Objective. Patients with rheumatoid arthritis (RA) are twice as likely to experience sudden cardiac death compared with individuals without RA. Although the underlying mechanisms of this have not been clarified, evidence points to the effects of systemic inflammation on ventricular repolarization. Accordingly, prolongation of the corrected QT (QTc) interval is more frequent in patients with RA compared with individuals without RA also correlating with C-reactive protein (CRP) and predicting all-cause mortality. Tocilizumab (TCZ) is an anti-interleukin-6 receptor antibody that potently inhibits inflammatory activation in RA, with rapid normalization of acute-phase reactant levels, including the CRP level. Therefore, we hypothesized that TCZ may normalize the QTc interval by dampening systemic inflammation, thus reducing the risk of arrhythmia in patients with RA. Methods. Seventeen consecutive patients with active RA who were scheduled to receive TCZ once every 4 weeks underwent a clinical examination, electrocardiography, and blood sampling just before the first injection with TCZ and again after 3 months and 6 months of treatment. Results. At baseline, 76% of patients displayed prolongation of the QTc interval (mean ؎ SD 452.3 ؎ 35.8 msec). TCZ treatment was associated with a rapid and significant reduction of the QTc interval to mean values <440 msec (up to 428.1 ؎ 34.3 msec). Throughout the study, QTc interval shortening correlated with decreases in both the CRP level, and more strongly, with circulating tumor necrosis factor ␣ level. Conclusion. These data provide further evidence of the close link between the degree of systemic inflammation and QTc interval duration in RA and also suggest an anti-arrhythmic potential for TCZ treatment, which may have a beneficial impact on the mortality of these patients.

Systemic sclerosis (SSc) is a connective tissue disease characterised by exaggerated collagen deposition in the skin and visceral organs. Adenosine A2A receptor stimulation (A2Ar) promotes dermal fibrosis, while the cannabinoid system modulates fibrogenesis in vitro and in animal models of SSc. Moreover, evidence in central nervous system suggests that A2A and cannabinoid (CB1) receptors may physically and functionally interact. On this basis, we investigated A2Ar expression and function in modulating collagen biosynthesis from SSc dermal fibroblasts and analysed the cross-talk with cannabinoid receptors. In sclerodermic cells, A2Ar expression (RT-PCR, Western blotting) was evaluated together with the effects of A2A agonists and/or antagonists on collagen biosynthesis (EIA, Western blotting). Putative physical and functional interactions between the A2A and cannabinoid receptors were respectively assessed by co-immuno-precipitation and co-incubating the cells with the unselective cannabinoid agonist WIN55,212-2, and the selective A2A antagonist ZM-241385. In SSc fibroblasts, (1) the A2Ar is overexpressed and its occupancy with the selective agonist CGS-21680 increases collagen production, myofibroblast trans-differentiation, and ERK-1/2 phosphorylation; (2) the A2Ar forms an heteromer with the cannabinoid CB1 receptor; and (3) unselective cannabinoid receptor stimulation with a per se ineffective dose of WIN55,212-2, results in a marked anti-fibrotic effect after A2Ar blockage. In conclusion, A2Ar stimulation induces a pro-fibrotic phenotype in SSc dermal fibroblasts, either directly, and indirectly, by activating the CB1 cannabinoid receptor. These findings increase our knowledge of the pathophysiology of sclerodermic fibrosis also further suggesting a new therapeutic approach to the disease.

SummaryAlzheimer's disease (AD) is a progressive neurodegenerative disorder associated with synaptic dysfunction, pathological accumulation of β‐amyloid (Aβ), and neuronal loss. The self‐association of Aβ monomers into soluble oligomers seems to be crucial for the development of neurotoxicity (J. Neurochem., 00, 2007 and 1172). Aβ oligomers have been suggested to compromise neuronal functions in AD by reducing the expression levels of the CREB target gene and brain‐derived neurotrophic factor (BDNF) (J. Neurosci., 27, 2007 and 2628; Neurobiol. Aging, 36, 2015 and 20406 Mol. Neurodegener., 6, 2011 and 60). We previously reported a broad neuroprotective activity of physiological Aβ monomers, involving the activation of type‐1 insulin‐like growth factor receptors (IGF‐IRs) (J. Neurosci., 29, 2009 and 10582, Front Cell Neurosci., 9, 2015 and 297). We now provide evidence that Aβ monomers, by activating the IGF‐IR‐stimulated PI3‐K/AKT pathway, induce the activation of CREB in neurons and sustain BDNF transcription and release.

