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1.
Anticancer Res ; 39(9): 4811-4816, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519583

RESUMO

BACKGROUND/AIM: γ-Glutamylcyclotransferase (GGCT) is highly expressed in many forms of cancer, and is a promising therapeutic target. The present study investigated whether inhibition of GGCT enhanced the antiproliferative effects of the drug docetaxel in prostate cancer cells. MATERIALS AND METHODS: Immunohistochemistry and western blot analysis were conducted to measure GGCT expression in prostate cancer tissue samples and cell lines. GGCT was inhibited using RNAi and a novel enzymatic inhibitor, pro-GA, and cell proliferation was evaluated with single and combination treatments of GGCT inhibitors and docetaxel. RESULTS: GGCT was highly expressed in cultured prostate cancer cells and patient samples. GGCT inhibition alone inhibited prostate cancer cell line proliferation and induced cellular senescence. GGCT inhibition in combination with apoptosis-inducing docetaxel had more potent antiproliferative effects than either drug used alone. CONCLUSION: GGCT inhibition may potentiate anticancer drug efficacy.


Assuntos
Antineoplásicos/farmacologia , Docetaxel/farmacologia , Inibidores Enzimáticos/farmacologia , gama-Glutamilciclotransferase/antagonistas & inibidores , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Expressão Gênica , Humanos , Imuno-Histoquímica , Masculino , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , RNA Interferente Pequeno/genética , gama-Glutamilciclotransferase/genética , gama-Glutamilciclotransferase/metabolismo
2.
Toxicol Lett ; 317: 13-23, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31562912

RESUMO

Combination antiretroviral therapy (cART) has been hugely successful in reducing the mortality associated with human immunodeficiency virus (HIV) infection, resulting in a growing population of people living with HIV (PLWH). Since PLWH now have a longer life expectancy, chronic comorbidities have become the focus of the clinical management of HIV. For example, cardiovascular complications are now one of the most prevalent causes of death in PLWH. Numerous epidemiological studies show that antiretroviral treatment increases cardiovascular disease (CVD) risk and early onset of CVD in PLWH. Nucleoside reverse transcriptase inhibitors (NRTIs) are the backbone of cART, and two NRTIs are typically used in combination with one drug from another drug class, e.g., a fusion inhibitor. NRTIs are known to induce mitochondrial dysfunction, contributing to toxicity in numerous tissues, such as myopathy, lipoatrophy, neuropathy, and nephropathy. In in vitro studies, short-term NRTI treatment induces an endothelial dysfunction with an increased reactive oxygen species (ROS) production; long-term NRTI treatment decreases cell replication capacity, while increasing mtROS production and senescent cell accumulation. These findings suggest that a mitochondrial oxidative stress is involved in the pathogenesis of NRTI-induced endothelial dysfunction and premature senescence. Mitochondrial dysfunction, defined by a compromised mitochondrial quality control via biogenesis and mitophagy, has a causal role in premature endothelial senescence and can potentially initiate early cardiovascular disease (CVD) development in PLWH. In this review, we explore the hypothesis and present literature supporting that long-term NRTI treatment induces vascular dysfunction by interfering with endothelial mitochondrial homeostasis and provoking mitochondrial genomic instability, resulting in premature endothelial senescence.


Assuntos
Fármacos Anti-HIV/efeitos adversos , Doenças Cardiovasculares/induzido quimicamente , Senescência Celular/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Infecções por HIV/tratamento farmacológico , Mitocôndrias/efeitos dos fármacos , Animais , Fármacos Anti-HIV/administração & dosagem , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/patologia , Esquema de Medicação , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Metabolismo Energético/efeitos dos fármacos , Infecções por HIV/metabolismo , Infecções por HIV/patologia , Humanos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Medição de Risco , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo
3.
Ecotoxicol Environ Saf ; 183: 109465, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31376806

RESUMO

Our group found that long-term low-dose exposure to hexavalent chromium [Cr(VI)] in L-02 hepatocytes resulted in premature senescence, which accompanied by the increased expression of Clusterin (CLU), but the functional role of CLU in premature senescence has never been explored. In the present study, the CLU overexpressed or silenced L-02 hepatocytes were established by lentiviral vector transfection. Cell viability assay, cell cycle analysis, western blotting, plate clone formation assay, and confocal microcopy were performed. The results indicated that Cr(VI)-induced premature senescence was associated with phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway inhibition, and high expression of CLU in the senescent cells exerted its functional role of promoting cell proliferation. CLU could complex with eukaryotic translation initiation factor 3 subunit I (EIF3I) and prevent its degradation, leading to the increase of AKT activity in Cr(VI)-exposed senescent hepatocytes. Blockage of the PI3K/AKT pathway with its inhibitor LY294002 eliminated the inhibitory effect of CLU on Cr(VI)-induced premature senescence. We concluded that high expression of CLU suppressed Cr(VI)-induced premature senescence through activation of PI3K/AKT pathway, which will provide the experimental basis for the study of Cr(VI)-induced liver cancer, especially for the elucidation of the mechanism of liver cancer cells escaping from senescence.


