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1.
Cell ; 179(4): 813-827, 2019 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-31675495

RESUMO

Cellular senescence is a cell state implicated in various physiological processes and a wide spectrum of age-related diseases. Recently, interest in therapeutically targeting senescence to improve healthy aging and age-related disease, otherwise known as senotherapy, has been growing rapidly. Thus, the accurate detection of senescent cells, especially in vivo, is essential. Here, we present a consensus from the International Cell Senescence Association (ICSA), defining and discussing key cellular and molecular features of senescence and offering recommendations on how to use them as biomarkers. We also present a resource tool to facilitate the identification of genes linked with senescence, SeneQuest (available at http://Senequest.net). Lastly, we propose an algorithm to accurately assess and quantify senescence, both in cultured cells and in vivo.


Assuntos
Envelhecimento/genética , Biomarcadores , Senescência Celular/genética , Doenças Genéticas Inatas/genética , Pontos de Checagem do Ciclo Celular/genética , Cromatina/genética , Regulação da Expressão Gênica/genética , Doenças Genéticas Inatas/terapia , Humanos
2.
Cell ; 167(5): 1264-1280.e18, 2016 11 17.
Artigo em Inglês | MEDLINE | ID: mdl-28084216

RESUMO

Granulomas are immune cell aggregates formed in response to persistent inflammatory stimuli. Granuloma macrophage subsets are diverse and carry varying copy numbers of their genomic information. The molecular programs that control the differentiation of such macrophage populations in response to a chronic stimulus, though critical for disease outcome, have not been defined. Here, we delineate a macrophage differentiation pathway by which a persistent Toll-like receptor (TLR) 2 signal instructs polyploid macrophage fate by inducing replication stress and activating the DNA damage response. Polyploid granuloma-resident macrophages formed via modified cell divisions and mitotic defects and not, as previously thought, by cell-to-cell fusion. TLR2 signaling promoted macrophage polyploidy and suppressed genomic instability by regulating Myc and ATR. We propose that, in the presence of persistent inflammatory stimuli, pathways previously linked to oncogene-initiated carcinogenesis instruct a long-lived granuloma-resident macrophage differentiation program that regulates granulomatous tissue remodeling.


Assuntos
Dano ao DNA , Granuloma/imunologia , Macrófagos/imunologia , Mycobacterium tuberculosis/imunologia , Animais , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Diferenciação Celular , Proliferação de Células , Humanos , Inflamação/imunologia , Lipoproteínas/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Mitose , Proteínas Proto-Oncogênicas c-myc/metabolismo , Receptor 2 Toll-Like
3.
Mol Cell ; 83(19): 3558-3573.e7, 2023 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-37802028

RESUMO

Cellular senescence is a stress-response mechanism implicated in various physiological processes, diseases, and aging. Current detection approaches have partially addressed the issue of senescent cell identification in clinical specimens. Effective methodologies enabling precise isolation or live tracking of senescent cells are still lacking. In-depth analysis of truly senescent cells is, therefore, an extremely challenging task. We report (1) the synthesis and validation of a fluorophore-conjugated, Sudan Black-B analog (GLF16), suitable for in vivo and in vitro analysis of senescence by fluorescence microscopy and flow cytometry and (2) the development and application of a GLF16-carrying micelle vector facilitating GLF16 uptake by living senescent cells in vivo and in vitro. The compound and the applied methodology render isolation of senescent cells an easy, rapid, and precise process. Straightforward nanocarrier-mediated GLF16 delivery in live senescent cells comprises a unique tool for characterization of senescence at an unprecedented depth.


Assuntos
Senescência Celular , Indicadores e Reagentes , Citometria de Fluxo
4.
Physiol Rev ; 103(1): 609-647, 2023 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-36049114

RESUMO

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.


Assuntos
Doenças Cardiovasculares , Humanos , Envelhecimento/fisiologia , Qualidade de Vida , Senescência Celular/fisiologia
5.
Mol Cell ; 81(9): 2041-2052.e6, 2021 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-33823141

