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1.
In Vivo ; 36(1): 140-152, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34972709

RESUMO

BACKGROUND/AIM: Human dermal fibroblasts (HDFs) are widely used as a skin model in cosmetic and pharmaceutical industry due their advantages for the cosmetic industry and medical aspects. Telomeres are key players in controlling cellular aging, in which telomeres and the telomerase enzyme (hTERT) can maintain proliferative capacity and prolong cellular senescence. The primary aim of the study was to elucidate the underlying mechanisms of hTERT/SV40 immortalization of human dermal fibroblasts. MATERIALS AND METHODS: Transgenic expression of hTERT and SV40 large antigen, as well as co-transfection of both factors was performed and their significance evaluated in terms of HDF immortalization efficiency. RESULTS: The results showed that the immortalized fibroblasts of all conditions can be cultured in over 60 passages and maintain their telomere length. Further, key markers of skin cells, such as COL1A1, KRT18 and ELASTIN, were up-regulated in immortalized cells. In addition, p53 expression was enhanced in all immortalized cells, in accordance with activation of the SIRT1 gene upon transgenic immortalization. The significant role of SIRT1 in fibroblast proliferation was assessed by shRNA-knockdown, and it was found that SIRT1 silencing led to loss of Ki67, a proliferation marker. Moreover, miR-93, a SIRT1-targeted miRNA, also had a significantly reduced expression in the co-transfected immortalized cells, highlighting the linkage of the miRNA and SIRT1 pathway in the immortalization of human dermal fibroblasts. CONCLUSION: This evidence from this study could benefit the efficient development of human skin cell lines for use in the cosmetic industry in the future.


Assuntos
MicroRNAs , Telomerase , Células Cultivadas , Senescência Celular/genética , Fibroblastos/metabolismo , Humanos , MicroRNAs/genética , Sirtuína 1/genética , Telomerase/genética , Telomerase/metabolismo
2.
Cancer Lett ; 525: 67-75, 2022 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-34728311

RESUMO

Genotoxic agents are widely used anti-cancer therapies because of their ability to interfere with highly proliferative cells. An important outcome of these interventions is the induction of a state of permanent arrest also known as cellular senescence. However, senescent cancer cells are characterized by genomic instability and are at risk of escaping the growth arrest to eventually facilitate cancer relapse. The tumor necrosis factor related apoptosis inducing ligand (TRAIL) signals extrinsic apoptosis via Death Receptors (DR) 4 and 5, while Decoy Receptors (DcR) 1 and 2, and Osteoprotegerin (OPG) are homologous to death receptors but incapable of transducing an apoptotic signal. The use of recombinant TRAIL as an anti-cancer strategy in combination with chemotherapy is currently in development, and a major question remains whether senescent cancer cells respond to TRAIL. Here, we show variable sensitivity of cancer cells to TRAIL after senescence induction, and upregulation of both pro-apoptotic and anti-apoptotic receptors in therapy-induced senescent cancer cells. A DR5-selective TRAIL variant (DHER), unable to bind to DcR1 or OPG, was more effective in inducing apoptosis of senescent cancer cells compared to wild-type TRAIL. Importantly, no apoptosis induction was observed in non-cancerous cells, even at the highest concentrations tested. Our results suggest that targeting DR5 can serve as a novel therapeutic strategy for the elimination of therapy-induced senescent cancer cells.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Osteoprotegerina/genética , Neoplasias Ovarianas/tratamento farmacológico , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/genética , Ligante Indutor de Apoptose Relacionado a TNF/genética , Apoptose/genética , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Senescência Celular/efeitos dos fármacos , Senescência Celular/genética , Doxorrubicina/farmacologia , Feminino , Proteínas Ligadas por GPI/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Instabilidade Genômica/efeitos dos fármacos , Humanos , Células MCF-7 , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Membro 10c de Receptores do Fator de Necrose Tumoral/genética , Transdução de Sinais/efeitos dos fármacos , Receptores Chamariz do Fator de Necrose Tumoral/genética
3.
Cells ; 10(12)2021 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-34944078

