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RAF KINASE INHIBITOR PROTEIN (RKIP) EXPRESSION AND FUNCTION IN UTERINE LEIOMYOMA
Full text linkI leiomiomi uterini (detti anche fibromi, miomi) sono tumori benigni che originano dallo strato muscolare dell’utero (miometrio) e rappresentano la principale indicazione dell’isterectomia nel mondo. I leiomiomi uterini colpiscono circa il 77% delle donne in eta fertile e circa il 25% di esse presenta tumori con sintomatologia clinica evidente, tra cui la presenza di forte o anomalo sanguinamento uterino, dolore o pressione pelvica, infertilità e aborti ricorrenti.
È comunemente noto che questi tumori sono caratterizzati da una elevata proliferazione cellulare ed una eccessiva deposizione di matrice extracellulare (ECM). Si ritiene che la crescita dei leiomiomi dipenda dall’azione degli ormoni ovarici mediante elementi intermedi come citochine e fattori di crescita.
La Proteina Inibitore della Raf Chinasi (RKIP) ha un ruolo emergente come regolatore in diversi pathway molecolari ed è associato a un numero crescente di malattie, essendo coinvolto indiverse vie di trasduzione del segnale.
Lo scopo della presente tesi è stato quello di indagare la presenza e il ruolo dell’RKIP nel leiomioma.
Abbiamo dimostrato che l’RKIP è espresso nel miometrio e nel leiomioma. Per individuare il ruolo dell’RKIP, abbiamo eseguito esperimenti in vitro con un composto chimico quale la locostatina, capace di legarsi all’RKIP bloccandolo. Abbiamo dimostrato che il trattamento con la locostatina porta all’attivazione della via di segnale MAPK (fosforilazione di ERK), fornendo una opportuna validazione dell’efficacia nel bloccare l’RKIP. Inoltre, abbiamo dimostrato che l'inibizione dell’RKIP con la locostatina riduce le componenti della ECM, tra cui il collagene 1A1, la fibronectina, e il versican. In aggiunta, l'inibizione dell’RKIP con la locostatina riduce la proliferazione cellulare e la migrazione sia nelle cellule miometriali che di leiomioma. Infine, abbiamo dimostrato che il trattamento con la locostatina riduce l’espressione del GSK3β. Pertanto, anche se l'attivazione delle MAPK dovrebbe far aumentare la proliferazione e la migrazione, la destabilizzazione e l’inattivazione del GSK3β porta alla riduzione della proliferazione e della migrazione delle cellule miometriali e di leiomioma
The Role of Exercise-Induced Molecular Processes and Vitamin D in Improving Cardiorespiratory Fitness and Cardiac Rehabilitation in Patients With Heart Failure
Full text linkHeart failure (HF) still affects millions of people worldwide despite great advances in therapeutic approaches in the cardiovascular field. Remarkably, unlike pathological hypertrophy, exercise leads to beneficial cardiac hypertrophy characterized by normal or enhanced contractile function. Exercise-based cardiac rehabilitation improves cardiorespiratory fitness and, as a consequence, ameliorates the quality of life of patients with HF. Particularly, multiple studies demonstrated the improvement in left ventricular ejection fraction (LVEF) among patients with HF due to the various processes in the myocardium triggered by exercise. Exercise stimulates IGF-1/PI3K/Akt pathway activation involved in muscle growth in both the myocardium and skeletal muscle by regulating protein synthesis and catabolism. Also, physical activity stimulates the activation of the mitogen-activated protein kinase (MAPK) pathway which regulates cellular proliferation, differentiation and apoptosis. In addition, emerging data pointed out the anti-inflammatory effects of exercises as well. Therefore, it is of utmost importance for clinicians to accurately evaluate the patient’s condition by performing a cardiopulmonary exercise test and/or a 6-min walking test. Portable devices with the possibility to measure exercise capacity proved to be very useful in this setting as well. The aim of this review is to gather together the molecular processes triggered by the exercise and available therapies in HF settings that could ameliorate heart performance, with a special focus on strategies such as exercise-based cardiac rehabilitation
Locostatin, a disrupter of Raf kinase inhibitor protein, inhibits extracellular matrix production, proliferation, and migration in human uterine leiomyoma and myometrial cells
