Current Medicinal Chemistry - Volume 25, Issue 35, 2018

From the discovery of Endothelial Progenitor Cells (EPC), these bone marrowderived precursors have been placed as crucial mediators of the endothelial repair. Accordingly, altered levels and function of EPC have been found in different scenarios of CV risk. Despite the fact that EPC exhibit important characteristics which support a link of this cell subset with a number of inflammatory and immune networks, little is known on the actual mediators involved and the clinical relevance of these features. Systemic diseases are generally hallmarked by a vascular repair failure and increased cardiovascular disease occurrence, EPC impairment having a pivotal role. Because of their immunemediated etiology, this group of conditions represents an invaluable scenario to unravel the connections between immune dysregulation and EPC dysfunction. In the present review, we summarize the current knowledge regarding the cutting-edge area of the modulation of EPC levels and function by inflammatory cytokines in systemic diseases. We also address the possibility of the available immunomodulatory drugs to counteract this situation. Finally, due to the emerging role of the vitamin D as a common mediator in the immune system and the cardiovascular axis, we cover the topic of the role of vitamin D as a potential player in the inflammatory-mediated EPC dysfunction in systemic diseases.

Background: Cardiovascular (CV) risk stratification is suboptimal if solely based on traditional CV risk factors, since individuals with similar risk profiles could exhibit diverging CV outcomes. Thus, there is a need for new risk factors to be identified. Recent studies emphasize the relevance of the endothelial homeostasis in the control of CV risk, but the clinical relevance of these findings is starting to be appreciated. Gaining insight into the actual players involved in this phenomenon would lead to the identification of novel biomarkers. Due to their central role in vascular repair, Endothelial Progenitor Cells (EPC) are promising candidates for this issue. Objective: Since excessive inflammation or imbalanced immune responses are known to underlie numerical or functional alterations of EPC, it can be speculated that these mediators may be considered as biomarkers for risk stratification. In the present narrative review, we aimed to compile and critically appraise all the current evidence linking inflammation and immune pathways with a compromised EPC functionality. Results: A mounting body of evidence points to an inflammation-driven traditional CV risk factorsrelated EPC dysfunction. The effect of aging on EPC was associated with the CXCR4 pathway, whereas that of hypertension was related to TNFα. Activation of Akt/eNOS was observed in response to diabetes- and dyslipidemia-related traits. Inflammation and oxidative stress underlie the EPC dysfunction during smoking. Conclusion: Inflammatory and immune networks can be proposed as feasible biomarkers for risk stratification in personalized medicine schemes.

Background: Circulating progenitor cells (CPCs) and endothelial progenitor cells (EPCs) are immature cells involved in vascular repair and related to many aspects of macro and microvascular disease. Objective: We aimed to review studies reporting the prognostic role of CPCs/EPCs measurement on development of cardiovascular disease and microangiopathy. Methods and Results: We reviewed the English language literature for prospective observational studies reporting the future development of cardiovascular disease or microangiopathy in patients having a baseline determination of CPCs/EPCs. We retrieved 34 studied reporting on cardiovascular outcomes and 2 studies reporting on microvascular outcomes. Overall, a reduced baseline level of CPCs/EPCs was associated with a significant increased risk of cardiovascular events, all-cause death, and onset/progression of microangiopathy. The most predictive phenotypes were CD34+ and CD34+CD133+. The main limitation was related to the high heterogeneity among studies in terms of patient characteristics and cell phenotypes. Conclusion: The present review shows that a reduced level of circulating progenitor cells is a risk factor for the development of future cardiovascular events and death. In addition, low CPCs/EPCs levels predict the onset or worsening of microalbuminuria and retinopathy in diabetic patients.

