12 research outputs found
Computational Approach to Aluminum Biochemistry and Development of New Chelation Strategies
299 p.DIPC:Donostia International Physics Center
SmartLigs Bioinformatica
Universidade do Port
Alcuni problemi di class field theory
Oggetto di studio di questa tesi sono alcuni problemi che riguardano le
estensioni abeliane di campi di numeri.
Inizialmente esponiamo alcuni risultati fondamentali di teoria algebrica dei numeri, che
costituiscono la base per il seguito del lavoro.
Introduciamo poi il concetto di divisore di un campo di numeri in modo da poter enunciare
i principali teoremi di class field theory nella formulazione più classica.
Il primo problema che affrontiamo riguarda la costruzione esplicita dell'Hilbert class field
del ventinovesimo campo ciclotomico. A tal scopo richiamiamo alcune delle proprietà che caratterizzano
i campi ciclotomici, in particolare quelle riguardanti il gruppo delle unità .
Pur essendo un problema essenzialmente di tipo computazionale,
la maggior parte del lavoro consiste
nel produrre un insieme sufficientemente piccolo di candidati generatori dell'estensione,
da cui sia possibile estrarre rapidamente, grazie all'utilizzo di un calcolatore, gli elementi cercati.
Calcoliamo quindi il gruppo di Galois assoluto dell'Hilbert class field in modo indipendente
da come abbiamo costruito l'estensione.
Presentiamo poi la teoria dei nodi di Scholz con alcune importanti conseguenze e studiamo
l'-rango del gruppo delle classi di ideali di un campo di numeri,
dove è un primo dispari, nel caso di estensioni cicliche assolute di grado .
Proponiamo infine una nuova dimostrazione di un risultato del di Nomura
che riguarda una condizione necessaria affinché la lunghezza dell'Hilbert -class field tower di
un campo ciclico cubico assoluto sia strettamente maggiore di
Aluminum's preferential binding site in proteins: sidechain of amino acids versus backbone interactions
The interaction of aluminum ion Al(III) with polypeptides is a subject of paramount importance, since it is a central feature to understand its deleterious effects in biological systems. Various drastic effects have been attributed to aluminum in its interaction with polypeptides and proteins. These interactions are thought to be established mainly through the binding of aluminum to phosphorylated and non-phosphorylated amino acid sidechains. However, a new structural paradigm has recently been proposed, in which aluminum interacts directly with the backbone of the proteins, provoking drastic changes in their secondary structure and leading ultimately to their denaturation. In the present paper, we use computational methods to discuss the possibility of aluminum to interact with the backbone of peptides and compare it with the known ability of aluminum to interact with amino acid sidechains. To do so, we compare the thermodynamics of formation of prototype aluminum-backbone structures with prototype aluminum-sidechain structures, and compare these results with previous data generated in our group in which aluminum interacts with various types of polypeptides and known aluminum biochelators. Our results clearly points to a preference of aluminum towards amino acid sidechains, rather than towards the peptide backbone. Thus, structures in which aluminum is interacting with the carbonyl group are only slightly exothermic, and they become even less favorable if the interaction implies additionally the peptide nitrogen. However, structures in which aluminum is interacting with negatively-charged sidechains like aspartic acid, or phosphorylated serines are highly favored thermodynamically.Technical and human support was provided by SGI/IZO (SGIker) of UPV/EHU and European funding (ERDF and ESF). Financial support comes from UPV/EHU (PES14/35), Eusko Jaurlaritza (IT588-13) and the Spanish Ministerio de Ciencia e Innovación (MINECO/FEDER) (CTQ2015-67608-P). GdT thanks the European Union for a Ph.D. grant inside the ITN-TCCM-642294 program
Quantitative live cell imaging of a tauopathy model enables the identification of a polypharmacological drug candidate that restores physiological microtubule interaction
Tauopathies such as Alzheimer's disease are characterized by aggregation and increased phosphorylation of the microtubule-associated protein tau. Tau's pathological changes are closely linked to neurodegeneration, making tau a prime candidate for intervention. We developed an approach to monitor pathological changes of aggregation-prone human tau in living neurons. We identified 2-phenyloxazole (PHOX) derivatives as putative polypharmacological small molecules that interact with tau and modulate tau kinases. We found that PHOX15 inhibits tau aggregation, restores tau's physiological microtubule interaction, and reduces tau phosphorylation at disease-relevant sites. Molecular dynamics simulations highlight cryptic channel-like pockets crossing tau protofilaments and suggest that PHOX15 binding reduces the protofilament's ability to adopt a PHF-like conformation by modifying a key glycine triad. Our data demonstrate that live-cell imaging of a tauopathy model enables screening of compounds that modulate tau-microtubule interaction and allows identification of a promising polypharmacological drug candidate that simultaneously inhibits tau aggregation and reduces tau phosphorylation.</p