RESUMO

Population aging is occurring rapidly worldwide, challenging the global economy and healthcare services. Brain aging is a significant contributor to various age-related neurological and neuropsychological disorders, including Alzheimer's disease and Parkinson's disease. Several extrinsic factors, such as exposure to ionizing radiation, can accelerate senescence. Multiple human and animal studies have reported that exposure to ionizing radiation can have varied effects on organ aging and lead to the prolongation or shortening of life span depending on the radiation dose or dose rate. This paper reviews the effects of radiation on the aging of different types of brain cells, including neurons, microglia, astrocytes, and cerebral endothelial cells. Further, the relevant molecular mechanisms are discussed. Overall, this review highlights how radiation-induced senescence in different cell types may lead to brain aging, which could result in the development of various neurological and neuropsychological disorders. Therefore, treatment targeting radiation-induced oxidative stress and neuroinflammation may prevent radiation-induced brain aging and the neurological and neuropsychological disorders it may cause.


Assuntos
Encéfalo/patologia , Senescência Celular/efeitos da radiação , Radiação Ionizante , Animais , Autofagia/efeitos da radiação , Humanos , Mitocôndrias/patologia , Mitocôndrias/efeitos da radiação , Estresse Oxidativo/efeitos da radiação
4.
Cells ; 10(12)2021 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-34943875

RESUMO

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in a global pandemic associated with substantial morbidity and mortality worldwide, with particular risk for severe disease and mortality in the elderly population. SARS-CoV-2 infection is driven by a pathological hyperinflammatory response which results in a dysregulated immune response. Current advancements in aging research indicates that aging pathways have fundamental roles in dictating healthspan in addition to lifespan. Our review discusses the aging immune system and highlights that senescence and aging together, play a central role in COVID-19 pathogenesis. In our review, we primarily focus on the immune system response to SARS-CoV-2 infection, the interconnection between severe COVID-19, immunosenescence, aging, vaccination, and the emerging problem of Long-COVID. We hope to highlight the importance of identifying specific senescent endotypes (or "sendotypes"), which can used as determinants of COVID-19 severity and mortality. Indeed, identified sendotypes could be therapeutically exploited for therapeutic intervention. We highlight that senolytics, which eliminate senescent cells, can target aging-associated pathways and therefore are proving attractive as potential therapeutic options to alleviate symptoms, prevent severe infection, and reduce mortality burden in COVID-19 and thus ultimately enhance healthspan.


Assuntos
Envelhecimento/patologia , COVID-19/patologia , SARS-CoV-2/fisiologia , Animais , Biomarcadores/metabolismo , Senescência Celular , Humanos
5.
Int J Mol Sci ; 22(24)2021 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-34948290

RESUMO

Salivary gland function is commonly and irreversibly damaged by radiation therapy for head and neck cancer. This damage greatly decreases the patient's quality of life and is difficult to remedy. Previously, we found that the transient activation of Hedgehog signaling alleviated salivary hypofunction after radiation in both mouse and pig models through the inhibition of radiation-induced cellular senescence that is mediated by resident macrophages in mouse submandibular glands. Here we report that in swine parotid glands sharing many features with humans, the Hedgehog receptor PTCH1 is mainly expressed in macrophages, and levels of PTCH1 and multiple macrophage markers are significantly decreased by radiation but recovered by transient Hedgehog activation. These parotid macrophages mainly express the M2 macrophage marker ARG1, while radiation promotes expression of pro-inflammatory cytokine that is reversed by transient Hedgehog activation. Hedgehog activation likely preserves parotid macrophages after radiation through inhibition of P53 signaling and consequent cellular senescence. Consistently, VEGF, an essential anti-senescence cytokine downstream of Hedgehog signaling, is significantly decreased by radiation but recovered by transient Hedgehog activation. These findings indicate that in the clinically-relevant swine model, transient Hedgehog activation restores the function of irradiated salivary glands through the recovery of resident macrophages and the consequent inhibition of cellular senescence and inflammation.


