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  1. Identification of 30 protein species involved in replicative senescence and stress-induced premature senescence

    DEFF Research Database (Denmark)

    Dierick, Jean François; Kalume, Dário E; Wenders, Frédéric

    2002-01-01

    Exposure of human proliferative cells to subcytotoxic stress triggers stress-induced premature senescence (SIPS) which is characterized by many biomarkers of replicative senescence. Proteomic comparison of replicative senescence and stress-induced premature senescence indicates that, at the level...

  2. Identification of novel senescence-associated genes in ionizing radiation-induced senescent carcinoma cells

    International Nuclear Information System (INIS)

    Lee, Jae Seon; Kim, Bong Cho; Han, Na Kyung; Hong, Mi Na; Park, Su Min; Yoo, Hee Jung; Chu, In Sun; Lee, Sun Hee

    2009-01-01

    Cellular senescence is considered as a defense mechanism to prevent tumorigenesis. Ionizing radiation (IR) induces stress-induced premature senescence as well as apoptosis in various cancer cells. Senescent cells undergo functional and morphological changes including large and flattened cell shape, senescence-associated β-galactosidase (SA-βGal) activity, and altered gene expressions. Even with the recent findings of several gene expression profiles and supporting functional data, it is obscure that mechanism of IR-induced premature senescence in cancer cells. We performed microarray analysis to identify the common regulated genes in ionizing radiation-induced prematurely senescent human carcinoma cell lines

  3. Oxidative Stress Induces Senescence in Cultured RPE Cells.

    Science.gov (United States)

    Aryan, Nona; Betts-Obregon, Brandi S; Perry, George; Tsin, Andrew T

    2016-01-01

    The aim of this research is to determine whether oxidative stress induces cellular senescence in human retinal pigment epithelial cells. Cultured ARPE19 cells were subjected to different concentrations of hydrogen peroxide to induce oxidative stress. Cells were seeded into 24-well plates with hydrogen peroxide added to cell medium and incubated at 37°C + 5% CO2 for a 90-minute period [at 0, 300, 400 and 800 micromolar (MCM) hydrogen peroxide]. The number of viable ARPE19 cells were recorded using the Trypan Blue Dye Exclusion Method and cell senescence was measured by positive staining for senescence-associated beta-galactosidase (SA-beta-Gal) protein. Without hydrogen peroxide treatment, the number of viable ARPE19 cells increased significantly from 50,000 cells/well to 197,000 within 72 hours. Treatment with hydrogen peroxide reduced this level of cell proliferation significantly (to 52,167 cells at 400 MCM; to 49,263 cells at 800 MCM). Meanwhile, cells with a high level of positive senescence-indicator SA-Beta-Gal-positive staining was induced by hydrogen peroxide treatment (from a baseline level of 12% to 80% at 400 MCM and at 800 MCM). Our data suggests that oxidative stress from hydrogen peroxide treatment inhibited ARPE19 cell proliferation and induced cellular senescence.

  4. A comparison of oncogene-induced senescence and replicative senescence: implications for tumor suppression and aging.

    Science.gov (United States)

    Nelson, David M; McBryan, Tony; Jeyapalan, Jessie C; Sedivy, John M; Adams, Peter D

    2014-06-01

    Cellular senescence is a stable proliferation arrest associated with an altered secretory pathway, the senescence-associated secretory phenotype. However, cellular senescence is initiated by diverse molecular triggers, such as activated oncogenes and shortened telomeres, and is associated with varied and complex physiological endpoints, such as tumor suppression and tissue aging. The extent to which distinct triggers activate divergent modes of senescence that might be associated with different physiological endpoints is largely unknown. To begin to address this, we performed gene expression profiling to compare the senescence programs associated with two different modes of senescence, oncogene-induced senescence (OIS) and replicative senescence (RS [in part caused by shortened telomeres]). While both OIS and RS are associated with many common changes in gene expression compared to control proliferating cells, they also exhibit substantial differences. These results are discussed in light of potential physiological consequences, tumor suppression and aging.

  5. CLCA2 as a p53-Inducible Senescence Mediator

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    Chizu Tanikawa

    2012-02-01

    Full Text Available p53 is a tumor suppressor gene that is frequently mutated in multiple cancer tissues. Activated p53 protein regulates its downstream genes and subsequently inhibits malignant transformation by inducing cell cycle arrest, apoptosis, DNA repair, and senescence. However, genes involved in the p53-mediated senescence pathway are not yet fully elucidated. Through the screening of two genome-wide expression profile data sets, one for cells in which exogenous p53 was introduced and the other for senescent fibroblasts, we have identified chloride channel accessory 2 (CLCA2 as a p53-inducible senescence-associated gene. CLCA2 was remarkably induced by replicative senescence as well as oxidative stress in a p53-dependent manner. We also found that ectopically expressed CLCA2 induced cellular senescence, and the down-regulation of CLCA2 by small interfering RNA caused inhibition of oxidative stress-induced senescence. Interestingly, the reduced expression of CLCA2 was frequently observed in various kinds of cancers including prostate cancer, whereas its expression was not affected in precancerous prostatic intraepithelial neoplasia. Thus, our findings suggest a crucial role of p53/CLCA2-mediated senescence induction as a barrier for malignant transformation.

  6. Rescuing loading induced bone formation at senescence.

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    Sundar Srinivasan

    2010-09-01

    Full Text Available The increasing incidence of osteoporosis worldwide requires anabolic treatments that are safe, effective, and, critically, inexpensive given the prevailing overburdened health care systems. While vigorous skeletal loading is anabolic and holds promise, deficits in mechanotransduction accrued with age markedly diminish the efficacy of readily complied, exercise-based strategies to combat osteoporosis in the elderly. Our approach to explore and counteract these age-related deficits was guided by cellular signaling patterns across hierarchical scales and by the insight that cell responses initiated during transient, rare events hold potential to exert high-fidelity control over temporally and spatially distant tissue adaptation. Here, we present an agent-based model of real-time Ca(2+/NFAT signaling amongst bone cells that fully described periosteal bone formation induced by a wide variety of loading stimuli in young and aged animals. The model predicted age-related pathway alterations underlying the diminished bone formation at senescence, and hence identified critical deficits that were promising targets for therapy. Based upon model predictions, we implemented an in vivo intervention and show for the first time that supplementing mechanical stimuli with low-dose Cyclosporin A can completely rescue loading induced bone formation in the senescent skeleton. These pre-clinical data provide the rationale to consider this approved pharmaceutical alongside mild physical exercise as an inexpensive, yet potent therapy to augment bone mass in the elderly. Our analyses suggested that real-time cellular signaling strongly influences downstream bone adaptation to mechanical stimuli, and quantification of these otherwise inaccessible, transient events in silico yielded a novel intervention with clinical potential.

  7. Exercise Prevents Diet-Induced Cellular Senescence in Adipose Tissue.

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    Schafer, Marissa J; White, Thomas A; Evans, Glenda; Tonne, Jason M; Verzosa, Grace C; Stout, Michael B; Mazula, Daniel L; Palmer, Allyson K; Baker, Darren J; Jensen, Michael D; Torbenson, Michael S; Miller, Jordan D; Ikeda, Yasuhiro; Tchkonia, Tamara; van Deursen, Jan M; Kirkland, James L; LeBrasseur, Nathan K

    2016-06-01

    Considerable evidence implicates cellular senescence in the biology of aging and chronic disease. Diet and exercise are determinants of healthy aging; however, the extent to which they affect the behavior and accretion of senescent cells within distinct tissues is not clear. Here we tested the hypothesis that exercise prevents premature senescent cell accumulation and systemic metabolic dysfunction induced by a fast-food diet (FFD). Using transgenic mice that express EGFP in response to activation of the senescence-associated p16(INK4a) promoter, we demonstrate that FFD consumption causes deleterious changes in body weight and composition as well as in measures of physical, cardiac, and metabolic health. The harmful effects of the FFD were associated with dramatic increases in several markers of senescence, including p16, EGFP, senescence-associated β-galactosidase, and the senescence-associated secretory phenotype (SASP) specifically in visceral adipose tissue. We show that exercise prevents the accumulation of senescent cells and the expression of the SASP while nullifying the damaging effects of the FFD on parameters of health. We also demonstrate that exercise initiated after long-term FFD feeding reduces senescent phenotype markers in visceral adipose tissue while attenuating physical impairments, suggesting that exercise may provide restorative benefit by mitigating accrued senescent burden. These findings highlight a novel mechanism by which exercise mediates its beneficial effects and reinforces the effect of modifiable lifestyle choices on health span. © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

  8. Stress-Induced Premature Senescence or Stress-Induced Senescence-Like Phenotype: One In Vivo Reality, Two Possible Definitions?

    OpenAIRE

    Toussaint, Olivier; Dumont, Patrick; Remacle, Jose; Dierick, Jean-Francois; Pascal, Thierry; Frippiat, Christophe; Magalhaes, Joao Pedro; Zdanov, Stephanie; Chainiaux, Florence

    2002-01-01

    No consensus exists so far on the definition of cellular senescence. The narrowest definition of senescence is irreversible growth arrest triggered by telomere shortening counting cell generations (definition 1). Other authors gave an enlarged functional definition encompassing any kind of irreversible arrest of proliferative cell types induced by damaging agents or cell cycle deregulations after overexpression of proto-oncogenes (definition 2). As stress increases, the proportion of cells in...

  9. PTTG1 attenuates drug-induced cellular senescence.

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    Yunguang Tong

    Full Text Available As PTTG1 (pituitary tumor transforming gene abundance correlates with adverse outcomes in cancer treatment, we determined mechanisms underlying this observation by assessing the role of PTTG1 in regulating cell response to anti-neoplastic drugs. HCT116 cells devoid of PTTG1 (PTTG1(-/- exhibited enhanced drug sensitivity as assessed by measuring BrdU incorporation in vitro. Apoptosis, mitosis catastrophe or DNA damage were not detected, but features of senescence were observed using low doses of doxorubicin and TSA. The number of drug-induced PTTG1(-/- senescent cells increased ∼4 fold as compared to WT PTTG1-replete cells (p<0.001. p21, an important regulator of cell senescence, was induced ∼3 fold in HCT116 PTTG1(-/- cells upon doxorubicin or Trichostatin A treatment. Binding of Sp1, p53 and p300 to the p21 promoter was enhanced in PTTG1(-/- cells after treatment, suggesting transcriptional regulation of p21. p21 knock down abrogated the observed senescent effects of these drugs, indicating that PTTG1 likely suppresses p21 to regulate drug-induced senescence. PTTG1 also regulated SW620 colon cancer cells response to doxorubicin and TSA mediated by p21. Subcutaneously xenografted PTTG1(-/- HCT116 cells developed smaller tumors and exhibited enhanced responses to doxorubicin. PTTG1(-/- tumor tissue derived from excised tumors exhibited increased doxorubicin-induced senescence. As senescence is a determinant of cell responses to anti-neoplastic treatments, these findings suggest PTTG1 as a tumor cell marker to predict anti-neoplastic treatment outcomes.

  10. Inactivation of AKT Induces Cellular Senescence in Uterine Leiomyoma

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    Xu, Xiaofei; Lu, Zhenxiao; Qiang, Wenan; Vidimar, Vania; Kong, Beihua

    2014-01-01

    Uterine leiomyomas (fibroids) are a major public health problem. Current medical treatments with GnRH analogs do not provide long-term benefit. Thus, permanent shrinkage or inhibition of fibroid growth via medical means remains a challenge. The AKT pathway is a major growth and survival pathway for fibroids. We propose that AKT inhibition results in a transient regulation of specific mechanisms that ultimately drive cells into cellular senescence or cell death. In this study, we investigated specific mechanisms of AKT inhibition that resulted in senescence. We observed that administration of MK-2206, an allosteric AKT inhibitor, increased levels of reactive oxygen species, up-regulated the microRNA miR-182 and several senescence-associated genes (including p16, p53, p21, and β-galactosidase), and drove leiomyoma cells into stress-induced premature senescence (SIPS). Moreover, induction of SIPS was mediated by HMGA2, which colocalized to senescence-associated heterochromatin foci. This study provides a conceivable molecular mechanism of SIPS by AKT inhibition in fibroids. PMID:24476133

  11. Chlorophyll loss associated with heat-induced senescence in bentgrass.

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    Jespersen, David; Zhang, Jing; Huang, Bingru

    2016-08-01

    Heat stress-induced leaf senescence is characterized by the loss of chlorophyll from leaf tissues. The objectives of this study were to examine genetic variations in the level of heat-induced leaf senescence in hybrids of colonial (Agrostis capillaris)×creeping bentgrass (Agrostis stolonifera) contrasting in heat tolerance, and determine whether loss of leaf chlorophyll during heat-induced leaf senescence was due to suppressed chlorophyll synthesis and/or accelerated chlorophyll degradation in the cool-season perennial grass species. Plants of two hybrid backcross genotypes ('ColxCB169' and 'ColxCB190') were exposed to heat stress (38/33°C, day/night) for 28 d in growth chambers. The analysis of turf quality, membrane stability, photochemical efficiency, and chlorophyll content demonstrated significant variations in the level of leaf senescence induced by heat stress between the two genotypes, with ColXCB169 exhibiting a lesser degree of decline in chlorophyll content, photochemical efficiency and membrane stability than ColXCB190. The assays of enzymatic activity or gene expression of several major chlorophyll-synthesizing (porphobilinogen deaminase, Mg-chelatase, protochlorophyllide-reductase) and chlorophyll-degrading enzymes (chlorophyllase, pheophytinase, and chlorophyll-degrading peroxidase) indicated heat-induced decline in leaf chlorophyll content was mainly due to accelerated chlorophyll degradation, as manifested by increased gene expression levels of chlorophyllase and pheophytinase, and the activity of pheophytinase (PPH), while chlorophyll-synthesizing genes and enzymatic activities were not differentially altered by heat stress in the two genotypes. The analysis of heat-induced leaf senescence of pph mutants of Arabidopsis further confirmed that PPH could be one enzymes that plays key roles in regulating heat-accelerated chlorophyll degradation. Further research on enzymes responsible in part for the loss of chlorophyll during heat-induced

  12. Stress-induced premature senescence of endothelial cells.

    Science.gov (United States)

    Chen, Jun; Patschan, Susann; Goligorsky, Michael S

    2008-01-01

    Stress-induced premature senescence (SIPS) is characterized by cell cycle arrest and curtailed Hayflick limit. Studies support a central role for Rb protein in controlling this process via signaling from the p53 and p16 pathways. Cellular senescence is considered an essential contributor to the aging process and has been shown to be an important tumor suppression mechanism. In addition, emerging evidence suggests that SIPS may be involved in the pathogenesis of chronic human diseases. Here, focusing on endothelial cells, we discuss recent advances in our understanding of SIPS and the pathways that trigger it, evaluate their correlation with the apoptotic response and examine their links to the development of chronic diseases, with the emphasis on vasculopathy. Emerging novel therapeutic interventions based on recent experimental findings are also reviewed.

  13. Oxidative stress induces senescence in human mesenchymal stem cells

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    Brandl, Anita [Department of Anesthesiology, University Medical Center Regensburg, Franz-Josef-Strauss-Allee 11, 93042 Regensburg (Germany); Meyer, Matthias; Bechmann, Volker [Department of Trauma Surgery, University Medical Center Regensburg, Franz-Josef-Strauss-Allee 11, 93042 Regensburg (Germany); Nerlich, Michael [Department of Anesthesiology, University Medical Center Regensburg, Franz-Josef-Strauss-Allee 11, 93042 Regensburg (Germany); Angele, Peter, E-mail: Peter.Angele@klinik.uni-regensburg.de [Department of Trauma Surgery, University Medical Center Regensburg, Franz-Josef-Strauss-Allee 11, 93042 Regensburg (Germany)

    2011-07-01

    Mesenchymal stem cells (MSCs) contribute to tissue repair in vivo and form an attractive cell source for tissue engineering. Their regenerative potential is impaired by cellular senescence. The effects of oxidative stress on MSCs are still unknown. Our studies were to investigate into the proliferation potential, cytological features and the telomere linked stress response system of MSCs, subject to acute or prolonged oxidant challenge with hydrogen peroxide. Telomere length was measured using the telomere restriction fragment assay, gene expression was determined by rtPCR. Sub-lethal doses of oxidative stress reduced proliferation rates and induced senescent-morphological features and senescence-associated {beta}-galactosidase positivity. Prolonged low dose treatment with hydrogen peroxide had no effects on cell proliferation or morphology. Sub-lethal and prolonged low doses of oxidative stress considerably accelerated telomere attrition. Following acute oxidant insult p21 was up-regulated prior to returning to initial levels. TRF1 was significantly reduced, TRF2 showed a slight up-regulation. SIRT1 and XRCC5 were up-regulated after oxidant insult and expression levels increased in aging cells. Compared to fibroblasts and chondrocytes, MSCs showed an increased tolerance to oxidative stress regarding proliferation, telomere biology and gene expression with an impaired stress tolerance in aged cells.

  14. NOX2-Induced Activation of Arginase and Diabetes-Induced Retinal Endothelial Cell Senescence

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    Modesto Rojas

    2017-06-01

    Full Text Available Increases in reactive oxygen species (ROS and decreases in nitric oxide (NO have been linked to vascular dysfunction during diabetic retinopathy (DR. Diabetes can reduce NO by increasing ROS and by increasing activity of arginase, which competes with nitric oxide synthase (NOS for their commons substrate l-arginine. Increased ROS and decreased NO can cause premature endothelial cell (EC senescence leading to defective vascular repair. We have previously demonstrated the involvement of NADPH oxidase 2 (NOX2-derived ROS, decreased NO and overactive arginase in DR. Here, we investigated their impact on diabetes-induced EC senescence. Studies using diabetic mice and retinal ECs treated with high glucose or H2O2 showed that increases in ROS formation, elevated arginase expression and activity, and decreased NO formation led to premature EC senescence. NOX2 blockade or arginase inhibition prevented these effects. EC senescence was also increased by inhibition of NOS activity and this was prevented by treatment with a NO donor. These results indicate that diabetes/high glucose-induced activation of arginase and decreases in NO bioavailability accelerate EC senescence. NOX2-generated ROS contribute importantly to this process. Blockade of NOX2 or arginase represents a strategy to prevent diabetes-induced premature EC senescence by preserving NO bioavailability.

  15. MicroRNA Regulation of Ionizing Radiation-Induced Premature Senescence

    International Nuclear Information System (INIS)

    Wang Yong; Scheiber, Melissa N.; Neumann, Carola; Calin, George A.; Zhou Daohong

    2011-01-01

    Purpose: MicroRNAs (miRNAs) have emerged as critical regulators of many cellular pathways. Ionizing radiation (IR) exposure causes DNA damage and induces premature senescence. However, the role of miRNAs in IR-induced senescence has not been well defined. Thus, the purpose of this study was to identify and characterize senescence-associated miRNAs (SA-miRNAs) and to investigate the role of SA-miRNAs in IR-induced senescence. Methods and Materials: In human lung (WI-38) fibroblasts, premature senescence was induced either by IR or busulfan (BU) treatment, and replicative senescence was accomplished by serial passaging. MiRNA microarray were used to identify SA-miRNAs, and real-time reverse transcription (RT)-PCR validated the expression profiles of SA-miRNAs in various senescent cells. The role of SA-miRNAs in IR-induced senescence was characterized by knockdown of miRNA expression, using anti-miRNA oligonucleotides or by miRNA overexpression through the transfection of pre-miRNA mimics. Results: We identified eight SA-miRNAs, four of which were up-regulated (miR-152, -410, -431, and -493) and four which were down-regulated (miR-155, -20a, -25, and -15a), that are differentially expressed in both prematurely senescent (induced by IR or BU) and replicatively senescent WI-38 cells. Validation of the expression of these SA-miRNAs indicated that down-regulation of miR-155, -20a, -25, and -15a is a characteristic miRNA expression signature of cellular senescence. Functional analyses revealed that knockdown of miR-155 or miR-20a, but not miR-25 or miR-15a, markedly enhanced IR-induced senescence, whereas ectopic overexpression of miR-155 or miR-20a significantly inhibited senescence induction. Furthermore, our studies indicate that miR-155 modulates IR-induced senescence by acting downstream of the p53 and p38 mitogen-activated protein kinase (MAPK) pathways and in part via regulating tumor protein 53-induced nuclear protein 1 (TP53INP1) expression. Conclusion: Our

  16. A decrease in cyclin B1 levels leads to polyploidization in DNA damage-induced senescence.

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    Kikuchi, Ikue; Nakayama, Yuji; Morinaga, Takao; Fukumoto, Yasunori; Yamaguchi, Naoto

    2010-05-04

    Adriamycin, an anthracycline antibiotic, has been used for the treatment of various types of tumours. Adriamycin induces at least two distinct types of growth repression, such as senescence and apoptosis, in a concentration-dependent manner. Cellular senescence is a condition in which cells are unable to proliferate further, and senescent cells frequently show polyploidy. Although abrogation of cell division is thought to correlate with polyploidization, the mechanisms underlying induction of polyploidization in senescent cells are largely unclear. We wished, therefore, to explore the role of cyclin B1 level in polyploidization of Adriamycin-induced senescent cells. A subcytotoxic concentration of Adriamycin induced polyploid cells having the features of senescence, such as flattened and enlarged cell shape and activated beta-galactosidase activity. In DNA damage-induced senescent cells, the levels of cyclin B1 were transiently increased and subsequently decreased. The decrease in cyclin B1 levels occurred in G2 cells during polyploidization upon treatment with a subcytotoxic concentration of Adriamycin. In contrast, neither polyploidy nor a decrease in cyclin B1 levels was induced by treatment with a cytotoxic concentration of Adriamycin. These results suggest that a decrease in cyclin B1 levels is induced by DNA damage, resulting in polyploidization in DNA damage-induced senescence.

  17. Human amnion-derived mesenchymal stem cells protect against UVA irradiation-induced human dermal fibroblast senescence, in vitro

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    Zhang, Chunli; Yuchi, Haishen; Sun, Lu; Zhou, Xiaoli; Lin, Jinde

    2017-01-01

    The aim of the present study was to determine if human amnion-derived mesenchymal stem cells (HAMSCs) exert a protective effect on ultraviolet A (UVA) irradiation-induced human dermal fibroblast (HDF) senescence. A senescence model was constructed as follows: HDFs (104–106 cells/well) were cultured in a six-well plate in vitro and then exposed to UVA irradiation at 9 J/cm2 for 30 min. Following the irradiation period, HDFs were co-cultured with HAMSCs, which were seeded on transwells. A total of 72 h following the co-culturing, senescence-associated β-galactosidase staining was performed and reactive oxygen species (ROS) content and mitochondrial membrane potential (Δψm) were detected in the HDFs via flow cytometric analysis. The results demonstrated that the percentage of HDFs, detected via staining with X-gal, were markedly decreased when co-cultured with human HAMSCs, compared with the group that were not co-cultured. The ROS content was decreased and the mitochondrial membrane potential (Δψm) recovered in cells treated with UVA and HAMSCs, compared with that of cells treated with UVA alone. Reverse transcription-quantitative polymerase chain reaction revealed the significant effects of HAMSCs on the HDF senescence marker genes p53 and matrix metalloproteinase-1 mRNA expression. In addition to this, western blot analysis verified the effects of HAMSCs on UVA induced senescence, providing a foundation for novel regenerative therapeutic methods. Furthermore, the results suggested that activation of the extracellular-signal regulated kinase 1/2 mitogen activated protein kinase signal transduction pathway, is essential for the HAMSC-mediated UVA protective effects. The decrease in ROS content additionally indicated that HAMSCs may exhibit the potential to treat oxidative stress-mediated UVA skin senescence in the future. PMID:28627622

  18. Mechanisms of Diabetes-Induced Endothelial Cell Senescence: Role of Arginase 1

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    Esraa Shosha

    2018-04-01

    Full Text Available We have recently found that diabetes-induced premature senescence of retinal endothelial cells is accompanied by NOX2-NADPH oxidase-induced increases in the ureohydrolase enzyme arginase 1 (A1. Here, we used genetic strategies to determine the specific involvement of A1 in diabetes-induced endothelial cell senescence. We used A1 knockout mice and wild type mice that were rendered diabetic with streptozotocin and retinal endothelial cells (ECs exposed to high glucose or transduced with adenovirus to overexpress A1 for these experiments. ABH [2(S-Amino-6-boronohexanoic acid] was used to inhibit arginase activity. We used Western blotting, immunolabeling, quantitative PCR, and senescence associated β-galactosidase (SA β-Gal activity to evaluate senescence. Analyses of retinal tissue extracts from diabetic mice showed significant increases in mRNA expression of the senescence-related proteins p16INK4a, p21, and p53 when compared with non-diabetic mice. SA β-Gal activity and p16INK4a immunoreactivity were also increased in retinal vessels from diabetic mice. A1 gene deletion or pharmacological inhibition protected against the induction of premature senescence. A1 overexpression or high glucose treatment increased SA β-Gal activity in cultured ECs. These results demonstrate that A1 is critically involved in diabetes-induced senescence of retinal ECs. Inhibition of arginase activity may therefore be an effective therapeutic strategy to alleviate diabetic retinopathy by preventing premature senescence.

  19. Proteome oxidative carbonylation during oxidative stress-induced premature senescence of WI-38 human fibroblasts

    DEFF Research Database (Denmark)

    Le Boulch, Marine; Ahmed, Emad K; Rogowska-Wrzesinska, Adelina

    2018-01-01

    Accumulation of oxidatively damaged proteins is a hallmark of cellular and organismal ageing, and is also a phenotypic feature shared by both replicative senescence and stress-induced premature senescence of human fibroblasts. Moreover, proteins that are building up as oxidized (i.e. the "Oxi-pro...

  20. Stress-induced premature senescence (SIPS)--influence of SIPS on radiotherapy.

    Science.gov (United States)

    Suzuki, Masatoshi; Boothman, David A

    2008-03-01

    Replicative senescence is a fundamental feature in normal human diploid cells and results from dysfunctional telomeres at the Hayflick cell division limit. Ionizing radiation (IR) prematurely induces the same phenotypes as replicative senescence prior to the Hayflick limit. This process is known as stress-induced premature senescence (SIPS). Since the cell cycle is irreversibly arrested in SIPS-induced cells, even if they are stimulated by various growth factors, it is thought that SIPS is a form of cell death, irreversibly eliminating replicating cells. IR-induced-focus formation of DNA repair proteins, a marker of DNA damage, is detected in SIPS as well as replicative senescent cells. Furthermore, both processes persistently induce cell cycle checkpoint mechanisms, indicating DNA damage created by ionizing radiation induces SIPS in normal cells, possibly by the same mechanisms as those occurring in replicative senescence. Interestingly, IR induces SIPS not only in normal cells, but also in tumor cells. Due to the expression of telomerase in tumor cells, telomere-dependent replicative senescence does not occur. However, SIPS is induced under certain conditions after IR exposure. Thus, cell death triggered by IR can be attributed to apoptosis or SIPS in tumor cells. However, metabolic function remains intact in SIPS-induced cancer cells, and recent studies show that senescence eliminate cells undergoing SIPS secrete various kinds of factors outside the cell, changing the microenvironment. Evidence using co-culture systems containing normal senescent stromal cells and epithelial tumor cells show that factors secreted from senescent stroma cells promote the growth of tumor epithelial cells both in vitro and in vivo. Thus, regulation of factors secreted from SIPS-induced stromal cells, as well as tumor cells, may affect radiotherapy.

  1. Stress-induced premature senescence (SIPS). Influence of SIPS on radiotherapy

    International Nuclear Information System (INIS)

    Suzuki, Masatoshi; Boothman, D.A.

    2008-01-01

    Replicative senescence is a fundamental feature in normal human diploid cells and results from dysfunctional telomeres at the Hayflick cell division limit. Ionizing radiation (IR) prematurely induces the same phenotypes as replicative senescence prior to the Hayflick limit. This process is known as stress-induced premature senescence (SIPS). Since the cell cycle is irreversibly arrested in SIPS-induced cells, even if they are stimulated by various growth factors, it is thought that SIPS is a form of cell death, irreversibly eliminating replicating cells. IR-induced-focus formation of DNA repair proteins, a marker of DNA damage, is detected in SIPS as well as replicative senescent cells. Furthermore, both processes persistently induce cell cycle checkpoint mechanisms, indicating DNA damage created by ionizing radiation induces SIPS in normal cells, possibly by the same mechanisms as those occurring in replicative senescence. Interestingly, IR induces SIPS not only in normal cells, but also in tumor cells. Due to the expression of telomerase in tumor cells, telomere-dependent replicative senescence does not occur. However, SIPS is induced under certain conditions after IR exposure. Thus, cell death triggered by IR can be attributed to apoptosis or SIPS in tumor cells. However, metabolic function remains intact in SIPS-induced cancer cells, and recent studies show that senescence eliminate cells undergoing SIPS secrete various kinds of factors outside the cell, changing the microenvironment. Evidence using co-culture systems containing normal senescent stromal cells and epithelial tumor cells show that factors secreted from senescent stroma cells promote the growth of tumor epithelial cells both in vitro and in vivo. Thus, regulation of factors secreted from SIPS-induced stromal cells, as well as tumor cells, may affect radiotherapy. (author)

  2. The role of hypoxia inducible factor-1 alpha in bypassing oncogene-induced senescence.

    Directory of Open Access Journals (Sweden)

    Mehtap Kilic Eren

    Full Text Available Oncogene induced senescence (OIS is a sustained anti-proliferative response acutely induced in primary cells via activation of mitogenic oncogenes such as Ras/BRAF. This mechanism acts as an initial barrier preventing normal cells transformation into malignant cell. Besides oncogenic activation and DNA damage response (DDR, senescence is modulated by a plethora of other factors, and one of the most important one is oxygen tension of the tissue. The aim of this study was to determine the impact of hypoxia on RasV12-induced senescence in human diploid fibroblasts (HDFs. We showed here that hypoxia prevents execution of oncogene induced senescence (OIS, through a strong down-regulation of senescence hallmarks, such as SA- β-galactosidase, H3K9me3, HP1γ, p53, p21CIP1 and p16INK4a in association with induction of hypoxia inducible factor-1α (HIF-1α. In addition, hypoxia also decreased marks of H-RasV12-induced DDR in both cell lines through down-regulation of ATM/ATR, Chk1 and Chk2 phosphorylation as well as decreased γ-H2AX positivity. Utilizing shRNA system targeting HIF-1α we show that HIF-1α is directly involved in down regulation of p53 and its target p21CIP1 but not p16INK4a. In line with this finding we found that knock down of HIF-1α leads to a strong induction of apoptotic response, but not restoration of senescence in Ras expressing HDFs in hypoxia. This indicates that HIF-1α is an important player in early steps of tumorigenesis, leading to suppression of senescence through its negative regulation of p53 and p21CIP1. In our work we describe a mechanism through which hypoxia and specifically HIF-1α preclude cells from maintaining senescence-driven anti proliferative response. These findings indicate the possible mechanism through which hypoxic environment helps premalignant cells to evade impingement of cellular failsafe pathways.

  3. Identification and characterization of secretory proteins during ionizing radiation-induced premature senescence

    International Nuclear Information System (INIS)

    Han, Na Kyung; Hong, Mi Na; Jung, Seung Hee; Kang, Kyoung Ah; Lee, Jae Seon; Chi, Seong Gil

    2011-01-01

    Cellular senescence was first described by Hayflick and Moorhead in 1961 who observed that cultures of normal human fibroblasts had a limited replicative potential and eventually became irreversibly arrest. The majority of senescent cells assume a characteristic flattened and enlarged morphological change, senescence associated β alactosidase positivity. Recently a large number of molecular phenotypes such as changes in gene expression, protein processing and chromatin organization have been also described. In contrast to apoptosis, senescence does not destroy the cells but leaves them metabolically and synthetically active and therefore able to affect their microenvironment. In particular, senescent fibroblasts and some cancer cells were found to secrete proteins with known or putative tumor-promoting functions such as growth factors or proteolytic enzymes. However, the knowledge about secreted proteins from senescent tumor cells and their functions to surrounding cells is still lacking. In this study, changes of senescence associated secretory protein expression profile were observed in MCF7 human breast cancer cells exposed to gamma-ray radiation using two dimensional electrophoresis. Also, we identified up-regulated secretory proteins during ionizing radiation-induced cellular senescence. Here, we show that senescent human breast cancer MCF7 cells promote the proliferation, invasion and migration of neighboring cells

  4. Identification and characterization of secretory proteins during ionizing radiation-induced premature senescence

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    Han, Na Kyung; Hong, Mi Na; Jung, Seung Hee; Kang, Kyoung Ah; Lee, Jae Seon [Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of); Chi, Seong Gil [Korea University, Seoul (Korea, Republic of)

    2011-05-15

    Cellular senescence was first described by Hayflick and Moorhead in 1961 who observed that cultures of normal human fibroblasts had a limited replicative potential and eventually became irreversibly arrest. The majority of senescent cells assume a characteristic flattened and enlarged morphological change, senescence associated {beta} alactosidase positivity. Recently a large number of molecular phenotypes such as changes in gene expression, protein processing and chromatin organization have been also described. In contrast to apoptosis, senescence does not destroy the cells but leaves them metabolically and synthetically active and therefore able to affect their microenvironment. In particular, senescent fibroblasts and some cancer cells were found to secrete proteins with known or putative tumor-promoting functions such as growth factors or proteolytic enzymes. However, the knowledge about secreted proteins from senescent tumor cells and their functions to surrounding cells is still lacking. In this study, changes of senescence associated secretory protein expression profile were observed in MCF7 human breast cancer cells exposed to gamma-ray radiation using two dimensional electrophoresis. Also, we identified up-regulated secretory proteins during ionizing radiation-induced cellular senescence. Here, we show that senescent human breast cancer MCF7 cells promote the proliferation, invasion and migration of neighboring cells

  5. Fatty acid and sterol contents during tulip leaf senescence induced by methyl jasmonate

    Directory of Open Access Journals (Sweden)

    Marian Saniewski

    2013-12-01

    Full Text Available It has been shown previously that methyl jasmonate (JA-Me applied in lanolin paste on the bottom surface of intact tulip leaves causes a rapid and intense its senescence. The aim of this work was to study the effect of JA-Me on free and bound fatty acid and sterol contents during tulip leaf senescence. The main free and bound fatty acids of tulip leaf, in decreasing order of their abundance, were linolenic, linoleic, palmitic, oleic, stearic and myristic acids. Only the content of free linolenic acid decreased after treatment with JA-Me during visible stage of senescence. ß-Sitosterol (highest concentration, campesterol, stigmasterol and cholesterol were identified in tulip leaf. Methyl jasmonate evidently increased the level of ß-sitosterol, campesterol and stigmasterol during induced senescence. It is suggested that the increase in sterol concentrations under the influence of methyl jasmonate induced changes in membrane fluidity and permeability, which may be responsible for senescence.

  6. Exercise Prevents Diet-Induced Cellular Senescence in Adipose Tissue

    NARCIS (Netherlands)

    Schafer, M.J.; White, T.A.; Evans, G.; Tonne, J.M.; Verzosa, G.C.; Stout, M.B.; Mazula, D.L.; Palmer, A.K.; Baker, D.J.; Jensen, M.D.; Torbenson, M.S.; Miller, J.D.; Ikeda, Y.; Tchkonia, T.; Deursen, J.M.A. van; Kirkland, J.L.; LeBrasseur, N.K.

    2016-01-01

    Considerable evidence implicates cellular senescence in the biology of aging and chronic disease. Diet and exercise are determinants of healthy aging; however, the extent to which they affect the behavior and accretion of senescent cells within distinct tissues is not clear. Here we tested the

  7. Lovastatin-induced RhoA modulation and its effect on senescence in prostate cancer cells

    International Nuclear Information System (INIS)

    Lee, Jeeyun; Lee, Inkyoung; Park, Chaehwa; Kang, Won Ki

    2006-01-01

    Lovastatin inhibits a 3-hydroxy 3-methylglutaryl coenzyme A reductase and prevents the synthesis of cholesterol precursors, such as farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP), responsible for important cell signaling in cell proliferation and migration. Recently, the anti-cancer effect of lovastatin has been suggested in various tumor types. In this study, we showed that a low dose lovastatin induced senescence and G1 cell cycle arrest in human prostate cancer cells. Addition of GGPP or mevalonate, but not FPP, prevented the lovastatin-induced G1 phase cell cycle arrest and cell senescence. We found that constitutively active RhoA (caRhoA) reversed lovastatin-induced senescence in caRhoA-transfected PC-3 cells. Thus, we postulate that modulation of RhoA may be critical in lovastatin-induced senescence in PC-3 cells

  8. Identification of Secreted Proteins from Ionizing Radiation-Induced Senescent MCF7 Cells Using Comparative Proteomics

    International Nuclear Information System (INIS)

    Han, Na Kyung; Kim, Han Na; Hong, Mi Na; Park, Su Min; Lee, Jae Seon; Chi, Seong Gil

    2010-01-01

    Cellular senescence was first described by Hayflick and Moorhead in 1961 who observed that cultures of normal human fibroblasts had a limited replicative potential and eventually became irreversibly arrest. The majority of senescent cells assume a characteristic flattened and enlarged morphological change, senescence associated β-galactosidase positivity and over the years a large number of molecular phenotypes have been described, such as changes in gene expression, protein processing and chromatin organization. In contrast to apoptosis, senescence does not destroy the cells but leaves them metabolically and synthetically active and therefore able to affect their microenvironment. In particular, senescent fibroblasts and some cancer cells were found to secrete proteins with known or putative tumor-promoting functions such as growth factors or proteolytic enzymes. However, the knowledge about secreted proteins from senescent tumor cells and their functions to surrounding cells is still lacking. In this study, changes of senescence-associated secretory protein expression profile were observed in MCF7 human breast cancer cells exposed to gamma-ray radiation using two dimensional electrophoresis. Also, we identified up-regulated secretory proteins during ionizing radiation-induced cellular senescence

  9. Identification of Secreted Proteins from Ionizing Radiation-Induced Senescent MCF7 Cells Using Comparative Proteomics

    Energy Technology Data Exchange (ETDEWEB)

    Han, Na Kyung; Kim, Han Na; Hong, Mi Na; Park, Su Min; Lee, Jae Seon [Korea Institue of Radiological and Medical Sciences, Seoul (Korea, Republic of); Chi, Seong Gil [Korea University, Seoul (Korea, Republic of)

    2010-05-15

    Cellular senescence was first described by Hayflick and Moorhead in 1961 who observed that cultures of normal human fibroblasts had a limited replicative potential and eventually became irreversibly arrest. The majority of senescent cells assume a characteristic flattened and enlarged morphological change, senescence associated beta-galactosidase positivity and over the years a large number of molecular phenotypes have been described, such as changes in gene expression, protein processing and chromatin organization. In contrast to apoptosis, senescence does not destroy the cells but leaves them metabolically and synthetically active and therefore able to affect their microenvironment. In particular, senescent fibroblasts and some cancer cells were found to secrete proteins with known or putative tumor-promoting functions such as growth factors or proteolytic enzymes. However, the knowledge about secreted proteins from senescent tumor cells and their functions to surrounding cells is still lacking. In this study, changes of senescence-associated secretory protein expression profile were observed in MCF7 human breast cancer cells exposed to gamma-ray radiation using two dimensional electrophoresis. Also, we identified up-regulated secretory proteins during ionizing radiation-induced cellular senescence

  10. Oxidative Stress Induces Endothelial Cell Senescence via Downregulation of Sirt6

    Directory of Open Access Journals (Sweden)

    Rong Liu

    2014-01-01

    Full Text Available Accumulating evidence has shown that diabetes accelerates aging and endothelial cell senescence is involved in the pathogenesis of diabetic vascular complications, including diabetic retinopathy. Oxidative stress is recognized as a key factor in the induction of endothelial senescence and diabetic retinopathy. However, specific mechanisms involved in oxidative stress-induced endothelial senescence have not been elucidated. We hypothesized that Sirt6, which is a nuclear, chromatin-bound protein critically involved in many pathophysiologic processes such as aging and inflammation, may have a role in oxidative stress-induced vascular cell senescence. Measurement of Sirt6 expression in human endothelial cells revealed that H2O2 treatment significantly reduced Sirt6 protein. The loss of Sirt6 was associated with an induction of a senescence phenotype in endothelial cells, including decreased cell growth, proliferation and angiogenic ability, and increased expression of senescence-associated β-galactosidase activity. Additionally, H2O2 treatment reduced eNOS expression, enhanced p21 expression, and dephosphorylated (activated retinoblastoma (Rb protein. All of these alternations were attenuated by overexpression of Sirt6, while partial knockdown of Sirt6 expression by siRNA mimicked the effect of H2O2. In conclusion, these results suggest that Sirt6 is a critical regulator of endothelial senescence and oxidative stress-induced downregulation of Sirt6 is likely involved in the pathogenesis of diabetic retinopathy.

  11. JNK inhibition sensitizes tumor cells to radiation-induced premature senescence via Bcl-2/ROS/DDR signaling pathway

    International Nuclear Information System (INIS)

    Lee, Jae Seon; Lee, Je Jung

    2009-01-01

    Premature senescence is considered as a cellular defense mechanism to prevent tumorigenesis. Although recent evidences demonstrate that c-Jun N-terminal kinase (JNK) is involved in the senescence process, the target and exact mechanism of JNK signaling in the regulation of cell proliferation has yet to be defined. In this study, we investigated the role of JNK in premature senescence and demonstrated JNK inhibition sensitized tumor cells to radiation-induced premature senescence

  12. Arctigenin induced gallbladder cancer senescence through modulating epidermal growth factor receptor pathway.

    Science.gov (United States)

    Zhang, Mingdi; Cai, Shizhong; Zuo, Bin; Gong, Wei; Tang, Zhaohui; Zhou, Di; Weng, Mingzhe; Qin, Yiyu; Wang, Shouhua; Liu, Jun; Ma, Fei; Quan, Zhiwei

    2017-05-01

    Gallbladder cancer has poor prognosis and limited therapeutic options. Arctigenin, a representative dibenzylbutyrolactone lignan, occurs in a variety of plants. However, the molecular mechanisms involved in the antitumor effect of arctigenin on gallbladder cancer have not been fully elucidated. The expression levels of epidermal growth factor receptor were examined in 100 matched pairs of gallbladder cancer tissues. A positive correlation between high epidermal growth factor receptor expression levels and poor prognosis was observed in gallbladder cancer tissues. Pharmacological inhibition or inhibition via RNA interference of epidermal growth factor receptor induced cellular senescence in gallbladder cancer cells. The antitumor effect of arctigenin on gallbladder cancer cells was primarily achieved by inducing cellular senescence. In gallbladder cancer cells treated with arctigenin, the expression level of epidermal growth factor receptor significantly decreased. The analysis of the activity of the kinases downstream of epidermal growth factor receptor revealed that the RAF-MEK-ERK signaling pathway was significantly inhibited. Furthermore, the cellular senescence induced by arctigenin could be reverted by pcDNA-epidermal growth factor receptor. Arctigenin also potently inhibited the growth of tumor xenografts, which was accompanied by the downregulation of epidermal growth factor receptor and induction of senescence. This study demonstrates arctigenin could induce cellular senescence in gallbladder cancer through the modulation of epidermal growth factor receptor pathway. These data identify epidermal growth factor receptor as a key regulator in arctigenin-induced gallbladder cancer senescence.

  13. Perception of Arabidopsis AtPep peptides, but not bacterial elicitors, accelerates starvation-induced senescence

    Directory of Open Access Journals (Sweden)

    Kay eGully

    2015-01-01

    Full Text Available Members of the AtPep group of Arabidopsis endogenous peptides have frequently been reported to induce pattern-triggered immunity and to increase resistance to diverse pathogens by amplifying the innate immune response. Here, we made the surprising observation that dark-induced leaf senescence was accelerated by the presence of Peps. Adult leaves as well as leaf discs of Col-0 wild type plants showed a Pep-triggered early onset of chlorophyll breakdown and leaf yellowing whereas pepr1 pepr2 double mutant plants were insensitive. In addition, this response was dependent on ethylene signaling and inhibited by the addition of cytokinins. Notably, addition of the bacterial elicitors flg22 or elf18, both potent inducers of pattern-triggered immunity, did not provoke an early onset of leaf senescence.Continuous darkness leads to energy deprivation and starvation and therewith promotes leaf senescence. We found that continuous darkness also strongly induced PROPEP3 transcription. Moreover, Pep-perception led to a rapid induction of PAO, APG7 and APG8a, genes indispensable for chlorophyll degradation as well as autophagy, respectively, and all three hallmarks of starvation and senescence. Notably, addition of sucrose as a source of energy inhibited the Pep-triggered early onset of senescence. In conclusion, we report that Pep-perception accelerates dark/starvation-induced senescence via an early induction of chlorophyll degradation and autophagy. This represents a novel and unique characteristic of PEPR signaling, unrelated to pattern-triggered immunity.

  14. Limited role of murine ATM in oncogene-induced senescence and p53-dependent tumor suppression.

    Directory of Open Access Journals (Sweden)

    Alejo Efeyan

    Full Text Available Recent studies in human fibroblasts have provided a new general paradigm of tumor suppression according to which oncogenic signaling produces DNA damage and this, in turn, results in ATM/p53-dependent cellular senescence. Here, we have tested this model in a variety of murine experimental systems. Overexpression of oncogenic Ras in murine fibroblasts efficiently induced senescence but this occurred in the absence of detectable DNA damage signaling, thus suggesting a fundamental difference between human and murine cells. Moreover, lung adenomas initiated by endogenous levels of oncogenic K-Ras presented abundant senescent cells, but undetectable DNA damage signaling. Accordingly, K-Ras-driven adenomas were also senescent in Atm-null mice, and the tumorigenic progression of these lesions was only modestly accelerated by Atm-deficiency. Finally, we have examined chemically-induced fibrosarcomas, which possess a persistently activated DNA damage response and are highly sensitive to the activity of p53. We found that the absence of Atm favored genomic instability in the resulting tumors, but did not affect the persistent DNA damage response and did not impair p53-dependent tumor suppression. All together, we conclude that oncogene-induced senescence in mice may occur in the absence of a detectable DNA damage response. Regarding murine Atm, our data suggest that it plays a minor role in oncogene-induced senescence or in p53-dependent tumor suppression, being its tumor suppressive activity probably limited to the maintenance of genomic stability.

  15. Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints

    DEFF Research Database (Denmark)

    Bartkova, Jirina; Rezaei, Nousin; Liontos, Michalis

    2006-01-01

    Recent studies have indicated the existence of tumorigenesis barriers that slow or inhibit the progression of preneoplastic lesions to neoplasia. One such barrier involves DNA replication stress, which leads to activation of the DNA damage checkpoint and thereby to apoptosis or cell cycle arrest...... and senescence markers cosegregate closely. Thus, senescence in human preneoplastic lesions is a manifestation of oncogene-induced DNA replication stress and, together with apoptosis, provides a barrier to malignant progression....

  16. Twist1 suppresses senescence programs and thereby accelerates and maintains mutant Kras-induced lung tumorigenesis.

    Directory of Open Access Journals (Sweden)

    Phuoc T Tran

    Full Text Available KRAS mutant lung cancers are generally refractory to chemotherapy as well targeted agents. To date, the identification of drugs to therapeutically inhibit K-RAS have been unsuccessful, suggesting that other approaches are required. We demonstrate in both a novel transgenic mutant Kras lung cancer mouse model and in human lung tumors that the inhibition of Twist1 restores a senescence program inducing the loss of a neoplastic phenotype. The Twist1 gene encodes for a transcription factor that is essential during embryogenesis. Twist1 has been suggested to play an important role during tumor progression. However, there is no in vivo evidence that Twist1 plays a role in autochthonous tumorigenesis. Through two novel transgenic mouse models, we show that Twist1 cooperates with Kras(G12D to markedly accelerate lung tumorigenesis by abrogating cellular senescence programs and promoting the progression from benign adenomas to adenocarcinomas. Moreover, the suppression of Twist1 to physiological levels is sufficient to cause Kras mutant lung tumors to undergo senescence and lose their neoplastic features. Finally, we analyzed more than 500 human tumors to demonstrate that TWIST1 is frequently overexpressed in primary human lung tumors. The suppression of TWIST1 in human lung cancer cells also induced cellular senescence. Hence, TWIST1 is a critical regulator of cellular senescence programs, and the suppression of TWIST1 in human tumors may be an effective example of pro-senescence therapy.

  17. Ionizing Radiation Induces Cellular Senescence of Articular Chondrocytes via Negative Regulation of SIRT1 by p38 Kinase

    Energy Technology Data Exchange (ETDEWEB)

    Hong, Eun Hee; Hwang, Sang Gu [Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of)

    2009-05-15

    Senescent cells exhibit irreversible growth arrest, large flat morphology, and up-regulated senescence-associated {beta}-galactosidase activity at pH 6.0. Several conditions, including oncogenic stress, oxidative stress, and DNA damage are associated with cellular senescence. Massive acute DNA double-strand breaks occurring as a result of mechanical and chemical stress can be repaired, but some DNA damage persists, eventually triggering premature senescence. Since ionizing radiation directly induces DBS, it is possible that cellular senescence is activated under these conditions. The biological events in chondrocytes following irradiation are poorly understood, and limited information is available on the molecular signal transduction mechanisms of cellular senescence at present. In this study, we identify SIRT1 as a target molecule of p38 kinase and demonstrate that the interactions between p38 kinase and SIRT1 protein play an important role in the regulation of cellular senescence in response to IR.

  18. Glycogen Synthase Kinase 3 Inactivation Induces Cell Senescence through Sterol Regulatory Element Binding Protein 1-Mediated Lipogenesis in Chang Cells.

    Science.gov (United States)

    Kim, You-Mie; Song, Insun; Seo, Yong-Hak; Yoon, Gyesoon

    2013-12-01

    Enhanced lipogenesis plays a critical role in cell senescence via induction of expression of the mature form of sterol regulatory element binding protein 1 (SREBP1), which contributes to an increase in organellar mass, one of the indicators of senescence. We investigated the molecular mechanisms by which signaling molecules control SREBP1-mediated lipogenesis and senescence. We developed cellular models for stress-induced senescence, by exposing Chang cells, which are immortalized human liver cells, to subcytotoxic concentrations (200 µM) of deferoxamine (DFO) and H2O2. In this model of stress-induced cell senescence using DFO and H2O2, the phosphorylation profile of glycogen synthase kinase 3α (GSK3α) and β corresponded closely to the expression profile of the mature form of SREBP-1 protein. Inhibition of GSK3 with a subcytotoxic concentration of the selective GSK3 inhibitor SB415286 significantly increased mature SREBP1 expression, as well as lipogenesis and organellar mass. In addition, GSK3 inhibition was sufficient to induce senescence in Chang cells. Suppression of GSK3 expression with siRNAs specific to GSK3α and β also increased mature SREBP1 expression and induced senescence. Finally, blocking lipogenesis with fatty acid synthase inhibitors (cerulenin and C75) and siRNA-mediated silencing of SREBP1 and ATP citrate lyase (ACL) significantly attenuated GSK3 inhibition-induced senescence. GSK3 inactivation is an important upstream event that induces SREBP1-mediated lipogenesis and consequent cell senescence.

  19. Cytokines shape chemotherapy-induced and 'bystander' senescence

    Czech Academy of Sciences Publication Activity Database

    Hodný, Zdeněk; Hubáčková, Soňa; Bartek, Jiří

    2010-01-01

    Roč. 2, č. 2 (2010), s. 375-376 ISSN 1945-4589 R&D Projects: GA ČR GA204/08/1418; GA ČR GA301/08/0353 Institutional research plan: CEZ:AV0Z50520514 Keywords : bystander cellular senescence * cytokines * PML Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.964, year: 2010

  20. Ageing induced vascular smooth muscle cell senescence in atherosclerosis.

    Science.gov (United States)

    Uryga, Anna K; Bennett, Martin R

    2016-04-15

    Atherosclerosis is a disease of ageing in that its incidence and prevalence increase with age. However, atherosclerosis is also associated with biological ageing, manifest by a number of typical hallmarks of ageing in the atherosclerotic plaque. Thus, accelerated biological ageing may be superimposed on the effects of chronological ageing in atherosclerosis. Tissue ageing is seen in all cells that comprise the plaque, but particularly in vascular smooth muscle cells (VSMCs). Hallmarks of ageing include evidence of cell senescence, DNA damage (including telomere attrition), mitochondrial dysfunction, a pro-inflammatory secretory phenotype, defects in proteostasis, epigenetic changes, deregulated nutrient sensing, and exhaustion of progenitor cells. In this model, initial damage to DNA (genomic, telomeric, mitochondrial and epigenetic changes) results in a number of cellular responses (cellular senescence, deregulated nutrient sensing and defects in proteostasis). Ultimately, ongoing damage and attempts at repair by continued proliferation overwhelm reparative capacity, causing loss of specialised cell functions, cell death and inflammation. This review summarises the evidence for accelerated biological ageing in atherosclerosis, the functional consequences of cell ageing on cells comprising the plaque, and the causal role that VSMC senescence plays in atherogenesis. © 2015 The Authors. The Journal of Physiology © 2015 The Physiological Society.

  1. Redox markers for drought-induced nodule senescence, a process occurring after drought-induced senescence of the lowest leaves in soybean (Glycine max).

