A co-ultramicronized palmitoylethanolamide/luteolin composite mitigates clinical score and disease-relevant molecular markers in a mouse model of experimental autoimmune encephalomyelitis

Background: Persistent and/or recurrent inflammatory processes are the main factor leading to multiple sclerosis (MS) lesions. The composite ultramicronized palmitoylethanolamide, an endogenous N-acylethanolamine, combined with the flavonoid luteolin, PEALut, have been found to exert neuroprotective activities in experimental models of spinal and brain injury and Alzheimer disease, as well as a clinical improvement in human stroke patients. Furthermore, PEALut enhances the expression of different myelin proteins in oligodendrocyte progenitor cells suggesting that this composite might have protective effects in MS experimental models. Methods: The mouse model of experimental autoimmune encephalomyelitis (EAE) based on active immunization with a fragment of myelin oligodendrocyte glycoprotein (MOG35-55) was used. The daily assessment of clinical score and the expression of serum amyloid A (SAA1), proinflammatory cytokines TNF-\u3b1, IL-1\u3b2, IFN-\u3b3, and NLRP3 inflammasome, as well as TLR2, Fpr2, CD137, CD3-\u3b3, and TCR-\u3b6 chain, heterodimers that form T cell surface glycoprotein (TCR), and cannabinoid receptors CB1, CB2, and MBP, were evaluated in the brainstem and cerebellum at different postimmunization days (PIDs). Results: Vehicle-MOG35-55-immunized (MOG35-55) mice developed ascending paralysis which peaked several days later and persisted until the end of the experiment. PEALut, given intraperitoneally daily starting on day 11 post-immunization, dose-dependently improved clinical score over the range 0.1-5 mg/kg. The mRNA expression of SAA1, TNF-\u3b1, IL-1\u3b2, IFN-\u3b3, and NLRP3 were significantly increased in MOG35-55 mice at 14 PID. In MOG35-55 mice treated with 5 mg /kg PEALut, the increase of SAA1, TNF- \u3b1, IL-1\u3b2, and IFN-\u3b3transcripts at 14 PID was statistically downregulated as compared to vehicle-MOG35-55 mice (p < 0.05). The expression of TLR2, Fpr2, CD137, CD3-\u3b3, TCR-\u3b6 chain, and CB2 receptors showed a significant upregulation in vehicle-MOG35-55 mice at 14 PID. Instead, CB1 and MBP transcripts have not changed in expression at any time. In MOG/PEALut-treated mice, TLR2, Fpr2, CD137, CD3-\u3b3, TCR-\u3b6 chain, and CB2 mRNAs were significantly downregulated as compared to vehicle MOG35-55 mice. Conclusions: The present results demonstrate that the intraperitoneal administration of the composite PEALut significantly reduces the development of clinical signs in the MOG35-55 model of EAE. The dose-dependent improvement of clinical score induced by PEALut was associated with a reduction in transcript expression of the acute-phase protein SAA1, TNF-\u3b1, IL-1\u3b2, IFN-\u3b3, and NLRP3 proinflammatory proteins and TLR2, Fpr2, CD137, CD3-\u3b3, TCR-\u3b6 chain, and CB2 receptors

Serum amyloid A primes microglia for ATP-dependent interleukin-1\u3b2 release

Acute-phase response is a systemic reaction to environmental/inflammatory insults and involves production of acute-phase proteins, including serum amyloid A (SAA). Interleukin-1\u3b2 (IL-1\u3b2), a master regulator of neuroinflammation produced by activated inflammatory cells of the myeloid lineage, in particular microglia, plays a key role in the pathogenesis of acute and chronic diseases of the peripheral nervous system and CNS. IL-1\u3b2 release is promoted by ATP acting at the purinergic P2X7 receptor (P2X7R) in cells primed with toll-like receptor (TLR) ligands

Surface Immobilized His-tagged Azurin as a Model Interface for the Investigation of Vectorial Electron Transfer in Biological Systems

