1,720,960 research outputs found
Effect of empagliflozin on plasma proprotein convertase subtilisin/kexin type 9 (PCSK9) in patients with type 2 diabetes
No full textP2X7 Receptor and Heart Function in a Mouse Model of Systemic Inflammation Due to High Fat Diet
No full textPurpose: Low-grade inflammation contributes to heart failure in obesity or type 2 diabetes mellitus. The P2X7 receptor (P2X7R) is a key regulator of several pro-inflammatory responses in multiple tissues and organs; however, its involvement in the onset of heart dysfunction remains unclear. The study evaluated the role of P2X7R as a cardiac function regulator in C57BL/6J wild-type (WT) and P2X7R knockout (KO) mice by inducing systemic inflammation with high fat diet (HFD). Methods: Specific parameters of systolic and diastolic function and heart morphology were measured in vivo before animal sacrifice by high-frequency ultrasonographic analysis. Gene and protein expression of cardiac biomarkers associated with inflammatory-oxidative pathways were evaluated by real-time PCR and Western Blotting. Results: P2X7R-mediated up-regulation of the NLRP3-caspase-1 complex, increased expression of key oxidative stress (NOS-2, TNFα), and chemotactic (MCP-1) mediators were revealed in WT-HFD animals. In KO-HFD mice, such inflammatory-oxidative pathway was silent. Nevertheless, HFD induced in vivo a clear alteration of diastolic pattern (E/A: p < 0.03 vs WT-HFD) and a cardiac morphologic remodelling (left ventricular mass: p < 0.05 vs WT-HFD) only in P2X7R KO animals. Surprisingly, the transcriptional and protein expression of IL-1β and IL-6, usually regulated through P2X7R activation, were significantly higher in KO-HFD than in WT-HFD mice (both p < 0.05). Furthermore, an up-regulation of miR-214 and a down-regulation of miR-126 in heart of HFD-KO mice were observed, suggesting a link between such epigenetic dysregulation and cytokine overexpression as a potential pathophysiologic mechanism concurring to the progressive cardiac dysfunction. Conclusion: These findings seem to suggest a cardioprotective role of P2X7R toward this tissue-specific inflammatory damage, likely through tissue homeostasis and organ functionality preservation
Lacking P2X7-receptors protects substantia nigra dopaminergic neurons and hippocampal-related cognitive performance from the deleterious effects of high-fat diet exposure in adult male mice
Full text linkBackgroundDietary fat consumption, involved in the pathogenesis of insulin resistance and impaired glucose metabolism, is linked with decline in cognitive functions, dementia, and development of Parkinson’s disease and Alzheimer’s disease. Mature IL-1β, requiring the activation of the P2X7 receptor (P2X7R)-inflammasome complex, is an important mediator of neuroinflammation. The aim of the study was to test whether P2X7R activation might interfere with systemic and cerebral metabolic homeostasis.MethodsWe treated WT and P2X7R KO mice with a high-fat diet (HFD) for 16 weeks, evaluating the effects on the Substantia Nigra and Hippocampus, target areas of damage in several forms of cognitive impairment.ResultsHFD-treated WT and P2X7R KO mice showed a different brain mRNA profile of Insulin and Igf-1, with these genes and relative receptors, more expressed in KO mice. Unlike P2X7R KO mice, WT mice treated with HFD displayed a diameter reduction in dopaminergic neurons in the Substantia Nigra, accompanied by an increased IBA1 expression in this area; they also showed poor performances during Y-Maze and Morris Water Maze, tasks involving Hippocampus activity. Conversely, Parkin, whose reduction might promote neuronal cell death, was increased in the brain of P2X7R KO animals.ConclusionWe report for the first time that HFD induces damage in dopaminergic neurons of the Substantia Nigra and a Hippocampus-related worse cognitive performance, both attenuated in the absence of P2X7R. The involved mechanisms might differ in the two brain areas, with a predominant role of inflammation in the Substantia Nigra and a metabolic derangement in the Hippocampus
MG53 does not mark cardiovascular risk and all-cause mortality in subjects with type 2 diabetes: A prospective, observational study