    Science.gov (United States)

    Marquez-Garcia, Belén; Shaw, Daniel; Cooper, James William; Karpinska, Barbara; Quain, Marian Dorcas; Makgopa, Eugene Matome; Kunert, Karl; Foyer, Christine Helen

    2015-09-01

    Water is an increasingly scarce resource that limits crop productivity in many parts of the world, and the frequency and severity of drought are predicted to increase as a result of climate change. Improving tolerance to drought stress is therefore important for maximizing future crop yields. The aim of this study was to compare the effects of drought on soybean (Glycine max) leaves and nodules in order to define phenotypic markers and changes in cellular redox state that characterize the stress response in different organs, and to characterize the relationships between leaf and nodule senescence during drought. Leaf and crown nodule metabolite pools were measured together with leaf and soil water contents, and leaf chlorophyll, total protein contents and chlorophyll a fluorescence quenching parameters in nodulated soybeans that were grown under either well-watered conditions or deprived of water for up to 21 d. Ureides, ascorbate, protein, chlorophyll and the ratios of variable chlorophyll a fluorescence (Fv') to maximal chlorophyll a fluorescence (Fm') fell to levels below detection in the oldest leaves after 21 d of drought. While these drought-induced responses were not observed in the youngest leaf ranks, the Fv'/Fm' ratios, pyridine nucleotide levels and the reduction state of the ascorbate pool were lower in all leaf ranks after 21 d of drought. In contrast to leaves, total nodule protein, pyridine nucleotides, ureides, ascorbate and glutathione contents increased as a result of the drought treatment. However, the nodule ascorbate pool was significantly less reduced as a result of drought. Higher levels of transcripts encoding two peroxiredoxins were detected in nodules exposed to drought stress but senescence-associated transcripts and other mRNAs encoding redox-related proteins were similar under both conditions. While the physiological impact of the drought was perceived throughout the shoot, stress-induced senescence occurred only in the oldest

  2. p53-independent upregulation of miR-34a during oncogene-induced senescence represses MYC

    DEFF Research Database (Denmark)

    Christoffersen, N R; Shalgi, R; Frankel, L B

    2010-01-01

    Aberrant oncogene activation induces cellular senescence, an irreversible growth arrest that acts as a barrier against tumorigenesis. To identify microRNAs (miRNAs) involved in oncogene-induced senescence, we examined the expression of miRNAs in primary human TIG3 fibroblasts after constitutive...

  3. Cytokine expression and signaling in drug-induced cellular senescence

    Czech Academy of Sciences Publication Activity Database

    Nováková, Zora; Hubáčková, Soňa; Košař, Martin; Janderová-Rossmeislová, Lenka; Dobrovolná, Jana; Vašicová, Pavla; Vančurová, Markéta; Hořejší, Zuzana; Hozák, Pavel; Bartek, Jiří; Hodný, Zdeněk

    2010-01-01

    Roč. 29, č. 2 (2010), s. 273-284 ISSN 0950-9232 R&D Projects: GA AV ČR IAA500390501; GA ČR GA204/08/1418; GA MŠk LC545 Grant - others:EC(XE) TRIREME Institutional research plan: CEZ:AV0Z50520514; CEZ:AV0Z50200510 Keywords : cellular senescence * cytokines * JAK/STAT signaling pathway Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 7.414, year: 2010

  4. Cytokinin delays dark-induced senescence in rice by maintaining the chlorophyll cycle and photosynthetic complexes.

    Science.gov (United States)

    Talla, Sai Krishna; Panigrahy, Madhusmita; Kappara, Saivishnupriya; Nirosha, P; Neelamraju, Sarla; Ramanan, Rajeshwari

    2016-03-01

    The phytohormone cytokinin (CK) is known to delay senescence in plants. We studied the effect of a CK analog, 6-benzyl adenine (BA), on rice leaves to understand the possible mechanism by which CK delays senescence in a drought- and heat-tolerant rice cultivar Nagina22 (N22) using dark-induced senescence (DIS) as a surrogate for natural senescence of leaves. Leaves of N22-H-dgl162, a stay-green mutant of N22, and BA-treated N22 showed retention of chlorophyll (Chl) pigments, maintenance of the Chl a/b ratio, and delay in reduction of both photochemical efficiency and rate of oxygen evolution during DIS. HPLC analysis showed accumulation of 7-hydroxymethyl chlorophyll (HmChl) during DIS, and the kinetics of its accumulation correlated with progression of senescence. Transcriptome analysis revealed that several plastid-localized genes, specifically those associated with photosystem II (PSII), showed higher transcript levels in BA-treated N22 and the stay-green mutant leaves compared with naturally senescing N22 leaves. Real-time PCR analyses showed that genes coding for enzymes associated with Chl a/b interconversion and proteins associated with light-harvesting complexes maintained higher transcript levels up to 72h of DIS following BA treatment. The pigment-protein complexes analyzed by green gel remained intact in both N22-H-dgl162 and BA-treated N22 leaves even after 96h of DIS. Thus, CK delays senescence by accumulation of HmChl and up-regulating genes in the Chl cycle, thereby maintaining the Chl a/b ratio. Also, CK treatment retains higher transcript levels of PSII-related genes, resulting in the stability of photosynthetic pigment complexes and functional stay-greenness in rice. © The Author 2016. Published by Oxford University Press on behalf of the Society for Experimental Biology.

  5. From the Hayflick mosaic to the mosaics of ageing. Role of stress-induced premature senescence in human ageing.

    Science.gov (United States)

    Toussaint, Olivier; Remacle, Jose; Dierick, Jean-François; Pascal, Thierry; Frippiat, Christophe; Zdanov, Stéphanie; Magalhaes, Joao Pedro; Royer, Véronique; Chainiaux, Florence

    2002-11-01

    The Hayflick limit-senescence of proliferative cell types-is a fundamental feature of proliferative cells in vitro. Various human proliferative cell types exposed in vitro to many types of subcytotoxic stresses undergo stress-induced premature senescence (SIPS) (also called stress-induced premature senescence-like phenotype, according to the definition of senescence). The known mechanisms of appearance the main features of SIPS are reviewed: senescent-like morphology, growth arrest, senescence-related changes in gene expression, telomere shortening. Long before telomere-shortening induces senescence, other factors such as culture conditions or lack of 'feeder cells' can trigger either SIPS or prolonged reversible G(0) phase of the cell cycle. In vivo, 'proliferative' cell types of aged individuals are likely to compose a mosaic made of cells irreversibly growth arrested or not. The higher level of stress to which these cells have been exposed throughout their life span, the higher proportion of the cells of this mosaic will be in SIPS rather than in telomere-shortening dependent senescence. All cell types undergoing SIPS in vivo, most notably the ones in stressful conditions, are likely to participate in the tissular changes observed along ageing. For instance, human diploid fibroblasts (HDFs) exposed in vivo and in vitro to pro-inflammatory cytokines display biomarkers of senescence and might participate in the degradation of the extracellular matrix observed in ageing.

  6. Rejuvenation of MPTP-induced human neural precursor cell senescence by activating autophagy

    Energy Technology Data Exchange (ETDEWEB)

    Zhu, Liang [East Hospital, Tongji University School of Medicine, Shanghai (China); Dong, Chuanming [East Hospital, Tongji University School of Medicine, Shanghai (China); Department of Anatomy and Neurobiology, The Jiangsu Key Laboratory of Neuroregeneration, Nantong University, Nantong (China); Sun, Chenxi; Ma, Rongjie; Yang, Danjing [East Hospital, Tongji University School of Medicine, Shanghai (China); Zhu, Hongwen, E-mail: hongwen_zhu@hotmail.com [Tianjin Hospital, Tianjin Academy of Integrative Medicine, Tianjin (China); Xu, Jun, E-mail: xunymc2000@yahoo.com [East Hospital, Tongji University School of Medicine, Shanghai (China)

    2015-08-21

    Aging of neural stem cell, which can affect brain homeostasis, may be caused by many cellular mechanisms. Autophagy dysfunction was found in aged and neurodegenerative brains. However, little is known about the relationship between autophagy and human neural stem cell (hNSC) aging. The present study used 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) to treat neural precursor cells (NPCs) derived from human embryonic stem cell (hESC) line H9 and investigate related molecular mechanisms involved in this process. MPTP-treated NPCs were found to undergo premature senescence [determined by increased senescence-associated-β-galactosidase (SA-β-gal) activity, elevated intracellular reactive oxygen species level, and decreased proliferation] and were associated with impaired autophagy. Additionally, the cellular senescence phenotypes were manifested at the molecular level by a significant increase in p21 and p53 expression, a decrease in SOD2 expression, and a decrease in expression of some key autophagy-related genes such as Atg5, Atg7, Atg12, and Beclin 1. Furthermore, we found that the senescence-like phenotype of MPTP-treated hNPCs was rejuvenated through treatment with a well-known autophagy enhancer rapamycin, which was blocked by suppression of essential autophagy gene Beclin 1. Taken together, these findings reveal the critical role of autophagy in the process of hNSC aging, and this process can be reversed by activating autophagy. - Highlights: • We successfully establish hESC-derived neural precursor cells. • MPTP treatment induced senescence-like state in hESC-derived NPCs. • MPTP treatment induced impaired autophagy of hESC-derived NPCs. • MPTP-induced hESC-derived NPC senescence was rejuvenated by activating autophagy.

  7. Senescence-Induced Alterations of Laminin Chain Expression Modulate Tumorigenicity of Prostate Cancer Cells1

    Science.gov (United States)

    Sprenger, Cynthia C T; Drivdahl, Rolf H; Woodke, Lillie B; Eyman, Daniel; Reed, May J; Carter, William G; Plymate, Stephen R

    2008-01-01

    Prostate cancer is an age-associated epithelial cancer, and as such, it contributes significantly to the mortality of the elderly. Senescence is one possible mechanism by which the body defends itself against various epithelial cancers. Senescent cells alter the microenvironment, in part, through changes to the extracellular matrix. Laminins (LMs) are extracellular proteins important to both the structure and function of the microenvironment. Overexpression of the senescence-associated gene mac25 in human prostate cancer cells resulted in increased mRNA levels of the LM α4 and β2 chains compared to empty vector control cells. The purpose of this study was to examine the effects of these senescence-induced LM chains on tumorigenicity of prostate cancer cells. We created stable M12 human prostate cancer lines overexpressing either the LM α4 or β2 chain or both chains. Increased expression of either the LM α4 or β2 chain resulted in increased in vitro migration and in vivo tumorigenicity of those cells, whereas high expression of both chains led to decreased in vitro proliferation and in vivo tumorigenicity compared to M12 control cells. This study demonstrates that senescent prostate epithelial cells can alter the microenvironment and that these changes modulate progression of prostate cancer. PMID:19048114

  8. Senescence-Induced Alterations of Laminin Chain Expression Modulate Tumorigenicity of Prostate Cancer Cells

    Directory of Open Access Journals (Sweden)

    Cynthia C.T. Sprenger

    2008-12-01

    Full Text Available Prostate cancer is an age-associated epithelial cancer, and as such, it contributes significantly to the mortality of the elderly. Senescence is one possible mechanism by which the body defends itself against various epithelial cancers. Senescent cells alter the microenvironment, in part, through changes to the extracellular matrix. Laminins (LMs are extracellular proteins important to both the structure and function of the microenvironment. Overexpression of the senescence-associated gene mac25 in human prostate cancer cells resulted in increased mRNA levels of the LM α4 and β2 chains compared to empty vector control cells. The purpose of this study was to examine the effects of these senescence-induced LM chains on tumorigenicity of prostate cancer cells. We created stable M12 human prostate cancer lines overexpressing either the LM α4 or β2 chain or both chains. Increased expression of either the LM α4 or β2 chain resulted in increased in vitro migration and in vivo tumorigenicity of those cells, whereas high expression of both chains led to decreased in vitro proliferation and in vivo tumorigenicity compared to M12 control cells. This study demonstrates that senescent prostate epithelial cells can alter the microenvironment and that these changes modulate progression of prostate cancer.

  9. The different fates of mitochondria and chloroplasts during dark-induced senescence in Arabidopsis leaves.

    Science.gov (United States)

    Keech, Olivier; Pesquet, Edouard; Ahad, Abdul; Askne, Anna; Nordvall, Dag; Vodnala, Sharvani Munender; Tuominen, Hannele; Hurry, Vaughan; Dizengremel, Pierre; Gardeström, Per

    2007-12-01

    Senescence is an active process allowing the reallocation of valuable nutrients from the senescing organ towards storage and/or growing tissues. Using Arabidopsis thaliana leaves from both whole darkened plants (DPs) and individually darkened leaves (IDLs), we investigated the fate of mitochondria and chloroplasts during dark-induced leaf senescence. Combining in vivo visualization of fates of the two organelles by three-dimensional reconstructions of abaxial parts of leaves with functional measurements of photosynthesis and respiration, we showed that the two experimental systems displayed major differences during 6 d of dark treatment. In whole DPs, organelles were largely retained in both epidermal and mesophyll cells. However, while the photosynthetic capacity was maintained, the capacity of mitochondrial respiration decreased. In contrast, IDLs showed a rapid decline in photosynthetic capacity while maintaining a high capacity for mitochondrial respiration throughout the treatment. In addition, we noticed an unequal degradation of organelles in the different cell types of the senescing leaf. From these data, we suggest that metabolism in leaves of the whole DPs enters a 'stand-by mode' to preserve the photosynthetic machinery for as long as possible. However, in IDLs, mitochondria actively provide energy and carbon skeletons for the degradation of cell constituents, facilitating the retrieval of nutrients. Finally, the heterogeneity of the degradation processes involved during senescence is discussed with regard to the fate of mitochondria and chloroplasts in the different cell types.

  10. The p53-reactivating small molecule RITA induces senescence in head and neck cancer cells.

    Directory of Open Access Journals (Sweden)

    Hui-Ching Chuang

    Full Text Available TP53 is the most commonly mutated gene in head and neck cancer (HNSCC, with mutations being associated with resistance to conventional therapy. Restoring normal p53 function has previously been investigated via the use of RITA (reactivation of p53 and induction of tumor cell apoptosis, a small molecule that induces a conformational change in p53, leading to activation of its downstream targets. In the current study we found that RITA indeed exerts significant effects in HNSCC cells. However, in this model, we found that a significant outcome of RITA treatment was accelerated senescence. RITA-induced senescence in a variety of p53 backgrounds, including p53 null cells. Also, inhibition of p53 expression did not appear to significantly inhibit RITA-induced senescence. Thus, this phenomenon appears to be partially p53-independent. Additionally, RITA-induced senescence appears to be partially mediated by activation of the DNA damage response and SIRT1 (Silent information regulator T1 inhibition, with a synergistic effect seen by combining either ionizing radiation or SIRT1 inhibition with RITA treatment. These data point toward a novel mechanism of RITA function as well as hint to its possible therapeutic benefit in HNSCC.

  11. The p53-reactivating small molecule RITA induces senescence in head and neck cancer cells.

    Science.gov (United States)

    Chuang, Hui-Ching; Yang, Liang Peng; Fitzgerald, Alison L; Osman, Abdullah; Woo, Sang Hyeok; Myers, Jeffrey N; Skinner, Heath D

    2014-01-01

    TP53 is the most commonly mutated gene in head and neck cancer (HNSCC), with mutations being associated with resistance to conventional therapy. Restoring normal p53 function has previously been investigated via the use of RITA (reactivation of p53 and induction of tumor cell apoptosis), a small molecule that induces a conformational change in p53, leading to activation of its downstream targets. In the current study we found that RITA indeed exerts significant effects in HNSCC cells. However, in this model, we found that a significant outcome of RITA treatment was accelerated senescence. RITA-induced senescence in a variety of p53 backgrounds, including p53 null cells. Also, inhibition of p53 expression did not appear to significantly inhibit RITA-induced senescence. Thus, this phenomenon appears to be partially p53-independent. Additionally, RITA-induced senescence appears to be partially mediated by activation of the DNA damage response and SIRT1 (Silent information regulator T1) inhibition, with a synergistic effect seen by combining either ionizing radiation or SIRT1 inhibition with RITA treatment. These data point toward a novel mechanism of RITA function as well as hint to its possible therapeutic benefit in HNSCC.

  12. The Arabidopsis transcription factor ABIG1 relays ABA signaled growth inhibition and drought induced senescence.

    Science.gov (United States)

    Liu, Tie; Longhurst, Adam D; Talavera-Rauh, Franklin; Hokin, Samuel A; Barton, M Kathryn

    2016-10-04

    Drought inhibits plant growth and can also induce premature senescence. Here we identify a transcription factor, ABA INSENSITIVE GROWTH 1 (ABIG1) required for abscisic acid (ABA) mediated growth inhibition, but not for stomatal closure. ABIG1 mRNA levels are increased both in response to drought and in response to ABA treatment. When treated with ABA, abig1 mutants remain greener and produce more leaves than comparable wild-type plants. When challenged with drought, abig1 mutants have fewer yellow, senesced leaves than wild-type. Induction of ABIG1 transcription mimics ABA treatment and regulates a set of genes implicated in stress responses. We propose a model in which drought acts through ABA to increase ABIG1 transcription which in turn restricts new shoot growth and promotes leaf senescence. The results have implications for plant breeding: the existence of a mutant that is both ABA resistant and drought resistant points to new strategies for isolating drought resistant genetic varieties.

  13. SORBS2 and TLR3 induce premature senescence in primary human fibroblasts and keratinocytes

    International Nuclear Information System (INIS)

    Liesenfeld, Melanie; Mosig, Sandy; Funke, Harald; Jansen, Lars; Runnebaum, Ingo B; Dürst, Matthias; Backsch, Claudia

    2013-01-01

    Genetic aberrations are required for the progression of HPV-induced cervical precancers. A prerequisite for clonal expansion of cancer cells is unlimited proliferative capacity. In a cell culture model for cervical carcinogenesis loss of genes located on chromosome 4q35→qter and chromosome 10p14-p15 were found to be associated with escape from senescence. Moreover, by LOH and I-FISH analyses a higher frequency of allele loss of these regions was also observed in cervical carcinomas as compared to CIN3. The aim of this study was to identify candidate senescence-related genes located on chromosome 4q35→qter and chromosome 10p14-p15 which may contribute to clonal expansion at the transition of CIN3 to cancer. Microarray expression analyses were used to identify candidate genes down-regulated in cervical carcinomas as compared to CIN3. In order to relate these genes with the process of senescence their respective cDNAs were overexpressed in HPV16-immortalized keratinocytes as well as in primary human fibroblasts and keratinocytes using lentivirus mediated gene transduction. Overall fifteen genes located on chromosome 4q35→qter and chromosome 10p14-p15 were identified. Ten of these genes could be validated in biopsies by RT-PCR. Of interest is the novel finding that SORBS2 and TLR3 can induce senescence in primary human fibroblasts and keratinocytes but not in HPV-immortalized cell lines. Intriguingly, the endogenous expression of both genes increases during finite passaging of primary keratinocytes in vitro. The relevance of the genes SORBS2 and TLR3 in the process of cellular senescence warrants further investigation. In ongoing experiments we are investigating whether this increase in gene expression is also characteristic of replicative senescence

  14. Proteomic and metabolomic analysis of H2O2-induced premature senescent human mesenchymal stem cells.

    Science.gov (United States)

    Kim, Ji-Soo; Kim, Eui-Jin; Kim, Hyun-Jung; Yang, Ji-Young; Hwang, Geum-Sook; Kim, Chan-Wha

    2011-06-01

    Stress induced premature senescence (SIPS) occurs after exposure to many different sublethal stresses including H(2)O(2), hyperoxia, or tert-butylhydroperoxide. Human mesenchymal stem cells (hMSCs) exhibit limited proliferative potential in vitro, the so-called Hayflick limit. According to the free-radical theory, reactive oxygen species (ROS) might be the candidates responsible for senescence and age-related diseases. H(2)O(2) may be responsible for the production of high levels of ROS, in which the redox balance is disturbed and the cells shift into a state of oxidative stress, which subsequently leads to premature senescence with shortening telomeres. H(2)O(2) has been the most commonly used inducer of SIPS, which shares features of replicative senescence (RS) including a similar morphology, senescence-associated β-galactosidase activity, cell cycle regulation, etc. Therefore, in this study, the senescence of hMSC during SIPS was confirmed using a range of different analytical methods. In addition, we determined five differentially expressed spots in the 2-DE map, which were identified as Annexin A2 (ANXA2), myosin light chain 2 (MLC2), peroxisomal enoyl-CoA hydratase 1 (ECH1), prosomal protein P30-33K (PSMA1) and mutant β-actin by ESI-Q-TOF MS/MS. Also, proton ((1)H) nuclear magnetic resonance spectroscopy (NMR) was used to elucidate the difference between metabolites in the control and hMSCs treated with H(2)O(2). Among these metabolites, choline and leucine were identified by (1)H-NMR as up-regulated metabolites and glycine and proline were identified as down-regulated metabolites. Copyright © 2011 Elsevier Inc. All rights reserved.

  15. Accelerated Telomere Shortening in Acromegaly; IGF-I Induces Telomere Shortening and Cellular Senescence.

    Science.gov (United States)

    Matsumoto, Ryusaku; Fukuoka, Hidenori; Iguchi, Genzo; Odake, Yukiko; Yoshida, Kenichi; Bando, Hironori; Suda, Kentaro; Nishizawa, Hitoshi; Takahashi, Michiko; Yamada, Shozo; Ogawa, Wataru; Takahashi, Yutaka

    2015-01-01

    Patients with acromegaly exhibit reduced life expectancy and increased prevalence of age-related diseases, such as diabetes, hypertension, and cardiovascular disease. However, the underlying mechanism has not been fully elucidated. Telomere shortening is reportedly associated with reduced life expectancy and increased prevalence of these age-related diseases. We measured telomere length in patients with acromegaly using quantitative PCR method. The effect of GH and IGF-I on telomere length and cellular senescence was examined in human skin fibroblasts. Patients with acromegaly exhibited shorter telomere length than age-, sex-, smoking-, and diabetes-matched control patients with non-functioning pituitary adenoma (0.62 ± 0.23 vs. 0.75 ± 0.35, respectively, P = 0.047). In addition, telomere length in acromegaly was negatively correlated with the disease duration (R2 = 0.210, P = 0.003). In vitro analysis revealed that not GH but IGF-I induced telomere shortening in human skin fibroblasts. Furthermore, IGF-I-treated cells showed increased senescence-associated β-galactosidase activity and expression of p53 and p21 protein. IGF-I-treated cells reached the Hayflick limit earlier than GH- or vehicle-treated cells, indicating that IGF-I induces cellular senescence. Shortened telomeres in acromegaly and cellular senescence induced by IGF-I can explain, in part, the underlying mechanisms by which acromegaly exhibits an increased morbidity and mortality in association with the excess secretion of IGF-I.

  16. Mitochondrial DNA Hypomethylation Is a Biomarker Associated with Induced Senescence in Human Fetal Heart Mesenchymal Stem Cells

    Directory of Open Access Journals (Sweden)

    Dehai Yu

    2017-01-01

    Full Text Available Background. Fetal heart can regenerate to restore its normal anatomy and function in response to injury, but this regenerative capacity is lost within the first week of postnatal life. Although the specific molecular mechanisms remain to be defined, it is presumed that aging of cardiac stem or progenitor cells may contribute to the loss of regenerative potential. Methods. To study this aging-related dysfunction, we cultured mesenchymal stem cells (MSCs from human fetal heart tissues. Senescence was induced by exposing cells to chronic oxidative stress/low serum. Mitochondrial DNA methylation was examined during the period of senescence. Results. Senescent MSCs exhibited flattened and enlarged morphology and were positive for the senescence-associated beta-galactosidase (SA-β-Gal. By scanning the entire mitochondrial genome, we found that four CpG islands were hypomethylated in close association with senescence in MSCs. The mitochondrial COX1 gene, which encodes the main subunit of the cytochrome c oxidase complex and contains the differentially methylated CpG island 4, was upregulated in MSCs in parallel with the onset of senescence. Knockdown of DNA methyltransferases (DNMT1, DNMT3a, and DNMT3B also upregulated COX1 expression and induced cellular senescence in MSCs. Conclusions. This study demonstrates that mitochondrial CpG hypomethylation may serve as a critical biomarker associated with cellular senescence induced by chronic oxidative stress.

  17. Suppressor of Overexpression of CO 1 Negatively Regulates Dark-Induced Leaf Degreening and Senescence by Directly Repressing Pheophytinase and Other Senescence-Associated Genes in Arabidopsis.

    Science.gov (United States)

    Chen, Junyi; Zhu, Xiaoyu; Ren, Jun; Qiu, Kai; Li, Zhongpeng; Xie, Zuokun; Gao, Jiong; Zhou, Xin; Kuai, Benke

    2017-03-01

    Although the biochemical pathway of chlorophyll (Chl) degradation has been largely elucidated, how Chl is rapidly yet coordinately degraded during leaf senescence remains elusive. Pheophytinase (PPH) is the enzyme for catalyzing the removal of the phytol group from pheophytin a , and PPH expression is significantly induced during leaf senescence. To elucidate the transcriptional regulation of PPH , we used a yeast ( Saccharomyces cerevisiae ) one-hybrid system to screen for its trans-regulators. SUPPRESSOR OF OVEREXPRESSION OF CO 1 (SOC1), a key flowering pathway integrator, was initially identified as one of the putative trans-regulators of PPH After dark treatment, leaves of an SOC1 knockdown mutant ( soc1-6 ) showed an accelerated yellowing phenotype, whereas those of SOC1 -overexpressing lines exhibited a partial stay-green phenotype. SOC1 and PPH expression showed a negative correlation during leaf senescence. Substantially, SOC1 protein could bind specifically to the CArG box of the PPH promoter in vitro and in vivo, and overexpression of SOC1 significantly inhibited the transcriptional activity of the PPH promoter in Arabidopsis ( Arabidopsis thaliana ) protoplasts. Importantly, soc1-6 pph-1 (a PPH knockout mutant) double mutant displayed a stay-green phenotype similar to that of pph-1 during dark treatment. These results demonstrated that SOC1 inhibits Chl degradation via negatively regulating PPH expression. In addition, measurement of the Chl content and the maximum photochemical efficiency of photosystem II of soc1-6 and SOC1-OE leaves after dark treatment suggested that SOC1 also negatively regulates the general senescence process. Seven SENESCENCE-ASSOCIATED GENES ( SAGs ) were thereafter identified as its potential target genes, and NONYELLOWING1 and SAG113 were experimentally confirmed. Together, we reveal that SOC1 represses dark-induced leaf Chl degradation and senescence in general in Arabidopsis. © 2017 American Society of Plant Biologists. All

  18. AMPK activation protects cells from oxidative stress-induced senescence via autophagic flux restoration and intracellular NAD(+) elevation.

    Science.gov (United States)

    Han, Xiaojuan; Tai, Haoran; Wang, Xiaobo; Wang, Zhe; Zhou, Jiao; Wei, Xiawei; Ding, Yi; Gong, Hui; Mo, Chunfen; Zhang, Jie; Qin, Jianqiong; Ma, Yuanji; Huang, Ning; Xiang, Rong; Xiao, Hengyi

    2016-06-01

    AMPK activation is beneficial for cellular homeostasis and senescence prevention. However, the molecular events involved in AMPK activation are not well defined. In this study, we addressed the mechanism underlying the protective effect of AMPK on oxidative stress-induced senescence. The results showed that AMPK was inactivated in senescent cells. However, pharmacological activation of AMPK by metformin and berberine significantly prevented the development of senescence and, accordingly, inhibition of AMPK by Compound C was accelerated. Importantly, AMPK activation prevented hydrogen peroxide-induced impairment of the autophagic flux in senescent cells, evidenced by the decreased p62 degradation, GFP-RFP-LC3 cancellation, and activity of lysosomal hydrolases. We also found that AMPK activation restored the NAD(+) levels in the senescent cells via a mechanism involving mostly the salvage pathway for NAD(+) synthesis. In addition, the mechanistic relationship of autophagic flux and NAD(+) synthesis and the involvement of mTOR and Sirt1 activities were assessed. In summary, our results suggest that AMPK prevents oxidative stress-induced senescence by improving autophagic flux and NAD(+) homeostasis. This study provides a new insight for exploring the mechanisms of aging, autophagy and NAD(+) homeostasis, and it is also valuable in the development of innovative strategies to combat aging. © 2016 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

  19. Loss of lamin B receptor is necessary to induce cellular senescence

    Czech Academy of Sciences Publication Activity Database

    Lukášová, Emilie; Kovařík, Aleš; Bačíková, Alena; Falk, Martin; Kozubek, Stanislav

    2017-01-01

    Roč. 474 (2017), s. 281-300 ISSN 0264-6021 R&D Projects: GA ČR GBP302/12/G157; GA ČR GBP501/12/G090 Institutional support: RVO:68081707 Keywords : oncogene-induced senescence * inner nuclear-membrane * dna-damage response Subject RIV: EB - Genetics ; Molecular Biology OBOR OECD: Genetics and heredity (medical genetics to be 3) Impact factor: 3.797, year: 2016

  20. Premature Senescence Induced by Ionizing Radiation Requires AKT Activity and Reactive Oxygen Species in Glioma

    International Nuclear Information System (INIS)

    Lee, Je Jung; Kim, Bong Cho; Yoo, Hee Jung; Lee, Jae Seon

    2010-01-01

    Loss of PTEN, a tumor suppressor gene has frequently observed in human gliomas, which conferred AKT activation and resistance to ionizing radiation (IR) and anti-cancer drugs. Recent reports have shown that AKT activation induces premature senescence through increase of oxygen consumption and inhibition of expression of ROS scavenging enzymes. In this study, we compared cellular response to IR in the PTEN-deficient U87, U251, U373 or PTEN-proficient LN18, LN428 glioma cells

  1. Accelerated Telomere Shortening in Acromegaly; IGF-I Induces Telomere Shortening and Cellular Senescence

    Science.gov (United States)

    Matsumoto, Ryusaku; Fukuoka, Hidenori; Iguchi, Genzo; Odake, Yukiko; Yoshida, Kenichi; Bando, Hironori; Suda, Kentaro; Nishizawa, Hitoshi; Takahashi, Michiko; Yamada, Shozo; Ogawa, Wataru; Takahashi, Yutaka

    2015-01-01

    Objective Patients with acromegaly exhibit reduced life expectancy and increased prevalence of age-related diseases, such as diabetes, hypertension, and cardiovascular disease. However, the underlying mechanism has not been fully elucidated. Telomere shortening is reportedly associated with reduced life expectancy and increased prevalence of these age-related diseases. Methods We measured telomere length in patients with acromegaly using quantitative PCR method. The effect of GH and IGF-I on telomere length and cellular senescence was examined in human skin fibroblasts. Results Patients with acromegaly exhibited shorter telomere length than age-, sex-, smoking-, and diabetes-matched control patients with non-functioning pituitary adenoma (0.62 ± 0.23 vs. 0.75 ± 0.35, respectively, P = 0.047). In addition, telomere length in acromegaly was negatively correlated with the disease duration (R 2 = 0.210, P = 0.003). In vitro analysis revealed that not GH but IGF-I induced telomere shortening in human skin fibroblasts. Furthermore, IGF-I-treated cells showed increased senescence-associated β-galactosidase activity and expression of p53 and p21 protein. IGF-I-treated cells reached the Hayflick limit earlier than GH- or vehicle-treated cells, indicating that IGF-I induces cellular senescence. Conclusion Shortened telomeres in acromegaly and cellular senescence induced by IGF-I can explain, in part, the underlying mechanisms by which acromegaly exhibits an increased morbidity and mortality in association with the excess secretion of IGF-I. PMID:26448623

  2. Accelerated Telomere Shortening in Acromegaly; IGF-I Induces Telomere Shortening and Cellular Senescence.

    Directory of Open Access Journals (Sweden)

    Ryusaku Matsumoto

    Full Text Available Patients with acromegaly exhibit reduced life expectancy and increased prevalence of age-related diseases, such as diabetes, hypertension, and cardiovascular disease. However, the underlying mechanism has not been fully elucidated. Telomere shortening is reportedly associated with reduced life expectancy and increased prevalence of these age-related diseases.We measured telomere length in patients with acromegaly using quantitative PCR method. The effect of GH and IGF-I on telomere length and cellular senescence was examined in human skin fibroblasts.Patients with acromegaly exhibited shorter telomere length than age-, sex-, smoking-, and diabetes-matched control patients with non-functioning pituitary adenoma (0.62 ± 0.23 vs. 0.75 ± 0.35, respectively, P = 0.047. In addition, telomere length in acromegaly was negatively correlated with the disease duration (R2 = 0.210, P = 0.003. In vitro analysis revealed that not GH but IGF-I induced telomere shortening in human skin fibroblasts. Furthermore, IGF-I-treated cells showed increased senescence-associated β-galactosidase activity and expression of p53 and p21 protein. IGF-I-treated cells reached the Hayflick limit earlier than GH- or vehicle-treated cells, indicating that IGF-I induces cellular senescence.Shortened telomeres in acromegaly and cellular senescence induced by IGF-I can explain, in part, the underlying mechanisms by which acromegaly exhibits an increased morbidity and mortality in association with the excess secretion of IGF-I.

  3. Hepatoprotective Effects of Swimming Exercise against D-Galactose-Induced Senescence Rat Model

    Directory of Open Access Journals (Sweden)

    Chi-Chang Huang

    2013-01-01

    Full Text Available This study investigates whether a 12-week swimming exercise training can prevent liver damage or senescence associated biomarkers in an experimental aging model in rats. Twenty-three male Sprague-Dawley rats were divided into four groups: vehicle treatment with sedentary control (C, , aging induction with sedentary (A, , vehicle treatment with swimming exercise (SW, , and aging induction with swimming exercise (A + SW, . Rats in groups A and AS received intraperitoneal D-galactose injections (150 mg/kg/day for 12 weeks to induce aging. Rats in groups SW and A + SW were subjected to swimming exercise training for 12 weeks. Body weight, liver weight, epididymal fat mass, blood biochemistry, and liver pathology were performed at the end of the experiment. Hepatic senescence protein markers such as β-galactosidase, p53, and p21, as well as the inflammatory mediator, IL-6, were examined. The D-galactose-treated rats exhibited increases in AST and γ-GT plasma levels and β-galactosidase protein expression compared to the control group. Swimming exercise significantly reduced BW, epididymal fat mass, γ-GT activity, and p53, p21, and IL-6 protein levels compared to the aging group. These results suggest that a 12-week swimming exercise program suppresses senescence markers and downregulates inflammatory mediator in the liver tissues of D-galactose-induced aging rats.

  4. Depletion of gamma-glutamylcyclotransferase in cancer cells induces autophagy followed by cellular senescence.

    Science.gov (United States)

    Taniguchi, Keiko; Matsumura, Kengo; Ii, Hiromi; Kageyama, Susumu; Ashihara, Eishi; Chano, Tokuhiro; Kawauchi, Akihiro; Yoshiki, Tatsuhiro; Nakata, Susumu

    2018-01-01

    Gamma-glutamylcyclotransferase (GGCT) was originally identified as a protein highly expressed in bladder cancer tissues by proteomic analysis, and its higher expression in a variety of cancers compared to normal tissues have been shown. Depletion of GGCT in various cancer cells results in antiproliferative effects both in vitro and in vivo ; thus it is considered a promising therapeutic target. Although it has been shown that knockdown of GGCT induces cellular senescence and non-apoptotic cell death, associated with upregulation of cyclin-dependent kinase inhibitors (CDKIs) including p21 WAF1/CIP1 , the cellular events that follow GGCT depletion are not fully understood. Here, we show that GGCT depletion induced autophagy in MCF7 breast and PC3 prostate cancer cells. Conversely, overexpression of GGCT in NIH3T3 fibroblast under conditions of serum deprivation inhibited autophagy and increased proliferation. Simultaneous knockdown of autophagy related-protein 5, a critical effector of autophagy, along with GGCT in MCF7 and PC3 cells led to significant attenuation of the multiple cellular responses, including upregulation of CDKIs, increased numbers of senescence-associated β-galactosidase positive senescent cells, and growth inhibition. Furthermore, we show that autophagy-promoting signaling cascades including activation of the AMPK-ULK1 pathway and/or inactivation of the mTORC2-Akt pathway were triggered in GGCT-depleted cells. These results indicate that autophagy plays an important role in the growth inhibition of cancer cells caused by GGCT depletion.

  5. Acute dyskerin depletion triggers cellular senescence and renders osteosarcoma cells resistant to genotoxic stress-induced apoptosis

    International Nuclear Information System (INIS)

    Lin, Ping; Mobasher, Maral E.; Alawi, Faizan

    2014-01-01

    Highlights: • Dyskerin depletion triggers cellular senescence in U2OS osteosarcoma cells. • Dyskerin-depleted cells are resistant to apoptosis induced by genotoxic stress. • Chromatin relaxation sensitizes dyskerin-depleted cells to apoptosis. - Abstract: Dyskerin is a conserved, nucleolar RNA-binding protein implicated in an increasing array of fundamental cellular processes. Germline mutation in the dyskerin gene (DKC1) is the cause of X-linked dyskeratosis congenita (DC). Conversely, wild-type dyskerin is overexpressed in sporadic cancers, and high-levels may be associated with poor prognosis. It was previously reported that acute loss of dyskerin function via siRNA-mediated depletion slowed the proliferation of transformed cell lines. However, the mechanisms remained unclear. Using human U2OS osteosarcoma cells, we show that siRNA-mediated dyskerin depletion induced cellular senescence as evidenced by proliferative arrest, senescence-associated heterochromatinization and a senescence-associated molecular profile. Senescence can render cells resistant to apoptosis. Conversely, chromatin relaxation can reverse the repressive effects of senescence-associated heterochromatinization on apoptosis. To this end, genotoxic stress-induced apoptosis was suppressed in dyskerin-depleted cells. In contrast, agents that induce chromatin relaxation, including histone deacetylase inhibitors and the DNA intercalator chloroquine, sensitized dyskerin-depleted cells to apoptosis. Dyskerin is a core component of the telomerase complex and plays an important role in telomere homeostasis. Defective telomere maintenance resulting in premature senescence is thought to primarily underlie the pathogenesis of X-linked DC. Since U2OS cells are telomerase-negative, this leads us to conclude that loss of dyskerin function can also induce cellular senescence via mechanisms independent of telomere shortening

  6. Promising markers for the detection of premature senescence tumor cells induced by ionizing radiation: Cathepsin D and eukaryotic translation elongation factor 1

    Energy Technology Data Exchange (ETDEWEB)

    Byun, Hae-Ok; Han, Na-Kyung; Lee, Jae-Seon [Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of)

    2008-05-15

    Recently, it has been proved that induction of senescence could be a promising way of tumor treatment. Senescence was originally described in normal human cells undergoing a finite number of divisions before permanent growth arrest. It has now become regarded more broadly as a general biological program of terminal growth arrest. A variety of stresses such as ionizing radiation (IR), oxidative stress, oncogenic transformation, DNA damaging agents triggers stress-induced premature senescence, i.e. rapid and permanent cell growth arrest. Therefore, premature senescence is bona fide barrier to tumorigenesis and hallmark of premalignant tumors. However, there is lack of obvious markers for senescent tumor cells. To identify useful premature senescence markers for tumor cells, we monitored the changes of protein expression profile in IR-induced premature senescence MCF7 human breast cancer cells. We identified biomarkers which evidently changed their expression levels in ionizing radiation-induced senescenct tumor cells.

  7. Promising markers for the detection of premature senescence tumor cells induced by ionizing radiation: Cathepsin D and eukaryotic translation elongation factor 1

    International Nuclear Information System (INIS)

    Byun, Hae-Ok; Han, Na-Kyung; Lee, Jae-Seon

    2008-01-01

    Recently, it has been proved that induction of senescence could be a promising way of tumor treatment. Senescence was originally described in normal human cells undergoing a finite number of divisions before permanent growth arrest. It has now become regarded more broadly as a general biological program of terminal growth arrest. A variety of stresses such as ionizing radiation (IR), oxidative stress, oncogenic transformation, DNA damaging agents triggers stress-induced premature senescence, i.e. rapid and permanent cell growth arrest. Therefore, premature senescence is bona fide barrier to tumorigenesis and hallmark of premalignant tumors. However, there is lack of obvious markers for senescent tumor cells. To identify useful premature senescence markers for tumor cells, we monitored the changes of protein expression profile in IR-induced premature senescence MCF7 human breast cancer cells. We identified biomarkers which evidently changed their expression levels in ionizing radiation-induced senescenct tumor cells

  8. Histone deacetylase inhibitor valproic acid promotes the induction of pluripotency in mouse fibroblasts by suppressing reprogramming-induced senescence stress

    Energy Technology Data Exchange (ETDEWEB)

    Zhai, Yingying; Chen, Xi; Yu, Dehai [Stem Cell and Cancer Center, First Affiliated Hospital, Jilin University, Changchun, Jilin 130061 (China); Stanford University Medical School, Palo Alto Veterans Institute for Research, Palo Alto, CA 94304 (United States); Li, Tao [Stanford University Medical School, Palo Alto Veterans Institute for Research, Palo Alto, CA 94304 (United States); Cui, Jiuwei; Wang, Guanjun [Stem Cell and Cancer Center, First Affiliated Hospital, Jilin University, Changchun, Jilin 130061 (China); Hu, Ji-Fan, E-mail: jifan@stanford.edu [Stem Cell and Cancer Center, First Affiliated Hospital, Jilin University, Changchun, Jilin 130061 (China); Stanford University Medical School, Palo Alto Veterans Institute for Research, Palo Alto, CA 94304 (United States); Li, Wei, E-mail: jdyylw@163.com [Stem Cell and Cancer Center, First Affiliated Hospital, Jilin University, Changchun, Jilin 130061 (China)

    2015-09-10

    Histone deacetylase inhibitor valproic acid (VPA) has been used to increase the reprogramming efficiency of induced pluripotent stem cell (iPSC) from somatic cells, yet the specific molecular mechanisms underlying this effect is unknown. Here, we demonstrate that reprogramming with lentiviruses carrying the iPSC-inducing factors (Oct4-Sox2-Klf4-cMyc, OSKM) caused senescence in mouse fibroblasts, establishing a stress barrier for cell reprogramming. Administration of VPA protected cells from reprogramming-induced senescent stress. Using an in vitro pre-mature senescence model, we found that VPA treatment increased cell proliferation and inhibited apoptosis through the suppression of the p16/p21 pathway. In addition, VPA also inhibited the G2/M phase blockage derived from the senescence stress. These findings highlight the role of VPA in breaking the cell senescence barrier required for the induction of pluripotency. - Highlights: • Histone deacetylase inhibitor valproic acid enhances iPSC induction. • Valproic acid suppresses reprogramming-induced senescence stress. • Valproic acid downregulates the p16/p21 pathway in reprogramming. • This study demonstrates a new mechanistic role of valproic acid in enhancing reprogramming.

  9. UV light induces premature senescence in Akt1-null mouse embryonic fibroblasts by increasing intracellular levels of ROS

    International Nuclear Information System (INIS)

    Jee, Hye Jin; Kim, Hyun-Ju; Kim, Ae Jeong; Bae, Yoe-Sik; Bae, Sun Sik; Yun, Jeanho

    2009-01-01

    Akt/PKB plays a pivotal role in cell survival and proliferation. Previously, we reported that UV-irradiation induces extensive cell death in Akt2 -/- mouse embryonic fibroblasts (MEFs) while Akt1 -/- MEFs show cell cycle arrest. Here, we find that Akt1 -/- MEFs exhibit phenotypic changes characteristics of senescence upon UV-irradiation. An enlarged and flattened morphology, a reduced cell proliferation and an increased senescence-associated β-galactosidase (SA β-gal) staining indicate that Akt1 -/- MEFs undergo premature senescence after UV-irradiation. Restoring Akt1 expression in Akt1 -/- MEFs suppressed SA β-gal activity, indicating that UV-induced senescence is due to the absence of Akt1 function. Notably, levels of ROS were rapidly increased upon UV-irradiation and the ROS scavenger NAC inhibits UV-induced senescence of Akt1 -/- MEFs, suggesting that UV light induces premature senescence in Akt1 -/- MEFs by modulating intracellular levels of ROS. In conjunction with our previous work, this indicates that different isoforms of Akt have distinct function in response to UV-irradiation.

  10. Autophagy and senescence, stress responses induced by the DNA-damaging mycotoxin alternariol

    International Nuclear Information System (INIS)

    Solhaug, A.; Torgersen, M.L.; Holme, J.A.; Lagadic-Gossmann, D.; Eriksen, G.S.

    2014-01-01

    Highlights: • AOH induces autophagy, lamellar bodies and senescence in RAW264.7 macrophages. • DNA damage is suggested as a triggering signal. • The Sestrin2-AMPK-mTOR-S6K pathway is proposed to link DNA damage to autophagy. - Abstract: The mycotoxin alternariol (AOH), a frequent contaminant in fruit and grain, is known to induce cellular stress responses such as reactive oxygen production, DNA damage and cell cycle arrest. Cellular stress is often connected to autophagy, and we employed the RAW264.7 macrophage model to test the hypothesis that AOH induces autophagy. Indeed, AOH treatment led to a massive increase in acidic vacuoles often observed upon autophagy induction. Moreover, expression of the autophagy marker LC3 was markedly increased and there was a strong accumulation of LC3-positive puncta. Increased autophagic activity was verified biochemically by measuring the degradation rate of long-lived proteins. Furthermore, AOH induced expression of Sestrin2 and phosphorylation of AMPK as well as reduced phosphorylation of mTOR and S6 kinase, common mediators of signaling pathways involved in autophagy. Transmission electron microscopy analyzes of AOH treated cells not only clearly displayed structures associated with autophagy such as autophagosomes and autolysosomes, but also the appearance of lamellar bodies. Prolonged AOH treatment resulted in changed cell morphology from round into more star-shaped as well as increased β-galactosidase activity. This suggests that the cells eventually entered senescence. In conclusion, our data identify here AOH as an inducer of both autophagy and senescence. These effects are suggested to be to be linked to AOH-induced DSB (via a reported effect on topoisomerase activity), resulting in an activation of p53 and the Sestrin2-AMPK-mTOR-S6K signaling pathway

  11. Disappearance of the telomere dysfunction-induced stress response in fully senescent cells.

    Science.gov (United States)

    Bakkenist, Christopher J; Drissi, Rachid; Wu, Jing; Kastan, Michael B; Dome, Jeffrey S

    2004-06-01

    Replicative senescence is a natural barrier to cellular proliferation that is triggered by telomere erosion and dysfunction. Here, we demonstrate that ATM activation and H2AX-gamma nuclear focus formation are sensitive markers of telomere dysfunction in primary human fibroblasts. Whereas the activated form of ATM and H2AX-gamma foci were rarely observed in early-passage cells, they were readily detected in late-passage cells. The ectopic expression of telomerase in late-passage cells abrogated ATM activation and H2AX-gamma focus formation, suggesting that these stress responses were the consequence of telomere dysfunction. ATM activation was induced in quiescent fibroblasts by inhibition of TRF2 binding to telomeres, indicating that telomere uncapping is sufficient to initiate the telomere signaling response; breakage of chromosomes with telomeric associations is not required for this activation. Although ATM activation and H2AX-gamma foci were readily observed in late-passage cells, they disappeared once cells became fully senescent, indicating that constitutive signaling from dysfunctional telomeres is not required for the maintenance of senescence.

  12. Melatonin protects bone marrow mesenchymal stem cells against iron overload-induced aberrant differentiation and senescence.

    Science.gov (United States)

    Yang, Fan; Yang, Lei; Li, Yuan; Yan, Gege; Feng, Chao; Liu, Tianyi; Gong, Rui; Yuan, Ye; Wang, Ning; Idiiatullina, Elina; Bikkuzin, Timur; Pavlov, Valentin; Li, Yang; Dong, Chaorun; Wang, Dawei; Cao, Yang; Han, Zhenbo; Zhang, Lai; Huang, Qi; Ding, Fengzhi; Bi, Zhengang; Cai, Benzhi

    2017-10-01

    Bone marrow mesenchymal stem cells (BMSCs) are an expandable population of stem cells which can differentiate into osteoblasts, chondrocytes and adipocytes. Dysfunction of BMSCs in response to pathological stimuli contributes to bone diseases. Melatonin, a hormone secreted from pineal gland, has been proved to be an important mediator in bone formation and mineralization. The aim of this study was to investigate whether melatonin protected against iron overload-induced dysfunction of BMSCs and its underlying mechanisms. Here, we found that iron overload induced by ferric ammonium citrate (FAC) caused irregularly morphological changes and markedly reduced the viability in BMSCs. Consistently, osteogenic differentiation of BMSCs was significantly inhibited by iron overload, but melatonin treatment rescued osteogenic differentiation of BMSCs. Furthermore, exposure to FAC led to the senescence in BMSCs, which was attenuated by melatonin as well. Meanwhile, melatonin was able to counter the reduction in cell proliferation by iron overload in BMSCs. In addition, protective effects of melatonin on iron overload-induced dysfunction of BMSCs were abolished by its inhibitor luzindole. Also, melatonin protected BMSCs against iron overload-induced ROS accumulation and membrane potential depolarization. Further study uncovered that melatonin inhibited the upregulation of p53, ERK and p38 protein expressions in BMSCs with iron overload. Collectively, melatonin plays a protective role in iron overload-induced osteogenic differentiation dysfunction and senescence through blocking ROS accumulation and p53/ERK/p38 activation. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  13. Resveratrol induces cellular senescence with attenuated mono-ubiquitination of histone H2B in glioma cells

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    Gao, Zhen; Xu, Michael S.; Barnett, Tamara L.; Xu, C. Wilson

    2011-01-01

    Research highlights: → Resveratrol induces cellular senescence in glioma cell. → Resveratrol inhibits mono-ubiquitination of histone H2B at K120. → Depletion of RNF20, phenocopies the inhibitory effects of resveratrol. → Mono-ubiquitination of histone H2B at K120 is a novel target of resveratrol. → RNF20 inhibits cellular senescence in proliferating glioma cells. -- Abstract: Resveratrol (3,4',5-trihydroxy-trans-stilbene), a polyphenol naturally occurring in grapes and other plants, has cancer chemo-preventive effects and therapeutic potential. Although resveratrol modulates multiple pathways in tumor cells, how resveratrol or its affected pathways converge on chromatin to mediate its effects is not known. Using glioma cells as a model, we showed here that resveratrol inhibited cell proliferation and induced cellular hypertrophy by transforming spindle-shaped cells to enlarged, irregular and flatten-shaped ones. We further showed that resveratrol-induced hypertrophic cells expressed senescence-associated-β-galactosidase, suggesting that resveratrol-induced cellular senescence in glioma cells. Consistent with these observations, we demonstrated that resveratrol inhibited clonogenic efficiencies in vitro and tumor growth in a xenograft model. Furthermore, we found that acute treatment of resveratrol inhibited mono-ubiquitination of histone H2B at K120 (uH2B) in breast, prostate, pancreatic, lung, brain tumor cells as well as primary human cells. Chronic treatment with low doses of resveratrol also inhibited uH2B in the resveratrol-induced senescent glioma cells. Moreover, we showed that depletion of RNF20, a ubiquitin ligase of histone H2B, inhibited uH2B and induced cellular senescence in glioma cells in vitro, thereby recapitulated the effects of resveratrol. Taken together, our results suggest that uH2B is a novel direct or indirect chromatin target of resveratrol and RNF20 plays an important role in inhibiting cellular senescence programs that are

  14. Resveratrol induces cellular senescence with attenuated mono-ubiquitination of histone H2B in glioma cells

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    Gao, Zhen; Xu, Michael S.; Barnett, Tamara L. [Nevada Cancer Institute, Las Vegas, NV 89135 (United States); Xu, C. Wilson, E-mail: wxu@nvcancer.org [Nevada Cancer Institute, Las Vegas, NV 89135 (United States)

    2011-04-08

    Research highlights: {yields} Resveratrol induces cellular senescence in glioma cell. {yields} Resveratrol inhibits mono-ubiquitination of histone H2B at K120. {yields} Depletion of RNF20, phenocopies the inhibitory effects of resveratrol. {yields} Mono-ubiquitination of histone H2B at K120 is a novel target of resveratrol. {yields} RNF20 inhibits cellular senescence in proliferating glioma cells. -- Abstract: Resveratrol (3,4',5-trihydroxy-trans-stilbene), a polyphenol naturally occurring in grapes and other plants, has cancer chemo-preventive effects and therapeutic potential. Although resveratrol modulates multiple pathways in tumor cells, how resveratrol or its affected pathways converge on chromatin to mediate its effects is not known. Using glioma cells as a model, we showed here that resveratrol inhibited cell proliferation and induced cellular hypertrophy by transforming spindle-shaped cells to enlarged, irregular and flatten-shaped ones. We further showed that resveratrol-induced hypertrophic cells expressed senescence-associated-{beta}-galactosidase, suggesting that resveratrol-induced cellular senescence in glioma cells. Consistent with these observations, we demonstrated that resveratrol inhibited clonogenic efficiencies in vitro and tumor growth in a xenograft model. Furthermore, we found that acute treatment of resveratrol inhibited mono-ubiquitination of histone H2B at K120 (uH2B) in breast, prostate, pancreatic, lung, brain tumor cells as well as primary human cells. Chronic treatment with low doses of resveratrol also inhibited uH2B in the resveratrol-induced senescent glioma cells. Moreover, we showed that depletion of RNF20, a ubiquitin ligase of histone H2B, inhibited uH2B and induced cellular senescence in glioma cells in vitro, thereby recapitulated the effects of resveratrol. Taken together, our results suggest that uH2B is a novel direct or indirect chromatin target of resveratrol and RNF20 plays an important role in inhibiting cellular

  15. The role of nibrin in doxorubicin-induced apoptosis and cell senescence in Nijmegen Breakage Syndrome patients lymphocytes.

