Cellular senescence and cardiovascular diseases: moving to the "heart" of the problem.

Cardiovascular diseases (CVDs) constitute the prime cause of global mortality, with an immense impact on patient quality of life and disability. Clinical evidence has revealed a strong connection between cellular senescence and worse cardiac outcomes in the majority of CVDs concerning both ischemic and nonischemic cardiomyopathies. Cellular senescence is characterized by cell cycle arrest accompanied by alterations in several metabolic pathways, resulting in morphological and functional changes. Metabolic rewiring of senescent cells results in marked paracrine activity, through a unique secretome, often exerting deleterious effects on neighboring cells. Here, we recapitulate the hallmarks and key molecular pathways involved in cellular senescence in the cardiac context and summarize the different roles of senescence in the majority of CVDs. In the last few years, the possibility of eliminating senescent cells in various pathological conditions has been increasingly explored, giving rise to the field of senotherapeutics. Therefore, we additionally attempt to clarify the current state of this field with a focus on cardiac senescence and discuss the potential of implementing senolytics as a treatment option in heart disease.

Molecular biomarkers in cardio-oncology: Where we stand and where we are heading.

Until recently, cardiotoxicity in the setting of a malignant disease was attributed solely to the detrimental effects of chemo- and/or radio-therapy to the heart. On this account, the focus was on the evaluation of well-established cardiac biomarkers for the early detection of myocardial damage. Currently, this view has been revised. Cardiotoxicity is not restricted to a single organ but instead affects the endothelium as a whole. Indeed, it has come into light that not only cancer therapy but also malignant cells per se can impair the cardiovascular system, through a paracrine and endocrine mode of action. Even more intriguingly, a clear interplay between molecular pathways involved in cancer and cardiovascular disease has become prevalent, suggesting a common nominator that governs the pathophysiology of these two entities. Taken together, our strategy in the quest of novel biomarkers in the emerging field of cardio-oncology should be critically reshaped.

Nanomedicine: Photo-activated nanostructured titanium dioxide, as a promising anticancer agent.

The multivariate condition of cancer disease has been approached in various ways, by the scientific community. Recent studies focus on individualized treatments, minimizing the undesirable consequences of the conventional methods, but the development of an alternative effective therapeutic scheme remains to be held. Nanomedicine could provide a solution, filling this gap, exploiting the unique properties of innovative nanostructured materials. Nanostructured titanium dioxide (TiO2) has a variety of applications of daily routine and of advanced technology. Due to its biocompatibility, it has also a great number of biomedical applications. It is now clear that photo-excited TiO2 nanoparticles, induce generation of pairs of electrons and holes which react with water and oxygen to yield reactive oxygen species (ROS) that have been proven to damage cancer cells, triggering controlled cellular processes. The aim of this review is to provide insights into the field of nanomedicine and particularly into the wide context of TiO2-NP-mediated anticancer effect, shedding light on the achievements of nanotechnology and proposing this nanostructured material as a promising anticancer photosensitizer.

Implications of Oxidative Stress and Cellular Senescence in Age-Related Thymus Involution.

The human thymus is a primary lymphoepithelial organ which supports the production of self-tolerant T cells with competent and regulatory functions. Paradoxically, despite the crucial role that it exerts in T cell-mediated immunity and prevention of systemic autoimmunity, the thymus is the first organ of the body that exhibits age-associated degeneration/regression, termed "thymic involution." A hallmark of this early phenomenon is a progressive decline of thymic mass as well as a decreased output of naïve T cells, thus resulting in impaired immune response. Importantly, thymic involution has been recently linked with cellular senescence which is a stress response induced by various stimuli. Accumulation of senescent cells in tissues has been implicated in aging and a plethora of age-related diseases. In addition, several lines of evidence indicate that oxidative stress, a well-established trigger of senescence, is also involved in thymic involution, thus highlighting a possible interplay between oxidative stress, senescence, and thymic involution.

The Role of E3, E4 Ubiquitin Ligase (UBE4B) in Human Pathologies.

The genome is exposed daily to many deleterious factors. Ubiquitination is a mechanism that regulates several crucial cellular functions, allowing cells to react upon various stimuli in order to preserve their homeostasis. Ubiquitin ligases act as specific regulators and actively participate among others in the DNA damage response (DDR) network. UBE4B is a newly identified member of E3 ubiquitin ligases that appears to be overexpressed in several human neoplasms. The aim of this review is to provide insights into the role of UBE4B ubiquitin ligase in DDR and its association with p53 expression, shedding light particularly on the molecular mechanisms of carcinogenesis.