RESUMO

Cellular senescence is a state of stable proliferative arrest triggered by damaging signals. Senescent cells persist during aging and promote age-related pathologies via the pro-inflammatory senescence-associated secretory phenotype (SASP), whose regulation depends on environmental factors. In vivo, a major environmental variable is oxygenation, which varies among and within tissues. Here, we demonstrate that senescent cells express lower levels of detrimental pro-inflammatory SASP factors in physiologically hypoxic environments, as measured in culture and in tissues. Mechanistically, exposure of senescent cells to low-oxygen conditions leads to AMPK activation and AMPK-mediated suppression of the mTOR-NF-κB signaling loop. Finally, we demonstrate that treatment with hypoxia-mimetic compounds reduces SASP in cells and tissues and improves strength in chemotherapy-treated and aged mice. Our findings highlight the importance of oxygen as a determinant for pro-inflammatory SASP expression and offer a potential new strategy to reduce detrimental paracrine effects of senescent cells.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Proliferação de Células , Senescência Celular , Hipóxia/enzimologia , Serina-Treonina Quinases TOR/metabolismo , Fatores Etários , Animais , Antibióticos Antineoplásicos/farmacologia , Hipóxia Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Doxorrubicina/farmacologia , Glicina/análogos & derivados , Glicina/farmacologia , Humanos , Hidroxibenzoatos/farmacologia , Hipóxia/patologia , Hipóxia/fisiopatologia , Mediadores da Inflamação/metabolismo , Isoquinolinas/farmacologia , Camundongos Endogâmicos C57BL , Força Muscular , NF-kappa B/metabolismo , Comunicação Parácrina , Fenótipo , Transdução de Sinais
6.
Mol Cell ; 81(23): 4907-4923.e8, 2021 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-34793711

RESUMO

Oncogene-induced senescence (OIS) is an inherent and important tumor suppressor mechanism. However, if not removed timely via immune surveillance, senescent cells also have detrimental effects. Although this has mostly been attributed to the senescence-associated secretory phenotype (SASP) of these cells, we recently proposed that "escape" from the senescent state is another unfavorable outcome. The mechanism underlying this phenomenon remains elusive. Here, we exploit genomic and functional data from a prototypical human epithelial cell model carrying an inducible CDC6 oncogene to identify an early-acquired recurrent chromosomal inversion that harbors a locus encoding the circadian transcription factor BHLHE40. This inversion alone suffices for BHLHE40 activation upon CDC6 induction and driving cell cycle re-entry of senescent cells, and malignant transformation. Ectopic overexpression of BHLHE40 prevented induction of CDC6-triggered senescence. We provide strong evidence in support of replication stress-induced genomic instability being a causative factor underlying "escape" from oncogene-induced senescence.


Assuntos
Senescência Celular , Inversão Cromossômica , Cromossomos/ultraestrutura , Transição Epitelial-Mesenquimal , Neoplasias/genética , Oncogenes , Recombinação Genética , Animais , Brônquios/metabolismo , Sistemas CRISPR-Cas , Ciclo Celular , Transformação Celular Neoplásica , Ritmo Circadiano , Biologia Computacional , Células Epiteliais/metabolismo , Citometria de Fluxo , Genômica , Humanos , Cariotipagem , Camundongos , Camundongos SCID , Neoplasias/metabolismo , Fenótipo , Ligação Proteica , Domínios Proteicos , Fenótipo Secretor Associado à Senescência
8.
Ann Rheum Dis ; 83(3): 342-350, 2024 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-38050005

RESUMO

OBJECTIVES: Age is the strongest risk factor of giant cell arteritis (GCA), implying a possible pathogenetic role of cellular senescence. To address this question, we applied an established senescence specific multimarker algorithm in temporal artery biopsies (TABs) of GCA patients. METHODS: 75(+) TABs from GCA patients, 22(-) TABs from polymyalgia rheumatica (PMR) patients and 10(-) TABs from non-GCA/non-PMR patients were retrospectively retrieved and analysed. Synovial tissue specimens from patients with inflammatory arthritis and aorta tissue were used as disease control samples. Senescent cells and their histological origin were identified with specific cellular markers; IL-6 and MMP-9 were investigated as components of the senescent associated secretory phenotype by triple costaining. GCA or PMR artery culture supernatants were applied to fibroblasts, HUVECs and monocytes with or without IL-6R blocking agent to explore the induction of IL-6-associated cellular senescence. RESULTS: Senescent cells were present in GCA arteries at higher proportion compared with PMR (9.50% vs 2.66%, respectively, p<0.0001) and were mainly originated from fibroblasts, macrophages and endothelial cells. IL-6 was expressed by senescent fibroblasts, and macrophages while MMP-9 by senescent fibroblasts only. IL-6(+) senescent cells were associated with the extension of vascular inflammation (transmural inflammation vs adventitia limited disease: 10.02% vs 4.37%, respectively, p<0.0001). GCA but not PMR artery culture supernatant could induce IL-6-associated senescence that was partially inhibited by IL-6R blockade. CONCLUSIONS: Senescent cells with inflammatory phenotype are present in GCA arteries and are associated with the tissue inflammatory bulk, suggesting a potential implication in disease pathogenesis.


