Non-healing wound- and tissue-injury are commonly experienced worldwide by the aging population. The persistence of disease commonly leads to tissue infection, resulting in severe clinical ...complications. In the last decade, extracellular vesicles (EVs) have been considered promising and emergent therapeutic tools to improve the healing processes. Therefore, efforts have been directed to develop a cell-free therapeutic platform based on EV administration to orchestrate tissue repair. EVs derived from different cell types, including fibroblast, epithelial, and immune cells are recruited to the injured sites and in turn take part in scar formation. EVs are nano-sized particles containing a heterogeneous cargo consisting of lipids, proteins, and nucleic acids protected from degradation by their lipid bilayer. Noteworthy, since EVs have natural biocompatibility and low immunogenicity, they represent the ideal therapeutic candidates for regenerative purposes. Indeed, EVs are released by several cell types, and even if they possess unique biological properties, their functional capability can be further improved by engineering their content and functionalizing their surface, allowing a specific cell cargo delivery. Herein, we provide an overview of preclinical data supporting the contribution of EVs in the repair and regenerative processes, focusing on different naïve EV sources, as well as on their engineering, to offer a scalable and low-cost therapeutic option for tissue repair.
Obesity and Cardioprotection Femminò, Saveria; Pagliaro, Pasquale; Penna, Claudia
Current medicinal chemistry,
01/2020, Letnik:
27, Številka:
2
Journal Article
Recenzirano
The incidence of obesity and diabetes is increasing rapidly worldwide. Obesity and metabolic syndrome are strictly linked and represent the basis of different cardiovascular risk factors, including ...hypertension and inflammatory processes predisposing to ischemic heart disease, which represent the most common causes of heart failure. Recent advances in the understanding of ischemia/reperfusion mechanisms of injury and mechanisms of cardioprotection are briefly considered. Resistance to cardioprotection may be correlated with the severity of obesity. The observation that heart failure obese patients have a better clinical condition than lean heart failure patients is known as "obesity paradox". It seems that obese patients with heart failure are younger, making age the most important confounder in some studies. Critical issues are represented by the "obesity paradox" and heart failure exacerbation by inflammation. For heart failure exacerbation by inflammation, an important role is played by NLRP3 inflammasome, which is emerging as a possible target for heart failure condition. These critical issues in the field of obesity and cardiovascular diseases need more studies to ascertain which metabolic alterations are crucial for alleged beneficial and deleterious effects of obesity.
In the last few decades extracellular vesicles (EVs), which include exosomes and microvesicles, have attracted significant interest in cardiovascular pathophysiology due to their intrinsic ...properties. Indeed, EVs by transferring their cargo, which contains miRNA, DNA, proteins and lipids, were found effective in preventive and regenerative medicine and in protecting the heart against an array of pathological conditions, including myocardial infarction and arrhythmias. EVs can attenuate cellular senescence, inflammation and myocardial injury. Cardiovascular structures may be targeted by circulating EVs derived by extra-cardiac cells and platelets, as well by EVs locally released from all major cardiovascular cell types, including endothelial cells, cardiomyocytes, macrophages and fibroblasts. Yet, EVs of cardiovascular origin can be also transferred to distant tissues by circulation. Therefore, EVs have been proposed not only as promising diagnostic tools (early disease biomarkers), but also as therapeutics. This review focuses on the protective effects exerted by EVs, released by different cell types in the cardiovascular system. Physical exercise is considered as a natural mechanism of EV production involved in preventive medicine. Particular attention will be devoted to describe the impact of EVs in cardioprotection after ischemia/reperfusion injury.
Display omitted
Antibody-based anti-cancer therapy is considered a successful approach to impair tumour progression. This study aimed to investigate the clinical impact of targeting the IL-3 signalling in the ...microenvironment of solid tumours. We intended to investigate whether the IL-3Rα blockade on tumour-derived endothelial cells (TEC) can modulate PD-L1 expression in tumour cells and peripheral blood mononuclear cells (PBMC) to reshape the anti-tumour immune response. Extracellular vesicles released by TEC after IL-3Rα blockade (aTEV) were used as the ultimate effectors of the antibody-based approach, while naive TEC-derived extracellular vesicles (nTEV) served as control. Firstly, we demonstrated that, either directly or indirectly via nTEV, IL-3 controls the expression of its receptor on TEC and PBMC respectively. Moreover, we found that nTEV, moulded by the autocrine secretion of IL-3, increased PD-L1 expression in myeloid cells both in vitro and in vivo. In addition, we found that nTEV-primed PBMC favour tumour cell growth (TEC and MDA-MB-231 cells), whereas PBMC-primed with aTEV still retain their anti-tumour properties. Isolated T-cells pre-conditioned with nTEV or aTEV and co-cultured with TEC or MDA-MB-231 cells have no effects, thereby sustaining the key role of myeloid cells in tumour immune editing. In vivo nTEV, but not aTEV, increased the expression of PD-L1 in primary tumours, lung and liver metastases. Finally, we demonstrated that the enrichment of miR-214 in aTEV impacts on PD-L1 expression in vivo. Overall, these data indicate that an approach based on IL-3Rα blockade in TEC rearranges EV cargo and may reshape the anti-tumour immune response.
