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1.
Cancer Genomics Proteomics ; 18(5): 661-673, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34479918

RESUMO

BACKGROUND/AIM: Coronavirus disease 2019 (COVID-19) poses a great challenge for the treatment of cancer patients. It presents as a severe respiratory infection in aged individuals, including some lung cancer patients. COVID-19 may be linked to the progression of aggressive lung cancer. In addition, the side effects of chemotherapy, such as chemotherapy resistance and the acceleration of cellular senescence, can worsen COVID-19. Given this situation, we investigated the role of paclitaxel (a chemotherapy drug) in the cell proliferation, apoptosis, and cellular senescence of gefitinib-resistant non-small-cell lung cancer (NSCLC) cells (PC9-MET) to clarify the underlying mechanisms. MATERIALS AND METHODS: PC9-MET cells were treated with paclitaxel for 72 h and then evaluated by a cell viability assay, DAPI staining, Giemsa staining, apoptosis assay, a reactive oxygen species (ROS) assay, SA-ß-Gal staining, a terminal deoxynucleotidyl transferase dUTP nick-end labeling assay and Western blotting. RESULTS: Paclitaxel significantly reduced the viability of PC9-MET cells and induced morphological signs of apoptosis. The apoptotic effects of paclitaxel were observed by increased levels of cleaved caspase-3 (Asp 175), cleaved caspase-9 (Asp 330) and cleaved PARP (Asp 214). In addition, paclitaxel increased ROS production, leading to DNA damage. Inhibition of ROS production by N-acetylcysteine attenuates paclitaxel-induced DNA damage. Importantly, paclitaxel eliminated cellular senescence, as observed by SA-ß-Gal staining. Cellular senescence elimination was associated with p53/p21 and p16/pRb signaling inactivation. CONCLUSION: Paclitaxel may be a promising anticancer drug and offer a new therapeutic strategy for managing gefitinib-resistant NSCLC during the COVID-19 pandemic.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Gefitinibe/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Paclitaxel/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos
2.
Nat Commun ; 12(1): 5213, 2021 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-34480023

RESUMO

Intervertebral disc degeneration is highly prevalent within the elderly population and is a leading cause of chronic back pain and disability. Due to the link between disc degeneration and senescence, we explored the ability of the Dasatinib and Quercetin drug combination (D + Q) to prevent an age-dependent progression of disc degeneration in mice. We treated C57BL/6 mice beginning at 6, 14, and 18 months of age, and analyzed them at 23 months of age. Interestingly, 6- and 14-month D + Q cohorts show lower incidences of degeneration, and the treatment results in a significant decrease in senescence markers p16INK4a, p19ARF, and SASP molecules IL-6 and MMP13. Treatment also preserves cell viability, phenotype, and matrix content. Although transcriptomic analysis shows disc compartment-specific effects of the treatment, cell death and cytokine response pathways are commonly modulated across tissue types. Results suggest that senolytics may provide an attractive strategy to mitigating age-dependent disc degeneration.


Assuntos
Envelhecimento/efeitos dos fármacos , Dasatinibe/uso terapêutico , Degeneração do Disco Intervertebral/tratamento farmacológico , Quercetina/uso terapêutico , Agrecanas/metabolismo , Envelhecimento/metabolismo , Animais , Anel Fibroso/efeitos dos fármacos , Anel Fibroso/metabolismo , Anel Fibroso/patologia , Sobrevivência Celular/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , Fibrose , Inflamação , Degeneração do Disco Intervertebral/metabolismo , Degeneração do Disco Intervertebral/patologia , Camundongos , Camundongos Endogâmicos C57BL , Núcleo Pulposo/efeitos dos fármacos , Núcleo Pulposo/metabolismo , Núcleo Pulposo/patologia , Fenótipo , Transcriptoma/efeitos dos fármacos
3.
Int J Mol Sci ; 22(15)2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34360912

RESUMO

Cellular senescence is a form of proliferative arrest triggered in response to a wide variety of stimuli and characterized by unique changes in cell morphology and function. Although unable to divide, senescent cells remain metabolically active and acquire the ability to produce and secrete bioactive molecules, some of which have recognized pro-inflammatory and/or pro-tumorigenic actions. As expected, this "senescence-associated secretory phenotype (SASP)" accounts for most of the non-cell-autonomous effects of senescent cells, which can be beneficial or detrimental for tissue homeostasis, depending on the context. It is now evident that many features linked to cellular senescence, including the SASP, reflect complex changes in the activities of mTOR and other metabolic pathways. Indeed, the available evidence indicates that mTOR-dependent signaling is required for the maintenance or implementation of different aspects of cellular senescence. Thus, depending on the cell type and biological context, inhibiting mTOR in cells undergoing senescence can reverse senescence, induce quiescence or cell death, or exacerbate some features of senescent cells while inhibiting others. Interestingly, autophagy-a highly regulated catabolic process-is also commonly upregulated in senescent cells. As mTOR activation leads to repression of autophagy in non-senescent cells (mTOR as an upstream regulator of autophagy), the upregulation of autophagy observed in senescent cells must take place in an mTOR-independent manner. Notably, there is evidence that autophagy provides free amino acids that feed the mTOR complex 1 (mTORC1), which in turn is required to initiate the synthesis of SASP components. Therefore, mTOR activation can follow the induction of autophagy in senescent cells (mTOR as a downstream effector of autophagy). These functional connections suggest the existence of autophagy regulatory pathways in senescent cells that differ from those activated in non-senescence contexts. We envision that untangling these functional connections will be key for the generation of combinatorial anti-cancer therapies involving pro-senescence drugs, mTOR inhibitors, and/or autophagy inhibitors.


