"These results in neural stem cells from HD patients are probably the most intriguing and significant of the study," says Kazantsev, who is now based at the Cambridge, Mass., startup company Effective Therapeutics, LLC, but continues collaborating with colleagues at MGH and other institutions. "It is interesting that antioxidant responses to NRF2 activation were only reduced in neural stem cells, which are known to be depleted in patients with HD, but remained intact in non-neuronal cells. While these results strongly suggest NRF2 activation as a promising therapeutic avenue, that can only be confirmed by human clinical trials."
Since MIND4-17 is unable to penetrate the blood brain barrier, future work is needed to develop powerful NRF2-activating compounds with enhanced brain permeability and to test their efficacy in models of HD and other neurodegenerative disorders. The previous and current work regarding therapeutic use of MIND4 and related compounds for conditions including HD, Parkinson disease and amytrophic lateral sclerosis is covered by an MGH-filed patent application.
Provided by: Massachusetts General Hospital