TL was involved in conceptualization, methodology, data curation and writing the original draft; MK provided formal analysis of in vitro and in vivo experiments; CG performed in vitro and in vivo experiments and provided formal analysis of the in vitro and in vivo studies; MC performed the animal studies; SF isolated and characterized extracellular vesicles; GL performed the animal study; EF performed in vitro studies; MFB was involved in conceptualization, supervision, writing, review and editing the Ms, as well as in providing resources. Display omitted
•Extracellular vesicles derived from tumour endothelial cells favour immune suppression.•IL-3 induces the expression of PD-L1 through tumour endothelial cell-derived extracellular vesicles.•Blocking IL-3 signalling in the TME reshapes tumour endothelial cell-EV cargo and rebuilds the anti-tumour immune response.
Mitochondria play a pivotal role in cardioprotection. Here we report some fundamental studies which considered the role of mitochondrial components (connexin 43, mitochondrial KATP channels and ...mitochondrial permeability transition pore) in postconditioning cardioprotection. We briefly discuss the role of mitochondria, reactive oxygen species and gaseous molecules in postconditioning. Also the effects of anesthetics-used as cardioprotective substances-is briefly considered in the context of postconditioning. The role of mitochondrial postconditioning signaling in determining the limitation of cell death is underpinned. Issues in clinical translation are briefly considered. The aim of the present mini-review is to discuss in a historical perspective the role of main mitochondria mechanisms in cardiac postconditioning.
During myocardial ischemia, timely reperfusion is critical to limit infarct area and the overall loss of cardiac contractile function. However, reperfusion further exacerbates the damage of the ...ischemic heart. This type of injury is known as ischemia-reperfusion injury (IRI). Ischemic conditioning is a procedure which consists of brief cycles of ischemia and reperfusion in order to protect the myocardium against IRI. Remote ischemic conditioning (RIC), namely transient brief episodes of ischemia at a remote site before a subsequent damaging ischemia/reperfusion procedure of the target organ (e.g., the heart), protects against IRI. However, how the stimulus of RIC is transduced from the remote organ to the ischemic heart is still unknown. Recently, extracellular vesicles (EVs) have been proposed to have a role in the RIC procedure. The endothelium releases EVs and is also one of the tissues mostly exposed to EVs during their journey to the target organ. Moreover, EVs may have important roles in angiogenesis and, therefore, in the remodeling of post-ischemic organs. Here we analyze how EVs may contribute to the overall cardioprotective effect and the implication of the endothelium and its EVs in RIC mediated acute cardioprotection as well as in angiogenesis.
Display omitted
Catestatin is a cationic and hydrophobic peptide derived from the enzymatic cleavage of the prohormone Chromogranin A. Initially identified as a potent endogenous nicotinic–cholinergic antagonist, ...Catestatin has recently been shown to act as a novel regulator of cardiac function and blood pressure and as a cardioprotective agent in both pre- and postconditioning through AKT-dependent mechanisms. The aim of this study is to investigate the potential role of Catestatin also on cardiac metabolism modulation, particularly on cardiomyocytes glucose uptake. Experiments were performed on isolated adult rat cardiomyocytes. Glucose uptake was assessed by fluorescent glucose incubation and confocal microscope analysis. Glut4 plasma membrane translocation was studied by immunofluorescence experiments and evaluation of the ratio peripheral vs internal Glut4 staining. Furthermore, we performed immunoblot experiments to investigate the involvement of the intracellular pathway AKT/AS160 in the Catestatin dependent Glut4 trafficking. Our results show that 10 nM Catestatin induces a significant increase in the fluorescent glucose uptake, comparable to that exerted by 100 nM Insulin. Moreover, Catestatin stimulates Glut4 translocation to plasma membrane and both AKT and AS160 phosphorylation. All these effects were inhibited by Wortmannin. On the whole, we show for the first time that Catestatin is able to modulate cardiac glucose metabolism, by inducing an increase in glucose uptake through Glut4 translocation to the plasma membrane and that this mechanism is mediated by the AKT/AS160 intracellular pathway.
Catestatin (Cst) is a 21-amino acid peptide deriving from Chromogranin A. Cst exerts an overall protective effect against an excessive sympathetic stimulation of cardiovascular system, being able to ...antagonize catecholamine secretion and to reduce their positive inotropic effect, by stimulating the release of nitric oxide (NO) from endothelial cells. Moreover, Cst reduces ischemia/reperfusion (I/R) injury, improving post-ischemic cardiac function and cardiomyocyte survival. To define the cardioprotective signaling pathways activated by Cst (5 nM) we used isolated adult rat cardiomyocytes undergoing simulated I/R. We evaluated cell viability rate with propidium iodide labeling and mitochondrial membrane potential (MMP) with the fluorescent probe JC-1. The involvement of Akt, GSK3beta, eNOS and phospholamban (PLN) cascade was studied by immunofluorescence. The role of PI3K-Akt/NO/cGMP pathway was also investigated by using the pharmacological blockers wortmannin (Wm), L-NMMA and ODQ. Our experiments revealed that Cst increased cell viability rate by 65% and reduced cell contracture in I/R cardiomyocytes. Wm, L-NMMA and ODQ limited the protective effect of Cst. The protective outcome of Cst was related to its ability to maintain MMP and to increase Akt.sup.Ser473, GSK3beta.sup.Ser9, PLN.sup.Thr17 and eNOS.sup.Ser1179 phosphorylation, while treatment with Wm abolished these effects. Thus, the present results show that Cst is able to exert a direct action on cardiomyocytes and give new insights into the molecular mechanisms involved in its protective effect, highlighting the PI3K/NO/cGMP pathway as the trigger and the MMP preservation as the end point of its action.
PDF