Assuntos
Senescência Celular/efeitos dos fármacos , Cromo/toxicidade , Clusterina/genética , Hepatócitos/efeitos dos fármacos , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Senescência Celular/genética , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética
4.
Ecotoxicol Environ Saf ; 182: 109384, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31272023

RESUMO

Exposure to polycyclic aromatic hydrocarbons (PAHs) and phthalates link to oxidative stress and inflammatory response, which exert cellular aging. However, modification effect of seasonal factor on the association of PAHs or phthalates exposure with relative telomere length (RTL) or mitochondrial DNA copy number (mtDNA-CN) has remained unclear. In this pilot study, 106 subjects were from an urban population (n = 1240) who lived in the two districts in Wuhan city, China. Participants completed physical examinations and provided 191 blood samples for RTL and mtDNA-CN analysis and 627 urine samples for monohydroxylated-PAHs (OH-PAHs) and phthalate metabolites measurements in the winter and summer seasons. We assessed the associations of urinary OH-PAHs or phthalates metabolites with RTL or mtDNA-CN by linear regression analysis and linear mixed-effect models. We found that urinary OH-PAHs were positively associated with mtDNA-CN at lag 2 day and 3-day moving average, but negatively related to RTL at lag 0, lag 1 and lag 2 day and 3-day moving average (p < 0.05). Urinary phthalate metabolites were negatively associated with mtDNA lag 0, lag 1 and lag 2 day and 3-day moving average, but positively related to RTL at lag 0 day (p < 0.05). Seasonal factor modified the association of urinary OH-PAHs with mtDNA-CN as well as urinary phthalate metabolites with RTL. In vitro experiment showed that under certain conditions, benzo[a]pyrene increased mtDNA-CN at 48 h and di (2-ethylhexyl) phthalate did RTL at 24 h in HepG2 cells. Seasonal variations in the metabolisms of PAHs or phthalates in human body may affect the relation of PAHs or phthalates exposure with cellular aging.


Assuntos
Senescência Celular/efeitos dos fármacos , Variações do Número de Cópias de DNA/efeitos dos fármacos , DNA Mitocondrial/sangue , Ácidos Ftálicos/toxicidade , Hidrocarbonetos Policíclicos Aromáticos/toxicidade , Telômero/efeitos dos fármacos , Adulto , Senescência Celular/genética , China , Células Hep G2 , Humanos , Masculino , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Ácidos Ftálicos/urina , Projetos Piloto , Hidrocarbonetos Policíclicos Aromáticos/urina , Estações do Ano , Adulto Jovem
5.
Life Sci ; 232: 116639, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31295472

RESUMO

AIMS: Sirtuins have been implicated in the aging process, however, the functions of SIRT2 in post-maturation aging of oocytes are not fully understood. The purpose of the present investigation was to assess the roles of SIRT2 in aged oocytes and mechanisms involved. MAIN METHODS: The fresh MII oocytes were aging in vitro, and treated with SIRT2 inhibitor (SirReal2), autophagy activator (Rapamycin), and autophagy inhibitor (3-Ma) for 24 h, respectively. Oocyte activation, cytoplasmic fragmentation, and spindle defects, mitochondrial distribution, ROS levels, ATP production, mitochondrial membrane potential, and early apoptosis were investigated. Western blotting was performed to determine LC3-II accumulation, SQSTM1 degradation, and caspase-3 activity. KEY FINDINGS: SIRT2 expression gradually decreased in a time-dependent manner during oocyte aging. Treatment with SirReal2 significantly increased the rates of oocyte activation, cytoplasmic fragmentation, and spindle defects. In particular, the high ROS levels, abnormal mitochondrial distribution, low ATP production, and lost ΔΨm were observed in SirReal2-exposed oocytes. Further analysis revealed that LC3-II accumulation and SQSTM1 degradation were induced by SIRT2 inhibition. By performing early apoptosis analysis showed that oocyte aging was accompanied with cellular apoptosis, and SIRT2 inhibition increased apoptosis rates of aged oocytes. Importantly, upregulating autophagy with Rapamycin could mimic the effects of SIRT2 inhibition on apoptosis by increasing caspase-3 activation, whereas downregulating autophagy with 3-MA could abolish those effects by blocking caspase-3 activation. SIGNIFICANCE: Our results suggest that SIRT2 inactivation is a key mechanism underlying of cellular aging, and SIRT2 inhibition contributes to autophagy-dependent cellular apoptosis in post-maturation oocytes.