Assuntos
Autofagia , Senescência Celular , Neoplasias/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Autofagia/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Neoplasias/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/antagonistas & inibidores
4.
FASEB J ; 35(9): e21795, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34403508

RESUMO

Intervertebral disc degeneration is an irreversible process associated with accumulation of senescent nucleus pulposus (NP) cells. This study investigates the hypothesis that Tumor necrosis factor-α (TNF-α)-treated senescent NP cells propagate senescence of neighboring healthy cells via a paracrine effect that involves p-Stat3 signaling and the cytokine interleukin-6 (IL-6). NP cells isolated from bovine caudal intervertebral disc (IVD) were treated with TNF-α to induce senescence which was confirmed by demonstrating upregulation of senescence-associated ß-galactosidase and p16. This was correlated with downregulation of NP-associated markers, Aggrecan, Col2A1, and Sox9. Direct contact and non-contact co-culture of healthy and senescent cells showed that TNF-α-treated cells increased the senescence in healthy cells via a paracrine effect. The senescent cells have a secretory phenotype as indicated by increased gene and protein levels of IL-6. Phosphorylated Signal Transducer and Activator of Transcription 3 (pStat3) levels were also high in treated cells and appeared to upregulate IL-6 as inhibition of Stat3 phosphorylation by StatticV downregulated IL-6 mRNA expression in cells and protein levels in the culture media. All trans retinoic acid, an IL-6 inhibitor, also decreased the secretion of IL-6 and reduced the paracrine effect of senescent cells on healthy cells. Decreased pStat3 levels and inhibition of IL-6 secretion did not fully restore NP gene expression of Col2A1 but importantly, appeared to cause senescent cells to undergo apoptosis and cell death. This study demonstrated the paracrine effect of senescent NP cells which involves Stat3 and IL-6 and may explain why senescent NP cells accumulate in IVD with age. The role of pSTAT3 and IL-6 in mediating NP senescence requires further study as it may be a novel strategy for modulating the senescent-inducing effects of TNF-α.


Assuntos
Senescência Celular/efeitos dos fármacos , Núcleo Pulposo/citologia , Núcleo Pulposo/efeitos dos fármacos , Comunicação Parácrina/efeitos dos fármacos , Fator de Necrose Tumoral alfa/farmacologia , Animais , Apoptose/efeitos dos fármacos , Bovinos , Morte Celular/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Interleucina-6/antagonistas & inibidores , Interleucina-6/metabolismo , Núcleo Pulposo/metabolismo , Fosforilação , Fator de Transcrição STAT3/metabolismo
5.
Nutrients ; 13(7)2021 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-34371895

RESUMO

BACKGROUND: Curcumin, a natural polyphenol and the principal bioactive compound in Curcuma longa, was reported to have anti-inflammatory, anti-cancer, anti-diabetic and anti-rheumatic activity. Curcumin is not only considered for preventive, but also for therapeutic, purposes in cancer therapy, which requires a killing effect on cancer cells. A drawback, however, is the low bioavailability of curcumin due to its insolubility in water. To circumvent this limitation, curcumin was administered in different water-soluble formulations, including liposomes or embedded into nanoscaled micelles. The high uptake rate of micellar curcumin makes it attractive also for cancer therapeutic strategies. Native curcumin solubilised in organic solvent was previously shown to be cytotoxic and bears a genotoxic potential. Corresponding studies with micellar curcumin are lacking. METHODS: We compared the cytotoxic and genotoxic activity of native curcumin solubilised in ethanol (Cur-E) with curcumin embedded in micells (Cur-M). We measured cell death by MTT assays, apoptosis, necrosis by flow cytometry, senolysis by MTT and C12FDG and genotoxicity by FPG-alkaline and neutral singe-cell gel electrophoresis (comet assay). RESULTS: Using a variety of primary and established cell lines, we show that Cur-E and Cur-M reduce the viability in all cell types in the same dose range. Cur-E and Cur-M induced dose-dependently apoptosis, but did not exhibit senolytic activity. In the cytotoxic dose range, Cur-E and Cur-M were positive in the alkaline and the neutral comet assay. Genotoxic effects vanished upon removal of curcumin, indicating efficient and complete repair of DNA damage. For inducing cell death, which was measured 48 h after the onset of treatment, permanent exposure was required while 60 min pulse-treatment was ineffective. In all assays, Cur-E and Cur-M were equally active, and the concentration above which significant cytotoxic and genotoxic effects were observed was 10 µM. Micelles not containing curcumin were completely inactive. CONCLUSIONS: The data show that micellar curcumin has the same cytotoxicity and genotoxicity profile as native curcumin. The effective concentration on different cell lines, including primary cells, was far above the curcumin concentration that can be achieved systemically in vivo, which leads us to conclude that native curcumin and curcumin administered as food supplement in a micellar formulation at the ADI level are not cytotoxic/genotoxic, indicating a wide margin of safety.