A model system for the electrochemical investigation of vectorial electron transfer in biological systems was designed, assembled and characterized. Gold electrodes, functionalized with a -OCH3 terminated, aromatic self-assembled monolayer, were used as a substrate for the adsorption of variants of copper- containing, redox metalloprotein azurin. The engineered azurin bears a polyhistidine tag at its C-terminus. Thanks to the presence of the solvent exposed tag, which chelates Cu2+ ions in solution, we introduced an exogenous redox centre. The different reduction potentials of the two redox centres and their positioning with respect to the surface are such that electron transfer from the exogenous copper centre and the electrode is mediated by the native azurin active site, closely paralleling electron transfer processes in naturally occurring multicentre metalloprotein

Neuroinflammation, Mast Cells, and Glia: Dangerous Liaisons

The perspective of neuroinflammation as an epiphenomenon following neuron damage is being replaced by the awareness of glia and their importance in neural functions and disorders. Systemic inflammation generates signals that communicate with the brain and leads to changes in metabolism and behavior, with microglia assuming a pro-inflammatory phenotype. Identification of potential peripheral-to-central cellular links is thus a critical step in designing effective therapeutics. Mast cells may fulfill such a role. These resident immune cells are found close to and within peripheral nerves and in brain parenchyma/meninges, where they exercise a key role in orchestrating the inflammatory process from initiation through chronic activation. Mast cells and glia engage in crosstalk that contributes to accelerate disease progression; such interactions become exaggerated with aging and increased cell sensitivity to stress. Emerging evidence for oligodendrocytes, independent of myelin and support of axonal integrity, points to their having strong immune functions, innate immune receptor expression, and production/response to chemokines and cytokines that modulate immune responses in the central nervous system while engaging in crosstalk with microglia and astrocytes. In this review, we summarize the findings related to our understanding of the biology and cellular signaling mechanisms of neuroinflammation, with emphasis on mast cell-glia interactions

