Development and Role in Therapy of Canakinumab in Adult-Onset Still's Disease

Adult-onset Still's disease (AOSD) is a rare inflammatory disease of unknown etiology typically characterized by episodes of spiking fever, evanescent rash, arthralgia, leukocytosis, and hyperferritinemia. The pivotal role of interleukin (IL)-1 and other pro-inflammatory cytokines gives rise to the development of new targeted therapies. Currently, AOSD patients can benefit from efficient and well tolerated biologic agents, such as IL-1, IL-6, and tumour necrosis factor (TNF)-\u3b1 antagonists. Canakinumab, a human monoclonal anti-IL-1\u3b2 antibody, is indicated for the treatment of different autoinflammatory syndromes in adults, adolescents, and children and it has recently been approved for AOSD treatment. In this article, we summarize the structural and biochemical data describing the molecular interactions between Canakinumab and its target antigen. Some special considerations of the pharmacological properties of Canakinumab are included. We also review the safety, efficacy and tolerability of this drug for the treatment of AOSD

OXIDATIVE CHANGES OF LIPIDS, PROTEINS AND ANTIOXIDANTS IN YOGURT DURING THE SHELF LIFE

Background: Oxidation processes in milk and yogurt during the shelf life can result in an alteration of protein and lipid constituents. Therefore, the antioxidant properties of yogurt in standard conditions of preservation were evaluated. Results: Total phenols, free radical scavenger activity, degree of lipid peroxidation and protein oxidation were determined in plain and skim yogurts with or without fruit puree. After production, plain, skim, plain berries and skim berries yogurts were compared during the shelf life up to 9 weeks. All types of yogurts revealed a basal antioxidant activity that was higher when a fruit puree was present but gradually decreased during the shelf life. However, after five-eight weeks, antioxidant activity increased again. Both in plain and berries yogurts lipid peroxidation increased until the seventh week of shelf life and after decreased, while protein oxidation of all yogurts was similar either in the absence or presence of berries and increased during shelf life. Conclusion: During the shelf life, a different behavior between lipid and protein oxidation takes place and the presence of berries determines a protection only against lipid peroxidation

Mitochondrial Thioredoxin System as a Modulator of Cyclophilin D Redox State

The mitochondrial thioredoxin system (NADPH, thioredoxin reductase, thioredoxin) is a major redox regulator. Here we have investigated the redox correlation between this system and the mitochondrial enzyme cyclophilin D. The peptidyl prolyl cis-trans isomerase activity of cyclophilin D was stimulated by the thioredoxin system, while it was decreased by cyclosporin A and the thioredoxin reductase inhibitor auranofin. The redox state of cyclophilin D, thioredoxin 1 and 2 and peroxiredoxin 3 was measured in isolated rat heart mitochondria and in tumor cell lines (CEM-R and HeLa) by redox Western blot analysis upon inhibition of thioredoxin reductase with auranofin, arsenic trioxide, 1-chloro-2,4-dinitrobenzene or after treatment with hydrogen peroxide. A concomitant oxidation of thioredoxin, peroxiredoxin and cyclophilin D was observed, suggesting a redox communication between the thioredoxin system and cyclophilin. This correlation was further confirmed by i) co-immunoprecipitation assay of cyclophilin D with thioredoxin 2 and peroxiredoxin 3, ii) molecular modeling and iii) depleting thioredoxin reductase by siRNA. We conclude that the mitochondrial thioredoxin system controls the redox state of cyclophilin D which, in turn, may act as a regulator of several processes including ROS production and pro-apoptotic factors release

Tamoxifen-like metallocifens target thioredoxin system determining mitochondrial impairment leading to apoptosis in Jurkat cells

Tamoxifen-like metallocifens (TLMs) of the group-8 metals (Fe, Ru, and Os) show strong anti-proliferative activity on cancer cell lines resistant to apoptosis, owing to their unique redox properties. In contrast, the thioredoxin system, which is involved in cellular redox balance, is often overexpressed in cancer cells, especially in tumour types resistant to standard chemotherapies. Therefore, we investigated the effect of these three TLMs on the thioredoxin system and evaluated the input of the metallocene unit in comparison with structurally related organic tamoxifens. In vitro, all three TLMs became strong inhibitors of the cytosolic (TrxR1) and mitochondrial (TrxR2) isoforms of thioredoxin reductase after enzymatic oxidation with HRP/H2O2 while none of the organic analogues was effective. In Jurkat cells, TLMs inhibited mainly TrxR2, resulting in the accumulation of oxidized thioredoxin 2 and cell redox imbalance. Overproduction of ROS resulted in a strong decrease in the mitochondrial membrane potential, translocation of cytochrome c to the cytosol and activation of caspase 3, thus leading to apoptosis. None of these events occurred with organic tamoxifens. The mitochondrial fraction of cells exposed to TLMs contained a high amount of the corresponding metal, as quantified by ICP-OES. The lipophilic and cationic character associated with the singular redox properties of the TLMs could explain why they alter the mitochondrial function. These results provide new insights into the mechanism of action of tamoxifen-like metallocifens, underlying their prodrug behaviour and the pivotal role played by the metallocenic entity in their cytotoxic activity associated with the induction of apoptosis