Assuntos
Senescência Celular/fisiologia , Proteínas Hedgehog/metabolismo , Inflamação/metabolismo , Macrófagos/metabolismo , Glândulas Salivares/metabolismo , Transdução de Sinais/fisiologia , Animais , Citocinas/metabolismo , Masculino , Glândula Parótida/metabolismo , Receptor Patched-1/metabolismo , Glândula Submandibular/metabolismo , Suínos , Proteína Supressora de Tumor p53/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
6.
Nutrients ; 13(12)2021 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-34960102

RESUMO

The role of the microbiome in human aging is important: the microbiome directly impacts aging through the gastrointestinal system. However, the microbial impact on skin has yet to be fully understood. For example, cellular senescence is an intrinsic aging process that has been recently associated with microbial imbalance. With age, cells become senescent in response to stress wherein they undergo irreversible growth arrest while maintaining high metabolic activity. An accumulation of senescent cells has been linked to various aging and chronic pathologies due to an overexpression of the senescence-associated secretory phenotype (SASP) comprised of proinflammatory cytokines, chemokines, growth factors, proteases, lipids and extracellular matrix components. In particular, dermatological disorders may be promoted by senescence as the skin is a common site of accumulation. The gut microbiota influences cellular senescence and skin disruption through the gut-skin axis and secretion of microbial metabolites. Metabolomics can be used to identify and quantify metabolites involved in senescence. Moreover, novel anti-senescent therapeutics are warranted given the poor safety profiles of current pharmaceutical drugs. Probiotics and prebiotics may be effective alternatives, considering the relationship between the microbiome and healthy aging. However, further research on gut composition under a senescent status is needed to develop immunomodulatory therapies.


Assuntos
Envelhecimento , Senescência Celular/fisiologia , Microbioma Gastrointestinal/fisiologia , Saúde , Envelhecimento Saudável/fisiologia , Longevidade , Prebióticos , Probióticos , Envelhecimento da Pele , Fenômenos Fisiológicos da Pele , Envelhecimento/metabolismo , Citocinas/metabolismo , Disbiose , Humanos , Mediadores da Inflamação/metabolismo , Fenômenos Fisiológicos da Nutrição/fisiologia
7.
Cancer Res ; 81(24): 6087-6089, 2021 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-34911777

RESUMO

Cellular senescence represents a double-edged sword in cancer and its therapy. On one side, senescence-associated growth arrest and immunomodulatory properties exert potent antimalignant functions. On the other side, senescence bypass and secretory phenotype are associated with tumor progression and relapse. Recent studies have demonstrated the enormous potential to combine pro- to antisenescence interventions as a new anticancer approach. However, the heterogeneity of senescence-associated features makes definition and targeting of therapy-induced senescent cells a challenging task. Here, we describe these challenges and discuss how to exploit senescence-associated features to improve treatment efficacy and tolerability.


Assuntos
Antineoplásicos/uso terapêutico , Senescência Celular , Imunomodulação , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Humanos , Neoplasias/imunologia
8.
Artigo em Inglês | MEDLINE | ID: mdl-34936295

RESUMO

Glioma is one of the most common types of primary intracranial tumors. The relationship between triiodothyronine (T3) and glioma is not clear. This study aimed to investigate the effect of T3 on the proliferation of glioma cells and its mechanism. Cell viability was analyzed by cell counting kit 8 assay. Flow cytometry analysis was used to detect cell apoptosis and cell cycle. Thyroid hormone receptor α (THRA) and thyroid hormone receptor ß (THRB) were silenced by transfecting si-THRA and si-THRB plasmids into HS683 and A172 glioma cells. Western blot was performed to assess the protein expressions. The results indicated that triiodothyronine (T3) affected the viability, apoptosis and cell cycle of HS683 and A172 glioma cells. Cell apoptosis was significantly inhibited in si-THRA and si-THRB experimental groups. Moreover, knockdown of THRA and THRB reversed the G1 and G2 phase arrest led by T3 and induced an up-regulation of cyclin D1 expression. The phosphorylated extracellular signal-regulated kinase (p-ERK), p-AKT, and phosphorylated signal transducer and activator of transcription (p-STAT3) proteins were markedly increased by inhibiting THRA and THRB in HS683 and A172 glioma cells. T3 affected apoptosis and cell cycle of glioma cells through regulating THRA and THRB expressions. THRA and THRB may affect glioma development through regulating, at least partially, the mitogen-activated protein kinase (MAPK)/ERK and phosphoinositide 3-kinase (PI3K)/Akt signaling pathways.