    Directory of Open Access Journals (Sweden)

    Olga Alster

    Full Text Available Nibrin plays an important role in the DNA damage response (DDR and DNA repair. DDR is a crucial signaling pathway in apoptosis and senescence. To verify whether truncated nibrin (p70, causing Nijmegen Breakage Syndrome (NBS, is involved in DDR and cell fate upon DNA damage, we used two (S4 and S3R spontaneously immortalized T cell lines from NBS patients, with the founding mutation and a control cell line (L5. S4 and S3R cells have the same level of p70 nibrin, however p70 from S4 cells was able to form more complexes with ATM and BRCA1. Doxorubicin-induced DDR followed by cell senescence could only be observed in L5 and S4 cells, but not in the S3R ones. Furthermore the S3R cells only underwent cell death, but not senescence after doxorubicin treatment. In contrary to doxorubicin treatment, cells from all three cell lines were able to activate the DDR pathway after being exposed to γ-radiation. Downregulation of nibrin in normal human vascular smooth muscle cells (VSMCs did not prevent the activation of DDR and induction of senescence. Our results indicate that a substantially reduced level of nibrin or its truncated p70 form is sufficient to induce DNA-damage dependent senescence in VSMCs and S4 cells, respectively. In doxorubicin-treated S3R cells DDR activation was severely impaired, thus preventing the induction of senescence.

  16. Inhibition of doxorubicin-induced senescence by PPARδ activation agonists in cardiac muscle cells: cooperation between PPARδ and Bcl6.

    Directory of Open Access Journals (Sweden)

    Paola Altieri

    Full Text Available Senescence and apoptosis are two distinct cellular programs that are activated in response to a variety of stresses. Low or high doses of the same stressor, i.e., the anticancer drug doxorubicin, may either induce apoptosis or senescence, respectively, in cardiac muscle cells. We have demonstrated that PPARδ, a ligand-activated transcriptional factor that controls lipid metabolism, insulin sensitivity and inflammation, is also involved in the doxorubicin-induced senescence program. This occurs through its interference with the transcriptional repressor protein B cell lymphoma-6 (Bcl6. Low doses of doxorubicin increase the expression of PPARδ that sequesters Bcl6, thus preventing it from exerting its anti-senescent effects. We also found that L-165041, a specific PPARδ activator, is highly effective in protecting cardiomyocytes from doxorubicin-induced senescence through a Bcl6 related mechanism. In fact, L-165041 increases Bcl6 expression via p38, JNK and Akt activation, and at the same time it induces the release of Bcl6 from PPARδ, thereby enabling Bcl6 to bind to its target genes. L-165041 also prevented apoptosis induced by higher doses of doxorubicin. However, while experiments performed with siRNA analysis techniques very clearly showed the weight of Bcl6 in the cellular senescence program, no role was found for Bcl6 in the anti-apoptotic effects of L-165041, thus confirming that senescence and apoptosis are two very distinct stress response cellular programs. This study increases our understanding of the molecular mechanism of anthracycline cardiotoxicity and suggests a potential role for PPARδ agonists as cardioprotective agents.

  17. Silencing of the CaCP Gene Delays Salt- and Osmotic-Induced Leaf Senescence in Capsicum annuum L.

    Directory of Open Access Journals (Sweden)

    Huai-Juan Xiao

    2014-05-01

    Full Text Available Cysteine proteinases have been known to participate in developmental processes and in response to stress in plants. Our present research reported that a novel CP gene, CaCP, was involved in leaf senescence in pepper (Capsicum annuum L.. The full-length CaCP cDNA is comprised of 1316 bp, contains 1044 nucleotides in open reading frame (ORF, and encodes a 347 amino acid protein. The deduced protein belongs to the papain-like cysteine proteases (CPs superfamily, containing a highly conserved ERFNIN motif, a GCNGG motif and a conserved catalytic triad. This protein localized to the vacuole of plant cells. Real-time quantitative PCR analysis revealed that the expression level of CaCP gene was dramatically higher in leaves and flowers than that in roots, stems and fruits. Moreover, CaCP transcripts were induced upon during leaf senescence. CaCP expression was upregulated by plant hormones, especially salicylic acid. CaCP was also significantly induced by abiotic and biotic stress treatments, including high salinity, mannitol and Phytophthora capsici. Loss of function of CaCP using the virus-induced gene-silencing technique in pepper plants led to enhanced tolerance to salt- and osmotic-induced stress. Taken together, these results suggest that CaCP is a senescence-associated gene, which is involved in developmental senescence and regulates salt- and osmotic-induced leaf senescence in pepper.

  18. Silencing of the CaCP Gene Delays Salt- and Osmotic-Induced Leaf Senescence in Capsicum annuum L.

    Science.gov (United States)

    Xiao, Huai-Juan; Yin, Yan-Xu; Chai, Wei-Guo; Gong, Zhen-Hui

    2014-01-01

    Cysteine proteinases have been known to participate in developmental processes and in response to stress in plants. Our present research reported that a novel CP gene, CaCP, was involved in leaf senescence in pepper (Capsicum annuum L.). The full-length CaCP cDNA is comprised of 1316 bp, contains 1044 nucleotides in open reading frame (ORF), and encodes a 347 amino acid protein. The deduced protein belongs to the papain-like cysteine proteases (CPs) superfamily, containing a highly conserved ERFNIN motif, a GCNGG motif and a conserved catalytic triad. This protein localized to the vacuole of plant cells. Real-time quantitative PCR analysis revealed that the expression level of CaCP gene was dramatically higher in leaves and flowers than that in roots, stems and fruits. Moreover, CaCP transcripts were induced upon during leaf senescence. CaCP expression was upregulated by plant hormones, especially salicylic acid. CaCP was also significantly induced by abiotic and biotic stress treatments, including high salinity, mannitol and Phytophthora capsici. Loss of function of CaCP using the virus-induced gene-silencing technique in pepper plants led to enhanced tolerance to salt- and osmotic-induced stress. Taken together, these results suggest that CaCP is a senescence-associated gene, which is involved in developmental senescence and regulates salt- and osmotic-induced leaf senescence in pepper. PMID:24823878

  19. Protein Kinase CK2 Regulates Cytoskeletal Reorganization during Ionizing Radiation-Induced Senescence of Human Mesenchymal Stem Cells

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    Wang, Daojing; Jang, Deok-Jin

    2009-08-21

    Human mesenchymal stem cells (hMSC) are critical for tissue regeneration. How hMSC respond to genotoxic stresses and potentially contribute to aging and cancer remain underexplored. We demonstrated that ionizing radiation induced cellular senescence of hMSC over a period of 10 days, showing a critical transition between day 3 and day 6. This was confirmed by senescence-associated beta-galactosidase (SA-{beta}-gal) staining, protein expression profiles of key cell cycle regulators (retinoblastoma (Rb) protein, p53, p21{sup waf1/Cip1}, and p16{sup INK4A}), and senescence-associated secretory phenotypes (SASPs) (IL-8, IL-12, GRO, and MDC). We observed dramatic cytoskeletal reorganization of hMSC through reduction of myosin-10, redistribution of myosin-9, and secretion of profilin-1. Using a SILAC-based phosphoproteomics method, we detected significant reduction of myosin-9 phosphorylation at Ser1943, coinciding with its redistribution. Importantly, through treatment with cell permeable inhibitors (4,5,6,7-tetrabromo-1H-benzotriazole (TBB) and 2-dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole (DMAT)), and gene knockdown using RNA interference, we identified CK2, a kinase responsible for myosin-9 phosphorylation at Ser1943, as a key factor contributing to the radiation-induced senescence of hMSC. We showed that individual knockdown of CK2 catalytic subunits CK2{alpha} and CK2{alpha}{prime} induced hMSC senescence. However, only knockdown of CK2{alpha} resulted in morphological phenotypes resembling those of radiation-induced senescence. These results suggest that CK2{alpha} and CK2{alpha}{prime} play differential roles in hMSC senescence progression, and their relative expression might represent a novel regulatory mechanism for CK2 activity.

  20. Small molecular antioxidants effectively protect from PUVA-induced oxidative stress responses underlying fibroblast senescence and photoaging.

    Science.gov (United States)

    Briganti, Stefania; Wlaschek, Meinhard; Hinrichs, Christina; Bellei, Barbara; Flori, Enrica; Treiber, Nicolai; Iben, Sebastian; Picardo, Mauro; Scharffetter-Kochanek, Karin

    2008-09-01

    Exposure of human fibroblasts to 8-methoxypsoralen plus ultraviolet-A irradiation (PUVA) results in stress-induced cellular senescence in fibroblasts. We here studied the role of the antioxidant defense system in the accumulation of reactive oxygen species (ROS) and the effect of the antioxidants alpha-tocopherol, N-acetylcysteine, and alpha-lipoic acid on PUVA-induced cellular senescence. PUVA treatment induced an immediate and increasing generation of intracellular ROS. Supplementation of PUVA-treated fibroblasts with alpha-tocopherol (alpha-Toc), N-acetylcysteine (NAC), or alpha-lipoic acid (alpha-LA) abrogated the increased ROS generation and rescued fibroblasts from the ROS-dependent changes into the cellular senescence phenotype, such as cytoplasmic enlargement, enhanced expression of senescence-associated-beta-galactosidase and matrix-metalloproteinase-1, hallmarks of photoaging and intrinsic aging. PUVA treatment disrupted the integrity of cellular membranes and impaired homeostasis and function of the cellular antioxidant system with a significant decrease in glutathione and hydrogen peroxide-detoxifying enzymes activities. Supplementation with NAC, alpha-LA, and alpha-Toc counteracted these changes. Our data provide causal evidence that (i) oxidative stress due to an imbalance in the overall cellular antioxidant capacity contributes to the induction and maintenance of the PUVA-induced fibroblast senescence and that (ii) low molecular antioxidants protect effectively against these deleterious alterations.

  1. Resveratrol Induced Premature Senescence Is Associated with DNA Damage Mediated SIRT1 and SIRT2 Down-Regulation.

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    Mehtap Kilic Eren

    Full Text Available The natural polyphenolic compound resveratrol (3,4,5-trihydroxy-trans-stilbene has broad spectrum health beneficial activities including antioxidant, anti-inflammatory, anti-aging, anti-cancer, cardioprotective, and neuroprotective effects. Remarkably, resveratrol also induces apoptosis and cellular senescence in primary and cancer cells. Resveratrol's anti-aging effects both in vitro and in vivo attributed to activation of a (NAD-dependent histone deacetylase family member sirtuin-1 (SIRT1 protein. In mammals seven members (SIRT1-7 of sirtuin family have been identified. Among those, SIRT1 is the most extensively studied with perceptive effects on mammalian physiology and suppression of the diseases of aging. Yet no data has specified the role of sirtuins, under conditions where resveratrol treatment induces senescence. Current study was undertaken to investigate the effects of resveratrol in human primary dermal fibroblasts (BJ and to clarify the role of sirtuin family members in particular SIRT1 and SIRT2 that are known to be involved in cellular stress responses and cell cycle, respectively. Here, we show that resveratrol decreases proliferation of BJ cells in a time and dose dependent manner. In addition the increase in senescence associated β-galactosidase (SA-β-gal activity and methylated H3K9-me indicate the induction of premature senescence. A significant increase in phosphorylation of γ-H2AX, a surrogate of DNA double strand breaks, as well as in levels of p53, p21CIP1 and p16INK4A is also detected. Interestingly, at concentrations where resveratrol induced premature senescence we show a significant decrease in SIRT1 and SIRT2 levels by Western Blot and quantitative RT-PCR analysis. Conversely inhibition of SIRT1 and SIRT2 via siRNA or sirtinol treatment also induced senescence in BJ fibroblasts associated with increased SA-β-gal activity, γ-H2AX phosphorylation and p53, p21CIP1 and p16INK4A levels. Interestingly DNA damaging

  2. A role for mitochondrial oxidants in stress-induced premature senescence of human vascular smooth muscle cells

    Directory of Open Access Journals (Sweden)

    Yogita Mistry

    2013-01-01

    Full Text Available Mitochondria are a major source of cellular oxidants and have been implicated in aging and associated pathologies, notably cardiovascular diseases. Vascular cell senescence is observed in experimental and human cardiovascular pathologies. Our previous data highlighted a role for angiotensin II in the induction of telomere-dependent and -independent premature senescence of human vascular smooth muscle cells and suggested this was due to production of superoxide by NADPH oxidase. However, since a role for mitochondrial oxidants was not ruled out we hypothesise that angiotensin II mediates senescence by mitochondrial superoxide generation and suggest that inhibition of superoxide may prevent vascular smooth muscle cell aging in vitro. Cellular senescence was induced using a stress-induced premature senescence protocol consisting of three successive once-daily exposure of cells to 1×10−8 mol/L angiotensin II and was dependent upon the type-1 angiotensin II receptor. Angiotensin stimulated NADPH-dependent superoxide production as estimated using lucigenin chemiluminescence in cell lysates and this was attenuated by the mitochondrial electron transport chain inhibitor, rotenone. Angiotensin also resulted in an increase in mitoSOX fluorescence indicating stimulation of mitochondrial superoxide. Significantly, the induction of senescence by angiotensin II was abrogated by rotenone and by the mitochondria-targeted superoxide dismutase mimetic, mitoTEMPO. These data suggest that mitochondrial superoxide is necessary for the induction of stress-induced premature senescence by angiotensin II and taken together with other data suggest that mitochondrial cross-talk with NADPH oxidases, via as yet unidentified signalling pathways, is likely to play a key role.

  3. Protective effect of curcumin (Curcuma longa) against D-galactose-induced senescence in mice.

    Science.gov (United States)

    Kumar, Anil; Prakash, Atish; Dogra, Samrita

    2011-01-01

    Brain senescence plays an important role in cognitive dysfunction and neurodegenerative disorders. Curcumin was reported to have beneficial effect against several neurodegenerative disorders including Alzheimer's disease. Therefore, the present study was conducted in order to explore the possible role of curcumin against D-galactose-induced cognitive dysfunction, oxidative damage, and mitochondrial dysfunction in mice. Chronic administration of D-galactose for 6 weeks significantly impaired cognitive function (both in Morris water maze and elevated plus maze), locomotor activity, oxidative defense (raised lipid peroxidation, nitrite concentration, depletion of reduced glutathione and catalase activity), and mitochondrial enzyme complex activities (I, II, and III) as compared to vehicle treated group. Curcumin (15 and 30 mg/kg) and galantamine (5 mg/kg) treatment for 6 weeks significantly improved cognitive tasks, locomotor activity, oxidative defense, and restored mitochondrial enzyme complex activity as compared to control (D-galactose). Chronic D-galactose treatment also significantly increased acetylcholine esterase activity that was attenuated by curcumin (15 and 30 mg/kg) and galantamine (5 mg/kg) treatment. In conclusion, the present study highlights the therapeutic potential of curcumin against d-galactose induced senescence in mice.

  4. Helicobacter pylori-induced premature senescence of extragastric cells may contribute to chronic skin diseases.

    Science.gov (United States)

    Lewinska, Anna; Wnuk, Maciej

    2017-04-01

    Helicobacter pylori, one of the most frequently observed bacterium in the human intestinal flora, has been widely studied since Marshall and Warren documented a link between the presence of H. pylori in the gastrointestinal tract and gastritis and gastric ulcers. Interestingly, H. pylori has also been found in several other epithelial tissues, including the eyes, ears, nose and skin that may have direct or indirect effects on host physiology and may contribute to extragastric diseases, e.g. chronic skin diseases. More recently, it has been shown that H. pylori cytotoxin CagA expression induces cellular senescence of human gastric nonpolarized epithelial cells that may lead to gastrointestinal disorders and systemic inflammation. Here, we hypothesize that also chronic skin diseases may be promoted by stress-induced premature senescence (SIPS) of skin cells, namely fibroblasts and keratinocytes, stimulated with H. pylori cytotoxins. Future studies involving cell culture models and clinical specimens are needed to verify the involvement of H. pylori in SIPS-based chronic skin diseases.

  5. Radiation promotes colorectal cancer initiation and progression by inducing senescence-associated inflammatory responses.

    Science.gov (United States)

    Kim, S B; Bozeman, R G; Kaisani, A; Kim, W; Zhang, L; Richardson, J A; Wright, W E; Shay, J W

    2016-06-30

    Proton radiotherapy is becoming more common as protons induce more precise DNA damage at the tumor site with reduced side effects to adjacent normal tissues. However, the long-term biological effects of proton irradiation in cancer initiation compared with conventional photon irradiation are poorly characterized. In this study, using a human familial adenomatous polyposis syndrome susceptible mouse model, we show that whole-body irradiation with protons are more effective in inducing senescence-associated inflammatory responses (SIRs), which are involved in colon cancer initiation and progression. After proton irradiation, a subset of SIR genes (Troy, Sox17, Opg, Faim2, Lpo, Tlr2 and Ptges) and a gene known to be involved in invasiveness (Plat), along with the senescence-associated gene (P19Arf), are markedly increased. Following these changes, loss of Casein kinase Iα and induction of chronic DNA damage and TP53 mutations are increased compared with X-ray irradiation. Proton irradiation also increases the number of colonic polyps, carcinomas and invasive adenocarcinomas. Pretreatment with the non-steroidal anti-inflammatory drug, 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid-ethyl amide (CDDO-EA), reduces proton irradiation-associated SIR and tumorigenesis. Thus exposure to proton irradiation elicits significant changes in colorectal cancer initiation and progression that can be mitigated using CDDO-EA.

  6. The thyroid hormone receptor β induces DNA damage and premature senescence.

    Science.gov (United States)

    Zambrano, Alberto; García-Carpizo, Verónica; Gallardo, María Esther; Villamuera, Raquel; Gómez-Ferrería, Maria Ana; Pascual, Angel; Buisine, Nicolas; Sachs, Laurent M; Garesse, Rafael; Aranda, Ana

    2014-01-06

    There is increasing evidence that the thyroid hormone (TH) receptors (THRs) can play a role in aging, cancer and degenerative diseases. In this paper, we demonstrate that binding of TH T3 (triiodothyronine) to THRB induces senescence and deoxyribonucleic acid (DNA) damage in cultured cells and in tissues of young hyperthyroid mice. T3 induces a rapid activation of ATM (ataxia telangiectasia mutated)/PRKAA (adenosine monophosphate-activated protein kinase) signal transduction and recruitment of the NRF1 (nuclear respiratory factor 1) and THRB to the promoters of genes with a key role on mitochondrial respiration. Increased respiration leads to production of mitochondrial reactive oxygen species, which in turn causes oxidative stress and DNA double-strand breaks and triggers a DNA damage response that ultimately leads to premature senescence of susceptible cells. Our findings provide a mechanism for integrating metabolic effects of THs with the tumor suppressor activity of THRB, the effect of thyroidal status on longevity, and the occurrence of tissue damage in hyperthyroidism.

  7. Radiation-induced senescence-like phenotype in proliferating and plateau-phase vascular endothelial cells

    International Nuclear Information System (INIS)

    Igarashi, Kaori; Sakimoto, Ippei; Kataoka, Keiko; Ohta, Keisuke; Miura, Masahiko

    2007-01-01

    The effects of ionizing radiation (IR) on tumor angiogenesis still remain largely unknown. In this study, we found that IR (8 Gy) induces a high-frequency (80-90%) senescence-like phenotype in vascular endothelial cells (ECs) undergoing exponential growth. This finding allowed us to characterize the IR-induced senescence-like (IRSL) phenotype by examining the gene expression profiles and in vitro angiogenic activities of these ECs. The expression levels of genes associated with cell cycle progression and DNA replication were remarkably reduced in the IRSL ECs. Additionally, the in vitro invasion and migration activities of these cells through Matrigel were significantly suppressed. We also found that confluent ECs exhibited a high-frequency IRSL phenotype when they were replated immediately after irradiation, whereas incubation in plateau-phase conditions reduced the induction of this phenotype and enhanced colony formation. The kinetics of DNA double-strand break repair, which showed a faster time course in confluent ECs than in growing ECs, may contribute to the protective mechanism associated with the IRSL phenotype. These results imply that the IRSL phenotype may be important for determining the angiogenic activity of ECs following irradiation. The present study should contribute to the understanding of the effects of IR on tumor angiogenesis

  8. Low concentrations of salicylic acid delay methyl jasmonate-induced leaf senescence by up-regulating nitric oxide synthase activity.

    Science.gov (United States)

    Ji, Yingbin; Liu, Jian; Xing, Da

    2016-09-01

    In plants, extensive efforts have been devoted to understanding the crosstalk between salicylic acid (SA) and jasmonic acid (JA) signaling in pathogen defenses, but this crosstalk has scarcely been addressed during senescence. In this study, the effect of SA application on methyl jasmonate (MeJA)-induced leaf senescence was assessed. We found that low concentrations of SA (1-50 μM) played a delayed role against the senescence promoted by MeJA. Furthermore, low concentrations of SA enhanced plant antioxidant defenses and restricted reactive oxygen species (ROS) accumulation in MeJA-treated leaves. When applied simultaneously with MeJA, low concentrations of SA triggered a nitric oxide (NO) burst, and the elevated NO levels were linked to the nitric oxide associated 1 (NOA1)-dependent pathway via nitric oxide synthase (NOS) activity. The ability of SA to up-regulate plant antioxidant defenses, reduce ROS accumulation, and suppress leaf senescence was lost in NO-deficient Atnoa1 plants. In a converse manner, exogenous addition of NO donors increased the plant antioxidant capacity and lowered the ROS levels in MeJA-treated leaves. Taken together, the results indicate that SA at low concentrations counteracts MeJA-induced leaf senescence through NOA1-dependent NO signaling and strengthening of the antioxidant defense. © The Author 2016. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  9. Mitotic Stress Is an Integral Part of the Oncogene-Induced Senescence Program that Promotes Multinucleation and Cell Cycle Arrest

    Directory of Open Access Journals (Sweden)

    Dina Dikovskaya

    2015-09-01

    Full Text Available Oncogene-induced senescence (OIS is a tumor suppression mechanism that blocks cell proliferation in response to oncogenic signaling. OIS is frequently accompanied by multinucleation; however, the origin of this is unknown. Here, we show that multinucleate OIS cells originate mostly from failed mitosis. Prior to senescence, mutant H-RasV12 activation in primary human fibroblasts compromised mitosis, concordant with abnormal expression of mitotic genes functionally linked to the observed mitotic spindle and chromatin defects. Simultaneously, H-RasV12 activation enhanced survival of cells with damaged mitoses, culminating in extended mitotic arrest and aberrant exit from mitosis via mitotic slippage. ERK-dependent transcriptional upregulation of Mcl1 was, at least in part, responsible for enhanced survival and slippage of cells with mitotic defects. Importantly, mitotic slippage and oncogene signaling cooperatively induced senescence and key senescence effectors p21 and p16. In summary, activated Ras coordinately triggers mitotic disruption and enhanced cell survival to promote formation of multinucleate senescent cells.

  10. Ethylene-induced senescence-related gene expression requires protein synthesis

    International Nuclear Information System (INIS)

    Lawton, K.A.; Raghothama, K.G.; Woodson, W.R.

    1990-01-01

    We have investigated the effects of inhibiting protein synthesis on the ethylene-induced expression of 3 carnation senescence-related genes, pSR5, pSR8, and pSR12. Treatment of preclimacteric carnation petal discs with 1μg/ml of cycloheximide, a cytoplasmic protein synthesis inhibitor, for 3h inhibited protein synthesis by >80% as quantitated by the incorporation of [35S]methionine into protein. Pre-treatment of petal discs with cycloheximide prevented ethylene-induced SR transcript accumulation. Cycloheximide treatment of petal discs held in air did not result in increased levels of SR mRNA. These results indicate that ethylene does not interact with pre-formed factors but rather that the activation of SR gene expression by ethylene is mediated by labile protein factor(s) synthesized on cytoplasmic ribosomes. Experiments are currently underway to determine if cycloheximide exerts its effect at the transcriptional or post-transcriptional level

  11. A cigarette component acrolein induces accelerated senescence in human diploid fibroblast IMR-90 cells.

    Science.gov (United States)

    Luo, Cheng; Li, Yan; Yang, Liang; Feng, Zhihui; Li, Yuan; Long, Jiangang; Liu, Jiankang

    2013-10-01

    Cigarette smoking causes various diseases, including lung cancer and cardiovascular disease, and reduces life span, though the mechanisms are not well understood. We hypothesize that smoking may cause cellular mitochondrial dysfunction and oxidative stress, leading to aging acceleration. In the present study, we tested the effects of acrolein, a major representative smoking toxicant, on human lung fibroblast IMR-90 cells with regard to cellular senescence, oxidative stress, and mitochondrial function. The results showed that subacute treatment with low dose of acrolein induces the following events compared to the control cells: cell senescence demonstrated by increases in the activity of β-galactosidase, the higher expression of p53 and p21, decreases in DNA synthesis, Sirt1 expression, and telomere length; oxidative stress occurred as the increases in the production of reactive oxygen species, DNA damage, and protein oxidation; and mitochondrial dysfunction shown as decreases in the mitochondrial membrane potential, mitochondrial biogenesis regulator PGC-1 alpha and mitochondria complex I, II, III, and V. These results suggest that acrolein may accelerate aging through the mechanism of increasing oxidative stress and mitochondrial dysfunction.

  12. Mitochondrial dysfunction induced by frataxin deficiency is associated with cellular senescence and abnormal calcium metabolism

    Directory of Open Access Journals (Sweden)

    Arantxa eBolinches-Amorós

    2014-05-01

    Full Text Available Friedreich ataxia is considered a neurodegenerative disorder involving both the peripheral and central nervous systems. Dorsal root ganglia (DRG are the major target tissue structures. This neuropathy is caused by mutations in the FXN gene that encodes frataxin. Here, we investigated the mitochondrial and cell consequences of frataxin depletion in a cellular model based on frataxin silencing in SH-SY5Y human neuroblastoma cells, a cell line that has been used widely as in vitro models for studies on neurological diseases. We showed that the reduction of frataxin induced mitochondrial dysfunction due to a bioenergetic deficit and abnormal Ca2+ homeostasis in the mitochondria that were associated with oxidative and endoplasmic reticulum stresses. The depletion of frataxin did not cause cell death but increased autophagy, which may have a cytoprotective effect against cellular insults such as oxidative stress. Frataxin silencing provoked slow cell growth associated with cellular senescence, as demonstrated by increased SA-βgal activity and cell cycle arrest at the G1 phase. We postulate that cellular senescence might be related to a hypoplastic defect in the DRG during neurodevelopment, as suggested by necropsy studies.

  13. MicroRNA miR-125b induces senescence in human melanoma cells.

    Science.gov (United States)

    Glud, Martin; Manfé, Valentina; Biskup, Edyta; Holst, Line; Dirksen, Anne Marie Ahlburg; Hastrup, Nina; Nielsen, Finn C; Drzewiecki, Krzysztof T; Gniadecki, Robert

    2011-06-01

    MicroRNAs (miRNAs) are small noncoding RNA molecules involved in gene regulation. Aberrant expression of miRNA has been associated with the development or progression of several diseases, including cancer. In a previous study, we found that the expression of miRNA-125b (miR-125b) was two-fold lower in malignant melanoma producing lymph node micrometastases than in nonmetastasizing tumors. To get further insight into the functional role of miR-125b, we assessed whether its overexpression or silencing affects apoptosis, proliferation, or senescence in melanoma cell lines. We showed that overexpression of miR-125b induced typical senescent cell morphology, including increased cytoplasmatic/nucleus ratio and intensive cytoplasmatic β-galactosidase expression. In contrast, inhibition of miR-125b resulted in 30-35% decreased levels of spontaneous apoptosis. We propose that downregulation of miR-125b in an early cutaneous malignant melanoma can contribute to the increased metastatic capability of this tumor.

  14. MDM2 inhibitor nutlin-3a induces apoptosis and senescence in cutaneous T-cell lymphoma: Role of p53

    DEFF Research Database (Denmark)

    Manfé, Valentina; Biskup, Edyta Urszula; Johansen, Peter

    2012-01-01

    cell lines, P53 mutation analysis identified a homozygous nonsense mutation (R196Stop in Hut-78) and a homozygous missense mutation (G245S in SeAx). In MyLa2000, Mac1, and Mac2a carrying wild-type P53, nutlin-3a induced apoptosis and senescence demonstrated by permanent G0/G1 cell-cycle block...... with intact p53 but also in Hut-78, SeAx, and Sézary cells. Thus, targeting p53 by nutlin-3a may constitute a therapeutic approach in CTCL because of increased apoptosis and senescence of tumor cells....

  15. Inducers of Senescence, Toxic Compounds, and Senolytics: The Multiple Faces of Nrf2-Activating Phytochemicals in Cancer Adjuvant Therapy

    Directory of Open Access Journals (Sweden)

    Marco Malavolta

    2018-01-01

    Full Text Available The reactivation of senescence in cancer and the subsequent clearance of senescent cells are suggested as therapeutic intervention in the eradication of cancer. Several natural compounds that activate Nrf2 (nuclear factor erythroid-derived 2-related factor 2 pathway, which is involved in complex cytoprotective responses, have been paradoxically shown to induce cell death or senescence in cancer. Promoting the cytoprotective Nrf2 pathway may be desirable for chemoprevention, but it might be detrimental in later stages and advanced cancers. However, senolytic activity shown by some Nrf2-activating compounds could be used to target senescent cancer cells (particularly in aged immune-depressed organisms that escape immunosurveillance. We herein describe in vitro and in vivo effects of fifteen Nrf2-interacting natural compounds (tocotrienols, curcumin, epigallocatechin gallate, quercetin, genistein, resveratrol, silybin, phenethyl isothiocyanate, sulforaphane, triptolide, allicin, berberine, piperlongumine, fisetin, and phloretin on cellular senescence and discuss their use in adjuvant cancer therapy. In light of available literature, it can be concluded that the meaning and the potential of adjuvant therapy with natural compounds in humans remain unclear, also taking into account the existence of few clinical trials mostly characterized by uncertain results. Further studies are needed to investigate the therapeutic potential of those compounds that display senolytic activity.

  16. Overexpression of HDAC1 induces cellular senescence by Sp1/PP2A/pRb pathway

    International Nuclear Information System (INIS)

    Chuang, Jian-Ying; Hung, Jan-Jong

    2011-01-01

    Highlights: → Overexpression of HDAC1 induces Sp1 deacetylation and raises Sp1/p300 complex formation to bind to PP2Ac promoter. → Overexpression of HDAC1 strongly inhibits the phosphorylation of pRb through up-regulation of PP2A. → Overexpressed HDAC1 restrains cell proliferaction and induces cell senescence though a novel Sp1/PP2A/pRb pathway. -- Abstract: Senescence is associated with decreased activities of DNA replication, protein synthesis, and cellular division, which can result in deterioration of cellular functions. Herein, we report that the growth and division of tumor cells were significantly repressed by overexpression of histone deacetylase (HDAC) 1 with the Tet-off induced system or transient transfection. In addition, HDAC1 overexpression led to senescence through both an accumulation of hypophosphorylated active retinoblastoma protein (pRb) and an increase in the protein level of protein phosphatase 2A catalytic subunit (PP2Ac). HDAC1 overexpression also increased the level of Sp1 deacetylation and elevated the interaction between Sp1 and p300, and subsequently that Sp1/p300 complex bound to the promoter of PP2Ac, thus leading to induction of PP2Ac expression. Similar results were obtained in the HDAC1-Tet-off stable clone. Taken together, these results indicate that HDAC1 overexpression restrained cell proliferation and induced premature senescence in cervical cancer cells through a novel Sp1/PP2A/pRb pathway.

  17. Mutants induced in winter rye (Secale cereale L.): Short straw-mutant No. 2714 and late-senescence mutant

    Energy Technology Data Exchange (ETDEWEB)

    Muszynski, S; Darlewska, M [Department of Plant Breeding and Seed Science, Warsaw Agricultural University, Warsaw (Poland)

    1990-01-01

    Full text: Mutants were induced by treating dormant seeds with ionizing radiation (fast neutrons) or chemicals (N-nitroso-N-ethyl urea or sodium azide). Among several mutants obtained, of special value is the short-straw mutant No. 2714 and a late senescent mutant. (author)

  18. Overexpression of HDAC1 induces cellular senescence by Sp1/PP2A/pRb pathway

    Energy Technology Data Exchange (ETDEWEB)

    Chuang, Jian-Ying [Department of Pharmacology, National Cheng-Kung University, Tainan 701, Taiwan (China); Hung, Jan-Jong, E-mail: petehung@mail.ncku.edu.tw [Department of Pharmacology, National Cheng-Kung University, Tainan 701, Taiwan (China); Institute of Bioinformatics and Biosignal Transduction, National Cheng-Kung University, Tainan 701, Taiwan (China)

    2011-04-15

    Highlights: {yields} Overexpression of HDAC1 induces Sp1 deacetylation and raises Sp1/p300 complex formation to bind to PP2Ac promoter. {yields} Overexpression of HDAC1 strongly inhibits the phosphorylation of pRb through up-regulation of PP2A. {yields} Overexpressed HDAC1 restrains cell proliferaction and induces cell senescence though a novel Sp1/PP2A/pRb pathway. -- Abstract: Senescence is associated with decreased activities of DNA replication, protein synthesis, and cellular division, which can result in deterioration of cellular functions. Herein, we report that the growth and division of tumor cells were significantly repressed by overexpression of histone deacetylase (HDAC) 1 with the Tet-off induced system or transient transfection. In addition, HDAC1 overexpression led to senescence through both an accumulation of hypophosphorylated active retinoblastoma protein (pRb) and an increase in the protein level of protein phosphatase 2A catalytic subunit (PP2Ac). HDAC1 overexpression also increased the level of Sp1 deacetylation and elevated the interaction between Sp1 and p300, and subsequently that Sp1/p300 complex bound to the promoter of PP2Ac, thus leading to induction of PP2Ac expression. Similar results were obtained in the HDAC1-Tet-off stable clone. Taken together, these results indicate that HDAC1 overexpression restrained cell proliferation and induced premature senescence in cervical cancer cells through a novel Sp1/PP2A/pRb pathway.

  19. Anti-Ageing Effects of Sonchus oleraceus L. (pūhā) Leaf Extracts on H2O2-Induced Cell Senescence

    DEFF Research Database (Denmark)

    Ou, Zong-Quan; Rades, Thomas; McDowell, Arlene

    2015-01-01

    Antioxidants protect against damage from free radicals and are believed to slow the ageing process. Previously, we have reported the high antioxidant activity of 70% methanolic Sonchus oleraceus L. (Asteraceae) leaf extracts. We hypothesize that S. oleraceus extracts protect cells against H2O2......-induced senescence by mediating oxidative stress. Premature senescence of young WI-38 cells was induced by application of H2O2. Cells were treated with S. oleraceus extracts before or after H2O2 stress. The senescence- associated β-galactosidase (SA-β-gal) activity was used to indicate cell senescence. S....... oleraceus extracts showed higher cellular antioxidant activity than chlorogenic acid in WI-38 cells. S. oleraceus extracts suppressed H2O2 stress-induced premature senescence in a concentration-dependent manner. At 5 and 20 mg/mL, S. oleraceus extracts showed better or equivalent effects of reducing stress...

  20. Glucagon-Like Peptide 1 Prevents Reactive Oxygen Species-Induced Endothelial Cell Senescence Through the Activation of Protein Kinase A

    NARCIS (Netherlands)

    Oeseburg, Hisko; de Boer, Rudolf A.; Buikema, Hendrik; van der Harst, Pim; van Gilst, Wiek H.; Sillje, Herman H. W.

    Objective-Endothelial cell senescence is an important contributor to vascular aging and is increased under diabetic conditions. Here we investigated whether the antidiabetic hormone glucagon-like peptide 1 (GLP-1) could prevent oxidative stress-induced cellular senescence in endothelial cells.

  1. Irradiation With Carbon Ion Beams Induces Apoptosis, Autophagy, and Cellular Senescence in a Human Glioma-Derived Cell Line

    International Nuclear Information System (INIS)

    Jinno-Oue, Atsushi; Shimizu, Nobuaki; Hamada, Nobuyuki; Wada, Seiichi; Tanaka, Atsushi; Shinagawa, Masahiko; Ohtsuki, Takahiro; Mori, Takahisa; Saha, Manujendra N.; Hoque, Ariful S.; Islam, Salequl; Kogure, Kimitaka; Funayama, Tomoo; Kobayashi, Yasuhiko

    2010-01-01

    Purpose: We examined biological responses of human glioma cells to irradiation with carbon ion beams (C-ions). Methods and Materials: A human glioma-derived cell line, NP-2, was irradiated with C-ions. Apoptotic cell nuclei were stained with Hoechst 33342. Induction of autophagy was examined either by staining cells with monodansylcadaverine (MDC) or by Western blotting to detect conversion of microtuble-associated protein light chain 3 (MAP-LC3) (LC3-I) to the membrane-bound form (LC3-II). Cellular senescence markers including induction of senescence-associated β-galactosidase (SA-β-gal) were examined. The mean telomere length of irradiated cells was determined by Southern blot hybridization. Expression of tumor suppressor p53 and cyclin/cyclin-dependent kinase inhibitor p21 WAF1/CIP1 in the irradiated cells was analyzed by Western blotting. Results: When NP-2 cells were irradiated with C-ions at 6 Gy, the major population of the cells died of apoptosis and autophagy. The residual fraction of attached cells ( WAF1/CIP1 was induced in NP-2 cells after irradiation. Furthermore, we found that irradiation with C-ions induced cellular senescence in a human glioma cell line lacking functional p53. Conclusions: Irradiation with C-ions induced apoptosis, autophagy, and cellular senescence in human glioma cells.

  2. Angelica Sinensis Polysaccharide Prevents Hematopoietic Stem Cells Senescence in D-Galactose-Induced Aging Mouse Model

    Directory of Open Access Journals (Sweden)

    Xinyi Mu

    2017-01-01

    Full Text Available Age-related regression in hematopoietic stem/progenitor cells (HSC/HPCs limits replenishment of the blood and immune system and hence contributes to hematopoietic diseases and declined immunity. In this study, we employed D-gal-induced aging mouse model and observed the antiaging effects of Angelica Sinensis Polysaccharide (ASP, a major active ingredient in dong quai (Chinese Angelica Sinensis, on the Sca-1+ HSC/HPCs in vivo. ASP treatment prevents HSC/HPCs senescence with decreased AGEs levels in the serum, reduced SA-β-Gal positive cells, and promoted CFU-Mix formation in the D-gal administrated mouse. We further found that multiple mechanisms were involved: (1 ASP treatment prevented oxidative damage as total antioxidant capacity was increased and levels of reactive oxygen species (ROS, 8-OHdG, and 4-HNE were declined, (2 ASP reduced the expression of γ-H2A.X which is a DNA double strand breaks (DSBs marker and decreased the subsequent ectopic expressions of effectors in p16Ink4a-RB and p19Arf-p21Cip1/Waf senescent pathways, and (3 ASP inhibited the excessive activation of Wnt/β-catenin signaling in aged HSC/HPCs, as the expressions of β-catenin, phospho-GSK-3β, and TCF-4 were decreased, and the cyto-nuclear translocation of β-catenin was inhibited. Moreover, compared with the positive control of Vitamin E, ASP exhibited a better antiaging effect and a weaker antioxidation ability, suggesting a novel protective role of ASP in the hematopoietic system.

  3. Senescence Meets Dedifferentiation

    Science.gov (United States)

    Givaty Rapp, Yemima; Ransbotyn, Vanessa; Grafi, Gideon

    2015-01-01

    Senescence represents the final stage of leaf development but is often induced prematurely following exposure to biotic and abiotic stresses. Leaf senescence is manifested by color change from green to yellow (due to chlorophyll degradation) or to red (due to de novo synthesis of anthocyanins coupled with chlorophyll degradation) and frequently culminates in programmed death of leaves. However, the breakdown of chlorophyll and macromolecules such as proteins and RNAs that occurs during leaf senescence does not necessarily represent a one-way road to death but rather a reversible process whereby senescing leaves can, under certain conditions, re-green and regain their photosynthetic capacity. This phenomenon essentially distinguishes senescence from programmed cell death, leading researchers to hypothesize that changes occurring during senescence might represent a process of trans-differentiation, that is the conversion of one cell type to another. In this review, we highlight attributes common to senescence and dedifferentiation including chromatin structure and activation of transposable elements and provide further support to the notion that senescence is not merely a deterioration process leading to death but rather a unique developmental state resembling dedifferentiation. PMID:27135333

  4. Proteomics and transcriptomics of broccoli subjected to exogenously supplied and transgenic senescence-induced cytokinin for amelioration of postharvest yellowing.

    Science.gov (United States)

    Liu, Mao-Sen; Li, Hui-Chun; Lai, Ying-Mi; Lo, Hsiao-Feng; Chen, Long-Fang O

    2013-11-20

    Previously, we investigated transgenic broccoli harboring senescence-associated-gene (SAG) promoter-triggered isopentenyltransferase (ipt), which encodes the key enzyme for cytokinin (CK) synthesis and mimics the action of exogenous supplied CK in delaying postharvest senescence of broccoli. Here, we used proteomics and transcriptomics to compare the mechanisms of ipt-transgenic and N(6)-benzylaminopurine (BA) CK treatment of broccoli during postharvest storage. The 2 treatments conferred common and distinct mechanisms. BA treatment decreased the quantity of proteins involved in energy and carbohydrate metabolism and amino acid metabolism, and ipt-transgenic treatment increased that of stress-related proteins and molecular chaperones and slightly affected levels of carbohydrate metabolism proteins. Both treatments regulated genes involved in CK signaling, sugar transport, energy and carbohydrate metabolism, amino acid metabolism and lipid metabolism, although ipt-transgenic treatment to a lesser extent. BA treatment induced genes encoding molecular chaperones, whereas ipt-transgenic treatment induced stress-related genes for cellular protection during storage. Both BA and ipt-transgenic treatments acted antagonistically on ethylene functions. We propose a long-term acclimation of metabolism and protection systems with ipt-transgenic treatment of broccoli and short-term modulation of metabolism and establishment of a protection system with both BA and ipt-transgenic treatments in delaying senescence of broccoli florets. Transgenic broccoli harboring senescence-associated-gene (SAG) promoter-triggered isopentenyltransferase (ipt), which encodes the key enzyme for cytokinin (CK) synthesis and N(6)-benzylaminopurine (BA) CK treated broccoli both showed retardation of postharvest senescence during storage. The mechanisms underlying the two treatments were compared. The combination of proteomic and transcriptomic evidences revealed that the 2 treatments conferred common

  5. WSB1 overcomes oncogene-induced senescence by targeting ATM for degradation

    Science.gov (United States)

    Kim, Jung Jin; Lee, Seung Baek; Yi, Sang-Yeop; Han, Sang-Ah; Kim, Sun-Hyun; Lee, Jong-Min; Tong, Seo-Yun; Yin, Ping; Gao, Bowen; Zhang, Jun; Lou, Zhenkun

    2017-01-01

    Oncogene-induced senescence (OIS) or apoptosis through the DNA-damage response is an important barrier of tumorigenesis. Overcoming this barrier leads to abnormal cell proliferation, genomic instability, and cellular transformation, and finally allows cancers to develop. However, it remains unclear how the OIS barrier is overcome. Here, we show that the E3 ubiquitin ligase WD repeat and SOCS box-containing protein 1 (WSB1) plays a role in overcoming OIS. WSB1 expression in primary cells helps the bypass of OIS, leading to abnormal proliferation and cellular transformation. Mechanistically, WSB1 promotes ATM ubiquitination, resulting in ATM degradation and the escape from OIS. Furthermore, we identify CDKs as the upstream kinase of WSB1. CDK-mediated phosphorylation activates WSB1 by promoting its monomerization. In human cancer tissue and in vitro models, WSB1-induced ATM degradation is an early event during tumorigenic progression. We suggest that WSB1 is one of the key players of early oncogenic events through ATM degradation and destruction of the tumorigenesis barrier. Our work establishes an important mechanism of cancer development and progression in premalignant lesions. PMID:27958289

  6. In vivo inhibition of cysteine proteases provides evidence for the involvement of 'senescence-associated vacuoles' in chloroplast protein degradation during dark-induced senescence of tobacco leaves.

    Science.gov (United States)

    Carrión, Cristian A; Costa, María Lorenza; Martínez, Dana E; Mohr, Christina; Humbeck, Klaus; Guiamet, Juan J

    2013-11-01

    Breakdown of leaf proteins, particularly chloroplast proteins, is a massive process in senescing leaves. In spite of its importance in internal N recycling, the mechanism(s) and the enzymes involved are largely unknown. Senescence-associated vacuoles (SAVs) are small, acidic vacuoles with high cysteine peptidase activity. Chloroplast-targeted proteins re-localize to SAVs during senescence, suggesting that SAVs might be involved in chloroplast protein degradation. SAVs were undetectable in mature, non-senescent tobacco leaves. Their abundance, visualized either with the acidotropic marker Lysotracker Red or by green fluorescent protein (GFP) fluorescence in a line expressing the senescence-associated cysteine protease SAG12 fused to GFP, increased during senescence induction in darkness, and peaked after 2-4 d, when chloroplast dismantling was most intense. Increased abundance of SAVs correlated with higher levels of SAG12 mRNA. Activity labelling with a biotinylated derivative of the cysteine protease inhibitor E-64 was used to detect active cysteine proteases. The two apparently most abundant cysteine proteases of senescing leaves, of 40kDa and 33kDa were detected in isolated SAVs. Rubisco degradation in isolated SAVs was completely blocked by E-64. Treatment of leaf disks with E-64 in vivo substantially reduced degradation of Rubisco and leaf proteins. Overall, these results indicate that SAVs contain most of the cysteine protease activity of senescing cells, and that SAV cysteine proteases are at least partly responsible for the degradation of stromal proteins of the chloroplast.

  7. Anti-Ageing Effects of Sonchus oleraceus L. (pūhā) Leaf Extracts on H2O2-Induced Cell Senescence

    OpenAIRE

    Zong-Quan Ou; Thomas Rades; Arlene McDowell

    2015-01-01

    Antioxidants protect against damage from free radicals and are believed to slow the ageing process. Previously, we have reported the high antioxidant activity of 70% methanolic Sonchus oleraceus L. (Asteraceae) leaf extracts. We hypothesize that S. oleraceus extracts protect cells against H2O2-induced senescence by mediating oxidative stress. Premature senescence of young WI-38 cells was induced by application of H2O2. Cells were treated with S. oleraceus extracts before or after H2O2 stress...

  8. PKCδ phosphorylation is an upstream event of GSK3 inactivation-mediated ROS generation in TGF-β1-induced senescence.

    Science.gov (United States)

    Byun, H-O; Jung, H-J; Kim, M-J; Yoon, G

    2014-09-01

    Transforming growth factor β1 (TGF-β1) induces Mv1Lu cell senescence through inactivating glycogen synthase kinase 3 (GSK3), thereby inactivating complex IV and increasing intracellular ROS. In the present study, we identified protein kinase C delta (PKCδ) as an upstream regulator of GSK3 inactivation in this mechanism of TGF-β1-induced senescence. When Mv1Lu cells were exposed to TGF-β1, PKCδ phosphorylation simultaneously increased with GSK3 phosphorylation, and then AKT and ERK were phosphorylated. AKT phosphorylation and Smad signaling were independent of GSK3 phosphorylation, but ERK phosphorylation was downstream of GSK3 inactivation. TGF-β1-triggered GSK3 phosphorylation was blocked by inhibition of PKCδ, using its pharmacological inhibitor, Rottlerin, or overexpression of a dominant negative PKCδ mutant, but GSK3 inhibition with SB415286 did not alter PKCδ phosphorylation. Activation of PKCδ by PMA delayed cell growth and increased intracellular ROS level, but did not induce senescent phenotypes. In addition, overexpression of wild type or a constitutively active PKCδ mutant was enough to delay cell growth and decrease the mitochondrial oxygen consumption rate and complex IV activity, but weakly induce senescence. However, PMA treatment on Mv1Lu cells, which overexpress wild type and constitutively active PKCδ mutants, effectively induced senescence. These results indicate that PKCδ plays a key role in TGF-β1-induced senescence of Mv1Lu cells through the phosphorylation of GSK3, thereby triggering mitochondrial complex IV dysfunction and intracellular ROS generation.

  9. Cytokine-induced 'bystander' senescence in DDR and immuno-surveillance

    Czech Academy of Sciences Publication Activity Database

    Hodný, Zdeněk; Hubáčková, Soňa; Bartek, Jiří

    2013-01-01

    Roč. 4, č. 10 (2013), s. 1552-1553 ISSN 1949-2553 Institutional support: RVO:68378050 Keywords : cell senescence * cytokines * immuno-surveillance Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 6.627, year: 2013

  10. Unhealthy diet and ultrafine carbon black particles induce senescence and disease associated phenotypic changes.

    Science.gov (United States)

    Büchner, Nicole; Ale-Agha, Niloofar; Jakob, Sascha; Sydlik, Ulrich; Kunze, Kerstin; Unfried, Klaus; Altschmied, Joachim; Haendeler, Judith

    2013-01-01

    Telomerase activity in endothelial and lung epithelial cells. As a consequence, ufCB increased senescence of endothelial cells. To investigate whether ufCB show also effects in vivo, we instilled ufCB in concentrations not inducing inflammation into mice. Indeed, eNOS expression was reduced in the abdominal aorta of animals treated with ufCB. Thus, a combination of fructose and LDL in the diet and ufCB, as a major constituent of air pollution, seem to accelerate respiratory and cardiovascular cellular changes, which may compromise "healthy aging" and can lead to cardiovascular and pulmonary diseases. Copyright © 2012 Elsevier Inc. All rights reserved.

  11. Activation of p53 by nutlin-3a induces apoptosis and cellular senescence in human glioblastoma multiforme.

    Directory of Open Access Journals (Sweden)

    Ruth Villalonga-Planells

    2011-04-01

    Full Text Available Glioblastoma multiforme (GBM is the most common and aggressive primary brain tumor in adults. Despite concerted efforts to improve current therapies and develop novel clinical approaches, patient survival remains poor. As such, increasing attention has focused on developing new therapeutic strategies that specifically target the apoptotic pathway in order to improve treatment responses. Recently, nutlins, small-molecule antagonists of MDM2, have been developed to inhibit p53-MDM2 interaction and activate p53 signaling in cancer cells. Glioma cell lines and primary cultured glioblastoma cells were treated with nutlin-3a. Nutlin-3a induced p53-dependent G1- and G2-M cell cycle arrest and apoptosis in glioma cell lines with normal TP53 status. In addition, nutlin-arrested glioma cells show morphological features of senescence and persistent induction of p21 protein. Furthermore, senescence induced by nutlin-3a might be depending on mTOR pathway activity. In wild-type TP53 primary cultured cells, exposure to nutlin-3a resulted in variable degrees of apoptosis as well as cellular features of senescence. Nutlin-3a-induced apoptosis and senescence were firmly dependent on the presence of functional p53, as revealed by the fact that glioblastoma cells with knockdown p53 with specific siRNA, or cells with mutated or functionally impaired p53 pathway, were completely insensitive to the drug. Finally, we also found that nutlin-3a increased response of glioma cells to radiation therapy. The results provide a basis for the rational use of MDM2 antagonists as a novel treatment option for glioblastoma patients.

  12. Molecular mechanisms of UVB-induced senescence of dermal fibroblasts and its relevance for photoaging of the human skin.

    Science.gov (United States)

    Cavinato, Maria; Jansen-Dürr, Pidder

    2017-08-01

    Due to its ability to cross the epidermis and reach the upper dermis where it causes cumulative DNA damage and increased oxidative stress, UVB is considered the most harmful component of sunlight to the skin. The consequences of chronic exposition to UVB are related to photoaging and photocarcinogenesis. There are limitations to the study of human skin aging and for this reason the use of models is required. Human dermal fibroblasts submitted to mild and repeated doses of UVB are considered a versatile model to study UVB effects in the process of skin photoaging, which depends on the accumulation of senescent cells, in particular in the dermis. Here we provide updated information about the current model of UVB-induced senescence with special emphasis on the process of protein quality control. Copyright © 2017 Elsevier Inc. All rights reserved.

  13. Anti-Ageing Effects of Sonchus oleraceus L. (pūhā Leaf Extracts on H2O2-Induced Cell Senescence

    Directory of Open Access Journals (Sweden)

    Zong-Quan Ou

    2015-03-01

    Full Text Available Antioxidants protect against damage from free radicals and are believed to slow the ageing process. Previously, we have reported the high antioxidant activity of 70% methanolic Sonchus oleraceus L. (Asteraceae leaf extracts. We hypothesize that S. oleraceus extracts protect cells against H2O2-induced senescence by mediating oxidative stress. Premature senescence of young WI-38 cells was induced by application of H2O2. Cells were treated with S. oleraceus extracts before or after H2O2 stress. The senescence- associated β-galactosidase (SA-β-gal activity was used to indicate cell senescence. S. oleraceus extracts showed higher cellular antioxidant activity than chlorogenic acid in WI-38 cells. S. oleraceus extracts suppressed H2O2 stress-induced premature senescence in a concentration-dependent manner. At 5 and 20 mg/mL, S. oleraceus extracts showed better or equivalent effects of reducing stress-induced premature senescence than the corresponding ascorbic acid treatments. These findings indicate the potential of S. oleraceus extracts to be formulated as an anti-ageing agent.

  14. Anti-ageing effects of Sonchus oleraceus L. (pūhā) leaf extracts on H₂O₂-induced cell senescence.

    Science.gov (United States)

    Ou, Zong-Quan; Rades, Thomas; McDowell, Arlene

    2015-03-12

    Antioxidants protect against damage from free radicals and are believed to slow the ageing process. Previously, we have reported the high antioxidant activity of 70% methanolic Sonchus oleraceus L. (Asteraceae) leaf extracts. We hypothesize that S. oleraceus extracts protect cells against H2O2-induced senescence by mediating oxidative stress. Premature senescence of young WI-38 cells was induced by application of H2O2. Cells were treated with S. oleraceus extracts before or after H2O2 stress. The senescence- associated β-galactosidase (SA-β-gal) activity was used to indicate cell senescence. S. oleraceus extracts showed higher cellular antioxidant activity than chlorogenic acid in WI-38 cells. S. oleraceus extracts suppressed H2O2 stress-induced premature senescence in a concentration-dependent manner. At 5 and 20 mg/mL, S. oleraceus extracts showed better or equivalent effects of reducing stress-induced premature senescence than the corresponding ascorbic acid treatments. These findings indicate the potential of S. oleraceus extracts to be formulated as an anti-ageing agent.