Assuntos
Apoptose/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Curcumina/toxicidade , Dano ao DNA , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ensaio Cometa , Curcumina/química , Relação Dose-Resposta a Droga , Composição de Medicamentos , Etanol/química , Humanos , Lipossomos , Micelas , Necrose , Medição de Risco , Solubilidade , Solventes/química
6.
Nutrients ; 13(7)2021 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-34371855

RESUMO

Aging is a biological process determined by multiple cellular mechanisms, such as genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication, that ultimately concur in the functional decline of the individual. The evidence that the old population is steadily increasing and will triplicate in the next 50 years, together with the fact the elderlies are more prone to develop pathologies such as cancer, diabetes, and degenerative disorders, stimulates an important effort in finding specific countermeasures. Calorie restriction (CR) has been demonstrated to modulate nutrient sensing mechanisms, inducing a better metabolic profile, enhanced stress resistance, reduced oxidative stress, and improved inflammatory response. Therefore, CR and CR-mimetics have been suggested as powerful means to slow aging and extend healthy life-span in experimental models and humans. Taking into consideration the difficulties and ethical issues in performing aging research and testing anti-aging interventions in humans, researchers initially need to work with experimental models. The present review reports the major experimental models utilized in the study of CR and CR-mimetics, highlighting their application in the laboratory routine, and their translation to human research.


Assuntos
Envelhecimento/fisiologia , Materiais Biomiméticos/farmacologia , Restrição Calórica , Modelos Teóricos , Pesquisa Médica Translacional/métodos , Envelhecimento/efeitos dos fármacos , Animais , Senescência Celular/efeitos dos fármacos , Senescência Celular/fisiologia , Humanos , Longevidade/efeitos dos fármacos , Longevidade/fisiologia
7.
Biomed Res Int ; 2021: 3456321, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34458366

RESUMO

Inflammation response is an important reason for disc cell senescence during disc degeneration. Recently, melatonin is suggested to protect against disc degeneration. However, the effects of melatonin on annulus fibrosus (AF) cell senescence are not fully studied. The main purpose of this study was to investigate the effects of melatonin on AF cell senescence in an inflammatory environment and the underlying mechanism. Rat disc AF cells were cultured in a medium with tumor necrosis factor-α (TNF-α). Melatonin was added along with the medium to observe its protective effects. Compared with the control AF cells, TNF-α significantly declined cell proliferation potency and telomerase activity, elevated senescence-associated ß-galactosidase (SA-ß-Gal) activity, upregulated protein expression of senescence markers (p16 and p53), and increased reactive oxygen species (ROS) content and activity of the NF-κB pathway. However, when the TNF-α-treated AF cells were incubated with melatonin, ROS content and activity of the NF-κB pathway were decreased, and those parameters reflecting cell senescence indicated that AF cell senescence was also partly alleviated. Together, melatonin suppresses AF cell senescence through regulating the ROS/NF-κB pathway in an inflammatory environment. This study sheds a new light that melatonin may be promising to retard inflammation-caused disc degeneration.


Assuntos
Anel Fibroso/efeitos dos fármacos , Inflamação/tratamento farmacológico , Degeneração do Disco Intervertebral/tratamento farmacológico , Melatonina/farmacologia , NF-kappa B/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Animais , Anel Fibroso/metabolismo , Anel Fibroso/patologia , Antioxidantes/farmacologia , Células Cultivadas , Senescência Celular/efeitos dos fármacos , Inflamação/metabolismo , Inflamação/patologia , Degeneração do Disco Intervertebral/metabolismo , Degeneração do Disco Intervertebral/patologia , Masculino , Modelos Animais , NF-kappa B/genética , Ratos , Ratos Sprague-Dawley , Telomerase/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
8.
Int J Mol Sci ; 22(13)2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34206404

RESUMO

Metabolic syndrome (MetS) is a cluster of several disorders, such as hypertension, central obesity, dyslipidemia, hyperglycemia, insulin resistance and non-alcoholic fatty liver disease. Despite health policies based on the promotion of physical exercise, the reduction of calorie intake and the consumption of healthy food, there is still a global rise in the incidence and prevalence of MetS in the world. This phenomenon can partly be explained by the fact that adverse events in the perinatal period can increase the susceptibility to develop cardiometabolic diseases in adulthood. Individuals born after intrauterine growth restriction (IUGR) are particularly at risk of developing cardiovascular diseases (CVD) and metabolic disorders later in life. It has been shown that alterations in the structural and functional integrity of the endothelium can lead to the development of cardiometabolic diseases. The endothelial progenitor cells (EPCs) are circulating components of the endothelium playing a major role in vascular homeostasis. An association has been found between the maintenance of endothelial structure and function by EPCs and their ability to differentiate and repair damaged endothelial tissue. In this narrative review, we explore the alterations of EPCs observed in individuals with cardiometabolic disorders, describe some mechanisms related to such dysfunction and propose some therapeutical approaches to reverse the EPCs dysfunction.


