2,931 research outputs found
A novel selective cell-permeable peptide disrupts presynaptic JNK2-STX1a interaction, providing neuroprotection and preventing glutamate-mediated excitotoxicity
No full textL-glutamate is the major excitatory neurotransmitter in the central nervous system of vertebrates. By playing a dual role as amino acid and neurotransmitter, glutamate fulfils a large array of physiological functions supporting neuronal development and cognitive performances. Consequently, the alteration of glutamate signaling entails profound detrimental effects that give rise to disease conditions, including excitotoxicity induced by cerebral ischemia.
Since plenty of reports have so far investigated the effects of cerebral ischemia at postsynaptic sites, little is known concerning the mechanisms activated by the ischemic injury at the presynaptic terminal.
NMDA receptors have been classically implicated in both postsynaptic and presynaptic pathways sustaining excitotoxicity, but only recently their intracellular association with the c-Jun N-terminal kinase (JNK) has also been involved in such pathological mechanisms.
Our previous findings already underlined a specific and unique involvement of the JNK2 isoform as a pivot player in glutamate release, when focusing on presynaptic sites. In the present dissertation we furthermore unveil the selective protein-protein interaction between JNK2 and Syntaxin-1a (STX1a), emphasizing their unexplored contribution in the docking and release of synaptic vesicles at the basis of the NMDA-evoked excitotoxicity. On purpose, we have developed JGRi1, a cell-permeable peptide able to selectively disrupt JNK2/STX1a interplay and pharmacologically prevent the downstream ischemic cascade. To uphold our hypothesis, we tested JGRi1 in several experimental settings, achieving a convincing neuroprotective effect also in a murine model of ischemia over a conveniently long therapeutic window. Conclusively, we analysed the presence of three single nucleotide polymorphisms (SNPs) on the STX1A gene in a cohort of stroke patients, evidencing a haplotype correlated with increased susceptibility to cerebral ischemia. Overall, we here confirm JNK fundamental implication in glutamate release at presynaptic level, moreover presenting for the first time JGRi1, a selective inhibitor of the JNK2/STX1a interaction that may represent a new therapeutic tool able to modulate glutamate overflow in various conditions, including neurodegenerative diseases and ischemia-linked pathologies
Tools and Avenues for Nanotechnology-based Vectors Exploitation for Biomarker Signature and Therapeutical Drug Delivery
No full textNanomedicine main goal is to ameliorate biodistribution and side effects of therapeutics. Proper Micro (MP) and Nanoparticles (NP) can i) protect therapeutic molecules from reticuloendothelial clearance, ii) transport them to the site of action minimizing their influence on normal tissues and iii) enhance drug concentration and effects in target tissues and cells, allowing the use of lower doses. However a single component nanovector cannot accomplish all those duties; therefore, our efforts are focused on the optimization and performance evaluation of multi-component drug-delivering nanosystems, made of silica, silicon, polymers, lipids and proteins from synthetic and biological sources. In recent years, the groups in Naples and in Houston in cooperation have studied many different strategies which permit MP and NP to overcome one or more biological barriers (BB) that hamper the delivery of therapeutics to the desired site of action. The two research groups have produced a series of results which will be briefly summarized in this report and then discussed in greater detail in the talk.
1) Diverse types of Multistage vector (MSV) were produced and used to enhance the delivery of free and encapsulated drugs in cellular and mice models of cancer. MSV is constituted by a silicon mesoporous microparticle which protect nanoparticles or free drugs from reticuloendothelial clearance, superbly marginates toward vessel walls and preferentially accumulates on inflamed endothelium [1-3].
2) A Biomimetic drug delivery platform was produced with a nanoporous silicon core and and a shell derived from the leukocyte cell membrane. This Leukolike vector (LLV) and it’s therapeutic potentialities were extensively investigated in vitro and in vivo, from a biological and biochemical point of view. LLV shows the ability to: 1) evade the immune system; 2) circulate longer in the blood stream; 3) communicate with endothelial cells through receptor–ligand interactions increasing endothelium permeability; 4) transport and release a payload across inflamed endothelium; 5) accumulate in a tumour [4-7].
3) Innovative microfluidic systems were developed to mimick blood capillary circulation, in order to study and to predict the in flow dynamics and the margination tendency of different types of MP, also in presence of blood cells, using real human blood as circulating solution [8].
4) Enzyme-functionalized silica NPs were conceived and produced to digest tumor extracellular matrix, in vitro and in vivo achieving a better penetration in the tumoral tissue [9].