Assuntos
Apoptose/genética , Senescência Celular/genética , Glioma/fisiopatologia , Receptores alfa dos Hormônios Tireóideos/genética , Receptores beta dos Hormônios Tireóideos/genética , Tri-Iodotironina/metabolismo , Linhagem Celular Tumoral , Inativação Gênica , Humanos , Receptores alfa dos Hormônios Tireóideos/metabolismo , Receptores beta dos Hormônios Tireóideos/metabolismo
9.
J Environ Pathol Toxicol Oncol ; 40(4): 53-60, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34936300

RESUMO

Ferroptosis is a classification of programmed cell death, which activates oxidative cell death in an iron and lipid peroxides-dependent manner. Targeting ferroptosis is a novel therapeutic approach for cancer therapy. Lung cancer is the leading cause of cancer related deaths all over the world. Circular RNAs (circRNAs), as a form of noncoding RNAs with a specific closed circular sequence are emerging as a new field in cancer research. However, the regulatory mechanisms of circRNAs in ferroptosis during lung cancer development are still elusive. In this work, we elucidate the potential prognostic value and the crucial role of circular RNA circFOXP1 in ferroptosis of lung cancer. We found that the expression of circFOXP1 was remarkably up-regulated in clinical lung sample tissues compared with adjacent tissues. The up-regulation of circFOXP1 was closely correlated with the poor overall survival of lung cancer patients. The knockdown of circFOXP1 suppressed the cell viability of lung cancer cells. The colony formation counts of lung cancer cells were repressed by the depletion of circFOXP1 as well. The Edu-positive lung cancer cells were attenuated by the silencing of circFOXP1. The migration and invasion of lung cancer cells were suppressed by circFOXP1 short hairpin RNA (shRNA). The expression of E-cadherin was enhanced, and vimentin expression was reduced by the knockdown of circFOXP1. Moreover, the treatment of ferroptosis activator erastin or RSL3 repressed the cell viability of lung cancer cells and the overexpression of circFOXP1 rescued the phenotype. The levels of malondialdehyde (MDA), iron, and lipid reactive oxygen species (ROS) were enhanced by the silencing of circFOXP1 in both erastin and RSL3-stimulated lung cancer cells. Mechanically, circFOXP1 increased SLC7A11 expression by directly sponging miR-520a-5p in lung cancer cells. The inhibitor of miR-520a-5p or the overexpression of SLC7A11 reversed circFOXP1 shRNA-induced ferroptosis phenotypes in lung cancer cells. Importantly, circFOXP1 contributed to tumor growth of lung cancer cells by enhancing SLC7A11 in vivo. Collectively, we concluded that circular RNA circFOXP1 is a potential diagnostic biomarker and contributes to malignant progression by repressing ferroptosis of lung cancer. Targeting circFOXP1 may be served as a promising therapeutic approach for lung cancer.


Assuntos
Antineoplásicos/farmacologia , Senescência Celular/efeitos dos fármacos , Curcumina/farmacologia , Ferroptose/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Quercetina/farmacologia , Sistema y+ de Transporte de Aminoácidos/genética , Sistema y+ de Transporte de Aminoácidos/metabolismo , Carcinogênese/efeitos dos fármacos , Ferroptose/genética , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Mitocôndrias , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo
10.
Cells ; 10(12)2021 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-34944052

RESUMO

Aging is the consequence of a lifelong accumulation of stochastic damage to tissues and cellular components. Advancing age closely associates with elevated markers of innate immunity and low-grade chronic inflammation, probably reflecting steady increasing incidents of cellular and tissue damage over the life course. The DNA sensing cGAS-STING signaling pathway is activated by misplaced cytosolic self-DNA, which then initiates the innate immune responses. Here, we hypothesize that the stochastic release of various forms of DNA from the nucleus and mitochondria, e.g., because of DNA damage, altered nucleus integrity, and mitochondrial damage, can result in chronic activation of inflammatory responses that characterize the aging process. This cytosolic self-DNA-innate immunity axis may perturb tissue homeostasis and function that characterizes human aging and age-associated pathology. Proper techniques and experimental models are available to investigate this axis to develop therapeutic interventions.