Assuntos
Células Progenitoras Endoteliais/metabolismo , Síndrome Metabólica/etiologia , Síndrome Metabólica/metabolismo , Animais , Senescência Celular/efeitos dos fármacos , Gerenciamento Clínico , Suscetibilidade a Doenças , Metabolismo Energético , Epigênese Genética/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Síndrome Metabólica/diagnóstico , Síndrome Metabólica/terapia , Especificidade de Órgãos , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais , Pesquisa Médica Translacional
9.
Int J Mol Sci ; 22(14)2021 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-34298945

RESUMO

Increased oxidative stress is a crucial factor for the progression of cellular senescence and aging. The present study aimed to investigate the effects of licochalcone D (Lico D) on oxidative stress-induced senescence, both in vitro and in vivo, and explore its potential mechanisms. Hydrogen peroxide (200 µM for double time) and D-galactose (D-Gal) (150 mg/kg) were used to induce oxidative stress in human bone marrow-mesenchymal stem cells (hBM-MSCs) and mice, respectively. We performed the SA-ß-gal assay and evaluated the senescence markers, activation of AMPK, and autophagy. Lico D potentially reduced oxidative stress-induced senescence by upregulating AMPK-mediated activation of autophagy in hBM-MSCs. D-Gal treatment significantly increased the expression levels of senescence markers, such as p53 and p21, in the heart and hippocampal tissues, while this effect was reversed in the Lico D-treated animals. Furthermore, a significant increase in AMPK activation was observed in both tissues, while the activation of autophagy was only observed in the heart tissue. Interestingly, we found that Lico D significantly reduced the expression levels of the receptors for advanced glycation end products (RAGE) in the hippocampal tissue. Taken together, our findings highlight the antioxidant, anti-senescent, and cardioprotective effects of Lico D and suggest that the activation of AMPK and autophagy ameliorates the oxidative stress-induced senescence.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Senescência Celular/efeitos dos fármacos , Chalconas/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Envelhecimento/efeitos dos fármacos , Envelhecimento/metabolismo , Animais , Antioxidantes/farmacologia , Autofagia/efeitos dos fármacos , Cardiotônicos/farmacologia , Células Cultivadas , Galactose/metabolismo , Coração/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Humanos , Peróxido de Hidrogênio/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Regulação para Cima/efeitos dos fármacos
10.
Int J Mol Sci ; 22(13)2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34209135

RESUMO

Radiation-induced damage to normal lung parenchyma remains a dose-limiting factor in thorax-associated radiotherapy (RT). Severe early and late complications with lungs can increase the risk of morbidity in cancer patients after RT. Herein, senescence of lung epithelial cells following RT-induced cellular stress, or more precisely the respective altered secretory profile, the senescence-associated secretory phenotype (SASP), was suggested as a central process for the initiation and progression of pneumonitis and pulmonary fibrosis. We previously reported that abrogation of certain aspects of the secretome of senescent lung cells, in particular, signaling inhibition of the SASP-factor Ccl2/Mcp1 mediated radioprotection especially by limiting endothelial dysfunction. Here, we investigated the therapeutic potential of a combined metformin treatment to protect normal lung tissue from RT-induced senescence and associated lung injury using a preclinical mouse model of radiation-induced pneumopathy. Metformin treatment efficiently limited RT-induced senescence and SASP expression levels, thereby limiting vascular dysfunctions, namely increased vascular permeability associated with increased extravasation of circulating immune and tumor cells early after irradiation (acute effects). Complementary in vitro studies using normal lung epithelial cell lines confirmed the senescence-limiting effect of metformin following RT finally resulting in radioprotection, while fostering RT-induced cellular stress of cultured malignant epithelial cells accounting for radiosensitization. The radioprotective action of metformin for normal lung tissue without simultaneous protection or preferable radiosensitization of tumor tissue might increase tumor control probabilities and survival because higher radiation doses could be used.