No full textObjective To investigate the presence of Raf kinase inhibitor protein (RKIP) in human myometrium and leiomyoma as well as to determine the effect of locostatin (RKIP inhibitor) on extracellular matrix (ECM) production, proliferation, and migration in human myometrial and leiomyoma cells. Design Laboratory study. Setting Human myometrium and leiomyoma. Patient(s) Thirty premenopausal women who were admitted to the hospital for myomectomy or hysterectomy. Intervention(s) Myometrial and leiomyoma tissues were used to investigate the localization and the expression level of RKIP through immunohistochemistry and Western blotting. Myometrial and leiomyoma cells were treated with locostatin (10 μM) to measure ECM expression by real-time polymerase chain reaction, GSK3β expression by Western blotting, cell migration by wound-healing assay, and cell proliferation by MTT assay and immunocytochemistry. Main Outcome Measure(s) The expression of RKIP in human myometrial and leiomyoma tissue; ECM components and GSK3β expression, migration, and proliferation in myometrial and leiomyoma cells. Result(s) RKIP is expressed in human myometrial and leiomyoma tissue. Locostatin treatment resulted in the activation of the mitogen-activated protein kinase (MAPK) signal pathway (ERK phosphorylation), providing a powerful validation of our targeting protocol. Further, RKIP inhibition by locostatin reduces ECM components. Moreover, the inhibition of RKIP by locostatin impaired cell proliferation and migration in both leiomyoma and myometrial cells. Finally, locostatin treatment reduced GSK3β expression. Therefore, even if the activation of MAPK pathway should increase proliferation and migration, the destabilization of GSK3β leads to the reduction of proliferation and migration of myometrial and leiomyoma cells. Conclusion(s) Our results indicate that RKIP may be involved in leiomyoma pathophysiology
Part 1—Cardiac Rehabilitation After an Acute Myocardial Infarction: Four Phases of the Programme—Where Do We Stand?
Full text linkCardiac rehabilitation is a well-established multidisciplinary interventional protocol that plays a pivotal role in the management and prevention of future cardiovascular events in patients with cardiovascular diseases. This patient-tailored approach includes educating patients about their cardiovascular condition and how to control the associated risk factors, an expert-designed lifestyle modification plan that may include exercise, proper nutrition, pharmacological treatment, and psychological support at each step. Exercise training represents a fundamental component of cardiac rehabilitation. It facilitates an enhancement of cardiovascular fitness, a reduction in heart rate, blood pressure and cardiac remodeling, an increase in the left ventricular ejection fraction, the optimization of endothelial function, and a reduction in inflammation and oxidative stress. Moreover, the beneficial physiological changes resulting from cardiac rehabilitation contribute to a reduction in morbidity and mortality in survivors of myocardial infarction (MI). Furthermore, the European Society of Cardiology Guidelines advocate for the initiation of cardiac rehabilitation as early as possible, while the patient who survived MI is still in hospital. This two-part comprehensive review commences with a historical overview of cardiac rehabilitation, followed by a detailed exploration of the four phases of the cardiac rehabilitation programme and its impact on cardiovascular health. In Part 2, the study aims to provide a detailed account of the optimal timing for starting cardiac rehabilitation programs and to examine the factors affecting low engagement in such programs, as well as gender-based differences in adherence
Protective role of the longevity-associated BPIFB4 gene on cardiac microvascular cells and cardiac aging
Full text linkIn recent years, the role of the cardiac microvasculature in modulating the symptoms and disease progression of patients affected by cardiac pathology has been reconsidered. The term cardiac microvascular disease (CMD) describes the set of functional and/or structural alterations of the cardiac microvasculature that reduce the ability of the heart to adequately increase its coronary blood flow to keep up with increased metabolic demand. CMD is involved in the evolution of heart disease of both ischemic and non-ischemic origin as well as in cardiac aging. The primary actors involved in this process are the cells of the stromal compartment, whose nature and biology are now investigated to a new level of detail thanks to single-cell omics studies. Recent studies on the genetics of extreme longevity have identified a polymorphic haplotype variant of the BPIFB4 gene that confers prolonged life span and health span, atheroprotective advantages, and an improved immune response. The aim of this review was to focus on the beneficial effects of the longevity-associated variant (LAV) of BPIFB4 on cardiac microvascular cell biology, providing novel and exciting mechanisms of its action directed against the development or progression of many age-related cardiovascular diseases, thus emphasizing its translational therapeutic potential
Unraveling the relationship among insulin resistance, IGF-1, and amyloid-beta 1–40: Is the definition of type 3 diabetes applicable in the cardiovascular field?