Assuntos
Envelhecimento/patologia , Citosol/metabolismo , DNA/metabolismo , Inflamação/patologia , Autofagia , Senescência Celular , Humanos
11.
Zhongguo Zhong Yao Za Zhi ; 46(23): 6216-6223, 2021 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-34951248

RESUMO

This study aims to explore the effect of extract of Ginseng Radix et Rhizoma, Notoginseng Radix et Rhizoma, and Chuanxiong Rhizoma(hereinafter referred to as GNS) on the SIRT1-autophagy pathway of endothelial cell senescence induced by hydrogen peroxide(H_2O_2). To be specific, vascular endothelial cells were classified into the blank control group(control), model group(model), model + DMSO group(DMSO), resveratrol group(RESV), and GNS low-dose(GNS-L), medium-dose(GNS-M), and high-dose(GNS-H) groups. They were treated with H_2O_2 for senescence induction except the control. After intervention of cells in each group with corresponding drugs for 24 h, cell growth status was observed under an inverted microscope, and the formation of autophagosome under the transmission electron microscope. In addition, the changes of microtubule-associated protein 1 light chain 3ß(LC3 B) were detected by immunofluorescence staining. The autophagy flux was tracked with the autophagy double-labeled adenovirus(mRFP-GFP-LC3) fusion protein. Dansylcadaverine(MDC) staining was employed to determine the autophagic vesicles, and Western blot the expression of sirtuin 1(SIRT1), ubiquitin-binding protein p62, and LC3Ⅱ. After H_2O_2 induction, cells demonstrated slow growth, decreased adhesion ability, raised number of SA-ß-gal-stained blue ones, a certain number of autophagosomes with bilayer membrane and secondary lysosomes in the cytoplasm, and slight rise of autophagy flux level. Compared with the model group, GNS groups showed improved morphology, moderate adhesion ability, complete and smooth membrane, decreased SA-ß-gal-stained blue cells, many autophagosomes, autophagic vesicles, and secondary lysosomes in the cytoplasm, increased autophagolysosomes, autophagy flux level, and fluorescence intensity of LC3 B and MDC, up-regulated expression of SIRT1 and LC3Ⅱ, and down-regulated expression of p62, suggesting the improvement of autophagy level. GNS can delay the senescence of vascular endothelial cells. After the intervention, the autophagy flux and related proteins SIRT1, LC3Ⅱand p62 changed significantly, and the autophagy level increased significantly. However, EX527 weakened the effect of Chinese medicine in delaying vascular senescence. GNS may delay the senescence of vascular endothelial cells through the SIRT1 autophagy pathway.


Assuntos
Autofagia , Medicamentos de Ervas Chinesas/farmacologia , Células Endoteliais/efeitos dos fármacos , Panax , Células Cultivadas , Senescência Celular , Peróxido de Hidrogênio , Panax/química , Sirtuína 1/genética
12.
Recurso na Internet em Português | LIS - Localizador de Informação em Saúde | ID: lis-48555

RESUMO

Casos graves de Covid-19 estão associados a um processo de envelhecimento do sistema imunológico e imunodeficiência aguda. É o que aponta um novo estudo liderado pelo Instituto Oswaldo Cruz (IOC/Fiocruz) e pela Universidade Federal do Rio de Janeiro (UFRJ), publicado na revista científica Journal of Infectious Diseases.