Assuntos
Brônquios , Células Epiteliais , Metformina/farmacologia , Lesões Experimentais por Radiação , Protetores contra Radiação/farmacologia , Animais , Brônquios/metabolismo , Brônquios/patologia , Senescência Celular/efeitos dos fármacos , Senescência Celular/efeitos da radiação , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Camundongos , Lesões Experimentais por Radiação/metabolismo , Lesões Experimentais por Radiação/patologia , Lesões Experimentais por Radiação/prevenção & controle
11.
Int J Mol Sci ; 22(11)2021 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-34204881

RESUMO

Mesenchymal stem cells (MSCs) are broadly applied in regenerative therapy to replace cells that are lost or impaired during disease. The low survival rate of MSCs after transplantation is one of the major limitations heavily influencing the success of the therapy. Unfavorable microenvironments with inflammation and oxidative stress in the damaged regions contribute to MSCs loss. Most of the strategies developed to overcome this obstacle are aimed to prevent stress-induced apoptosis, with little attention paid to senescence-another common stress reaction of MSCs. Here, we proposed the strategy to prevent oxidative stress-induced senescence of human endometrial stem cells (hMESCs) based on deferoxamine (DFO) application. DFO prevented DNA damage and stress-induced senescence of hMESCs, as evidenced by reduced levels of reactive oxygen species, lipofuscin, cyclin D1, decreased SA-ß-Gal activity, and improved mitochondrial function. Additionally, DFO caused accumulation of HIF-1α, which may contribute to the survival of H2O2-treated cells. Importantly, cells that escaped senescence due to DFO preconditioning preserved all the properties of the initial hMESCs. Therefore, once protecting cells from oxidative damage, DFO did not alter further hMESCs functioning. The data obtained may become the important prerequisite for development of a new strategy in regenerative therapy based on MSCs preconditioning using DFO.


Assuntos
Desferroxamina/farmacologia , Endométrio/efeitos dos fármacos , Inflamação/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Microambiente Celular/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Ciclina D1/genética , Endométrio/citologia , Endométrio/crescimento & desenvolvimento , Feminino , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Humanos , Peróxido de Hidrogênio/toxicidade , Inflamação/induzido quimicamente , Inflamação/patologia , Lipofuscina/genética , Células-Tronco Mesenquimais/efeitos dos fármacos , Espécies Reativas de Oxigênio , Medicina Regenerativa , Transdução de Sinais/efeitos dos fármacos
12.
Int J Mol Sci ; 22(13)2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34201952

RESUMO

Skin aging is associated with the accumulation of senescent cells and is related to many pathological changes, including decreased protection against pathogens, increased susceptibility to irritation, delayed wound healing, and increased cancer susceptibility. Senescent cells secrete a specific set of pro-inflammatory mediators, referred to as a senescence-associated secretory phenotype (SASP), which can cause profound changes in tissue structure and function. Thus, drugs that selectively eliminate senescent cells (senolytics) or neutralize SASP (senostatics) represent an attractive therapeutic strategy for age-associated skin deterioration. There is growing evidence that plant-derived compounds (flavonoids) can slow down or even prevent aging-associated deterioration of skin appearance and function by targeting cellular pathways crucial for regulating cellular senescence and SASP. This review summarizes the senostatic and senolytic potential of flavonoids in the context of preventing skin aging.


Assuntos
Senescência Celular/efeitos dos fármacos , Flavonoides/farmacologia , Envelhecimento da Pele/efeitos dos fármacos , Pele/efeitos dos fármacos , Envelhecimento/efeitos dos fármacos , Envelhecimento/genética , Envelhecimento/metabolismo , Animais , Flavonoides/química , Flavonoides/uso terapêutico , Humanos , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Células de Langerhans/efeitos dos fármacos , Células de Langerhans/metabolismo , Pele/metabolismo , Envelhecimento da Pele/genética
13.
Nat Cell Biol ; 23(7): 704-717, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34253898

RESUMO

Haematopoietic stem cells (HSCs) are normally quiescent, but have evolved mechanisms to respond to stress. Here, we evaluate haematopoietic regeneration induced by chemotherapy. We detect robust chromatin reorganization followed by increased transcription of transposable elements (TEs) during early recovery. TE transcripts bind to and activate the innate immune receptor melanoma differentiation-associated protein 5 (MDA5) that generates an inflammatory response that is necessary for HSCs to exit quiescence. HSCs that lack MDA5 exhibit an impaired inflammatory response after chemotherapy and retain their quiescence, with consequent better long-term repopulation capacity. We show that the overexpression of ERV and LINE superfamily TE copies in wild-type HSCs, but not in Mda5-/- HSCs, results in their cycling. By contrast, after knockdown of LINE1 family copies, HSCs retain their quiescence. Our results show that TE transcripts act as ligands that activate MDA5 during haematopoietic regeneration, thereby enabling HSCs to mount an inflammatory response necessary for their exit from quiescence.


