Human and rat monoamine oxidase-A are differentially inhibited by (S)-4-alkylthioamphetamine derivatives: insights from molecular modeling studies

Four enantiomerically pure (S)-4-alkylthioamphetamine derivatives were evaluated as monoamine oxidase (MAO) inhibitors using the human and rat isoforms of the enzyme. Molecular dockings were performed in order to gain insights regarding the binding mode of these inhibitors. All compounds were potent and selective MAO-A inhibitors although different rank orders of potencies were observed against the enzymes from different species. This behavior can be rationalized on the basis of different binding modes to each enzyme, as determined in silico. These findings further support the concept that MAO inhibitory activity of novel compounds, determined with enzymes from diverse mammalian species, should be considered with caution if human MAO is the final target to be addressed.     

Characterization of mitochondrial iron uptake in HepG2 cells

There is increasing evidence that accumulation of redox-active iron in mitochondria leads to oxidative damage and contributes to various neurodegenerative diseases, such as Friedreich's ataxia and Parkinsons disease. In this work, we examined the existence of regulatory mechanisms for mitochondrial iron uptake and storage. To that end, we used rhodamine B-[(1,10-phenanthrolin-5-yl)amino carbonyl] benzyl ester, a new fluorescent iron-sensitive probe that is targeted specifically to the mitochondrion. We found that extracellular iron was incorporated readily into mitochondria in an apparently saturable process. Moreover, the rate of iron incorporation responded to the Fe status of the cell, an indication that the mitochondrion actively regulates its iron content.     

Identification of DNA sequence variation in Campylobacter jejuni strains associated with the Guillain-Barré syndrome by high-throughput AFLP analysis

Background  

Campylobacter jejuni is the predominant cause of antecedent infection in post-infectious neuropathies such as the Guillain-Barré (GBS) and Miller Fisher syndromes (MFS). GBS and MFS are probably induced by molecular mimicry between human gangliosides and bacterial lipo-oligosaccharides (LOS). This study describes a new C. jejuni-specific high-throughput AFLP (htAFLP) approach for detection and identification of DNA polymorphism, in general, and of putative GBS/MFS-markers, in particular.     

Synthesis and evaluation of N(1)-alkylindole-3-ylalkylammonium compounds as nicotinic acetylcholine receptor ligands

In this study thirty-three novel indole derivatives were designed and synthesized based on the structure of deformylflustrabromine B (1), a metabolite isolated from the marine bryozoan Flustra foliacea L. The syntheses were carried out using standard methodologies and in good yields. The molecules were tested for their affinities for the α4β2¹, α3β4¹, α7¹ and (α1)₂β1γδ nicotinic acetylcholine receptor (nAChR) subtypes. Binding assays showed that, among these ligands, compound 7c exhibited the highest affinity with K_i = 136.1, 93.9 and 862.4 nM for the α4β2¹, α3β4¹, and α7¹ nAChRs subtypes, respectively. These results indicated that the indole core might be a useful scaffold for the development of new potent and selective nAChR ligands.     

Functional roles of T3.37 and S5.46 in the activation mechanism of the dopamine D1 receptor

The activation mechanism of dopamine receptors is unknown. The amino acids S5.42, S5.43, and S5.46 located in helix 5 appear to be crucial, but their specific roles in receptor activation have not been studied. We modeled the D1 dopamine receptor using the crystal structures of the D3 dopamine and β2 adrenergic receptors. Molecular dynamics simulations show that the interaction of dopamine with the D1 receptor leads to the formation of a hydrogen-bond network with its catechol group and helices 3, 5, and 6, including water molecules. The para hydroxyl group of dopamine binds directly to S5.42 and N6.55, the latter also interacting with S5.43. Unexpectedly, S5.46 does not interact directly with the catechol; instead, it interacts through a water molecule with S5.42 and directly with T3.37. The formation of this hydrogen-bond network, part of which was previously observed in docking studies with dopamine agonists, triggers the opening of the E6.30–R3.60 ionic lock associated with the activation of GPCRs. These changes do not occur in the unbonded (apo) receptor or when it is in a complex with the antagonist 3-methoxy-5,6,7,8,9,14-hexahydrodibenz[d,g]azecine. Our results provide valuable insight into the T3.37–S5.46–water–S5.43–ligand interaction, which may be crucial to the activation of the D1 dopamine receptor and should be considered during the design of novel agonists.

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Graphical Abstract General representation of the relationship between the formation of the HBN and the opening of the R3.50–E6.30 ionic lock

     

Characterization of the TRBP domain required for Dicer interaction and function in RNA interference

Background  

Dicer, Ago2 and TRBP are the minimum components of the human RNA-induced silencing complex (RISC). While Dicer and Ago2 are RNases, TRBP is the double-stranded RNA binding protein (dsRBP) that loads small interfering RNA into the RISC. TRBP binds directly to Dicer through its C-terminal domain.     

The cellular prion protein and its role in Alzheimer disease

The cellular prion protein (PrP^C) is a membrane-bound glycoprotein especially abundant in the central nervous system (CNS). The scrapie prion protein (PrP^Sc, also termed prions) is responsible of transmissible spongiform encephalopathies (TSE), a group of neurodegenerative diseases which affect humans and other mammal species, although the presence of PrP^C is needed for the establishment and further evolution of prions.The present work compares the expression and localization of PrP^C between healthy human brains and those suffering from Alzheimer disease (AD).In both situations we have observed a rostrocaudal decrease in the amount of PrP^C within the CNS, both by immunoblotting and immunohistochemistry techniques. PrP^C is higher expressed in our control brains than in AD cases. There was a neuronal loss and astogliosis in our AD cases. There was a tendency of a lesser expression of PrP^C in AD cases than in healthy ones. And in AD cases, the intensity of the expression of the unglycosylated band is higher than the di- and monoglycosylated bands.With regards to amyloid plaques, those present in AD cases were positively labeled for PrP^C, a result which is further supported by the presence of PrP^C in the amyloid plaques of a transgenic line of mice mimicking AD.The work was done according to Helsinki Declaration of 1975, and approved by the Ethics Committee of the Faculty of Medicine of the University of Navarre.Key words: cellular prion protein, Alzheimer disease, transgenic mice