Assuntos
Arterite de Células Gigantes , Polimialgia Reumática , Humanos , Arterite de Células Gigantes/complicações , Interleucina-6/genética , Metaloproteinase 9 da Matriz/genética , Células Endoteliais/metabolismo , Estudos Retrospectivos , Polimialgia Reumática/complicações , Fenótipo , Senescência Celular , Inflamação/complicações
9.
EMBO Rep ; 23(2): e51287, 2022 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-34897944

RESUMO

RASSF1A promoter methylation has been correlated with tumor dedifferentiation and aggressive oncogenic behavior. Nevertheless, the underlying mechanism of RASSF1A-dependent tumor dedifferentiation remains elusive. Here, we show that RASSF1A directly uncouples the NOTCH-HES1 axis, a key suppressor of differentiation. Interestingly, the crosstalk of RASSF1A with HES1 occurs independently from the signaling route connecting RASSF1A with the Hippo pathway. At the molecular level, we demonstrate that RASSF1A acts as a scaffold essential for the SUMO-targeted E3 ligase SNURF/RNF4 to target HES1 for degradation. The reciprocal relationship between RASSF1A and HES1 is evident across a wide range of human tumors, highlighting the clinical significance of the identified pathway. We show that HES1 upregulation in a RASSF1A-depleted environment renders cells non-responsive to the downstream effects of γ-secretase inhibitors (GSIs) which restrict signaling at the level of the NOTCH receptor. Taken together, we report a mechanism through which RASSF1A exerts autonomous regulation of the critical Notch effector HES1, thus classifying RASSF1A expression as an integral determinant of the clinical effectiveness of Notch inhibitors.


Assuntos
Receptores Notch , Transdução de Sinais , Fatores de Transcrição HES-1 , Proteínas Supressoras de Tumor , Humanos , Proteínas Nucleares/metabolismo , Receptores Notch/genética , Receptores Notch/metabolismo , Fatores de Transcrição HES-1/genética , Fatores de Transcrição HES-1/metabolismo , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação
10.
J Pathol ; 260(5): 649-665, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37550877

RESUMO

Cellular senescence constitutes a stress response mechanism in reaction to a plethora of stimuli. Senescent cells exhibit cell-cycle arrest and altered function. While cell-cycle withdrawal has been perceived as permanent, recent evidence in cancer research introduced the so-called escape-from-senescence concept. In particular, under certain conditions, senescent cells may resume proliferation, acquiring highly aggressive features. As such, they have been associated with tumour relapse, rendering senescence less effective in inhibiting cancer progression. Thus, conventional cancer treatments, incapable of eliminating senescence, may benefit if revisited to include senolytic agents. To this end, it is anticipated that the assessment of the senescence burden in everyday clinical material by pathologists will play a crucial role in the near future, laying the foundation for more personalised approaches. Here, we provide an overview of the investigations that introduced the escape-from-senescence phenomenon, the identified mechanisms, as well as the major implications for pathology and therapy. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.


Assuntos
Senescência Celular , Neoplasias , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Pontos de Checagem do Ciclo Celular , Reino Unido
11.
Mol Cell ; 64(6): 1127-1134, 2016 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-27984746

RESUMO

Human cancers are characterized by the presence of oncogene-induced DNA replication stress (DRS), making them dependent on repair pathways such as break-induced replication (BIR) for damaged DNA replication forks. To better understand BIR, we performed a targeted siRNA screen for genes whose depletion inhibited G1 to S phase progression when oncogenic cyclin E was overexpressed. RAD52, a gene dispensable for normal development in mice, was among the top hits. In cells in which fork collapse was induced by oncogenes or chemicals, the Rad52 protein localized to DRS foci. Depletion of Rad52 by siRNA or knockout of the gene by CRISPR/Cas9 compromised restart of collapsed forks and led to DNA damage in cells experiencing DRS. Furthermore, in cancer-prone, heterozygous APC mutant mice, homozygous deletion of the Rad52 gene suppressed tumor growth and prolonged lifespan. We therefore propose that mammalian RAD52 facilitates repair of collapsed DNA replication forks in cancer cells.