5) pH-responsive hybrid nanoparticles (HNP) were conceived, produced, characterized and successfully used to achieve efficient siRNA delivery in cell culture and in mice models of human breast cancer. HNP are constituted by a shell of cationic hydrogel able to electrostatically bind siRNA and by a supporting nanostructured core of silica that provides mechanical stability to the system. HNP are able to escape from endolysosomal compartment through a proton sponge effect [5,10].
In the light of what has been briefly outlined, the following avenues will be pursued in the near future and will be discussed:
(i) Production and evaluation of different types of MSV for cancer therapy
(ii) Protein and peptide functionalization of NPs to enhance tumor recognition and penetration
(iii) Production and evaluation of different types of NP for siRNA delivery
(iv) Production of Organ-on-chip microfluidic devices able to study and predict the fluidic and biological performance of MP and NP.
(v) Characterization of plasma Protein Corona (PC) [11] of MP and NP by proteomic approaches and correlations between PC composition and targeting of specific tissues.
References
[1] Tasciotti E, Liu X, Bhavane R, Plant K, Leonard AD, Price BK, Cheng MM, Decuzzi P, Tour JM, Robertson F, Ferrari M. Mesoporous silicon particles as a multistage delivery system for imaging and therapeutic applications. Nat Nanotechnol 3, 151-7 (2008).
[2] Martinez JO, Evangelopoulos M, Karun V, Shegog E, Wang JA, Boada C, Liu X, Ferrari M, Tasciotti E. The effect of multistage nanovector targeting of VEGFR2 positive tumor endothelia on cell adhesion and local payload accumulation. Biomaterials 35, 9824-32 (2014).
[3] Martinez JO, Evangelopoulos M, Bhavane R, Acciardo S, Salvatore F, Liu X, Ferrari M, Tasciotti E. Multistage Nanovectors Enhance the Delivery of Free and Encapsulated Drugs. Drug Targets [Epub ahead of print] (2014).
[4] Parodi A, Quattrocchi N, van de Ven AL, Chiappini C, Evangelopoulos M, Martinez JO, Brown BS, Khaled SZ, Yazdi IK, Enzo MV, Isenhart L, Ferrari M, Tasciotti E. Synthetic nanoparticles functionalized with biomimetic leukocyte membranes possess cell-like functions. Nat Nanotechnol 8,61-8 (2013).
[5] Parodi A, Corbo C, Cevenini A, Molinaro R, Palomba R, Pandolfi L, Agostini M, Salvatore F, Tasciotti E. Enabling cytoplasmic delivery and organelle targeting by surface modification of nanocarriers. Nanomedicine UK 10,1923-40 (2015).
[6] Corbo C, Parodi A, Evangelopoulos M, Engler DA, Matsunami RK, Engler AC, Molinaro R, Scaria S, Salvatore F, Tasciotti E. Proteomic profiling of a biomimetic drug delivery platform. Curr Drug Targets [Epub ahead of print] (2014).
[7] Palomba R, Parodi A, Evangelopoulos M, Acciardo S, Corbo C, De Rosa E, Yazdi I, Scaria S, Salvatore F, Tasciotti E. A leukolike vector increase the permeability of tumor vasculature. Submitted.
[8] D'Apolito R, Tomaiuolo G, Taraballi F, Minardi S, Kirui D, Liu X, Cevenini A, Palomba R, Ferrari M, Salvatore F, Tasciotti E, Guido S. Red blood cells affect the margination of microparticles in synthetic microcapillaries and intravital microcirculation as a function of their size and shape. J Control Release [Epub ahead of print] (2015).
[9] Parodi A, Haddix SG, Taghipour N, Scaria S, Taraballi F, Cevenini A, Yazdi IK, Corbo C, Palomba R, Khaled SZ, Martinez JO, Brown BS, Isenhart L, Tasciotti E. Bromelain surface modification increases the diffusion of silica nanoparticles in the tumor extracellular matrix. ACS Nano 8,9874-83 (2014).
[10] Khaled SZ, Cevenini A, Yazdi IK, Parodi A, Evangelopoulos M, Corbo C, Scaria S, Hu Y, Chiappini C, Haddix SG, Corradetti B, Salvatore F, Tasciotti E. One-pot synthesis of pH-responsive hybrid nanogel particles for the intracellular delivery of small interfering RNA. Under review for pubblication in Biomaterials.