CIRCOLAZIONE DELLE AZIONI. CADUCAZIONE DEL TRASFERIMENTO E CONSEGUENZE SULLO STATUS DI SOCIO

Il presente scritto tratta dei problemi derivanti della caducazione di un atto di trasferimento, nell\u2019ambito della circolazione delle azioni, sullo status di socio. Delimitato il perimetro dell\u2019indagine, si \ue8 suddiviso lo scritto in due macro aree. Si \ue8 trattato prima il piano (endosocietario) dei rapporti tra l\u2019emittente, il socio alienante e l\u2019acquirente (socio apparente), al fine di verificare le conseguenze sul piano dell\u2019organizzazione della rimozione degli effetti traslativi, e poi quello dei rapporti restitutori tra il tradens (il socio titolare) e l\u2019accipiens (il \u201csocio\u201d apparente). Il primo tema \ue8 stato a sua volta suddiviso in due sotto-categorie problematiche: la prima volta ad analizzare i requisiti per il valido ed efficace esercizio dei diritti sociali da parte del socio apparente; la seconda tesa a verificare l\u2019ultrattivit\ue0 degli atti posti in essere avendo riguardo alle caratteristiche soggettive del socio apparente, una volta che la partecipazione fosse ritornata nella disponibilit\ue0 del titolare. Sviluppando il primo tema, si \ue8 giunti a suddividere le posizioni soggettive attive dell\u2019azionista in due insiemi: (i) i diritti sociali, che sono quelle pretese che trovano il loro compimento o la loro estrinsecazione all\u2019interno del procedimento assembleare, per l\u2019esercizio dei quali \ue8 sufficiente la mera legittimazione; (ii) i diritti individuali, che sono invece quelli direttamente opponibili alla societ\ue0 e che richiedono, ai fini dell\u2019efficacia, il possesso congiunto tanto della legittimazione quanto della titolarit\ue0. Quanto ai diritti sociali, si \ue8 visto come gli effetti dell\u2019esercizio di questi ultimi siano suscettibili di consolidamento, nonostante la rimozione degli effetti traslativi del trasferimento della partecipazione, in ragione della preminenza dell\u2019interesse alla stabilit\ue0 dell\u2019organizzazione sulla pretesa del socio. Argomento, questo, che si \ue8 ricavato dalla disciplina \u2013 tanto procedimentale quanto rimediale \u2013 delle decisioni assembleari e che ha trovato poi riscontro testuale in una lettura a contrariis dell\u2019art. 2352 c.c. Con riguardo ai diritti individuali, invece, questi ultimi, essendo per loro natura estranei a quell\u2019ambito di sostanziale eteronomia che si era ravvisato all\u2019interno del novero dei diritti sociali, rimangono retti dal principio generalissimo del nemo plus iuris, e dunque gli atti che derivano dal loro esercizio verranno in linea di massima caducati, giacch\ue9 condividono gli effetti e gli esiti della restitutio in integrum. L\u2019altro aspetto del piano societario, invece, ha coinvolto la situazione di soggezione del titolare all\u2019esercizio dell\u2019altrui potere, cio\ue8, in concreto, depurata l\u2019ipotesi di indagine dalle fattispecie non problematiche e sistematicamente non determinanti, l\u2019idoneit\ue0 degli atti emessi medio tempore dalla societ\ue0 avendo riguardo alla specifica soggettivit\ue0 del socio apparente ad incidere sullo status di socio del titolare, una volta che questi sia stato reintegrato all\u2019interno della compagine sociale. Si sono risolte le varie fattispecie dubbie alla luce delle norme che tutelano i terzi, temperando alcune soluzioni ragionando ancora attorno alle logiche dell\u2019organizzazione qualora la posizione di terzo fosse occupata dalla societ\ue0. La riflessione relativa all\u2019ambito endosocietario ha poi influito anche sull\u2019analisi della seconda parte: quella esterna all\u2019ambito strettamente organizzativo, che si proponeva di verificare come la peculiarit\ue0 del bene trasferito, intrinsecamente dinamico e mutevole, potesse influire sulla restitutio in integrum. Nelle ultime pagine, in particolare, si \ue8 visto come la natura dell\u2019azione quale \uabbene di secondo grado\ubb, e dunque chiave di accesso alla partecipazione alla vita sociale, non possa essere tralasciata nemmeno l\uec dove a farla da padrone sono le norme civilistiche dell\u2019indebito. Si \ue8 identificato, per una serie di ragioni, l\u2019oggetto dell\u2019obbligo restitutorio nella quota a suo tempo trasferita. Da ci\uf2 ne sono discesi una serie di corollari applicativi che ruotano attorno ai concetti di \uabfrutto\ubb, \uabperimento\ubb, \uabdeterioramento\ubb e \uabmiglioramento\ubb. Da ultimo si \ue8 verificato la possibilit\ue0 di integrare la disciplina restitutoria con il generale rimedio risarcitorio.This essay considers the consequences of the voidance of shares transfer on the status of the shareholder. The research is set out in two parts. The first one addresses the consequences resulting from the termination of the effects of the contract from the corporation point of view. The second one considers the repercussions of the termination from the civil law point of view, examining the buyer-seller relationship and the possible claims between them and the way in which trades affects the ordinary application of the rules. In this connection, in the first part, the problem is approached from a double perspective. The essay starts providing a clear analysis of the relationship among the company, the seller and the purchaser. Firstly, it analyses, in general, the conditions under which the shareholder may exercise his company rights, and secondly, based on the requirements thus identified, examines the boundaries of validity and effectiveness of decisions taken in the meanwhile with or by the apparent shareholder. Focusing on the shareholder\u2019s position and the conditions for the exercise of the rights attached to his status, the conclusions are different if the set of the shareholder\u2019s company rights or the set of his individual ones are considered. In specific, the shareholder\u2019s company rights concern the prerogatives of the shareholders within the general meeting, while the shareholders\u2019 individual ones are directly addressed against the company; the first one has as sole condition the legitimation of the person who votes, while the other requires, in addition to the formal legitimacy, also the ownership of the shares. This distinction, which acquires a new meaning here, has been obtained from the analysis of the discipline that concerns the assembly decisions, and then also confirmed by Article 2352 Italian Civil Code. In case of voidance of the shares transfer, the exercise of these two different categories of rights results differently. The study illustrates how, when the apparent shareholder enforced his company rights, the decisions taken with his vote are considered valid. Notwithstanding the invalidation of the contract, indeed, the general interests to stable and secure company management prevails over the individual interests of the shareholders involved. For the exercise of individual rights, on the contrary, a different principle predominates. According to the general rule of \u201cnemo plus iuris\u201d, indeed, the voidance of the contract does not allow the apparent shareholder to exercise the prerogatives based on the ownership of the shares. The research then considers the situation of subjection of the \u201creal\u201d shareholder (the owner of the shares) in the occasion of the exercise of a power performed by another person. To simplify, the essay treats the ability of the acts issued by the company to affect the holder\u2019s member status, once he has been reinstated within the company structure. The analysis then moves forward focusing on possible subsequent claims for the repayment of the values frustrated by the non-exercise of company and individual rights. Considering this situation, however, since share has to be considered as a \u201csecond-order good\u201d, the principles and the rules applicable suggest the use of traditional civil law remedies. The restitution therefore regards the so-called \uabquota\ubb rights, i.e. portion of the shares including powers prerogatives. This premise finds as supports all the following corollaries connected with the right to the beneficial use of assets, the accidental destruction of the good, such as its improvement or deterioration. Eventually, this second part analyses the potential integrations of the described framework, adding to the restitution the possibility of seeking compensation for the damages occurred