  15. Ectopic AP4 expression induces cellular senescence via activation of p53 in long-term confluent retinal pigment epithelial cells.

    Science.gov (United States)

    Wang, Yiping; Wong, Matthew Man-Kin; Zhang, Xiaojian; Chiu, Sung-Kay

    2015-11-15

    When cells are grown to confluence, cell-cell contact inhibition occurs and drives the cells to enter reversible quiescence rather than senescence. Confluent retinal pigment epithelial (RPE) cells exhibiting contact inhibition was used as a model in this study to examine the role of overexpression of transcription factor AP4, a highly expressed transcription factor in many types of cancer, in these cells during long-term culture. We generated stable inducible RPE cell clones expressing AP4 or AP4 without the DNA binding domain (DN-AP4) and observed that, when cultured for 24 days, RPE cells with a high level of AP4 exhibit a large, flattened morphology and even cease proliferating; these changes were not observed in DN-AP4-expressing cells or non-induced cells. In addition, AP4-expressing cells exhibited senescence-associated β-galactosidase activity and the senescence-associated secretory phenotype. We demonstrated that the induced cellular senescence was mediated by enhanced p53 expression and that AP4 regulates the p53 gene by binding directly to two of the three E-boxes present on the promoter of the p53 gene. Moreover, we showed that serum is essential for AP4 in inducing p53-associated cellular senescence. Collectively, we showed that overexpression of AP4 mediates cellular senescence involving in activation of p53 in long-term post-confluent RPE cells. Copyright © 2015 Elsevier Inc. All rights reserved.

  16. Oxidative stress inhibits adhesion and transendothelial migration, and induces apoptosis and senescence of induced pluripotent stem cells.

    Science.gov (United States)

    Wu, Yi; Zhang, Xueqing; Kang, Xueling; Li, Ning; Wang, Rong; Hu, Tiantian; Xiang, Meng; Wang, Xinhong; Yuan, Wenjun; Chen, Alex; Meng, Dan; Chen, Sifeng

    2013-09-01

    Oxidative stress caused by cellular accumulation of reactive oxygen species (ROS) is a major contributor to disease and cell death. However, how induced pluripotent stem cells (iPSC) respond to different levels of oxidative stress is largely unknown. Here, we investigated the effect of H2 O2 -induced oxidative stress on iPSC function in vitro. Mouse iPSC were treated with H2 O2 (25-100 μmol/L). IPSC adhesion, migration, viability, apoptosis and senescence were analysed. Expression of adhesion-related genes, stress defence genes, and osteoblast- and adipocyte-associated genes were determined by reverse transcription polymerase chain reaction. The present study found that H2 O2 (25-100 μmol/L) decreased iPSC adhesion to matrix proteins and endothelial cells, and downregulated gene expression levels of adhesion-related molecules, such as integrin alpha 7, cadherin 1 and 5, melanoma cell adhesion molecule, vascular cell adhesion molecule 1, and monocyte chemoattractant protein-1. H2 O2 (100 μmol/L) decreased iPSC viability and inhibited the capacity of iPSC migration and transendothelial migration. iPSC were sensitive to H2 O2 -induced G2/M arrest, senescence and apoptosis when exposed to H2 O2 at concentrations above 25 μmol/L. H2 O2 increased the expression of stress defence genes, including catalase, cytochrome B alpha, lactoperoxidase and thioredoxin domain containing 2. H2 O2 upregulated the expression of osteoblast- and adipocyte-associated genes in iPSC during their differentiation; however, short-term H2 O2 -induced oxidative stress did not affect the protein expression of the pluripotency markers, octamer-binding transcription factor 4 and sex-determining region Y-box 2. The present results suggest that iPSC are sensitive to H2 O2 toxicity, and inhibition of oxidative stress might be a strategy for improving their functions. © 2013 Wiley Publishing Asia Pty Ltd.

  17. The Immortal Senescence.

    Science.gov (United States)

    Bianchi-Smiraglia, Anna; Lipchick, Brittany C; Nikiforov, Mikhail A

    2017-01-01

    Activation of oncogenic signaling paradoxically results in the permanent withdrawal from cell cycle and induction of senescence (oncogene-induced senescence (OIS)). OIS is a fail-safe mechanism used by the cells to prevent uncontrolled tumor growth, and, as such, it is considered as the first barrier against cancer. In order to progress, tumor cells thus need to first overcome the senescent phenotype. Despite the increasing attention gained by OIS in the past 20 years, this field is still rather young due to continuous emergence of novel pathways and processes involved in OIS. Among the many factors contributing to incomplete understanding of OIS are the lack of unequivocal markers for senescence and the complexity of the phenotypes revealed by senescent cells in vivo and in vitro. OIS has been shown to play major roles at both the cellular and organismal levels in biological processes ranging from embryonic development to barrier to cancer progression. Here we will briefly outline major advances in methodologies that are being utilized for induction, identification, and characterization of molecular processes in cells undergoing oncogene-induced senescence. The full description of such methodologies is provided in the corresponding chapters of the book.

  18. Depletion of HPV16 early genes induces autophagy and senescence in a cervical carcinogenesis model, regardless of viral physical state.

    Science.gov (United States)

    Hanning, Jennifer E; Saini, Harpreet K; Murray, Matthew J; Caffarel, Maria M; van Dongen, Stijn; Ward, Dawn; Barker, Emily M; Scarpini, Cinzia G; Groves, Ian J; Stanley, Margaret A; Enright, Anton J; Pett, Mark R; Coleman, Nicholas

    2013-11-01

    In cervical carcinomas, high-risk human papillomavirus (HR-HPV) may be integrated into host chromosomes or remain extra-chromosomal (episomal). We used the W12 cervical keratinocyte model to investigate the effects of HPV16 early gene depletion on in vitro cervical carcinogenesis pathways, particularly effects shared by cells with episomal versus integrated HPV16 DNA. Importantly, we were able to study the specific cellular consequences of viral gene depletion by using short interfering RNAs known not to cause phenotypic or transcriptional off-target effects in keratinocytes. We found that while cervical neoplastic progression in vitro was characterized by dynamic changes in HPV16 transcript levels, viral early gene expression was required for cell survival at all stages of carcinogenesis, regardless of viral physical state, levels of early gene expression or histology in organotypic tissue culture. Moreover, HPV16 early gene depletion induced changes in host gene expression that were common to both episome-containing and integrant-containing cells. In particular, we observed up-regulation of autophagy genes, associated with enrichment of senescence and innate immune-response pathways, including the senescence-associated secretory phenotype (SASP). In keeping with these observations, HPV16 early gene depletion induced autophagy in both episome-containing and integrant-containing W12 cells, as evidenced by the appearance of autophagosomes, punctate expression of the autophagy marker LC3, conversion of LC3B-I to LC3B-II, and reduced levels of the autophagy substrate p62. Consistent with the reported association between autophagy and senescence pathways, HPV16 early gene depletion induced expression of the senescence marker beta-galactosidase and increased secretion of the SASP-related protein IGFBP3. Together, these data indicate that depleting HR-HPV early genes would be of potential therapeutic benefit in all cervical carcinogenesis pathways, regardless of viral

  19. Molecular Insights into SIRT1 Protection Against UVB-Induced Skin Fibroblast Senescence by Suppression of Oxidative Stress and p53 Acetylation.

    Science.gov (United States)

    Chung, Ki Wung; Choi, Yeon Ja; Park, Min Hi; Jang, Eun Ji; Kim, Dae Hyun; Park, Byung Hyun; Yu, Byung Pal; Chung, Hae Young

    2015-08-01

    Stresses, such as exposure to ultraviolet radiation and those associated with aging, are known to cause premature cellular senescence that is characterized by growth arrest and morphological and gene expression changes. This study was designed to investigate the protective effect of Sirtuin1 (SIRT1) on the UVB-induced premature senescence. Under in vitro experimental conditions, exposure to a subcytotoxic dose of UVB enhanced human skin fibroblasts senescence, as characterized by increased β-galactosidase activity and increased levels of senescence-associated proteins. However, adenovirus-mediated SIRT1 overexpression significantly protected fibroblasts from UVB-induced cellular deterioration. Exposure to UVB-induced cell senescence was associated with oxidative stress and p38 mitogen-activated protein kinase activation. Molecular analysis demonstrated that deacetylation of Forkhead box O3α (FOXO3α) by SIRT1 changed the transcriptional activity of FOXO3α and increased resistance to the oxidative stress. In addition, SIRT1 suppressed UVB-induced p53 acetylation and its transcriptional activity, which directly affected the cell cycle arrest induced by UVB. Further study demonstrated that SIRT1 activation inhibited cell senescence in the skin of the HR1 hairless mouse exposed to UVB. The study identifies a new role for SIRT1 in the UVB-induced senescence of skin fibroblats and provides a potential target for skin protection through molecuar insights into the mechanisms responsible for UVB-induced photoaging. © The Author 2014. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  20. Transcriptional up-regulation of antioxidant genes by PPARδ inhibits angiotensin II-induced premature senescence in vascular smooth muscle cells

    International Nuclear Information System (INIS)

    Kim, Hyo Jung; Ham, Sun Ah; Paek, Kyung Shin; Hwang, Jung Seok; Jung, Si Young; Kim, Min Young; Jin, Hanna; Kang, Eun Sil; Woo, Im Sun; Kim, Hye Jung; Lee, Jae Heun; Chang, Ki Churl; Han, Chang Woo; Seo, Han Geuk

    2011-01-01

    Research highlights: → Activation of PPARδ by GW501516 significantly inhibited Ang II-induced premature senescence in hVSMCs. → Agonist-activated PPARδ suppressed generation of Ang II-triggered ROS with a concomitant reduction in DNA damage. → GW501516 up-regulated expression of antioxidant genes, such as GPx1, Trx1, Mn-SOD and HO-1. → Knock-down of these antioxidant genes abolished the effects of GW501516 on ROS production and premature senescence. -- Abstract: This study evaluated peroxisome proliferator-activated receptor (PPAR) δ as a potential target for therapeutic intervention in Ang II-induced senescence in human vascular smooth muscle cells (hVSMCs). Activation of PPARδ by GW501516, a specific agonist of PPARδ, significantly inhibited the Ang II-induced premature senescence of hVSMCs. Agonist-activated PPARδ suppressed the generation of Ang II-triggered reactive oxygen species (ROS) with a concomitant reduction in DNA damage. Notably, GW501516 up-regulated the expression of antioxidant genes, such as glutathione peroxidase 1, thioredoxin 1, manganese superoxide dismutase and heme oxygenase 1. siRNA-mediated down-regulation of these antioxidant genes almost completely abolished the effects of GW501516 on ROS production and premature senescence in hVSMCs treated with Ang II. Taken together, the enhanced transcription of antioxidant genes is responsible for the PPARδ-mediated inhibition of premature senescence through sequestration of ROS in hVSMCs treated with Ang II.

  1. Mechanism of phytohormone involvement in feedback regulation of cotton leaf senescence induced by potassium deficiency.

    Science.gov (United States)

    Wang, Ye; Li, Bo; Du, Mingwei; Eneji, A Egrinya; Wang, Baomin; Duan, Liusheng; Li, Zhaohu; Tian, Xiaoli

    2012-10-01

    To elucidate the phytohormonal basis of the feedback regulation of leaf senescence induced by potassium (K) deficiency in cotton (Gossypium hirsutum L.), two cultivars contrasting in sensitivity to K deficiency were self- and reciprocally grafted hypocotyl-to-hypocotyl, using standard grafting (one scion grafted onto one rootstock), Y grafting (two scions grafted onto one rootstock), and inverted Y grafting (one scion grafted onto two rootstocks) at the seedling stage. K deficiency (0.03mM for standard and Y grafting, and 0.01mM for inverted Y grafting) increased the root abscisic acid (ABA) concentration by 1.6- to 3.1-fold and xylem ABA delivery rates by 1.8- to 4.6-fold. The K deficiency also decreased the delivery rates of xylem cytokinins [CKs; including the zeatin riboside (ZR) and isopentenyl adenosine (iPA) type] by 29-65% and leaf CK concentration by 16-57%. The leaf ABA concentration and xylem ABA deliveries were consistently greater in CCRI41 (more sensitive to K deficiency) than in SCRC22 (less sensitive to K deficiency) scions under K deficiency, and ZR- and iPA-type levels were consistently lower in the former than in the latter, irrespective of rootstock cultivar or grafting type, indicating that cotton shoot influences the levels of ABA and CKs in leaves and xylem sap. Because the scions had little influence on phytohormone levels in the roots (rootstocks) of all three types of grafts and rootstock xylem sap (collected below the graft union) of Y and inverted Y grafts, it appears that the site for basipetal feedback signal(s) involved in the regulation of xylem phytohormones is the hypocotyl of cotton seedlings. Also, the target of this feedback signal(s) is more likely to be the changes in xylem phytohormones within tissues of the hypocotyl rather than the export of phytohormones from the roots.

  2. Resveratrol prevents oxidative stress-induced senescence and proliferative dysfunction by activating the AMPK-FOXO3 cascade in cultured primary human keratinocytes.

    Directory of Open Access Journals (Sweden)

    Yasuo Ido

    Full Text Available The aging process is perceived as resulting from a combination of intrinsic factors such as changes in intracellular signaling and extrinsic factors, most notably environmental stressors. In skin, the relationship between intrinsic changes and keratinocyte function is not clearly understood. Previously, we found that increasing the activity of AMP-activated protein kinase (AMPK suppressed senescence in hydrogen peroxide (H2O2-treated human primary keratinocytes, a model of oxidative stress-induced cellular aging. Using this model in the present study, we observed that resveratrol, an agent that increases the activities of both AMPK and sirtuins, ameliorated two age-associated phenotypes: cellular senescence and proliferative dysfunction. In addition, we found that treatment of keratinocytes with Ex527, a specific inhibitor of sirtuin 1 (SIRT1, attenuated the ability of resveratrol to suppress senescence. In keeping with the latter observation, we noted that compared to non-senescent keratinocytes, senescent cells lacked SIRT1. In addition to these effects on H2O2-induced senescence, resveratrol also prevented the H2O2-induced decrease in proliferation (as indicated by 3H-thymidine incorporation in the presence of insulin. This effect was abrogated by inhibition of AMPK but not SIRT1. Compared to endothelium, we found that human keratinocytes expressed relatively high levels of Forkhead box O3 (FOXO3, a downstream target of both AMPK and SIRT1. Treatment of keratinocytes with resveratrol transactivated FOXO3 and increased the expression of its target genes including catalase. Resveratrol's effects on both senescence and proliferation disappeared when FOXO3 was knocked down. Finally, we performed an exploratory study which showed that skin from humans over 50 years old had lower AMPK activity than skin from individuals under age 20. Collectively, these findings suggest that the effects of resveratrol on keratinocyte senescence and proliferation

  3. Overexpression of MpCYS4, a phytocystatin gene from Malus prunifolia (Willd.) Borkh., delays natural and stress-induced leaf senescence in apple.

    Science.gov (United States)

    Tan, Yanxiao; Yang, Yingli; Li, Chao; Liang, Bowen; Li, Mingjun; Ma, Fengwang

    2017-06-01

    Phytocystatins are a well-characterized class of naturally occurring protease inhibitors that prevent the catalysis of papain-like cysteine proteases. The action of cystatins in stress tolerance has been studied intensively, but relatively little is known about their functions in plants during leaf senescence. Here, we examined the potential roles of the apple cystatin, MpCYS4, in leaf photosynthesis as well as the concentrations and composition of leaf proteins when plants encounter natural or stress-induced senescence. Overexpression of this gene in apple rootstock M26 effectively slowed the senescence-related declines in photosynthetic activity and chlorophyll concentrations and prevented the action of cysteine proteinases during the process of degrading proteins (e.g., Rubisco) in senescing leaves. Moreover, MpCYS4 alleviated the associated oxidative damage and enhanced the capacity of plants to eliminate reactive oxygen species by activating antioxidant enzymes such as ascorbate peroxidase, peroxidase, and catalase. Consequently, plant cells were protected against damage from free radicals during leaf senescence. Based on these results, we conclude that MpCYS4 functions in delaying natural and stress-induced senescence of apple leaves. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  4. Differential impact of lipoxygenase 2 and jasmonates on natural and stress-induced senescence in Arabidopsis.

    Science.gov (United States)

    Seltmann, Martin A; Stingl, Nadja E; Lautenschlaeger, Jens K; Krischke, Markus; Mueller, Martin J; Berger, Susanne

    2010-04-01

    Jasmonic acid and related oxylipins are controversially discussed to be involved in regulating the initiation and progression of leaf senescence. To this end, we analyzed profiles of free and esterified oxylipins during natural senescence and upon induction of senescence-like phenotypes by dark treatment and flotation on sorbitol in Arabidopsis (Arabidopsis thaliana). Jasmonic acid and free 12-oxo-phytodienoic acid increased during all three processes, with the strongest increase of jasmonic acid after dark treatment. Arabidopside content only increased considerably in response to sorbitol treatment. Monogalactosyldiacylglycerols and digalactosyldiacylglycerols decreased during these treatments and aging. Lipoxygenase 2-RNA interference (RNAi) plants were generated, which constitutively produce jasmonic acid and 12-oxo-phytodienoic acid but do not exhibit accumulation during natural senescence or upon stress treatment. Chlorophyll loss during aging and upon dark incubation was not altered, suggesting that these oxylipins are not involved in these processes. In contrast, lipoxygenase 2-RNAi lines and the allene oxid synthase-deficient mutant dde2 were less sensitive to sorbitol than the wild type, indicating that oxylipins contribute to the response to sorbitol stress.

  5. An ethylene-induced regulatory module delays rose flower senescence by regulating cytokinin content

    Science.gov (United States)

    In many plant species, including rose (Rosa hybrida), flower senescence is promoted by the gaseous hormone, ethylene, and inhibited by cytokinin (CTK) class of hormones. However, the molecular mechanisms underlying these antagonistic effects are not well understood. In this current study, we charact...

  6. Knockdown of human deubiquitinase PSMD14 induces cell cycle arrest and senescence

    Energy Technology Data Exchange (ETDEWEB)

    Byrne, Ann; McLaren, Rajashree P.; Mason, Paul; Chai, Lilly; Dufault, Michael R.; Huang, Yinyin; Liang, Beirong; Gans, Joseph D.; Zhang, Mindy; Carter, Kara; Gladysheva, Tatiana B.; Teicher, Beverly A.; Biemann, Hans-Peter N.; Booker, Michael; Goldberg, Mark A.; Klinger, Katherine W.; Lillie, James [Genzyme Corporation, 49 New York Avenue, Framingham, MA 01701 (United States); Madden, Stephen L., E-mail: steve.madden@genzyme.com [Genzyme Corporation, 49 New York Avenue, Framingham, MA 01701 (United States); Jiang, Yide, E-mail: yide.jiang@genzyme.com [Genzyme Corporation, 49 New York Avenue, Framingham, MA 01701 (United States)

    2010-01-15

    The PSMD14 (POH1, also known as Rpn11/MPR1/S13/CepP1) protein within the 19S complex (19S cap; PA700) is responsible for substrate deubiquitination during proteasomal degradation. The role of PSMD14 in cell proliferation and senescence was explored using siRNA knockdown in carcinoma cell lines. Our results reveal that down-regulation of PSMD14 by siRNA transfection had a considerable impact on cell viability causing cell arrest in the G0-G1 phase, ultimately leading to senescence. The molecular events associated with decreased cell proliferation, cell cycle arrest and senescence include down-regulation of cyclin B1-CDK1-CDC25C, down-regulation of cyclin D1 and up-regulation of p21{sup /Cip} and p27{sup /Kip1}. Most notably, phosphorylation of the retinoblastoma protein was markedly reduced in PSMD14 knockdown cells. A comparative study with PSMB5, a subunit of the 20S proteasome, revealed that PSMB5 and PSMD14 have different effects on cell cycle, senescence and associated molecular events. These data support the view that the 19S and 20S subunits of the proteasome have distinct biological functions and imply that targeting 19S and 20S would have distinct molecular consequences on tumor cells.

  7. GSK3 inactivation is involved in mitochondrial complex IV defect in transforming growth factor (TGF) {beta}1-induced senescence

    Energy Technology Data Exchange (ETDEWEB)

    Byun, Hae-Ok; Jung, Hyun-Jung; Seo, Yong-Hak; Lee, Young-Kyoung [Department of Biochemistry and Molecular Biology, Ajou University School of Medicine, Suwon 443-721 (Korea, Republic of); Department of Molecular Science and Technology, The Graduate School, Ajou University, Suwon 443-721 (Korea, Republic of); Hwang, Sung-Chul [Department of Pulmonary and Critical Care Medicine, Ajou University School of Medicine, Suwon 443-721 (Korea, Republic of); Seong Hwang, Eun [Department of Life Science, University of Seoul, Seoul 130-743 (Korea, Republic of); Yoon, Gyesoon, E-mail: ypeace@ajou.ac.kr [Department of Biochemistry and Molecular Biology, Ajou University School of Medicine, Suwon 443-721 (Korea, Republic of); Department of Molecular Science and Technology, The Graduate School, Ajou University, Suwon 443-721 (Korea, Republic of)

    2012-09-10

    Transforming growth factor {beta}1 (TGF {beta}1) induces Mv1Lu cell senescence by persistently producing mitochondrial reactive oxygen species (ROS) through decreased complex IV activity. Here, we investigated the molecular mechanism underlying the effect of TGF {beta}1 on mitochondrial complex IV activity. TGF {beta}1 progressively phosphorylated the negative regulatory sites of both glycogen synthase kinase 3 (GSK3) {alpha} and {beta}, corresponding well to the intracellular ROS generation profile. Pre-treatment of N-acetyl cysteine, an antioxidant, did not alter this GSK3 phosphorylation (inactivation), whereas pharmacological inhibition of GSK3 by SB415286 significantly increased mitochondrial ROS, implying that GSK3 phosphorylation is an upstream event of the ROS generation. GSK3 inhibition by SB415286 decreased complex IV activity and cellular O{sub 2} consumption rate and eventually induced senescence of Mv1Lu cell. Similar results were obtained with siRNA-mediated knockdown of GSK3. Moreover, we found that GSK3 not only exists in cytosol but also in mitochondria of Mv1Lu cell and the mitochondrial GSK3 binds complex IV subunit 6b which has no electron carrier and is topologically located in the mitochondrial intermembrane space. Involvement of subunit 6b in controlling complex IV activity and overall respiration rate was proved with siRNA-mediated knockdown of subunit 6b. Finally, TGF {beta}1 treatment decreased the binding of the subunit 6b to GSK3 and subunit 6b phosphorylation. Taken together, our results suggest that GSK3 inactivation is importantly involved in TGF {beta}1-induced complex IV defects through decreasing phosphorylation of the subunit 6b, thereby contributing to senescence-associated mitochondrial ROS generation.

  8. Flow-induced plastic collapse of stacked fuel plates

    Energy Technology Data Exchange (ETDEWEB)

    Davis, D C; Scarton, H A

    1985-03-01

    Flow-induced plastic collapse of stacked fuel plate assemblies was first noted in experimental reactors such as the ORNL High Flux Reactor Assembly and the Engineering Test Reactor (ETR). The ETR assembly is a stack of 19 thin flat rectangular fuel plates separated by narrow channels through which a coolant flows to remove the heat generated by fission of the fuel within the plates. The uranium alloyed plates have been noted to buckle laterally and plastically collapse at the system design coolant flow rate of 10.7 m/s, thus restricting the coolant flow through adjacent channels. A methodology and criterion are developed for predicting the plastic collapse of ETR fuel plates. The criterion is compared to some experimental results and the Miller critical velocity theory.

  9. Metformin and Resveratrol Inhibited High Glucose-Induced Metabolic Memory of Endothelial Senescence through SIRT1/p300/p53/p21 Pathway.

    Science.gov (United States)

    Zhang, Erli; Guo, Qianyun; Gao, Haiyang; Xu, Ruixia; Teng, Siyong; Wu, Yongjian

    2015-01-01

    Endothelial senescence plays crucial roles in diabetic vascular complication. Recent evidence indicated that transient hyperglycaemia could potentiate persistent diabetic vascular complications, a phenomenon known as "metabolic memory." Although SIRT1 has been demonstrated to mediate high glucose-induced endothelial senescence, whether and how "metabolic memory" would affect endothelial senescence through SIRT1 signaling remains largely unknown. In this study, we investigated the involvement of SIRT1 axis as well as the protective effects of resveratrol (RSV) and metformin (MET), two potent SIRT1 activators, during the occurrence of "metabolic memory" of cellular senescence (senescent "memory"). Human umbilical vascular endothelial cells (HUVECs) were cultured in either normal glucose (NG)/high glucose (HG) media for 6 days, or 3 days of HG followed by 3 days of NG (HN), with or without RSV or MET treatment. It was shown that HN incubation triggered persistent downregulation of deacetylase SIRT1 and upregulation of acetyltransferase p300, leading to sustained hyperacetylation (at K382) and activation of p53, and subsequent p53/p21-mediated senescent "memory." In contrast, senescent "memory" was abrogated by overexpression of SIRT1 or knockdown of p300. Interestingly, we found that SIRT1 and p300 could regulate each other in response to HN stimulation, suggesting that a delicate balance between acetyltransferases and deacetylases may be particularly important for sustained acetylation and activation of non-histone proteins (such as p53), and eventually the occurrence of "metabolic memory." Furthermore, we found that RSV or MET treatment prevented senescent "memory" by modulating SIRT1/p300/p53/p21 pathway. Notably, early and continuous treatment of MET, but not RSV, was particularly important for preventing senescent "memory." In conclusion, short-term high glucose stimulation could induce sustained endothelial senescence via SIRT1/p300/p53/p21 pathway. RVS or MET

  10. Dehydration induced loss of photosynthesis in Arabidopsis leaves during senescence is accompanied by the reversible enhancement in the activity of cell wall β-glucosidase.

    Science.gov (United States)

    Patro, Lichita; Mohapatra, Pranab Kishor; Biswal, Udaya Chand; Biswal, Basanti

    2014-08-01

    The physiology of loss of photosynthetic production of sugar and the consequent cellular sugar reprogramming during senescence of leaves experiencing environmental stress largely remains unclear. We have shown that leaf senescence in Arabidopsis thaliana causes a significant reduction in the rate of oxygen evolution and net photosynthetic rate (Pn). The decline in photosynthesis is further aggravated by dehydration. During dehydration, primary photochemical reaction of thylakoids and net photosynthesis decrease in parallel with the increase in water deficit. Senescence induced loss in photosynthesis is accompanied by a significant increase in the activity of cell wall hydrolyzing enzyme such as β-glucosidase associated with cell wall catabolism. The activity of this enzyme is further enhanced when the senescing leaves experience dehydration stress. It is possible that both senescence and stress separately or in combination result in the loss in photosynthesis which could be a signal for an enhancement in the activity of β-glucosidase that breaks down cell wall polysaccharides to sugar to sustain respiration for metabolic activities of plants experiencing stress. Thus dehydration response of cell wall hydrolases of senescing leaves is considered as plants' strategy to have cell wall polysaccharides as an alternative energy source for completion of energy requiring senescence process, stress survival and maintenance of recovery potential of energy deficit cells in the background of loss in photosynthesis. Withdrawal of stress (rehydration) distinctly exhibits recovery of photosynthesis and suppression of enzyme activity. Retention of the signaling for sugar reprogramming through breakdown of cell wall polysaccharides in the senescing leaves exposed to severe drought stress suggests that senescing leaves like mature ones possess potential for stress recovery. The precise mechanism of stress adaptation of senescing leaves is yet to be known. A significant

  11. Chronic Low Dose Rate Ionizing Radiation Exposure Induces Premature Senescence in Human Fibroblasts that Correlates with Up Regulation of Proteins Involved in Protection against Oxidative Stress

    Directory of Open Access Journals (Sweden)

    Olga Loseva

    2014-07-01

    Full Text Available The risks of non-cancerous diseases associated with exposure to low doses of radiation are at present not validated by epidemiological data, and pose a great challenge to the scientific community of radiation protection research. Here, we show that premature senescence is induced in human fibroblasts when exposed to chronic low dose rate (LDR exposure (5 or 15 mGy/h of gamma rays from a 137Cs source. Using a proteomic approach we determined differentially expressed proteins in cells after chronic LDR radiation compared to control cells. We identified numerous proteins involved in protection against oxidative stress, suggesting that these pathways protect against premature senescence. In order to further study the role of oxidative stress for radiation induced premature senescence, we also used human fibroblasts, isolated from a patient with a congenital deficiency in glutathione synthetase (GS. We found that these GS deficient cells entered premature senescence after a significantly shorter time of chronic LDR exposure as compared to the GS proficient cells. In conclusion, we show that chronic LDR exposure induces premature senescence in human fibroblasts, and propose that a stress induced increase in reactive oxygen species (ROS is mechanistically involved.

  12. ATM-deficient human fibroblast cells are resistant to low levels of DNA double-strand break induced apoptosis and subsequently undergo drug-induced premature senescence

    International Nuclear Information System (INIS)

    Park, Jun; Jo, Yong Hwa; Cho, Chang Hoon; Choe, Wonchae; Kang, Insug; Baik, Hyung Hwan; Yoon, Kyung-Sik

    2013-01-01

    Highlights: ► A-T cells were not hypersensitive to low levels of DNA DSBs. ► A-T cells have enhanced Akt but defect in activation of p53 and apoptotic proteins. ► A-T cells underwent premature senescence after DNA damage accumulated. ► Chemotherapeutic effect in cancer therapy may be associated with premature senescence. -- Abstract: DNA DSBs are induced by IR or radiomimetic drugs such as doxorubicin. It has been indicated that cells from ataxia-telangiectasia patients are highly sensitive to radiation due to defects in DNA repair, but whether they have impairment in apoptosis has not been fully elucidated. A-T cells showed increased sensitivity to high levels of DNA damage, however, they were more resistant to low doses. Normal cells treated with combination of KU55933, a specific ATM kinase inhibitor, and doxorubicin showed increased resistance as they do in a similar manner to A-T cells. A-T cells have higher viability but more DNA breaks, in addition, the activations of p53 and apoptotic proteins (Bax and caspase-3) were deficient, but Akt expression was enhanced. A-T cells subsequently underwent premature senescence after treatment with a low dose of doxorubicin, which was confirmed by G2 accumulation, senescent morphology, and SA-β-gal positive until 15 days repair incubation. Finally, A-T cells are radio-resistant at low doses due to its defectiveness in detecting DNA damage and apoptosis, but the accumulation of DNA damage leads cells to premature senescence.

  13. Androgen depletion induces senescence in prostate cancer cells through down-regulation of Skp2

    Czech Academy of Sciences Publication Activity Database

    Pernicová, Zuzana; Slabáková, Eva; Kharaishvili, G.; Bouchal, J.; Král, M.; Kunická, Z.; Machala, M.; Kozubík, Alois; Souček, Karel

    2011-01-01

    Roč. 13, č. 6 (2011), s. 526-536 ISSN 1522-8002 R&D Projects: GA ČR(CZ) GA310/07/0961; GA MZd NS9600; GA MZd NS9956 Institutional research plan: CEZ:AV0Z50040507; CEZ:AV0Z50040702 Keywords : prostate cancer * senescence * Skp2 Subject RIV: BO - Biophysics Impact factor: 5.946, year: 2011

  14. miR-125b induces cellular senescence in malignant melanoma

    DEFF Research Database (Denmark)

    Nyholm, Anne Marie; Lerche, Catharina M; Manfé, Valentina

    2014-01-01

    transfected melanoma cell line Mel-Juso and then investigated the effect of the presence of a stable overexpression of miR-125b on growth by western blotting, flow cytometry and β-galactosidase staining. The tumourogenicity of the transfected cells was tested using a murine model and the tumours were further...... examined with in-situ-hybridization. RESULTS: In primary human tumours and in lymph node metastases increased expression of miR-125b was found in single, large tumour cells with abundant cytoplasm. A stable overexpression of miR-125b in human melanoma cell line Mel-Juso resulted in a G0/G1 cell cycle block...... and emergence of large cells expressing senescence markers: senescence-associated beta-galactosidase, p21, p27 and p53. Mel-Juso cells overexpressing miR-125b were tumourigenic in mice, but the tumours exhibited higher level of cell senescence and decreased expression of proliferation markers, cyclin D1 and Ki...

  15. Silicon Promotes Growth of Brassica napus L. and Delays Leaf Senescence Induced by Nitrogen Starvation

    Directory of Open Access Journals (Sweden)

    Cylia Haddad

    2018-04-01

    Full Text Available Silicon (Si is the second most abundant element in soil and has several beneficial effects, especially in plants subjected to stress conditions. However, the effect of Si in preventing nitrogen (N starvation in plants is poorly documented. The aim of this work was to study the effect of a short Si supply duration (7 days on growth, N uptake, photosynthetic activity, and leaf senescence progression in rapeseed subjected (or not to N starvation. Our results showed that after 1 week of Si supply, Si improves biomass and increases N uptake and root expression of a nitrate transporter gene. After 12 days of N starvation, compared to -Si plants, mature leaf from +Si plants showed a high chlorophyll content, a maintain of net photosynthetic activity, a decrease of oxidative stress markers [hydrogen peroxide (H2O2 and malondialdehyde (MDA] and a significant delay in senescence. When N-deprived plants were resupplied with N, a greening again associated with an increase of photosynthetic activity was observed in mature leaves of plants pretreated with Si. Moreover, during the duration of N resupply, an increase of N uptake and nitrate transporter gene expression were observed in plants pretreated with Si. In conclusion, this study has shown a beneficial role of Si to alleviate damage associated with N starvation and more especially its role in delaying of leaf senescence.

  16. Stable SREBP-1a knockdown decreases the cell proliferation rate in human preadipocyte cells without inducing senescence

    International Nuclear Information System (INIS)

    Alvarez, María Soledad; Fernandez-Alvarez, Ana; Cucarella, Carme; Casado, Marta

    2014-01-01

    Highlights: • SGBS cells mostly expressed SREBP-1a variant. • SREBP-1a knockdown decreased the proliferation of SGBS cells without inducing senescence. • We have identified RBBP8 and CDKN3 genes as potential SREBP-1a targets. - Abstract: Sterol regulatory element binding proteins (SREBP), encoded by the Srebf1 and Srebf2 genes, are important regulators of genes involved in cholesterol and fatty acid metabolism. Whereas SREBP-2 controls the cholesterol synthesis, SREBP-1 proteins (-1a and -1c) function as the central hubs in lipid metabolism. Despite the key function of these transcription factors to promote adipocyte differentiation, the roles of SREBP-1 proteins during the preadipocyte state remain unknown. Here, we evaluate the role of SREBP-1 in preadipocyte proliferation using RNA interference technology. Knockdown of the SREBP-1a gene decreased the proliferation rate in human SGBS preadipocyte cell strain without inducing senescence. Furthermore, our data identified retinoblastoma binding protein 8 and cyclin-dependent kinase inhibitor 3 genes as new potential SREBP-1 targets, in addition to cyclin-dependent kinase inhibitor 1A which had already been described as a gene regulated by SREBP-1a. These data suggested a new role of SREBP-1 in adipogenesis via regulation of preadipocyte proliferation

  17. Stable SREBP-1a knockdown decreases the cell proliferation rate in human preadipocyte cells without inducing senescence

    Energy Technology Data Exchange (ETDEWEB)

    Alvarez, María Soledad [Instituto de Biomedicina de Valencia (IBV-CSIC), Jaime Roig 11, E-46010 Valencia (Spain); Fernandez-Alvarez, Ana [Fundación Instituto Leloir, IIBBA-CONICET, Av. Patricias Argentinas 435, Ciudad Autónoma de Buenos Aires C1405BWE (Argentina); Cucarella, Carme [Instituto de Biomedicina de Valencia (IBV-CSIC), Jaime Roig 11, E-46010 Valencia (Spain); Casado, Marta, E-mail: mcasado@ibv.csic.es [Instituto de Biomedicina de Valencia (IBV-CSIC), Jaime Roig 11, E-46010 Valencia (Spain)

    2014-04-25

    Highlights: • SGBS cells mostly expressed SREBP-1a variant. • SREBP-1a knockdown decreased the proliferation of SGBS cells without inducing senescence. • We have identified RBBP8 and CDKN3 genes as potential SREBP-1a targets. - Abstract: Sterol regulatory element binding proteins (SREBP), encoded by the Srebf1 and Srebf2 genes, are important regulators of genes involved in cholesterol and fatty acid metabolism. Whereas SREBP-2 controls the cholesterol synthesis, SREBP-1 proteins (-1a and -1c) function as the central hubs in lipid metabolism. Despite the key function of these transcription factors to promote adipocyte differentiation, the roles of SREBP-1 proteins during the preadipocyte state remain unknown. Here, we evaluate the role of SREBP-1 in preadipocyte proliferation using RNA interference technology. Knockdown of the SREBP-1a gene decreased the proliferation rate in human SGBS preadipocyte cell strain without inducing senescence. Furthermore, our data identified retinoblastoma binding protein 8 and cyclin-dependent kinase inhibitor 3 genes as new potential SREBP-1 targets, in addition to cyclin-dependent kinase inhibitor 1A which had already been described as a gene regulated by SREBP-1a. These data suggested a new role of SREBP-1 in adipogenesis via regulation of preadipocyte proliferation.

  18. Biomarkers of replicative senescence revisited

    DEFF Research Database (Denmark)

    Nehlin, Jan

    2016-01-01

    Biomarkers of replicative senescence can be defined as those ultrastructural and physiological variations as well as molecules whose changes in expression, activity or function correlate with aging, as a result of the gradual exhaustion of replicative potential and a state of permanent cell cycle...... arrest. The biomarkers that characterize the path to an irreversible state of cell cycle arrest due to proliferative exhaustion may also be shared by other forms of senescence-inducing mechanisms. Validation of senescence markers is crucial in circumstances where quiescence or temporary growth arrest may...... be triggered or is thought to be induced. Pre-senescence biomarkers are also important to consider as their presence indicate that induction of aging processes is taking place. The bona fide pathway leading to replicative senescence that has been extensively characterized is a consequence of gradual reduction...

  19. Green tea extracts ameliorate high-fat diet-induced muscle atrophy in senescence-accelerated mouse prone-8 mice.

    Science.gov (United States)

    Onishi, Shintaro; Ishino, Mayu; Kitazawa, Hidefumi; Yoto, Ai; Shimba, Yuki; Mochizuki, Yusuke; Unno, Keiko; Meguro, Shinichi; Tokimitsu, Ichiro; Miura, Shinji

    2018-01-01

    Muscle atrophy (loss of skeletal muscle mass) causes progressive deterioration of skeletal function. Recently, excessive intake of fats was suggested to induce insulin resistance, followed by muscle atrophy. Green tea extracts (GTEs), which contain polyphenols such as epigallocatechin gallate, have beneficial effects on obesity, hyperglycemia, and insulin resistance, but their effects against muscle atrophy are still unclear. Here, we found that GTEs prevented high-fat (HF) diet-induced muscle weight loss in senescence-accelerated mouse prone-8 (SAMP8), a murine model of senescence. SAMP8 mice were fed a control diet, an HF diet, or HF with 0.5% GTEs (HFGT) diet for 4 months. The HF diet induced muscle weight loss with aging (measured as quadriceps muscle weight), whereas GTEs prevented this loss. In HF diet-fed mice, blood glucose and plasma insulin concentrations increased in comparison with the control group, and these mice had insulin resistance as determined by homeostasis model assessment of insulin resistance (HOMA-IR). In these mice, serum concentrations of leukocyte cell-derived chemotaxin 2 (LECT2), which is known to induce insulin resistance in skeletal muscle, were elevated, and insulin signaling in muscle, as determined by the phosphorylation levels of Akt and p70 S6 kinases, tended to be decreased. In HFGT diet-fed mice, these signs of insulin resistance and elevation of serum LECT2 were not observed. Although our study did not directly show the effect of serum LECT2 on muscle weight, insulin resistance examined using HOMA-IR indicated an intervention effect of serum LECT2 on muscle weight, as revealed by partial correlation analysis. Accordingly, GTEs might have beneficial effects on age-related and HF diet-induced muscle weight loss, which correlates with insulin resistance and is accompanied by a change in serum LECT2.

  20. Ectopic expression of Capsicum-specific cell wall protein Capsicum annuum senescence-delaying 1 (CaSD1) delays senescence and induces trichome formation in Nicotiana benthamiana.

    Science.gov (United States)

    Seo, Eunyoung; Yeom, Seon-In; Jo, Sunghwan; Jeong, Heejin; Kang, Byoung-Cheorl; Choi, Doil

    2012-04-01

    Secreted proteins are known to have multiple roles in plant development, metabolism, and stress response. In a previous study to understand the roles of secreted proteins, Capsicum annuum secreted proteins (CaS) were isolated by yeast secretion trap. Among the secreted proteins, we further characterized Capsicum annuum senescence-delaying 1 (CaSD1), a gene encoding a novel secreted protein that is present only in the genus Capsicum. The deduced CaSD1 contains multiple repeats of the amino acid sequence KPPIHNHKPTDYDRS. Interestingly, the number of repeats varied among cultivars and species in the Capsicum genus. CaSD1 is constitutively expressed in roots, and Agrobacterium-mediated transient overexpression of CaSD1 in Nicotiana benthamiana leaves resulted in delayed senescence with a dramatically increased number of trichomes and enlarged epidermal cells. Furthermore, senescence- and cell division-related genes were differentially regulated by CaSD1-overexpressing plants. These observations imply that the pepper-specific cell wall protein CaSD1 plays roles in plant growth and development by regulating cell division and differentiation.

  1. The ROS-mediated activation of IL-6/STAT3 signaling pathway is involved in the 27-hydroxycholesterol-induced cellular senescence in nerve cells.

    Science.gov (United States)

    Liu, Jiao; Liu, Yun; Chen, Juan; Hu, Chunyan; Teng, Mengying; Jiao, Kailin; Shen, Zhaoxia; Zhu, Dongmei; Yue, Jia; Li, Zhong; Li, Yuan

    2017-12-01

    The oxysterol 27-hydroxycholesterol (27HC) is a selective estrogen receptor modulator (SERMs), which like endogenous estrogen 17β-estradiol (E 2 ) induces the proliferation of ER-positive breast cancer cells in vitro. Interestingly, the observation that 27HC induces adverse effects in neural system, distinguishing it from E 2 . It has been suggested that high levels of circulating cholesterol increase the entry of 27HC into the brain, which may induce learning and memory impairment. Based on this evidence, 27HC may be associated with neurodegenerative processes and interrupted cholesterol homeostasis in the brain. However, the biological events that participate in this process remain largely elusive. In the present study, we demonstrated that 27HC induced apparent cellular senescence in nerve cells. Senescence-associated β-galactosidase (SA-β-Gal) assay revealed that 27HC induced senescence in both BV2 cells and PC12 cells. Furthermore, we demonstrated that 27HC promoted the accumulation of cellular reactive oxygen species (ROS) in nerve cells and subsequently activation of IL-6/STAT3 signaling pathway. Notably, treatment with the ROS scavenger N-acetylcysteine (NAC) markedly blocked 27HC-induced ROS production and activation of IL-6/STAT3 signaling pathway. Either blocking the generation of ROS or inhibition of IL-6/STAT3 both attenuated 27HC-induced cellular senescence. In sum, these findings not only suggested a mechanism whereby 27HC induced cellular senescence in nerve cells, but also helped to recognize the 27HC as a novel harmful factor in neurodegenerative diseases. Copyright © 2017. Published by Elsevier Ltd.

  2. Glucose metabolite glyoxal induces senescence in telomerase-immortalized human mesenchymal stem cells

    DEFF Research Database (Denmark)

    Larsen, Simon Asbjørn; Kassem, Moustapha; Rattan, Suresh

    2012-01-01

    ). Furthermore, the in vitro differentiation potential of hMSC-TERT to become functional osteoblasts was highly reduced in GO-treated stem cells, as determined by alkaline phosphatase (ALP) activity and mineralized matrix (MM) formation. Conclusions The results of our study imply that an imbalanced glucose...... physiological metabolite produced by the auto-oxidation of glucose, and can form covalent adducts known as advanced glycation endproducts (AGE). We have previously reported that GO accelerates ageing and causes premature senescence in normal human skin fibroblasts. Results Using a bone marrow-derived telomerase...

  3. Plant senescence and crop productivity

    DEFF Research Database (Denmark)

    Gregersen, Per L.; Culetic, Andrea; Boschian, Luca

    2013-01-01

    Senescence is a developmental process which in annual crop plants overlaps with the reproductive phase. Senescence might reduce crop yield when it is induced prematurely under adverse environmental conditions. This review covers the role of senescence for the productivity of crop plants....... With the aim to enhance productivity, a number of functional stay-green cultivars have been selected by conventional breeding, in particular of sorghum and maize. In many cases, a positive correlation between leaf area duration and yield has been observed, although in a number of other cases, stay...... plants, the expression of the IPT gene under control of senescence-associated promoters has been the most successful. The promoters employed for senescence-regulated expression contain cis-elements for binding of WRKY transcription factors and factors controlled by abscisic acid. In most crops...

  4. Inhibition of Mitochondrial Cytochrome c Release and Suppression of Caspases by Gamma-Tocotrienol Prevent Apoptosis and Delay Aging in Stress-Induced Premature Senescence of Skin Fibroblasts

    Directory of Open Access Journals (Sweden)

    Suzana Makpol

    2012-01-01

    Full Text Available In this study, we determined the molecular mechanism of γ-tocotrienol (GTT in preventing cellular aging by focusing on its anti-apoptotic effect in stress-induced premature senescence (SIPS model of human diploid fibroblasts (HDFs. Results obtained showed that SIPS exhibited senescent-phenotypic characteristic, increased expression of senescence-associated β-galactosidase (SA β-gal and promoted G0/G1 cell cycle arrest accompanied by shortening of telomere length with decreased telomerase activity. Both SIPS and senescent HDFs shared similar apoptotic changes such as increased Annexin V-FITC positive cells, increased cytochrome c release and increased activation of caspase-9 and caspase-3 (P<0.05. GTT treatment resulted in a significant reduction of Annexin V-FITC positive cells, inhibited cytochrome c release and decreased activation of caspase-9 and caspase-3 (P<0.05. Gene expression analysis showed that GTT treatment down regulated BAX mRNA, up-regulated BCL2A1 mRNA and decreased the ratio of Bax/Bcl-2 protein expression (P<0.05 in SIPS. These findings suggested that GTT inhibits apoptosis by modulating the upstream apoptosis cascade, causing the inhibition of cytochrome c release from the mitochondria with concomitant suppression of caspase-9 and caspase-3 activation. In conclusion, GTT delays cellular senescence of human diploid fibroblasts through the inhibition of intrinsic mitochondria-mediated pathway which involved the regulation of pro- and anti-apoptotic genes and proteins.

  5. A Screen Identifies the Oncogenic Micro-RNA miR-378a-5p as a Negative Regulator of Oncogene-Induced Senescence

    DEFF Research Database (Denmark)

    Kooistra, Susanne Marije; Rudkjær, Lise Christine; Lees, Michael James

    2014-01-01

    Oncogene-induced senescence (OIS) can occur in response to hyperactive oncogenic signals and is believed to be a fail-safe mechanism protecting against tumorigenesis. To identify new factors involved in OIS, we performed a screen for microRNAs that can overcome or inhibit OIS in human diploid fib...

  6. Selective insulin resistance in hepatocyte senescence

    International Nuclear Information System (INIS)

    Aravinthan, Aloysious; Challis, Benjamin; Shannon, Nicholas; Hoare, Matthew; Heaney, Judith; Alexander, Graeme J.M.

    2015-01-01

    Insulin resistance has been described in association with chronic liver disease for decades. Hepatocyte senescence has been demonstrated in chronic liver disease and as many as 80% of hepatocytes show a senescent phenotype in advanced liver disease. The aim of this study was to understand the role of hepatocyte senescence in the development of insulin resistance. Senescence was induced in HepG2 cells via oxidative stress. The insulin metabolic pathway was studied in control and senescent cells following insulin stimulation. GLUT2 and GLUT4 expressions were studied in HepG2 cells and human liver tissue. Further, GLUT2 and GLUT4 expressions were studied in three independent chronic liver disease cohorts. Signalling impairment distal to Akt in phosphorylation of AS160 and FoxO1 was evident in senescent HepG2 cells. Persistent nuclear localisation of FoxO1 was demonstrated in senescent cells despite insulin stimulation. Increased GLUT4 and decreased GLUT2 expressions were evident in senescent cells, human cirrhotic liver tissue and publically available liver disease datasets. Changes in GLUT expressions were associated with a poor clinical prognosis. In conclusion, selective insulin resistance is evident in senescent HepG2 cells and changes in GLUT expressions can be used as surrogate markers of hepatocyte senescence. - Highlights: • Senescent hepatocytes demonstrate selective insulin resistance. • GLUT changes act as markers of hepatocyte senescence and have prognostic value. • Study offers insight into long noticed intimacy of cirrhosis and insulin resistance

  7. Selective insulin resistance in hepatocyte senescence

    Energy Technology Data Exchange (ETDEWEB)

    Aravinthan, Aloysious [Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Cambridge (United Kingdom); Challis, Benjamin [Institute of Metabolic Sciences, University of Cambridge, Cambridge (United Kingdom); Shannon, Nicholas [Cancer Research UK Cambridge Institute, Cambridge (United Kingdom); Hoare, Matthew [Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Cambridge (United Kingdom); Cancer Research UK Cambridge Institute, Cambridge (United Kingdom); Heaney, Judith [Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Cambridge (United Kingdom); Foundation for Liver Research, Institute of Hepatology, London (United Kingdom); Alexander, Graeme J.M., E-mail: gja1000@doctors.org.uk [Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Cambridge (United Kingdom)

    2015-02-01

    Insulin resistance has been described in association with chronic liver disease for decades. Hepatocyte senescence has been demonstrated in chronic liver disease and as many as 80% of hepatocytes show a senescent phenotype in advanced liver disease. The aim of this study was to understand the role of hepatocyte senescence in the development of insulin resistance. Senescence was induced in HepG2 cells via oxidative stress. The insulin metabolic pathway was studied in control and senescent cells following insulin stimulation. GLUT2 and GLUT4 expressions were studied in HepG2 cells and human liver tissue. Further, GLUT2 and GLUT4 expressions were studied in three independent chronic liver disease cohorts. Signalling impairment distal to Akt in phosphorylation of AS160 and FoxO1 was evident in senescent HepG2 cells. Persistent nuclear localisation of FoxO1 was demonstrated in senescent cells despite insulin stimulation. Increased GLUT4 and decreased GLUT2 expressions were evident in senescent cells, human cirrhotic liver tissue and publically available liver disease datasets. Changes in GLUT expressions were associated with a poor clinical prognosis. In conclusion, selective insulin resistance is evident in senescent HepG2 cells and changes in GLUT expressions can be used as surrogate markers of hepatocyte senescence. - Highlights: • Senescent hepatocytes demonstrate selective insulin resistance. • GLUT changes act as markers of hepatocyte senescence and have prognostic value. • Study offers insight into long noticed intimacy of cirrhosis and insulin resistance.

  8. β2-Microglobulin participates in development of lung emphysema by inducing lung epithelial cell senescence.

    Science.gov (United States)

    Gao, Na; Wang, Ying; Zheng, Chun-Ming; Gao, Yan-Li; Li, Hui; Li, Yan; Fu, Ting-Ting; Xu, Li-Li; Wang, Wei; Ying, Sun; Huang, Kewu

    2017-05-01

    β 2 -Microglobulin (β 2 M), the light chain of the major histocompatibility complex class I (MHC I), has been identified as a proaging factor and is involved in the pathogenesis of neurodegenerative disorders by driving cognitive and regenerative impairments. However, little attention has focused on the effect of β 2 M in the development of lung emphysema. Here, we found that concentrations of β 2 M in plasma were significantly elevated in patients with lung emphysema than those in normal control subjects (1.89 ± 0.12 vs. 1.42 ± 0.06 mg/l, P lung tissue of emphysema (39.90 ± 1.97 vs. 23.94 ± 2.11%, P lung emphysema through induction of lung epithelial cell senescence and inhibition. Copyright © 2017 the American Physiological Society.

  9. Androgen receptor drives cellular senescence.

    Directory of Open Access Journals (Sweden)

    Yelena Mirochnik

    Full Text Available The accepted androgen receptor (AR role is to promote proliferation and survival of prostate epithelium and thus prostate cancer progression. While growth-inhibitory, tumor-suppressive AR effects have also been documented, the underlying mechanisms are poorly understood. Here, we for the first time link AR anti-cancer action with cell senescence in vitro and in vivo. First, AR-driven senescence was p53-independent. Instead, AR induced p21, which subsequently reduced ΔN isoform of p63. Second, AR activation increased reactive oxygen species (ROS and thereby suppressed Rb phosphorylation. Both pathways were critical for senescence as was proven by p21 and Rb knock-down and by quenching ROS with N-Acetyl cysteine and p63 silencing also mimicked AR-induced senescence. The two pathways engaged in a cross-talk, likely via PML tumor suppressor, whose localization to senescence-associated chromatin foci was increased by AR activation. All these pathways contributed to growth arrest, which resolved in senescence due to concomitant lack of p53 and high mTOR activity. This is the first demonstration of senescence response caused by a nuclear hormone receptor.

  10. Prenatal exposure to chromium induces early reproductive senescence by increasing germ cell apoptosis and advancing germ cell cyst breakdown in the F1 offspring.