Assuntos
Oócitos/fisiologia , Sirtuína 2/fisiologia , Acetamidas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Autofagia/efeitos dos fármacos , Autofagia/fisiologia , Bovinos , Senescência Celular/efeitos dos fármacos , Senescência Celular/fisiologia , Feminino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Oócitos/classificação , Oócitos/efeitos dos fármacos , Oócitos/metabolismo , Sirolimo/farmacologia , Sirtuína 2/antagonistas & inibidores , Sirtuína 2/metabolismo , Tiazóis/farmacologia
6.
Life Sci ; 232: 116677, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31340166

RESUMO

AIMS: Senescence is a state ensuing aging to eliminate age-associated damage with an irreversible cell-cycle arrest mechanism, which is historically believed to be one of the tumor responses to therapy. Doxorubicin as an anti-cancer drug has been used in cancer treatment for a long time. Liposomal doxorubicin (Ldox) is a liposomal formulation of doxorubicin, which increases the doxorubicin permanency. The aim of this study was to examine the toxicity of these two formulations by comparing them in terms of their ability to induce cellular senescence. MAIN METHODS: The study groups included a control group, three DOX (0.75, 0.5, 0.1 mg/kg/BW) and three Ldox groups (0.1, 0.05, 0.025 mg/kg/BW). Heart tissues were studied regarding oxidative stress assessment, mitochondrial function, inflammatory markers and biochemical and histopathological evaluation. Real-Time PCR was used for P53 and SA ß-gal expression. KEY FINDINGS: Based on the results, the highest doses of Dox and Ldox (0.75 and 0.1 mg/kg/BW respectively) significantly increased the level of inflammatory markers and according to other factors especially p53 and SA ß-gal expression, both were able to induce senescence but the changes in Ldox were less tangible than the Dox.


Assuntos
Senescência Celular/efeitos dos fármacos , Doxorrubicina/farmacologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , NF-kappa B/metabolismo , Animais , Biomarcadores/metabolismo , Doxorrubicina/análogos & derivados , Glutationa Peroxidase/metabolismo , Humanos , Mediadores da Inflamação/metabolismo , Masculino , Miocárdio/patologia , Estresse Oxidativo/efeitos dos fármacos , Polietilenoglicóis/farmacologia , Ratos , Ratos Wistar , Superóxido Dismutase/metabolismo , Proteína Supressora de Tumor p53/metabolismo
7.
Zhongguo Zhong Yao Za Zhi ; 44(11): 2348-2352, 2019 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-31359662

RESUMO

The aim of this paper was to investigate the effect of SIRT1/TSC_2 signal axis on leukemia stem cell senescence induced by ginsenoside Rg_1. CD34~+CD38~- leukemia stem cells(CD34~+CD38~-LSCs) was isolated by magnetic cell sorting(MACS) and divided into two groups. The control group cells were routinely cultured, 40 µmol·L~(-1) ginsenoside Rg_1 was added to the control group for co-culture in Rg_1 group. The effect of Rg_l to induce CD34~+CD38~-LSCs senescence were evaluated by senescence-associated ß-Galactosidase(SA-ß-Gal) staining, cell cycle assay, CCK-8 and Colony-Assay. The expression of senescence associated SIRT1, TSC_2 mRNA and protein was examined by Real-time fluorescence quantitative PCR(FQ-PCR) and Western blot. The results showed that the CD34~+CD38~-LSCs could effectively be isolated by MACS, and the purity of CD34~+CD38~-LSCs is up to(95.86±3.04)%. Compared with the control group, the percentage of positive cells expressed SA-ß-Gal in the Rg_1 group is increased, the senescence morphological changes were observed in the CD34~+CD38~-LSCs in the Rg_1 group. The proliferation inhibition rate and the number of cells entered G_0/G_1 phase in the Rg_1 group were increased, but the colony-formed ability was decreased, Rg_1 could significantly inhibit the proliferation and self-renewal ability of CD34~+CD38~-LSCs. The expression of SIRT1 and TSC_2 mRNA and protein were down regulated in the Rg_1 group compared with the control group. Our research implied that Rg_1 may induce the senescence of CD34~+CD38~-LSCs and SIRT1/TSC_2 signal axis plays a significant role in this process.


Assuntos
Senescência Celular/efeitos dos fármacos , Ginsenosídeos/farmacologia , Leucemia Mieloide Aguda , Células-Tronco Neoplásicas/efeitos dos fármacos , Transdução de Sinais , Sirtuína 1/metabolismo , Proteína 2 do Complexo Esclerose Tuberosa/metabolismo , Humanos , Células Tumorais Cultivadas
8.
Nat Commun ; 10(1): 2538, 2019 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-31182708

