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DIFFERENZE DI GENERE NEL POTENZIALE ANGIOGENICO DI LIQUIDI SINOVIALI DA PAZIENTI CON ARTRITE E NEL TRAFFICKING ENDOTELIALE DI IMMUNE CHECKPOINTS
No full textL’artrite reumatoide (AR) e l’artrite psoriasica (PSA) sono malattie cronico infiammatorie caratterizzate da sinovite. In questo lavoro abbiamo indagato le potenziali differenze di genere nell’infiltrato infiammatorio dei liquidi sinoviali (LS) e nel contenuto di fattori pro-angiogenici di pazienti con AR e PSA. Abbiamo inoltre indagato l’effetto della digitossina e polidatina nella migrazione e tubularizzazione indotta dai LS. I LS sono stati ottenuti da pazienti con AR e PSA, grazie al contributo dell’unità di Reumatologia del policlinico di Padova. Non abbiamo riscontrato differenze di genere nella conta totale e differenziale dei globuli bianchi. Abbiamo analizzato i LS, differenziati in base al genere, per il loro contenuto di fattori pro-angiogenici e rilascio di metalloproteasi (MMP) 2/9. I livelli di IL-1β, IL-10, IL-6, IL-8, IL-10, MCP-1, TGF-β e VEGF sono stati valutati tramite kit ELISA, la valutazione dell’attività delle MMP tramite zimografia. Livelli più elevati di quasi tutti questi fattori sono stati misurati nel LS dei pazienti con AR e PSA rispetto a quelli di pazienti con OA. I livelli della pro-MMP9 sono correlati ai livelli dei polimorfonucleati. La migrazione delle HUVEC indotta dai liquidi di AR e PSA è maggiore di quella indotta dai liquidi di OA; i LS inducono inoltre la formazione di strutture capillaro-simili. Le HUVEC derivate da donatrici migrano maggiormente delle HUVEC derivate da donatori; questa differenza di genere è visibile anche nella tubularizzazione. I LS inducono l’aumento della fosforilazione di FAK e la digitossina, a concentrazioni terapeutiche, inibisce la fosforilazione di FAK indotta dai LS nelle HUVEC. Inoltre, la digitossina e la polidatina sono risultate efficaci nel ridurre la migrazione e la tubularizzazione delle HUVEC indotta dai LS. Ci siamo poi focalizzati nel valutare un possibile meccanismo coinvolto nelle differenze di genere nelle malattie cronico-infiammatorie, prendendo in considerazione l’espressione del PD-L1 a livello endoteliale. Gli Immune checkpoints regolano la risposta immunitaria. Nei pazienti trattati con immune checkpoints inhibitors il blocco farmacologico del PD-1 o PD-L1 può portare ad effetti avversi con sintomi simili a quelli riscontrati in alcune malattie reumatiche. PD-L1 è costitutivamente espresso in diversi tipi cellulari, incluse le cellule endoteliali, e può essere indotto da stimoli infiammatori come segnale immunosoppressivo. Il VEGF aumenta l’espressione del PD-L1/PD-1 nei leucociti e farmaci diretti contro il VEGF o il segnale mediato da esso, modulano questa espressione. Le HUVEC sono state stimolate con IFN-γ, IL-1β, IL-6 or VEGF dalle 3 alle 24h. Alcuni esperimenti sono stati condotti in presenza del bevacizumab o dell’inibitore delle metalloproteasi GM6601. PD-L1 di membrana (mPD-L1) è espresso in condizioni basali nelle HUVEC, ma non abbiamo osservato differenze di genere nella sua espressione. Stimolando per 24h le cellule con IFN-γ o IL-1β non abbiamo riscontrato variazioni nei livelli di espressione di mPD-L1. Invece, l’espressione di PD-L1 intracellulare (iPD-L1) aumenta dopo 24h nelle HUVEC derivate da donatrici e stimolate con IFN-γ, IL-1β, IL-6 o VEGF; nelle stesse condizioni i livelli di iPD-L1 nelle mHUVEC restano costanti. Inoltre, le HUVEC stimolate fino a 24h con IL-1β e VEGF rilasciano PD-L1 solubile (sPD-L1). Nelle HUVEC trattate con il VEGF il rilascio di sPD-L1 è inibito dal bevacizumab. Nelle HUVEC pretrattate con il GM6001, il trattamento con IL-1β non aumenta il rilascio del sPD-L1 suggerendo che questo venga rilasciato tramite taglio proteolitico ad opera delle MMP. In conclusione, l’espressione di PD-L1 endoteliale è regolata da diversi stimoli infiammatori, in maniera genere specifica, suggerendo un meccanismo di regolazione negativa nella donna per controllare l’autoimmunità.Gender differences can be identified at multiple levels of the immune response. Rheumatoid arthritis (RA) and psoriatic arthritis (PSA) are chronic systemic disorders characterized by synovitis. We explored potential gender differences in recruited inflammatory cells and angiogenic potential of synovial fluids (SFs) from RA and PSA patients, and tested the effects of digitoxin and polydatin treatment on SF-induced endothelial cell migration. SF was collected by arthrocentesis from untreated RA and PSA patients attending the Outpatient Clinic of the Rheumatology Unit (Padua University Hospital). White blood cell count in SFs from RA and PSA patients did not highlight gender differences. We then investigated potential gender differences in the levels of proangiogenic factors and metalloproteinases (MMP) 2 and 9 released during inflammation. Quantification of IL-1β, IL-10, IL-6, IL-8, IL-10, MCP-1, TGF-β and VEGF in SFs was performed using ELISA kits. Levels of pro-angiogenic factors and MMPs were higher in the SFs from RA and PSA patients compared to OA patients without significant gender differences. The presence of MMP-9 was associated