Electron transfer and CO addition to polynitrido cobalt carbonyl clusters: Parallel pathways for conversion of the [Co10N2(CO)(19)](4-) anion to the novel [Co11N2(CO)(21)](3-) anion

The redox aptitude of the dinitrido anion [Co10N2(CO)19]4- has been tested from both chemical and electrochemical points of view, together with its reactivity toward CO that induces disproportionation. In any case, through a remarkable overlapping of intermediate steps, the new anion [Co11N2(CO)21]3- (4) is eventually obtained. A detailed study of the pathways to 4 allowed the identification of three labile intermediates by their characteristic IR spectra as well as their electrochemical and paramagnetic properties. The unprecedented structure of trianion 4 has been studied in details in two different crystalline salts

A sex-stratified analysis of neuroimmune gene expression signatures in Alzheimer's disease brains

Alzheimer’s disease (AD) is the most common form of progressively disabling dementia. The chitinases CHI3L1 and CHI3L2 have long been known as biomarkers for microglial and astrocytic activation in neurodegeneration. Here, we collected microarray datasets from the National Center for Biotechnology Information (NCBI) brain samples of non-demented controls (NDC) (n = 460), and of deceased patients with AD (n = 697). The AD patients were stratified according to sex. Comparing the high CHI3L1 and CHI3L2 expression group (75th percentile), and low CHI3L1 and CHI3L2 expression group (25th percentile), we obtained eight signatures according to the sex of patients and performed a genomic deconvolution analysis using neuroimmune signatures (NIS) belonging to twelve cell populations. Expression analysis revealed significantly higher CHI3L1 and CHI3L2 expression in AD compared with NDC, and positive correlations of these genes with GFAP and TMEM119. Furthermore, deconvolution analysis revealed that CHI3L1 and CHI3L2 high expression was associated with inflammatory signatures in both sexes. Neuronal activation profiles were significantly activated in AD patients with low CHI3L1 and CHI3L2 expression levels. Furthermore, gene ontology analysis of common genes regulated by the two chitinases unveiled immune response as a main biological process. Finally, microglia NIS significantly correlated with CHI3L2 expression levels and were more than 98% similar to microglia NIS determined by CHI3L1. According to our results, high levels of CHI3L1 and CHI3L2 in the brains of AD patients are associated with inflammatory transcriptomic signatures. The high correlation between CHI3L1 and CHI3L2 suggests strong co-regulation

Sex, age, and regional differences in CHRM1 and CHRM3 genes expression levels in the human brain biopsies: potential targets for Alzheimer's disease-related sleep disturbances

Cholinergic hypofunction and sleep disturbance are hallmarks of Alzheimer's disease (AD), a progressive disorder leading to neuronal deterioration. Muscarinic acetylcholine receptor (M1-5 or mAChRs), expressed in hippocampus and cerebral cortex, play a pivotal role in the aberrant alterations of cognitive processing, memory, and learning, observed in AD. Recent evidence shows that two mAChRs, M1 and M3, encoded by CHRM1 and CHRM3 genes respectively, are involved in sleep functions, and, peculiarly, in the rapid eye movement (REM) sleep. We used twenty microarray datasets, extrapolated from post-mortem brain tissue of non-demented healthy controls (NDHC) and AD patients, to examine the expression profile of CHRM1 and CHRM3 genes. Samples were from eight brain regions and stratified according to age and sex. CHRM1 and CHRM3 expression levels were significantly reduced in AD compared with age- and sex-matched NDHC brains. A negative correlation with age emerged for both CHRM1 and CHRM3 in NDHC but not in AD brains. Notably, a marked positive correlation was also revealed between the neurogranin (NRGN) and both CHRM1 and CHRM3 genes. These associations were modulated by sex, accordingly in the temporal and occipital regions of NDHC subjects, males expressed higher levels of CHRM1 and CHRM3, respectively, than females. In AD patients, males expressed higher levels of CHRM1 and CHRM3 in the temporal and frontal regions, respectively, than females. Thus, substantial differences, all strictly linked to the brain region analyzed, age, and sex, exist in CHRM1 and CHRM3 brain levels both in NDHC subjects and in AD patients