Assuntos
COVID-19 , Senescência Celular , Sistema Imunitário
13.
Front Cell Infect Microbiol ; 11: 744013, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34746026

RESUMO

The cellular changes occurring due to senescence like proliferation arrest, increase in free radical levels, and secretion of pro-inflammatory cytokines have been well studied, but its associated alteration in intracellular signalling networks has been scarcely explored. In this study, we examine the roles of three major kinases viz. p38 MAPK, ERK, and STAT3 in regulating iNOS expression and thereby the levels of the free radical Nitric oxide in senescent cells. Our study revealed that these kinases could differentially regulate iNOS in senescent cells compared to non-senescent cells. Further, we tested the physiological relevance of these alterations with Salmonella infection assays and established an inter-regulatory network between these kinases unique to infected senescent cells. Overall, our findings show how key signalling networks may be rewired in senescent cells rendering them phenotypically different.


Assuntos
Sistema de Sinalização das MAP Quinases , Infecções por Salmonella , Senescência Celular , Humanos , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Fator de Transcrição STAT3 , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
14.
EMBO Mol Med ; 13(11): e14146, 2021 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-34725920

RESUMO

The mechanisms underlying the development of glomerular lesions during aging are largely unknown. It has been suggested that senescence might play a role, but the pathophysiological link between senescence and lesion development remains unexplained. Here, we uncovered an unexpected role for glomerular endothelial cells during aging. In fact, we discovered a detrimental cross-talk between senescent endothelial cells and podocytes, through PAI-1. In vivo, selective inactivation of PAI-1 in endothelial cells protected glomeruli from lesion development and podocyte loss in aged mice. In vitro, blocking PAI-1 in supernatants from senescent endothelial cells prevented podocyte apoptosis. Consistently, depletion of senescent cells prevented podocyte loss in old p16 INK-ATTAC transgenic mice. Importantly, these experimental findings are relevant to humans. We showed that glomerular PAI-1 expression was predictive of poor outcomes in transplanted kidneys from elderly donors. In addition, we observed that in elderly patients, urinary PAI-1 was associated with age-related chronic kidney disease. Altogether, these results uncover a novel mechanism of kidney disease and identify PAI-1 as a promising biomarker of kidney dysfunction in allografts from elderly donors.


Assuntos
Nefropatias , Podócitos , Idoso , Animais , Senescência Celular , Células Endoteliais , Humanos , Glomérulos Renais , Camundongos , Inibidor 1 de Ativador de Plasminogênio
15.
Biogerontology ; 22(6): 623-637, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34637040

RESUMO

Cell surface glycoproteins, which are good indicators of cellular types and biological function; are suited for cell evaluation. Tissue remodeling using various cells is a key feature of regenerative therapy. For artificial heart remodeling, a mixture of heart constituent cells has been investigated for organ assembly, however, the cellular characteristics remain unclear. In this study, the glycan profiles of human cardiomyocytes (HCMs), human cardiac fibroblasts (HCFs), and human vascular endothelial cells (ECs) were analyzed using evanescent-field lectin microarray analysis, a tool of glycan profiling, to clarify the required cellular characteristics. We found that ECs had more "α1-2fucose" and "core α1-6fucose" residues than other cells, and that "α2-6sialic acid" residue was more abundant in ECs and HCMs than in HCFs. HCFs showed higher abundance of "ß-galactose" and "ß-N-acetylgalactosamine" residues on N-glycan and O-glycan, respectively, compared to other cells. Interestingly, cardiac glycan profiles were insignificantly changed with cellular senescence. The residues identified in this study may participate in organ maintenance by contributing to the preservation of glycan components. Therefore, future studies should investigate the roles of glycans in optimal tissue remodeling since identifying cellular characteristics is important for the development of regenerative therapies.