RESUMO

The pathological mechanisms of radiation ulcer remain unsolved and there is currently no effective medicine. Here, we demonstrate that persistent DNA damage foci and cell senescence are involved in radiation ulcer development. Further more, we identify cordycepin, a natural nucleoside analogue, as a potent drug to block radiation ulcer (skin, intestine, tongue) in rats/mice by preventing cell senescence through the increase of NRF2 nuclear expression (the assay used is mainly on skin). Finally, cordycepin is also revealed to activate AMPK by binding with the α1 and γ1 subunit near the autoinhibitory domain of AMPK, then promotes p62-dependent autophagic degradation of Keap1, to induce NRF2 dissociate from Keap1 and translocate to the nucleus. Taken together, our findings identify cordycepin prevents radiation ulcer by inhibiting cell senescence via NRF2 and AMPK in rodents, and activation of AMPK or NRF2 may thus represent therapeutic targets for preventing cell senescence and radiation ulcer.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Senescência Celular/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Desoxiadenosinas/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Lesões Experimentais por Radiação/prevenção & controle , Úlcera/prevenção & controle , Animais , Apoptose , Linhagem Celular , Senescência Celular/efeitos da radiação , Dano ao DNA/efeitos da radiação , Desoxiadenosinas/toxicidade , Fibroblastos , Humanos , Masculino , Camundongos Endogâmicos C57BL , Lesões Experimentais por Radiação/tratamento farmacológico , Lesões Experimentais por Radiação/patologia , Ratos Sprague-Dawley , Úlcera/tratamento farmacológico , Úlcera/patologia , Raios X/efeitos adversos
9.
Environ Pollut ; 252(Pt A): 317-329, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31158660

RESUMO

Fine dust (FD) is a form of air pollution and is responsible for a wide range of diseases. Specially, FD is associated with several cardiovascular diseases (CVDs); long-term exposure to FD was shown to decrease endothelial function, but the underlying mechanism remains unclear. We investigated whether exposure to FD causes premature senescence-associated endothelial dysfunction in endothelial cells (ECs) isolated from porcine coronary arteries. The cells were treated with different concentrations of FD and senescence associated-beta galactosidase (SA-ß-gal) activity, cell cycle progression, expression of endothelial nitric oxide synthase (eNOS), oxidative stress level, and vascular function were evaluated. We found that FD increased SA-ß-gal activity, caused cell cycle arrest, and increased oxidative stress, suggesting the premature induction of senescence; on the other hand, eNOS expression was downregulated and platelet aggregation was enhanced. FD exposure impaired vasorelaxation in response to bradykinin and activated the local angiotensin system (LAS), which was inhibited by treatment with the antioxidant N-acetyl cysteine (NAC) and angiotensin II receptor type 1 (AT1) antagonist losartan (LOS). NAC and LOS also suppressed FD-induced SA-ß-gal activity, increased EC proliferation and eNOS expression, and improved endothelial function. These results demonstrate that FD induces premature senescence of ECs and is associated with increased oxidative stress and activation of LAS. This study can serve as a pharmacological target for prevention and/or treatment of air pollution-associated CVD.


Assuntos
Poluição do Ar/efeitos adversos , Angiotensinas/metabolismo , Senescência Celular/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/fisiologia , Material Particulado/farmacologia , Receptor Tipo 1 de Angiotensina/metabolismo , Acetilcisteína/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Antioxidantes/metabolismo , Plaquetas/citologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Vasos Coronários/citologia , Endotélio Vascular/citologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Losartan/farmacologia , Óxido Nítrico Sintase Tipo III/biossíntese , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Suínos , beta-Galactosidase/antagonistas & inibidores , beta-Galactosidase/metabolismo
10.
Food Chem Toxicol ; 131: 110544, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31201898

RESUMO

Aging is a multifactorial universal process characterized by a gradual decrease in physiological and biochemical functions. Given that life expectancy is on the rise, a better understanding of molecular mechanisms of the aging process is necessary in order to develop anti-aging interventions. Uncontrolled cellular senescence promotes persistent inflammation and accelerates the aging process by decreasing tissue renewal, repair and regeneration. Senescence of immune cells, immunesenescence, is another hallmark of aging. Targeting pro-senescent enzymes increases survival and therefore the lifespan. Although the upregulation of Mitogen Activated Protein Kinases (MAPK) enzymes in aging is still controversial, increasing evidence shows that dysregulation of those enzymes are associated with biological processes that contribute to aging such as irreversible senescence. In this manuscript components of the MAPK pathway will be summarized, including extracellular signal-regulated kinase 1 and 2 (ERK1/2), c-Jun N-terminal kinase (JNK) and p38, as well as natural flavonoids, phenolic and diterpenoids with anti-senescence activity that shows positive effects on longevity and MAPK inhibition. Although more studies using additional aging models are needed, we suggest that these selected natural bioactive compounds that regulate MAPK enzymes and reduce senescent cells can be potentially used to improve longevity and prevent/treat age-related diseases.