specifically with polymorphonuclear (PMN) cell infiltration. HUVEC migration induced by inflammatory SFs was greater than that induced by non-inflammatory SFs. SFs induced the formation of capillary-like structures compared to negative control. HUVECs from female donors (fHUVECs) migrated more than male HUVECs in response to SFs from RA and PSA patients. Topological parameters of the capillary-like network were markedly enhanced in fHUVECs compared to mHUVECs stimulated with inflammatory SFs. Digitoxin and polydatin treatment were effective in impairing SF-induced migration and formation of capillary-like structures. In this thesis work we also showed that SFs from RA and PSA patients induced tyrosine phosphorylation of focal adhesion kinase (FAK). Digitoxin treatment at therapeutic concentrations inhibited FAK activation in HUVECs exposed to SFs from RA and PSA patients at different time points. We then focused on a possible endothelial mechanism that could be involved in gender differences in chronic inflammatory diseases. Immune checkpoints are negative regulators of the immune response. Pharmacological blockade of PD-1 or PD-L1 often leads to immune-related adverse events. PD-L1 is constitutively expressed in endothelial cells and can be upregulated by inflammatory stimuli as a suppressive signal. Of note, VEGF has been reported to upregulate the expression of PD-L1/PD1, and anti-VEGF agents show immunosupportive properties. However, it is unclear (a) whether and to what extent endothelial PD-L1 is a source of circulating sPD-L1 via proteolytic cleavage; and (b) if gender differences occur in the regulation of this system. HUVECs were stimulated with IFN-γ, IL-1β, IL-6 or VEGF for 3 to 24 hours. Selected experiments were carried out in the presence of bevacizumab or the pan MMP inhibitor GM6001. Membrane PD-L1 was expressed on resting HUVECs, and no baseline differences between fHUVECs and mHUVECs were observed. Stimulation with IFN-γ or IL-1β for 24 h failed to increase membrane PD-L1 abundance. Conversely, the amount of intracellular PD-L1 after 24-h stimulation with IFN-γ, IL-1β, IL-6 or VEGF increased in fHUVECs but not in mHUVECs. In addition, sPD-L1 released by IL-1β-stimulated fHUVECs increased in a time-dependent manner. Similarly, sPD-L1 also increased upon treatment of fHUVECs with VEGF for 6 or 24 h, an effect that was significantly inhibited by bevacizumab. In fHUVEC pretreated with the MPP inhibitor GM6001, IL-1β stimulation did not increase sPD-L1 release, suggesting that proteolytic cleavage of membrane PD-L1 occurred over time. In conclusion, endothelial PD-L1 was expressed and released in response to various inflammatory stimuli in a gender-specific manner, suggesting a feedback compensatory mechanism to control autoimmunity in females
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Hydrogen Peroxide Modulates the Timely Activation of Jun and Erk in Schwann Cells at the Injury Site and Is Required for Motor Axon Regeneration
No full textPeripheral nervous system (PNS) neurons, including motor neurons (MNs), possess a remarkable ability to regenerate and reinnervate target muscles following nerve injury. This process is orchestrated by a combination of intrinsic neuronal properties and extrinsic factors, with Schwann cells (SCs) playing a central role. Upon injury, SCs transition into a repair phenotype that allows axonal regeneration through molecular signaling and structural guidance. However, the identity of the SCs’ reprogramming factors is only partially known. We previously identified hydrogen peroxide (H2O2) as an early and key driver of nerve repair, inducing gene expression rewiring in SCs to support nerve re-growth. In this study, we quantitatively assessed the role of H2O2 in the activation of key pro-regenerative signaling pathways in SCs following sciatic nerve compression, specifically the extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun, which are essential for functional nerve recovery. Notably, we found that H2O2 neutralization does not impact degeneration, but it significantly affects the regenerative response. Collectively, our findings establish H2O2 as a promising regulator of the Schwann cell injury response at the injury site, linking oxidative signaling to the molecular mechanisms governing nerve regeneration
Targeting of PFKFB3 with miR-206 but not mir-26b inhibits ovarian cancer cell proliferation and migration involving FAK downregulation
