Federico Herrera

A new diethylenetriamine-derived macrocycle bearing 2-methylpyridyl arms and containing m-xylyl spacers, L, was prepared, and its dinuclear copper(II) and zinc(II) complexes were used as receptors for the recognition in aqueous solution of a phosphorylated peptide derived from a sequence of the STAT3 protein. A detailed study of the acid-base behavior of L and of its complexation properties as well as of the association of the phosphorylated peptide to the receptor was carried out by potentiometry in aqueous solution at 298.2 K and I = 0.10 M in KNO3. The data revealed that the receptor forms stable associations with several protonated forms of the substrate, with constant values ranging from 3.32 to 4.25 log units. The affinity of the receptor for the phosphorylated substrate studied is higher at a pH value where the receptor is mainly in the [Cu2L](4+) form and the pY residue of the substrate is in the dianionic form (pH 6.55). These results, also supported by (31)P NMR studies, s...

Melatonin (N-acetyl-5-methoxytryptamine) is a highly pleiotropic hormone with antioxidant, antiproliferative, oncolytic and neuroprotective properties. Here, we present evidence that the N-acetyl side chain plays a key role in melatonin's antiproliferative effect in HT22 and sw-1353 cells, but it does so at the expense of antioxidant and neuroprotective properties. Removal of the N-acetyl group enhances the antioxidant and neuroprotective properties of the indole, but it can lead to toxic methamphetamine-like effects in several cell lines. Inhibition of NFkB mimicked melatonin's antiproliferative and antioxidant effects, but not neuroprotection. Our results strongly suggest that neuroprotective and antiproliferative effects of melatonin rely on different parts of the molecule and are likely mediated by different mechanisms. We also predict that melatonin metabolism by target cells could determine whether melatonin inhibits cell proliferation, prevents toxicity or induces cell death (e.g. apoptosis or autophagy). These observations could have important implications for the rational use of melatonin in personalized medicine.

Protein glycation is an age-dependent posttranslational modification associated with several neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. By modifying amino-groups, glycation interferes with folding of proteins, increasing their aggregation potential. Here, we studied the effect of pharmacological and genetic manipulation of glycation on huntingtin (HTT), the causative protein in Huntington's disease (HD). We observed that glycation increased the aggregation of mutant HTT exon 1 fragments associated with HD (HTT72Q and HTT103Q) in yeast and mammalian cell models. We found that glycation impairs HTT clearance thereby promoting its intracellular accumulation and aggregation. Interestingly, under these conditions autophagy increased and the levels of mutant HTT released to the culture medium decreased. Furthermore, increased glycation enhanced HTT toxicity in human cells and neurodegeneration in fruit flies, impairing eclosion and decreasing life span. Overall, our study provides evidence that glycation modulates HTT exon-1 aggregation and toxicity, and suggests it may constitute a novel target for therapeutic intervention in HD. Huntington's disease (HD) is an autosomal-dominant neurodegenerative disorder affecting 5–10 per 100 000 individuals 1–3. Its clinical features include progressive motor dysfunction, cognitive impairment, and psychiatric disturbance and dementia 4. HD is caused by a CAG triplet repeat expansion in exon 1 of the HTT gene, which encodes a polyglutamine (polyQ) stretch in huntingtin (HTT) protein. The number of CAG repeats varies from 16 to 35 in healthy individuals, while expansions of > 35 CAG repeats are found in HD patients 1. The length of the polyQ tract in the protein modulates HTT aggregation, thereby causing cytotoxicity by mechanisms that are still not fully understood, with medium spiny neurons in the striatum particularly affected 5. Glucose is the major energy supply of neurons and is essential for their survival. However, impaired glucose metabolism can also damage neurons and lead to neurodegeneration. For example, diabetic patients who neglect their circulating glucose levels frequently develop severe neuropathy that results in the amputation of limbs 6,7. Glucose metabolism drives the formation of by-products that are highly reactive with free amino-groups of proteins. This non-enzymatic reaction, named glycation, induces the formation of advanced glycation end-products (AGEs) that frequently have deleterious effects on proteins 8,9. For example, glycation has been reported in several neurodegenerative disorders such as Alzheimer's and Parkinson's diseases, where it potentiates the aggregation and toxicity of proteins such as amyloid-β (Aβ) and α-synuclein, respectively 8,9. Methylglyoxal (MGO) is an unavoidable by-product of glycolysis and the most reactive glycation agent. It is mainly produced by the non-enzymatic decomposition of the phosphate group of the triose phosphates (glycer-aldeyde 3-phosphate and dihydroxyacetone phosphate) 8. MGO can also arise from the interconversion between