Age-related differences in the expression of circulating microRNAs: miR-21 as a new circulating marker of inflammaging.

none15noopenF Olivieri; L Spazzafumo; G Santini; R Lazzarini; MC Albertini; MR Rippo; R Galeazzi; AM Abbatecola; F Marcheselli; D Monti; R Ostan; E Cevenini; R Antonicelli; C Franceschi; AD Procopio.F., Olivieri; L., Spazzafumo; G., Santini; R., Lazzarini; Albertini, MARIA CRISTINA; Mr, Rippo; R., Galeazzi; Am, Abbatecola; F., Marcheselli; D., Monti; R., Ostan; E., Cevenini; R., Antonicelli; C., Franceschi; Ad, Procopi

Treatment Outcome of metastatic lesions from renal cell carcinoma underGoing Extra-cranial stereotactic body radioTHERapy: The together retrospective study

Abstract Objectives stereotactic body radiation therapy (SBRT) use has increased overtime for the management of metastatic renal cell carcinoma (mRCC) patients, with a likely good control of irradiated lesions. We planned a retrospective multicenter Italian study, with the aim of investigating the outcome of treatment with SBRT for non-brain secondary lesions in mRCC patients. Methods all consecutive metastatic non-brain lesions from mRCC that underwent SBRT at nine Italian institutions from January 2015 to June 2017 were considered. The primary endpoint of the study was the lesion-PFS, calculated from SBRT initiation to the local progression of the irradiated lesion. Results 57 extracranial metastatic lesions from 48 patients with primary mRCC were treated with SBRT. At the median follow-up of 26.4 months, the median lesion-PFS was not reached (43 censored); 72.4% of lesions were progression-free at 40 months, with significantly better lesion-PFS for small metastatic lesions ( Conclusions consistently with the previous literature, our findings support the use of SBRT in selected mRCC patients

8-Amide and 8-carbamate substitution patterns as modulators of 7-hydroxy-4-methylcoumarin's antidepressant profile: Synthesis, biological evaluation and docking studies

Psychiatric and neurological disorders affect millions of people worldwide. Currently available treatments may help to improve symptoms, but they cannot cure the diseases. Therefore, there is an urgent need for potent and safe therapeutic solutions. 8-Amide and 8-carbamatecoumarins were synthetized and evaluated as human monoamine oxidase A and B (hMAO-A and hMAO-B) inhibitors. Comparison between both scaffolds has been established, and we hypothesized that the introduction of different substituents can modulate hMAO activity and selectivity. N-(7-Hydroxy-4-methylcoumarin-8-yl)-4-methylbenzamide (9) and ethyl N-(7-hydroxy-4-methylcoumarin-8-yl)carbamate (20) proved to be the most active and selective hMAO-A inhibitors (IC50 = 15.0 nM and IC50 = 22.0 nM, respectively), being compound 9 an irreversible hMAO-A inhibitor twenty-four times more active in vitro than moclobemide, a drug used in the treatment of depression and anxiety. Based on PAMPA assay results, both compounds proved to be good candidates to cross the blood-brain barrier. In addition, these compounds showed non-significant cytotoxicity on neuronal viability assays. Also, the best compound proved to have a t1/2 of 6.84 min, an intrinsic clearance of 195.63 μL min−1 mg−1 protein, and to be chemically stable at pH 3.0, 7.4 and 10.0. Docking studies were performed to better understand the binding affinities and selectivity profiles for both hMAO isoforms. Finally, theoretical drug-like properties calculations corroborate the potential of both scaffolds on the search for new therapeutic solutions for psychiatric disorders as depressionThis research was funded by Consellería de Cultura, Educación e Ordenación Universitaria (EM2014/016), Ministerio de Ciencia e Innovación (PID2020-116076RJ-I00/AEI/10.13039/501100011033) and Fundação para a Ciência e Tecnologia (PTDC/ASP-PES/28397/2017, CEECIND/02423/2018, UIDB/00081/2020, LA/P/0056/2020 and EXPL/BIA-BQM/0492/2021). Financial support from the Xunta de Galicia (Centro de investigación de Galicia accreditation 2019–2022) and the European Union (European Regional Development Fund - ERDF), is also gratefully acknowledged. M.I.R.-F. acknowledges the economic support from the Spanish Ministry of Science, Innovation and Universities; Spanish Research Agency; and European Regional Development Funds (grant PID2021-122650OB-I00) and from CSIC (PIE-202080E118)S

Role of Adenosine and Purinergic Receptors in Myocardial Infarction: Focus on Different Signal Transduction Pathways

Myocardial infarction (MI) is a dramatic event often caused by atherosclerotic plaque erosion or rupture and subsequent thrombotic occlusion of a coronary vessel. The low supply of oxygen and nutrients in the infarcted area may result in cardiomyocytes necrosis, replacement of intact myocardium with non-contractile fibrous tissue and left ventricular (LV) function impairment if blood flow is not quickly restored. In this review, we summarized the possible correlation between adenosine system, purinergic system and Wnt/β-catenin pathway and their role in the pathogenesis of cardiac damage following MI. In this context, several pathways are involved and, in particular, the adenosine receptors system shows different interactions between its members and purinergic receptors: their modulation might be effective not only for a normal functional recovery but also for the treatment of heart diseases, thus avoiding fibrosis, reducing infarcted area and limiting scaring. Similarly, it has been shown that Wnt/β catenin pathway is activated following myocardial injury and its unbalanced activation might promote cardiac fibrosis and, consequently, LV systolic function impairment. In this regard, the therapeutic benefits of Wnt inhibitors use were highlighted, thus demonstrating that Wnt/β-catenin pathway might be considered as a therapeutic target to prevent adverse LV remodeling and heart failure following MI

Right ventricular dysfunction in left ventricular assist device candidates: is it time to change our prospective?