    Science.gov (United States)

    Sivakumar, Kirthiram K; Stanley, Jone A; Arosh, Joe A; Pepling, Melissa E; Burghardt, Robert C; Banu, Sakhila K

    2014-04-01

    Hexavalent chromium (CrVI), one of the more toxic heavy metals, is widely used in more than 50 industries such as chrome plating, welding, wood processing and tanneries. As one of the world's leading producers of chromium compounds, the U.S. is facing growing challenges in protecting human health against multiple adverse effects of CrVI. CrVI is rapidly converted to CrIII intracellularly, and can induce apoptosis through different mechanisms. Our previous studies demonstrated postnatal exposure to CrVI results in a delay or arrest in follicle development and puberty. Pregnant rats were treated with 25 ppm potassium dichromate (CrVI) from gestational day (GD) 9.5 to 14.5 through drinking water, placentae were removed on GD 20, and total Cr was estimated in the placentae; ovaries were removed from the F1 offspring on postnatal day (PND)-1 and various analyses were performed. Our results show that gestational exposure to CrVI resulted in (i) increased Cr concentration in the placenta, (ii) increased germ cell apoptosis by up-regulating p53/p27-Bax-caspase-3 proteins and by increasing p53-SOD-2 co-localization; (iii) accelerated germ cell cyst (GCC) breakdown; (iv) advanced primordial follicle assembly and primary follicle transition and (v) down regulation of p-AKT, p-ERK and XIAP. As a result of the above events, CrVI induced early reproductive senescence and decrease in litter size in F1 female progeny. Published by Elsevier Inc.

  11. Zinc regulates Nox1 expression through a NF-κB and mitochondrial ROS dependent mechanism to induce senescence of vascular smooth muscle cells.

    Science.gov (United States)

    Salazar, G; Huang, J; Feresin, R G; Zhao, Y; Griendling, K K

    2017-07-01

    The role of oxidative stress and inflammation in the development and progression of cardiovascular diseases (CVD) is well established. Increases in oxidative stress can further exacerbate the inflammatory response and lead to cellular senescence. We previously reported that angiotensin II (Ang II) and zinc increase reactive oxygen species (ROS) and cause senescence of vascular smooth muscle cells (VSMCs) and that senescence induced by Ang II is a zinc-dependent process. Zinc stimulated NADPH oxidase (Nox) activity; however, the role of Nox isoforms in zinc effects was not determined. Here, we show that downregulation of Nox1, but not Nox4, by siRNA prevented both Ang II- and zinc-induced senescence in VSMCs. On the other hand, overexpression of Nox1 induced senescence, which was associated with reduced proliferation, reduced expression of telomerase and increased DNA damage. Zinc increased Nox1 protein expression, which was inhibited by chelation of zinc with TPEN and by overexpression of the zinc exporters ZnT3 and ZnT10. These transporters work to reduce cytosolic zinc, suggesting that increased cytosolic zinc mediates Nox1 upregulation. Other metals including copper, iron, cobalt and manganese failed to upregulate Nox1, suggesting that this pathway is zinc specific. Nox1 upregulation was inhibited by actinomycin D (ACD), an inhibitor of transcription, by inhibition of NF-κB, a known Nox1 transcriptional regulator and by N-acetyl cysteine (NAC) and MitoTEMPO, suggesting that NF-κB and mitochondrial ROS mediate zinc effects. Supporting this idea, we found that zinc increased NF-κB activation in the cytosol, stimulated the translocation of the p65 subunit to the nucleus, and that zinc accumulated in mitochondria increasing mitochondrial ROS, measured using MitoSox. Further, zinc-induced senescence was reduced by inhibition of NF-κB or reduction of mitochondrial ROS with MitoTEMPO. NF-κB activity was also reduced by MitoTEMPO, suggesting that mitochondrial ROS

  12. Laser Induced Selective Activation For Subsequent Autocatalytic Electroless Plating

    DEFF Research Database (Denmark)

    Zhang, Yang

    . The third hypothesis is that the activation and rinsing process can be described by diffusion. This hypothesis is proved using Fick’s diffusion laws combined with the short-time-plating experiment. The influence of laser parameters on the surface structure is investigated for Nd:YAG, UV, and fiber lasers......The subject of this PhD thesis is “Laser induced selective activation for subsequent autocatalytic electroless plating.” The objective of the project is to investigate the process chains for micro structuring of polymer surfaces for selective micro metallization. Laser induced selective activation...... (LISA) is introduced and studied as a new technique for producing 3D moulded interconnect devices (3D-MIDs). This technique enables the metallization of polymer surface modified by laser and subsequently activated by a PdCl2/SnCl2 system. Various technologies exist on an industrial level...

  13. N-Cadherin Attenuates High Glucose-Induced Nucleus Pulposus Cell Senescence Through Regulation of the ROS/NF-κB Pathway.

    Science.gov (United States)

    Hou, Gang; Zhao, Huiqing; Teng, Haijun; Li, Pei; Xu, Wenbin; Zhang, Junbin; Lv, Lulu; Guo, Zhiliang; Wei, Li; Yao, Hui; Xu, Yichun

    2018-05-11

    Diabetes mellitus (DM) is a potential etiology of disc degeneration. N-cadherin (N-CDH) helps maintain the cell viability, cell phenotype and matrix biosynthesis of nucleus pulposus (NP) cells. Here, we mainly aimed to investigate whether N-CDH can attenuate high glucose-induced NP cell senescence and its potential mechanism. Rat NP cells were cultured in a base culture medium and base culture medium with a 0.2 M glucose concentration. Recombinant lentiviral vectors were used to enhance N-CDH expression in NP cells. Senescence-associated β-galactosidase (SA-β-Gal) activity was measured by SA-β-Gal staining. NP cell proliferation was evaluated by CCK-8 assay. Telomerase activity and intracellular reactive oxygen species (ROS) content were tested by specific chemical kits according to the manufacturer's instructions. G0/G1 cell cycle arrest was evaluated by flow cytometry. Real-time PCR and Western blotting were used to analyze mRNA and protein expressions of senescence markers (p16 and p53) and matrix macromolecules (aggrecan and collagen II). Additionally, p-NF-κB expression was also analyzed by Western blotting to evaluate NF-κB pathway activity. High glucose significantly decreased N-CDH expression, increased ROS generation and NF-κB pathway activity, and promoted NP cell senescence, which was reflected in the increase in SA-β-Gal activity and senescence marker (p16 and p53) expression, compared to the control group. High glucose decreased telomerase activity and cell proliferation potency. However, N-CDH overexpression partially attenuated NP cell senescence, decreased ROS content and inhibited the activation of the NF-κB pathway under the high glucose condition. High glucose decreases N-CDH expression and promotes NP cell senescence. N-CDH overexpression can attenuate high glucose-induced NP cell senescence through the regulation of the ROS/ NF-κB pathway. This study suggests that N-CDH is a potential therapeutic target to slow DM-mediated disc NP

  14. Laser-induced selective copper plating of polypropylene surface

    Science.gov (United States)

    Ratautas, K.; Gedvilas, M.; Stankevičiene, I.; JagminienÄ--, A.; Norkus, E.; Li Pira, N.; Sinopoli, S.; Emanuele, U.; Račiukaitis, G.

    2016-03-01

    Laser writing for selective plating of electro-conductive lines for electronics has several significant advantages, compared to conventional printed circuit board technology. Firstly, this method is faster and cheaper at the prototyping stage. Secondly, material consumption is reduced, because it works selectively. However, the biggest merit of this method is potentiality to produce moulded interconnect device, enabling to create electronics on complex 3D surfaces, thus saving space, materials and cost of production. There are two basic techniques of laser writing for selective plating on plastics: the laser-induced selective activation (LISA) and laser direct structuring (LDS). In the LISA method, pure plastics without any dopant (filler) can be used. In the LDS method, special fillers are mixed in the polymer matrix. These fillers are activated during laser writing process, and, in the next processing step, the laser modified area can be selectively plated with metals. In this work, both methods of the laser writing for the selective plating of polymers were investigated and compared. For LDS approach, new material: polypropylene with carbon-based additives was tested using picosecond and nanosecond laser pulses. Different laser processing parameters (laser pulse energy, scanning speed, the number of scans, pulse durations, wavelength and overlapping of scanned lines) were applied in order to find out the optimal regime of activation. Areal selectivity tests showed a high plating resolution. The narrowest width of a copper-plated line was less than 23 μm. Finally, our material was applied to the prototype of the electronic circuit board on a 2D surface.

  15. Interferon-β induces cellular senescence in cutaneous human papilloma virus-transformed human keratinocytes by affecting p53 transactivating activity.

    Directory of Open Access Journals (Sweden)

    Maria V Chiantore

    Full Text Available Interferon (IFN-β inhibits cell proliferation and affects cell cycle in keratinocytes transformed by both mucosal high risk Human Papilloma Virus (HPV and cutaneous HPV E6 and E7 proteins. In particular, upon longer IFN-β treatments, cutaneous HPV38 expressing cells undergo senescence. IFN-β appears to induce senescence by upregulating the expression of the tumor suppressor PML, a well known IFN-induced gene. Indeed, experiments in gene silencing via specific siRNAs have shown that PML is essential in the execution of the senescence programme and that both p53 and p21 pathways are involved. IFN-β treatment leads to a modulation of p53 phosphorylation and acetylation status and a reduction in the expression of the p53 dominant negative ΔNp73. These effects allow the recovery of p53 transactivating activity of target genes involved in the control of cell proliferation. Taken together, these studies suggest that signaling through the IFN pathway might play an important role in cellular senescence. This additional understanding of IFN antitumor action and mechanisms influencing tumor responsiveness or resistance appears useful in aiding further promising development of biomolecular strategies in the IFN therapy of cancer.

  16. Pentoxifylline sensitizes human cervical tumor cells to cisplatin-induced apoptosis by suppressing NF-kappa B and decreased cell senescence

    International Nuclear Information System (INIS)

    Hernandez-Flores, Georgina; Bravo-Cuellar, Alejandro; Ortiz-Lazareno, Pablo C; Lerma-Diaz, Jose Manuel; Dominguez-Rodriguez, Jorge R; Jave-Suarez, Luis F; Aguilar-Lemarroy, Adriana del C; Celis-Carrillo, Ruth de; Toro-Arreola, Susana del; Castellanos-Esparza, Yessica C

    2011-01-01

    Worldwide, cervical cancer is the second most common causes of cancer in women and represents an important mortality rate. Cisplatin (CIS) is a very important antitumoral agent and can lead tumor cells toward two important cellular states: apoptosis and senescence. In some types of cancers pentoxifylline (PTX) sensitizes these cells to the toxic action of chemotherapeutics drugs such as adriamycin, inducing apoptosis. In the present work, we studied in vitro whether PTX alone or in combination with CIS induces apoptosis and/or senescence in cervix cancer HeLa and SiHa cell lines infected with HPV types 16 and 18, respectively, as well as in immortalized keratinocytyes HaCaT cells. HeLa (HPV 18+), SiHa (HPV 16+) cervix cancer cells and non-tumorigenic immortalized HaCaT cells (control) were treated with PTX, CIS or both. The cellular toxicity and survival fraction of PTX and CIS were determinate by WST-1 and clonogenic assays respectively. Apoptosis, caspase activation and phosphorylation of ERK1/2, p38, p65 (NF-κB), Bcl-2 and Bcl-XL anti-apoptotic proteins were determinated by flow cytometry. Senescence by microscopy. Phosphorylation of IκBα and IκB total were measured by ELISA. Pro-apoptotic, anti-apoptotic and senescence genes, as well as HPV-E6/7 mRNA expression, were detected by RT-PCR. Our results show that after 24 hours of incubation PTX per se is toxic for cancer cells affecting cell viability and inducing apoptosis. The toxicity in HaCaT cells was minimal. CIS induces apoptosis in HeLa and SiHa cells and its effect was significantly increases when the cells were treated with PTX + CIS. In all studies there was a direct correlation with levels of caspases (-3, -6, -7, -9 and -8) activity and apoptosis. CIS induces important levels of senescence and phosphorylation of ERK1/2, p38, p65/RELA, and IκBα, and decreased the expression of anti-apoptotic protein Bcl-XL. Surprisingly these levels were significantly reduced by PTX in tumor cells, and at the same

  17. Agmatine Ameliorates High Glucose-Induced Neuronal Cell Senescence by Regulating the p21 and p53 Signaling.

    Science.gov (United States)

    Song, Juhyun; Lee, Byeori; Kang, Somang; Oh, Yumi; Kim, Eosu; Kim, Chul-Hoon; Song, Ho-Taek; Lee, Jong Eun

    2016-02-01

    Neuronal senescence caused by diabetic neuropathy is considered a common complication of diabetes mellitus. Neuronal senescence leads to the secretion of pro-inflammatory cytokines, the production of reactive oxygen species, and the alteration of cellular homeostasis. Agmatine, which is biosynthesized by arginine decarboxylation, has been reported in previous in vitro to exert a protective effect against various stresses. In present study, agmatine attenuated the cell death and the expression of pro-inflammatory cytokines such as IL-6, TNF-alpha and CCL2 in high glucose in vitro conditions. Moreover, the senescence associated-β-galatosidase's activity in high glucose exposed neuronal cells was reduced by agmatine. Increased p21 and reduced p53 in high glucose conditioned cells were changed by agmatine. Ultimately, agmatine inhibits the neuronal cell senescence through the activation of p53 and the inhibition of p21. Here, we propose that agmatine may ameliorate neuronal cell senescence in hyperglycemia.

  18. Iron-induced nitric oxide leads to an increase in the expression of ferritin during the senescence of Lotus japonicus nodules.

    Science.gov (United States)

    Chungopast, Sirinapa; Duangkhet, Mallika; Tajima, Shigeyuki; Ma, Jian Feng; Nomura, Mika

    2017-01-01

    Iron is an essential nutrient for legume-rhizobium symbiosis and accumulates abundantly in the nodules. However, the concentration of free iron in the cells is strictly controlled to avoid toxicity. It is known that ferritin accumulates in the cells as an iron storage protein. During nodule senescence, the expression of the ferritin gene, Ljfer1, was induced in Lotus japonicus. We investigated a signal transduction pathway leading to the increase of Ljfer1 in the nodule. The Ljfer1 promoter of L. japonicus contains a conserved Iron-Dependent Regulatory Sequence (IDRS). The expression of Ljfer1 was induced by the application of iron or sodium nitroprusside, which is a nitric oxide (NO) donor. The application of iron to the nodule increased the level of NO. These data strongly suggest that iron-induced NO leads to increased expression of Ljfer1 during the senescence of L. japonicus nodules. Copyright © 2016 Elsevier GmbH. All rights reserved.

  19. ABI3 ectopic expression reduces in vitro and in vivo cell growth properties while inducing senescence

    Directory of Open Access Journals (Sweden)

    Riggins Gregory J

    2011-01-01

    Full Text Available Abstract Background Mounting evidence has indicated that ABI3 (ABI family member 3 function as a tumor suppressor gene, although the molecular mechanism by which ABI3 acts remains largely unknown. Methods The present study investigated ABI3 expression in a large panel of benign and malignant thyroid tumors and explored a correlation between the expression of ABI3 and its potential partner ABI3-binding protein (ABI3BP. We next explored the biological effects of ABI3 ectopic expression in thyroid and colon carcinoma cell lines, in which its expression was reduced or absent. Results We not only observed that ABI3 expression is reduced or lost in most carcinomas but also that there is a positive correlation between ABI3 and ABI3BP expression. Ectopic expression of ABI3 was sufficient to lead to a lower transforming activity, reduced tumor in vitro growth properties, suppressed in vitro anchorage-independent growth and in vivo tumor formation while, cellular senescence increased. These responses were accompanied by the up-regulation of the cell cycle inhibitor p21 WAF1 and reduced ERK phosphorylation and E2F1 expression. Conclusions Our result links ABI3 to the pathogenesis and progression of some cancers and suggests that ABI3 or its pathway might have interest as therapeutic target. These results also suggest that the pathways through which ABI3 works should be further characterized.

  20. Senescence is not inevitable

    DEFF Research Database (Denmark)

    Jones, Owen; Vaupel, James W.

    2017-01-01

    trajectories exists. These empirical observations support theoretical work indicating that a wide range of mortality and fertility trajectories is indeed possible, including senescence, negligible senescence and even negative senescence (improvement). Although many mysteries remain in the field...

  1. Red Yeast Rice Protects Circulating Bone Marrow-Derived Proangiogenic Cells against High-Glucose-Induced Senescence and Oxidative Stress: The Role of Heme Oxygenase-1

    Directory of Open Access Journals (Sweden)

    Jung-Tung Liu

    2017-01-01

    Full Text Available The inflammation and oxidative stress of bone marrow-derived proangiogenic cells (PACs, also named endothelial progenitor cells, triggered by hyperglycemia contributes significantly to vascular dysfunction. There is supporting evidence that the consumption of red yeast rice (RYR; Monascus purpureus-fermented rice reduces the vascular complications of diabetes; however, the underlying mechanism remains unclear. This study aimed to elucidate the effects of RYR extract in PACs, focusing particularly on the role of a potent antioxidative enzyme, heme oxygenase-1 (HO-1. We found that treatment with RYR extract induced nuclear factor erythroid-2-related factor nuclear translocation and HO-1 mRNA and protein levels in PACs. RYR extract inhibited high-glucose-induced (30 mM PAC senescence and the development of reactive oxygen species (ROS in a dose-dependent manner. The HO-1 inducer cobalt protoporphyrin IX also decreased high-glucose-induced cell senescence and oxidative stress, whereas the HO-1 enzyme inhibitor zinc protoporphyrin IX and HO-1 small interfering RNA significantly reversed RYR extract-caused inhibition of senescence and reduction of oxidative stress in high-glucose-treated PACs. These results suggest that RYR extract serves as alternative and complementary medicine in the treatment of these diseases, by inducing HO-1, thereby decreasing the vascular complications of diabetes.

  2. Arctiin blocks hydrogen peroxide-induced senescence and cell death though microRNA expression changes in human dermal papilla cells

    Directory of Open Access Journals (Sweden)

    Seunghee Bae

    2014-01-01

    Full Text Available BACKGROUND: Accumulating evidence indicates that reactive oxygen species (ROS are an important etiological factor for the induction of dermal papilla cell senescence and hair loss, which is also known alopecia. Arctiin is an active lignin isolated from Arctium lappa and has anti-inflammation, anti-microbial, and anti-carcinogenic effects. In the present study, we found that arctiin exerts anti-oxidative effects on human hair dermal papilla cells (HHDPCs. RESULTS: To better understand the mechanism, we analyzed the level of hydrogen peroxide (H2O2-induced cytotoxicity, cell death, ROS production and senescence after arctiin pretreatment of HHDPCs. The results showed that arctiin pretreatment significantly inhibited the H2O2-induced reduction in cell viability. Moreover, H2O2-induced sub-G1 phase accumulation and G2 cell cycle arrest were also downregulated by arctiin pretreatment. Interestingly, the increase in intracellular ROS mediated by H2O2 was drastically decreased in HHDPCs cultured in the presence of arctiin. This effect was confirmed by senescence associated-beta galactosidase (SA-β-gal assay results; we found that arctiin pretreatment impaired H2O2-induced senescence in HHDPCs. Using microRNA (miRNA microarray and bioinformatic analysis, we showed that this anti-oxidative effect of arctiin in HHDPCs was related with mitogen-activated protein kinase (MAPK and Wnt signaling pathways. CONCLUSIONS: Taken together, our data suggest that arctiin has a protective effect on ROS-induced cell dysfunction in HHDPCs and may therefore be useful for alopecia prevention and treatment strategies.

  3. In response to partial plant shading, the lack of phytochrome A does not directly induce leaf senescence but alters the fine-tuning of chlorophyll biosynthesis

    Science.gov (United States)

    Brouwer, Bastiaan; Gardeström, Per; Keech, Olivier

    2014-01-01

    Phytochrome is thought to control the induction of leaf senescence directly, however, the signalling and molecular mechanisms remain unclear. In the present study, an ecophysiological approach was used to establish a functional connection between phytochrome signalling and the physiological processes underlying the induction of leaf senescence in response to shade. With shade it is important to distinguish between complete and partial shading, during which either the whole or only a part of the plant is shaded, respectively. It is first shown here that, while PHYB is required to maintain chlorophyll content in a completely shaded plant, only PHYA is involved in maintaining the leaf chlorophyll content in response to partial plant shading. Second, it is shown that leaf yellowing associated with strong partial shading in phyA-mutant plants actually correlates to a decreased biosynthesis of chlorophyll rather than to an increase of its degradation. Third, it is shown that the physiological impact of this decreased biosynthesis of chlorophyll in strongly shaded phyA-mutant leaves is accompanied by a decreased capacity to adjust the Light Compensation Point. However, the increased leaf yellowing in phyA-mutant plants is not accompanied by an increase of senescence-specific molecular markers, which argues against a direct role of PHYA in inducing leaf senescence in response to partial shade. In conclusion, it is proposed that PHYA, but not PHYB, is essential for fine-tuning the chlorophyll biosynthetic pathway in response to partial shading. In turn, this mechanism allows the shaded leaf to adjust its photosynthetic machinery to very low irradiances, thus maintaining a positive carbon balance and repressing the induction of leaf senescence, which can occur under prolonged periods of shade. PMID:24604733

  4. A prototypical non-malignant epithelial model to study genome dynamics and concurrently monitor micro-RNAs and proteins in situ during oncogene-induced senescence.

    Science.gov (United States)

    Komseli, Eirini-Stavroula; Pateras, Ioannis S; Krejsgaard, Thorbjørn; Stawiski, Konrad; Rizou, Sophia V; Polyzos, Alexander; Roumelioti, Fani-Marlen; Chiourea, Maria; Mourkioti, Ioanna; Paparouna, Eleni; Zampetidis, Christos P; Gumeni, Sentiljana; Trougakos, Ioannis P; Pefani, Dafni-Eleftheria; O'Neill, Eric; Gagos, Sarantis; Eliopoulos, Aristides G; Fendler, Wojciech; Chowdhury, Dipanjan; Bartek, Jiri; Gorgoulis, Vassilis G

    2018-01-10

    Senescence is a fundamental biological process implicated in various pathologies, including cancer. Regarding carcinogenesis, senescence signifies, at least in its initial phases, an anti-tumor response that needs to be circumvented for cancer to progress. Micro-RNAs, a subclass of regulatory, non-coding RNAs, participate in senescence regulation. At the subcellular level micro-RNAs, similar to proteins, have been shown to traffic between organelles influencing cellular behavior. The differential function of micro-RNAs relative to their subcellular localization and their role in senescence biology raises concurrent in situ analysis of coding and non-coding gene products in senescent cells as a necessity. However, technical challenges have rendered in situ co-detection unfeasible until now. In the present report we describe a methodology that bypasses these technical limitations achieving for the first time simultaneous detection of both a micro-RNA and a protein in the biological context of cellular senescence, utilizing the new commercially available SenTraGor TM compound. The method was applied in a prototypical human non-malignant epithelial model of oncogene-induced senescence that we generated for the purposes of the study. For the characterization of this novel system, we applied a wide range of cellular and molecular techniques, as well as high-throughput analysis of the transcriptome and micro-RNAs. This experimental setting has three advantages that are presented and discussed: i) it covers a "gap" in the molecular carcinogenesis field, as almost all corresponding in vitro models are fibroblast-based, even though the majority of neoplasms have epithelial origin, ii) it recapitulates the precancerous and cancerous phases of epithelial tumorigenesis within a short time frame under the light of natural selection and iii) it uses as an oncogenic signal, the replication licensing factor CDC6, implicated in both DNA replication and transcription when over

  5. Enhanced adhesion of early endothelial progenitor cells to radiation-induced senescence-like vascular endothelial cells in vitro

    International Nuclear Information System (INIS)

    Sermsathanasawadi, N.; Inoue, Yoshinori; Iwai, Takehisa; Ishii, Hideto; Yoshida, Masayuki; Igarashi, Kaori; Miura, Masahiko

    2009-01-01

    The effects of ionizing radiation (IR) on tumor neovascularization are still unclear. We previously reported that vascular endothelial cells (ECs) expressing the IR-induced senescence-like (IRSL) phenotype exhibit a significant decrease in angiogenic activity in vitro. In this study, we examined the effects of the IRSL phenotype on adhesion to early endothelial progenitor cells (early EPCs). Adhesion of human peripheral blood-derived early EPCs to human umbilical vein endothelial cells (HUVECs) expressing the IRSL phenotype was evaluated by an adhesion assay under static conditions. It was revealed that the IRSL HUVECs supported significantly more adhesion of early EPCs than normal HUVECs. Expressions of ICAM-1, VCAM-1 and E-selectin were up-regulated in IRSL HUVECs. Pre-treatment of IRSL HUVECs with adhesion-blocking monoclonal antibodies against E-selectin and VCAM-1 significantly reduced early EPC adhesion to IRSL HUVECs, suggesting a potential role for the E-selectin and VCAM-1 in the adhesion between IRSL ECs and early EPCs. Therefore, the IRSL phenotype expressed in ECs may enhance neovascularization via increased homing of early EPCs. Our findings are first to implicate the complex effects of this phenotype on tumor neovascularization following irradiation. (author)

  6. Forging a signature of in vivo senescence.

    Science.gov (United States)

    Sharpless, Norman E; Sherr, Charles J

    2015-07-01

    'Cellular senescence', a term originally defining the characteristics of cultured cells that exceed their replicative limit, has been broadened to describe durable states of proliferative arrest induced by disparate stress factors. Proposed relationships between cellular senescence, tumour suppression, loss of tissue regenerative capacity and ageing suffer from lack of uniform definition and consistently applied criteria. Here, we highlight caveats in interpreting the importance of suboptimal senescence-associated biomarkers, expressed either alone or in combination. We advocate that more-specific descriptors be substituted for the now broadly applied umbrella term 'senescence' in defining the suite of diverse physiological responses to cellular stress.

  7. Orphan nuclear receptor TLX functions as a potent suppressor of oncogene-induced senescence in prostate cancer via its transcriptional co-regulation of the CDKN1A (p21(WAF1) (/) (CIP1) ) and SIRT1 genes.

    Science.gov (United States)

    Wu, Dinglan; Yu, Shan; Jia, Lin; Zou, Chang; Xu, Zhenyu; Xiao, Lijia; Wong, Kam-Bo; Ng, Chi-Fai; Chan, Franky L

    2015-05-01

    Oncogene-induced senescence is an important tumour-suppressing mechanism to prevent both premalignant transformation and cancer progression. Overcoming this process is a critical step in early cancer development. The druggable orphan nuclear receptor TLX (NR2E1) is characterized as an important regulator of neural stem cells and is also implicated in the development of some brain tumours. However, its exact functional roles in cancer growth regulation still remain unclear. Here we report that TLX can act as a promoter of tumourigenesis in prostate cancer by suppressing oncogene-induced senescence. We determined that TLX exhibited an increased expression in high-grade prostate cancer tissues and many prostate cancer cell lines. Functional studies revealed that TLX could perform an oncogenic function in prostate cancer cells, as its knockdown triggered cellular senescence and cell growth arrest in vitro and in vivo, whereas its over-expression promoted the malignant growth of prostate cancer cells. Furthermore, enhancement of TLX activity, by either ectopic expression or ligand stimulation, could potently prevent doxorubicin-induced senescence in prostate cancer cells and also allow prostatic epithelial cells to escape oncogene-induced senescence induced either by activated oncogene H-Ras(G12V) or knockdown of tumour suppressor PTEN, via a mechanism of direct but differential transcriptional regulation of two senescence-associated genes, repression of CDKN1A and transactivation of SIRT1. Together, our present study shows, for the first time, that TLX may play an important role in prostate carcinogenesis through its suppression of oncogene-induced senescence, and also suggests that targeting the senescence-regulatory TLX is of potential therapeutic significance in prostate cancer. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  8. Delayed Senescence

    Science.gov (United States)

    2004-01-01

    Researcher Dr. Yi Li developed a technique to manipulate certain characteristics of plant growth such as anit-senescence. For example, the tobacco leaf was clipped from a transgenic plant (right), and a wildtype plant (left). During ground-based laboratory studies, both leaves were left in a darkened area for 4 months. When retrieved, the wildtype plant leaf was dried-out and the transgenic leaf remained fresh and green. A variation of this technology that involves manipulating plant hormones has been conducted in space-based studies on tomato plants through BioServe Space Technologies. The transport and distribution of auxin, an important plant hormone has shown to be influenced by microgravity, which could lead to improving the quality of fruits and vegetables grown on Earth.

  9. Therapeutic doses of doxorubicin induce premature senescence of human mesenchymal stem cells derived from menstrual blood, bone marrow and adipose tissue.

    Science.gov (United States)

    Kozhukharova, Irina; Zemelko, Victoria; Kovaleva, Zoya; Alekseenko, Larisa; Lyublinskaya, Olga; Nikolsky, Nikolay

    2018-03-01

    Doxorubicin (Dox) is an effective anticancer drug with known activity against a wide spectrum of malignancies, hematologic malignancies in particular. Despite extensive clinical use, the mechanisms of its side effects and negative action on normal cells remain under study. The aim of this study was to investigate the effect of Dox on cultured human mesenchymal stem cells (MSCs) derived from menstrual blood (eMSCs), bone marrow (BMSCs) and adipose tissue (AMSCs). Dox treatment in high doses decreased the survival of MSCs in a dose-dependent manner. Clinically relevant low doses of Dox induced premature senescence of eMSCs, BMSCs and AMSCs, but did not kill the cells. Dox caused cell cycle arrest and formation of γ-H2AX foci, and increased the number of SA-β-gal-positive cells. BMSCs entered premature senescence earlier than other MSCs. It has been reported that neural-like cells differentiated from MSCs of various origins are more sensitive to Dox than their parent cells. Dox-treated differentiated MSCs exhibited lower viability and earlier generation of γ-H2AX foci. Dox administration inhibited secretory activity in neural-like cells. These findings suggest that a clinically relevant Dox dose damages cultured MSCs, inducing their premature senescence. MSCs are more resistant to this damage than differentiated cells.

  10. Role of TGF-beta1-independent changes in protein neosynthesis, p38alphaMAPK, and cdc42 in hydrogen peroxide-induced senescence-like morphogenesis

    DEFF Research Database (Denmark)

    Chrétien, Aline; Dierick, Jean-François; Delaive, Edouard

    2008-01-01

    for p38(MAPK) activation, in turn triggering phosphorylation of L-caldesmon and HSP27. Cdc42 was also shown to be mainly responsible for the increase in TGF-beta1 mRNA level observed at 24 h after treatment with H(2)O(2) and onward. This study further clarified the mechanisms of senescence......The role of TGF-beta1 in hydrogen peroxide-induced senescence-like morphogenesis has been described. The aim of this work was to investigate whether TGF-beta1-independent changes in protein synthesis are involved in this morphogenesis and to study possible mechanisms occurring earlier than TGF-beta......1 overexpression. Among the multiple TGF-beta1-independent changes in protein neosynthesis, followed or not by posttranslational modifications, identified by proteomic analysis herein, those of ezrin, L-caldesmon, and HSP27 were particularly studied. Rho-GTPase cdc42 was shown to be responsible...

  11. Emerging roles of lncRNAs in senescence

    DEFF Research Database (Denmark)

    Montes Resano, Marta; Lund, Anders H

    2016-01-01

    Cellular senescence is a complex stress response that leads to an irreversible state of cell growth arrest. Senescence may be induced by different stimuli such as telomere shortening, DNA damage or oncogenic insult among others. Senescent cells are metabolically highly active producing a wealth...

  12. Down-regulation of Wild-type p53-induced Phosphatase 1 (Wip1) Plays a Critical Role in Regulating Several p53-dependent Functions in Premature Senescent Tumor Cells*

    Science.gov (United States)

    Crescenzi, Elvira; Raia, Zelinda; Pacifico, Francesco; Mellone, Stefano; Moscato, Fortunato; Palumbo, Giuseppe; Leonardi, Antonio

    2013-01-01

    Premature or drug-induced senescence is a major cellular response to chemotherapy in solid tumors. The senescent phenotype develops slowly and is associated with chronic DNA damage response. We found that expression of wild-type p53-induced phosphatase 1 (Wip1) is markedly down-regulated during persistent DNA damage and after drug release during the acquisition of the senescent phenotype in carcinoma cells. We demonstrate that down-regulation of Wip1 is required for maintenance of permanent G2 arrest. In fact, we show that forced expression of Wip1 in premature senescent tumor cells induces inappropriate re-initiation of mitosis, uncontrolled polyploid progression, and cell death by mitotic failure. Most of the effects of Wip1 may be attributed to its ability to dephosphorylate p53 at Ser15 and to inhibit DNA damage response. However, we also uncover a regulatory pathway whereby suppression of p53 Ser15 phosphorylation is associated with enhanced phosphorylation at Ser46, increased p53 protein levels, and induction of Noxa expression. On the whole, our data indicate that down-regulation of Wip1 expression during premature senescence plays a pivotal role in regulating several p53-dependent aspects of the senescent phenotype. PMID:23612976

  13. Identification and characterization of MOR-CP, a cysteine protease induced by ozone and developmental senescence in maize (Zea mays L.) leaves.

    Science.gov (United States)

    Ahmad, Rafiq; Zuily-Fodil, Yasmine; Passaquet, Chantal; Bethenod, Olivier; Roche, Romain; Repellin, Anne

    2014-08-01

    Among the different classes of endoproteases, cysteine proteases are consistently associated with senescence, defense signaling pathways and cellular responses to abiotic stresses. The objectives of this work were to study the effects of various concentrations of ozone on gene expression and enzymatic activity for papain-like cysteine proteases (PLCPs), in the leaves of maize plants grown under field conditions. Leaves from ranks 12 and 10 (cob leaf) were harvested regularly over a long-term artificial ozone fumigation experiment (50 d). Tissues were tested for transcriptional and activity changes concerning cysteine proteases, using qRT-PCR for the newly identified ozone-responsive PLCP gene (Mor-CP) and synthetic oligopeptide Boc-Val-Leu-Lys-AMC as a PLCP-specific substrate, respectively. Results showed that developmental senescence induced a significant and progressive rise in CP activity, only in the older leaves 10 and had no effect on Mor-CP gene expression levels. On the other hand, ozone dramatically enhanced Mor-CP mRNA levels and global PLCP enzymatic activity in leaves 12 and 10, particularly toward the end of the treatment. Ozone impact was more pronounced in the older leaves 10. Together, these observations concurred to conclude that ozone stress enhances natural senescence processes, such as those related to proteolysis. Copyright © 2014 Elsevier Ltd. All rights reserved.

  14. Transcriptional analyses of natural leaf senescence in maize.

    Directory of Open Access Journals (Sweden)

    Wei Yang Zhang

    Full Text Available Leaf senescence is an important biological process that contributes to grain yield in crops. To study the molecular mechanisms underlying natural leaf senescence, we harvested three different developmental ear leaves of maize, mature leaves (ML, early senescent leaves (ESL, and later senescent leaves (LSL, and analyzed transcriptional changes using RNA-sequencing. Three sets of data, ESL vs. ML, LSL vs. ML, and LSL vs. ESL, were compared, respectively. In total, 4,552 genes were identified as differentially expressed. Functional classification placed these genes into 18 categories including protein metabolism, transporters, and signal transduction. At the early stage of leaf senescence, genes involved in aromatic amino acids (AAAs biosynthetic process and transport, cellular polysaccharide biosynthetic process, and the cell wall macromolecule catabolic process, were up-regulated. Whereas, genes involved in amino acid metabolism, transport, apoptosis, and response to stimulus were up-regulated at the late stage of leaf senescence. Further analyses reveals that the transport-related genes at the early stage of leaf senescence potentially take part in enzyme and amino acid transport and the genes upregulated at the late stage are involved in sugar transport, indicating nutrient recycling mainly takes place at the late stage of leaf senescence. Comparison between the data of natural leaf senescence in this study and previously reported data for Arabidopsis implies that the mechanisms of leaf senescence in maize are basically similar to those in Arabidopsis. A comparison of natural and induced leaf senescence in maize was performed. Athough many basic biological processes involved in senescence occur in both types of leaf senescence, 78.07% of differentially expressed genes in natural leaf senescence were not identifiable in induced leaf senescence, suggesting that differences in gene regulatory network may exist between these two leaf senescence

  15. Effect of etoposide-induced alteration of the Mdm2-Rb signaling pathway on cellular senescence in A549 lung adenocarcinoma cells.

    Science.gov (United States)

    Dai, Wenjing; Jiang, Yi; Chen, Kairong; Qiu, Jing; Sun, Jian; Zhang, Wei; Zhou, Xiafei; Huang, Na; Li, Yunhui; Li, Wancheng

    2017-10-01

    The present study aimed to investigate the effect of various concentrations of etoposide (VP-16) on the E3 ubiquitin-protein ligase Mdm2 (Mdm2)-retinoblastoma (Rb) signaling pathway in the cellular senescence of A549 lung adenocarcinoma cells. A549 cells were randomly divided into the following four groups: Control group (no treatment), group 1 (1 µmol/l VP-16), group 2 (5 µmol/l VP-16) and group 3 (25 µmol/l VP-16). Each group was cultured for 48 h after treatment prior to observation of the alterations to cellular morphology. The cell cycle distribution of each group was also detected by flow cytometry. In addition, the activity of cellular senescence-associated β-galactosidase, and the expression of Mdm2 and phosphorylated (p-) Rb protein, was measured. The percentage of senescent cells was significantly higher following VP-16 treatment compared with the control group. The percentage of G 1 phase cells, and p-Rb protein and Mdm2 protein expression were also significantly different following VP-16 treatment compared with the control group. VP-16 increased the activity of β-galactosidase in the A459 cells. VP-16 also decreased the expression level of Mdm2 and p-Rb protein and inhibited cell cycle progression in G 1 . These results indicate that VP-16 induces the cellular senescence of A549 cells via the Mdm2-Rb signaling pathway. However, further investigations are required to validate the mechanisms underlying these effects of VP-16.

  16. Metformin induces a Senescence-associated gene Signature in Breast Cancer Cells

    Science.gov (United States)

    Williams, Christopher C.; Singleton, Brittany A.; Llopis, Shawn D.; Skripnikova, Elena V.

    2013-01-01

    Diabetic patients taking metformin have lower incidence of breast cancer than those taking other anti-diabetic medications. Additionally, triple negative breast cancer (TNBC), a form of breast cancer disproportionately afflicting premenopausal African American women, shows atypical susceptibility to metformin’s antiproliferative effect. The mechanisms involved in metformin’s function in TNBC has not yet been fully elucidated. Therefore, we sought to identify pathways regulated by metformin in using the MDA-MB-468 TNBC cell model. Metformin dose-dependently caused apoptosis, decreased cell viability, and induced cell morphology/chromatin condensation consistent with the permanent proliferative arrest. Furthermore, gene expression arrays revealed that metformin caused expression of stress markers DDIT3, CYP1A1, and GDF-15 and a concomitant reduction in PTGS1 expression. Our findings show that metformin may affect the viability and proliferative capacity of TNBC by inducing an antiproliferative gene signature, and that metformin may be effective in the treatment/prevention of TNBC. PMID:23395946

  17. Ionizing radiation induces senescence and differentiation of human dental pulp stem cells.

    Science.gov (United States)

    Havelek, R; Soukup, T; Ćmielová, J; Seifrtová, M; Suchánek, J; Vávrová, J; Mokrý, J; Muthná, D; Řezáčová, M

    2013-01-01

    Head and neck cancer is one of the most common cancers in Europe. Many current anti-cancer treatments, including ionizing radiation, induce apoptosis via DNA damage. Unfortunately, such treatments are non-selective to cancer cells and produce similar toxicity in normal cells, including adult stem cells. One of the fundamental properties of an adult stem cell is that it does not have any tissue-specific structures that allow it to perform specialized functions. However, under certain stimuli, unspecialized adult stem cells can give rise to specialized cells to generate replacements for cells that are lost during one's life or due to injury or disease. Nevertheless, specialization of stem cells must be controlled by specific milieu and also initiated at the proper time, making the entire process beneficial for tissue recovery and maintaining it for a long time. In this paper we assess whether irradiated dental pulp stem cells have maintained open their options to mature into specialized cells, or whether they have lost their unspecialized (immature) state following irradiation. Our findings showed radiation-induced premature differentiation of dental pulp stem cells towards odonto-/osteoblast lineages in vitro. Matrix calcification was visualized from Day 6 or Day 9 following irradiation of cells expressing low or high levels of CD146, respectively.

  18. Induction of 33-kD and 60-kD peroxidases during ethylene-induced senescence of cucumber cotyledons

    International Nuclear Information System (INIS)

    Abeles, F.B.; Dunn, L.J.; Morgens, P.; Callahan, A.; Dinterman, R.E.; Schmidt, J.

    1988-01-01

    Ethylene enhanced the senescence of cucumber (Cucumis sativus L. cv Poinsett 76) cotyledons. The effect of 10 microliters per liter ethylene was inhibited by 1 millimolar silver thiosulfate, an inhibitor of ethylene action. An increase in proteins with molecular weights of 33 to 30 kilodaltons and lower molecular weights (25, 23, 20, 16, 12 and 10 kilodaltons) were observed in sodium dodecyl sulfate-polyacrylamide gel electrophoresis gels after ethylene enhanced senescence. The measurement of DNase and RNase activity in gels indicated that these new proteins were not nucleases. Two proteins from ethylene-treated cotyledons were purified on the basis of their association with a red chromaphore and subsequently were identified as peroxidases. The molecular weights and isoelectric points (pI) of two of these peroxidases were 33 kilodaltons (cationic, pI = 8.9) and 60 kilodaltons (anionic, pI = 4.0). The observation that [ 35 S]Na 2 SO 4 was incorporated into these proteins during ethylene-enhanced senescence suggests that these peroxidases represent newly synthesized proteins. Antibodies to the 33-kilodalton peroxidase precipitated two in vitro translation products from RNA isolated from ethylene-treated but not from control cucumber seedlings. This indicates that the increase in 33-kilodalton peroxidase activity represents de novo protein synthesis. Both forms of peroxidase degraded chlorophyll in vitro, which is consistent with the hypothesis that peroxidases have catabolic or scavenging functions in senescent tissues

  19. Tumor growth accelerated by chemotherapy-induced senescent cells is suppressed by treatment with IL-12 producing cellular vaccines

    Czech Academy of Sciences Publication Activity Database

    Šímová, Jana; Sapega, Olena; Imrichová, Terezie; Štěpánek, Ivan; Kyjacová, Lenka; Mikyšková, Romana; Indrová, Marie; Bieblová, Jana; Bubeník, Jan; Bartek, Jiří; Hodný, Zdeněk; Reiniš, Milan

    2016-01-01

    Roč. 7, č. 34 (2016), s. 54952-54964 ISSN 1949-2553 R&D Projects: GA MZd NT14461 Institutional support: RVO:68378050 Keywords : cellular senescence * cancer chemotherapy * docetaxel * IL-12 * cell therapy Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 5.168, year: 2016

  20. Possible Roles of Strigolactones during Leaf Senescence

    Directory of Open Access Journals (Sweden)

    Yusuke Yamada

    2015-09-01

    Full Text Available Leaf senescence is a complicated developmental process that involves degenerative changes and nutrient recycling. The progress of leaf senescence is controlled by various environmental cues and plant hormones, including ethylene, jasmonic acid, salicylic acid, abscisic acid, cytokinins, and strigolactones. The production of strigolactones is induced in response to nitrogen and phosphorous deficiency. Strigolactones also accelerate leaf senescence and regulate shoot branching and root architecture. Leaf senescence is actively promoted in a nutrient-poor soil environment, and nutrients are transported from old leaves to young tissues and seeds. Strigolactones might act as important signals in response to nutrient levels in the rhizosphere. In this review, we discuss the possible roles of strigolactones during leaf senescence.

  1. Metabolite responses to exogenous application of nitrogen, cytokinin, and ethylene inhibitors in relation to heat-induced senescence in creeping bentgrass.

    Directory of Open Access Journals (Sweden)

    David Jespersen

    Full Text Available The exogenous application of ethylene inhibitors, cytokinins, or nitrogen has previously been shown to suppress heat-induced senescence and improve heat tolerance in cool-season grasses. The objectives of this study were to examine metabolic profiles altered by exogenous treatment of creeping bentgrass with an ethylene inhibitor, cytokinin or nitrogen under heat stress and to determine metabolic pathways regulated by those compounds in association with their effectiveness for improving heat tolerance. Creeping bentgrass (Agostis stolonifera plants (cv. Penncross were foliar sprayed with 18 mM carbonyldiamide (N source, 25 μM aminoethoxyvinylglycine (AVG, ethylene inhibitor, 25 μM zeatin riboside (ZR, cytokinin, or a water control, and then exposed to 20/15°C (day/night or 35/30°C (heat stress in growth chambers. All three exogenous treatments suppressed leaf senescence, as manifested by increased turf quality and chlorophyll content, and reduced electrolyte leakage under heat stress. Polar metabolite profiling identified increases in the content of certain organic acids (i.e. citric and malic acid, sugar alcohols, disaccharides (sucrose, and decreased accumulations of monosaccharides (i.e. glucose and fructose with exogenous treatment of N, AVG, or ZR at the previously mentioned concentrations when compared to the untreated control under heat stress. Nitrogen stimulated amino acid accumulation whereas AVG and ZR reduced amino acid accumulation compared to the untreated control under heat stress. These results revealed that the alleviation of heat-induced leaf senescence by N, AVG, and ZR could be due to changes in the accumulation of metabolites involved in osmoregulation, antioxidant metabolism, carbon and nitrogen metabolism, as well as stress signaling molecules.

  2. Mitochondrial DNA deletion and impairment of mitochondrial biogenesis are mediated by reactive oxygen species in ionizing radiation-induced premature senescence

    International Nuclear Information System (INIS)

    Eom, Hyeon Soo; Jung, U Hee; Jo, Sung Kee; Kim, Young Sang

    2011-01-01

    Mitochondrial DNA (mtDNA) deletion is a well-known marker for oxidative stress and aging, and contributes to harmful effects in cultured cells and animal tissues. mtDNA biogenesis genes (NRF-1, TFAM) are essential for the maintenance of mtDNA, as well as the transcription and replication of mitochondrial genomes. Considering that oxidative stress is known to affect mitochondrial biogenesis, we hypothesized that ionizing radiation (IR)-induced reactive oxygen species (ROS) causes mtDNA deletion by modulating the mitochondrial biogenesis, thereby leading to cellular senescence. Therefore, we examined the effects of IR on ROS levels, cellular senescence, mitochondrial biogenesis, and mtDNA deletion in IMR-90 human lung fibroblast cells. Young IMR-90 cells at population doubling (PD) 39 were irradiated at 4 or 8 Gy. Old cells at PD55, and H2O2-treated young cells at PD 39, were compared as a positive control. The IR increased the intracellular ROS level, senescence-associated β-galactosidase (SA-β-gal) activity, and mtDNA common deletion (4977 bp), and it decreased the mRNA expression of NRF-1 and TFAM in IMR-90 cells. Similar results were also observed in old cells (PD 55) and H 2 O 2 -treated young cells. To confirm that a increase in ROS level is essential for mtDNA deletion and changes of mitochondrial biogenesis in irradiated cells, the effects of N-acetylcysteine (NAC) were examined. In irradiated and H 2 O 2 -treated cells, 5 mM NAC significantly attenuated the increases of ROS, mtDNA deletion, and SA-β-gal activity, and recovered from decreased expressions of NRF-1 and TFAM mRNA. These results suggest that ROS is a key cause of IR-induced mtDNA deletion, and the suppression of the mitochondrial biogenesis gene may mediate this process.

  3. Mitochondrial DNA deletion and impairment of mitochondrial biogenesis are mediated by reactive oxygen species in ionizing radiation-induced premature senescence

    Energy Technology Data Exchange (ETDEWEB)

    Eom, Hyeon Soo; Jung, U Hee; Jo, Sung Kee [Radiation Biotechnology Research Division, Korea Atomic Energy Research Institute, Daejeon (Korea, Republic of); Kim, Young Sang [College of Natural Sciences, Chungnam National University, Daejeon (Korea, Republic of)

    2011-09-15

    Mitochondrial DNA (mtDNA) deletion is a well-known marker for oxidative stress and aging, and contributes to harmful effects in cultured cells and animal tissues. mtDNA biogenesis genes (NRF-1, TFAM) are essential for the maintenance of mtDNA, as well as the transcription and replication of mitochondrial genomes. Considering that oxidative stress is known to affect mitochondrial biogenesis, we hypothesized that ionizing radiation (IR)-induced reactive oxygen species (ROS) causes mtDNA deletion by modulating the mitochondrial biogenesis, thereby leading to cellular senescence. Therefore, we examined the effects of IR on ROS levels, cellular senescence, mitochondrial biogenesis, and mtDNA deletion in IMR-90 human lung fibroblast cells. Young IMR-90 cells at population doubling (PD) 39 were irradiated at 4 or 8 Gy. Old cells at PD55, and H2O2-treated young cells at PD 39, were compared as a positive control. The IR increased the intracellular ROS level, senescence-associated {beta}-galactosidase (SA-{beta}-gal) activity, and mtDNA common deletion (4977 bp), and it decreased the mRNA expression of NRF-1 and TFAM in IMR-90 cells. Similar results were also observed in old cells (PD 55) and H{sub 2}O{sub 2}-treated young cells. To confirm that a increase in ROS level is essential for mtDNA deletion and changes of mitochondrial biogenesis in irradiated cells, the effects of N-acetylcysteine (NAC) were examined. In irradiated and H{sub 2}O{sub 2}-treated cells, 5 mM NAC significantly attenuated the increases of ROS, mtDNA deletion, and SA-{beta}-gal activity, and recovered from decreased expressions of NRF-1 and TFAM mRNA. These results suggest that ROS is a key cause of IR-induced mtDNA deletion, and the suppression of the mitochondrial biogenesis gene may mediate this process.

  4. THE EFFECT OF SUPPORT PLATE ON DRILLING-INDUCED DELAMINATION

    Directory of Open Access Journals (Sweden)

    Navid Zarif Karimi

    2016-02-01

    Full Text Available Delamination is considered as a major problem in drilling of composite materials, which degrades the mechanical properties of these materials. The thrust force exerted by the drill is considered as the major cause of delamination; and one practical approach to reduce delamination is to use a back-up plate under the specimen. In this paper, the effect of exit support plate on delamination in twist drilling of glass fiber reinforced composites is studied. Firstly, two analytical models based on linear fracture mechanics and elastic bending theory of plates are described to find critical thrust forces at the beginning of crack growth for drilling with and without back-up plate. Secondly, two series of experiments are carried out on glass fiber reinforced composites to determine quantitatively the effect of drilling parameters on the amount of delamination. Experimental findings verify a large reduction in the amount of delaminated area when a back-up plate is placed under the specimen.

  5. Senescence-associated barley NAC (NAM, ATAF1,2, CUC) transcription factor interacts with radical-induced cell death 1 through a disordered regulatory domain

    DEFF Research Database (Denmark)

    Kjaersgaard, Trine; Jensen, Michael K; Christiansen, Michael W

    2011-01-01

    as a transcriptional activator suggesting that an involvement of HvNAC013 and HvNAC005 in senescence will be different. HvNAC013 interacted with barley radical-induced cell death 1 (RCD1) via the very C-terminal part of its TRD, outside of the region containing the LP motif. No significant secondary structure...... (NAM, ATAF1,2, CUC) TF family are up-regulated during senescence in barley (Hordeum vulgare). Both HvNAC005 and HvNAC013 bound the conserved NAC DNA target sequence. Computational and biophysical analyses showed that both proteins are intrinsically disordered in their large C-terminal domains, which...... was induced in the HvNAC013 TRD upon interaction with RCD1. RCD1 also interacted with regions dominated by intrinsic disorder in TFs of the MYB and basic helix-loop-helix families. We propose that RCD1 is a regulatory protein capable of interacting with many different TFs by exploiting their intrinsic...