Thymosin β4 Is an Endogenous Iron Chelator and Molecular Switcher of Ferroptosis
Thymosin β4 (Tβ4) was extracted forty years agofrom calf thymus. Since then, it has been identified as a G-actin binding protein involved in blood clotting, tissue regeneration, angiogenesis, and anti-inflammatory processes. Tβ4 has also been implicated in tumor metastasis and neurodegeneration. However, the precise roles and mechanism(s) of action of Tβ4 in these processes remain largely unknown, with the binding of the G-actin protein being insufficient to explain these multi-actions. Here we identify for the first time the important role of Tβ4 mechanism in ferroptosis, an iron-dependent form of cell death, which leads to neurodegeneration and somehow protects cancer cells against cell death. Specifically, we demonstrate four iron2+ and iron3+ binding regions along the peptide and show that the presence of Tβ4 in cell growing medium inhibits erastin and glutamate-induced ferroptosis in the macrophage cell line. Moreover, Tβ4 increases the expression of oxidative stress-related genes, namely BAX, hem oxygenase-1, heat shock protein 70 and thioredoxin reductase 1, which are downregulated during ferroptosis. We state the hypothesis that Tβ4 is an endogenous iron chelator and take part in iron homeostasis in the ferroptosis process. We discuss the literature data of parallel involvement of Tβ4 and ferroptosis in different human pathologies, mainly cancer and neurodegeneration. Our findings confronted with literature data show that controlled Tβ4 release could command on/off switching of ferroptosis and may provide novel therapeutic opportunities in cancer and tissue degeneration pathologies.Financial support from FIR 2019 and from Regione Autonoma della Sardegna (grant RASSR79857) is gratefully acknowledged
Study of the DNA binding mechanism and in vitro activity against cancer cells of iron(III) and aluminium(III) kojic acid derivative complexes
: Metal ions have unique electrochemical and spectroscopical properties that cannot be attained by purely organic compounds. Most of the metal ions are toxic to humans, but paradoxically, metallodrugs are used in medicine as therapeutics and theranostics. Metallodrugs are eliminated in urine and faeces, and therefore release toxic metals and ligands into aquatic ecosystems, thereby raising concerns regarding environmental risks. The use of metallodrugs based on essential metal ions (i.e., iron, copper and zinc), instead of toxic ions, is a new alternative with minor hazards. Kojic acid is an Asperigillus oryzae metabolite of low toxicity used in the food and cosmetics industries. Its derivatives form stable complexes with iron(III) ions, which bind effectively to DNA and inhibit DNA polymerization. The iron(III)/S2 ligand complexes reduce in vitro colon carcinoma (Caco2) cell viability and significantly decrease the cell number. The kojic acid derivative complexes with iron(III) presented here are an alternative to the currently used platinum complexes in cancer therapy
Kojic acid derivatives as double face ligands for metal and phosphate ions.
A family of combined Kojic acid and polyamine derivatives has been synthesized as phosphate anion and metal
ion ligands. The stoichiometry, stability and structure of the ion/ligand adducts were determined by 1H NMR
spectroscopy, potentiometry, EXAFS and DFT calculations. The presented dual ligands bind effectively both
phosphate anions and metal ions and could be used as effective ion receptors in challenging water conditions in
the broad pH range. A careful analysis of the heatmaps of the stability constants allows to choose the most
appropriate ligand for the ion for qualitative and/or quantitative analysis in water, without analyte pretreatment.
Extremely high-water solubility (>0.6 M) and ion(s)/ligand stability of the adducts in the pH 3–11
are the greatest advantages of the presented here molecules over other known ion sensors. The presented here
molecules represent an innovative class of dual metal/anion ligands, with perspective of medical and environmental
use
L'altra resistenza. I movimenti fascisti nell'Italia liberata dagli Alleati (1943-1945)
La ricerca in questione si propone di illustrare il fenomeno della ''resistenza'' fascista nell'Italia
liberata dagli Alleati, ovvero quei gruppi di persone che tentarono di organizzarsi per cercare, anche
se velleitariamente, di lottare per continuare a sostenere il regime e sperare nel ribaltamento delle
sorti della guerra. Le loro azioni passavano dal semplice volantinaggio e affissione di manifestini o
scritte murali inneggianti al fascismo, al Duce, all'alleato germanico e denigratori nei confronti del
Re e degli Alleati, agli atti di sabotaggio e terrorismo vero e proprio grazie agli agenti inviati ''oltre
le linee''.
