Nuclear Factor-kB (NF-kB), is a transcription factor composed of dimeric complexes of p50 (NF-kB1) or p52 (NF-kB2) usually associated with members of the Rel family (p65, c-Rel, Rel B) which have potent transactivation domains. Different combinations of NF-kB/Rel proteins bind distinct kB sites to regulate the transcription of different genes. In resting cells NF-kB resides in the cytoplasm in inactive form, complexed to members of a family of inhibitory proteins referred to as IkB. The bound IkB masks the NF-kB nuclear localization signal and thereby inhibits its nuclear transport. NF-kB can be activated by a variety of signals relevant to pathophysiology including inflammatory cytokines and bacterial lipopolysaccharides (LPS) as well as oxidative and fluid mechanical stress. Upon activation by these stimuli, IkB is phosphorylated and subsequently degraded. Phosphorylation targets IkB for ubiquitination and degradation by the 26S proteasome thus leading to NF-kB nuclear translocation. The same proteolytic pathway is involved in the processing of the p105 and p100 precursors to generate mature p50 and p52 subunits, respectively. Once in the nucleus, NF-kB is able to regulate the expression of many genes involved in the immune and inflammatory responses (i.e. inflammatory cytokines and adhesion molecules). Thus, new approaches to modulating NF-kB activation, and as a consequence inflammatory or metastatic processes, may take advantage of the selectivity of the ubiquitination and ATP-dependent proteolytic processes leading to IkB turnover. This review will analyze the current strategies aimed at interfering with NF-kB activation and will consider the ubiquitination system as a new selective target for the development of new anti-inflammatory therapies.
The polyamines putrescine (put), spermidine (spd), and spermine (spm) are natural aliphatic polycations ubiquitous in living organisms and essential for cell growth, proliferation, and differentiation. For a long time the polyamine biosynthetic pathway has been considered to be the unique target for antineoplastic therapy [1][2][3]. The importance of the polyamine catabolic pathway has recently been re-evaluated, as its involvement in determining the cell response to antitumour polyamine analogues has been demonstrated [4].In animals, polyamine catabolism is a recycling pathway that converts spm to spd and spd to put, with the production of toxic aldehydes and H 2 O 2 . Polyamine catabolism is achieved via the concerted action Polyamine oxidase (PAO) and spermine oxidase (SMO) are involved in the catabolism of polyamines -basic regulators of cell growth and proliferation. The discovery of selective inhibitors of PAO and SMO represents an important tool in studying the involvement of these enzymes in polyamine homeostasis and a starting point for the development of novel antineoplastic drugs. Here, a comparative study on murine PAO (mPAO) and SMO (mSMO) inhibition by the polyamine analogues 1,8-diaminooctane, 1,12-diaminododecane, N-prenylagmatine (G3), guazatine and N,N 1 -bis(2,3-butadienyl)-1,4-butanediamine (MDL72527) is reported. Interestingly, 1,12-Diaminododecane and G3 behave as specific inhibitors of mPAO, values of K i for mPAO inhibition being lower than those for mSMO inactivation by several orders of magnitude. The analysis of molecular models of mPAO and mSMO indicates a significant reduction of the hydrophobic pocket located in maize PAO (MPAO) at the wider catalytic tunnel opening. This observation provides a rationale to explain the lower affinity displayed by G3, guazatine and MDL72527 for mPAO and mSMO as compared to MPAO. The different behaviour displayed by 1,12-diaminododecane towards mPAO and mSMO reveals the occurrence of basic differences in the ligand binding mode of the two enzymes, the first enzyme interacting mainly with substrate secondary amino groups and the second one with substrate primary amino groups. Thus, the data reported here provide the basis for the development of novel and selective inhibitors able to discriminate between mammalian SMO and PAO activities.Abbreviations
An important determinant for the success of every new therapy is the ability to deliver the molecules of interest to the target cells or organ. This selective delivery is even Erythrocytes as drug delivery systemsThe selective delivery of new therapeutic agents to target cells or organs is an important challenge in every clinical approach where peptides, oligonucleotides and/or genes are used.1 These molecules, although specific, do not easily cross the cell membranes, are usually not very stable in biological fluids and, because of their production costs, should be used in low amounts. The delivery of genes is usually achieved by viral vectors.2-5 The delivery of oligonucleotides and peptides is instead mediated by coupling or entrapping these therapeutics to, or in a carrier system that has a significant affinity for one or more cell types within the body. A number of attempts have been made to improve the targeting of drugs by engineering the properties of the carrier system. Examples include the use of Tat, VP22, etc. engineered peptides 6,7 or the development of drugs conjugated to ligands specific for receptors known to have a selective cell distribution. [8][9][10][11] Although these delivery systems are very interesting, they suffer a number of limitations including the limited number of molecules delivered and potential adverse effects.Based on these considerations we have developed a cellular drug delivery system which is based on the use of autologous erythrocytes. The carrier system is totally
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