Assuntos
Células Endoteliais , Polissacarídeos , Senescência Celular , Fibroblastos , Galactose , Humanos
16.
Nat Commun ; 12(1): 5899, 2021 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-34625566

RESUMO

Histones are closely related to the state of chromatin, and epigenetic modification of their tail results in regulation in cells. Therefore, developing various analytical tools to map the changes in position and distribution of histone modifications is helpful in studying underlying mechanisms. Herein, we propose a high-spatial and colourimetric imaging method using plasmonic nanoparticles as probes to visualize heterochromatin histone markers in a single nucleus. We visualized the reorganization between repressive histone markers, H3K9me3 and H3K27me3, caused by oncogene-induced senescence based on the scattering colours and spectral shift of plasmonic nanoprobes to longer wavelengths using their distance-dependent coupling effect. The measured scattering profiles were correlated with the computation results simulating the scattering spectra according to the arrangements and distances among the plasmonic nanoprobes. The plasmonic nanoprobe-based high-spatial hyperspectral imaging provides an advanced way to study the dynamics of histone modifications for predicting the progression of diseases or senescence.


Assuntos
Colorimetria/métodos , Código das Histonas , Processamento de Proteína Pós-Traducional , Animais , Senescência Celular , Cromatina , Epigênese Genética , Heterocromatina , Histonas/metabolismo , Humanos , Camundongos , Nanopartículas
17.
Anal Chem ; 93(41): 13800-13806, 2021 10 19.
Artigo em Inglês | MEDLINE | ID: mdl-34606237

RESUMO

Aging is a biological process, and its gradual degeneration of physiological functions leads to an increase in morbidity and mortality. At present, more and more studies on aging and anti-aging drugs have been conducted, which are of great significance for promoting human health, treating aging-related diseases, and prolonging human life. In the process of aging research and evaluation of anti-aging drugs, ß-galactosidase, as an important criterion of aging, has received extensive attention. However, there is a scarcity of effective and reliable tools for aging research and anti-aging drug evaluation based on the aging markers. Hence, we developed a new highly sensitive fluorescent probe, YDGAL, for ß-galactosidase, which exhibited good affinity for ß-gal (Km = 12.35 µM), fast response speed (stable within 10 min), and extremely low detection limit (2.185 × 10-6 U/mL). Owing to the above advantages, the robust probe can visualize aging and evaluate the efficacy of anti-aging drugs at the cellular and organ levels by detecting ß-galactosidase. Through visual imaging of mouse organs, we found that the organs had different degrees of aging; dasatinib and quercetin combination therapy had a therapeutic effect on the mice, but the different organs showed distinct clearance rates on the senescent cells, which may be the limitation of the drugs. We believe that this interesting finding could provide a powerful guidance for the research on aging and the evaluation of anti-aging drugs in the future.


Assuntos
Envelhecimento , Preparações Farmacêuticas , Animais , Biomarcadores , Senescência Celular , Corantes Fluorescentes , Camundongos , beta-Galactosidase
18.
Elife ; 102021 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-34617510

RESUMO

Senescent cells have detrimental effects across tissues with aging but may have beneficial effects on tissue repair, specifically on skin wound healing. However, the potential role of senescent cells in fracture healing has not been defined. Here, we performed an in silico analysis of public mRNAseq data and found that senescence and senescence-associated secretory phenotype (SASP) markers increased during fracture healing. We next directly established that the expression of senescence biomarkers increased markedly during murine fracture healing. We also identified cells in the fracture callus that displayed hallmarks of senescence, including distension of satellite heterochromatin and telomeric DNA damage; the specific identity of these cells, however, requires further characterization. Then, using a genetic mouse model (Cdkn2aLUC) containing a Cdkn2aInk4a-driven luciferase reporter, we demonstrated transient in vivo senescent cell accumulation during callus formation. Finally, we intermittently treated young adult mice following fracture with drugs that selectively eliminate senescent cells ('senolytics', Dasatinib plus Quercetin), and showed that this regimen both decreased senescence and SASP markers in the fracture callus and significantly accelerated the time course of fracture healing. Our findings thus demonstrate that senescent cells accumulate transiently in the murine fracture callus and, in contrast to the skin, their clearance does not impair but rather improves fracture healing.