Assuntos
Produtos Biológicos/farmacologia , Senescência Celular/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Animais , Linhagem Celular Tumoral , Humanos , Transdução de Sinais/efeitos dos fármacos
11.
Cancer Sci ; 110(9): 2690-2699, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31250942

RESUMO

Senescence is a state of growth arrest induced not only in normal cells but also in cancer cells by aging or stress, which triggers DNA damage. Despite growth suppression, senescent cancer cells promote tumor formation and recurrence by producing cytokines and growth factors; this state is designated as the senescence-associated secretory phenotype. In this study, we examined the susceptibility of senescent human breast cancer cells to immune cell-mediated cytotoxicity. Doxorubicin (DXR) treatment induced senescence in 2 human breast cancer cell lines, MDA-MB-231 and BT-549, with the induction of γH2AX expression and increased expression of p21 or p16. Treatment with DXR also induced the expression of senescence-associated ß-galactosidase and promoted the production of pro-inflammatory cytokines. Importantly, DXR-treated senescent MDA-MB-231 cells showed increased sensitivity to 2 types of immune cell-mediated cytotoxicity: cytotoxicity of activated CD4+ T cells and Ab-dependent cellular cytotoxicity by natural killer cells. This increased sensitivity to cytotoxicity was partially dependent on tumor necrosis factor-related apoptosis-inducing ligand and perforin, respectively. This increased sensitivity was not observed following treatment with the senescence-inducing cyclin-dependent kinase-4/6 inhibitor, abemaciclib. In addition, treatment with DXR, but not abemaciclib, decreased the expression of antiapoptotic proteins in cancer cells. These results indicated that DXR and abemaciclib induced senescence in breast cancer cells, but that they differed in their sensitivity to immune cell-mediated cytotoxicity. These findings could provide an indication for combining anticancer immunotherapy with chemotherapeutic drugs or molecular targeting drugs.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias da Mama/tratamento farmacológico , Linfócitos T CD4-Positivos/imunologia , Senescência Celular/imunologia , Células Matadoras Naturais/imunologia , Aminopiridinas/farmacologia , Aminopiridinas/uso terapêutico , Citotoxicidade Celular Dependente de Anticorpos/efeitos dos fármacos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Apoptose/imunologia , Proteínas Reguladoras de Apoptose/imunologia , Proteínas Reguladoras de Apoptose/metabolismo , Benzimidazóis/farmacologia , Benzimidazóis/uso terapêutico , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linhagem Celular Tumoral , Senescência Celular/efeitos dos fármacos , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Células Matadoras Naturais/efeitos dos fármacos , Terapia de Alvo Molecular/métodos , Recidiva Local de Neoplasia
12.
Gastroenterology ; 157(3): 793-806.e14, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31170413

RESUMO

BACKGROUND & AIMS: The role of aryl hydrocarbon receptor (AhR) in liver fibrosis is controversial because loss and gain of AhR activity both lead to liver fibrosis. The goal of this study was to investigate how the expression of AhR by different liver cell types, hepatic stellate cells (HSCs) in particular, affects liver fibrosis in mice. METHODS: We studied the effects of AhR on primary mouse and human HSCs, measuring their activation and stimulation of fibrogenesis using RNA-sequencing analysis. C57BL/6J mice were given the AhR agonists 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE); were given carbon tetrachloride (CCl4); or underwent bile duct ligation. We also performed studies in mice with disruption of Ahr specifically in HSCs, hepatocytes, or Kupffer cells. Liver tissues were collected from mice and analyzed by histology, immunohistochemistry, and immunoblotting. RESULTS: AhR was expressed at high levels in quiescent HSCs, but the expression decreased with HSC activation. Activation of HSCs from AhR-knockout mice was accelerated compared with HSCs from wild-type mice. In contrast, TCDD or ITE inhibited spontaneous and transforming growth factor ß-induced activation of HSCs. Mice with disruption of Ahr in HSCs, but not hepatocytes or Kupffer cells, developed more severe fibrosis after administration of CCl4 or bile duct ligation. C57BL/6J mice given ITE did not develop CCl4-induced liver fibrosis, whereas mice without HSC AhR given ITE did develop CCl4-induced liver fibrosis. In studies of mouse and human HSCs, we found that AhR prevents transforming growth factor ß-induced fibrogenesis by disrupting the interaction of Smad3 with ß-catenin, which prevents the expression of genes that mediate fibrogenesis. CONCLUSIONS: In studies of human and mouse HSCs, we found that AhR prevents HSC activation and expression of genes required for liver fibrogenesis. Development of nontoxic AhR agonists or strategies to activate AhR signaling in HSCs might be developed to prevent or treat liver fibrosis.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Senescência Celular , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Células Estreladas do Fígado/metabolismo , Cirrose Hepática Experimental/prevenção & controle , Fígado/metabolismo , Receptores de Hidrocarboneto Arílico/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/agonistas , Fatores de Transcrição Hélice-Alça-Hélice Básicos/deficiência , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Proliferação de Células , Células Cultivadas , Senescência Celular/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Regulação da Expressão Gênica , Células Estreladas do Fígado/efeitos dos fármacos , Células Estreladas do Fígado/patologia , Indóis/farmacologia , Fígado/efeitos dos fármacos , Fígado/patologia , Cirrose Hepática Experimental/genética , Cirrose Hepática Experimental/metabolismo , Cirrose Hepática Experimental/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , Receptores de Hidrocarboneto Arílico/agonistas , Receptores de Hidrocarboneto Arílico/deficiência , Receptores de Hidrocarboneto Arílico/genética , Transdução de Sinais , Proteína Smad3/metabolismo , Tiazóis/farmacologia , beta Catenina/metabolismo
13.
Chem Commun (Camb) ; 55(50): 7175-7178, 2019 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-31162503

