The end of the Western Civilization? The Intellectual Journey of Humanity to Adulthood

Civilizations can be perceived as living human beings that are born, mature, age, and ultimately die and disappear, passing their legacy to the future generations. These transitions may be projected to the different stages of cognitive development of children. The Western Civilization, which embodies our current state of cultural advancement from the Classic Greek to the modern period, can be paralleled by the gradual transitions of human beings toward adulthood. From this perspective, the ancient Greek era resembles the toddler years of humanity at which the first “why”-type questions are being asked. The theocratic period that followed until the Renaissance can be seen as our childhood, when people lived their lives under the tight boundaries set by religious authorities. The period spanning from the Enlightenment until almost the end of the 20th century can be considered as our teenage years when people rediscover their past, are liberated from superstition, and set the path forward based on reason by a manner at which the distinction between plausible and feasible is vague. Within this scheme, postmodernism also finds its place in our teenhood. The last few decades, from this perspective, signify our entrance to adulthood at which major questions are considered answered, or at least settled, and the only path forward perceived as feasible is the one that is followed already, a state that is bringing us closer to our intellectual aging and its inevitable death. Some signs of aging-related pathologies are already manifested in today’s technology-intensive society. By identifying our intellectual age and by appreciating our health status, we may be able to proactively delay or even avert our intellectual aging and death

The end of selection as a driver of human evolution

The future of human evolution triggers many discussions, in the intersection of biological, technological, and philosophical enquiry. I will discuss the proposition that the evolution of the human species will rely increasingly in stochastic phenomena in the future, by a manner at which selection will play a minimal role only. This is the direct consequence of our cultural evolution that was intensified after the Enlightenment and combined with the scientific, technological, and medical advances of our civilization, renders the perseverance of our species, as its ultimate goal. This supersedes the goals instructed by biology alone as they apply to all other species. To that end, H. sapiens will be the first and only species that through its logic-based progress, defies the rationale of natural selection as an evolutionary force and forecasts a rather unpredictable future path

A crosstalk between p21 and UPR-induced transcription factor C/EBP homologous protein (chop) linked to type 2 diabetes

Type 2 diabetes (T2D) is a disease that is characterized by raised levels of glucose in the blood combined with insulin resistance and relative insulin deficiency. The pathogenesis of type 2 diabetes is associated with the induction of the unfolded protein response (UPR). While UPR aims to restore tissue homeostasis following stress of the endoplasmic reticulum (ER), prolonged ER stress triggers apoptosis at least in part through the unfolded protein response (UPR)-activated transcription factor C/EBP (CCAAT/enhancer binding protein) homologous protein (CHOP). CHOP has elevated as a critical mediator connecting accumulation and aggregation of unfolded proteins in the ER and oxidative stress and also contributes to the induction of apoptosis in β-cell (beta-cell) – cells under conditions of increased insulin demand. p21 is a cell cycle regulator that is implicated in the regulation of the UPR by various mechanisms involving inhibition of apoptosis and facilitation of the regeneration capacity of the β cells. In this review we summarize the role of ER stress in the pathogenesis of type 2 diabetes which is associated with the induction of the unfolded protein response (UPR). We also review recent evidence associating p21 activity with β cell health and regenerative capacity by mechanisms that may interfere with the effects of p21 in the UPR or operate independently of ER stress. Most likely understanding the molecular details of the pathogenesis of type 2 diabetes will be beneficial for the management of the disease

Chop-dependent regulation of p21/waf1 during ER stress

The transcription factor CHOP/GADD153 is induced during the unfolded protein response (UPR) and is associated to the induction of ER stress-related apoptosis. However, how the transition between the pro-survival and the pro-apoptotic role of ER stress is being orchestrated remains poorly understood. Here we show that tunicamycin, an antibiotic promoting ER stress, suppresses the expression of p21, a tumor suppressor that induces cell cycle arrest and inhibits apoptosis. This suppression of p21 levels was independent of p53 that is the major transcriptional regulator of p21, but could be reproduced by forced expression of CHOP. Consistently with these findings, siRNA-mediated inhibition of p21 levels restored the sensitivity of CHOP-deficient cells to tunicamycin. Our findings are consistent with a CHOP-dependent role for p21 in the shift from the pro-survival to the pro-apoptotic function of UPR

Advanced glycation end-products induce endoplasmic reticulum stress in human aortic endothelial cells