Mitochondrial Homeostasis and Cellular Senescence.

Cellular senescence refers to a stress response aiming to preserve cellular and, therefore, organismal homeostasis. Importantly, deregulation of mitochondrial homeostatic mechanisms, manifested as impaired mitochondrial biogenesis, metabolism and dynamics, has emerged as a hallmark of cellular senescence. On the other hand, impaired mitostasis has been suggested to induce cellular senescence. This review aims to provide an overview of homeostatic mechanisms operating within mitochondria and a comprehensive insight into the interplay between cellular senescence and mitochondrial dysfunction.

Correction to: A Novel Quantitative Method for the Detection of Lipofuscin, the Main By-Product of Cellular Senescence, in Fluids.

In Chapter 12, figure 1 was published with truncated texts within. This figure has now been replaced with a revised figure with the updated text.

Senescence and senotherapeutics: a new field in cancer therapy.

Cellular senescence is a stress response mechanism ensuring homeostasis. Its temporal activation during embryonic development or normal adult life is linked with beneficial properties. In contrast, persistent (chronic) senescence seems to exert detrimental effects fostering aging and age-related disorders, such as cancer. Due to the lack of a reliable marker able to detect senescence in vivo, its precise impact in age-related diseases is to a large extent still undetermined. A novel reagent termed GL13 (SenTraGorTM) that we developed, allowing senescence recognition in any type of biological material, emerges as a powerful tool to study the phenomenon of senescence in vivo. Exploiting the advantages of this novel methodological approach, scientists will be able to detect and connect senescence with aggressive behavior in human malignancies, such as tolerance to chemotherapy in classical Hodgkin Lymphoma and Langerhans Cell Histiocytosis. The latter depicts the importance of developing the new and rapidly expanding field of senotherapeutic agents targeting and driving to cell death senescent cells. We discuss in detail the current progress of this exciting area of senotherapeutics and suggest its future perspectives and applications.

A Novel Quantitative Method for the Detection of Lipofuscin, the Main By-Product of Cellular Senescence, in Fluids.

Lipofuscin accumulation is a hallmark of senescence. This nondegradable material aggregates in the cytoplasm of stressed or damaged cells due to metabolic imbalance associated with aging and age-related diseases. Indications of a soluble state of lipofuscin have also been provided, rendering the perspective of monitoring such processes via lipofuscin quantification in liquids intriguing. Therefore, the development of an accurate and reliable method is of paramount importance. Currently available assays are characterized by inherent pitfalls which demote their credibility. We herein describe a simple, highly specific and sensitive protocol for measuring lipofuscin levels in any type of liquid. The current method represents an evolution of a previously described assay, developed for in vitro and in vivo senescent cell recognition that exploits a newly synthesized Sudan Black-B analog (GL13). Analysis of human clinical samples with the modified protocol provided strong evidence of its usefulness for the exposure and surveillance of age-related conditions.

Principal Aspects Regarding the Maintenance of Mammalian Mitochondrial Genome Integrity.

Mitochondria have emerged as key players regarding cellular homeostasis not only due to their contribution regarding energy production through oxidative phosphorylation, but also due to their involvement in signaling, ion regulation, and programmed cell death. Indeed, current knowledge supports the notion that mitochondrial dysfunction is a hallmark in the pathogenesis of various diseases. Mitochondrial biogenesis and function require the coordinated action of two genomes: nuclear and mitochondrial. Unfortunately, both intrinsic and environmental genotoxic insults constantly threaten the integrity of nuclear as well as mitochondrial DNA. Despite the extensive research that has been made regarding nuclear genome instability, the importance of mitochondrial genome integrity has only recently begun to be elucidated. The specific architecture and repair mechanisms of mitochondrial DNA, as well as the dynamic behavior that mitochondria exert regarding fusion, fission, and autophagy participate in mitochondrial genome stability, and therefore, cell homeostasis.

Erythropoietin administration facilitates return of spontaneous circulation and improves survival in a pig model of cardiac arrest.

