RESUMO
The reactivation of senescence in cancer and the subsequent clearance of senescent cells are suggested as therapeutic intervention in the eradication of cancer. Several natural compounds that activate Nrf2 (nuclear factor erythroid-derived 2-related factor 2) pathway, which is involved in complex cytoprotective responses, have been paradoxically shown to induce cell death or senescence in cancer. Promoting the cytoprotective Nrf2 pathway may be desirable for chemoprevention, but it might be detrimental in later stages and advanced cancers. However, senolytic activity shown by some Nrf2-activating compounds could be used to target senescent cancer cells (particularly in aged immune-depressed organisms) that escape immunosurveillance. We herein describe in vitro and in vivo effects of fifteen Nrf2-interacting natural compounds (tocotrienols, curcumin, epigallocatechin gallate, quercetin, genistein, resveratrol, silybin, phenethyl isothiocyanate, sulforaphane, triptolide, allicin, berberine, piperlongumine, fisetin, and phloretin) on cellular senescence and discuss their use in adjuvant cancer therapy. In light of available literature, it can be concluded that the meaning and the potential of adjuvant therapy with natural compounds in humans remain unclear, also taking into account the existence of few clinical trials mostly characterized by uncertain results. Further studies are needed to investigate the therapeutic potential of those compounds that display senolytic activity.
Assuntos
Senescência Celular/fisiologia , Fator 2 Relacionado a NF-E2/metabolismo , Neoplasias/metabolismo , Animais , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Modelos MolecularesRESUMO
Impaired zinc homeostasis is observed in diabetes mellitus (DM2) and its complications. Zinc has a specific role in pancreatic ß-cells via insulin synthesis, storage, and secretion. Intracellular zinc homeostasis is tightly controlled by zinc transporters (ZnT and Zip families) and metallothioneins (MT) which modulate the uptake, storage, and distribution of zinc. Several investigations in animal models demonstrate the protective role of MT in DM2 and its cardiovascular or renal complications, while a copious literature shows that a common polymorphism (R325W) in ZnT8, which affects the protein's zinc transport activity, is associated with increased DM2 risk. Emerging studies highlight a role of other zinc transporters in ß-cell function, suggesting that targeting them could make a possible contribution in managing the hyperglycemia in diabetic patients. This article summarizes the current findings concerning the role of zinc homeostasis in DM2 pathogenesis and development of diabetic cardiomyopathy and nephropathy and suggests novel therapeutic targets. © 2017 BioFactors, 43(6):770-784, 2017.
Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Cardiomiopatias Diabéticas/metabolismo , Nefropatias Diabéticas/metabolismo , Suplementos Nutricionais , Células Secretoras de Insulina/metabolismo , Zinco/metabolismo , Animais , Transporte Biológico , Diabetes Mellitus Tipo 2/dietoterapia , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patologia , Cardiomiopatias Diabéticas/genética , Cardiomiopatias Diabéticas/patologia , Cardiomiopatias Diabéticas/prevenção & controle , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/patologia , Nefropatias Diabéticas/prevenção & controle , Modelos Animais de Doenças , Regulação da Expressão Gênica , Homeostase/fisiologia , Humanos , Insulina/genética , Insulina/metabolismo , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/patologia , Metalotioneína/genética , Metalotioneína/metabolismo , Zinco/administração & dosagem , Transportador 8 de Zinco/genética , Transportador 8 de Zinco/metabolismoRESUMO
Zinc dyshomeostasis may lead to an augmented production of proinflammatory cytokines promoting chronic inflammation and increasing the susceptibility to age-related diseases. Several studies suggest that the zinc transporter protein ZIP2 may play a relevant role in the immune system especially during zinc deficiency, while a polymorphism on the coding region of ZIP2 gene (Gln/Arg/Leu) has been associated with severe carotid artery disease. The aim of this study is to investigate the role of ZIP2 SNP on zinc and inflammatory status in 1090 elderly healthy free-living subjects enrolled in the ZincAge project and to assess the effect of zinc supplementation on zinc status, inflammatory mediators, and zinc transporter expression depending on ZIP2 genotype. ZIP2 Leu- (Arg43Arg) carriers showed enhanced IL-6, TNF-α, and RANTES plasma levels associated with decreased free cytosolic zinc in PBMCs and an upregulation of zinc transporters ZIP2, ZIP8, and Znt1. Moreover, Leu- subjects displayed significant decrement of inflammatory mediators such as MCP-1, TNF-α, and RANTES following zinc supplementation. In summary, this investigation provides new evidence on the effect of ZIP2 Gln/Arg/Leu polymorphism on proinflammatory mediators and zinc homeostasis in elderly population with a more pronounced anti-inflammatory effect of zinc supplementation in subjects carrying ZIP2 Leu- (Arg43Arg) genotype. These novel findings could be useful in identifying elderly subjects who may benefit of zinc intervention to decrease the inflammatory status and to prevent or delay the development of age-related diseases.
Assuntos
Envelhecimento/genética , Proteínas de Transporte de Cátions/genética , Inflamação/sangue , Zinco/sangue , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/metabolismo , Envelhecimento/patologia , Proteínas de Transporte de Cátions/metabolismo , Quimiocina CCL5/sangue , Suplementos Nutricionais , Feminino , Genótipo , Homeostase , Humanos , Sistema Imunitário/metabolismo , Inflamação/dietoterapia , Inflamação/genética , Inflamação/patologia , Interleucina-6/sangue , Leucócitos Mononucleares , Masculino , Polimorfismo de Nucleotídeo Único , Fator de Necrose Tumoral alfa/sangue , Zinco/deficiência , Zinco/farmacologia , Zinco/uso terapêuticoRESUMO
Cellular senescence is considered an important mechanism to prevent malignant transformation of potentially mutated cells but, persistence of senescent cells within tissues alters microenvironment in ways that can promote cancer and aging phenotype thus underlining pathophysiologic processes of different age-related diseases. Coincident with this increased knowledge, understanding and finding modulators of the dynamics that control senescent-cell formation, fate and subsequent effect on tissue function has gained critical interest in experimental gerontology and cancer research. The purpose of this review is to discuss the evidence that various dietary bioactive compounds can modulate cellular senescence in vitro and to summarize findings and mechanisms that might be useful for the development of health-promoting nutraceuticals. An overview of cellular senescence and its impact in aging and cancer is described along with the strategies and pathways that are currently being investigated to target cellular senescence. Particular emphasis is given to the mechanisms by which bioactive dietary factors (i.e., most polyphenols) can delay or induce cellular senescence in vitro and how this knowledge could be used to explain the opposite effects shown in cancer lines and primary cells by some of these compounds. In addition, the problems to translate findings from modulation of cellular senescence in vitro into experimental treatments or clinical trials able to prevent or counteract age-related diseases are briefly described. The information herein provided might be useful to design further research in the field as well as to develop new nutraceuticals to be tested in experimental models and clinical trials.