[11] Corbo C, Molinaro R, Parodi A, Toldeno Furman NE, Salvatore F, Tasciotti E. The impact of the protein corona on nanoparticles and implications for toxicity, immunotoxicity and target drug delivery. Under review for publication in Nanomedicine UK
Public finance, trade, and development : the Chilean experience
No full textThis paper analyzes the role of public finance and trade policies in the adjustment experience of Chile over the past 15 years. The purpose is to first review the Chilean public sector and trade reforms, and then to examine their role in the economic development of Chile. The paper is divided into six sections. After the Introduction, Section II presents a brief summary of the conditions in 1973 on the eve of the shift in Chilean policy. Section III focuses on the main policy reforms introduced by the military government over the 1973-82 period. Section IV takes a detailed look at Chile's public finance and trade reforms. The effect of the reforms on aggregate incentives and on the macroeconomic adjustment is the subject of Section V. Lastly, Section VI presents the following main conclusions. First, liberalization and stabilization reforms succeeded until late 1978 in slowing down inflation. Second, the reduction of a large public sector deficit required strong action. Third, the elimination of a large public sector deficit is a necessary but not sufficient condition for the control of inflation. Finally, once the macroeconomic mistakes of the late 1970's and early 1980's were corrected, Chile recovered its growth and reduced inflation.Economic Stabilization,Banks&Banking Reform,Economic Theory&Research,Environmental Economics&Policies,Public Sector Economics&Finance
Alcuni aspetti di nursing geriatrico: igiene personale, abbigliamento, mobilizzazione, alimentazione
No full textCell-replacement therapy with stem cells in neurodegenerative diseases
No full textIn the past few years, research on stem cells has expanded greatly as a tool to develop potential therapies to treat incurable neurodegenerative diseases. Stem cell transplantation has been effective in several animal models, but the underlying restorative mechanisms are still unknown. Several mechanisms such as cell fusion, neurotrophic factor release, endogenous stem cell proliferation, and transdifferentiation may explain positive therapeutic results, in addition to replacement of lost cells. The biological issue needs to be clarified in order to maximize the potential for effective therapies. The absence of any effective pharmacological treatment and preliminary data both in experimental and clinical settings has recently identified Amyotrophic Lateral Sclerosis (ALS) as an ideal candidate disease for the development of stem cell therapy in humans. Preliminary stem transplantation trials have already been performed in patients. The review discusses relevant topics regarding the application of stem cell research to ALS but in general to other neurodegenerative diseases debating in particular the issue of transdifferentiation, endogenous neural stem cell, and factors influencing the stem cell fate
Il ruolo della madre nell’affidamento dei figli nell’esperienza giuridica romana
No full textAttraverso l’analisi delle fonti giuridiche in nostro possesso, sia pregiustinianee sia giustinianee, inerenti alla tematica dell’affidamento dei figli in caso di separazione o divorzio dei genitori, si intende descrivere il lento processo di trasformazione della familia romana, con specifica attenzione alla relazione madre-figlio.
Al riguardo, le fonti esaminate attestano il graduale passaggio da una concezione familiare di tipo rigidamente patriarcale, imperniata sulla figura onnicomprensiva del pater familias, a un’idea di famiglia più flessibile e ‘aperta’, che tenga conto del ruolo fondamentale svolto dalla madre, non solo nell’ambito naturale e procreativo, ma anche nel processo educativo dei figli, i quali, in determinate circostanze, possono essere a lei affidati dal giudice, allorquando la separazione dei genitori determini la rottura degli equilibri intrafamiliari, con la conseguente necessità di un intervento del legislatore in grado di garantire la formazione e la crescita della prole, tutelandone esigenze e diritti
Influence of packaging on shelf-life and microbiological quality of minimally processed fennels (Foeniculum vulgare)
No full textThe influence of different packaging techniques on microbiology of minimally processed fennels was studied. In the ready-to-use fennels packaged in ordinary atmosphere the most of the microorganisms belonged to Pseudomonadaceoe; on the contrary Vibrionaceae and Enterobacteriaceae are predominant in vacuum packaged samples. The combination of vacuum packaging and refrigeration (+4°C) was able to extend the product "shelf-life"
Forces on a current loop and magnetic moment
No full textWe compute the action of a static magnetic field on a current loop. From this we recover the definition of m as given in textbooks. The presentation is accessible to undergraduate students with a knowledge of the basic notions of classical electromagnetism
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