Full text linkThe concept of "type 3 diabetes" has emerged to define alterations in glucose metabolism that predispose individuals to the development of Alzheimer's disease (AD). Novel evidence suggests that changes in the insulin/insulin-like growth factor 1 (IGF-1)/growth hormone (GH) axis, which are characteristic of Diabetes Mellitus, are one of the major factors contributing to excessive amyloid-beta (Aβ) production and neurodegenerative processes in AD. Moreover, molecular findings suggest that insulin resistance and dysregulated IGF-1 signaling promote atherosclerosis via endothelial dysfunction and a pro-inflammatory state. As the pathophysiological role of Aβ1-40 in patients with cardiovascular disease has attracted attention due to its involvement in plaque formation and destabilization, it is of great interest to explore whether a paradigm similar to that in AD exists in the cardiovascular field. Therefore, this review aims to elucidate the intricate interplay between insulin resistance, IGF-1, and Aβ1-40 in the cardiovascular system and assess the applicability of the type 3 diabetes concept. Understanding these relationships may offer novel therapeutic targets and diagnostic strategies to mitigate cardiovascular risk in patients with insulin resistance and dysregulated IGF-1 signaling
Intra-hospital variation of gut microbiota product, trimethylamine N-oxide (TMAO) predicts future major adverse cardiovascular events after myocardial infarction
No full textBackground and aims: Trimethylamine N-oxide (TMAO) has been associated with atherosclerosis and poor outcome. We evaluated the prognostic impact of intra-hospital TMAO variation on patient outcome. Methods and results: Blood samples from 149 patients with acute myocardial infarction (AMI) were taken on admission and discharge. Plasma TMAO was determined by HPLC-MS. The endpoint was a composite three-point MACE (major adverse cardiovascular events) including all-cause mortality, re-infarction or the heart failure (HF) development. Median TMAO concentration on admission was significantly higher than on discharge, (respectively, 7.81 [3.47 - 19.98] vs 3.45 [2.3 - 4.78] μM,p<0.001). After estimating the 3.45 μM TMAO cut-off with the analysis of continuous hazard ratio, we divided our cohort into two groups. The first group included 75 (50.3%) patients whose TMAO levels remained below or decreased under cut-off (low-low/high-low; LL/HL), while the second group included 74 (49.7%) patients whose TMAO levels remained high or increased above the cut-off during hospitalisation (high-high/low-high; HH/LH). During the median 30-month follow-up, 21.5% patients experienced the composite endpoint. At Kaplan-Meier analysis, a trend of increasing MACE risk was observed in patients in the HH/LH group (p=0.05). At multivariable Cox analysis, patients from HH/LH group had more than two times higher risk of MACE during the follow-up than LL/HL group (HR=2.15 [95% CI, 1.03 - 4.5], p=0.04). Other independent predictors of MACE were older age and worse left ventricular systolic function. Conclusions: In patients with AMI, permanently high or increasing TMAO levels during hospitalisation are associated with a higher risk of MACE during long-term follow-up
Common Shared Pathogenic Aspects of Small Vessels in Heart and Brain Disease
Full text linkSmall-vessel disease (SVD), also known as microvascular endothelial dysfunction, is a disorder with negative consequences for various organs such as the heart and brain. Impaired dilatation and constriction of small vessels in the heart lead to reduced blood flow and ischemia independently of coronary artery disease (CAD) and are associated with major cardiac events. SVD is usually a silent form of subcortical vascular burden in the brain with various clinical manifestations, such as silent-lacunar-ischemic events and confluent white-matter hyperintensities. Imaging techniques are the main help for clinicians to diagnose cardiac and brain SVD correctly. Markers of inflammation, such as C-reactive protein, tumor-necrosis-factor α, and interleukin 6, provide insight into the disease and markers that negatively influence nitric-oxide bioavailability and promote oxidative stress. Unfortunately, the therapeutic approach against SVD is still not well-defined. In the last decades, various antioxidants, oxidative stress inhibitors, and superoxide scavengers have been the target of extensive investigations due to their potential therapeutic effect, but with unsatisfactory results. In clinical practice, traditional anti-ischemic and risk-reduction therapies for CAD are currently in use for SVD treatment
Growth factors and pathogenesis
No full textGrowth factors are relatively small and stable, secreted or membrane-bound polypeptide ligands, which play an important role in proliferation, differentiation, angiogenesis, survival, inflammation, and tissue repair, or fibrosis. They exert multiple effects through the activation of signal transduction pathways by binding to their receptors on the surface of target cells. A number of studies have demonstrated the central role of growth factors and their signaling pathways in the pathogenesis of uterine leiomyomas. Numerous differentially expressed growth factors have been identified in leiomyoma and myometrial cells. These growth factors can activate multiple signaling pathways (Smad 2/3, ERK 1/2, PI3K, and β-catenin) and regulate major cellular processes, including inflammation, proliferation, angiogenesis, and fibrosis which are linked to uterine leiomyoma development and growth. In this chapter, we discuss the role of growth factors and their signaling pathways in the pathogenesis of uterine leiomyomas
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