Assuntos
Proteína da Polipose Adenomatosa do Colo/genética , Ciclina E/genética , Quebras de DNA de Cadeia Dupla , DNA/genética , Osteossarcoma/genética , Proteína Rad52 de Recombinação e Reparo de DNA/genética , Reparo de DNA por Recombinação , Proteína da Polipose Adenomatosa do Colo/deficiência , Animais , Sistemas CRISPR-Cas , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ciclina E/metabolismo , DNA/metabolismo , Fase G1 , Expressão Gênica , Instabilidade Genômica , Humanos , Camundongos , Camundongos Knockout , Nocodazol/farmacologia , Osteossarcoma/metabolismo , Osteossarcoma/mortalidade , Osteossarcoma/patologia , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Proteína Rad52 de Recombinação e Reparo de DNA/antagonistas & inibidores , Proteína Rad52 de Recombinação e Reparo de DNA/metabolismo , Fase S , Estresse Fisiológico , Análise de Sobrevida
12.
Int J Mol Sci ; 25(5)2024 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-38473720

RESUMO

The currently available anti-cancer therapies, such as gamma-radiation and chemotherapeutic agents, induce cell death and cellular senescence not only in cancer cells but also in the adjacent normal tissue. New anti-tumor approaches focus on limiting the side effects on normal cells. In this frame, the potential anti-tumor properties of Pulsed Electromagnetic Fields (PEMFs) through the irradiation of breast cancer epithelial cells (MCF-7 and MDA-MB-231) and normal fibroblasts (FF95) were investigated. PEMFs had a frequency of 8 Hz, full-square wave type and magnetic flux density of 0.011 T and were applied twice daily for 5 days. The data collected showcase that PEMF application decreases the proliferation rate and viability of breast cancer cells while having the opposite effect on normal fibroblasts. Moreover, PEMF irradiation induces cell death and cellular senescence only in breast cancer cells without any effect in the non-cancerous cells. These findings suggest PEMF irradiation as a novel, non-invasive anti-cancer strategy that, when combined with senolytic drugs, may eliminate both cancer and the remaining senescent cells, while simultaneously avoiding the side effects of the current treatments.


Assuntos
Neoplasias da Mama , Campos Eletromagnéticos , Humanos , Feminino , Morte Celular , Senescência Celular , Fibroblastos
13.
Int J Mol Sci ; 25(7)2024 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-38612698

RESUMO

Helicobacter pylori (H. pylori) infection induces DNA Double-Strand Breaks (DSBs) and consequently activates the DNA Damage Response pathway (DDR) and senescence in gastric epithelium. We studied DDR activation and senescence before and after the eradication of the pathogen. Gastric antral and corpus biopsies of 61 patients with H. pylori infection, prior to and after eradication treatment, were analyzed by means of immunohistochemistry/immunofluorescence for DDR marker (γH2AΧ, phosporylated ataxia telangiectasia-mutated (pATM), p53-binding protein (53BP1) and p53) expression. Samples were also evaluated for Ki67 (proliferation index), cleaved caspase-3 (apoptotic index) and GL13 staining (cellular senescence). Ten H. pylori (-) dyspeptic patients served as controls. All patients were re-endoscoped in 72-1361 days (mean value 434 days), and tissue samples were processed in the same manner. The eradication of the microorganism, in human gastric mucosa, downregulates γH2AΧ expression in both the antrum and corpus (p = 0.00019 and p = 0.00081 respectively). The expression of pATM, p53 and 53BP1 is also reduced after eradication. Proliferation and apoptotic indices were reduced, albeit not significantly, after pathogen clearance. Moreover, cellular senescence is increased in H. pylori-infected mucosa and remains unaffected after eradication. Interestingly, senescence was statistically increased in areas of intestinal metaplasia (IM) compared with adjacent non-metaplastic mucosa (p < 0.001). In conclusion, H. pylori infection triggers DSBs, DDR and senescence in the gastric epithelium. Pathogen eradication reverses the DDR activation but not senescence. Increased senescent cells may favor IM persistence, thus potentially contributing to gastric carcinogenesis.