Assuntos
Proliferação de Células/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Elementos de DNA Transponíveis , Hematopoese/efeitos dos fármacos , Células-Tronco Hematopoéticas/efeitos dos fármacos , Helicase IFIH1 Induzida por Interferon/metabolismo , Agonistas Mieloablativos/farmacologia , Animais , Montagem e Desmontagem da Cromatina/efeitos dos fármacos , Retrovirus Endógenos/genética , Ativação Enzimática , Células HEK293 , Células-Tronco Hematopoéticas/enzimologia , Humanos , Helicase IFIH1 Induzida por Interferon/genética , Ligantes , Elementos Nucleotídeos Longos e Dispersos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais
14.
Toxicol Lett ; 350: 10-21, 2021 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-34192554

RESUMO

BACKGROUND: Hepatocyte senescence is a core event that mediates the occurrence and development of alcoholic liver disease. Nuclear factor of activated T-cells 4 (NFATc4) is a key driver of nonalcoholic steatohepatitis. However, little was known about the implication of NFATc4 for alcoholic liver disease. This study was aimed to investigate the role of NFATc4 in hepatocyte senescence and further elucidate the underlying mechanism. METHODS: Real-time PCR, Western blot, immunofluorescence staining, and enzyme-linked immunosorbent assay were performed to explore the role of NFATc4 in hepatocyte senescence. RESULTS: NFATc4 was induced in ethanol-incubated hepatocytes. NFATc4 knockdown recovered cell viability and reduced the release of aspartate transaminase, alanine transaminase, and lactic dehydrogenase from ethanol-incubated hepatocytes. NFATc4 knockdown protected mice from alcoholic liver injury and inflammation. NFATc4 knockdown counteracted ethanol-induced hepatocyte senescence, evidenced by decreased senescence-associated ß-galactosidase positivity and reduced p16, p21, HMGA1, and γH2AX, which was validated in in vivo studies. Peroxisome proliferator-activated receptor (PPAR)γ was inhibited by NFATc4 in ethanol-treated hepatocytes. PPARγ deficiency abrogated the inhibitory effects of NFATc4 knockdown on hepatocyte senescence, oxidative stress, and hepatic steatosis in mice with alcoholic liver disease. CONCLUSIONS: This work discovered that ethanol enhanced NFATc4 expression, which further triggered hepatocyte senescence via repression of PPARγ.


Assuntos
Senescência Celular/efeitos dos fármacos , Etanol/efeitos adversos , Etanol/metabolismo , Hepatócitos/efeitos dos fármacos , Hepatopatias Alcoólicas/tratamento farmacológico , Hepatopatias Alcoólicas/fisiopatologia , Fatores de Transcrição NFATC/metabolismo , Fatores de Transcrição NFATC/farmacologia , Animais , Células Cultivadas/efeitos dos fármacos , Humanos , Hepatopatias Alcoólicas/metabolismo , Camundongos , Modelos Animais
15.
Aging (Albany NY) ; 13(12): 16567-16576, 2021 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-34181580

RESUMO

BACKGROUND: Stem cell aging, characterized by elevated p16INK4a expression, decreases cell repopulating and self-renewal abilities, which results in elevated inflammation and slow recovery against stress. METHODS: Biopsied muscles were analyzed at baseline and 24 h after squat exercise in 12 trained men (22 ± 2 y). Placebo (PLA) and immunostimulant Rg1 (5 mg) were supplemented 1 h before a squat exercise, using a double-blind counterbalanced crossover design. RESULTS: Perceived exertion at the end of resistance exercise session was significantly lowered after Rg1 supplementation. Exercise doubled endothelial progenitor cells (EPC) (p < 0.001) and decreased p16INK4a mRNA to 50% of baseline (d = 0.865, p < 0.05) in muscle tissues, despite p16INK4a+ cell and beta-galactosidase+ (ß-Gal+) cell counts being unaltered. Rg1 further lowered p16INK4a mRNA to 35% of baseline with greater effect size than the PLA level (d = 1.302, p < 0.01) and decreased myeloperoxidase (MPO) mRNA to 39% of baseline (p < 0.05). A strong correlation between MPO and p16INK4a expression in muscle tissues was observed (r = 0.84, p < 0.001). CONCLUSION: EPC in skeletal muscle doubled 1 d after an acute bout of resistance exercise. The exercised effects in lowering EPC aging and tissue inflammation were enhanced by immunostimulant Rg1, suggesting the involvement of immune stimulation on EPC rejuvenation.


Assuntos
Senescência Celular , Exercício Físico/fisiologia , Ginsenosídeos/farmacologia , Músculo Esquelético/fisiologia , Células-Tronco/citologia , Biomarcadores/metabolismo , Senescência Celular/efeitos dos fármacos , Células Progenitoras Endoteliais/efeitos dos fármacos , Células Progenitoras Endoteliais/metabolismo , Humanos , Masculino , Músculo Esquelético/efeitos dos fármacos , Peroxidase/genética , Peroxidase/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Células-Tronco/efeitos dos fármacos , Adulto Jovem
16.
Int J Mol Sci ; 22(9)2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-34067074