RESUMO

The identification and removal of senescent cells is very important to improve human health and prolong life. In this study, we introduced a novel strategy of ß-galactosidase (ß-Gal) instructed peptide self-assembly to selectively form nanofibers and hydrogels in senescent cells. We demonstrated that the in situ formed nanofibers could alleviate endothelial cell senescence by reducing p53, p21, and p16INK4a expression levels. We also demonstrated that our strategy could selectively remove senescent endothelial cells by inducing cell apoptosis, with an increase in the BAX/BCL-2 ratio and caspase-3 expression. Our study reports the first example of enzyme-instructed self-assembly (EISA) by a sugar hydrolase, which may lead to the development of supramolecular nanomaterials for the diagnosis and treatment of many diseases, such as cancer, and for other applications, such as wound healing and senescence.


Assuntos
Senescência Celular/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/fisiologia , Nanofibras , beta-Galactosidase/metabolismo , Regulação da Expressão Gênica , Humanos , Hidrolases/metabolismo , Lipopolissacarídeos/toxicidade
14.
Int J Mol Sci ; 20(11)2019 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-31159515

RESUMO

: Cellular senescence is a state of cell cycle arrest characterized by a distinct morphology, gene expression pattern, and secretory phenotype. It can be triggered by multiple mechanisms, including those involved in telomere shortening, the accumulation of DNA damage, epigenetic pathways, and the senescence-associated secretory phenotype (SASP), and so on. In current cancer therapy, cellular senescence has emerged as a potent tumor suppression mechanism that restrains proliferation in cells at risk for malignant transformation. Therefore, compounds that stimulate the growth inhibition effects of senescence while limiting its detrimental effects are believed to have great clinical potential. In this review article, we first review the current knowledge of the pro- and antitumorigeneic functions of senescence and summarize the key roles of telomerase in the regulation of senescence in tumors. Second, we review the current literature regarding the anticancer effects of stilbene compounds that are mediated by the targeting of telomerase and cell senescence. Finally, we provide future perspectives on the clinical utilization of stilbene compounds, especially resveratrol and pterostilbene, as novel cancer therapeutic remedies. We conclude and propose that stilbene compounds may induce senescence and may potentially be used as the therapeutic or adjuvant agents for cancers with high telomerase activity.


Assuntos
Antineoplásicos/uso terapêutico , Senescência Celular/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Estilbenos/uso terapêutico , Telomerase/antagonistas & inibidores , Animais , Antineoplásicos/farmacologia , Humanos , Neoplasias/metabolismo , Neoplasias/patologia , Resveratrol/farmacologia , Resveratrol/uso terapêutico , Estilbenos/farmacologia , Telomerase/metabolismo
15.
Cell Biol Int ; 43(7): 835-843, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31038250

RESUMO

Calmodulin-like skin protein (CLSP) is a secreted peptide that is produced by skin keratinocytes and some related epithelial cells. It has previously been shown that CLSP is recruited via the bloodstream into the central nervous system where it likely exerts a neuroprotective effect against toxicity related to Alzheimer's disease (AD) by binding to the heterotrimeric humanin receptor and activating intracellular survival signaling. However, it remains to be elucidated whether secreted CLSP shows a protective effect in the skin tissues. In the current study, using primary keratinocytes treated with hydrogen peroxide (H2 O2 ) or exposed to ultraviolet (UV) irradiation as senescence models of keratinocytes, we addressed whether CLSP affects senescence in skin keratinocytes. We found that CLSP expression was upregulated by H2 O2 or UV in keratinocytes. Furthermore, co-incubation with recombinant CLSP reduced the increase in senescence-associated ß-galactosidase-positivity in keratinocytes that were induced by H2 O2 or UV. These results suggest that CLSP may function as a senescence-suppressing factor in keratinocytes.