  6. Oridonin induces apoptosis and senescence in colorectal cancer cells by increasing histone hyperacetylation and regulation of p16, p21, p27 and c-myc

    International Nuclear Information System (INIS)

    Gao, Feng-Hou; Liu, Feng; Zhao, Ying-Zheng; Fang, Yong; Chen, Fang-Yuan; Wu, Ying-Li; Hu, Xiao-Hui; Li, Wei; Liu, Hua; Zhang, Yan-Jie; Guo, Zhu-Ying; Xu, Mang-Hua; Wang, Shi-Ting; Jiang, Bin

    2010-01-01

    Oridonin, a tetracycline diterpenoid compound, has the potential antitumor activities. Here, we evaluate the antitumor activity and action mechanisms of oridonin in colorectal cancer. Effects of oridonin on cell proliferation were determined by using a CCK-8 Kit. Cell cycle distribution was determined by flow cytometry. Apoptosis was examined by analyzing subdiploid population and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay. Senescent cells were determined by senescence-associated β-galactosidase activity analysis. Semi-quantitative RT-PCR was used to examine the changes of mRNA of p16, p21, p27 and c-myc. The concomitant changes of protein expression were analyzed with Western blot. Expression of AcH3 and AcH4 were examined by immunofluorescence staining and Western blots. Effects of oridonin on colony formation of SW1116 were examined by Soft Agar assay. The in vivo efficacy of oridonin was detected using a xenograft colorectal cancer model in nude mice. Oridonin induced potent growth inhibition, cell cycle arrest, apoptosis, senescence and colony-forming inhibition in three colorectal cancer cell lines in a dose-dependent manner in vitro. Daily i.p. injection of oridonin (6.25, 12.5 or 25 mg/kg) for 28 days significantly inhibited the growth of SW1116 s.c. xenografts in BABL/C nude mice. With western blot and reverse transcription-PCR, we further showed that the antitumor activities of oridonin correlated with induction of histone (H3 and H4) hyperacetylation, activation of p21, p27 and p16, and suppression of c-myc expression. Oridonin possesses potent in vitro and in vivo anti-colorectal cancer activities that correlated with induction of histone hyperacetylation and regulation of pathways critical for maintaining growth inhibition and cell cycle arrest. Therefore, oridonin may represent a novel therapeutic option in colorectal cancer treatment

  7. Oridonin induces apoptosis and senescence in colorectal cancer cells by increasing histone hyperacetylation and regulation of p16, p21, p27 and c-myc

    Directory of Open Access Journals (Sweden)

    Zhao Ying-Zheng

    2010-11-01

    Full Text Available Abstract Background Oridonin, a tetracycline diterpenoid compound, has the potential antitumor activities. Here, we evaluate the antitumor activity and action mechanisms of oridonin in colorectal cancer. Methods Effects of oridonin on cell proliferation were determined by using a CCK-8 Kit. Cell cycle distribution was determined by flow cytometry. Apoptosis was examined by analyzing subdiploid population and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay. Senescent cells were determined by senescence-associated β-galactosidase activity analysis. Semi-quantitative RT-PCR was used to examine the changes of mRNA of p16, p21, p27 and c-myc. The concomitant changes of protein expression were analyzed with Western blot. Expression of AcH3 and AcH4 were examined by immunofluorescence staining and Western blots. Effects of oridonin on colony formation of SW1116 were examined by Soft Agar assay. The in vivo efficacy of oridonin was detected using a xenograft colorectal cancer model in nude mice. Results Oridonin induced potent growth inhibition, cell cycle arrest, apoptosis, senescence and colony-forming inhibition in three colorectal cancer cell lines in a dose-dependent manner in vitro. Daily i.p. injection of oridonin (6.25, 12.5 or 25 mg/kg for 28 days significantly inhibited the growth of SW1116 s.c. xenografts in BABL/C nude mice. With western blot and reverse transcription-PCR, we further showed that the antitumor activities of oridonin correlated with induction of histone (H3 and H4 hyperacetylation, activation of p21, p27 and p16, and suppression of c-myc expression. Conclusion Oridonin possesses potent in vitro and in vivo anti-colorectal cancer activities that correlated with induction of histone hyperacetylation and regulation of pathways critical for maintaining growth inhibition and cell cycle arrest. Therefore, oridonin may represent a novel therapeutic option in colorectal cancer treatment.

  8. Autocrine IL-6 mediates pituitary tumor senescence

    Science.gov (United States)

    Fuertes, Mariana; Ajler, Pablo; Carrizo, Guillermo; Cervio, Andrés; Sevlever, Gustavo; Stalla, Günter K.; Arzt, Eduardo

    2017-01-01

    Cellular senescence is a stable proliferative arrest state. Pituitary adenomas are frequent and mostly benign, but the mechanism for this remains unknown. IL-6 is involved in pituitary tumor progression and is produced by the tumoral cells. In a cell autonomous fashion, IL-6 participates in oncogene-induced senescence in transduced human melanocytes. Here we prove that autocrine IL-6 participates in pituitary tumor senescence. Endogenous IL-6 inhibition in somatotroph MtT/S shRNA stable clones results in decreased SA-β-gal activity and p16INK4a but increased pRb, proliferation and invasion. Nude mice injected with IL-6 silenced clones develop tumors contrary to MtT/S wild type that do not, demonstrating that clones that escape senescence are capable of becoming tumorigenic. When endogenous IL-6 is silenced, cell cultures derived from positive SA-β-gal human tumor samples decrease the expression of the senescence marker. Our results establish that IL-6 contributes to maintain senescence by its autocrine action, providing a natural model of IL-6 mediated benign adenoma senescence. PMID:27902467

  9. Cell-penetrating superoxide dismutase attenuates oxidative stress-induced senescence by regulating the p53-p21Cip1 pathway and restores osteoblastic differentiation in human dental pulp stem cells

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    Park YJ

    2012-09-01

    Full Text Available Yoon Jung Choi,1,* Jue Yeon Lee,2,* Chong Pyoung Chung,2 Yoon Jeong Park,1,21Craniomaxillofacial Reconstructive Sciences, Dental Research Institute, School of Dentistry, Seoul National University, Seoul, Republic of Korea; 2Research Institute, Nano Intelligent Biomedical Engineering, Seoul, Republic of Korea*These authors contributed equally to this workBackground: Human dental pulp stem cells (DPSCs have potential applications in tissue regeneration because of their convenient cell harvesting procedures and multipotent capacity. However, the tissue regenerative potential of DPSCs is known to be negatively regulated by aging in long-term culture and under oxidative stress. With an aim of reducing cellular senescence and oxidative stress in DPSCs, an intracellular delivery system for superoxide dismutase 1 (SOD1 was developed. We conjugated SOD1 with a cell-penetrating peptide known as low-molecular weight protamine (LMWP, and investigated the effect of LMWP-SOD1 conjugates on hydrogen peroxide-induced cellular senescence and osteoblastic differentiation.Results: LMWP-SOD1 significantly attenuated enlarged and flattened cell morphology and increased senescence-associated β-galactosidase activity. Under the same conditions, LMWP-SOD1 abolished activation of the cell cycle regulator proteins, p53 and p21Cip1, induced by hydrogen peroxide. In addition, LMWP-SOD1 reversed the inhibition of osteoblastic differentiation and downregulation of osteogenic gene markers induced by hydrogen peroxide. However, LMWP-SOD1 could not reverse the decrease in odontogenesis caused by hydrogen peroxide.Conclusion: Overall, cell-penetrating LMWP-SOD1 conjugates are effective for attenuation of cellular senescence and reversal of osteoblastic differentiation of DPSCs caused by oxidative stress inhibition. This result suggests potential application in the field of antiaging and tissue engineering to overcome the limitations of senescent stem cells.Keywords: superoxide

  10. Dike-induced contraction along oceanic and continental divergent plate boundaries

    KAUST Repository

    Trippanera, D.

    2014-10-28

    The axis of divergent plate boundaries shows extension fractures and normal faults at the surface. Here we present evidence of contraction along the axis of the oceanic ridge of Iceland and the continental Main Ethiopian Rift. Contraction is found at the base of the tilted hanging wall of dilational normal faults, balancing part of their extension. Our experiments suggest that these structures result from dike emplacement. Multiple dike injection induces subsidence above and uplift to the sides of the dikes; the transition in between is accommodated by reverse faults and subsequent peripheral inward dipping normal faults. Our results suggest that contraction is a direct product of magma emplacement along divergent plate boundaries, at various scales, marking a precise evolutionary stage and initiating part of the extensional structures (extension fractures and normal faults). Key Points Contraction along divergent plate boundaries results from dike emplacementContraction generates extensional structures along divergent plate boundariesSurface deformation along divergent plate boundaries may be magma induced

  11. Dike-induced contraction along oceanic and continental divergent plate boundaries

    KAUST Repository

    Trippanera, D.; Acocella, V.; Ruch, Joel

    2014-01-01

    The axis of divergent plate boundaries shows extension fractures and normal faults at the surface. Here we present evidence of contraction along the axis of the oceanic ridge of Iceland and the continental Main Ethiopian Rift. Contraction is found at the base of the tilted hanging wall of dilational normal faults, balancing part of their extension. Our experiments suggest that these structures result from dike emplacement. Multiple dike injection induces subsidence above and uplift to the sides of the dikes; the transition in between is accommodated by reverse faults and subsequent peripheral inward dipping normal faults. Our results suggest that contraction is a direct product of magma emplacement along divergent plate boundaries, at various scales, marking a precise evolutionary stage and initiating part of the extensional structures (extension fractures and normal faults). Key Points Contraction along divergent plate boundaries results from dike emplacementContraction generates extensional structures along divergent plate boundariesSurface deformation along divergent plate boundaries may be magma induced

  12. Electroless Plating on Plastic Induced by Selective Laser Activation

    DEFF Research Database (Denmark)

    Zhang, Yang; Tang, Peter Torben; Hansen, Hans Nørgaard

    2009-01-01

    This paper presents a new method for selective micro metallization of polymers. A Nd:YAG laser is employed to draw patterns on polymer surfaces that are submerged in a liquid (usually water). After subsequent activation with palladium chloride and followed by auto-catalytic electroless plating, c...

  13. The Mechanism of Memory Enhancement of Acteoside (Verbascoside) in the Senescent Mouse Model Induced by a Combination of D-gal and AlCl3.

    Science.gov (United States)

    Peng, Xiao-Ming; Gao, Li; Huo, Shi-Xia; Liu, Xin-Min; Yan, Ming

    2015-08-01

    Acteoside (verbsacoside), one of the main active phenylethanoid glycosides from Cistanche deserticola, is known to have antioxidant and neuroprotective activity, and herbs containing it are used to enhance memory. However, there is relatively little direct experimental evidence to support the use of acteoside in Alzheimer's disease (AD). The purpose of this study was to elucidate the effects of acteoside in improving learning and memory, using a mouse model of senescence induced by a combination of d-galactose and AlCl3 , and investigate its potential mechanisms compared with the positive controls vitamin E and piracetam. Acteoside was administered intragastrically at doses of 30, 60 and 120 mg/kg/day for 30 days after AD was induced. Memory function was evaluated using a step-down test. The number of neuron was analysed by haematoxylin and eosin staining and the number of Nissl bodies by Nissl staining. The expression of caspase-3 protein in hippocampus was detected by immunohistochemistry and western blot. Nitric oxide and total nitric oxide synthase level in hippocampus were also assessed. Our results showed that the latency of step down was shortened in AD model mice and the number of errors decreased after treatment with all doses of acteoside. Neurons and Nissl bodies in the hippocampus were increased significantly with higher doses (60 and 120 mg/kg/day) of acteoside. The content of nitric oxide, the activity of nitric oxide synthase and the expression of caspase-3 protein were decreased by 120 mg/kg/day acteoside compared with that of the AD model group. Our results support the results obtained previously using the Morris maze test in the same mouse model of senescence, and the use of traditional medicinal herbs containing acteoside for neuroprotection and memory loss. Copyright © 2015 John Wiley & Sons, Ltd.

  14. Ozone exposure induces the activation of leaf senescence-related processes and morphological and growth changes in seedlings of Mediterranean tree species

    International Nuclear Information System (INIS)

    Ribas, Angela; Pen-tilde uelas, Josep; Elvira, Susana; Gimeno, Benjamin S.

    2005-01-01

    Four Mediterranean tree taxa, Quercus ilex subsp. ilex, Quercus ilex subsp. ballota, Olea europaea cv. vulgaris and Ceratonia siliqua, were exposed to different ozone (O 3 ) concentrations in open top chambers (OTCs) during 2 years. Three treatments were applied: charcoal-filtered air (CF), non-filtered air (NF) and non-filtered air plus 40 ppb v of O 3 (NF+). The photochemical maximal efficiency, Fv/Fm, decreased in NF+ plants during the second year of exposure, especially during the most stressful Mediterranean seasons (winter and summer). An increase of δ 13 C was found in three of the four studied species during the first year of exposure. This finding was only maintained in C. siliqua during the second year. Decreases in the chlorophyll content were detected during the first year of fumigations in all the species studied, but not during the second year. The NF+ treatment induced changes in foliar anatomical characteristics, especially in leaf mass per area (LMA) and spongy parenchyma thickness, which increased in some species. A reduction in N content and an increase in δ 15 N were found in all species during the second year when exposed in the NF+ OTCs, suggesting a change in their retranslocation pattern linked to an acceleration of leaf senescence, as also indicated by the above mentioned biochemical and anatomical foliar changes. The two Q. ilex subspecies were the most sensitive species since the changes in N concentration, δ 15 N, chlorophyll, leaf area, LMA and biomass occurred at ambient O 3 concentrations. However, C. siliqua was the most responsive species (29% biomass reduction) when exposed to the NF+ treatment, followed by the two Q. ilex subspecies (14-20%) and O. europaea (no significant reduction). Ozone resistance of the latter species was linked to some plant traits such as chlorophyll concentrations, or spongy parenchyma thickness. - Ozone induces species-specific leaf senescence-related processes and morphological and growth changes in

  15. PML, SUMOylation and senescence

    Directory of Open Access Journals (Sweden)

    Hugues eDe Thé

    2013-07-01

    Full Text Available Since its discovery, 25 years ago, PML has been an enigma. Implicated in the oncogenic PML/RARA fusion, forming elusive intranuclear domains, triggering cell death or senescence, controlled by and perhaps controlling SUMOylation... there are multiple PML-related issues. Here we review the reciprocal interactions between PML, senescence and SUMOylation, notably in the context of cellular transformation.

  16. Tracking senescence-induced patterns in leaf litter leachate using parallel factor analysis (PARAFAC) modeling and self-organizing maps

    Science.gov (United States)

    Wheeler, K. I.; Levia, D. F.; Hudson, J. E.

    2017-09-01

    In autumn, the dissolved organic matter (DOM) contribution of leaf litter leachate to streams in forested watersheds changes as trees undergo resorption, senescence, and leaf abscission. Despite its biogeochemical importance, little work has investigated how leaf litter leachate DOM changes throughout autumn and how any changes might differ interspecifically and intraspecifically. Since climate change is expected to cause vegetation migration, it is necessary to learn how changes in forest composition could affect DOM inputs via leaf litter leachate. We examined changes in leaf litter leachate fluorescent DOM (FDOM) from American beech (Fagus grandifolia Ehrh.) leaves in Maryland, Rhode Island, Vermont, and North Carolina and from yellow poplar (Liriodendron tulipifera L.) leaves from Maryland. FDOM in leachate samples was characterized by excitation-emission matrices (EEMs). A six-component parallel factor analysis (PARAFAC) model was created to identify components that accounted for the majority of the variation in the data set. Self-organizing maps (SOM) compared the PARAFAC component proportions of leachate samples. Phenophase and species exerted much stronger influence on the determination of a sample's SOM placement than geographic origin. As expected, FDOM from all trees transitioned from more protein-like components to more humic-like components with senescence. Percent greenness of sampled leaves and the proportion of tyrosine-like component 1 were found to be significantly different between the two genetic beech clusters, suggesting differences in photosynthesis and resorption. Our results highlight the need to account for interspecific and intraspecific variations in leaf litter leachate FDOM throughout autumn when examining the influence of allochthonous inputs to streams.

  17. Evolution of plant senescence

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    Young Mike

    2009-07-01

    Full Text Available Abstract Background Senescence is integral to the flowering plant life-cycle. Senescence-like processes occur also in non-angiosperm land plants, algae and photosynthetic prokaryotes. Increasing numbers of genes have been assigned functions in the regulation and execution of angiosperm senescence. At the same time there has been a large expansion in the number and taxonomic spread of plant sequences in the genome databases. The present paper uses these resources to make a study of the evolutionary origins of angiosperm senescence based on a survey of the distribution, across plant and microbial taxa, and expression of senescence-related genes. Results Phylogeny analyses were carried out on protein sequences corresponding to genes with demonstrated functions in angiosperm senescence. They include proteins involved in chlorophyll catabolism and its control, homeoprotein transcription factors, metabolite transporters, enzymes and regulators of carotenoid metabolism and of anthocyanin biosynthesis. Evolutionary timelines for the origins and functions of particular genes were inferred from the taxonomic distribution of sequences homologous to those of angiosperm senescence-related proteins. Turnover of the light energy transduction apparatus is the most ancient element in the senescence syndrome. By contrast, the association of phenylpropanoid metabolism with senescence, and integration of senescence with development and adaptation mediated by transcription factors, are relatively recent innovations of land plants. An extended range of senescence-related genes of Arabidopsis was profiled for coexpression patterns and developmental relationships and revealed a clear carotenoid metabolism grouping, coordinated expression of genes for anthocyanin and flavonoid enzymes and regulators and a cluster pattern of genes for chlorophyll catabolism consistent with functional and evolutionary features of the pathway. Conclusion The expression and phylogenetic

  18. The oxidative hypothesis of senescence

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    Gilca M

    2007-01-01

    Full Text Available The oxidative hypothesis of senescence, since its origin in 1956, has garnered significant evidence and growing support among scientists for the notion that free radicals play an important role in ageing, either as "damaging" molecules or as signaling molecules. Age-increasing oxidative injuries induced by free radicals, higher susceptibility to oxidative stress in short-lived organisms, genetic manipulations that alter both oxidative resistance and longevity and the anti-ageing effect of caloric restriction and intermittent fasting are a few examples of accepted scientific facts that support the oxidative theory of senescence. Though not completely understood due to the complex "network" of redox regulatory systems, the implication of oxidative stress in the ageing process is now well documented. Moreover, it is compatible with other current ageing theories (e.g., those implicating the mitochondrial damage/mitochondrial-lysosomal axis, stress-induced premature senescence, biological "garbage" accumulation, etc. This review is intended to summarize and critically discuss the redox mechanisms involved during the ageing process: sources of oxidant agents in ageing (mitochondrial -electron transport chain, nitric oxide synthase reaction- and non-mitochondrial- Fenton reaction, microsomal cytochrome P450 enzymes, peroxisomal β -oxidation and respiratory burst of phagocytic cells, antioxidant changes in ageing (enzymatic- superoxide dismutase, glutathione-reductase, glutathion peroxidase, catalase- and non-enzymatic glutathione, ascorbate, urate, bilirubine, melatonin, tocopherols, carotenoids, ubiquinol, alteration of oxidative damage repairing mechanisms and the role of free radicals as signaling molecules in ageing.

  19. Unsteady free convection MHD flow between two heated vertical parallel plates in induced magnetic field

    International Nuclear Information System (INIS)

    Chakraborty, S.; Borkakati, A.K.

    1999-01-01

    An unsteady viscous incompressible free convection flow of an electrically conducting fluid between two heated vertical parallel plates is considered in presence of a uniform magnetic field applied transversely to the flow. The approximate analytical solutions for velocity, induced field and temperature distributions are obtained for small and large magnetic Reynolds number. The skin-friction on the two plates are obtained and plotted graphically. The problem is extended for thermometric case. (author)

  20. Cellular Senescence in Postmitotic Cells: Beyond Growth Arrest.

    Science.gov (United States)

    Sapieha, Przemyslaw; Mallette, Frédérick A

    2018-04-25

    In mitotic cells, cellular senescence is a permanent state of G1 arrest, that may have evolved in parallel to apoptosis, to limit proliferation of damaged cells and oncogenesis. Recent studies have suggested that postmitotic cells are also capable of entering a state of senescence, although the repercussions of postmitotic cellular senescence (PoMiCS) on tissue health and function are currently ill-defined. In tissues made largely of post-mitotic cells, it is evolutionary advantageous to preserve cellular integrity and cellular senescence of post-mitotic cells may prevent stressor-induced tissue degeneration and promote tissue repair. Paradoxically, PoMiCS may also contribute to disease progression through the generation of inflammatory mediators, termed the senescence-associated secretory phenotype. Here, we discuss the potential roles of PoMiCS and propose to enlarge the current definition of cellular senescence to postmitotic terminally differentiated cells. Copyright © 2018 Elsevier Ltd. All rights reserved.

  1. N-Methyl-N'-nitro-N-nitrosoguanidine-induced senescence-like growth arrest in colon cancer cells is associated with loss of adenomatous polyposis coli protein, microtubule organization, and telomeric DNA

    Directory of Open Access Journals (Sweden)

    Narayan Satya

    2004-01-01

    Full Text Available Abstract Background Cellular senescence is a state in which mammalian cells enter into an irreversible growth arrest and altered biological functions. The senescence response in mammalian cells can be elicited by DNA-damaging agents. In the present study we report that the DNA-damaging agent N-methyl-N'-nitro-N-nitrosoguanidine (MNNG is able to induce senescence in the HCT-116 colon cancer cell line. Results Cells treated with lower concentrations of MNNG (0–25 microM for 50 h showed a dose-dependent increase in G2/M phase arrest and apoptosis; however, cells treated with higher concentrations of MNNG (50–100 microM showed a senescence-like G0/G1 phase arrest which was confirmed by increased expression of β-galactosidase, a senescence induced marker. The G2/M phase arrest and apoptosis were found to be associated with increased levels of p53 protein, but the senescence-like G0/G1 phase arrest was dissociated with p53 protein levels, since the p53 protein levels decreased in senescence-like arrested cells. We further, determined whether the decreased level of p53 was a transcriptional or a translational phenomenon. The results revealed that the decreased level of p53 protein in senescence-like arrested cells was a transcriptional phenomenon since p53 mRNA levels simultaneously decreased after treatment with higher concentrations of MNNG. We also examined the effect of MNNG treatment on other cell cycle-related proteins such as p21, p27, cyclin B1, Cdc2, c-Myc and max. The expression levels of these proteins were increased in cells treated with lower concentrations of MNNG, which supported the G2/M phase arrest. However, cells treated with higher concentrations of MNNG showed decreased levels of these proteins, and hence, may not play a role in cell cycle arrest. We then examined a possible association of the expression of APC protein and telomeric DNA signals with cellular senescence in MNNG-treated cells. We found that protein and m

  2. Unlocking the chromatin of adenoid cystic carcinomas using HDAC inhibitors sensitize cancer stem cells to cisplatin and induces tumor senescence

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    Luciana O. Almeida

    2017-05-01

    Full Text Available Adenoid cystic carcinoma (ACC is an uncommon malignancy of the salivary glands that is characterized by local recurrence and distant metastasis due to its resistance to conventional therapy. Platinum-based therapies have been extensively explored as a treatment for ACC, but they show little effectiveness. Studies have shown that a specific group of tumor cells, harboring characteristics of cancer stem cells (CSCs, are involved in chemoresistance of myeloid leukemias, breast, colorectal and pancreatic carcinomas. Therapeutic strategies that target CSCs improve the survival of patients by decreasing the rates of tumor relapse, and epigenetic drugs, such as histone deacetylase inhibitors (HDACi, have shown promising results in targeting CSCs. In this study, we investigated the effect of the HDACi Suberoylanilide hydroxamic acid (Vorinostat, and cisplatin, alone or in combination, on CSCs and non-CSCs from ACC. We used CSCs as a biological marker for tumor resistance to therapy in patient-derived xenograft (PDX samples and ACC primary cells. We found that cisplatin reduced tumor viability, but enriched the population of CSCs. Systemic administration of Vorinostat reduced the number of detectable CSCs in vivo and in vitro, and a low dose of Vorinostat decreased tumor cell viability. However, the combination of Vorinostat and cisplatin was extremely effective in depleting CSCs and reducing tumor viability in all ACC primary cells by activating cellular senescence. These observations suggest that HDACi and intercalating agents act more efficiently in combination to destroy tumor cells and their stem cells.

  3. Transcriptome Changes Associated with Delayed Flower Senescence on Transgenic Petunia by Inducing Expression of etr1-1, a Mutant Ethylene Receptor

    Science.gov (United States)

    Lin, Jing; Liu, Gang; Zhang, Zhen; Chang, Youhong; Reid, Michael S.; Jiang, Cai-Zhong

    2013-01-01

    Flowers of ethylene-sensitive ornamental plants transformed with ethylene-insensitive 1-1(etr1-1), a mutant ethylene receptor first isolated from Arabidopsis, are known to have longer shelf lives. We have generated petunia plants in which the etr1-1 gene was over-expressed under the control of a chemically-inducible promoter, which would allow expression of etr1-1 to be initiated at the desired time and stage of development. Here, we showed that transgenic plants grew and developed normally without a chemical inducer. Semi-quantitative RT-PCR demonstrated that the abundance of transcripts of Arabidopsis etr1-1 gene was substantially induced in flowers with 30 μM dexamethasone (DEX). Consequently, t he life of the flowers was almost doubled and the peak of ethylene production was delayed. We compared gene expression changes of petals with DEX to those without DEX at 24 h and 48 h by microarray. Our results indicated that transcripts of many putative genes encoding transcription factors were down-regulated by etr1-1 induced expression at the early stage. In addition, putative genes involved in gibberellin biosynthesis, response to jasmonic acid/gibberellins stimulus, cell wall modification, ethylene biosynthesis, and cell death were down-regulated associating with etr1-1 induced expression. We investigated time-course gene expression profiles and found two profiles which displayed totally opposite expression patterns under these two treatments. In these profiles, ‘the regulation of transcription’ was predominant in GO categories. Taking all results together, we concluded those transcription factors down-regulated at early stage might exert a major role in regulating the senescence process which were consequently characterized by cell wall modification and cell death. PMID:23874385

  4. Transcriptome changes associated with delayed flower senescence on transgenic petunia by inducing expression of etr1-1, a mutant ethylene receptor.

    Directory of Open Access Journals (Sweden)

    Hong Wang

    Full Text Available Flowers of ethylene-sensitive ornamental plants transformed with ethylene-insensitive 1-1(etr1-1, a mutant ethylene receptor first isolated from Arabidopsis, are known to have longer shelf lives. We have generated petunia plants in which the etr1-1 gene was over-expressed under the control of a chemically-inducible promoter, which would allow expression of etr1-1 to be initiated at the desired time and stage of development. Here, we showed that transgenic plants grew and developed normally without a chemical inducer. Semi-quantitative RT-PCR demonstrated that the abundance of transcripts of Arabidopsis etr1-1 gene was substantially induced in flowers with 30 μM dexamethasone (DEX. Consequently, t he life of the flowers was almost doubled and the peak of ethylene production was delayed. We compared gene expression changes of petals with DEX to those without DEX at 24 h and 48 h by microarray. Our results indicated that transcripts of many putative genes encoding transcription factors were down-regulated by etr1-1 induced expression at the early stage. In addition, putative genes involved in gibberellin biosynthesis, response to jasmonic acid/gibberellins stimulus, cell wall modification, ethylene biosynthesis, and cell death were down-regulated associating with etr1-1 induced expression. We investigated time-course gene expression profiles and found two profiles which displayed totally opposite expression patterns under these two treatments. In these profiles, 'the regulation of transcription' was predominant in GO categories. Taking all results together, we concluded those transcription factors down-regulated at early stage might exert a major role in regulating the senescence process which were consequently characterized by cell wall modification and cell death.

  5. Strigolactone Regulates Leaf Senescence in Concert with Ethylene in Arabidopsis.

    Science.gov (United States)

    Ueda, Hiroaki; Kusaba, Makoto

    2015-09-01

    Leaf senescence is not a passive degenerative process; it represents a process of nutrient relocation, in which materials are salvaged for growth at a later stage or to produce the next generation. Leaf senescence is regulated by various factors, such as darkness, stress, aging, and phytohormones. Strigolactone is a recently identified phytohormone, and it has multiple functions in plant development, including repression of branching. Although strigolactone is implicated in the regulation of leaf senescence, little is known about its molecular mechanism of action. In this study, strigolactone biosynthesis mutant strains of Arabidopsis (Arabidopsis thaliana) showed a delayed senescence phenotype during dark incubation. The strigolactone biosynthesis genes MORE AXIALLY GROWTH3 (MAX3) and MAX4 were drastically induced during dark incubation and treatment with the senescence-promoting phytohormone ethylene, suggesting that strigolactone is synthesized in the leaf during leaf senescence. This hypothesis was confirmed by a grafting experiment using max4 as the stock and Columbia-0 as the scion, in which the leaves from the Columbia-0 scion senesced earlier than max4 stock leaves. Dark incubation induced the synthesis of ethylene independent of strigolactone. Strigolactone biosynthesis mutants showed a delayed senescence phenotype during ethylene treatment in the light. Furthermore, leaf senescence was strongly accelerated by the application of strigolactone in the presence of ethylene and not by strigolactone alone. These observations suggest that strigolactone promotes leaf senescence by enhancing the action of ethylene. Thus, dark-induced senescence is regulated by a two-step mechanism: induction of ethylene synthesis and consequent induction of strigolactone synthesis in the leaf. © 2015 American Society of Plant Biologists. All Rights Reserved.

  6. Insulin-like growth factor binding protein-6 delays replicative senescence of human fibroblasts

    DEFF Research Database (Denmark)

    Micutkova, Lucia; Diener, Thomas; Li, Chen

    2011-01-01

    Cellular senescence can be induced by a variety of mechanisms, and recent data suggest a key role for cytokine networks to maintain the senescent state. Here, we have used a proteomic LC-MS/MS approach to identify new extracellular regulators of senescence in human fibroblasts. We identified 26 e...

  7. Targeting Senescent Cells : Possible Implications for Delaying Skin Aging: A Mini-Review

    NARCIS (Netherlands)

    Velarde, Michael C.; Demaria, Marco

    2016-01-01

    Senescent cells are induced by a wide variety of stimuli. They accumulate in several tissues during aging, including the skin. Senescent cells secrete proinflammatory cytokines, chemokines, growth factors, and proteases, a phenomenon called senescence-associated secretory phenotype (SASP), which are

  8. Senescent vs. non-senescent cells in the human annulus in vivo: Cell harvest with laser capture microdissection and gene expression studies with microarray analysis

    Directory of Open Access Journals (Sweden)

    Ingram Jane A

    2010-01-01

    Full Text Available Abstract Background Senescent cells are well-recognized in the aging/degenerating human disc. Senescent cells are viable, cannot divide, remain metabolically active and accumulate within the disc over time. Molecular analysis of senescent cells in tissue offers a special challenge since there are no cell surface markers for senescence which would let one use fluorescence-activated cell sorting as a method for separating out senescent cells. Methods We employed a novel laser capture microdissection (LCM design to selectively harvest senescent and non-senescent annulus cells in paraffin-embedded tissue, and compared their gene expression with microarray analysis. LCM was used to separately harvest senescent and non-senescent cells from 11 human annulus specimens. Results Microarray analysis revealed significant differences in expression levels in senescent cells vs non-senescent cells: 292 genes were upregulated, and 321 downregulated. Genes with established relationships to senescence were found to be significantly upregulated in senescent cells vs. non-senescent cells: p38 (MPAK14, RB-Associated KRAB zinc finger, Discoidin, CUB and LCCL domain, growth arrest and DNA-damage inducible beta, p28ING5, sphingosine-1-phosphate receptor 2 and somatostatin receptor 3; cyclin-dependent kinase 8 showed significant downregulation in senescent cells. Nitric oxidase synthase 1, and heat shock 70 kDa protein 6, both of which were significantly down-regulated in senescent cells, also showed significant changes. Additional genes related to cytokines, cell proliferation, and other processes were also identified. Conclusions Our LCM-microarray analyses identified a set of genes associated with senescence which were significantly upregulated in senescent vs non-senescent cells in the human annulus. These genes include p38 MAP kinase, discoidin, inhibitor of growth family member 5, and growth arrest and DNA-damage-inducible beta. Other genes, including genes

  9. Ozone exposure induces the activation of leaf senescence-related processes and morphological and growth changes in seedlings of Mediterranean tree species

    Energy Technology Data Exchange (ETDEWEB)

    Ribas, Angela [CSIC-CEAB-CREAF Ecophysiology Unit, CREAF-Center for Ecological Research and Forestry Applications, Edifici C, Universitat Autonoma de Barcelona, 08193 Bellaterra, Barcelona (Spain)]. E-mail: a.ribas@creaf.uab.es; Pen-tilde uelas, Josep [CSIC-CEAB-CREAF Ecophysiology Unit, CREAF-Center for Ecological Research and Forestry Applications, Edifici C, Universitat Autonoma de Barcelona, 08193 Bellaterra, Barcelona (Spain)]. E-mail: josep.penuelas@uab.es; Elvira, Susana [CIEMAT, Avd. Complutense 22, 28040 Madrid (Spain); Gimeno, Benjamin S. [CIEMAT, Avd. Complutense 22, 28040 Madrid (Spain)

    2005-03-01

    Four Mediterranean tree taxa, Quercus ilex subsp. ilex, Quercus ilex subsp. ballota, Olea europaea cv. vulgaris and Ceratonia siliqua, were exposed to different ozone (O{sub 3}) concentrations in open top chambers (OTCs) during 2 years. Three treatments were applied: charcoal-filtered air (CF), non-filtered air (NF) and non-filtered air plus 40 ppb{sub v} of O{sub 3} (NF+). The photochemical maximal efficiency, Fv/Fm, decreased in NF+ plants during the second year of exposure, especially during the most stressful Mediterranean seasons (winter and summer). An increase of {delta}{sup 13}C was found in three of the four studied species during the first year of exposure. This finding was only maintained in C. siliqua during the second year. Decreases in the chlorophyll content were detected during the first year of fumigations in all the species studied, but not during the second year. The NF+ treatment induced changes in foliar anatomical characteristics, especially in leaf mass per area (LMA) and spongy parenchyma thickness, which increased in some species. A reduction in N content and an increase in {delta}{sup 15}N were found in all species during the second year when exposed in the NF+ OTCs, suggesting a change in their retranslocation pattern linked to an acceleration of leaf senescence, as also indicated by the above mentioned biochemical and anatomical foliar changes. The two Q. ilex subspecies were the most sensitive species since the changes in N concentration, {delta}{sup 15}N, chlorophyll, leaf area, LMA and biomass occurred at ambient O{sub 3} concentrations. However, C. siliqua was the most responsive species (29% biomass reduction) when exposed to the NF+ treatment, followed by the two Q. ilex subspecies (14-20%) and O. europaea (no significant reduction). Ozone resistance of the latter species was linked to some plant traits such as chlorophyll concentrations, or spongy parenchyma thickness. - Ozone induces species-specific leaf senescence

  10. Senescent intervertebral disc cells exhibit perturbed matrix homeostasis phenotype.

    Science.gov (United States)

    Ngo, Kevin; Patil, Prashanti; McGowan, Sara J; Niedernhofer, Laura J; Robbins, Paul D; Kang, James; Sowa, Gwendolyn; Vo, Nam

    2017-09-01

    Aging greatly increases the risk for intervertebral disc degeneration (IDD) as a result of proteoglycan loss due to reduced synthesis and enhanced degradation of the disc matrix proteoglycan (PG). How disc matrix PG homeostasis becomes perturbed with age is not known. The goal of this study is to determine whether cellular senescence is a source of this perturbation. We demonstrated that disc cellular senescence is dramatically increased in the DNA repair-deficient Ercc1 -/Δ mouse model of human progeria. In these accelerated aging mice, increased disc cellular senescence is closely associated with the rapid loss of disc PG. We also directly examine PG homeostasis in oxidative damage-induced senescent human cells using an in vitro cell culture model system. Senescence of human disc cells treated with hydrogen peroxide was confirmed by growth arrest, senescence-associated β-galactosidase activity, γH2AX foci, and acquisition of senescence-associated secretory phenotype. Senescent human disc cells also exhibited perturbed matrix PG homeostasis as evidenced by their decreased capacity to synthesize new matrix PG and enhanced degradation of aggrecan, a major matrix PG. of the disc. Our in vivo and in vitro findings altogether suggest that disc cellular senescence is an important driver of PG matrix homeostatic perturbation and PG loss. Published by Elsevier B.V.

  11. A position sensitive parallel plate avalanche fission detector for use in particle induced fission coincidence measurements

    NARCIS (Netherlands)

    Plicht, J. van der

    1980-01-01

    A parallel plate avalanche detector developed for the detection of fission fragments in particle induced fission reactions is described. The active area is 6 × 10 cm2; it is position sensitive in one dimension with a resolution of 2.5 mm. The detector can withstand a count rate of 25000 fission

  12. Overexpression of cyclic adenosine monophosphate effluent protein MRP4 induces an altered response to β-adrenergic stimulation in the senescent rat heart.

    Science.gov (United States)

    Carillion, Aude; Feldman, Sarah; Jiang, Cheng; Atassi, Fabrice; Na, Na; Mougenot, Nathalie; Besse, Sophie; Hulot, Jean-Sébastien; Riou, Bruno; Amour, Julien

    2015-02-01

    In the senescent heart, the positive inotropic response to β-adrenoceptor stimulation is reduced, partly by dysregulation of β1- and β3-adrenoceptors. The multidrug resistance protein 4 (MRP4) takes part in the control of intracellular cyclic adenosine monophosphate concentration by controlling its efflux but the role of MRP4 in the β-adrenergic dysfunction of the senescent heart remains unknown. The β-adrenergic responses to isoproterenol were investigated in vivo (stress echocardiography) and in vitro (isolated cardiomyocyte by Ionoptix with sarcomere shortening and calcium transient) in young (3 months old) and senescent (24 months old) rats pretreated or not with MK571, a specific MRP4 inhibitor. MRP4 was quantified in left ventricular homogenates by Western blotting. Data are mean ± SD expressed as percent of baseline value. The positive inotropic effect of isoproterenol was reduced in senescent rats in vivo (left ventricular shortening fraction 120 ± 16% vs. 158 ± 20%, P < 0.001, n = 16 rats) and in vitro (sarcomere shortening 129 ± 37% vs. 148 ± 35%, P = 0.004, n = 41 or 43 cells) as compared to young rats. MRP4 expression increased 3.6-fold in senescent compared to young rat myocardium (P = 0.012, n = 8 rats per group). In senescent rats, inhibition of MRP4 by MK571 restored the positive inotropic effect of isoproterenol in vivo (143 ± 11%, n = 8 rats). In vitro in senescent cardiomyocytes pretreated with MK571, both sarcomere shortening (161 ± 45% vs. 129 ± 37%, P = 0.007, n = 41 cells per group) and calcium transient amplitude (132 ± 25% vs. 113 ± 27%, P = 0.007) increased significantly. MRP4 overexpression contributes to the reduction of the positive inotropic response to β-adrenoceptor stimulation in the senescent heart.

  13. Magnesium Lithospermate B from Salvia miltiorrhiza Bunge Ameliorates Aging-Induced Renal Inflammation and Senescence via NADPH Oxidase-Mediated Reactive Oxygen Generation.

    Science.gov (United States)

    Park, Chan Hum; Shin, Sung Ho; Lee, Eun Kyeong; Kim, Dae Hyun; Kim, Min-Jo; Roh, Seong-Soo; Yokozawa, Takako; Chung, Hae Young

    2017-05-01

    The present study was conducted to examine whether magnesium lithospermate B (MLB) extracted from Salviae miltiorrhizae radix was renoprotective in pathways related to age-related oxidative stress in aged rats. Magnesium lithospermate B was orally administered at a dose of 2- or 8-mg/kg body weight for 16 consecutive days, and the effects were compared with those of vehicle in old and young rats. Magnesium lithospermate B administration to old rats ameliorated renal oxidative stress through reduction of reactive oxygen species. The old rats exhibited a dysregulation of the expression of proteins related to oxidative stress and inflammation in the kidneys, and MLB administration significantly reduced the protein expression of major subunits of nicotinamide adenine dinucleotide phosphate oxidase (Nox4 and p22 phox ), phospho-p38, nuclear factor-kappa B p65, cyclooxygenase-2, and inducible nitric oxide synthase. In addition, MLB-treated old rats showed lower levels of senescence-related proteins such as p16, ADP-ribosylation factor 6, p53, and p21 through effects on the mitogen-activated protein kinase pathway. Magnesium lithospermate B administration also significantly attenuated the age-related increase in serum urea nitrogen, reflecting renal dysfunction, up-regulated podocyte structural proteins, and reduced renal structural injury. Our results provide important evidence that MLB reduces the renal damage of oxidative stress in old rats. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

  14. Disruption of Aneuploidy and Senescence Induced by Aurora Inhibition Promotes Intrinsic Apoptosis in Double Hit or Double Expressor Diffuse Large B-cell Lymphomas.

    Science.gov (United States)

    Islam, Shariful; Qi, Wenqing; Morales, Carla; Cooke, Laurence; Spier, Catherine; Weterings, Eric; Mahadevan, Daruka

    2017-10-01

    Double hit (DH) or double expressor (DE) diffuse large B-cell lymphomas (DLBCL) are aggressive non-Hodgkin's lymphomas (NHL) with translocations and/or overexpressions of MYC and BCL-2 , which are difficult to treat. Aurora kinase (AK) inhibition with alisertib in DH/DE-DLBCL induces cell death in ∼30%, while ∼70% are aneuploid and senescent cells (AASC), a mitotic escape mechanism contributing to drug resistance. These AASCs elaborated a high metabolic rate by increased AKT/mTOR and ERK/MAPK activity via BTK signaling through the chronic active B-cell receptor (BCR) pathway. Combinations of alisertib + ibrutinib or alisertib + ibrutinib + rituximab significantly reduced AASCs with enhanced intrinsic cell death. Inhibition of AK + BTK reduced phosphorylation of AKT/mTOR and ERK-1/2, upregulated phospho-H2A-X and Chk-2 (DNA damage), reduced Bcl-6, and decreased Bcl-2 and Bcl-xL and induced apoptosis by PARP cleavage. In a DE-DLBCL SCID mouse xenograft model, ibrutinib alone was inactive, while alisertib + ibrutinib was additive with a tumor growth inhibition (TGI) rate of ∼25%. However, TGI for ibrutinib + rituximab was ∼50% to 60%. In contrast, triple therapy showed a TGI rate of >90%. Kaplan-Meier survival analysis showed that 67% of mice were alive at day 89 with triple therapy versus 20% with ibrutinib + rituximab. All treatments were well tolerated with no changes in body weights. A novel triple therapy consisting of alisertib + ibrutinib + rituximab inhibits AASCs induced by AK inhibition in DH/DE-DLBCL leading to a significant antiproliferative signal, enhanced intrinsic apoptosis and may be of therapeutic potential in these lymphomas. Mol Cancer Ther; 16(10); 2083-93. ©2017 AACR . ©2017 American Association for Cancer Research.

  15. SM22α-induced activation of p16INK4a/retinoblastoma pathway promotes cellular senescence caused by a subclinical dose of γ-radiation and doxorubicin in HepG2 cells

    International Nuclear Information System (INIS)

    Kim, Tae Rim; Lee, Hee Min; Lee, So Yong; Kim, Eun Jin; Kim, Kug Chan; Paik, Sang Gi; Cho, Eun Wie; Kim, In Gyu

    2010-01-01

    Research highlights: → SM22α overexpression in HepG2 cells leads cells to a growth arrest state, and the treatment of a subclinical dose of γ-radiation or doxorubicin promotes cellular senescence. → SM22α overexpression elevates p16 INK4a followed by pRB activation, but there are no effects on p53/p21 WAF1/Cip1 pathway. → SM22α-induced MT-1G activates p16 INK4a /pRB pathway, which promotes cellular senescence by damaging agents. -- Abstract: Smooth muscle protein 22-alpha (SM22α) is known as a transformation- and shape change-sensitive actin cross-linking protein found in smooth muscle tissue and fibroblasts; however, its functional role remains uncertain. We reported previously that SM22α overexpression confers resistance against anti-cancer drugs or radiation via induction of metallothionein (MT) isozymes in HepG2 cells. In this study, we demonstrate that SM22α overexpression leads cells to a growth arrest state and promotes cellular senescence caused by treatment with a subclinical dose of γ-radiation (0.05 and 0.1 Gy) or doxorubicin (0.01 and 0.05 μg/ml), compared to control cells. Senescence growth arrest is known to be controlled by p53 phosphorylation/p21 WAF1/Cip1 induction or p16 INK4a /retinoblastoma protein (pRB) activation. SM22α overexpression in HepG2 cells elevated p16 INK4a followed by pRB activation, but did not activate the p53/p21 WAF1/Cip1 pathway. Moreover, MT-1G, which is induced by SM22α overexpression, was involved in the activation of the p16 INK4a /pRB pathway, which led to a growth arrest state and promoted cellular senescence caused by damaging agents. Our findings provide the first demonstration that SM22α modulates cellular senescence caused by damaging agents via regulation of the p16 INK4a /pRB pathway in HepG2 cells and that these effects of SM22α are partially mediated by MT-1G.

  16. SM22{alpha}-induced activation of p16{sup INK4a}/retinoblastoma pathway promotes cellular senescence caused by a subclinical dose of {gamma}-radiation and doxorubicin in HepG2 cells

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Tae Rim; Lee, Hee Min; Lee, So Yong; Kim, Eun Jin; Kim, Kug Chan [Department of Radiation Biology, Environmental Radiation Research Group, Korea Atomic Energy Research Institute, Daejeon (Korea, Republic of); Paik, Sang Gi [Department of Biology, School of Biosciences and Biotechnology, Chungnam National University, Daejeon (Korea, Republic of); Cho, Eun Wie, E-mail: ewcho@kribb.re.kr [Daejeon-KRIBB-FHCRC Cooperation Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon (Korea, Republic of); Kim, In Gyu, E-mail: igkim@kaeri.re.kr [Department of Radiation Biology, Environmental Radiation Research Group, Korea Atomic Energy Research Institute, Daejeon (Korea, Republic of)

    2010-09-10

    Research highlights: {yields} SM22{alpha} overexpression in HepG2 cells leads cells to a growth arrest state, and the treatment of a subclinical dose of {gamma}-radiation or doxorubicin promotes cellular senescence. {yields} SM22{alpha} overexpression elevates p16{sup INK4a} followed by pRB activation, but there are no effects on p53/p21{sup WAF1/Cip1} pathway. {yields} SM22{alpha}-induced MT-1G activates p16{sup INK4a}/pRB pathway, which promotes cellular senescence by damaging agents. -- Abstract: Smooth muscle protein 22-alpha (SM22{alpha}) is known as a transformation- and shape change-sensitive actin cross-linking protein found in smooth muscle tissue and fibroblasts; however, its functional role remains uncertain. We reported previously that SM22{alpha} overexpression confers resistance against anti-cancer drugs or radiation via induction of metallothionein (MT) isozymes in HepG2 cells. In this study, we demonstrate that SM22{alpha} overexpression leads cells to a growth arrest state and promotes cellular senescence caused by treatment with a subclinical dose of {gamma}-radiation (0.05 and 0.1 Gy) or doxorubicin (0.01 and 0.05 {mu}g/ml), compared to control cells. Senescence growth arrest is known to be controlled by p53 phosphorylation/p21{sup WAF1/Cip1} induction or p16{sup INK4a}/retinoblastoma protein (pRB) activation. SM22{alpha} overexpression in HepG2 cells elevated p16{sup INK4a} followed by pRB activation, but did not activate the p53/p21{sup WAF1/Cip1} pathway. Moreover, MT-1G, which is induced by SM22{alpha} overexpression, was involved in the activation of the p16{sup INK4a}/pRB pathway, which led to a growth arrest state and promoted cellular senescence caused by damaging agents. Our findings provide the first demonstration that SM22{alpha} modulates cellular senescence caused by damaging agents via regulation of the p16{sup INK4a}/pRB pathway in HepG2 cells and that these effects of SM22{alpha} are partially mediated by MT-1G.

  17. NSC666715 and Its Analogs Inhibit Strand-Displacement Activity of DNA Polymerase β and Potentiate Temozolomide-Induced DNA Damage, Senescence and Apoptosis in Colorectal Cancer Cells.

    Directory of Open Access Journals (Sweden)

    Aruna S Jaiswal

    Full Text Available Recently approved chemotherapeutic agents to treat colorectal cancer (CRC have made some impact; however, there is an urgent need for newer targeted agents and strategies to circumvent CRC growth and metastasis. CRC frequently exhibits natural resistance to chemotherapy and those who do respond initially later acquire drug resistance. A mechanism to potentially sensitize CRC cells is by blocking the DNA polymerase β (Pol-β activity. Temozolomide (TMZ, an alkylating agent, and other DNA-interacting agents exert DNA damage primarily repaired by a Pol-β-directed base excision repair (BER pathway. In previous studies, we used structure-based molecular docking of Pol-β and identified a potent small molecule inhibitor (NSC666715. In the present study, we have determined the mechanism by which NSC666715 and its analogs block Fen1-induced strand-displacement activity of Pol-β-directed LP-BER, cause apurinic/apyrimidinic (AP site accumulation and induce S-phase cell cycle arrest. Induction of S-phase cell cycle arrest leads to senescence and apoptosis of CRC cells through the p53/p21 pathway. Our initial findings also show a 10-fold reduction of the IC50 of TMZ when combined with NSC666715. These results provide a guide for the development of a target-defined strategy for CRC chemotherapy that will be based on the mechanisms of action of NSC666715 and TMZ. This combination strategy can be used as a framework to further reduce the TMZ dosages and resistance in CRC patients.

  18. Exogenous melatonin suppresses dark-induced leaf senescence by activating the superoxide dismutase-catalase antioxidant pathway and down-regulating chlorophyll degradation in excised leaves of perennial ryegrass (Lolium perenne L.

    Directory of Open Access Journals (Sweden)

    Jing Zhang

    2016-10-01

    Full Text Available Leaf senescence is a typical symptom in plants exposed to dark and may be regulated by plant growth regulators. The objective of this study was to determine whether exogenous application of melatonin (N-acetyl-5-methoxytryptamine suppresses dark-induced leaf senescence and the effects of melatonin on reactive oxygen species (ROS scavenging system and chlorophyll degradation pathway in perennial grass species. Mature perennial ryegrass (Lolium perenne L. cv. ‘Pinnacle’ leaves were excised and incubated in 3 mM 2-(N-morpholino ethanesulfonic buffer (pH 5.8 supplemented with melatonin or water (control and exposed to dark treatment for 8 d. Leaves treated with melatonin maintained significantly higher endogenous melatonin level, chlorophyll content, photochemical efficiency, and cell membrane stability expressed by lower electrolyte leakage and malondialdehyde (MDA content compared to the control. Exogenous melatonin treatment also reduced the transcript level of chlorophyll degradation-associated genes and senescence marker genes (LpSAG12.1, Lph36, and Lpl69 during the dark treatment. The endogenous O2- production rate and H2O2 content were significantly lower in these excised leaves treated with melatonin compared to the water control. Exogenous melatonin treatment caused increases in enzymatic activity and transcript levels of superoxide dismutase and catalase but had no significant effects on ascorbate peroxidase, glutathione reductase, dehydroascorbate reductase, and monohydroascorbate reductase. The content of non-enzymatic antioxidants, such as ascorbate and dehydroascorbate, were decreased by melatonin treatment, while the content of glutathione and oxidized glutathione was not affected by melatonin. These results suggest that the suppression of dark-induced leaf senescence by exogenous melatonin may be associated with its roles in regulating ROS scavenging through activating the superoxide dismutase-catalase enzymatic antioxidant

  19. Role of P53 in Mammary Epithelial Cell Senescence

    National Research Council Canada - National Science Library

    Dimri, Goberdhan P

    2006-01-01

    .... We also chose several other targets of p53 that are induced by DNA damage. The RT PCR analysis aws carried out using mRNA prepared from young growing early passage and senescent late passage HMECs...

  20. Deregulated E2F activity induces hyperplasia and senescence-like features in the mouse pituitary gland

    DEFF Research Database (Denmark)

    Lazzerini Denchi, Eros; Attwooll, Claire; Pasini, Diego

    2005-01-01

    The retinoblastoma gene, RB1, is one of the most frequently mutated genes in human cancer. Rb heterozygous mice develop pituitary tumors with 100% incidence, and the E2F transcription factors are required for this. To assess whether deregulated E2F activity is sufficient to induce pituitary tumors...

  1. Drying without senescence in resurrection plants

    Science.gov (United States)

    Griffiths, Cara A.; Gaff, Donald F.; Neale, Alan D.