The use of left ventricular assist devices (LVAD) has significantly increased in the last years, trying to offer a therapeutic alternative to heart transplantation, in light also to the significant heart donor shortage compared to the growing advanced heart failure population. Despite technological improvements in the devices, LVAD-related mortality is still fairly high, with right heart failure being one of the predominant predictors. Therefore, many efforts have been made toward a thorough right ventricular (RV) evaluation prior to LVAD implant, considering clinical, laboratory, echocardiographic, and invasive hemodynamic parameters. However, there is high heterogeneity regarding both which predictor is the strongest as well as the relative cut-off values, and a consensus has not been reached yet, increasing the risk of facing patients in which the distinction between good or poor RV function cannot be surely reached. In parallel, due to technological development and availability of mechanical circulatory support of the RV, LVADs are being considered even in patients with suboptimal RV function. The aim of our review is to analyze the current evidence regarding the role of RV function prior to LVAD and its evaluation, pointing out the extreme variability in parameters that are currently assessed and future prospective regarding new diagnostic tools. Finally, we attempt to gather the available information on the therapeutic strategies to use in the peri-operative phase, in order to reduce the incidence of RV failure, especially in patients in which the preoperative evaluation highlighted some conflicting results with regard to ventricular function

Kidney Protein Dynamics and Ammoniagenesis in Humans with Chronic Metabolic Acidosis

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DNA damage response (DDR) and senescence: shuttled inflamma-miRNAs on the stage of inflamm-aging

A major issue in aging research is how cellular phenomena affect aging at the systemic level. Emerging evidence suggests that DNA damage response (DDR) signaling is a key mechanism linking DNA damage accumulation, cell senescence, and organism aging. DDR activation in senescent cells promotes acquisition of a proinflammatory secretory phenotype (SASP), which in turn elicits DDR and SASP activation in neighboring cells, thereby creating a proinflammatory environment extending at the local and eventually the systemic level. DDR activation is triggered by genomic lesions as well as emerging bacterial and viral metagenomes. Therefore, the buildup of cells with an activated DDR probably fuels inflamm-aging and predisposes to the development of the major age-related diseases (ARDs). Micro (mi)-RNAs - non-coding RNAs involved in gene expression modulation - are released locally and systemically by a variety of shuttles (exosomes, lipoproteins, proteins) that likely affect the efficiency of their biological effects. Here we suggest that some miRNAs, previously found to be associated with inflammation and senescence - miR-146, miR-155, and miR-21 - play a central role in the interplay among DDR, cell senescence and inflamm-aging. The identification of the functions of shuttled senescence-associated miRNAs is expected to shed light on the aging process and on how to delay ARD development

From Oxidative Stress Damage to Pathways, Networks, and Autophagy via MicroRNAs

Oxidative stress can alter the expression level of many microRNAs (miRNAs), but how these changes are integrated and related to oxidative stress responses is poorly understood. In this article, we addressed this question by using in silico tools. We reviewed the literature for miRNAs whose expression is altered upon oxidative stress damage and used them in combination with various databases and software to predict common gene targets of oxidative stress-modulated miRNAs and affected pathways. Furthermore, we identified miRNAs that simultaneously target the predicted oxidative stress-modulated miRNA gene targets. This generated a list of novel candidate miRNAs potentially involved in oxidative stress responses. By literature search and grouping of pathways and cellular responses, we could classify these candidate miRNAs and their targets into a larger scheme related to oxidative stress responses. To further exemplify the potential of our approach in free radical research, we used our explorative tools in combination with ingenuity pathway analysis to successfully identify new candidate miRNAs involved in the ubiquitination process, a master regulator of cellular responses to oxidative stress and proteostasis. Lastly, we demonstrate that our approach may also be useful to identify novel candidate connections between oxidative stress-related miRNAs and autophagy. In summary, our results indicate novel and important aspects with regard to the integrated biological roles of oxidative stress-modulated miRNAs and demonstrate how this type of in silico approach can be useful as a starting point to generate hypotheses and guide further research on the interrelation between miRNA-based gene regulation, oxidative stress signaling pathways, and autophagy

From oxidative stress damage to pathways, networks and autophagy via microRNAs

Oxidative stress can alter the expression level of many microRNAs (miRNAs), but how these changes are integrated and related to oxidative stress responses is poorly understood. In this article, we addressed this question by using in silico tools. We reviewed the literature for miRNAs whose expression is altered upon oxidative stress damage, and used them in combination with various databases and software to predict common gene targets of oxidative stress-modulated miRNAs, and affected pathways. Furthermore, we identified miRNAs that simultaneously target the predicted oxidative stress-modulated miRNAs gene targets. This generated a list of novel candidate miRNAs potentially involved in oxidative stress responses. By literature search and grouping of pathways and cellular responses, we could classify these candidate miRNAs and their targets into a larger scheme related to oxidative stress responses. To further exemplify the potential of our approach in free radical research, we used our explorative tools in combination with ingenuity pathway analysis to successfully identify new candidate miRNAs involved in the ubiquitination process, a master regulator of cellular responses to oxidative stress and proteostasis. Lastly, we demonstrate that our approach may also be useful to identify novel candidate connections between oxidative stress-related miRNAs and autophagy. In summary, our results indicate novel and important aspects with regard to the integrated biological roles of oxidative stress-modulated miRNAs, and demonstrate how this type of in silico approach can be useful as a starting point to generate hypotheses and guide further research on the interrelation between miRNA-based gene regulation, oxidative stress signaling pathways, and autophagy