RESUMO

The recently discovered interleukin (IL)- 32 isoform IL-32θ exerts anti-metastatic effects in the breast tumor microenvironment. However, the involvement of IL-32θ in breast cancer cell proliferation is not yet fully understood; therefore, the current study aimed to determine how IL-32θ affects cancer cell growth and evaluated the responses of IL-32θ-expressing cells to other cancer therapy. We compared the functions of IL-32θ in triple-negative breast cancer MDA-MB-231 cells that stably express IL-32θ, with MDA-MB-231 cells transfected with a mock vector. Slower growth was observed in cells expressing IL-32θ than in control cells, and changes were noted in nuclear morphology, mitotic division, and nucleolar size between the two groups of cells. Interleukin-32θ significantly reduced the colony-forming ability of MDA-MB-231 cells and induced permanent cell cycle arrest at the G1 phase. Long-term IL-32θ accumulation triggered permanent senescence and chromosomal instability in MDA-MB-231 cells. Genotoxic drug doxorubicin (DR) reduced the viability of MDA-MB-231 cells not expressing IL-32θ more than in cells expressing IL-32θ. Overall, these findings suggest that IL-32θ exerts antiproliferative effects in breast cancer cells and initiates senescence, which may cause DR resistance. Therefore, targeting IL-32θ in combination with DR treatment may not be suitable for treating metastatic breast cancer.


Assuntos
Senescência Celular/efeitos dos fármacos , Doxorrubicina/farmacologia , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Interleucinas/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Neoplasias da Mama/patologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Forma do Núcleo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Feminino , Instabilidade Genômica , Humanos , Fenótipo , Ploidias
17.
Int J Mol Sci ; 22(9)2021 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-34063608

RESUMO

Cellular senescence and lung aging are associated with the pathogenesis of chronic obstructive pulmonary disease (COPD). COPD progresses with aging, and chronic smoking is the key susceptibility factor in lung pathological changes concurrent with mitochondrial dysfunction and biological aging. However, these processes involving cigarette smoke (CS)-mediated lung cellular senescence are difficult to distinguish. One of the impediments to studying cellular senescence in relation to age-related lung pathologies is the lack of a suitable in vivo model. In view of this, we provide evidence that supports the suitability of p16-3MR mice to studying cellular senescence in CS-mediated and age-related lung pathologies. p16-3MR mice have a trimodal reporter fused to the promoter of the p16INK4a gene that enables detection, isolation, and selective elimination of senescent cells, thus making them a suitable model to study cellular senescence. To determine their suitability in CS-mediated lung pathologies, we exposed young (12-14 months) and old (17-20 months) p16-3MR mice to 30 day CS exposure and studied the expression of senescent genes (p16, p21, and p53) and SASP-associated markers (MMP9, MMP12, PAI-1, and FN-1) in air- and CS-exposed mouse lungs. Our results showed that this model could detect cellular senescence using luminescence and isolate cells undergoing senescence with the help of tissue fluorescence in CS-exposed young and old mice. Our results from the expression of senescence markers and SASP-associated genes in CS-exposed young and old p16-3MR mice were comparable with increased lung cellular senescence and SASP in COPD. We further showed alteration in the; (i) tissue luminescence and fluorescence, (ii) mRNA and protein expressions of senescent markers and SASP genes, and (iii) SA-ß-gal activity in CS-exposed young and old p16-3MR mice as compared to their air controls. Overall, we showed that p16-3MR is a competent model for studying the cellular senescence in CS-induced pathologies. Hence, the p16-3MR reporter mouse model may be used as a novel tool for understanding the pathobiology of cellular senescence and other underlying mechanisms involved in COPD and fibrosis.


Assuntos
Senescência Celular/genética , Fumar Cigarros/efeitos adversos , Inibidor p16 de Quinase Dependente de Ciclina/genética , Lesão Pulmonar/genética , Doença Pulmonar Obstrutiva Crônica/genética , Envelhecimento/genética , Envelhecimento/patologia , Animais , Senescência Celular/efeitos dos fármacos , Fumar Cigarros/genética , Fumar Cigarros/patologia , Modelos Animais de Doenças , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Fibronectinas/genética , Regulação da Expressão Gênica/genética , Humanos , Lesão Pulmonar/induzido quimicamente , Lesão Pulmonar/patologia , Metaloproteinase 12 da Matriz/genética , Metaloproteinase 9 da Matriz/genética , Doença Pulmonar Obstrutiva Crônica/induzido quimicamente , Doença Pulmonar Obstrutiva Crônica/patologia , Enfisema Pulmonar/induzido quimicamente , Enfisema Pulmonar/genética , Enfisema Pulmonar/patologia , Serpina E2/genética
18.
Science ; 373(6552)2021 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-34103349

RESUMO

The COVID-19 pandemic has revealed the pronounced vulnerability of the elderly and chronically ill to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced morbidity and mortality. Cellular senescence contributes to inflammation, multiple chronic diseases, and age-related dysfunction, but effects on responses to viral infection are unclear. Here, we demonstrate that senescent cells (SnCs) become hyper-inflammatory in response to pathogen-associated molecular patterns (PAMPs), including SARS-CoV-2 spike protein-1, increasing expression of viral entry proteins and reducing antiviral gene expression in non-SnCs through a paracrine mechanism. Old mice acutely infected with pathogens that included a SARS-CoV-2-related mouse ß-coronavirus experienced increased senescence and inflammation, with nearly 100% mortality. Targeting SnCs by using senolytic drugs before or after pathogen exposure significantly reduced mortality, cellular senescence, and inflammatory markers and increased antiviral antibodies. Thus, reducing the SnC burden in diseased or aged individuals should enhance resilience and reduce mortality after viral infection, including that of SARS-CoV-2.