    2014-01-01

    Research into extreme drought tolerance in resurrection plants using species such as Craterostigma plantagineum, C. wilmsii, Xerophyta humilis, Tortula ruralis, and Sporobolus stapfianus has provided some insight into the desiccation tolerance mechanisms utilized by these plants to allow them to persist under extremely adverse environmental conditions. Some of the mechanisms used to ensure cellular preservation during severe dehydration appear to be peculiar to resurrection plants. Apart from the ability to preserve vital cellular components during drying and rehydration, such mechanisms include the ability to down-regulate growth-related metabolism rapidly in response to changes in water availability, and the ability to inhibit dehydration-induced senescence programs enabling reconstitution of photosynthetic capacity quickly following a rainfall event. Extensive research on the molecular mechanism of leaf senescence in non-resurrection plants has revealed a multi-layered regulatory network operates to control programed cell death pathways. However, very little is known about the molecular mechanisms that resurrection plants employ to avoid undergoing drought-related senescence during the desiccation process. To survive desiccation, dehydration in the perennial resurrection grass S. stapfianus must proceed slowly over a period of 7 days or more. Leaves detached from the plant before 60% relative water content (RWC) is attained are desiccation-sensitive indicating that desiccation tolerance is conferred in vegetative tissue of S. stapfianus when the leaf RWC has declined to 60%. Whilst some older leaves remaining attached to the plant during dehydration will senesce, suggesting dehydration-induced senescence may be influenced by leaf age or the rate of dehydration in individual leaves, the majority of leaves do not senesce. Rather these leaves dehydrate to air-dryness and revive fully following rehydration. Hence it seems likely that there are genes expressed in

  2. Cytokine loops driving senescence

    Czech Academy of Sciences Publication Activity Database

    Bartek, Jiří; Hodný, Zdeněk; Lukáš, Jan

    2008-01-01

    Roč. 10, č. 8 (2008), s. 887-889 ISSN 1465-7392 Institutional research plan: CEZ:AV0Z50520514 Keywords : cellular senescence * cytokines * autocrine feedback loop Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 17.774, year: 2008

  3. Analysis of individual cells identifies cell-to-cell variability following induction of cellular senescence.

    Science.gov (United States)

    Wiley, Christopher D; Flynn, James M; Morrissey, Christapher; Lebofsky, Ronald; Shuga, Joe; Dong, Xiao; Unger, Marc A; Vijg, Jan; Melov, Simon; Campisi, Judith

    2017-10-01

    Senescent cells play important roles in both physiological and pathological processes, including cancer and aging. In all cases, however, senescent cells comprise only a small fraction of tissues. Senescent phenotypes have been studied largely in relatively homogeneous populations of cultured cells. In vivo, senescent cells are generally identified by a small number of markers, but whether and how these markers vary among individual cells is unknown. We therefore utilized a combination of single-cell isolation and a nanofluidic PCR platform to determine the contributions of individual cells to the overall gene expression profile of senescent human fibroblast populations. Individual senescent cells were surprisingly heterogeneous in their gene expression signatures. This cell-to-cell variability resulted in a loss of correlation among the expression of several senescence-associated genes. Many genes encoding senescence-associated secretory phenotype (SASP) factors, a major contributor to the effects of senescent cells in vivo, showed marked variability with a subset of highly induced genes accounting for the increases observed at the population level. Inflammatory genes in clustered genomic loci showed a greater correlation with senescence compared to nonclustered loci, suggesting that these genes are coregulated by genomic location. Together, these data offer new insights into how genes are regulated in senescent cells and suggest that single markers are inadequate to identify senescent cells in vivo. © 2017 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

  4. Bozepinib, a novel small antitumor agent, induces PKR-mediated apoptosis and synergizes with IFNα triggering apoptosis, autophagy and senescence

    Directory of Open Access Journals (Sweden)

    Marchal JA

    2013-10-01

    Full Text Available Juan Antonio Marchal,1,2 Esther Carrasco,1 Alberto Ramirez,1,3 Gema Jiménez,1,2 Carmen Olmedo,4 Macarena Peran,1,3 Ahmad Agil,5 Ana Conejo-García,6 Olga Cruz-López,6 Joaquin María Campos,6 María Ángel García4,7 1Biopathology and Regenerative Medicine Institute, Centre for Biomedical Research, 2Department of Human Anatomy and Embryology, Faculty of Medicine, University of Granada, Granada, 3Department of Health Sciences, University of Jaén, Jaén, 4Experimental Surgery Research Unit, Virgen de las Nieves University Hospital, Granada, 5Department of Pharmacology and Neurosciences Institute, Faculty of Medicine, 6Department of Pharmaceutical and Organic Chemistry, Faculty of Pharmacy, University of Granada, Granada, 7Department of Oncology, Virgen de las Nieves University Hospital, Granada, Spain Abstract: Bozepinib [(RS-2,6-dichloro-9-[1-(p-nitrobenzenesulfonyl-1,2,3,5-tetrahydro-4,1- benzoxazepin-3-yl]-9H-purine] is a potent antitumor compound that is able to induce apoptosis in breast cancer cells. In the present study, we show that bozepinib also has antitumor activity in colon cancer cells, showing 50% inhibitory concentration (IC50 values lower than those described for breast cancer cells and suggesting great potential of this synthetic drug in the treatment of cancer. We identified that the double-stranded RNA-dependent protein kinase (PKR is a target of bozepinib, being upregulated and activated by the drug. However, p53 was not affected by bozepinib, and was not necessary for induction of apoptosis in either breast or colon cancer cells. In addition, the efficacy of bozepinib was improved when combined with the interferon-alpha (IFNα cytokine, which enhanced bozepinib-induced apoptosis with involvement of protein kinase PKR. Moreover, we report here, for the first time, that in combined therapy, IFNα induces a clear process of autophagosome formation, and prior treatment with chloroquine, an autophagy inhibitor, is able to

  5. Vortex shedding induced by a solitary wave propagating over a submerged vertical plate

    International Nuclear Information System (INIS)

    Lin Chang; Ho, T.-C.; Chang, S.-C.; Hsieh, S.-C.; Chang, K.-A.

    2005-01-01

    Experimental study was conducted on the vortex shedding process induced by the interaction between a solitary wave and a submerged vertical plate. Particle image velocimetry (PIV) was used for quantitative velocity measurement while a particle tracing technique was used for qualitative flow visualization. Vortices are generated at the tip of each side of the plate. The largest vortices at each side of the plate eventually grow to the size of the water depth. Although the fluid motion under the solitary wave is only translatory, vortices are shed in both the upstream and downstream directions due to the interaction of the generated vortices as well as the vortices with the plate and the bottom. The process can be divided into four phases: the formation of a separated shear layer, the generation and shedding of vortices, the formation of a vertical jet, and the impingement of the jet onto the free surface. Similarity velocity profiles were found both in the separated shear layer and in the vertical jet

  6. Vortex-Induced Vibrations of a Flexibly-Mounted Cyber-Physical Rectangular Plate

    Science.gov (United States)

    Onoue, Kyohei; Strom, Benjamin; Song, Arnold; Breuer, Kenneth

    2013-11-01

    We have developed a cyber-physical system to explore the vortex-induced vibration (VIV) behavior of a flat plate mounted on a virtual spring damper support. The plate is allowed to oscillate about its mid-chord and the measured angular position, velocity, and torque are used as inputs to a feedback control system that provides a restoring torque and can simulate a wide range of structural dynamic behavior. A series of experiments were carried out using different sized plates, and over a range of freestream velocities, equilibrium angles of attack, and simulated stiffness and damping. We observe a synchronization phenomenon over a wide range of parameter space, wherein the plate oscillates at moderate to large amplitude with a frequency dictated by the natural structural frequency of the system. Additionally, the existence of bistable states is reflected in the hysteretic response of the system. The cyber-physical damping extracts energy from the flow and the efficiency of this harvesting mechanism is characterized over a range of dimensionless stiffness and damping parameters. This research is funded by the Air Force Office of Scientific Research (AFOSR).

  7. Different transcriptional profiling between senescent and non-senescent human coronary artery endothelial cells (HCAECs) by Omeprazole and Lansoprazole treatment.

    Science.gov (United States)

    Costarelli, Laura; Giacconi, Robertina; Malavolta, Marco; Basso, Andrea; Piacenza, Francesco; Provinciali, Mauro; Maggio, Marcello G; Corsonello, Andrea; Lattanzio, Fabrizia

    2017-04-01

    Recent evidence suggests that high dose and/or long term use of proton pump inhibitors (PPIs) may increase the risk of adverse cardiovascular events in older patients, but mechanisms underlying these detrimental effects are not known. Taking into account that the senescent endothelial cells have been implicated in the genesis or promotion of age-related cardiovascular disease, we hypothesized an active role of PPIs in senescent cells. The aim of this study is to investigate the changes in gene expression occurring in senescent and non-senescent human coronary artery endothelial cells (HCAECs) following Omeprazole (OPZ) or Lansoprazole (LPZ) treatment. Here, we show that atherogenic response is among the most regulated processes in PPI-treated HCAECs. PPIs induced down-regulation of anti-atherogenic chemokines (CXCL11, CXCL12 and CX3CL1) in senescent but not in non-senescent cells, while the same chemokines were up-regulated in untreated senescent cells. These findings support the hypothesis that up-regulated anti-atherogenic chemokines may represent a defensive mechanism against atherosclerosis during cellular senescence, and suggest that PPIs could activate pro-atherogenic pathways by changing the secretory phenotype of senescent HCAECs. Moreover, the genes coding for fatty acid binding protein 4 (FABP4) and piezo-type mechanosensitive ion channel component 2 (PIEZO2) were modulated by PPIs treatment with respect to untreated cells. In conclusions, our results show that long-term and high dose use of PPI could change the secretory phenotype of senescent cells, suggesting one of the potential mechanisms by which use of PPI can increase adverse outcomes in older subjects.

  8. A prototypical non-malignant epithelial model to study genome dynamics and concurrently monitor micro-RNAs and proteins in situ during oncogene-induced senescence

    DEFF Research Database (Denmark)

    Komseli, Eirini Stavroula; Pateras, Ioannis S.; Krejsgaard, Thorbjørn

    2018-01-01

    limitations achieving for the first time simultaneous detection of both a micro-RNA and a protein in the biological context of cellular senescence, utilizing the new commercially available SenTraGorTM compound. The method was applied in a prototypical human non-malignant epithelial model of oncogene...

  9. Differences between winter oilseed rape (Brassica napus L.) cultivars in nitrogen starvation-induced leaf senescence are governed by leaf-inherent rather than root-derived signals

    Czech Academy of Sciences Publication Activity Database

    Koeslin-Findeklee, F.; Becker, M. A.; van der Graaff, E.; Roitsch, Thomas; Horst, W. J.

    2015-01-01

    Roč. 66, č. 13 (2015), s. 3669-3681 ISSN 0022-0957 Institutional support: RVO:67179843 Keywords : Brassica napus * cytokinins * genotypic differences * leaf senescence * nitrogen efficiency * nitrogen starvation * reciprocal grafting * stay-green Subject RIV: EH - Ecology, Behaviour Impact factor: 5.677, year: 2015

  10. Cellular Senescence: A Translational Perspective

    Directory of Open Access Journals (Sweden)

    James L. Kirkland

    2017-07-01

    Full Text Available Cellular senescence entails essentially irreversible replicative arrest, apoptosis resistance, and frequently acquisition of a pro-inflammatory, tissue-destructive senescence-associated secretory phenotype (SASP. Senescent cells accumulate in various tissues with aging and at sites of pathogenesis in many chronic diseases and conditions. The SASP can contribute to senescence-related inflammation, metabolic dysregulation, stem cell dysfunction, aging phenotypes, chronic diseases, geriatric syndromes, and loss of resilience. Delaying senescent cell accumulation or reducing senescent cell burden is associated with delay, prevention, or alleviation of multiple senescence-associated conditions. We used a hypothesis-driven approach to discover pro-survival Senescent Cell Anti-apoptotic Pathways (SCAPs and, based on these SCAPs, the first senolytic agents, drugs that cause senescent cells to become susceptible to their own pro-apoptotic microenvironment. Several senolytic agents, which appear to alleviate multiple senescence-related phenotypes in pre-clinical models, are beginning the process of being translated into clinical interventions that could be transformative.

  11. Aberrant localization of lamin B receptor (LBR) in cellular senescence in human cells

    Energy Technology Data Exchange (ETDEWEB)

    Arai, Rumi; En, Atsuki; Ukekawa, Ryo [Graduate School of Nanobioscience, Yokohama City University, 22-2 Seto, Kanazawa-ku, Yokohama 236-0027 (Japan); Miki, Kensuke [Graduate School of Nanobioscience, Yokohama City University, 22-2 Seto, Kanazawa-ku, Yokohama 236-0027 (Japan); Ichiban Life Corporation, 1-1-7 Horai-cho, Naka-ku, Yokohama 231-0048 (Japan); Fujii, Michihiko, E-mail: mifuji@yokohama-cu.ac.jp [Graduate School of Nanobioscience, Yokohama City University, 22-2 Seto, Kanazawa-ku, Yokohama 236-0027 (Japan); Ayusawa, Dai [Graduate School of Nanobioscience, Yokohama City University, 22-2 Seto, Kanazawa-ku, Yokohama 236-0027 (Japan); Ichiban Life Corporation, 1-1-7 Horai-cho, Naka-ku, Yokohama 231-0048 (Japan)

    2016-05-13

    5-Bromodeoxyuridine (BrdU), a thymidine analogue, induces cellular senescence in mammalian cells. BrdU induces cellular senescence probably through the regulation of chromatin because BrdU destabilizes or disrupts nucleosome positioning and decondenses heterochromatin. Since heterochromatin is tethered to the nuclear periphery through the interaction with the nuclear envelope proteins, we examined the localization of the several nuclear envelope proteins such as lamins, lamin-interacting proteins, nuclear pore complex proteins, and nuclear transport proteins in senescent cells. We have shown here that lamin B receptor (LBR) showed a change in localization in both BrdU-induced and replicative senescent cells.

  12. Radiated flow of chemically reacting nanoliquid with an induced magnetic field across a permeable vertical plate

    Directory of Open Access Journals (Sweden)

    B. Mahanthesh

    Full Text Available Impact of induced magnetic field over a flat porous plate by utilizing incompressible water-copper nanoliquid is examined analytically. Flow is supposed to be laminar, steady and two-dimensional. The plate is subjected to a regular free stream velocity as well as suction velocity. Flow formulation is developed by considering Maxwell–Garnetts (MG and Brinkman models of nanoliquid. Impacts of thermal radiation, viscous dissipation, temperature dependent heat source/sink and first order chemical reaction are also retained. The subjected non-linear problems are non-dimensionalized and analytic solutions are presented via series expansion method. The graphs are plotted to analyze the influence of pertinent parameters on flow, magnetism, heat and mass transfer fields as well as friction factor, current density, Nusselt and Sherwood numbers. It is found that friction factor at the plate is more for larger magnetic Prandtl number. Also the rate of heat transfer decayed with increasing nanoparticles volume fraction and the strength of magnetism. Keywords: Induced magnetic field, Nanoliquids, Heat source/sink, Series expansion method, Chemical reaction, Thermal radiation

  13. Sirtuins, Cell Senescence, and Vascular Aging.

    Science.gov (United States)

    Kida, Yujiro; Goligorsky, Michael S

    2016-05-01

    The sirtuins (SIRTs) constitute a class of proteins with nicotinamide adenine dinucleotide-dependent deacetylase or adenosine diphosphate-ribosyltransferase activity. Seven SIRT family members have been identified in mammals, from SIRT1, the best studied for its role in vascular aging, to SIRT7. SIRT1 and SIRT2 are localized in the nucleus and cytoplasm. SIRT3, SIRT4, and SIRT5 are mitochondrial, and SIRT6 and SIRT7 are nuclear. Extensive studies have clearly revealed that SIRT proteins regulate diverse cell functions and responses to stressors. Vascular aging involves the aging process (senescence) of endothelial and vascular smooth muscle cells. Two types of cell senescence have been identified: (1) replicative senescence with telomere attrition; and (2) stress-induced premature senescence without telomere involvement. Both types of senescence induce vascular cell growth arrest and loss of vascular homeostasis, and contribute to the initiation and progression of cardiovascular diseases. Previous mechanistic studies have revealed in detail that SIRT1, SIRT3, and SIRT6 show protective functions against vascular aging, and definite vascular function of other SIRTs is under investigation. Thus, direct SIRT modulation and nicotinamide adenine dinucleotide stimulation of SIRT are promising candidates for cardiovascular disease therapy. A small number of pilot studies have been conducted to assess SIRT modulation in humans. These clinical studies have not yet provided convincing evidence that SIRT proteins alleviate morbidity and mortality in patients with cardiovascular diseases. The outcomes of multiple ongoing clinical trials are awaited to define the efficacy of SIRT modulators and SIRT activators in cardiovascular diseases, along with the potential adverse effects of chronic SIRT modulation. Copyright © 2016 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.

  14. Selective elimination of senescent cells by mitochondrial targeting is regulated by ANT2

    DEFF Research Database (Denmark)

    Hubackova, Sona; Davidova, Eliska; Rohlenova, Katerina

    2018-01-01

    and development of age-related diseases. We found that the anticancer agent mitochondria-targeted tamoxifen (MitoTam), unlike conventional anticancer agents, kills cancer cells without inducing senescence in vitro and in vivo. Surprisingly, it also selectively eliminates both malignant and non-cancerous senescent...... cells. In naturally aged mice treated with MitoTam for 4 weeks, we observed a significant decrease of senescence markers in all tested organs compared to non-treated animals. Mechanistically, we found that the susceptibility of senescent cells to MitoTam is linked to a very low expression level...... of adenine nucleotide translocase-2 (ANT2), inherent to the senescent phenotype. Restoration of ANT2 in senescent cells resulted in resistance to MitoTam, while its downregulation in non-senescent cells promoted their MitoTam-triggered elimination. Our study documents a novel, translationally intriguing role...

  15. [Immunological theory of senescence].

    Science.gov (United States)

    Drela, Nadzieja

    2014-01-01

    Senescence can result from decreased potential of the immune system to respond to foreign and self antigens. The most common effect is the inhibition to destroy dying and cancer cells and the decrease of the immune response to pathogens. Aging is closely related to inflammatory phenotype, which facilitate the development of age-related diseases. The mammal immune system is highly organized and adapted to react to a wide range of antigens. According to the immunological theory, the causative agents of senescence are multilevel changes of development and functions of immune cells. Some of changes can be beneficial for the maintenance of homeostasis and lifespan in continuously changing endogenous environment and immune history of the organism.

  16. Cellular senescence and organismal aging.

    Science.gov (United States)

    Jeyapalan, Jessie C; Sedivy, John M

    2008-01-01

    Cellular senescence, first observed and defined using in vitro cell culture studies, is an irreversible cell cycle arrest which can be triggered by a variety of factors. Emerging evidence suggests that cellular senescence acts as an in vivo tumor suppression mechanism by limiting aberrant proliferation. It has also been postulated that cellular senescence can occur independently of cancer and contribute to the physiological processes of normal organismal aging. Recent data have demonstrated the in vivo accumulation of senescent cells with advancing age. Some characteristics of senescent cells, such as the ability to modify their extracellular environment, could play a role in aging and age-related pathology. In this review, we examine current evidence that links cellular senescence and organismal aging.

  17. F4/80+ Macrophages Contribute to Clearance of Senescent Cells in the Mouse Postpartum Uterus.

    Science.gov (United States)

    Egashira, Mahiro; Hirota, Yasushi; Shimizu-Hirota, Ryoko; Saito-Fujita, Tomoko; Haraguchi, Hirofumi; Matsumoto, Leona; Matsuo, Mitsunori; Hiraoka, Takehiro; Tanaka, Tomoki; Akaeda, Shun; Takehisa, Chiaki; Saito-Kanatani, Mayuko; Maeda, Kei-Ichiro; Fujii, Tomoyuki; Osuga, Yutaka

    2017-07-01

    Cellular senescence, defined as an irreversible cell cycle arrest, exacerbates the tissue microenvironment. Our previous study demonstrated that mouse uterine senescent cells were physiologically increased according to gestational days and that their abnormal accumulation was linked to the onset of preterm delivery. We hypothesized that there is a mechanism for removal of senescent cells after parturition to maintain uterine function. In the current study, we noted abundant uterine senescent cells and their gradual disappearance in wild-type postpartum mice. F4/80+ macrophages were present specifically around the area rich in senescent cells. Depletion of macrophages in the postpartum mice using anti-F4/80 antibody enlarged the area of senescent cells in the uterus. We also found excessive uterine senescent cells and decreased second pregnancy success rate in a preterm birth model using uterine p53-deleted mice. Furthermore, a decrease in F4/80+ cells and an increase in CD11b+ cells with a senescence-associated inflammatory microenvironment were observed in the p53-deleted uterus, suggesting that uterine p53 deficiency affects distribution of the macrophage subpopulation, interferes with senescence clearance, and promotes senescence-induced inflammation. These findings indicate that the macrophage is a key player in the clearance of uterine senescent cells to maintain postpartum uterine function. Copyright © 2017 Endocrine Society.

  18. Longevity in mice is promoted by probiotic-induced suppression of colonic senescence dependent on upregulation of gut bacterial polyamine production.

    Directory of Open Access Journals (Sweden)

    Mitsuharu Matsumoto

    Full Text Available BACKGROUND: Chronic low-grade inflammation is recognized as an important factor contributing to senescence and age-related diseases. In mammals, levels of polyamines (PAs decrease during the ageing process; PAs are known to decrease systemic inflammation by inhibiting inflammatory cytokine synthesis in macrophages. Reductions in intestinal luminal PAs levels have been associated with intestinal barrier dysfunction. The probiotic strain Bifidobacterium animalis subsp. lactis LKM512 is known to increase intestinal luminal PA concentrations. METHODOLOGY/PRINCIPAL FINDINGS: We supplemented the diet of 10-month-old Crj:CD-1 female mice with LKM512 for 11 months, while the controls received no supplementation. Survival rates were compared using Kaplan-Meier survival curves. LKM512-treated mice survived significantly longer than controls (P<0.001; moreover, skin ulcers and tumors were more common in the control mice. We then analyzed inflammatory and intestinal conditions by measuring several markers using HPLC, ELISA, reverse transcription-quantitative PCR, and histological slices. LKM512 mice showed altered 16S rRNA gene expression of several predominant intestinal bacterial groups. The fecal concentrations of PAs, but not of short-chain fatty acids, were significantly higher in LKM512-treated mice (P<0.05. Colonic mucosal function was also better in LKM512 mice, with increased mucus secretion and better maintenance of tight junctions. Changes in gene expression levels were evaluated using the NimbleGen mouse DNA microarray. LKM512 administration also downregulated the expression of ageing-associated and inflammation-associated genes and gene expression levels in 21-month-old LKM512-treated mice resembled those in 10-month-old untreated (younger mice. CONCLUSION/SIGNIFICANCE: Our study demonstrated increased longevity in mice following probiotic treatment with LKM512, possibly due to the suppression of chronic low-grade inflammation in the colon

  19. Using parallel factor analysis modeling (PARAFAC) and self-organizing maps to track senescence-induced patterns in leaf litter leachate

    Science.gov (United States)

    Wheeler, K. I.; Levia, D. F., Jr.; Hudson, J. E.

    2017-12-01

    As trees undergo autumnal processes such as resorption, senescence, and leaf abscission, the dissolved organic matter (DOM) contribution of leaf litter leachate to streams changes. However, little research has investigated how the fluorescent DOM (FDOM) changes throughout the autumn and how this differs inter- and intraspecifically. Two of the major impacts of global climate change on forested ecosystems include altering phenology and causing forest community species and subspecies composition restructuring. We examined changes in FDOM in leachate from American beech (Fagus grandifolia Ehrh.) leaves in Maryland, Rhode Island, Vermont, and North Carolina and yellow poplar (Liriodendron tulipifera L.) leaves from Maryland throughout three different phenophases: green, senescing, and freshly abscissed. Beech leaves from Maryland and Rhode Island have previously been identified as belonging to the same distinct genetic cluster and beech trees from Vermont and the study site in North Carolina from the other. FDOM in samples was characterized using excitation-emission matrices (EEMs) and a six-component parallel factor analysis (PARAFAC) model was created to identify components. Self-organizing maps (SOMs) were used to visualize variation and patterns in the PARAFAC component proportions of the leachate samples. Phenophase and species had the greatest influence on determining where a sample mapped on the SOM when compared to genetic clusters and geographic origin. Throughout senescence, FDOM from all the trees transitioned from more protein-like components to more humic-like ones. Percent greenness of the sampled leaves and the proportion of the tyrosine-like component 1 were found to significantly differ between the two genetic beech clusters. This suggests possible differences in photosynthesis and resorption between the two genetic clusters of beech. The use of SOMs to visualize differences in patterns of senescence between the different species and genetic

  20. The coupling of mechanical dynamics and induced currents in plates and surfaces

    International Nuclear Information System (INIS)

    Weissenburger, D.W.; Bialek, J.M.

    1986-10-01

    Significant mechanical reactions and deflections may be produced when electrical eddy currents induced in a conducting structure by transformer-like electromotive forces interact with background magnetic fields. Additional eddy currents induced by structural motion through the background fields modify both the mechanical and electrical dynamic behavior of the system. The observed effects of these motional eddy currents are sometimes referred to as magnetic damping and magnetic stiffness. This paper addresses the coupled structural deformation and eddy currents in flat plates and simple two-dimensional surfaces in three-space. A coupled system of equations has been formulated using finite element techniques for the mechanical aspects and a mesh network method for the electrical aspects of the problem

  1. LASER INDUCED SELECTIVE ACTIVATION UTILIZING AUTO-CATALYTIC ELECTROLESS PLATING ON POLYMER SURFACE

    DEFF Research Database (Denmark)

    Zhang, Yang; Nielsen, Jakob Skov; Tang, Peter Torben

    2009-01-01

    . Characterization of the deposited copper layer was used to select and improve laser parameters. Several types of polymers with different melting points were used as substrate. Using the above mentioned laser treatment, standard grades of thermoplastic materials such as ABS, SAN, PE, PC and others have been......This paper presents a new method for selective micro metallization of polymers induced by laser. An Nd: YAG laser was employed to draw patterns on polymer surfaces using a special set-up. After subsequent activation and auto-catalytic electroless plating, copper only deposited on the laser tracks....... Induced by the laser, porous and rough structures are formed on the surface, which favours the palladium attachment during the activation step prior to the metallization. Laser focus detection, scanning electron microscopy (SEM) and other instruments were used to analyze the topography of the laser track...

  2. Melatonin reverses H2 O2 -induced senescence in SH-SY5Y cells by enhancing autophagy via sirtuin 1 deacetylation of the RelA/p65 subunit of NF-κB.

    Science.gov (United States)

    Nopparat, Chutikorn; Sinjanakhom, Puritat; Govitrapong, Piyarat

    2017-08-01

    Autophagy, a degradation mechanism that plays a major role in maintaining cellular homeostasis and diminishes in aging, is considered an aging characteristic. Melatonin is an important hormone that plays a wide range of physiological functions, including the anti-aging effect, potentially via the regulation of the Sirtuin1 (SIRT1) pathway. The deacetylation ability of SIRT1 is important for controlling the function of several transcription factors, including nuclear factor kappa B (NF-ĸB). Apart from inflammation, NF-ĸB can regulate autophagy by inhibiting Beclin1, an initiator of autophagy. Although numerous studies have revealed the role of melatonin in regulating autophagy, very limited experiments have shown that melatonin can increase autophagic activity via SIRT1 in a senescent model. This study focuses on the effect of melatonin on autophagy via the deacetylation activity of SIRT1 on RelA/p65, a subunit of NF-ĸB, to determine whether melatonin can attenuate the aging condition. SH-SY5Y cells were treated with H 2 O 2 to induce the senescent state. These results demonstrated that melatonin reduced a number of beta-galactosidase (SA-βgal)-positive cells, a senescent marker. In addition, melatonin increased the protein levels of SIRT1, Beclin1, and LC3-II, a hallmark protein of autophagy, and reduced the levels of acetylated-Lys310 in the p65 subunit of NF-ĸB in SH-SY5Y cells treated with H 2 O 2 . Furthermore, in the presence of SIRT1 inhibitor, melatonin failed to increase autophagic markers. The present data indicate that melatonin enhances autophagic activity via the SIRT1 signaling pathway. Taken together, we propose that in modulating autophagy, melatonin may provide a therapeutically beneficial role in the anti-aging processes. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  3. Transcriptional profile of genes involved in ascorbate glutathione cycle in senescing leaves for an early senescence leaf (esl) rice mutant.

    Science.gov (United States)

    Li, Zhaowei; Su, Da; Lei, Bingting; Wang, Fubiao; Geng, Wei; Pan, Gang; Cheng, Fangmin

    2015-03-15

    To clarify the complex relationship between ascorbate-glutathione (AsA-GSH) cycle and H2O2-induced leaf senescence, the genotype-dependent difference in some senescence-related physiological parameters and the transcript levels and the temporal patterns of genes involved in the AsA-GSH cycle during leaf senescence were investigated using two rice genotypes, namely, the early senescence leaf (esl) mutant and its wild type. Meanwhile, the triggering effect of exogenous H2O2 on the expression of OsAPX genes was examined using detached leaves. The results showed that the esl mutant had higher H2O2 level than its wild type at the initial stage of leaf senescence. At transcriptional level, the association of expression of various genes involved in the AsA-GSH cycle with leaf senescence was isoform dependent. For OsAPXs, the transcripts of two cytosolic OsAPX genes (OsAPX1 and OsAPX2), thylakoid-bound OsAPX8, chloroplastic OsAPX7 and peroxisomal OsAPX4 exhibited remarkable genotype-dependent variation in their expression levels and temporal patterns during leaf senescence, there were significantly increasing transcripts of OsAXP1 and OsAPX7, severely repressed transcripts of OsAPX4 and OsAPX8 for the esl rice at the initial leaf senescence. In contrast, the repressing transcript of OsAPX8 was highly sensitive to the increasing H2O2 level in the senescing rice leaves, while higher H2O2 concentration resulted in the enhancing transcripts of two cytosolic OsAPX genes, OsAPX7 transcript was greatly variable with different H2O2 concentrations and incubating duration, suggesting that the different OsAPXs isoforms played a complementary role in perceiving and scavenging H2O2 accumulation at various H2O2 concentrations during leaf senescence. Higher H2O2 level, increased AsA level, higher activities of APX and glutathione reductase (GR), and relatively stable GSH content during the entire sampling period in the leaves of esl mutant implied that a close interrelationship existed

  4. The Role of the S40 Gene Family in Leaf Senescence

    Directory of Open Access Journals (Sweden)

    Muhammad Jehanzeb

    2017-10-01

    Full Text Available Senescence affect different traits of plants, such as the ripening of fruit, number, quality and timing of seed maturation. While senescence is induced by age, growth hormones and different environmental stresses, a highly organized genetic mechanism related to substantial changes in gene expression regulates the process. Only a few genes associated to senescence have been identified in crop plants despite the vital significance of senescence for crop yield. The S40 gene family has been shown to play a role in leaf senescence. The barley HvS40 gene is one of the senescence marker genes which shows expression during age-dependent as well as dark-induced senescence. Like barley HvS40, the Arabidopsis AtS40-3 gene is also induced during natural senescence as well as in response to treatment with abscisic acid, salicylic acid, darkness and pathogen attack. It is speculated that rice OsS40 has a similar function in the leaf senescence of rice.

  5. Oxygen concentration modulates cellular senescence and autophagy in human trophoblast cells.

    Science.gov (United States)

    Seno, Kotomi; Tanikawa, Nao; Takahashi, Hironori; Ohkuchi, Akihide; Suzuki, Hirotada; Matsubara, Shigeki; Iwata, Hisataka; Kuwayama, Takehito; Shirasuna, Koumei

    2018-02-15

    We investigated the effect of oxygen concentrations on cellular senescence and autophagy and examined the role of autophagy in human trophoblast cells. Human first-trimester trophoblast cells (Sw.71) were incubated under 21%, 5%, or 1% O 2 concentrations for 24 hours. We examined the extent of senescence caused using senescence-associated β-galactosidase (SA-β-Gal) and senescence-associated secretory phenotype (SASP) as markers. Moreover, we examined the role of autophagy in causing cellular senescence using an autophagy inhibitor (3-methyladenine, 3MA). Physiological normoxia (5% O 2 ) decreased SA-β-Gal-positive cells and SASP including interleukin-6 (IL-6) and IL-8 compared with cultured cells in 21% O 2 . Pathophysiological hypoxia (1% O 2 ) caused cytotoxicity, including extracellular release of ATP and lactate dehydrogenase, and decreased senescence phenotypes. 3MA-treated trophoblast cells significantly suppressed senescence markers (SA-β-Gal-positive cells and SASP secretion) in O 2 -independent manner. We conclude that O 2 concentration modulates cellular senescence phenotypes regulating autophagy in the human trophoblast cells. Moreover, inhibiting autophagy suppresses cellular senescence, suggesting that autophagy contributes to oxygen stress-induced cellular senescence. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  6. Effects of hypobaric Endurance Training on Graded Exercise Induced Lymphocyte Mobilization, Senescence and Their Surface Thiol Levels in Elite Male Athletes

    Directory of Open Access Journals (Sweden)

    Karim - Azali Alamdari

    2018-03-01

    Full Text Available The effects of each hypoxemic exercise session or overall training period still remains to be more elucidated in elite athletes. Therefore, we investigated the effects of hypobaric endurance training on lymphocytes mobilization and senescence and also their surface Thiol levels following to graded exercise test (GXT in elite male athletes. Fourty six volunteer subjects were randomized into normobaric control (NC, hypobaric control (HC, normobaric exercise (NE and hypobaric exercise (HE groups. The NE and HE groups were exposed to homeland (700 mmHg and 2800 meters above sea level (570 mmHg simulated barometric pressures respectively, while HC and NC groups were remained sedentary at the same conditions. The training was included on treadmill running for four weeks, five sessions/week, 45 min/ session. Each session was consisted of three-min warmed up period, three cycles of 10-min running at 65% maximal heart rate reserve (HRRmax interspersed with a three-min active recovery and three-min cool-down running period. Two GXTs were performed before (baseline and after the interventions and blood samples were collected three times at both occasions. In all groups, mobilization of CD8+lymphocytes and senescent phenotype population of their both CD4+ and CD8+ subsets were increased after both GXTs, however; these changes were reversed following to recovery period(P<0.05. Moreover, HE were decreased lymphocytes surface thiol levels before and after the second GXT (P<0.05.it can be concluded that HE has no additional benefits for elite athletes regarded to lymphocytes mobilization and senescence, however; it may render them to oxidative stress.  

  7. Accumulation of senescent cells in mitotic tissue of aging primates.

    Science.gov (United States)

    Jeyapalan, Jessie C; Ferreira, Mark; Sedivy, John M; Herbig, Utz

    2007-01-01

    Cellular senescence, a stress induced growth arrest of somatic cells, was first documented in cell cultures over 40 years ago, however its physiological significance has only recently been demonstrated. Using novel biomarkers of cellular senescence we examined whether senescent cells accumulate in tissues from baboons of ages encompassing the entire lifespan of this species. We show that dermal fibroblasts, displaying markers of senescence such as telomere damage, active checkpoint kinase ATM, high levels of heterochromatin proteins and elevated levels of p16, accumulate in skin biopsies from baboons with advancing age. The number of dermal fibroblasts containing damaged telomeres reaches a value of over 15% of total fibroblasts, whereas 80% of cells contain high levels of the heterochromatin protein HIRA. In skeletal muscle, a postmitotic tissue, only a small percentage of myonuclei containing damaged telomeres were detected regardless of animal age. The presence of senescent cells in mitotic tissues might therefore be a contributing factor to aging and age related pathology and provides further evidence that cellular senescence is a physiological event.

  8. Gene pathways that delay Caenorhabditis elegans reproductive senescence.

    Directory of Open Access Journals (Sweden)

    Meng C Wang

    2014-12-01

    Full Text Available Reproductive senescence is a hallmark of aging. The molecular mechanisms regulating reproductive senescence and its association with the aging of somatic cells remain poorly understood. From a full genome RNA interference (RNAi screen, we identified 32 Caenorhabditis elegans gene inactivations that delay reproductive senescence and extend reproductive lifespan. We found that many of these gene inactivations interact with insulin/IGF-1 and/or TGF-β endocrine signaling pathways to regulate reproductive senescence, except nhx-2 and sgk-1 that modulate sodium reabsorption. Of these 32 gene inactivations, we also found that 19 increase reproductive lifespan through their effects on oocyte activities, 8 of them coordinate oocyte and sperm functions to extend reproductive lifespan, and 5 of them can induce sperm humoral response to promote reproductive longevity. Furthermore, we examined the effects of these reproductive aging regulators on somatic aging. We found that 5 of these gene inactivations prolong organismal lifespan, and 20 of them increase healthy life expectancy of an organism without altering total life span. These studies provide a systemic view on the genetic regulation of reproductive senescence and its intersection with organism longevity. The majority of these newly identified genes are conserved, and may provide new insights into age-associated reproductive senescence during human aging.

  9. Redox regulation of peroxiredoxin and proteinases by ascorbate and thiols during pea root nodule senescence.

    Science.gov (United States)

    Groten, Karin; Dutilleul, Christelle; van Heerden, Philippus D R; Vanacker, Hélène; Bernard, Stéphanie; Finkemeier, Iris; Dietz, Karl-Josef; Foyer, Christine H

    2006-02-20

    Redox factors contributing to nodule senescence were studied in pea. The abundance of the nodule cytosolic peroxiredoxin but not the mitochondrial peroxiredoxin protein was modulated by ascorbate. In contrast to redox-active antioxidants such as ascorbate and cytosolic peroxiredoxin that decreased during nodule development, maximal extractable nodule proteinase activity increased progressively as the nodules aged. Cathepsin-like activities were constant throughout development but serine and cysteine proteinase activities increased during senescence. Senescence-induced cysteine proteinase activity was inhibited by cysteine, dithiotreitol, or E-64. Senescence-dependent decreases in redox-active factors, particularly ascorbate and peroxiredoxin favour decreased redox-mediated inactivation of cysteine proteinases.

  10. The Dual Role of Cellular Senescence in Developing Tumors and Their Response to Cancer Therapy

    Directory of Open Access Journals (Sweden)

    Markus Schosserer

    2017-11-01

    Full Text Available Cellular senescence describes an irreversible growth arrest characterized by distinct morphology, gene expression pattern, and secretory phenotype. The final or intermediate stages of senescence can be reached by different genetic mechanisms and in answer to different external and internal stresses. It has been maintained in the literature but never proven by clearcut experiments that the induction of senescence serves the evolutionary purpose of protecting the individual from development and growth of cancers. This hypothesis was recently scrutinized by new experiments and found to be partly true, but part of the gene activities now known to happen in senescence are also needed for cancer growth, leading to the view that senescence is a double-edged sword in cancer development. In current cancer therapy, cellular senescence is, on the one hand, intended to occur in tumor cells, as thereby the therapeutic outcome is improved, but might, on the other hand, also be induced unintentionally in non-tumor cells, causing inflammation, secondary tumors, and cancer relapse. Importantly, organismic aging leads to accumulation of senescent cells in tissues and organs of aged individuals. Senescent cells can occur transiently, e.g., during embryogenesis or during wound healing, with beneficial effects on tissue homeostasis and regeneration or accumulate chronically in tissues, which detrimentally affects the microenvironment by de- or transdifferentiation of senescent cells and their neighboring stromal cells, loss of tissue specific functionality, and induction of the senescence-associated secretory phenotype, an increased secretory profile consisting of pro-inflammatory and tissue remodeling factors. These factors shape their surroundings toward a pro-carcinogenic microenvironment, which fuels the development of aging-associated cancers together with the accumulation of mutations over time. We are presenting an overview of well-documented stress

  11. Heat transfer effects on a viscous dissipative fluid flow past a vertical plate in the presence of induced magnetic field

    Directory of Open Access Journals (Sweden)

    M.C. Raju

    2015-03-01

    Full Text Available A theoretical analysis is performed to study induced magnetic field effects on free convection flow past a vertical plate. The x¯-axis is taken vertically upwards along the plate, y¯-axis normal to the plate into the fluid region. It is assumed that the plate is electrically non-conducting and the applied magnetic field is of uniform strength (H0 and perpendicular to the plate. The magnetic Reynolds number of the flow is not taken to be small enough so that the induced magnetic field is taken into account. The coupled nonlinear partial differential equations are solved by Perturbation technique and the effects of various physical parameters on velocity, temperature, and induced magnetic fields are studied through graphs and tables. Variations in Skin friction and rate of heat transfer are also studied. It is observed that an increase in magnetic parameter decreases the velocity for both water and air. It is also seen that there is a fall in induced magnetic field as magnetic Prandtl number, and magnetic field parameter increase.

  12. Identification and measurement of dirt composition of manufactured steel plates using laser-induced breakdown spectroscopy.

    Science.gov (United States)

    Orzi, Daniel J O; Bilmes, Gabriel M

    2004-12-01

    Laser-induced breakdown spectroscopy (LIBS) was used for the characterization of the main components of the surface residual dirt produced in cold-rolled steel plates as a consequence of the manufacturing stages. At laser fluences between 0.05 J/cm(2) manufacturing process carbon residuals can also be found. By measuring light emission from the lambda = 495.9 nm line of Fe(I) after laser ablation, we developed a real-time on-line method for the determination of the concentration of iron particles present in the surface dirt. The obtained results open new possibilities in the design of real-time instruments for industrial applications as a quality control of products and processes.

  13. Improving poor fill factors for solar cells via light-induced plating

    International Nuclear Information System (INIS)

    Xing Zhao; Jia Rui; Ding Wuchang; Meng Yanlong; Jin Zhi; Liu Xinyu

    2012-01-01

    Silicon solar cells are prepared following the conventional fabrication processes, except for the metallization firing process. The cells are divided into two groups with higher and lower fill factors, respectively. After light-induced plating (LIP), the fill factors of the solar cells in both groups with different initial values reach the same level. Scanning electron microscope (SEM) images are taken under the bulk silver electrodes, which prove that the improvement for cells with a poor factor after LIP should benefit from sufficient exploitation of the high density silver crystals formed during the firing process. Moreover, the application of LIP to cells with poor electrode contact performance, such as nanowire cells and radial junction solar cells, is proposed. (semiconductor devices)

  14. Residual γH2AX foci induced by low dose x-ray radiation in bone marrow mesenchymal stem cells do not cause accelerated senescence in the progeny of irradiated cells.

    Science.gov (United States)

    Pustovalova, Margarita; Astrelina, Тatiana A; Grekhova, Anna; Vorobyeva, Natalia; Tsvetkova, Anastasia; Blokhina, Taisia; Nikitina, Victoria; Suchkova, Yulia; Usupzhanova, Daria; Brunchukov, Vitalyi; Kobzeva, Irina; Karaseva, Тatiana; Ozerov, Ivan V; Samoylov, Aleksandr; Bushmanov, Andrey; Leonov, Sergey; Izumchenko, Evgeny; Zhavoronkov, Alex; Klokov, Dmitry; Osipov, Andreyan N

    2017-11-21

    Mechanisms underlying the effects of low-dose ionizing radiation (IR) exposure (10-100 mGy) remain unknown. Here we present a comparative study of early (less than 24h) and delayed (up to 11 post-irradiation passages) radiation effects caused by low (80 mGy) vs intermediate (1000 mGy) dose X-ray exposure in cultured human bone marrow mesenchymal stem cells (MSCs). We show that γН2АХ foci induced by an intermediate dose returned back to the control value by 24 h post-irradiation. In contrast, low-dose irradiation resulted in residual γН2АХ foci still present at 24 h. Notably, these low dose induced residual γН2АХ foci were not co-localized with рАТМ foci and were observed predominantly in the proliferating Кi67 positive (Кi67+) cells. The number of γН2АХ foci and the fraction of nonproliferating (Кi67-) and senescent (SA-β-gal+) cells measured at passage 11 were increased in cultures exposed to an intermediate dose compared to unirradiated controls. These delayed effects were not seen in the progeny of cells that were irradiated with low-dose X-rays, although such exposure resulted in residual γН2АХ foci in directly irradiated cells. Taken together, our results support the hypothesis that the low-dose IR induced residual γH2AХ foci do not play a role in delayed irradiation consequences, associated with cellular senescence in cultured MSCs.

  15. Numerical investigation of hypersonic flat-plate boundary layer transition mechanism induced by different roughness shapes

    Science.gov (United States)

    Zhou, Yunlong; Zhao, Yunfei; Xu, Dan; Chai, Zhenxia; Liu, Wei

    2016-10-01

    The roughness-induced laminar-turbulent boundary layer transition is significant for high-speed aerospace applications. The transition mechanism is closely related to the roughness shape. In this paper, high-order numerical method is used to investigate the effect of roughness shape on the flat-plate laminar-to-turbulent boundary layer transition. Computations are performed in both the supersonic and hypersonic regimes (free-stream Mach number from 3.37 up to 6.63) for the square, cylinder, diamond and hemisphere roughness elements. It is observed that the square and diamond roughness elements are more effective in inducing transition compared with the cylinder and hemisphere ones. The square roughness element has the longest separated region in which strong unsteadiness exists and the absolute instability is formed, thus resulting in the earliest transition. The diamond roughness element has a maximum width of the separated region leading to the widest turbulent wake region far downstream. Furthermore, transition location moves backward as the Mach number increases, which indicates that the compressibility significantly suppresses the roughness-induced boundary layer transition.

  16. Hippocampal neurochemical changes in senescent mice induced with chronic injection of D-galactose and NaNO₂: an in vitro high-resolution NMR spectroscopy study at 9.4T.

    Directory of Open Access Journals (Sweden)

    Yan Lin

    Full Text Available Proton magnetic resonance spectroscopy (¹H-MRS has been used to provide useful information about the neurochemical changes reflecting early pathological alterations in Alzheimer's disease (AD brain. In this study, we have longitudinally measured the hippocampal neurochemical profile in vitro in senescent mice induced with chronic injection of D-Galactose and NaNO₂, at different time point from day 30 to day 70 with a 10-day interval. Pathological brain alterations induced by D-Galactose and NaNO₂ were monitored through hematoxylin and eosin (HE staining, Congo red staining and bielschowsky silver staining, and the cognition deficits were assessed via Morris Water Maze (MWM test. This D-galactose and NaNO₂ treated mouse model, characterized by an early-onset memory dysfunction, a robust neuronal loss, amyloid plaques and neurofibrillary tangles in hippocampal subdivision, well mimics a prodromal Alzheimer's phenotype. Consistent with previously published in vivo ¹H MRS findings in human AD patients and AD transgenic mice, our in vitro ¹H MRS on the perchloric acid extractions of hippocampus in senescent mice observed significant decreases of N-acetylaspartate (NAA and Glutamate (Glu but an increase in Myo-inositol (mIns. Elevated mIns occurred prior to the reduction of NAA and Glu during the progression of aging. In addition, changes in mIns, NAA and Glu were found to precede pathological abnormalities. Overall, our in vitro findings in senescent mice validated the concept that hippocampal neurochemical alternations preceded the pathological changes of the brain, and could serve as potential markers of AD progression. Reductions of NAA and Glu can be interpreted in terms of neuronal degeneration and dysfunctions in glutamatergic activity that may contribute to the pathophysiological mechanisms underlying AD. Elevated mIns might be related to glial activation. Further experiments are needed to explore the potential value of mIns in the

  17. MicroRNA-33 promotes the replicative senescence of mouse embryonic fibroblasts by suppressing CDK6

    Energy Technology Data Exchange (ETDEWEB)

    Xu, Shun; Huang, Haijiao; Li, Nanhong; Zhang, Bing; Jia, Yubin; Yang, Yukun; Yuan, Yuan; Xiong, Xing-dong; Wang, Dengchuan; Zheng, Hui-ling [Institute of Aging Research, Guangdong Medical University, Dongguan (China); Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Dongguan (China); Institute of Biochemistry & Molecular Biology, Guangdong Medical University, Zhanjiang (China); Liu, Xinguang, E-mail: xgliu64@126.com [Institute of Aging Research, Guangdong Medical University, Dongguan (China); Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Dongguan (China); Institute of Biochemistry & Molecular Biology, Guangdong Medical University, Zhanjiang (China)

    2016-05-13

    MicroRNAs are a large class of tiny noncoding RNAs, which have emerged as critical regulators of gene expression, and thus are involved in multiple cellular processes, including cellular senescence. MicroRNA-33 has previously been established to exert crucial effect on cell proliferation, lipid metabolism and cholesterol metabolism. Nonetheless, the association between microRNA-33 and cellular senescence and its underlying molecular mechanism are far to be elucidated. The present study has attempted to probe into the effect of microRNA-33 on MEFs senescence. Our data unveiled that microRNA-33 was dramatically down-regulated in senescent MEFs compared to the young MEFs, and ectopic expression of microRNA-33 promoted MEFs senescence, while knock-down of microRNA-33 exhibited a protective effect against senescence phenotype. Moreover, we verified CDK6 as a direct target of microRNA-33 in mouse. Silencing of CDK6 induced the premature senescence phenotype of MEFs similarly as microRNA-33, while enforced expression of CDK6 significantly reverse the senescence-induction effect of microRNA-33. Taken together, our results suggested that microRNA-33 enhanced the replicative senescence of MEFs potentially by suppressing CDK6 expression. -- Highlights: •MicroRNA-33 was dramatically down-regulated in senescent MEF cells. •Altered expression of microRNA-33 exerted a critical role in MEFs senescence. •MicroRNA-33 promoted the replicative senescence of MEFs via targeting of CDK6.

  18. MicroRNA-33 promotes the replicative senescence of mouse embryonic fibroblasts by suppressing CDK6

    International Nuclear Information System (INIS)

    Xu, Shun; Huang, Haijiao; Li, Nanhong; Zhang, Bing; Jia, Yubin; Yang, Yukun; Yuan, Yuan; Xiong, Xing-dong; Wang, Dengchuan; Zheng, Hui-ling; Liu, Xinguang

    2016-01-01

    MicroRNAs are a large class of tiny noncoding RNAs, which have emerged as critical regulators of gene expression, and thus are involved in multiple cellular processes, including cellular senescence. MicroRNA-33 has previously been established to exert crucial effect on cell proliferation, lipid metabolism and cholesterol metabolism. Nonetheless, the association between microRNA-33 and cellular senescence and its underlying molecular mechanism are far to be elucidated. The present study has attempted to probe into the effect of microRNA-33 on MEFs senescence. Our data unveiled that microRNA-33 was dramatically down-regulated in senescent MEFs compared to the young MEFs, and ectopic expression of microRNA-33 promoted MEFs senescence, while knock-down of microRNA-33 exhibited a protective effect against senescence phenotype. Moreover, we verified CDK6 as a direct target of microRNA-33 in mouse. Silencing of CDK6 induced the premature senescence phenotype of MEFs similarly as microRNA-33, while enforced expression of CDK6 significantly reverse the senescence-induction effect of microRNA-33. Taken together, our results suggested that microRNA-33 enhanced the replicative senescence of MEFs potentially by suppressing CDK6 expression. -- Highlights: •MicroRNA-33 was dramatically down-regulated in senescent MEF cells. •Altered expression of microRNA-33 exerted a critical role in MEFs senescence. •MicroRNA-33 promoted the replicative senescence of MEFs via targeting of CDK6.

  19. Premature aging/senescence in cancer cells facing therapy: good or bad?

    Science.gov (United States)

    Gonzalez, Llilians Calvo; Ghadaouia, Sabrina; Martinez, Aurélie; Rodier, Francis

    2016-02-01

    Normal and cancer cells facing their demise following exposure to radio-chemotherapy can actively participate in choosing their subsequent fate. These programmed cell fate decisions include true cell death (apoptosis-necroptosis) and therapy-induced cellular senescence (TIS), a permanent "proliferative arrest" commonly portrayed as premature cellular aging. Despite a permanent loss of proliferative potential, senescent cells remain viable and are highly bioactive at the microenvironment level, resulting in a prolonged impact on tissue architecture and functions. Cellular senescence is primarily documented as a tumor suppression mechanism that prevents cellular transformation. In the context of normal tissues, cellular senescence also plays important roles in tissue repair, but contributes to age-associated tissue dysfunction when senescent cells accumulate. Theoretically, in multi-step cancer progression models, cancer cells have already bypassed cellular senescence during their immortalization step (see hallmarks of cancer). It is then perhaps surprising to find that cancer cells often retain the ability to undergo TIS, or premature aging. This occurs because cellular senescence results from multiple signalling pathways, some retained in cancer cells, aiming to prevent cell cycle progression in damaged cells. Since senescent cancer cells persist after therapy and secrete an array of cytokines and growth factors that can modulate the tumor microenvironment, these cells may have beneficial and detrimental effects regarding immune modulation and survival of remaining proliferation-competent cancer cells. Similarly, while normal cells undergoing senescence are believed to remain indefinitely growth arrested, whether this is true for senescent cancer cells remains unclear, raising the possibility that these cells may represent a reservoir for cancer recurrence after treatment. This review discusses our current knowledge on cancer cell senescence and highlight questions

  20. The emerging role of senescent cells in tissue homeostasis and pathophysiology

    Directory of Open Access Journals (Sweden)

    Kaoru Tominaga

    2015-05-01

    Full Text Available Cellular senescence is a state of permanent growth arrest and is thought to play a pivotal role in tumor suppression. Cellular senescence may play an important role in tumor suppression, wound healing, and protection against tissue fibrosis in physiological conditions in vivo. However, accumulating evidence that senescent cells may have harmful effects in vivo and may contribute to tissue remodeling, organismal aging, and many age-related diseases also exists. Cellular senescence can be induced by various intrinsic and extrinsic factors. Both p53/p21 and p16/RB pathways are important for irreversible growth arrest in senescent cells. Senescent cells secret numerous biologically active factors. This specific secretion phenotype by senescent cells may largely contribute to physiological and pathological consequences in organisms. Here I review the molecular basis of cell cycle arrest and the specific secretion phenotype in cellular senescence. I also summarize the current knowledge of the role of cellular senescence in vivo in physiological and pathological settings.

  1. Physiological and biochemical aspects of flower development and senescence in Nicotiana plumbaginifolia Viv.

    Directory of Open Access Journals (Sweden)

    Nisar Shaziya

    2017-06-01

    Full Text Available Healthy buds of Nicotiana plumbaginifolia growing in the Kashmir University Botanic Garden were selected for the present study. Flower development and senescence was divided into seven stages, viz., tight bud stage (I, mature bud stage (II, pencil stage (III, partially open stage (IV, open stage (V, partially senescent stage (VI and senescent stage (VII. Various physiological and biochemical changes were recorded at each stage of flower development and senescence. Floral diameter, fresh mass, dry mass and water content showed an increase up to flower opening (stage V and thereafter a significant decrease was recorded as the flower development progressed towards senescence through stages VI and VII. An increase in α-amino acids, total phenols and sugars was registered towards anthesis (stage V and a decrease in these parameters was recorded with senescence. Protease activity showed a significant increase towards senescence with a concomitant decrease in soluble proteins. Based on the quantitative analysis of various biochemical parameters, the flower opening in N. plumbaginifolia seems to be accompanied by an increase in the water content, soluble proteins, α‑amino acids and phenols. A decrease in these parameters, besides an increase in protease activity induces senescence in the beautiful flowers of N. plumbaginifolia. Understanding flower senescence may help in improving the postharvest performance of this beautiful ornamental flower to make it a potential material for the floriculture industry.

  2. On the thermally-induced residual stresses in thick fiber-thermoplastic matrix (PEEK) cross-ply laminated plates

    Science.gov (United States)

    Hu, Shoufeng; Nairn, John A.

    1992-01-01

    An analytical method for calculating thermally-induced residual stresses in laminated plates is applied to cross-ply PEEK laminates. We considered three cooling procedures: slow cooling (uniform temperature distribution); convective and radiative cooling; and rapid cooling by quenching (constant surface temperature). Some of the calculated stresses are of sufficient magnitude to effect failure properties such as matrix microcracking.

  3. Air bubble-induced detachment of polystyrene particles with different sizes from collector surfaces in a parallel plate flow chamber

    NARCIS (Netherlands)

    Gomez-Suarez, C; van der Mei, HC; Busscher, HJ

    2001-01-01

    Particle size was found to be an important factor in air bubble-induced detachment of colloidal particles from collector surfaces in a parallel plate flow chamber and generally polystyrene particles with a diameter of 806 nm detached less than particles with a diameter of 1400 nm. Particle

  4. Aging of mice is associated with p16(Ink4a)- and β-galactosidase-positive macrophage accumulation that can be induced in young mice by senescent cells.