Background: Autologous cell therapy represents a novel treatment option for vascular regeneration in different disease conditions, with experimental and clinical studies indicating a therapeutic potential for proangiogenic cells (PCs), including endothelial progenitor cells, in the treatment of coronary and peripheral artery disease. Objective: To provide a summary of the therapeutic potential of PCs administration or mobilization in peripheral artery disease, ischemic heart and cerebrovascular diseases, diabetic microvascular complications and inflammatory rheumatic diseases. Methods: We undertook a search of bibliographic databases for peer-reviewed research literature on the role of PCs in vascular regeneration in preclinical and clinical models. Results: Improvement of ischemic symptoms has been reported in different trials evaluating PCs for the treatment of critical limb ischemia. However, in this setting, contrasting results from meta-analyses question the long-term clinical efficacy of PC-based approaches. Preclinical studies and clinical trials support the safety and feasibility of PC therapy in the treatment of ischemic heart and cerebrovascular diseases, while evidence indicating a benefit on hard clinical outcomes is uncertain. Despite accumulating experimental results support a therapeutic role for PCs in diabetic retinopathy, results from randomized clinical trials are lacking. Whether PC therapy may limit premature atherosclerosis and reduce cardiovascular risk in inflammatory rheumatic diseases needs to be investigated. Conclusion: Although the potential clinical applications of PCs are accumulating, there is also evidence of multiple limitations for autologous PC therapy. Thus, novel strategies aimed at improving PC viability and angiogenic function are warranted in order to improve the efficacy of cell therapy applications.

Background: Circulating endothelial cells (CECs), originated form endothelial progenitors (EPCs) are mature cells not associated with vessel walls and detached from the endothelium. Normally, they are present in insignificant amounts in the peripheral blood of healthy individuals. On the other hand, elevated CECs and EPCs levels have been reported in the peripheral blood of patients with different types of cancers and other diseases. Objective: This review aims to provide an overview on the characterization of CECs and EPCs, to describe isolation methods and to identify the potential role of these cells in hematological diseases and hematopoietic stem cell transplantation. Methods: We performed a detailed search of peer-reviewed literature using keywords related to CECs, EPCs, allogeneic hematopoietic stem cell transplantation, and hematological diseases (hemoglobinopathies, hodgkin and non-hodgkin lymphoma, acute leukemia, myeloproliferative syndromes, chronic lymphocytic leukemia). Results: CECs and EPCs are potential biomarkers for several clinical conditions involving endothelial turnover and remodeling, such as in hematological diseases. These cells may be involved in disease progression and in the neoplastic process. Moreover, CECs and EPCs are probably involved in endothelial damage which is a marker of several complications following allogeneic hematopoietic stem cell transplantation. Conclusion: This review provides information about the role of CECs and EPCs in hematological malignancies and shows their implication in predicting disease activity as well as improving HSCT outcomes.

Background: The ‘epidemic’ diffusion of chronic kidney disease (CKD) needs the development of new therapeutic approaches to slow down the progression to end-stage renal disease. Endothelial Progenitor Cells (EPCs) are promising tools for the treatment of many human diseases as they promote the repair of damaged tissues. They were also suggested as therapy to repair renal tissue after an injury. Strategies using EPCs to induce a reparative process with functional restoring of a diseased kidney or to delay CKD are of two types: direct stem cells infusion or stimulating endogenous release of EPCs. The repair process following endothelial damage occurs in three steps: 1) mobilization from bone marrow; 2) homing on the sites of vascular injury; 3) incorporation of the endothelium into the injured blood vessels. Objective: In this narrative review we pointed our view to the role of EPCs in endothelial repair and the potential in retarding the progression to renal function loss. Conclusions: Physicians need the development of new preventive strategies for detecting patients at risk and discover renal damage. In this way they could slow, by a conservative therapy, the evolution of renal disease and decrease associated morbidity. EPCs have instead well recognized reparative capabilities in many organs. We summarized some recent preclinical and clinical models of EPCs mobilization during CKD and we emphasized the potential use of EPCs to slow the progression of renal disease.

Within the last two decades, the field of nanomedicine has not developed as successfully as has widely been hoped for. The main reason for this is the immense complexity of the biological systems, including the physico-chemical properties of the biological fluids as well as the biochemistry and the physiology of living systems. The nanoparticles' physicochemical properties are also highly important. These differ profoundly from those of freshly synthesized particles when applied in biological/living systems as recent research in this field reveals. The physico-chemical properties of nanoparticles are predefined by their structural and functional design (core and coating material) and are highly affected by their interaction with the environment (temperature, pH, salt, proteins, cells). Since the coating material is the first part of the particle to come in contact with the environment, it does not only provide biocompatibility, but also defines the behavior (e.g. colloidal stability) and the fate (degradation, excretion, accumulation) of nanoparticles in the living systems. Hence, the coating matters, particularly for a nanoparticle system for biomedical applications, which has to fulfill its task in the complex environment of biological fluids, cells and organisms. In this review, we evaluate the performance of different coating materials for nanoparticles concerning their ability to provide colloidal stability in biological media and living systems.

