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The exponential growth of the aged population worldwide is followed by an increase in the prevalence of age-related disorders. Oxidative stress plays central role in damage accumulation during ageing and cell senescence. Thus, a major target of today's anti-ageing research has been focused on antioxidants counteracting senescence. In the current work, six novel 5,7,8-trimethyl-1,4-benzoxazine/catechol or resorcinol hybrids were synthesized connected through a methoxymethyl-1,2,3-triazolyl or a 1,2,3-triazoly linker. The compounds were evaluated for their antioxidant capacity in a cell-free system and for their ability to reduce intracellular ROS levels in human skin fibroblasts, both young (early-passage) and senescent. The most efficient compounds were further tested in these cells for their ability to induce the expression of the gene heme oxygenase-1 (ho-1), known to regulate redox homeostasis, and cellular glutathione (GSH) levels. Overall, the two catechol derivatives were found to be more potent than the resorcinol analogues. Furthermore, these two derivatives were shown to act coordinately as radical scavengers, ROS inhibitors, ho-1 gene expression inducers, and GSH enhancers. Interestingly, one of the two catechol derivatives was also found to enhance human skin fibroblast viability. The properties of the synthesized compounds support their potential use in cosmetic applications, especially in products targeting skin ageing. [ABSTRACT FROM AUTHOR]

Objective: To compare the mechanotransduction caused by cyclic and static mechanical strains in human periodontal ligament fibroblasts (hPDLFs) cultured under identical conditions. Materials and methods: hPDLFs, originating from the same donors, were exposed either to cyclic or to static tensile strain using specially designed devices and under identical culture conditions. Activation of all members of mitogen-activated protein kinases (MAPKs) was monitored by western immunoblot analysis. Expression levels of immediate/early genes c-fos and c-jun were assessed with quantitative real-time polymerase chain reaction. Results: Time course experiments revealed that both types of stresses activate the three members of MAPK, that is ERK, p38, and JNK, with cyclic stress exhibiting a slightly more extended activation. Further downstream, both stresses upregulate the immediate/early genes c-fos and c-jun, encoding components of the activator protein-1 (AP-1), a key transcription factor in osteoblastic differentiation; again cyclic strain provokes a more intense upregulation. Six hours after the application of both strains, MAPK activation and gene expression return to basal levels. Finally, cells exposed to cyclic stress for longer periods are distributed approximately perpendicular to the axis of the applied strain, whereas cells exposed to static loading remain in a random orientation in culture. Conclusion: The findings of the present study indicate similar, although not identical, immediate/early responses of hPDLs to cyclic and static stretching, with cyclic strain provoking a more intense adaptive response of these cells to mechanical deformation. [ABSTRACT FROM AUTHOR]

After publication of the original article, authors found that there has been a minor mistake in the units of kcat and kcat/Km in Table 2. The units should be 10 min g FAE for kcat and mM min g FAE for kcat/Km. This correction does not affect any conclusions drawn within the article. [ABSTRACT FROM AUTHOR]

The extracellular matrix (ECM) is a dynamic structural network that provides a physical scaffolding, as well as biochemical factors that maintain normal tissue homeostasis and thus its disruption is implicated in many pathological conditions. On the other hand, senescent cells express a particular secretory phenotype, affecting the composition and organization of the surrounding ECM and modulating their microenvironment. As accumulation of senescent cells may be linked to the manifestation of several age-related conditions, senescence-associated ECM alterations may serve as targets for novel anti-aging treatment modalities. Here, we will review characteristic changes in the ECM elicited by cellular senescence and we will discuss the complex interplay between ECM and senescent cells, in relation to normal aging and selected age-associated pathologies.

Cellular senescence, being the result of serial subculturing or of exogenous stresses, is considered to be a potent anticancer mechanism. However, it has been proposed that senescent cells may enhance the growth of adjacent malignant epithelial cells. On the other hand, exposure of tumors to repeated low doses of γ-irradiation is a common treatment regime. Nevertheless, γ-irradiation also affects the neighboring stromal cells and the interaction of the latter with cancer cells. Accordingly, in this study, we have exposed confluent cultures of human lung fibroblasts to repeated subcytotoxic doses of 4 Gy of γ-irradiation. We found that a single dose immediately activates a DNA damage response, leading to an intense, but reversible, cell cycle arrest. After a series of doses (total dose approximately 50 Gy) cellular senescence was accelerated, as shown by permanent growth arrest and the upregulation of specific biochemical and morphological senescence-associated markers. This process was found to be p53-dependent. Next, we studied the effect of these prematurely senescent cells on the growth of human malignant lung cell lines (A549 and H1299) and found that the presence of irradiation-mediated senescent cells strongly enhances the growth of these cancer cells in vitro and in immunocompromised (SCID) mice in vivo. This effect seems not to be related to an induction of epithelial-to-mesenchymal transdifferentiation but, to a significant extent, to the increased expression of matrix metalloproteases (MMPs), as a specific MMP inhibitor significantly restrains the growth of cancer in the presence of senescent fibroblasts. These findings indicate that lung fibroblasts that become senescent after ionizing radiation may contribute to lung cancer progression.