Assuntos
Helicobacter pylori , Humanos , Proteína Supressora de Tumor p53/genética , Mucosa Gástrica , Reparo do DNA , Epitélio
14.
Eur Respir J ; 60(2)2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35086840

RESUMO

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection of the respiratory system can progress to a multisystemic disease with aberrant inflammatory response. Cellular senescence promotes chronic inflammation, named senescence-associated secretory phenotype (SASP). We investigated whether coronavirus disease 2019 (COVID-19) is associated with cellular senescence and SASP. METHODS: Autopsy lung tissue samples from 11 COVID-19 patients and 43 age-matched non-COVID-19 controls with similar comorbidities were analysed by immunohistochemistry for SARS-CoV-2, markers of senescence and key SASP cytokines. Virally induced senescence was functionally recapitulated in vitro, by infecting epithelial Vero-E6 cells and a three-dimensional alveosphere system of alveolar type 2 (AT2) cells with SARS-CoV-2 strains isolated from COVID-19 patients. RESULTS: SARS-CoV-2 was detected by immunocytochemistry and electron microscopy predominantly in AT2 cells. Infected AT2 cells expressed angiotensin-converting enzyme 2 and exhibited increased senescence (p16INK4A and SenTraGor positivity) and interleukin (IL)-1ß and IL-6 expression. In vitro, infection of Vero-E6 cells with SARS-CoV-2 induced senescence (SenTraGor), DNA damage (γ-H2AX) and increased cytokine (IL-1ß, IL-6, CXCL8) and apolipoprotein B mRNA-editing (APOBEC) enzyme expression. Next-generation sequencing analysis of progenies obtained from infected/senescent Vero-E6 cells demonstrated APOBEC-mediated SARS-CoV-2 mutations. Dissemination of the SARS-CoV-2-infection and senescence was confirmed in extrapulmonary sites (kidney and liver) of a COVID-19 patient. CONCLUSIONS: We demonstrate that in severe COVID-19, AT2 cells infected by SARS-CoV-2 exhibit senescence and a proinflammatory phenotype. In vitro, SARS-CoV-2 infection induces senescence and inflammation. Importantly, infected senescent cells may act as a source of SARS-CoV-2 mutagenesis mediated by APOBEC enzymes. Therefore, SARS-CoV-2-induced senescence may be an important molecular mechanism of severe COVID-19, disease persistence and mutagenesis.


Assuntos
COVID-19 , SARS-CoV-2 , Senescência Celular , Citocinas/metabolismo , Humanos , Inflamação , Interleucina-6 , Pulmão/metabolismo , Mutagênese , Fenótipo
15.
J Autoimmun ; 108: 102381, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31919014

RESUMO

Primary Sjögren's syndrome (SS) is characterized by chronic periductal inflammatory infiltrates in the salivary glands. Several previous studies have indicated that the ductal epithelia of SS patients play a pro-inflammatory role and manifest an intrinsically activated status, as demonstrated in cultured non-neoplastic ductal salivary gland epithelial cell (SGEC) lines. Herein, we investigated the activation of inflammasomes in the salivary epithelia of SS patients and non-SS controls, using salivary biopsy tissues and SGEC lines. The ductal epithelial cells of SS patients were found to display significant activation of the AIM2 (absent in melanoma-2) inflammasome. Such activation occurred in a cell-autonomous manner, as it was illustrated by the constitutively high expression of AIM2 activation-related genes, the presence of cytoplasmic ASC specks and the increased spontaneous IL-1ß production observed in patients' SGEC lines. Since AIM2 activation is known to occur in response to cytoplasmic DNA, we further searched for the presence of undegraded extranuclear DNA in the SGEC lines and SG tissues of patients and controls. This investigation revealed marked cytoplasmic accumulations of damaged genomic DNA that co-localized with AIM2 in the specimens of SS patients (but not controls). The SGEC lines and the ductal tissues of SS patients were also found to manifest impaired DNase1 expression and activity, which possibly denotes defective cytoplasmic DNA degradation in patients' cells and AIM2 triggering thereof. In corroboration, DNase1-silencing in normal SGEC was shown to lead to high AIM2-related gene expression and IL-1ß production. Our findings indicate that the cell-intrinsic activation status of ductal epithelia in SS patients owes to persistent epithelial AIM2 activation by aberrant cytoplasmic DNA build-up.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Regulação da Expressão Gênica , Inflamassomos/metabolismo , Síndrome de Sjogren/etiologia , Biomarcadores , Biópsia , Citocinas/metabolismo , Células Epiteliais/metabolismo , Humanos , Mediadores da Inflamação/metabolismo , Glândulas Salivares/metabolismo , Síndrome de Sjogren/patologia
16.
Int J Mol Sci ; 19(10)2018 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-30261683