Current applications and future potential for bioinorganic chemistry in the development of anticancer drugs

This review illustrates notable recent progress in the field of medicinal bioinorganic chemistry as many new approaches to the design of innovative metal-based anticancer drugs are emerging. Current research addressing the problems associated with platinum drugs has focused on other metal-based therapeutics that have different modes of action and on prodrug and targeting strategies in an effort to diminish the side-effects of cisplatin chemotherapy

Dielectrophoretic trapping of multilayer DNA origami nanostructures and DNA origami-induced local destruction of silicon dioxide

Peer reviewe

Environmental toxicity, redox signaling and lung inflammation:the role of glutathione

Glutathione (γ-glutamyl-cysteinyl-glycine, GSH) is the most abundant intracellular antioxidant thiol and is central to redox defense during oxidative stress. GSH metabolism is tightly regulated and has been implicated in redox signaling and also in protection against environmental oxidant-mediated injury. Changes in the ratio of the reduced and disulfide form (GSH/GSSG) can affect signaling pathways that participate in a broad array of physiological responses from cell proliferation, autophagy and apoptosis to gene expression that involve H(2)O(2) as a second messenger. Oxidative stress due to oxidant/antioxidant imbalance and also due to environmental oxidants is an important component during inflammation and respiratory diseases such as chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, acute respiratory distress syndrome, and asthma. It is known to activate multiple stress kinase pathways and redox sensitive transcription factors such as Nrf2, NF-κB and AP-1, which differentially regulate the genes for pro-inflammatory cytokines as well as the protective antioxidant genes. Understanding the regulatory mechanisms for the induction of antioxidants, such as GSH, versus pro-inflammatory mediators at sites of oxidant-directed injuries may allow for the development of novel therapies which will allow pharmacological manipulation GSH synthesis during inflammation and oxidative injury. This article features the current knowledge about the role of GSH in redox signaling, GSH biosynthesis and particularly the regulation of transcription factor Nrf2 by GSH and downstream signaling during oxidative stress and inflammation in various pulmonary diseases. We also discussed the current therapeutic clinical trials using GSH and other thiol compounds, such as N-acetyl-L-cysteine, fudosteine, carbocysteine, erdosteine in environment-induced airways disease

Dimers of Glutaredoxin 2 as Mitochondrial Redox Sensors in Selenite-induced Oxidative Stress

Glutaredoxin 2 (Grx2) has been previously shown to link thioredoxin and glutathione systems by receiving reducing equivalents by both thioredoxin reductase and glutathione. Grx2 catalyzes protein glutathionylation/deglutathionylation and can coordinate an iron-sulfur cluster, forming inactive dimers stabilized by two molecules of glutathione. This protein is mainly located in the mitochondrial matrix, though other isoforms have been found in the cytosolic and nuclear cell compartments. In the present study, we have analyzed the monomeric and dimeric states of Grx2 under different redox conditions in HeLa cells, and sodium selenite was utilized as the principal oxidizing agent. After selenite treatment, an increased glutathione oxidation was associated to Grx2 monomerization and activation, specifically in the mitochondrial compartment. Interestingly, in mitochondria, a large decline of thioredoxin reductase activity was also observed concomitantly to Grx2 activity stimulation. In addition, Grx2 monomerization led to an increase free iron ions concentration in the mitochondrial matrix, induction of lipid peroxidation and decrease of the mitochondrial membrane potential, indicating that the disassembly of Grx2 dimer involved the release of the iron-sulfur cluster in the mitochondrial matrix. Moreover, sodium selenite-triggered lipid and protein oxidation was partially prevented by deferiprone, an iron chelator with mitochondriotropic properties, suggesting a role of the iron-sulfur cluster release in the observed impairment of mitochondrial functions. Thus, by sensing the overall cellular redox conditions, mitochondrial Grx2 dimers become active monomers upon oxidative stress induced by sodium selenite with the consequent release of the iron-sulfur cluster, leading to activation of the intrinsic apoptotic pathway

Milk-derived bioactive peptides exhibit antioxidant activity through the Keap1-Nrf2 signaling pathway

Bioactive peptides are relevant nutritional factors that exhibit many functions including antioxidant, anti-hypertensive, anticancer and antimicrobial properties. In this paper, four synthetic peptides ARHPHPHLSFM (A-11-M), AVPYPQR (A-7-R), NPYVPR (N-6-R) and KVLPVPEK (K-8-K) with sequences present in milk proteinswere examined for their antioxidant properties. The compounds show moderate free radical scavenging activityin the ABTS and crocin assays (A-7-R and N-6-R) and lipid peroxidation inhibition in Caco-2 cells (N-6-R and K-8-K). All peptides, in particular K-8-K, activate the Keap1-Nrf2 system by allowing the translocation of the tran-scription factor Nrf2 from the cytosol to nucleus. This activation triggers the overexpression of the antioxidantenzymes Trx1, TrxR1, GR, NQO1 and SOD1. Furthermore, molecular modeling shows that K-8-K is able to hinderthe interaction of Nrf2 with Keap1. The reported results show that the antioxidant action in cells of thesebioactive peptides is mostly due to the activation of Keap1-Nrf2 signaling pathwa