I primi gruppi si svilupparono, in modo autonomo, sin dal 1943 nel Sud e nelle isole occupate dagli
Alleati. Dopo la nascita della Repubblica Sociale, i fascisti dell'Italia liberata tentarono di creare dei
nuclei del Partito fascista repubblicano nelle loro regioni. L'obiettivo, oltre a cercare un contatto con
il regime, era quello innanzitutto di coordinare i piccoli gruppi di coloro i quali credevano ancora
nell'Italia fascista e, impossibilitati a raggiungere il Duce nel Nord, si rendevano disponibili a
operare clandestinamente. Contemporaneamente l'ultimo segretario del PNF Carlo Scorza aveva
incaricato il Principe Valerio Pignatelli, figura singolare di fascista non ortodosso, di dare vita ad
un'organizzazione di volontari, le cosiddette Guardie ai Labari, preparati per agire alle spalle degli
invasori tramite azioni di guerriglia e sabotaggi. Nel periodo compreso tra il settembre 1943 e
l'aprile 1944, Pignatelli oper\uf2 attivamente per dare vita a nuclei di resistenza agli Alleati fino a
quando il movimento fascista clandestino organizzato dal Principe venne stroncato dalle retate delle
forze di polizia. Non c'era soltanto la rete di Pignatelli ad operare nel Sud Italia ma anche i
neocostituiti servizi della Repubblica sociale, addestrati dagli agenti dell'Abwehr e del
Sicherheitsdienst nazista nella cosiddetta ''guerra oltre le linee''. Non erano necessari tuttavia solo
gli atti di sabotaggio per provare a garantire la sopravvivenza del fascismo come movimento
politico. Occorreva organizzare una rete occulta la cui costruzione doveva essere affidata ai servizi
segreti della Repubblica sociale. Fu Pavolini ad istituire un ufficio preposto per tale scopo, a
dirigere il quale fu chiamato Puccio Pucci ex ufficiale dei moschettieri di Mussolini, coadiuvato
dallo scrittore Aniceto Del Massa. Una delle propaggini dell'organizzazione Pucci-Del Massa fu
sicuramente il gruppo denominato ''Onore'' che si venne a creare nei primi mesi del 1945 a Roma e
capeggiato dall'ex federale della capitale Alessandro Ratti. Nonostante la vita breve pure di questa
banda, stroncata sul nascere dall'azione congiunta delle forze di polizia alleate e italiane, il vero
merito dei molteplici raggruppamenti fascisti presenti nell'Italia liberata fu quello di aver
contribuito a creare i presupposti per la sopravvivenza del movimento e dell'idea fascista.
Il lavoro si propone di approfondire, grazie a fonti documentarie molte delle quali inedite, questo
tema poco conosciuto e, con le eccezioni ad esempio del saggio di Giuseppe Conti, La RSI e
l'attivit\ue0 del fascismo clandestino nell'Italia liberata dal settembre 1943 all'aprile 1945, e il volume
di Giuseppe Parlato, Fascisti senza Mussolini, trascurato da parte degli storici
Metal self-assembly mimosine peptides with enhanced antimicrobial activity: towards a new generation of multitasking chelating agentsts
Mimosine is a non-protein amino acid with various properties, such as antibacterial, anti-inflammatory, anti-cancer and anti-virus among others. Due to its structural similarity with deferiprone (DFP), mimosine is a potential excellent metal chelator. In the present work, we combine experimental and theoretical (DFT) approaches in order to investigate the properties of mimosine peptides. Six different peptides were synthesized and their complex stoichiometry and stability were characterized by means of UV-Vis spectrophotometry. Then, the binding mode and self-assembly features of the peptides were evaluated using a DFT approach, taking into account different number of mimosine amino acids and varying the length of the spacer between the mimosine residues, and there was good agreement between experimental data and computational calculations. Further elucidations of the structural properties of these peptides allowed us to propose improvements in the structure of the mimosine moiety which can lead to enhanced affinity for high-valent metals. Moreover, we demonstrate that these peptides show an antimicrobial activity against Gram positive bacteria that is enhanced by the formation of a complex with iron (III) ions. The mimosine peptides could be an alternative to antimicrobial peptides (AMPs), which are expensive and susceptible to proteolytic degradation. In summary, in the present work, we propose a new generation of multipurpose mimosine-based peptides as new metal self-assembly chelators which could be a turning point in biomedical and nanotechnological applications