Assuntos
Proteínas de Ligação ao Cálcio/fisiologia , Senescência Celular/fisiologia , Queratinócitos/metabolismo , Envelhecimento da Pele , Pele/metabolismo , Proteínas de Ligação ao Cálcio/farmacologia , Células Cultivadas , Senescência Celular/efeitos dos fármacos , Humanos , Peróxido de Hidrogênio/efeitos adversos , Peróxido de Hidrogênio/metabolismo , Proteínas Recombinantes/farmacologia , Pele/efeitos da radiação , Raios Ultravioleta/efeitos adversos , beta-Galactosidase/metabolismo
16.
Mol Cell Biochem ; 458(1-2): 171-183, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31004310

RESUMO

There is a striking interaction of genes and environment in the etiology of type 2 diabetes mellitus (T2DM). While endocrine disrupting chemicals (EDCs) like bisphenol-A (BPA) have received special attention for their mechanistic role in metabolic disruption, there is a lack of clinically relevant data on BPA levels in Asian Indians, a population which is more susceptible to type 2 diabetes mellitus (T2DM) and cardiovascular diseases. Therefore, we measured systemic levels of BPA in patients with T2DM compared to individuals with normal glucose tolerance (n = 30 each). Serum BPA levels were estimated using ELISA kit, and biochemical determinations were done by standard protocols. Peripheral blood mononuclear cells (PBMCs) were used to profile the gene expression alterations with special reference to inflammation, estrogen receptors, and cellular senescence in these subjects. Serum levels of BPA were significantly higher in patients with T2DM compared to control individuals and positively correlated to poor glycemic control and insulin resistance. Patients with T2DM exhibited significantly elevated mRNA levels of senescence (GLB1, p16, p21, and p53) and inflammatory (IL6 and TNF-α) markers, shortened telomeres as well as elevated levels of estrogen-related receptor gamma (ERRγ), a recently identified receptor for BPA. BPA levels were positively correlated to senescence indicators, inflammatory markers and ERRγ and negatively correlated to telomere length. Our study is the first data in the clinical diabetes setting to demonstrate an association of increased BPA levels with cellular senescence, proinflammation, poor glycemic control, insulin resistance, and shortened telomeres in patients with T2DM.


Assuntos
Compostos Benzidrílicos/toxicidade , Senescência Celular/efeitos dos fármacos , Diabetes Mellitus Tipo 2/sangue , Hiperglicemia/sangue , Resistência à Insulina , Fenóis/toxicidade , Encurtamento do Telômero/efeitos dos fármacos , Adulto , Compostos Benzidrílicos/farmacocinética , Biomarcadores/sangue , Diabetes Mellitus Tipo 2/patologia , Feminino , Humanos , Hiperglicemia/patologia , Masculino , Pessoa de Meia-Idade , Fenóis/farmacocinética
17.
Mol Med Rep ; 19(5): 4326-4334, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30942392

RESUMO

Long­term exposure to vehicle exhaust gas may lead to various age­associated disorders, including cardiovascular disease and cancer. Polycyclic aromatic hydrocarbons (PAHs) belong to an important class of carcinogens, which are released into the environment by vehicles and are detectable at high levels in Chinese urban areas. However, whether vehicle exhaust gas (EG), and in particular the PAHs derived from EG, are able to induce cell senescence remains unclear. In the present study, vehicle EG and pure PAHs were used as pollution sources to investigate the effects of long­term exposure to PAH on the cellular processes occurring in mouse lung fibroblast cells (mLFCs). Using cell proliferation and apoptosis assays, it was demonstrated that benzopyrene (BaP) suppressed the proliferation of mLFCs, and benzanthracene (BaA) and BaP induced cell apoptosis. Molecular analysis suggested that long­term exposure to BaA and BaP was able to increase the protein expression levels of p53, p21 and the apoptotic factors involved in the caspase cascade, including caspase­3 and ­9. Notably, the present study suggested that PAH exposure was able to promote cell senescence in mLFCs by activating the ATM serine/threonine kinase/H2A histone family member X pathway. The present study may provide novel insights into the underlying mechanism of vehicle EG and PAHs in promoting the development of age­associated diseases.


Assuntos
Senescência Celular/efeitos dos fármacos , Hidrocarbonetos Policíclicos Aromáticos/toxicidade , Poluentes Atmosféricos/toxicidade , Animais , Apoptose/efeitos dos fármacos , Benzo(a)Antracenos/toxicidade , Caspase 3/metabolismo , Células Cultivadas , Inibidor p16 de Quinase Dependente de Ciclina/genética , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Metilação de DNA , Feminino , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Pulmão/citologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Regiões Promotoras Genéticas , Proteína Supressora de Tumor p53/metabolismo , Emissões de Veículos
18.
Mol Carcinog ; 58(8): 1362-1375, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30997718

RESUMO

The main focus of this study is exploring the effect and mechanism of two HIV-protease inhibitors: Ritonavir and Ritonavir-nitric oxide (Ritonavir-NO) on in vitro growth of melanoma cell lines. NO modification significantly improved the antitumor potential of Ritonavir, as the IC50 values of Ritonavir-NO were approximately two times lower than IC50 values of the parental compound. Our results showed for the first time, that both compounds induced senescence in primary and metastatic melanoma cell lines. This transformation was manifested as a change in cell morphology, enlargement of nuclei, increased cellular granulation, upregulation of ß-galactosidase activity, lipofuscin granules appearance, higher production of reactive oxygen species and persistent inhibition of proliferation. The expression of p53, as one of the key regulators of senescence, was upregulated after 48 hours of Ritonavir-NO treatment only in metastatic B16F10 cells, ranking it as a late-response event. The development of senescent phenotype was consistent with the alteration of the cytoskeleton-as we observed diminished expression of vinculin, α-actin, and ß-tubulin. Permanent inhibition of S6 protein by Ritonavir-NO, but not Ritonavir, could be responsible for a stronger antiproliferative potential of the NO-modified compound. Taken together, induction of senescent phenotype may provide an excellent platform for developing therapeutic approaches based on selective killing of senescent cells.