I doveri degli amministratori e la dispensa del Deber de Lealtad nella riformata Ley de Sociedades de capital spagnola : un&apos;occasione per riflettere sull&apos;obbligo di fedelt&#224;

L\u2019ultima crisi economica, iniziata negli Stati Uniti nel 2007 e giunta in Europa l\u2019anno successivo, \ue8 stata per molti ordinamenti l\u2019occasione per riflettere sulle regole che fino a quel momento avevano disciplinato il mercato e i soggetti economici che vi operano, tra cui, su tutti, le societ\ue0 di capitali. In Spagna, in particolare, sono recentemente state introdotte delle rilevanti novit\ue0 in materia di corporate governance attraverso la riforma della Ley de Sociedades de Capital (d\u2019ora innanzi LSC) ad opera della legge del 3 dicembre 2014, n. 31. L'elaborato in oggetto si propone di analizzare uno dei molteplici elementi di novit\ue0 introdotti: la dispensa dal dovere di lealt\ue0 degli amministratori (\uabdispensa del deber de lealtad\ubb) di cui all\u2019art. 230 LSC, istituto assolutamente nuovo per l\u2019ordinamento spagnolo e non previsto dall\u2019ordinamento italiano. L\u2019analisi di questo peculiare istituto si rivela di particolare interesse in quanto l\u2019osservazione del suo concreto operare e degli effetti che produce nella corporate governance permette di fare chiarezza sul problematico rapporto tra obblighi generali di condotta e obblighi specifici positivizzati dal legislatore come estrinsecazione e specificazione dei primi. Le riflessioni generate dall\u2019analisi della novella in commento offrirono quindi l\u2019opportunit\ue0 di sviluppare un ragionamento sistematico pi\uf9 ampio sulle clausole generali e sul loro concreto operare all\u2019interno dell\u2019ordinamento. Specificamente, lo studio dell\u2019istituto della \uabdispensa dal dovere di lealt\ue0\ubb consentir\ue0 di \u201criempire\u201d di contenuto e di significato la clausola generale riferita alla fedelt\ue0 degli amministratori nel perseguire l\u2019oggetto sociale. Tale operazione, bench\ue9 condotta sulla scorta di una disciplina straniera, andr\ue0 a beneficio anche dell\u2019interprete italiano, il quale, se volesse ragionare sul tema rimanendo ancorato solamente al dato normativo interno, si troverebbe in difficolt\ue0 difronte al ben conosciuto dato normativo, che si dimostra particolarmente scarno, quand\u2019anche non addirittura reticente

Concordato di gruppo e autonomia privata

Alcune recenti pronunce giurisprudenziali hanno (ri)acceso un certo interesse tra gli studiosi attorno al tema del concordato preventivo di gruppo, istituto non preso in considerazione dalle norme fallimentari rispetto al quale l’interprete si trova costretto a ragionare forte dei soli principî. Nella presente relazione si sono valutati i margini di cui dispone l'autonomia privata rispetto alla possibile composizione della crisi di un gruppo di società

Expression and Differential Responsiveness of Central Nervous System Glial Cell Populations to the Acute Phase Protein Serum Amyloid A