BACKGROUND: In addition to its role in the endogenous control of erythropoiesis, recombinant human erythropoietin (rh-EPO) has been shown to exert tissue protective properties in various experimental models. However, its role in the cardiac arrest (CA) setting has not yet been adequately investigated. AIM: The aim of this study is to examine the effect of rh-EPO in a pig model of ventricular fibrillation (VF)-induced CA. METHODS: Ventricular fibrillation was electrically induced in 20 piglets and maintained untreated for 8 minutes before attempting resuscitation. Animals were randomized to receive rh-EPO (5000 IU/kg, erythropoietin [EPO] group, n = 10) immediately before the initiation of chest compressions or to receive 0.9% Sodium chloride solution instead (control group, n = 10). RESULTS: Compared with the control, the EPO group had higher rates of return of spontaneous circulation (ROSC) (100% vs 60%, P = .011) and higher 48-hour survival (100% vs 40%, P = .001). Diastolic aortic pressure and coronary perfusion pressure during cardiopulmonary resuscitation were significantly higher in the EPO group compared with the control group. Erythropoietin-treated animals required fewer number of shocks in comparison with animals that received normal saline (P = .04). Furthermore, the neurologic alertness score was higher in the EPO group compared with that of the control group at 24 (P = .004) and 48 hours (P = .021). CONCLUSION: Administration of rh-EPO in a pig model of VF-induced CA just before reperfusion facilitates ROSC and improves survival rates as well as hemodynamic variables.

Interleukin-6 as a marker of inflammation secondary to endotracheal intubation in pediatric patients.

Ιnterleukin-6 (IL-6) has been identified as an early biochemical marker of inflammation both in animal and human studies. With this study, we sought to examine the development of local inflammation of the glottic tissues in correlation with the duration of intubation in anesthetized pediatric patients. We measured IL-6 levels in the organic material isolated from the tip of the tube post-extubation in 48 children aged 7 months to 14 years old who were submitted to a total of 72 surgical procedures. A statistically significant positive correlation (ρ = 0.28, p = 0.05) was detected among duration of anesthesia and IL-6 concentration. The odds of having detectable IL-6 levels rose by 36.7 % for every 10 min of anesthetic duration (p = 0.045). In conclusion, the increase of IL-6 in relation to the duration of the intubation indicates an increased risk of inflammation.

Evaluation of the willingness for cadaveric donation in Greece: a population-based study.

Despite the importance of body donation for medical education and the advancement of medical science, cadaveric donation remains suboptimal worldwide. The purpose of this study was to evaluate the willingness of body donation in Greece and determine the characteristics of donors. This cross-sectional questionnaire survey was conducted from January to June 2011. A specially designed questionnaire was distributed to 1,700 individuals who were randomly selected from five major Greek cities. It was found that higher educational levels (P = 0.002), annual family income below 30,000 Euros (P = 0.001), guaranteed employment status (P = 0.02), and the presence of comorbid conditions (P = 0.004) seemed to affect potential donors' willingness for cadaveric donation. Those with strong religious beliefs were found to be unwilling to donate their bodies to medical science. Interestingly, the majority of participants who believed that hospitalized patients are deceived or are used for harmful experiments were willing to become whole body donors (P = 0.043). In Greece, the rate of body donation to medical science remains low, and most Greek citizens are not willing to become body donors. Efforts to encourage discussions about whole body donation should be implemented in order to improve current low levels of donation.

The potential role of erythropoietin as a pleiotropic agent in post-cardiac arrest syndrome.

Sudden cardiac arrest is a leading cause of death worldwide with survival rates still remaining suboptimal. Unfortunately, most cardiac arrest patients, who achieve return of spontaneous circulation (ROSC), develop a multi-faceted post-cardiac arrest syndrome, including post-cardiac arrest brain injury, myocardial dysfunction, and systemic ischemia/reperfusion response. Erythropoietin (EPO), the principal hematopoietic hormone regulating erythropoiesis, exhibits diverse cellular effects in nonhematopoietic tissues. Due to its anti-apoptotic, anti-inflammatory, and anti-oxidant properties, as well as its angiogenic action, EPO plays a role in neuroprotection and cardioprotection. In this regard, EPO represents a promising agent in the cardiac arrest setting, based on a therapeutic strategy that focuses on the post-resuscitation phase. This review aims to provide a comprehensive account of EPO's role in the treatment of each individual component of post-cardiac arrest syndrome.