No full textAims: Subjects with type 2 diabetes (T2D) are characterized by a high cardiovascular morbidity and mortality. MG53, a marker of peripheral insulin resistance, has been linked with impaired 13-cell function and decreased 13-cell survival, and its circulating levels are increased in T2D. Its relationship with the cardiovascular risk profile and mortality in T2D is currently unknown. Methods: In this longitudinal study, MG53 was measured in serum samples collected at baseline for 296 Caucasian participants in the MIND.IT study, relating its circulating levels with the cardiovascular risk profile and all-cause mortality over a 17-years follow up. Results: As compared to a reference cohort of 234 healthy subjects, MG53 levels were higher in T2D individuals (p < 0.001), and higher in T2D women than in men (p = 0.001). In the whole study cohort, MG53 levels were directly related to HbA1c (r2 0.029; p = 0.006) and systolic blood pressure (r(2) 0.032; p = 0.004). There was no difference in baseline MG53 levels between deceased and alive participants, neither predict all-cause mortality. Conclusions: MG53 does not mark the cardiovascular risk profile neither predict long-term mortality in Caucasian T2D individuals
Ruolo dell'inflammasoma nel fegato: confronto tra NAFLD/NASH ed epatiti virali
No full textL’inflammasoma è un complesso intracellulare attivato da stimoli di danno per salvaguardare l’integrità delle cellule. Tra i vari tipi di inflammasoma esistenti uno dei più studiati è NLRP3 che può attivarsi attraverso il recettore P2X7, sensibile all’ATP extracellulare. Scopo del mio lavoro di tesi è caratterizzare il ruolo dell’inflammasoma nel fegato, dettagliare le vie di segnale intracellulari in esso coinvolte e confrontare due patologie epatiche: NAFLD/NASH e l’infezione da virus dell’epatite C. Sono stati effettuati studi di espressione genica su RNA estratto da 46 agobiopsie epatiche per valutare i livelli di P2X7R, P2X4R, NLRP3, CASP1, AIM2 e IL-2; è stato costruito un database con i dati anamnestici dei pazienti per eseguire delle correlazioni con i dati di espressione molecolare; infine sono stati effettuati esperimenti di immunofluorescenza per valutare la localizzazione subcellulare di P2X7R e AIM2. Dai risultati è emerso che P2X7R, P2X4R, NLRP3 e CASP1 sembrano più espressi nei pazienti con infezione cronica da HCV associata a danno metabolico; AIM2 risulta più espresso nei pazienti con infezione cronica da HCV, a prescindere dalla coesistenza di patologie metaboliche; IL2, virtualmente assente nei pazienti NAFLD, sembra discriminare la steatosi rispetto alla steatoepatite; NLRP3 e AIM2 sono correlati ad AST solo in condizioni di HCV; l’inflammasoma NLRP3 e AIM2 sembrano immunolocalizzati in tipi cellulari diversi nel tessuto epatico
Empagliflozin and Renal Sodium-Hydrogen Exchange in Healthy Subjects
No full textContext Sodium glucose co-transporter-2 inhibitors exert clinically relevant cardiorenal protection. Among several mechanisms, inhibition of sodium-hydrogen exchanger-3 (NHE3) in proximal renal tubules has been proposed in rodents. Demonstration of this mechanism with the associated electrolyte and metabolic changes in humans is lacking. Objective The present proof-of-concept study was designed to explore the involvement of NHE3 in modulating the response to sodium glucose co-transporter-2 inhibitors in humans. Methods Twenty healthy male volunteers received 2 tablets of empagliflozin 25 mg during a standardized hydration scheme; freshly voided urines and blood samples were collected at timed intervals for 8 hours. Protein expression of relevant transporters was examined in exfoliated tubular cells. Results Urine pH levels increased after empagliflozin (from 5.81 +/- 0.5 to 6.16 +/- 0.6 at 6 hours, P = .008) as did urinary output (from median, 1.7; interquartile range [IQR, 0.6; 2.5] to 2.5 [IQR, 1.7; 3.5] mL/min(-1), P = .008) and glucose (from median, 0.03 [IQR, 0.02; 0.04] to 34.8 [IQR, 31.6; 40.2] %, P < .0001), and sodium fractional excretion rates (from median, 0.48 [IQR, 0.34; 0.65] to 0.71 [IQR, 0.55; 0.85] %, P = .0001), whereas plasma glucose and insulin concentrations decreased and plasma and urinary ketones increased. Nonsignificant changes in NHE3, phosphorylated NHE3, and membrane-associated protein 17 protein expression were detected in urinary exfoliated tubular cells. In a time-control study in 6 participants, neither urine pH nor plasma and urinary parameters changed. Conclusions In healthy young volunteers, empagliflozin acutely increases urinary pH while inducing a substrate shift toward lipid utilization and ketogenesis, without significant changes in renal NHE3 protein expression
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
- …