Full text link: Few studies explored the role of microRNAs (miRNAs) in the post-transcriptional regulation of glycolytic proteins and downstream effectors in ovarian cancer cells. We recently showed that the functional activation of the cytoskeletal regulator FAK in endothelial cells is fostered by the glycolytic enhancer 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3). We tested the hypothesis that miR-206 and mir-26b, emerging onco-suppressors targeting PFKFB3 in estrogen-dependent tumors, would regulate proliferation and migration of serous epithelial ovarian cancer (EOC) cells via common glycolytic proteins, i.e., GLUT1 and PFKFB3, and downstream FAK. PFKFB3 was overexpressed in SKOV3, and its pharmacological inhibition with 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO) significantly reduced cell proliferation and motility. Both miR-206 and miR-26b directly targeted PFKFB3 as evaluated by a luciferase reporter assay. However, endogenous levels of miR-26b were higher than those of miR-206, which was barely detectable in SKOV3 as well as OVCAR5 and CAOV3 cells. Accordingly, only the anti-miR-26b inhibitor concentration-dependently increased PFKFB3 levels. While miR-206 overexpression impaired proliferation and migration by downregulating PFKFB3 levels, the decreased PFKFB3 protein levels related to miR-26 overexpression had no functional consequences in all EOC cell lines. Finally, consistent with the migration outcome, exogenous miR-206 and miR-26b induced opposite effects on the levels of total FAK and of its phosphorylated form at Tyr576/577. 3PO did not prevent miR-26b-induced SKOV3 migration. Overall, these results support the inverse relation between endogenous miRNA levels and their tumor-suppressive effects and suggest that restoring miR-206 expression represents a potential dual anti-PFKFB3/FAK strategy to control ovarian cancer progression
Gout: one year in review 2025
No full text: The incidence of gout has increased steadily over the last decades and its management is still unsatisfactory. Growing evidence highlights the multifactorial etiology of this disease encompassing genetic predisposition, environmental stimuli and gut dysbiosis. Recent advances in biomolecular and computer sciences allowed to gain more and more genetic, epigenetic, transcriptomic, proteomics and metabolomics insights into hyperuricaemia and gout-related molecular mechanisms. Moreover, the interplay between gout and cardiovascular, metabolic and renal diseases may potentially offer novel targets for anti-inflammatory and urate-lowering therapies.This annual review aims to provide the latest updates on gout research, epidemiology, genetics, molecular mechanisms, diagnostic approach, and therapeutic advances
Endomyocardial biopsy in the clinical context: current indications and challenging scenarios
Full text linkEndomyocardial biopsy (EMB) is an invasive procedure originally developed for the monitoring of heart transplant rejection. Over the year, this procedure has gained a fundamental complementary role in the diagnostic work-up of several cardiac disorders, including cardiomyopathies, myocarditis, drug-related cardiotoxicity, amyloidosis, other infiltrative and storage disorders, and cardiac tumours. Major advances in EMB equipment and techniques for histological analysis have significantly improved diagnostic accuracy of EMB. In recent years, advanced imaging modalities such as echocardiography with three-dimensional and myocardial strain analysis, cardiac magnetic resonance and bone scintigraphy have transformed the non-invasive approach to diagnosis and prognostic stratification of several cardiac diseases. Therefore, it emerges the need to re-define the current role of EMB for diagnostic work-up and management of cardiovascular diseases. The aim of this review is to summarize current knowledge on EMB in light of the most recent evidences and to discuss current indications, including challenging scenarios encountered in clinical practice. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10741-022-10247-5
Gender differences and pharmacological regulation of angiogenesis induced by synovial fluids in inflammatory arthritis
Full text linkSeveral mediators including cytokines, growth factors and metalloproteinases (MMP) modulate pathological angiogenesis associated with inflammatory arthritis. The biological factors underlying sex disparities in the incidence and severity of rheumatic musculoskeletal diseases are only partially understood. We hypothesized that synovial fluids (SFs) from rheumatoid arthritis (RA) and psoriatic arthritis (PsA) patients would impact on endothelial biology in a sexually dimorphic fashion. Immune cell counts and levels of pro-angiogenic cytokines found in SFs from RA and PsA patients (n = 17) were higher than in osteoarthritis patients (n = 6). Synovial VEGF concentration was significantly higher in male than in female RA patients. Zymography revealed that SFs comprised solely MMP-9 and MMP-2, with significantly higher MMP-9 levels in male than female RA patients. Using in vitro approaches that mimic the major steps of the angiogenic process, SFs from RA and PsA patients induced endothelial migration and formation of capillary-like structures compared to control. Notably, endothelial cells from female donors displayed enhanced angiogenic response to SFs with respect to males. Treatment with the established anti-angiogenic agent digitoxin prevented activation of focal adhesion kinase and SF-induced in vitro angiogenesis. Thus, despite higher synovial VEGF and MMP-9 levels in male patients, the responsiveness of vascular endothelium to SF priming was higher in females, suggesting that gender differences in angiogenic responses were mainly related to the endothelial genotype. These findings may have implications for pathogenesis and targeted therapies of inflammatory arthritis
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