Delivery of nanomedicines to extracellular and intracellular compartments of a solid tumor

Advances in molecular medicines have led to identification of promising targets on cellular and molecular levels. These targets are located in extracellular and intracellular compartments. The latter include cytosol, nucleus, mitochondrion, Golgi apparatus and endoplasmic reticulum. This report gives an overview on the barriers to delivering nanomedicines to various target sites within a solid tumor, the experimental approaches to overcome such barriers, and the potential utility of nanotechnology.     

Pathogen-derived effectors trigger protective immunity via activation of the Rac2 enzyme and the IMD or Rip kinase signaling pathway

Although infections with virulent pathogens often induce a strong inflammatory reaction, what drives the increased immune response to pathogens compared to nonpathogenic microbes is poorly understood. One possibility is that the immune system senses the level of threat from a microorganism and augments the response accordingly. Here, focusing on cytotoxic necrotizing factor 1 (CNF1), an Escherichia coli-derived effector molecule, we showed the host indirectly sensed the pathogen by monitoring for the effector that modified RhoGTPases. CNF1 modified Rac2, which then interacted with the innate immune adaptors IMD and Rip1-Rip2 in flies and mammalian cells, respectively, to drive an immune response. This response was protective and increased the ability of the host to restrict pathogen growth, thus defining a mechanism of effector-triggered immunity that contributes to how metazoans defend against microbes with pathogenic potential.     

Genetic variations of the melatonin pathway in patients with attention-deficit and hyperactivity disorders

Melatonin is a powerful antioxidant and a synchronizer of many physiological processes. Alteration in melatonin signaling has been reported in a broad range of diseases, but little is known about the genetic variability of this pathway in humans. Here, we sequenced all the genes of the melatonin pathway -AA-NAT, ASMT, MTNR1A, MTNR1B and GPR50 - in 321 individuals from Sweden including 101 patients with attention-deficit/hyperactivity disorder (ADHD) and 220 controls from the general population. We could find several damaging mutations in patients with ADHD, but no significant enrichment compared with the general population. Among these variations, we found a splice site mutation in ASMT (IVS5+2T>C) and one stop mutation in MTNR1A (Y170X) - detected exclusively in patients with ADHD - for which biochemical analyses indicated that they abolish the activity of ASMT and MTNR1A. These genetic and functional results represent the first comprehensive ascertainment of melatonin signaling deficiency in ADHD.     

Inhibition of Phosphodiesterases Leads to Prevention of the Mitochondrial Permeability Transition Pore Opening and Reperfusion Injury in Cardiac H9c2 Cells

Purpose  

We tested if inhibition of phosphodiesterases (PDEs) with IBMX (1-methyl-3-isobutylxanthine) can modulate the mitochondrial permeability transition pore (mPTP) opening by inactivating glycogen synthase kinase 3β (GSK-3β).