Assuntos
Envelhecimento , Senescência Celular/efeitos dos fármacos , Infecções por Coronavirus/mortalidade , Flavonóis/uso terapêutico , Padrões Moleculares Associados a Patógenos/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo , Animais , COVID-19/tratamento farmacológico , COVID-19/imunologia , COVID-19/mortalidade , Linhagem Celular , Infecções por Coronavirus/imunologia , Dasatinibe/farmacologia , Dasatinibe/uso terapêutico , Feminino , Flavonóis/farmacologia , Regulação da Expressão Gênica , Humanos , Lipopolissacarídeos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Vírus da Hepatite Murina/imunologia , Quercetina/farmacologia , Quercetina/uso terapêutico , Receptores de Coronavírus/genética , Receptores de Coronavírus/metabolismo , Organismos Livres de Patógenos Específicos
19.
Commun Biol ; 4(1): 656, 2021 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-34079050

RESUMO

Pharmacological reversal of brain aging is a long-sought yet challenging strategy for the prevention and treatment of age-related neurodegeneration, due to the diverse cell types and complex cellular pathways impacted by the aging process. Here, we report the genome-wide reversal of transcriptomic aging signatures in multiple major brain cell types, including glial and mural cells, by systemic glucagon-like peptide-1 receptor (GLP-1R) agonist (GLP-1RA) treatment. The age-related expression changes reversed by GLP-1RA encompass both shared and cell type-specific functional pathways that are implicated in aging and neurodegeneration. Concomitantly, Alzheimer's disease (AD)-associated transcriptomic signature in microglia that arises from aging is reduced. These results show the feasibility of reversing brain aging by pharmacological means, provide mechanistic insights into the neurological benefits of GLP-1RAs, and imply that GLP-1R agonism may be a generally applicable pharmacological intervention for patients at risk of age-related neurodegeneration.


Assuntos
Encéfalo/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Senescência Celular/genética , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Neuroglia/efeitos dos fármacos , Envelhecimento/efeitos dos fármacos , Envelhecimento/genética , Doença de Alzheimer/genética , Animais , Encéfalo/citologia , Encéfalo/metabolismo , Exenatida/farmacologia , Estudos de Viabilidade , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/genética , Neuroglia/metabolismo , Transcriptoma/efeitos dos fármacos , Transcriptoma/genética
20.
Sci Rep ; 11(1): 12787, 2021 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-34140611

RESUMO

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection that causes coronavirus disease 2019 (COVID-19) has resulted in a pandemic affecting the most vulnerable in society, triggering a public health crisis and economic collapse around the world. Effective treatments to mitigate this viral infection are needed. Since the eye is a route of virus entrance, we use an in vivo rat model of corneal inflammation as well as human corneal epithelial cells (HCEC) in culture challenged with IFNγ as models of the eye surface to study this issue. We explore ways to block the receptor-binding domain (RBD) of SARS-CoV-2 Spike (S) protein to angiotensin-converting enzyme 2 (ACE2). We found that the lipid mediators, elovanoid (ELV)-N32 or Resolvin D6-isomer (RvD6i) decreased the expression of the ACE2 receptor, furin, and integrins in damaged corneas or IFNγ-stimulated HCEC. There was also a concomitant decrease in the binding of Spike RBD with the lipid treatments. Using RNA-seq analysis, we uncovered that the lipid mediators also attenuated the expression of pro-inflammatoy cytokines participating in hyper-inflammation and senescence programming. Thus, the bioactivity of these lipid mediators will contribute to open therapeutic avenues to counteract virus attachment and entrance to the body.


Assuntos
Enzima de Conversão de Angiotensina 2/metabolismo , Senescência Celular/efeitos dos fármacos , Lesões da Córnea/metabolismo , Citocinas/metabolismo , Ácidos Docosa-Hexaenoicos/análogos & derivados , Ácidos Docosa-Hexaenoicos/farmacologia , Descoberta de Drogas/métodos , Domínios Proteicos , Transdução de Sinais/efeitos dos fármacos , Glicoproteína da Espícula de Coronavírus/metabolismo , Animais , COVID-19/metabolismo , COVID-19/virologia , Células Cultivadas , Modelos Animais de Doenças , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Epitélio Corneano/citologia , Humanos , Lipoxinas/farmacologia , Masculino , Ligação Proteica , Ratos , Ratos Sprague-Dawley , SARS-CoV-2/metabolismo , Glicoproteína da Espícula de Coronavírus/química , Ligação Viral/efeitos dos fármacos , Internalização do Vírus/efeitos dos fármacos
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