Acute-phase response is a systemic reaction to environmental/inflammatory insults and involves hepatic production of acute-phase proteins, including serum amyloid A (SAA). Extrahepatically, SAA immunoreactivity is found in axonal myelin sheaths of cortex in Alzheimer's disease and multiple sclerosis (MS), although its cellular origin is unclear. We examined the responses of cultured rat cortical astrocytes, microglia and oligodendrocyte precursor cells (OPCs) to master pro-inflammatory cytokine tumour necrosis factor (TNF)-\u3b1 and lipopolysaccaride (LPS). TNF-\u3b1 time-dependently increased Saa1 (but not Saa3) mRNA expression in purified microglia, enriched astrocytes, and OPCs (as did LPS for microglia and astrocytes). Astrocytes depleted of microglia were markedly less responsive to TNF-\u3b1 and LPS, even after re-addition of microglia. Microglia and enriched astrocytes showed complementary Saa1 expression profiles following TNF-\u3b1 or LPS challenge, being higher in microglia with TNF-\u3b1 and higher in astrocytes with LPS. Recombinant human apo-SAA stimulated production of both inflammatory mediators and its own mRNA in microglia and enriched, but not microglia-depleted astrocytes. Co-ultramicronized palmitoylethanolamide/luteolin, an established anti-inflammatory/neuroprotective agent, reduced Saa1 expression in OPCs subjected to TNF-\u3b1 treatment. These last data, together with past findings suggest that co-ultramicronized palmitoylethanolamide/luteolin may be a novel approach in the treatment of inflammatory demyelinating disorders like MS

Electron Transport Properties of Single-Molecule-Bearing Multiple Redox Levels Studied by EC-STM/STS

Multielectron systems as possible components of molecular electronics devices are attracting compelling experimental and theoretical interest. Here we studied by electrochemical scanning tunneling techniques (EC-STMicroscopy and EC-STSpectroscopy) the electron transport properties of a redox molecule endowed with two redox levels, namely, the hydroquinone/quinone (H2Q/Q) couple. By forming self-assembled monolayers on Au(111) of oligo-phenylene-vinylene (OPV) derivatized H2Q/Q moieties, we were able to explore the features of the tunneling current/overpotential relation in the EC-STS setup. The behavior of the tunneling current sheds light onto the mechanism of electron transport involving the redox levels of the H2Q/Q redox pair coupled to tip and substrate electrodes

Negative consequences of conflict-related sexual violence on survivors: a systematic review of qualitative evidence

BackgroundConflicts exacerbate dynamics of power and inequalities through violence normalization, which acts as a facilitator for conflict-related sexual violence. Literature addressing its negative outcomes on survivors is scant. The aim of this systematic review was to analyze the qualitative evidence reported in scientific literature and focusing on the negative consequences of conflict-related sexual violence on victims' physical, psychological, and social dimensions of health in a gender-inclusive and disaggregated form.MethodsA literature search was conducted on January 13, 2023 on Pubmed, Scopus, and PsychArticles. The search strings combined two blocks of terms related to sexual violence and conflict. A time filter was applied, limiting the search to studies published in the last ten years. Information regarding the main characteristics and design of the study, survivors and their experience, and about conflict-related sexual violence was collected. The negative consequences of conflict-related sexual violence on the physical, psychological, and social dimension of victims were extracted according to the Biopsychosocial model of health. The review followed the Joanna Briggs Institute methodology for systematic reviews and relied on the Preferred Reporting Items for Systematic reviews and Meta-Analyses.ResultsAfter full text review, 23 articles met the inclusion criteria, with 18 of them reporting negative repercussions on physical health, all of them highlighting adverse psychological outcomes, and 21 disclosing unfavorable social consequences. The negative outcomes described in multiple studies were sexual and reproductive health issues, the most mentioned being pregnancy, manifestations of symptoms attributable to post-traumatic stress disorder, and stigma. A number of barriers to access to care were presented as emerging findings.ConclusionsThis review provided an analysis of the negative consequences of conflict-related sexual violence on survivors, thus highlighting the importance of qualitative evidence in understanding these outcomes and addressing barriers to access to care. Conflict-related sexual violence is a sexual and reproductive health issue. Sexuality education is needed at individual, community, and provider level, challenging gender norms and roles and encompassing gender-based violence. Gender-inclusive protocols and services need to be implemented to address the specific needs of all victims. Governments should advocate for SRHRs and translate health policies into services targeting survivors of CRSV