Background: Advanced glycation end products (AGEs), the final products of the Maillard reaction, have been shown to impair endothelial proliferation and function, thus contributing to endothelial cell injury present in diabetes, inflammatory and cardiovascular diseases. Endoplasmic reticulum (ER) stress triggered under hyperglycemic, hypoxic and oxidative conditions has been implicated in endothelial dysfunction through activation of the unfolded protein response (UPR). The present study investigates the role of AGEs in ER stress induction in human aortic endothelial cells exposed to variable AGE treatments. Methods: Human aortic endothelial cells (HAEC) were treated with increasing concentrations (100, 200 μg/mL) of AGE-bovine serum albumin (AGE-BSA) at different time-points (24, 48, 72 h). The induction of ER stress and the involved UPR components were investigated on mRNA and protein levels. Apoptosis was quantitatively determined by flow cytometry detecting propidium iodide expression and annexin V binding simultaneously. Results: AGEs administration significantly reduced HAEC proliferation in a time- and dose-dependent manner. An immediate induction of the ER chaperones GRP78, GRP94 and the transcriptional activator, XBP-1 was observed at 24 h and 48 h. A later induction of the phospho-lF2α and proapoptotic transcription factor CHOP was observed at 48 h and 72 h, being correlated with elevated early apoptotic cell numbers at the same time-points. Conclusions: The present study demonstrates that AGEs directly induce ER stress in human aortic endothelial cells, playing an important role in endothelial cell apoptosis. Targeting AGEs signaling pathways in order to alleviate ER stress may prove of therapeutic potential to endothelial dysfunction-related disorders

Inhibition of CDK8 Mediator Kinase Suppresses Estrogen Dependent Transcription and the Growth of Estrogen Receptor Positive Breast Cancer

Hormone therapy targeting estrogen receptor (ER) is the principal treatment for ER-positive breast cancers. However, many cancers develop resistance to hormone therapy while retaining ER expression. Identifying new druggable mediators of ER function can help to increase the efficacy of ER-targeting drugs. Cyclin-dependent kinase 8 (CDK8) is a Mediator complex-associated transcriptional regulator with oncogenic activities. Expression of CDK8, its paralog CDK19 and their binding partner Cyclin C are negative prognostic markers in breast cancer. Meta-analysis of transcriptome databases revealed an inverse correlation between CDK8 and ERα expression, suggesting that CDK8 could be functionally associated with ER. We have found that CDK8 inhibition by CDK8/19-selective small-molecule kinase inhibitors, by shRNA knockdown or by CRISPR/CAS9 knockout suppresses estrogen-induced transcription in ER-positive breast cancer cells; this effect was exerted downstream of ER. Estrogen addition stimulated the binding of CDK8 to the ER-responsive GREB1 gene promoter and CDK8/19 inhibition reduced estrogen-stimulated association of an elongation-competent phosphorylated form of RNA Polymerase II with GREB1. CDK8/19 inhibitors abrogated the mitogenic effect of estrogen on ER-positive cells and potentiated the growth-inhibitory effects of ER antagonist fulvestrant. Treatment of estrogen-deprived ER-positive breast cancer cells with CDK8/19 inhibitors strongly impeded the development of estrogen independence. In vivo treatment with a CDK8/19 inhibitor Senexin B suppressed tumor growth and augmented the effects of fulvestrant in ER-positive breast cancer xenografts. These results identify CDK8 as a novel downstream mediator of ER and suggest the utility of CDK8 inhibitors for ER-positive breast cancer therapy

Molecular and genetic analysis of human tumours of the neck

Η διατριβή αποσκοπούσε στη μοριακή και γενετική ανάλυση του καρκίνου κεφαλής και τραχήλου. Μελετήθηκε η εμπλοκή των γονιδίων Ras, το φαινόμενο απώλειας της ετεροζυγωτίας και η αστάθεια του μικροδορυφορικού DNA. Μεταλλάξεις στα γονίδια Ras βρέθηκαν σε ελάχιστο ποσοστό των δειγμάτων, ωστόσο, υπερέκφρασή τους ανιχνεύθηκε σε πολλές περιπτώσεις. Απώλεια της ετεροζυγωτίας βρέθηκε στα περισσότερα αντισώματα του ανθρώπου, υποδεικνύοντας την παρουσία ογκοκατασταλτικών γονιδίων ενώ ανιχνεύθηκε επίσης και αστάθεια μικροδορυφορικού DNA που αντιστοιχεί σε αύξηση του ρυθμού μεταλλαξογένεσης στους αντίστοιχους όγκους

Fibroblast independency in tumors: implications in cancer therapy

While the presence of stromal fibroblasts within malignant tumors was established many decades ago, it is only recently that their role in tumorigenesis has begun to unravel. Probably the most important finding in this line of research is that, contrary to the conventional notion that views them as a static entity, stromal fibroblasts progress in parallel with the cancer cells, interacting continuously with them and affecting the kinetic profile and the morphology of the tumor. However, while the tumor is highly dependent on the stromal fibroblast during the early stages of disease development, it is likely that it abolishes this dependency at later stages. The aim of this article is to outline the evidence implying this differential dependency of the cancer cells against the stromal fibroblasts, and to discuss their implication in the management of the disease, especially in view of the evolving concept of stroma-targeting anticancer therapies