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Senescent cells are characterized by an increased secretion of inflammatory and growth factors, known as the "senescence-associated secretory phenotype" (SASP), producing a pro-tumoral and pro-angiogenic microenvironment. This work proposes chronic resveratrol treatment (5 µM for 5 weeks, termed R5) of senescent MRC5 fibroblasts as a mean to mimic and target the angiogenic trait of stromal fibroblast SASP. Senescent fibroblast conditioned medium (CM sen) was effective in enhancing the angiogenic properties of endothelial colony-forming cells (ECFCs), that is, invasive activity and capillary morphogenesis capability in vitro, that were significantly reduced when conditioned media were collected after resveratrol pretreatment (CM senR5). The attenuation of ECFC angiogenic phenotype induced by CM senR5 was accompanied by reduced protein levels of epidermal growth factor and urokinase plasminogen activator receptors (EGFR, uPAR), and by a related decreased activation of receptor-tyrosine-kinase signaling pathways. IL8 levels were found reduced in CM senR5 compared to CM sen, with the associated reduction of IL8-CXCR2 binding in ECFCs. IL8-subtraction mitigated the pro-angiogenic features of CM sen and the associated intracellular signaling in ECFCs, indicating a prominent role of IL8 in the pro-angiogenic effects of CM sen. IL8 modulation is an important mechanism underlying the antiangiogenic activity of resveratrol on MRC5 SASP. [ABSTRACT FROM AUTHOR]

Cellular senescence is related to organismal aging and is observed after DNA damaging cancer therapies, that induce tumor-suppressive modifications, but it is characterized by a strong increase in secreted factors, termed the "senescence-associated secretory phenotype" (SASP). Particularly, SASP from stroma senescent fibroblasts creates a cancer-favoring microenvironment, providing targets for anti-cancer interventions. In the present article, chronic treatment (5 weeks) with 5 µM resveratrol has been used to modulate senescence-related protumoral features of MRC5 fibroblasts, reducing SASP-related interleukins IL1α, IL1β, IL6, and IL8; transforming-growth-factor-β (TGFβ); matrix metallo-proteinases MMP3 and MMP2; urokinase plasminogen activator (uPA); receptor proteins uPAR, IL6R, insulin growth factor receptor-1 (IGF-1R), TGFβ-R2, and CXCR4. The cellular nuclear-factor-kB (NF-kB) protein level was also reduced, confirming its role in the induction of SASP. Resveratrol pretreated MRC5 fibroblasts were resistant to activation by TGFβ. Resveratrol treatment of senescent MRC5 induced the production of conditioned media (CM) which counteracted the protumoral effect of senescent CM on A375 and A375-M6 melanoma cell proliferation and invasiveness, and reduced the expression of epithelial-to-mesenchymal transition markers related to malignant features. This experimental approach proposes a treatment that targets the senescent stromal cell phenotype to induce an anti-tumor hosting microenvironment, which is suitable for both preventive and therapeutic purposes. [ABSTRACT FROM AUTHOR]

We evaluated the effect of resveratrol on the senescence-associated secretory phenotype (SASP) and on adhesion-related processes in cultured human MRC5 fibroblasts. Presenescent cultures were chronically treated with or without 5 µM resveratrol. The development of SASP in MRC5 fibroblasts approaching senescence was significantly attenuated by resveratrol treatment, which reduced both gene expression and release of proinflammatory cytokines. Although to a lesser extent, 1 µM resveratrol proved to be effective on cytokine gene expression. Cell spreading capacity and plating efficiency were strikingly increased and accompanied by recovery of type I collagen expression to presenescent levels. As p16INK4a protein expression was not significantly modified, and based on our previous data, we propose that resveratrol does not affect fibroblast replicative senescence, but improves tissue maintenance and repair during normal cellular aging. Considering these low concentrations proved effective in vitro, translation of these data to human research on inflammation-related pathologies can be envisaged. [ABSTRACT FROM PUBLISHER]

Recent research has focused on natural compounds possibly endowed with antiaging effects. Resveratrol is a stilbene compound produced by different plants with many biologic activities, including an antiaging effect, which has been demonstrated both in vitro in eukaryotic cells and in vivo in mice. We studied the effect of resveratrol on cultured human MRC5 fibroblasts, a widely used in vitro model in aging studies. The chronic treatment of MRC5 cells until senescence with 5 μM resveratrol induced a small increase in the total number of replications completed by the cultures at senescence, showed protective effects against DNA oxidative damage, and reduced senescence-associated increases in nuclear size and DNA content. A reduction in the levels of acetylated forms of H3 and H4 histones and p53 protein was also found. [ABSTRACT FROM PUBLISHER]