Electron Transfer and CO Addition to Polynitrido Cobalt Carbonyl Clusters: Parallel Pathways for Conversion of the [Co10N2(CO)19]4-Anion to the Novel [Co11N2(CO)21]3-Anion

The redox aptitude of the dinitrido anion [Co10N2(CO)19]4-has been tested from both chemical and electrochemical points of view, together with its reactivity toward CO that induces disproportionation. In any case, through a remarkable overlapping of intermediate steps, the new anion [Co11N2(CO)21]3-(4) is eventually obtained. A detailed study of the pathways to 4 allowed the identification of three labile intermediates by their characteristic IR spectra as well as their electrochemical and paramagnetic properties. The unprecedented structure of trianion 4 has been studied in details in two different crystalline salts

Development of novel cyclic peptides as pro-apoptotic agents

Our recent finding that paclitaxel behaves as a peptidomimetic of the endogenous protein Nur77 inspired the design of two peptides (PEP1 and PEP2) reproducing the effects of paclitaxel on Bcl-2 and tubulin, proving the peptidomimetic nature of paclitaxel. Starting from these peptide-hits, we herein describe the synthesis and the biological investigation of linear and cyclic peptides structurally related to PEP2. While linear peptides (2a,b, 3a,b, 4, 6a-f) were found inactive in cell-based assays, biological analysis revealed a pro-apoptotic effect for most of the cyclic peptides (5a-g). Cellular permeability of 5a (and also of 2a,b) on HL60 cells was assessed through confocal microscopy analysis. Further cellular studies on a panel of leukemic cell lines (HL60, Jurkat, MEC, EBVB) and solid tumor cell lines (breast cancer MCF-7 cells, human melanoma A375 and 501Mel cells, and murine melanoma B16F1 cells) confirmed the pro-apoptotic effect of the cyclic peptides. Cell cycle analysis revealed that treatment with 5a, 5c, 5d or 5f resulted in an increase in the number of cells in the sub-G0/G1 peak. Direct interaction with tubulin (turbidimetric assay) and with microtubules (immunostaining experiments) was assessed in vitro for the most promising compounds

Design and synthesis of multifunctional microtubule targeting agents endowed with dual pro-apoptotic and anti-autophagic efficacy

Autophagy is a lysosome dependent cell survival mechanism and is central to the maintenance of organismal homeostasis in both physiological and pathological situations. Targeting autophagy in cancer therapy attracted considerable attention in the past as stress-induced autophagy has been demonstrated to contribute to both drug resistance and malignant progression and recently interest in this area has re- emerged. Unlocking the therapeutic potential of autophagy modulation could be a valuable strategy for designing innovative tools for cancer treatment. Microtubule-targeting agents (MTAs) are some of the most successful anti-cancer drugs used in the clinic to date. Scaling up our efforts to develop new anti- cancer agents, we rationally designed multifunctional agents 5a-l with improved potency and safety that combine tubulin depolymerising efficacy with autophagic flux inhibitory activity. Through a combination of computational, biological, biochemical, pharmacokinetic-safety, metabolic studies and SAR analyses we identified the hits 5i,k. These MTAs were characterised as potent pro-apoptotic agents and also demonstrated autophagy inhibition efficacy. To measure their efficacy at inhibiting autophagy, we investigated their effects on basal and starvation-mediated autophagic flux by quantifying the expression of LC3II/LC3I and p62 proteins in oral squamous cell carcinoma and human leukaemia through western blotting and by immunofluorescence study of LC3 and LAMP1 in a cervical carcinoma cell line. Analogues 5i and 5k, endowed with pro-apoptotic activity on a range of hematological cancer cells (including ex-vivo chronic lymphocytic leukaemia (CLL) cells) and several solid tumor cell lines, also behaved as late- stage autophagy inhibitors by impairing autophagosome-lysosome fusion

Ospitalità narrativa e senso della ‘Matria’ Narrative Hospitality and Sense of Homeland

The Myth of Man, his ontological condition of exile, its ontological need to grow, his ontological need to acquire knowledge from others and, therefor, to emigrate is a myth that intercultural education should never stop telling, starting from a “migrant thought”, which could be a cultural model for the era of conflicts in which we leav