Assuntos
Senescência Celular , Consolidação da Fratura , Animais , Biomarcadores , Dano ao DNA , Feminino , Humanos , Masculino , Camundongos , Modelos Animais
19.
Toxicol Lett ; 352: 61-69, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34624459

RESUMO

Mitomycin treatment induces pulmonary toxicity, and alveolar epithelial cell senescence is crucial in the pathogenesis of the latter. However, the mechanism by which mitomycin induces alveolar epithelial cell senescence has yet to be elucidated. In this work, different doses (37.5-300 nM) of mitomycin induced the senescence of human alveolar type II-like epithelial cells and enhanced the phosphorylation of GSK3ß (S9). The GSK3ß (S9A) mutant reversed the senescence of mitomycin-treated alveolar epithelial cells. Pharmacological inhibition and gene deletion of Akt1, a kinase that regulates the phosphorylation of GSK3ß (S9), suppressed mitomycin-induced alveolar epithelial cell senescence. The knockdown of p53, a downstream effector of GSK3ß and an important regulator of cell senescence, repressed mitomycin-induced alveolar epithelial cell senescence. Treatment with baicalein weakened the phosphorylation of GSK3ß (S9) and alleviated the senescence of alveolar epithelial cells brought about by mitomycin treatment. GSK3ß (S9) phosphorylation appears to be the first signal involved in the mitomycin-induced senescence of alveolar epithelial cells and may present a potential target for attenuating mitomycin-induced pulmonary toxicity.


Assuntos
Alquilantes/toxicidade , Regulação para Baixo/efeitos dos fármacos , Glicogênio Sintase Quinase 3 beta/metabolismo , Mitomicina/toxicidade , Alvéolos Pulmonares/efeitos dos fármacos , Células A549 , Senescência Celular/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Flavanonas/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Glicogênio Sintase Quinase 3 beta/genética , Humanos , Imidazóis/farmacologia , Inibidor 1 de Ativador de Plasminogênio/genética , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Alvéolos Pulmonares/citologia , Piridinas/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
20.
Life Sci ; 285: 119997, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34597608

RESUMO

AIM: Sirtuin 2 (SIRT2) is a NAD+-dependent deacetylase involved in various biological functions via deacetylation of proteins, including histone protein. Hepatic fat accumulation from aging and excess caloric intake contribute to development of non-alcoholic fatty liver disease. The study aim was to elucidate the role of SIRT2 in lipid metabolism homeostasis. MATERIALS AND METHODS: SIRT2+/+ (C57BL/6) and SIRT2-/- were randomly assigned to normal diet or high-fat diet (HFD) groups and fed for 6 weeks. Histological features of the livers were evaluated by hematoxylin and eosin and Masson's trichrome staining, and the levels of selected factors were determined by quantitative reverse transcription-polymerase chain reaction and western blot analysis. KEY FINDINGS: Although the SIRT2-/- mice were viable, their livers exhibited higher glycogen accumulation, and skeletal muscle showed features of increased metabolic demand. The SIRT2-/- mice attenuated HFD-induced weight gain, visceral adipose tissue formation, and fat accumulation in the liver in which the expressions of genes involved in metabolic substrate transport were modified. Additionally, the hepatocellular senescence and upregulated cell-cycle factors upon HFD intake in SIRT2-/- livers suggested a role of SIRT2 in gene expression during abnormal metabolism. Moreover, the fibrotic phenotype of liver tissue without fat accumulation and the increased expression of genes involved in liver fibrosis in the HFD-fed SIRT2-/- mice indicated that SIRT2 had a role in hepatocyte and hepatic stellate cell activation. SIGNIFICANCE: Our results indicated that SIRT2 has a critical role in regulating lipid metabolic homeostasis and in sustaining liver integrity by modulating related gene expression.


Assuntos
Gorduras/metabolismo , Cirrose Hepática/metabolismo , Sirtuína 2/fisiologia , Animais , Senescência Celular , Dieta Hiperlipídica , Glicogênio/metabolismo , Homeostase , Gordura Intra-Abdominal/metabolismo , Fígado/citologia , Fígado/patologia , Cirrose Hepática/genética , Cirrose Hepática/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Sirtuína 2/genética , Ganho de Peso/genética
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