Assuntos
Proliferação de Células/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Inibidores da Protease de HIV/farmacologia , Melanoma/tratamento farmacológico , Ritonavir/farmacologia , Actinas/biossíntese , Linhagem Celular Tumoral , Humanos , Lipofuscina/metabolismo , Melanoma/patologia , Espécies Reativas de Oxigênio/metabolismo , Proteínas Quinases S6 Ribossômicas/antagonistas & inibidores , Tubulina (Proteína)/biossíntese , Proteína Supressora de Tumor p53/biossíntese , Vinculina/biossíntese , beta-Galactosidase/metabolismo
19.
BMC Genomics ; 20(1): 290, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30987592

RESUMO

BACKGROUND: Diverse stresses including genotoxic therapy can induce proliferating cancer cells to undergo cellular senescence and take on the characteristic phenotypes of replicative cellular aging. This accelerated or therapy-induced senescence has been alternatively proposed to contribute to therapeutic efficacy or resistance. Toward better understanding this cell state, we sought to define the core transcriptome of accelerated senescence in cancer cells. RESULTS: We examined senescence induced by ionizing irradiation or ectopic overexpression of the stoichiometric cyclin-dependent kinase (CDK) inhibitor p21CIP/WAF1/SDI1 in the human breast cancer cell line MCF7. While radiation produces a strong DNA damage response, ectopic expression of p21 arrests cell cycle progression independently of DNA damage. Both conditions promoted senescence within 5 days. Microarray analysis revealed 378 up- and 391 down-regulated genes that were shared between the two conditions, representing a candidate signature. Systems analysis of the shared differentially expressed genes (DEGs) revealed strong signals for cell cycle control and DNA damage response pathways and predicted multiple upstream regulators previously linked to senescence. Querying the shared DEGs against the Connectivity Map (cmap) database of transcriptional responses to small molecules yielded 20 compounds that induce a similar gene expression pattern in MCF7 cells. Of 16 agents evaluated, six induced senescence on their own. Of these, the selective estrogen receptor degrader fulvestrant and the histone acetyltransferase inhibitor vorinostat did so without causing chromosomal damage. CONCLUSIONS: Using a systems biology approach with experimental validation, we have defined a core gene expression signature for therapy-induced senescence.


Assuntos
Senescência Celular/efeitos dos fármacos , Senescência Celular/genética , Biologia Computacional/métodos , Bibliotecas de Moléculas Pequenas/farmacologia , Transcriptoma/efeitos dos fármacos , Humanos , Células MCF-7 , Quinases Ativadas por p21/metabolismo
20.
Nat Neurosci ; 22(5): 719-728, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30936558

RESUMO

Neuritic plaques, a pathological hallmark in Alzheimer's disease (AD) brains, comprise extracellular aggregates of amyloid-beta (Aß) peptide and degenerating neurites that accumulate autolysosomes. We found that, in the brains of patients with AD and in AD mouse models, Aß plaque-associated Olig2- and NG2-expressing oligodendrocyte progenitor cells (OPCs), but not astrocytes, microglia, or oligodendrocytes, exhibit a senescence-like phenotype characterized by the upregulation of p21/CDKN1A, p16/INK4/CDKN2A proteins, and senescence-associated ß-galactosidase activity. Molecular interrogation of the Aß plaque environment revealed elevated levels of transcripts encoding proteins involved in OPC function, replicative senescence, and inflammation. Direct exposure of cultured OPCs to aggregating Aß triggered cell senescence. Senolytic treatment of AD mice selectively removed senescent cells from the plaque environment, reduced neuroinflammation, lessened Aß load, and ameliorated cognitive deficits. Our findings suggest a role for Aß-induced OPC cell senescence in neuroinflammation and cognitive deficits in AD, and a potential therapeutic benefit of senolytic treatments.


Assuntos
Doença de Alzheimer/metabolismo , Doença de Alzheimer/psicologia , Peptídeos beta-Amiloides/metabolismo , Senescência Celular , Dasatinibe/administração & dosagem , Células Precursoras de Oligodendrócitos/metabolismo , Quercetina/administração & dosagem , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/administração & dosagem , Animais , Senescência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos Transgênicos , Placa Amiloide/ultraestrutura , Prosencéfalo/metabolismo , Prosencéfalo/ultraestrutura
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