Angiogenesis critically sustains the progression of both physiological and pathological processes. Copper behaves as an obligatory co-factor throughout the angiogenic signalling cascades, so much so that a deficiency causes neovascularization to abate. Moreover, the progress of several angiogenic pathologies (e.g. diabetes, cardiac hypertrophy and ischaemia) can be tracked by measuring serum copper levels, which are being increasingly investigated as a useful prognostic marker. Accordingly, the therapeutic modulation of body copper has been proven effective in rescuing the pathological angiogenic dysfunctions underlying several disease states. Vascular copper transport systems profoundly influence the activation and execution of angiogenesis, acting as multi-functional regulators of apparently discrete pro-angiogenic pathways. This review concerns the complex relationship among copper-dependent angiogenic factors, copper transporters and common pathological conditions, with an unusual accent on the multi-faceted involvement of the proteins handling vascular copper. Functions regulated by the major copper transport proteins (CTR1 importer, ATP7A efflux pump and metallo-chaperones) include the modulation of endothelial migration and vascular superoxide, known to activate angiogenesis within a narrow concentration range. The potential contribution of prion protein, a controversial regulator of copper homeostasis, is discussed, even though its angiogenic involvement seems to be mainly associated with the modulation of endothelial motility and permeability.

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Carnosine (CAR) is an endogenous dipeptide physiologically present in excitable tissues, such as central nervous system (CNS) and muscle. CAR is acknowledged as a substrate involved in many homeostatic pathways and mechanisms and, due to its biochemical properties, as a molecule intertwined with the homeostasis of heavy metals such as copper (Cu). In CNS, Cu excess and dysregulation imply oxidative stress, free-radical production, and functional impairment leading to neurodegeneration. Here, we report that CAR intercepts the regulatory routes of Cu homeostasis in nervous cells and tissues. Specifically, in a murine neuron-derived cell model, i.e., the B104 neuroblastoma cells, extracellular CAR exposure up to 24 h influenced intracellular Cu entry and affected (downregulated) the key Cu-sensing system, consisting of the gene coding for the Slc31a1 transmembrane Cu importer (alias Ctr1), and the gene coding for the Cu-responsive transcription factor Sp1 ( Sp1). Also, CAR exposure upregulated CAR biosynthesis ( Carns1), extracellular degradation ( Cndp1), and transport ( Slc15a4, alias Pht1) genes and elicited CAR intracellular accumulation, contributing to the outline of functional association between CAR and Cu within the cell. Interestingly, the same gene modulation scheme acting in vitro operates in vivo in brains of mice undergoing dietary administration of CAR in drinking water for 2 wk. Overall, our findings describe for the first time a regulatory interaction between CAR and Cu pathways in CNS and indicate CAR as a novel active molecule within the network of ligands and chaperones that physiologically regulate Cu homeostasis.

Copper transporter 1 (CTR1), cellular prion protein (PrP(C)), natural resistance-associated macrophage protein 2 (NRAMP2) and ATP7A proteins control the cell absorption and efflux of copper (Cu) ions in nervous tissues upon physiological conditions. Little is known about their regulation under reduced Cu availability, a condition underlying the onset of diffused neurodegenerative disorders. In this study, rat neuron-like cells were exposed to Cu starvation for 48 h. The activation of Caspase-3 enzymes and the impairment of Cu,Zn superoxide dismutase (Cu,Zn SOD) activity depicted the initiation of a pro-apoptotic program, preliminary to the appearance of the morphological signs of apoptosis. The transcriptional response related to Cu transport proteins has been investigated. Notably, PrP(C) transcript and protein levels were consistently elevated upon Cu deficiency. The CTR1 protein amount was stable, despite a two-fold increase in the transcript amount, meaning the activation of post-translational regulatory mechanisms. NRAMP2 and ATP7A expressions were unvaried. The up-regulated PrP(C) has been demonstrated to enhance the cell Cu uptake ability by about 50% with respect to the basal transport, and so sustain the Cu delivery to the Cu,Zn SOD cuproenzymes. Conclusively, the study suggests a pivotal role for PrP(C) in the cell adaptation to Cu limitation through a direct activity of ion uptake. In this view, the PrP(C) accumulation observed in several cancer cell lines could be interpreted as a molecular marker of cell Cu deficiency and a potential target of therapeutic interventions against disorders caused by metal imbalances.

RESUMENEl láser en odontología, gracias a su capacidad antibacteriana, hemostática y de menor sintomatología operatoria, encuentra un amplio campo de aplicación en el ámbito de la terapia periodontal.En este estudio ha sido probada la eficacia de un protocolo que prevé el utilizo asociado de irradiación láser y de agua oxigenada con el fin de reducir a carga bacteriana de cepas comúnmente presentes en las bolsas periodontales activas y resistentes a la acción bactericida de solamente la irradiación láser como la Prevotella intermedia, Fusobacterium nucleatum y Peptostreptococcus micron.La metodología de laboratorio preveía el siguiente protocolo: cada una de las suspensiones bacterianas ha sido expuesta al agua oxigenada a una concentración del 3% y ha sido irradiada con láser por 10, 15 o 20 segundos utilizando tubos estériles Eppendorf de 1,5 ml.Los resultados confirman la mayor eficacia bactericida de la acción combinada de agua oxigenada y láser. Los cultivos microbiológicos efectuados revelan como, no obstante el efecto bactericida, el láser tiene una escasa acción sobre las cepas bacterianas testeadas si no es asociado al agua oxigenada. En particular, en el caso de la Prevotela intermedia y del Fusobacterium nucleatum la utilización de agua oxigenada al 3% solamente ha dado resultado mejores respecto a solamente el láser, mientras que la asociación de los dos tratamientos ha dado siempre óptimos resultados. En el caso del Peptostreptococcus micron, la utilización de agua oxigenada y el láser separadamente han dado una escasa disminución de la cuenta bacteriana mientras que la asociación de los tratamientos ha potenciado la acción bactericida.Palabras clave: Láser de diodo, bacterias, peróxido de hidrógeno. SUMMARYLaser in odontology, thanks to its antibacterial capabilities, haemostatic and of minor operating symptomatology, finds a vast field of application within the framework of periodontal therapy.In this study has been tested the effectiveness of a protocol that foresees the associated use of laser irradiation and hydrogen peroxide with the goal of reducing the bacterial charge of stocks commonly present in the active periodontal pockets and resistant to the bactericide action of laser irradiation alone such as Prevotella intermedia, Fusobacterium nucleatum, Peptostreptococcus micron.The laboratory method used foresees the following protocol: each bacterial suspension has been exposed to hydrogen peroxide at 3% concentrations and it has been irradiated with laser for 10, 15 or 20 seconds, using sterile 1.5 ml Eppendorf tubes.The results confirm the higher bactericide effectiveness of the combined action of hydrogen peroxide and laser.The microbiological cultivations carried out reveal how, in spite of the bactericide effect, the laser has an insufficient action on bacterial stocks tested if it isn't associated with hydrogen peroxide. Particularly in the case

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