Background: Nanosafety aims for a solution through the safer design (and re-design) of nanostructured materials, optimizing both performance and safety, by resolving which structural features lead to the desired properties and modifying them to avoid their detrimental effects without losing their desired nanoscale properties in the process. Starting with known toxic NPs, the final aim should be the re-design of such detrimental specific NP characteristics and to redefine the way they should be manipulated from the beginning to the end of their life cycle. Methods: The researchers reviewed literature in the area of novel nanosafety strategies addressing the “safe-by-design” paradigm. Results: The potential hazards of engineered NPs are not only determined by the physicochemical properties of the engineered NPs per se but also on the interactions of these NPs with immediate surrounding environments. The aim of promoting the timely and safe development of NPs cannot be achieved via traditional studies as they address one material at one time. The development of a safer design strategy of engineered NPs requires an understanding of both intrinsic (synthetic) properties together with their extrinsic responses to external stimuli. Conclusions: We have summarized recent developments of novel nanosafety strategies addressing the “safe-by-design” paradigm for optimizing both performance and safety, allowing the comparison of results of different studies and ultimately providing guidelines for the re-design of safer NPs. The resulting discussion is intended to provide guidelines for synthetic nanochemists on how to design NPs to be safe during their full life cycle while maintaining their parental desired properties.

Background: Alzheimer's disease (AD) is a public health priority all over the world. The difficulty of fighting the disease consists mostly in the complexity of symptoms and causes, in the still poor knowledge of its mechanisms and in the existence of a latent, asymptomatic, preclinical stage. Although many drugs are continuously screened in clinical studies for the treatment of Alzheimer's disease, the unexpected lack of patient response and sometimes the important adverse effects make it a potential field of application for personalized medicine. Objective: This perspective review proposes nanotechnology as a valuable tool for the application of personalized medicine to AD. Methods: The aim of personalized medicine is the development of more patient-precise treatments based mostly on the knowledge of individual genetics as well as of disease progress, and of pharmacokinetics and metabolic response to available drugs. The optimization of new and more sensitive detection techniques is an important tool for obtaining the pool of data needed for prediction and understanding of patient response. Results: Research in bionanosensors is already providing examples with high sensitivity for core and new biomarkers for AD. In therapy the functionalization of nanoparticle surface can add specificity for biological recognition or for improving the bioavailability. This would allow the administration of lower doses with less adverse effects due to the local targeting. Conclusion: Taking into account the promising characteristics of nanoparticles as excellent candidate tools for precision medicine development, the establishment of better standard methods for safety assessment and production scale up would be desirable for the nanomaterial fruitful employment.

In the present review, we describe three hot topics in cancer research such as circulating tumor cells, exosomes, and 3D environment models. The first section is dedicated to microfluidic platforms for detecting circulating tumor cells, including both affinity-based methods that take advantage of antibodies and aptamers, and “label-free” approaches, exploiting cancer cells physical features and, more recently, abnormal cancer metabolism. In the second section, we briefly describe the biology of exosomes and their role in cancer, as well as conventional techniques for their isolation and innovative microfluidic platforms. In the third section, the importance of tumor microenvironment is highlighted, along with techniques for modeling it in vitro. Finally, we discuss limitations of two-dimensional monolayer methods and describe advantages and disadvantages of different three-dimensional tumor systems for cell-cell interaction analysis and their potential applications in cancer management.

This review overviews the impact in biomedicine of surface enhanced. Raman scattering motivated by the great potential we believe this technique has. We present the advantages and limitations of this technique relevant to bioanalysis in vitro and in vivo and how this technique goes beyond the state of the art of traditional analytical, labelling and healthcare diagnostic technologies.