Although fibrillara myloid beta peptide( A b)a ggregates are one of the major hallmarks of Alzheimer's disease, increasing evidences uggeststhat soluble Ab oligomers are the primaryt oxic species. Ta rgeting the oligomeric speciesc ould represent an effective strategy to interfere with Ab toxicity. In this work, the biological properties of 5[4-(6-O-b-cyclodextrin)-phenyl],10,15,20-tri(4-hydroxyphenyl)-porphyrina nd its zinc complex were tested, as new molecules that interactw ith Ab and effectively preventi ts cytotoxicity.W ef ound that these systems can cross the cell membrane to deliver Ab intracellularlya nd promote its clearance. Our resultsp rovide evidencef or the use of cyclodextrin-porphyrin derivatives as ap romising strategy to target amyloid aggregation.The amyloid beta peptide( A b)h as been implicated as am ajor component in the development of Alzheimer's disease (AD). Much efforth as therefore been made to investigate the compositiono fa myloid plaques, the mechanism underlying Ab fibril formation,a nd the parameters that could contribute to the Ab toxicity. Although fibrillar Ab aggregates are one of the major hallmarks of AD, increasing evidence suggestst hat soluble oligomers of the peptide are the primary toxic species. [1] The structure and formation of Ab oligomers have been largely investigated. However,t he interplay between conformation and size in determining their toxicityi sstill underd ebate.It has been reported that soluble Ab oligomers are organized into different structures ranging from dimers to dodecamers, Ab*56, [2] and Ab-derived diffusible ligands(ADDLs). [3] Therefore, targeting one of theset oxic oligomeric species could represent an effective strategy to interferew ith Ab toxicity. [4] Several small molecules, including tetrapyrrolic compounds, have been reported to modulate the amyloid aggregation of several proteins, such as tau, Ab,a nd a-synuclein. [5,6] Among these,p hthalocyanines are the most commonly investigated compounds, [7][8][9] whereas the effect of porphyrins on Ab aggregationa nd toxicity has been less explored. [10,11] Moreover,n umerous studies have also shown that sugars such as trehalose (Tre) and cyclodextrins (CDs)m ay be protectivea gainst neuronal degeneration observed in AD. [12,13] We have recently reported that the conjugation of Tre [14,15] and CDs [16][17][18] with aromatic moieties could provide an ew strategy to prevent Ab aggregation.Herein, we show that a bCD derivativeb earing ap orphyrin moiety 5[4-(6-O-b-cyclodextrin)-phenyl],10,15,20-tri(4-hydroxyphenyl)-porphyrin (CDTHPP,F igure 1A and Figure S1 in the Supporting Information) is effective in inhibiting Ab 42 cytotoxicity.C ontrarily, bCD is not effective, and THPP is toxic. We also report the synthesis of the Zn complex of CDTHPP (ZnCDTHPP), that was studiedt ot est the effect of the metali n modulating the biological properties of the conjugate CDTHPP. Moreover,w ei nvestigated in parallel the activity of bCD or 5,10,15,20-tetra(4-hydroxyphenyl)-porphyrin (THPP).First, we studied th...

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We synthesized a new ratiometric fluorescent Cu probe, bearing a morpholine moiety for selective binding to lysosomes and two picolylamine arms for the specific chelation of divalent copper ions. The probe capability to detect lysosomal Cu was demonstrated in human differentiated neuroblastoma cells by confocal microscopy.

Mutations in Cu/Zn Superoxide Dismutase (SOD1) gene represent one of the most common causes of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder that specifically affects motor neurons (MNs). The dismutase-active SOD1 G93A mutant is responsible for the formation of toxic aggregates onto the mitochondrial surface, using the Voltage-Dependent Anion Channel 1 (VDAC1) as an anchor point to the organelle. VDAC1 is the master regulator of cellular bioenergetics and by binding to hexokinases (HKs) it controls apoptosis. In ALS, however, SOD1 G93A impairs VDAC1 activity and displaces HK1 from mitochondria, promoting organelle dysfunction, and cell death. Using an ALS cell model, we demonstrate that a small synthetic peptide derived from the HK1 sequence (NHK1) recovers the cell viability in a dose–response manner and the defective mitochondrial respiration profile relative to the ADP phosphorylation. This correlates with an unexpected increase of VDAC1 expression and a reduction of SOD1 mutant accumulation at the mitochondrial level. Overall, our findings provide important new insights into the development of therapeutic molecules to fight ALS and help to better define the link between altered mitochondrial metabolism and MNs death in the disease.

Alzheimer's disease (AD) is linked to the abnormal accumulation of amyloid β peptide (Aβ) aggregates in the brain. Silybin B, a natural compound extracted from milk thistle (Silybum marianum), has been shown to significantly inhibit Aβ aggregation in vitro and to exert neuroprotective properties in vivo. However, further explorations of silybin B's clinical potential are currently limited by three main factors: (a) poor solubility, (b) instability in blood serum, and (c) only partial knowledge of silybin's mechanism of action. Here, we address these three limitations. We demonstrate that conjugation of a trehalose moiety to silybin significantly increases both water solubility and stability in blood serum without significantly compromising its antiaggregation properties. Furthermore, using a combination of biophysical techniques with different spatial resolution, that is, TEM, ThT fluorescence, CD, and NMR spectroscopy, we profile the interactions of the trehalose conjugate with both Aβ monomers and oligomers and evidence that silybin may shield the "toxic" surfaces formed by the N-terminal and central hydrophobic regions of Aβ. Finally, comparative analysis with silybin A, a less active diastereoisomer of silybin B, revealed how even subtle differences in chemical structure may entail different effects on amyloid inhibition. The resulting insight on the mechanism of action of silybins as aggregation inhibitors is anticipated to facilitate the future investigation of silybin's therapeutic potential.