RESUMO

Ageing is a major risk factor for developing many neurodegenerative diseases. Cellular senescence is a homeostatic biological process that has a key role in driving ageing. There is evidence that senescent cells accumulate in the nervous system with ageing and neurodegenerative disease and may predispose a person to the appearance of a neurodegenerative condition or may aggravate its course. Research into senescence has long been hindered by its variable and cell-type specific features and the lack of a universal marker to unequivocally detect senescent cells. Recent advances in senescence markers and genetically modified animal models have boosted our knowledge on the role of cellular senescence in ageing and age-related disease. The aim now is to fully elucidate its role in neurodegeneration in order to efficiently and safely exploit cellular senescence as a therapeutic target. Here, we review evidence of cellular senescence in neurons and glial cells and we discuss its putative role in Alzheimer's disease, Parkinson's disease and multiple sclerosis and we provide, for the first time, evidence of senescence in neurons and glia in multiple sclerosis, using the novel GL13 lipofuscin stain as a marker of cellular senescence.


Assuntos
Envelhecimento/genética , Senescência Celular , Doenças Neurodegenerativas/genética , Envelhecimento/patologia , Animais , Humanos , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/fisiopatologia
18.
AJR Am J Roentgenol ; 208(2): 434-445, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27897437

RESUMO

OBJECTIVE: The purposes of this article are to review the common biologic features of cancer and coronary artery disease assessed with PET tracers, focusing on those already used in the clinic and those with translational potential, and to discuss the current value and expected contribution of PET in diagnosis, risk stratification, and treatment monitoring. CONCLUSION: PET using a wide variety of radiotracers enhances understanding of pathophysiologic changes shared by cancer and coronary artery disease, helps establish an accurate diagnosis, and aids in prognostic assessment and management decisions. It is likely that with the evolution of therapeutic strategies for blocking the development and progression of both diseases and with the introduction of novel, specific ligands in clinical practice, PET will play an ever stronger role in diagnosis, risk stratification, and monitoring of therapy.


Assuntos
Doença da Artéria Coronariana/diagnóstico por imagem , Imagem Molecular/métodos , Neoplasias/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos , Humanos
19.
Int J Mol Sci ; 18(9)2017 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-28880214

RESUMO

Autophagy is a catabolic process that preserves cellular homeostasis. Its exact role during carcinogenesis is not completely defined. Specifically in head and neck cancer, such information from clinical settings that comprise the whole spectrum of human carcinogenesis is very limited. Towards this direction, we examined the in situ status of the autophagy-related factors, Beclin-1, microtubule-associated protein 1 light chain 3, member B (LC3B) and sequestosome 1/p62 (p62) in clinical material covering all histopathological stages of human head and neck carcinogenesis. This material is unique as each panel of lesions is derived from the same patient and moreover we have previously assessed it for the DNA damage response (DDR) activation status. Since Beclin-1, LC3B and p62 reflect the nucleation, elongation and degradation stages of autophagy, respectively, their combined immunohistochemical (IHC) expression profiles could grossly mirror the autophagic flux. This experimental approach was further corroborated by ultrastructural analysis, applying transmission electron microscopy (TEM). The observed Beclin-1/LC3B/p62 IHC patterns, obtained from serial sections analysis, along with TEM findings are suggestive of a declined authophagic activity in preneoplastic lesions that was restored in full blown cancers. Correlating these findings with DDR status in the same pathological stages are indicative of: (i) an antitumor function of autophagy in support to that of DDR, possibly through energy deprivation in preneoplastic stages, thus preventing incipient cancer cells from evolving; and (ii) a tumor-supporting role in the cancerous stage.


Assuntos
Autofagia/fisiologia , Neoplasias de Cabeça e Pescoço/metabolismo , Imuno-Histoquímica/métodos , Autofagia/genética , Proteína Beclina-1/genética , Proteína Beclina-1/metabolismo , Dano ao DNA/genética , Dano ao DNA/fisiologia , Neoplasias de Cabeça e Pescoço/genética , Humanos
20.
Autophagy ; : 1-3, 2024 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-38825325

RESUMO

The DNA damage response (DDR) pathway is a cardinal cellular stress response mechanism that during cancer development follows an antagonistic pleiotropy mode of action. Given that DDR activation is an energy demanding process, interplay with macroautophagy/autophagy, a stress response and energy providing mechanism, is likely to take place. While molecular connections between both mechanisms have been reported, an open question regards whether autophagy activation follows solely or is entangled with DDR in a similar antagonistic pleiotropy pattern during cancer development. Combing evidence on the spatiotemporal relationship of DDR and autophagy in the entire spectrum of carcinogenesis from our previous studies, we discuss these issues in the current addendum.Abbreviation: AMPK: AMP-dependent protein kinase; DDR: DNA damage response.

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