    Science.gov (United States)

    Hall, Brandon M; Balan, Vitaly; Gleiberman, Anatoli S; Strom, Evguenia; Krasnov, Peter; Virtuoso, Lauren P; Rydkina, Elena; Vujcic, Slavoljub; Balan, Karina; Gitlin, Ilya; Leonova, Katerina; Polinsky, Alexander; Chernova, Olga B; Gudkov, Andrei V

    2016-07-01

    Senescent cells (SCs) have been considered a source of age-related chronic sterile systemic inflammation and a target for anti-aging therapies. To understand mechanisms controlling the amount of SCs, we analyzed the phenomenon of rapid clearance of human senescent fibroblasts implanted into SCID mice, which can be overcome when SCs were embedded into alginate beads preventing them from immunocyte attack. To identify putative SC killers, we analyzed the content of cell populations in lavage and capsules formed around the SC-containing beads. One of the major cell types attracted by secretory factors of SCs was a subpopulation of macrophages characterized by p16(Ink4a) gene expression and β-galactosidase activity at pH6.0 (β-gal(pH6)), thus resembling SCs. Consistently, mice with p16(Ink4a) promoter-driven luciferase, developed bright luminescence of their peritoneal cavity within two weeks following implantation of SCs embedded in alginate beads. p16(Ink4a)/β-gal(pH6)-expressing cells had surface biomarkers of macrophages F4/80 and were sensitive to liposomal clodronate used for the selective killing of cells capable of phagocytosis. At the same time, clodronate failed to kill bona fide SCs generated in vitro by genotoxic stress. Old mice with elevated proportion of p16(Ink4a)/β-gal(pH6)-positive cells in their tissues demonstrated reduction of both following systemic clodronate treatment, indicating that a significant proportion of cells previously considered to be SCs are actually a subclass of macrophages. These observations point at a significant role of p16(Ink4a)/β-gal(pH6)-positive macrophages in aging, which previously was attributed solely to SCs. They require re-interpretation of the mechanisms underlying rejuvenating effects following eradication of p16(Ink4a)/β-gal(pH6)-positive cells and reconsideration of potential cellular target for anti-aging treatment.

  5. Blocking negative effects of senescence in human skin fibroblasts with a plant extract.

    Science.gov (United States)

    Lämmermann, Ingo; Terlecki-Zaniewicz, Lucia; Weinmüllner, Regina; Schosserer, Markus; Dellago, Hanna; de Matos Branco, André Dargen; Autheried, Dominik; Sevcnikar, Benjamin; Kleissl, Lisa; Berlin, Irina; Morizot, Frédérique; Lejeune, Francois; Fuzzati, Nicola; Forestier, Sandra; Toribio, Alix; Tromeur, Anaïs; Weinberg, Lionel; Higareda Almaraz, Juan Carlos; Scheideler, Marcel; Rietveld, Marion; El Ghalbzouri, Abdoel; Tschachler, Erwin; Gruber, Florian; Grillari, Johannes

    2018-01-01

    There is increasing evidence that senescent cells are a driving force behind many age-related pathologies and that their selective elimination increases the life- and healthspan of mice. Senescent cells negatively affect their surrounding tissue by losing their cell specific functionality and by secreting a pro-tumorigenic and pro-inflammatory mixture of growth hormones, chemokines, cytokines and proteases, termed the senescence-associated secretory phenotype (SASP). Here we identified an extract from the plant Solidago virgaurea subsp. alpestris , which exhibited weak senolytic activity, delayed the acquisition of a senescent phenotype and induced a papillary phenotype with improved functionality in human dermal fibroblasts. When administered to stress-induced premature senescent fibroblasts, this extract changed their global mRNA expression profile and particularly reduced the expression of various SASP components, thereby ameliorating the negative influence on nearby cells. Thus, the investigated plant extract represents a promising possibility to block age-related loss of tissue functionality.

  6. Suppression of vortex-induced vibrations in a flexible cylinder with elastic splitter plates

    Science.gov (United States)

    Huera-Huarte, Francisco

    2013-11-01

    Suppression of vortex-induced vibrations (VIV) is a topic that has received a lot of attention due to its practical implications in engineering design. Experiments have been conducted in a recirculating free surface water channel, with a working section of dimensions 1 × 1.1 × 2.5 m. A cylinder model made of a spring and a plastic cover was used for the experiments. It was placed horizontally and fully submerged in the water channel's free stream, hanging from two submersible load cells arranged to measure the total drag force on the cylinder. The model had several white points painted on its surface, so its VIV motion was obtained by imaging it with two cameras synchronised with a strobe light. Image processing allowed to obtain the displacements along the length of the cylinder with sub-pixel accuracy. Digital Particle Image Velocimetry (DPIV) was also used to quantify the wake downstream the cylinder. A full set of experiments was made for reference purposes with a plain cylinder without suppressors, and for the same conditions, several passive suppression devices such as elastic splitter plates of different sizes and shapes, were installed on the cylinder. Passive VIV suppression with drag reduction was achieved with some of the configurations tested. Funding provided by the Spanish Ministry of Science through grant DPI2012-37904 is acknowledged.

  7. Failure Analysis of a Nickel-Plated Electronic Connector Due to Salt-Induced Corrosion (ENGE 2014).

    Science.gov (United States)

    Lee, Na-Ri; Choi, Hyoung-Seuk; Choi, Duck-Kyun

    2015-10-01

    When electronic connectors in mobile devices are miniaturized, the thickness of plating decreases. However, this thin plating is expected to decrease the life of the connector due to problems with corrosion. In this study, salt spray aging tests were performed on miniaturized nickel-plated stainless steel electronic connectors to observe failure mechanisms in realistic environments. The tests were performed three times using a 5% NaCl solution in an atmosphere of 45 °C; each test included several cycles where one cycle was one 24-h period consisting of 8 h of salt spray and 16 h without salt spray. The nickel-plating layers were periodically observed by electron probe X-ray micro-analyzer, wavelength dispersive spectroscopy, and field-emission scanning electron microscopy to analyze and identify the corrosion mechanism. We found that the primary failure mode of the nickel plating is blistering and delamination. The corrosion mechanism is typically a chain reaction of several corrosion mechanisms: pitting corrosion --> stress corrosion cracking --> hydrogen-induced cracking --> blistering and delamination. Finally, we discuss countermeasures to prevent corrosion of the nickel layer based on the corrosion mechanisms identified in this study.

  8. Predatory senescence in ageing wolves.

    Science.gov (United States)

    MacNulty, Daniel R; Smith, Douglas W; Vucetich, John A; Mech, L David; Stahler, Daniel R; Packer, Craig

    2009-12-01

    It is well established that ageing handicaps the ability of prey to escape predators, yet surprisingly little is known about how ageing affects the ability of predators to catch prey. Research into long-lived predators has assumed that adults have uniform impacts on prey regardless of age. Here we use longitudinal data from repeated observations of individually-known wolves (Canis lupus) hunting elk (Cervus elaphus) in Yellowstone National Park to demonstrate that adult predatory performance declines with age and that an increasing ratio of senescent individuals in the wolf population depresses the rate of prey offtake. Because this ratio fluctuates independently of population size, predatory senescence may cause wolf populations of equal size but different age structure to have different impacts on prey populations. These findings suggest that predatory senescence is an important, though overlooked, factor affecting predator-prey dynamics.

  9. Predatory senescence in aging wolves

    Science.gov (United States)

    MacNulty, Daniel R.; Smith, Douglas W.; Vucetich, John A.; Mech, L. David; Stahler, Daniel R.; Packer, Craig

    2009-01-01

    It is well established that ageing handicaps the ability of prey to escape predators, yet surprisingly little is known about how ageing affects the ability of predators to catch prey. Research into long-lived predators has assumed that adults have uniform impacts on prey regardless of age. Here we use longitudinal data from repeated observations of individually-known wolves (Canis lupus) hunting elk (Cervus elaphus) in Yellowstone National Park to demonstrate that adult predatory performance declines with age and that an increasing ratio of senescent individuals in the wolf population depresses the rate of prey offtake. Because this ratio fluctuates independently of population size, predatory senescence may cause wolf populations of equal size but different age structure to have different impacts on prey populations. These findings suggest that predatory senescence is an important, though overlooked, factor affecting predator-prey dynamics.

  10. Predatory senescence in ageing wolves

    Science.gov (United States)

    MacNulty, D.R.; Smith, D.W.; Vucetich, J.A.; Mech, L.D.; Stahler, D.R.; Packer, C.

    2009-01-01

    It is well established that ageing handicaps the ability of prey to escape predators, yet surprisingly little is known about how ageing affects the ability of predators to catch prey. Research into long-lived predators has assumed that adults have uniform impacts on prey regardless of age. Here we use longitudinal data from repeated observations of individually-known wolves (Canis lupus) hunting elk (Cervus elaphus) in Yellowstone National Park to demonstrate that adult predatory performance declines with age and that an increasing ratio of senescent individuals in the wolf population depresses the rate of prey offtake. Because this ratio fluctuates independently of population size, predatory senescence may cause wolf populations of equal size but different age structure to have different impacts on prey populations. These findings suggest that predatory senescence is an important, though overlooked, factor affecting predator-prey dynamics. ?? 2009 Blackwell Publishing Ltd/CNRS.

  11. The nuclear receptor NR2E1/TLX controls senescence

    Science.gov (United States)

    Krusche, Benjamin; Pemberton, Helen; Alonso, Marta M.; Chandler, Hollie; Brookes, Sharon; Parrinello, Simona; Peters, Gordon; Gil, Jesús

    2014-01-01

    The nuclear receptor NR2E1 (also known as TLX or tailless) controls the self-renewal of neural stem cells (NSCs) and has been implied as an oncogene which initiates brain tumours including glioblastomas. Despite NR2E1 regulating targets like p21CIP1 or PTEN we still lack a full explanation for its role in NSC self-renewal and tumorigenesis. We know that Polycomb repressive complexes (PRC) also control stem cell self-renewal and tumorigenesis, but so far, no formal connection has been established between NR2E1 and PRCs. In a screen for transcription factors regulating the expression of the Polycomb protein CBX7, we identified NR2E1 as one of its more prominent regulators. NR2E1 binds at the CBX7 promoter, inducing its expression. Notably CBX7 represses NR2E1 as part of a regulatory loop. Ectopic NR2E1 expression inhibits cellular senescence, extending cellular lifespan in fibroblasts via CBX7-mediated regulation of p16INK4a and direct repression of p21CIP1. In addition NR2E1 expression also counteracts oncogene-induced senescence (OIS). The importance of NR2E1 to restrain senescence is highlighted through the process of knocking down its expression, which causes premature senescence in human fibroblasts and epithelial cells. We also confirmed that NR2E1 regulates CBX7 and restrains senescence in NSCs. Finally, we observed that the expression of NR2E1 directly correlates with that of CBX7 in human glioblastoma multiforme. Overall we identified control of senescence and regulation of Polycomb action as two possible mechanisms that can join those so far invoked to explain the role of NR2E1 in control of NSC self-renewal and cancer. PMID:25328137

  12. The nuclear receptor NR2E1/TLX controls senescence.

    Science.gov (United States)

    O'Loghlen, Ana; Martin, Nadine; Krusche, Benjamin; Pemberton, Helen; Alonso, Marta M; Chandler, Hollie; Brookes, Sharon; Parrinello, Simona; Peters, Gordon; Gil, Jesús

    2015-07-30

    The nuclear receptor NR2E1 (also known as TLX or tailless) controls the self-renewal of neural stem cells (NSCs) and has been implied as an oncogene which initiates brain tumors including glioblastomas. Despite NR2E1 regulating targets like p21(CIP1) or PTEN we still lack a full explanation for its role in NSC self-renewal and tumorigenesis. We know that polycomb repressive complexes also control stem cell self-renewal and tumorigenesis, but so far, no formal connection has been established between NR2E1 and PRCs. In a screen for transcription factors regulating the expression of the polycomb protein CBX7, we identified NR2E1 as one of its more prominent regulators. NR2E1 binds at the CBX7 promoter, inducing its expression. Notably CBX7 represses NR2E1 as part of a regulatory loop. Ectopic NR2E1 expression inhibits cellular senescence, extending cellular lifespan in fibroblasts via CBX7-mediated regulation of p16(INK4a) and direct repression of p21(CIP1). In addition NR2E1 expression also counteracts oncogene-induced senescence. The importance of NR2E1 to restrain senescence is highlighted through the process of knocking down its expression, which causes premature senescence in human fibroblasts and epithelial cells. We also confirmed that NR2E1 regulates CBX7 and restrains senescence in NSCs. Finally, we observed that the expression of NR2E1 directly correlates with that of CBX7 in human glioblastoma multiforme. Overall we identified control of senescence and regulation of polycomb action as two possible mechanisms that can join those so far invoked to explain the role of NR2E1 in control of NSC self-renewal and cancer.

  13. Oblique Wave-Induced Responses of A VLFS Edged with A Pair of Inclined Perforated Plates

    Science.gov (United States)

    Cheng, Yong; Ji, Chun-yan; Zhai, Gang-jun; Oleg, Gaidai

    2018-03-01

    This paper is concerned with the hydroelastic responses of a mat-like, rectangular very large floating structure (VLFS) edged with a pair of horizontal/inclined perforated anti-motion plates in the context of the direct coupling method. The updated Lagrangian formulae are applied to establish the equilibrium equations of the VLFS and the total potential formula is employed for fluids in the numerical model including the viscous effect of the perforated plates through the Darcy's law. The hybrid finite element-boundary element (FE-BE) method is implemented to determine the response reduction of VLFS with attached perforated plates under various oblique incident waves. Also, the numerical solutions are validated against a series of experimental tests. The effectiveness of the attached perforated plates in reducing the deflections of the VLFS can be significantly improved by selecting the proper design parameters such as the porous parameter, submergence depth, plate width and inclination angle for the given sea conditions.

  14. Lipid profiling demonstrates that suppressing Arabidopsis phospholipase Dδ retards ABA-promoted leaf senescence by attenuating lipid degradation.

    Directory of Open Access Journals (Sweden)

    Yanxia Jia

    Full Text Available Senescence is the last phase of the plant life cycle and has an important role in plant development. Degradation of membrane lipids is an essential process during leaf senescence. Several studies have reported fundamental changes in membrane lipids and phospholipase D (PLD activity as leaves senesce. Suppression of phospholipase Dα1 (PLDα1 retards abscisic acid (ABA-promoted senescence. However, given the absence of studies that have profiled changes in the compositions of membrane lipid molecules during leaf senescence, there is no direct evidence that PLD affects lipid composition during the process. Here, we show that application of n-butanol, an inhibitor of PLD, and N-Acylethanolamine (NAE 12∶0, a specific inhibitor of PLDα1, retarded ABA-promoted senescence to different extents. Furthermore, phospholipase Dδ (PLDδ was induced in leaves treated with ABA, and suppression of PLDδ retarded ABA-promoted senescence in Arabidopsis. Lipid profiling revealed that detachment-induced senescence had different effects on plastidic and extraplastidic lipids. The accelerated degradation of plastidic lipids during ABA-induced senescence in wild-type plants was attenuated in PLDδ-knockout (PLDδ-KO plants. Dramatic increases in phosphatidic acid (PA and decreases in phosphatidylcholine (PC during ABA-induced senescence were also suppressed in PLDδ-KO plants. Our results suggest that PLDδ-mediated hydrolysis of PC to PA plays a positive role in ABA-promoted senescence. The attenuation of PA formation resulting from suppression of PLDδ blocks the degradation of membrane lipids, which retards ABA-promoted senescence.

  15. Enhancement of Energy Harvesting Performance by a Coupled Bluff Splitter Body and PVEH Plate through Vortex Induced Vibration near Resonance

    Directory of Open Access Journals (Sweden)

    Wei Ken Chin

    2017-09-01

    Full Text Available Inspired by vortex induced vibration energy harvesting development as a new source of renewable energy, a T-shaped design vibration energy harvester is introduced with the aim of enhancing its performance through vortex induced vibration at near resonance conditions. The T-shaped structural model designed consists of a fixed boundary aluminum bluff splitter body coupled with a cantilever piezoelectric vibration energy harvesters (PVEH plate model which is a piezoelectric bimorph plate made of a brass plate sandwiched between 2 lead zirconate titanate (PZT plates. A 3-dimensional Fluid-Structure Interaction simulation analysis is carried out with Reynolds Stress Turbulence Model under wind speed of 7, 10, 12, 14, 16, 18, 19, 20, 22.5, and 25 m/s. The results showed that with 19 m/s wind speed, the model generates 75.758 Hz of vortex frequency near to the structural model’s natural frequency of 76.9 Hz. Resonance lock-in therefore occurred, generating a maximum displacement amplitude of 2.09 mm or a 49.76% increment relatively in vibrational amplitude. Under the effect of resonance at the PVEH plate’s fundamental natural frequency, it is able to generate the largest normalized power of 13.44 mW/cm3g2.

  16. Transgenic plants with altered senescence characteristics

    Science.gov (United States)

    Amasino, Richard M.; Gan, Susheng; Noh, Yoo-Sun

    2002-03-19

    The identification of senescence-specific promoters from plants is described. Using information from the first senescence-specific promoter, SAG12 from Arabidopsis, other homologous promoters from another plant have been identified. Such promoters may be used to delay senescence in commercially important plants.

  17. Evaluation and reduction of magnetic resonance imaging artifacts induced by distinct plates for osseous fixation: an in vitro study @ 3T.

    Science.gov (United States)

    Rendenbach, Carsten; Schoellchen, Maximilian; Bueschel, Julie; Gauer, Tobias; Sedlacik, Jan; Kutzner, Daniel; Vallittu, Pekka K; Heiland, Max; Smeets, Ralf; Fiehler, Jens; Siemonsen, Susanne

    2018-05-02

    To analyze Magnetic Resonance Imaging (MRI) artifact induced at 3 Tesla by bioresorbable, titanium and glass fiber reinforced composite (GFRC) plates for osseous reconstruction. Fixation plates including bioresorbable polymers (Inion CPS, Inion Oy, Tampere, Finland; Rapidsorb, DePuy Synthes, Umkirch, Germany; Resorb X, Gebrueder KLS Martin GmbH, Tuttlingen, Germany), Glass fiber reinforced composite (Skulle Implants Oy, Turku, Finland) and titanium plates of varying thickness and design (DePuy Synthes, Umkirch, Germany) were embedded in agarose gel and a 3T MRI was performed using a standard protocol for head and neck imaging including T1w and T2w sequences. Additionally, different artifact reducing sequence techniques (slice encoding for metal artifact reduction (SEMAC) & ultrashort echotime (UTE)) were used and their impact on the extent of artifacts evaluated for each material. All titanium plates induced significantly more artefacts than resorbable plates in T1w and T2w sequences. Glass fiber-reinforced composites induced the least artefacts in both sequences. The total extent of artefacts increased with plate thickness and height. Plate thickness had no influence on the percentage of overestimation in all three dimensions. Titanium induced artefacts were significantly reduced by both artifact reducing sequence techniques. Polylactide, glass fiber-reinforced composite and magnesium plates produce less susceptibility artefacts in MRI compared to titanium, while the dimensions of titanium plates directly influence artifact extension. SEMAC and UTE significantly reduce metal artefacts at the expense of image resolution.

  18. Long noncoding RNA PANDA and scaffold-attachment-factor SAFA control senescence entry and exit.

    Science.gov (United States)

    Puvvula, Pavan Kumar; Desetty, Rohini Devi; Pineau, Pascal; Marchio, Agnés; Moon, Anne; Dejean, Anne; Bischof, Oliver

    2014-11-19

    Cellular senescence is a stable cell cycle arrest that limits the proliferation of pre-cancerous cells. Here we demonstrate that scaffold-attachment-factor A (SAFA) and the long noncoding RNA PANDA differentially interact with polycomb repressive complexes (PRC1 and PRC2) and the transcription factor NF-YA to either promote or suppress senescence. In proliferating cells, SAFA and PANDA recruit PRC complexes to repress the transcription of senescence-promoting genes. Conversely, the loss of SAFA-PANDA-PRC interactions allows expression of the senescence programme. Accordingly, we find that depleting either SAFA or PANDA in proliferating cells induces senescence. However, in senescent cells where PANDA sequesters transcription factor NF-YA and limits the expression of NF-YA-E2F-coregulated proliferation-promoting genes, PANDA depletion leads to an exit from senescence. Together, our results demonstrate that PANDA confines cells to their existing proliferative state and that modulating its level of expression can cause entry or exit from senescence.

  19. The Splicing Factor SRSF1 as a Marker for Endothelial Senescence

    Science.gov (United States)

    Blanco, Francisco Javier; Bernabéu, Carmelo

    2012-01-01

    Aging is the major risk factor per se for the development of cardiovascular diseases. The senescence of the endothelial cells (ECs) that line the lumen of blood vessels is the cellular basis for these age-dependent vascular pathologies, including atherosclerosis and hypertension. During their lifespan, ECs may reach a stage of senescence by two different pathways; a replicative one derived from their preprogrammed finite number of cell divisions; and one induced by stress stimuli. Also, certain physiological stimuli, such as transforming growth factor-β, are able to modulate cellular senescence. Currently, the cellular aging process is being widely studied to identify novel molecular markers whose changes correlate with senescence. This review focuses on the regulation of alternative splicing mediated by the serine–arginine splicing factor 1 (SRSF1, or ASF/SF2) during endothelial senescence, a process that is associated with a differential subcellular localization of SRSF1, which typically exhibits a scattered distribution throughout the cytoplasm. Based on its senescence-dependent involvement in alternative splicing, we postulate that SRSF1 is a key marker of EC senescence, regulating the expression of alternative isoforms of target genes such as endoglin (ENG), vascular endothelial growth factor A (VEGFA), tissue factor (T3), or lamin A (LMNA) that integrate in a common molecular senescence program. PMID:22470345

  20. Protective effect of a phenolic extract containing indoline amides from Portulaca oleracea against cognitive impairment in senescent mice induced by large dose of D-galactose /NaNO2.

    Science.gov (United States)

    Wang, Peipei; Sun, Hongxiang; Liu, Dianyu; Jiao, Zezhao; Yue, Su; He, Xiuquan; Xia, Wen; Ji, Jianbo; Xiang, Lan

    2017-05-05

    Portulaca oleracea L. is a potherb and also a widely used traditional Chinese medicine. In accordance with its nickname "longevity vegetable", pharmacological study demonstrated that this plant possessed antioxidant, anti-aging, and cognition-improvement function. Active principles pertaining to these functions of P. oleracea need to be elucidated. The present study evaluated the effect of a phenolic extract (PAAs) from P. oleracea which contained specific antioxidant indoline amides on cognitive impairment in senescent mice. PAAs was prepared through AB-8 macroporous resin column chromatography. Total phenol content was determined using colorimetric method, and contents of indoline amides were determined using HPLC-UV method. Senescent Kunming mice with cognitive dysfunction were established by intraperitoneal injection of D-galactose (D-gal, 1250mg/kg/day) and NaNO 2 (90mg/kg/day) for 8 weeks, L-PAAs (360mg/kg/day), H-PAAs (720mg/kg/day), and nootropic drug piracetam (PA, 400mg/kg/day) as the positive control were orally administered. Spatial learning and memory abilities were evaluated by Morris water maze experiment. Activities of AChE, SOD, CAT, and levels of GSH and MDA in the brain or plasma were measured. Hippocampal morphology was observed by HE staining. Chronic treatment of large dose of D-gal/NaNO 2 significantly reduced lifespan, elevated AChE activity, decreased CAT activity, compensatorily up-regulated SOD activity and GSH level, increased MDA level, induced neuronal damage in hippocampal CA1, CA3 and CA4 regions, and impaired cognitive function. Similar to PA, PAAs prolonged the lifespan and improved spatial memory ability. Moreover, PAAs improved learning ability. H-PAAs significantly reversed compensatory increase in SOD activity to the normal level, elevated serum CAT activity, and reduced MDA levels in brain and plasma, more potent than L-PAAs. Besides these, PAAs evidently inhibited hippocampal neuronal damage. However, it had no effect on

  1. IL1-and TGF beta-Nox4 signaling, oxidative stress and DNA damage response are shared features of replicative, oncogene-induced, and drug-induced paracrine 'Bystander senescence'

    Czech Academy of Sciences Publication Activity Database

    Hubáčková, Soňa; Krejčíková, Kateřina; Bartek, Jiří; Hodný, Zdeněk

    2012-01-01

    Roč. 4, č. 12 (2012), 932-951 ISSN 1945-4589 R&D Projects: GA ČR GA204/08/1418; GA ČR GAP301/10/1525 Institutional support: RVO:68378050 Keywords : senescence-associated secretome * DNA damage response * cytokines * JAK/STAT3 * TGF beta * NF kappa B * IL6 * IL beta * Nox4 * autocrine and paracrine signaling * tumor Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 4.696, year: 2012

  2. NAC transcription factors in senescence

    DEFF Research Database (Denmark)

    Podzimska-Sroka, Dagmara; O'Shea, Charlotte; Gregersen, Per L.

    2015-01-01

    involving the hormone abscisic acid, Arabidopsis NAP promotes chlorophyll degradation, a hallmark of senescence. Furthermore, studies of the functional rice ortholog, OsNAP, suggest that NAC genes can be targeted to obtain specific changes in lifespan control and nutrient remobilization in crop plants...

  3. Laser Induced Forced Motion and Stress Waves in Plates and Shells.

    Science.gov (United States)

    1981-08-01

    the plate at the center, normal to the plate surface. The Laser used was a Holobeam model 630-QNd glass system. This Laser produces an output power (in...V o 0 0 I lue ceill I Ii 1)r1 i 11im and hot nchary\\ cond i t i ons S or tile i n it i aI I St ate toget her with ji(. 38c ) iiav he u ISed to

  4. Senescent T-Cells Promote Bone Loss in Rheumatoid Arthritis

    Directory of Open Access Journals (Sweden)

    Johannes Fessler

    2018-02-01

    Full Text Available ObjectiveT-cells are critical players in the pathogenesis of osteoporosis in patients with rheumatoid arthritis (RA. Premature senescence of lymphocytes including the accumulation of senescent CD4+ T-cells is a hallmark feature of RA. Whether T-cell senescence is associated with bone loss in RA patients is elusive so far.MethodsThis includes a prospective study of consecutive patients with RA (n = 107, patients with primary osteopenia/-porosis (n = 75, and healthy individuals (n = 38. Bone mineral density (BMD was determined by dual-energy X-ray absorptiometry scan. Flow cytometry, magnetic-associated cell sorting, and cell culture experiments were performed to analyze the pro-osteoclastic phenotype and the function of senescent CD4+CD28− T-cells.ResultsPatients with osteopenia/-porosis yielded a higher prevalence of senescent CD4+CD28− T-cells than individuals with normal BMD, in the RA, as well as in the non-RA cohort. Receptor activator of nuclear factor kappa-B ligand (RANKL was expressed at higher levels on CD4+CD28− T-cells as compared to CD28+ T-cells. Stimulation with interleukin-15 led to an up-regulation of RANKL expression, particularly on CD28− T-cells. CD4+CD28− T-cells induced osteoclastogenesis more efficiently than CD28+ T-cells.ConclusionOur data indicate that senescent T-cells promote osteoclastogenesis more efficiently than conventional CD28+ T-cells, which might contribute to the pathogenesis of systemic bone loss in RA and primary osteoporosis.

  5. Dynamic temperature field in the ferromagnetic plate induced by moving high frequency inductor

    Directory of Open Access Journals (Sweden)

    Milošević-Mitić Vesna

    2014-01-01

    Full Text Available The subject of the paper is the temperature distribution in the thin metallic ferromagnetic plate influenced by moving linear high frequency induction heater. As a result of high frequency electromagnetic field, conducting currents appear in the part of the plate. Distribution of the eddy-current power across the plate thickness is obtained by use of complex analysis. The influences of the heater frequency, magnetic field intensity and plate thickness on the heat power density were discussed. By treating this power as a moving heat source, differential equations governing distribution of the temperature field are formulated. Temperature across the plate thickness is assumed to be in linear form. Differential equations are analytically solved by using integral-transform technique, Fourier finite-sine and finite-cosine transform and Laplace transform. The influence of the heater velocity to the plate temperature is presented on numerical examples based on theoretically obtained results. [Projekat Ministarstva nauke Republike Srbije, br. TR 35040 i br. TR 35011

  6. Coupled effects of director orientations and boundary conditions on light induced bending of monodomain nematic liquid crystalline polymer plates

    International Nuclear Information System (INIS)

    You, Yue; Ding, Shurong; Huo, Yongzhong; Xu, Changwei

    2012-01-01

    A photo-chromic liquid crystal polymers (LCPs) is a smart material for large light-activated variation or bending to transfer luminous energy into mechanical energy. We study the light induced behavior by modeling planar and homeotropic nematic network polymer plates. We effectively illustrate some reported experimental outcomes and theoretically predict some possible bending patterns. This paper constructs an understanding between the bending behaviors and interactions among the alignments, aspect ratios and boundary conditions, etc. Our work provides information on optimizing light induced bending in the process of micro-opto-mechanical system (MOMS) design. (paper)

  7. Nitric oxide prevents alveolar senescence and emphysema in a mouse model.

    Directory of Open Access Journals (Sweden)

    Amanda E Boe

    Full Text Available Nω-nitro-L-arginine methyl ester (L-NAME treatment induces arteriosclerosis and vascular senescence. Here, we report that the systemic inhibition of nitric oxide (NO production by L-NAME causes pulmonary emphysema. L-NAME-treated lungs exhibited both the structural (alveolar tissue destruction and functional (increased compliance and reduced elastance characteristics of emphysema development. Furthermore, we found that L-NAME-induced emphysema could be attenuated through both genetic deficiency and pharmacological inhibition of plasminogen activator inhibitor-1 (PAI-1. Because PAI-1 is an important contributor to the development of senescence both in vitro and in vivo, we investigated whether L-NAME-induced senescence led to the observed emphysematous changes. We found that L-NAME treatment was associated with molecular and cellular evidence of premature senescence in mice, and that PAI-1 inhibition attenuated these increases. These findings indicate that NO serves to protect and defend lung tissue from physiological aging.

  8. Detachment of polystyrene particles from collector surfaces by surface tension forces induced by air-bubble passage through a parallel plate flow chamber

    NARCIS (Netherlands)

    Wit, PJ; vanderMei, HC; Busscher, HJ

    1997-01-01

    By allowing an air-bubble to pass through a parallel plate flow chamber with negatively charged, colloidal polystyrene particles adhering to the bottom collector plate of the chamber, the detachment of adhering particles stimulated by surface tension forces induced by the passage of a liquid-air

  9. Curcumin elevates sirtuin level but does not postpone in vitro senescence of human cells building the vasculature

    Science.gov (United States)

    Grabowska, Wioleta; Suszek, Małgorzata; Wnuk, Maciej; Lewinska, Anna; Wasiak, Emilia; Sikora, Ewa; Bielak-Zmijewska, Anna

    2016-01-01

    It is believed that curcumin, a component of the turmeric that belongs to hormetins, possesses anti-aging propensity. This property of curcumin can be partially explained by its influence on the level of sirtuins. Previously, we have shown that relatively high (2.5-10 μM) doses of curcumin induce senescence of cancer cells and cells building the vasculature. In the present study we examined whether curcumin at low doses (0.1 and 1 μM) is able to delay cell senescence and upregulate the level of sirtuins in human cells building the vasculature, namely vascular smooth muscle (VSMC) and endothelial (EC) cells. To this end we used cells senescing in a replicative and premature manner. We showed that low doses of curcumin in case of VSMC neither postponed the replicative senescence nor protected from premature senescence induced by doxorubicin. Moreover, curcumin slightly accelerated replicative senescence of EC. Despite some fluctuations, a clear increasing tendency in the level of sirtuins was observed in curcumin-treated young, senescing or already senescent cells. Sirtuin activation could be caused by the activation of AMPK resulting from superoxide elevation and ATP reduction. Our results show that curcumin at low doses can increase the level of sirtuins without delaying senescence of VSMC. PMID:27034011

  10. Overexpression of the novel senescence marker β-galactosidase (GLB1 in prostate cancer predicts reduced PSA recurrence.

    Directory of Open Access Journals (Sweden)

    Jennifer Wagner

    Full Text Available Senescence is a terminal growth arrest that functions as a tumor suppressor in aging and precancerous cells and is a response to selected anticancer compounds. Lysosomal-β-galactosidase (GLB1 hydrolyzes β-galactose from glycoconjugates and is the origin of senescence-associated β-gal activity (SA-β-gal. Using a new GLB1 antibody, senescence biology was investigated in prostate cancer (PCa tissues.In vitro characterization of GLB1 was determined in primary prostate epithelial cell cultures passaged to replicative senescence and in therapy-induced senescence in PCa lines using chemotherapeutic agents. FFPE tissue microarrays were subjected to immunofluorescent staining for GLB1, Ki67 and HP1γ and automated quantitative imaging initially using AQUA in exploratory samples and Vectra in a validation series.GLB1 expression accumulates in replicative and induced senescence and correlates with senescent morphology and P16 (CDKN2 expression. In tissue arrays, quantitative imaging detects increased GLB1 expression in high-grade prostatic intraepithelial neoplasia (HGPIN, known to contain senescent cells, and cancer compared to benign prostate tissues (p<0.01 and senescent cells contain low Ki67 and elevated HP1γ. Within primary tumors, elevated GLB1 associates with lower T stage (p=0.01, localized versus metastatic disease (p=0.0003 and improved PSA-free survival (p=0.03. Increased GLB1 stratifies better PSA-free survival in intermediate grade PCa (0.01. Tissues that elaborate higher GLB1 display increased uniformity of expression.Increased GLB1 is a valuable marker in formalin-fixed paraffin-embedded (FFPE tissues for the senescence-like phenotype and associates with improved cancer outcomes. This protein addresses a lack of senescence markers and should be applicable to study the biologic role of senescence in other cancers.

  11. IGF-I enhances cellular senescence via the reactive oxygen species-p53 pathway

    Energy Technology Data Exchange (ETDEWEB)

    Handayaningsih, Anastasia-Evi; Takahashi, Michiko; Fukuoka, Hidenori; Iguchi, Genzo; Nishizawa, Hitoshi; Yamamoto, Masaaki; Suda, Kentaro [Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe (Japan); Takahashi, Yutaka, E-mail: takahash@med.kobe-u.ac.jp [Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe (Japan)

    2012-08-24

    Highlights: Black-Right-Pointing-Pointer Cellular senescence plays an important role in tumorigenesis and aging process. Black-Right-Pointing-Pointer We demonstrated IGF-I enhanced cellular senescence in primary confluent cells. Black-Right-Pointing-Pointer IGF-I enhanced cellular senescence in the ROS and p53-dependent manner. Black-Right-Pointing-Pointer These results may explain the underlying mechanisms of IGF-I involvement in tumorigenesis and in regulation of aging. -- Abstract: Cellular senescence is characterized by growth arrest, enlarged and flattened cell morphology, the expression of senescence-associated {beta}-galactosidase (SA-{beta}-gal), and by activation of tumor suppressor networks. Insulin-like growth factor-I (IGF-I) plays a critical role in cellular growth, proliferation, tumorigenesis, and regulation of aging. In the present study, we show that IGF-I enhances cellular senescence in mouse, rat, and human primary cells in the confluent state. IGF-I induced expression of a DNA damage marker, {gamma}H2AX, the increased levels of p53 and p21 proteins, and activated SA-{beta}-gal. In the confluent state, an altered downstream signaling of IGF-I receptor was observed. Treatment with a reactive oxygen species (ROS) scavenger, N-acetylcystein (NAC) significantly suppressed induction of these markers, indicating that ROS are involved in the induction of cellular senescence by IGF-I. In p53-null mouse embryonic fibroblasts, the IGF-I-induced augmentation of SA-{beta}-gal and p21 was inhibited, demonstrating that p53 is required for cellular senescence induced by IGF-I. Thus, these data reveal a novel pathway whereby IGF-I enhances cellular senescence in the ROS and p53-dependent manner and may explain the underlying mechanisms of IGF-I involvement in tumorigenesis and in regulation of aging.

  12. IGF-I enhances cellular senescence via the reactive oxygen species–p53 pathway

    International Nuclear Information System (INIS)

    Handayaningsih, Anastasia-Evi; Takahashi, Michiko; Fukuoka, Hidenori; Iguchi, Genzo; Nishizawa, Hitoshi; Yamamoto, Masaaki; Suda, Kentaro; Takahashi, Yutaka

    2012-01-01

    Highlights: ► Cellular senescence plays an important role in tumorigenesis and aging process. ► We demonstrated IGF-I enhanced cellular senescence in primary confluent cells. ► IGF-I enhanced cellular senescence in the ROS and p53-dependent manner. ► These results may explain the underlying mechanisms of IGF-I involvement in tumorigenesis and in regulation of aging. -- Abstract: Cellular senescence is characterized by growth arrest, enlarged and flattened cell morphology, the expression of senescence-associated β-galactosidase (SA-β-gal), and by activation of tumor suppressor networks. Insulin-like growth factor-I (IGF-I) plays a critical role in cellular growth, proliferation, tumorigenesis, and regulation of aging. In the present study, we show that IGF-I enhances cellular senescence in mouse, rat, and human primary cells in the confluent state. IGF-I induced expression of a DNA damage marker, γH2AX, the increased levels of p53 and p21 proteins, and activated SA-β-gal. In the confluent state, an altered downstream signaling of IGF-I receptor was observed. Treatment with a reactive oxygen species (ROS) scavenger, N-acetylcystein (NAC) significantly suppressed induction of these markers, indicating that ROS are involved in the induction of cellular senescence by IGF-I. In p53-null mouse embryonic fibroblasts, the IGF-I-induced augmentation of SA-β-gal and p21 was inhibited, demonstrating that p53 is required for cellular senescence induced by IGF-I. Thus, these data reveal a novel pathway whereby IGF-I enhances cellular senescence in the ROS and p53-dependent manner and may explain the underlying mechanisms of IGF-I involvement in tumorigenesis and in regulation of aging.

  13. Integrin Beta 3 Regulates Cellular Senescence by Activating the TGF-β Pathway

    Directory of Open Access Journals (Sweden)

    Valentina Rapisarda

    2017-03-01

    Full Text Available Cellular senescence is an important in vivo mechanism that prevents the propagation of damaged cells. However, the precise mechanisms regulating senescence are not well characterized. Here, we find that ITGB3 (integrin beta 3 or β3 is regulated by the Polycomb protein CBX7. β3 expression accelerates the onset of senescence in human primary fibroblasts by activating the transforming growth factor β (TGF-β pathway in a cell-autonomous and non-cell-autonomous manner. β3 levels are dynamically increased during oncogene-induced senescence (OIS through CBX7 Polycomb regulation, and downregulation of β3 levels overrides OIS and therapy-induced senescence (TIS, independently of its ligand-binding activity. Moreover, cilengitide, an αvβ3 antagonist, has the ability to block the senescence-associated secretory phenotype (SASP without affecting proliferation. Finally, we show an increase in β3 levels in a subset of tissues during aging. Altogether, our data show that integrin β3 subunit is a marker and regulator of senescence.

  14. Extracellular cystatin SN and cathepsin B prevent cellular senescence by inhibiting abnormal glycogen accumulation.

    Science.gov (United States)

    Oh, Sang-Seok; Park, Soojong; Lee, Ki-Won; Madhi, Hamadi; Park, Sae Gwang; Lee, Hee Gu; Cho, Yong-Yeon; Yoo, Jiyun; Dong Kim, Kwang

    2017-04-06

    Cystatin SN (CST1), a known inhibitor of cathepsin B (CatB), has important roles in tumor development. Paradoxically, CatB is a member of the cysteine cathepsin family that acts in cellular processes, such as tumor development and invasion. However, the relationship between CST1 and CatB, and their roles in tumor development are poorly understood. In this study, we observed that the knockdown of CST1 induced the activity of senescence-associated β-galactosidase, a marker of cellular senescence, and expression of senescence-associated secretory phenotype genes, including interleukin-6 and chemokine (C-C motif) ligand 20, in MDA-MB-231 and SW480 cancer cells. Furthermore, CST1 knockdown decreased extracellular CatB activity, and direct CatB inhibition, using specific inhibitors or shCatB, induced cellular senescence. Reconstitution of CST1 restored CatB activity and inhibited cellular senescence in CST1 knockdown cells. CST1 knockdown or CatB inhibition increased glycogen synthase (GS) kinase 3β phosphorylation at serine 9, resulting in the activation of GS and the induction of glycogen accumulation associated with cellular senescence. Importantly, CST1 knockdown suppressed cancer cell proliferation, soft agar colony growth and tumor growth in a xenograft model. These results indicate that CST1-mediated extracellular CatB activity enhances tumor development by preventing cellular senescence. Our findings suggest that antagonists of CST1 or inhibitors of CatB are potential anticancer agents.

  15. Customization of flexographic printing plates related to uvc-induced changes in the crosslinking degree

    Directory of Open Access Journals (Sweden)

    Tamara Tomašegović

    2016-11-01

    Full Text Available In this paper, the swelling properties of photopolymer flexographic printing plates related to the variations of UVC post-treatment have been analysed. The aim of the research was to interconnect the changes in the crosslinking degree of the photopolymer material occurring due to the modified UVC radiation of the printing plate and the changes of its surface free energy crucial in the graphic reproduction process. Changes in the crosslinking degree in the photopolymer materials have been analysed by the swelling experiments. Results have proven that the partial dissolution of the photopolymer material caused by the immersion of the printing plates in various solvents is in the direct relation with the changes of the dispersive surface free energy. UVC post-treatment, used for the crosslinking termination and the definition of the surface properties of printing plates, is therefore directly affecting the resistivity of the printing plate in the solvent environment. By calculating the correlation coefficients for the weight loss of the photopolymer material in solvents and the dispersive surface free energy, the relation between the crosslinking degree and the UVC post-treatment has been established.

  16. Comparative Effects of Biodynes, Tocotrienol-Rich Fraction, and Tocopherol in Enhancing Collagen Synthesis and Inhibiting Collagen Degradation in Stress-Induced Premature Senescence Model of Human Diploid Fibroblasts

    Science.gov (United States)

    Jam, Faidruz Azura; Ismail, Zahariah; Wan Ngah, Wan Zurinah

    2013-01-01

    Biodynes, tocotrienol-rich fraction (TRF), and tocopherol have shown antiaging properties. However, the combined effects of these compounds on skin aging are yet to be investigated. This study aimed to elucidate the skin aging effects of biodynes, TRF, and tocopherol on stress-induced premature senescence (SIPS) model of human diploid fibroblasts (HDFs) by determining the expression of collagen and MMPs at gene and protein levels. Primary HDFs were treated with biodynes, TRF, and tocopherol prior to hydrogen peroxide (H2O2) exposure. The expression of COL1A1, COL3A1, MMP1, MMP2, MMP3, and MMP9 genes was determined by qRT-PCR. Type I and type III procollagen proteins were measured by Western blotting while the activities of MMPs were quantified by fluorometric Sensolyte MMP Kit. Our results showed that biodynes, TRF, and tocopherol upregulated collagen genes and downregulated MMP genes (P < 0.05). Type I procollagen and type III procollagen protein levels were significantly increased in response to biodynes, TRF, and tocopherol treatment (P < 0.05) with reduction in MMP-1, MMP-2, MMP-3, and MMP-9 activities (P < 0.05). These findings indicated that biodynes, TRF, and tocopherol effectively enhanced collagen synthesis and inhibited collagen degradation and therefore may protect the skin from aging. PMID:24396567

  17. Comparative Effects of Biodynes, Tocotrienol-Rich Fraction, and Tocopherol in Enhancing Collagen Synthesis and Inhibiting Collagen Degradation in Stress-Induced Premature Senescence Model of Human Diploid Fibroblasts

    Directory of Open Access Journals (Sweden)

    Suzana Makpol

    2013-01-01

    Full Text Available Biodynes, tocotrienol-rich fraction (TRF, and tocopherol have shown antiaging properties. However, the combined effects of these compounds on skin aging are yet to be investigated. This study aimed to elucidate the skin aging effects of biodynes, TRF, and tocopherol on stress-induced premature senescence (SIPS model of human diploid fibroblasts (HDFs by determining the expression of collagen and MMPs at gene and protein levels. Primary HDFs were treated with biodynes, TRF, and tocopherol prior to hydrogen peroxide (H2O2 exposure. The expression of COL1A1, COL3A1, MMP1, MMP2, MMP3, and MMP9 genes was determined by qRT-PCR. Type I and type III procollagen proteins were measured by Western blotting while the activities of MMPs were quantified by fluorometric Sensolyte MMP Kit. Our results showed that biodynes, TRF, and tocopherol upregulated collagen genes and downregulated MMP genes (P<0.05. Type I procollagen and type III procollagen protein levels were significantly increased in response to biodynes, TRF, and tocopherol treatment (P<0.05 with reduction in MMP-1, MMP-2, MMP-3, and MMP-9 activities (P<0.05. These findings indicated that biodynes, TRF, and tocopherol effectively enhanced collagen synthesis and inhibited collagen degradation and therefore may protect the skin from aging.

  18. Thermally induced dispersion mechanisms for aluminum-based plate-type fuels under rapid transient energy deposition

    International Nuclear Information System (INIS)

    Georgevich, V.; Taleyarkham, R.P.; Navarro-Valenti, S.; Kim, S.H.

    1995-01-01

    A thermally induced dispersion model was developed to analyze for dispersive potential and determine onset of fuel plate dispersion for Al-based research and test reactor fuels. Effect of rapid energy deposition in a fuel plate was simulated. Several data types for Al-based fuels tested in the Nuclear Safety Research Reactor in Japan and in the Transient Reactor Test in Idaho were reviewed. Analyses of experiments show that onset of fuel dispersion is linked to a sharp rise in predicted strain rate, which futher coincides with onset of Al vaporization. Analysis also shows that Al oxidation and exothermal chemical reaction between the fuel and Al can significantly affect the energy deposition characteristics, and therefore dispersion onset connected with Al vaporization, and affect onset of vaporization

  19. Occlusal adjustment using the bite plate-induced occlusal position as a reference position for temporomandibular disorders: a pilot study

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    Chiwata Ichiro

    2010-03-01

    Full Text Available Abstract Background Many researchers have not accepted the use of occlusal treatments for temporomandibular disorders (TMDs. However, a recent report described a discrepancy between the habitual occlusal position (HOP and the bite plate-induced occlusal position (BPOP and discussed the relation of this discrepancy to TMD. Therefore, the treatment outcome of evidence-based occlusal adjustments using the bite plate-induced occlusal position (BPOP as a muscular reference position should be evaluated in patients with TMD. Methods The BPOP was defined as the position at which a patient voluntarily closed his or her mouth while sitting in an upright posture after wearing an anterior flat bite plate for 5 minutes and then removing the plate. Twenty-one patients with TMDs underwent occlusal adjustment using the BPOP. The occlusal adjustments were continued until bilateral occlusal contacts were obtained in the BPOP. The treatment outcomes were evaluated using the subjective dysfunction index (SDI and the Helkimo Clinical Dysfunction Index (CDI before and after the occlusal adjustments; the changes in these two indices between the first examination and a one-year follow-up examination were then analyzed. In addition, the difference between the HOP and the BPOP was three-dimensionally measured before and after the treatment. Results The percentage of symptom-free patients after treatment was 86% according to the SDI and 76% according to the CDI. The changes in the two indices after treatment were significant (p 0.1. Conclusion Although the results of the present study should be confirmed in other studies, a randomized clinical trial examining occlusal adjustments using the BPOP as a reference position appears to be warranted.

  20. Acrolein-exposed normal human lung fibroblasts in vitro: cellular senescence, enhanced telomere erosion, and degradation of Werner's syndrome protein.

    Science.gov (United States)

    Jang, Jun-Ho; Bruse, Shannon; Huneidi, Salam; Schrader, Ronald M; Monick, Martha M; Lin, Yong; Carter, A Brent; Klingelhutz, Aloysius J; Nyunoya, Toru

    2014-09-01

    Acrolein is a ubiquitous environmental hazard to human health. Acrolein has been reported to activate the DNA damage response and induce apoptosis. However, little is known about the effects of acrolein on cellular senescence. We examined whether acrolein induces cellular senescence in cultured normal human lung fibroblasts (NHLF). We cultured NHLF in the presence or absence of acrolein and determined the effects of acrolein on cell proliferative capacity, senescence-associated β-galactosidase activity, the known senescence-inducing pathways (e.g., p53, p21), and telomere length. We found that acrolein induced cellular senescence by increasing both p53 and p21. The knockdown of p53 mediated by small interfering RNA (siRNA) attenuated acrolein-induced cellular senescence. Acrolein decreased Werner's syndrome protein (WRN), a member of the RecQ helicase family involved in DNA repair and telomere maintenance. Acrolein-induced down-regulation of WRN protein was rescued by p53 knockdown or proteasome inhibition. Finally, we found that acrolein accelerated p53-mediated telomere shortening. These results suggest that acrolein induces p53-mediated cellular senescence accompanied by enhanced telomere attrition and WRN protein down-regulation.

  1. Deacetylation of H4-K16Ac and heterochromatin assembly in senescence

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    Contrepois Kévin

    2012-08-01

    Full Text Available Abstract Background Cellular senescence is a stress response of mammalian cells leading to a durable arrest of cell proliferation that has been implicated in tumor suppression, wound healing, and aging. The proliferative arrest is mediated by transcriptional repression of genes essential for cell division by the retinoblastoma protein family. This repression is accompanied by varying degrees of heterochromatin assembly, but little is known regarding the molecular mechanisms involved. Results We found that both deacetylation of H4-K16Ac and expression of HMGA1/2 can contribute to DNA compaction during senescence. SIRT2, an NAD-dependent class III histone deacetylase, contributes to H4-K16Ac deacetylation and DNA compaction in human fibroblast cell lines that assemble striking senescence-associated heterochromatin foci (SAHFs. Decreased H4-K16Ac was observed in both replicative and oncogene-induced senescence of these cells. In contrast, this mechanism was inoperative in a fibroblast cell line that did not assemble extensive heterochromatin during senescence. Treatment of senescent cells with trichostatin A, a class I/II histone deacetylase inhibitor, also induced rapid and reversible decondensation of SAHFs. Inhibition of DNA compaction did not significantly affect the stability of the senescent state. Conclusions Variable DNA compaction observed during senescence is explained in part by cell-type specific regulation of H4 deacetylation and HMGA1/2 expression. Deacetylation of H4-K16Ac during senescence may explain reported decreases in this mark during mammalian aging and in cancer cells.

  2. Senescence-associated microRNAs target cell cycle regulatory genes in normal human lung fibroblasts.

    Science.gov (United States)

    Markopoulos, Georgios S; Roupakia, Eugenia; Tokamani, Maria; Vartholomatos, George; Tzavaras, Theodore; Hatziapostolou, Maria; Fackelmayer, Frank O; Sandaltzopoulos, Raphael; Polytarchou, Christos; Kolettas, Evangelos

    2017-10-01

    Senescence recapitulates the ageing process at the cell level. A senescent cell stops dividing and exits the cell cycle. MicroRNAs (miRNAs) acting as master regulators of transcription, have been implicated in senescence. In the current study we investigated and compared the expression of miRNAs in young versus senescent human fibroblasts (HDFs), and analysed the role of mRNAs expressed in replicative senescent HFL-1 HDFs. Cell cycle analysis confirmed that HDFs accumulated in G 1 /S cell cycle phase. Nanostring analysis of isolated miRNAs from young and senescent HFL-1 showed that a distinct set of 15 miRNAs were significantly up-regulated in senescent cells including hsa-let-7d-5p, hsa-let-7e-5p, hsa-miR-23a-3p, hsa-miR-34a-5p, hsa-miR-122-5p, hsa-miR-125a-3p, hsa-miR-125a-5p, hsa-miR-125b-5p, hsa-miR-181a-5p, hsa-miR-221-3p, hsa-miR-222-3p, hsa-miR-503-5p, hsa-miR-574-3p, hsa-miR-574-5p and hsa-miR-4454. Importantly, pathway analysis of miRNA target genes down-regulated during replicative senescence in a public RNA-seq data set revealed a significant high number of genes regulating cell cycle progression, both G 1 /S and G 2 /M cell cycle phase transitions and telomere maintenance. The reduced expression of selected miRNA targets, upon replicative and oxidative-stress induced senescence, such as the cell cycle effectors E2F1, CcnE, Cdc6, CcnB1 and Cdc25C was verified at the protein and/or RNA levels. Induction of G1/S cell cycle phase arrest and down-regulation of cell cycle effectors correlated with the up-regulation of miR-221 upon both replicative and oxidative stress-induced senescence. Transient expression of miR-221/222 in HDFs promoted the accumulation of HDFs in G1/S cell cycle phase. We propose that miRNAs up-regulated during replicative senescence may act in concert to induce cell cycle phase arrest and telomere erosion, establishing a senescent phenotype. Copyright © 2017 Elsevier Inc. All rights reserved.

  3. Escherichia coli producing colibactin triggers premature and transmissible senescence in mammalian cells.

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    Thomas Secher

    Full Text Available Cellular senescence is an irreversible state of proliferation arrest evoked by a myriad of stresses including oncogene activation, telomere shortening/dysfunction and genotoxic insults. It has been associated with tumor activation, immune suppression and aging, owing to the secretion of proinflammatory mediators. The bacterial genotoxin colibactin, encoded by the pks genomic island is frequently harboured by Escherichia coli strains of the B2 phylogenetic group. Mammalian cells exposed to live pks+ bacteria exhibit DNA-double strand breaks (DSB and undergo cell-cycle arrest and death. Here we show that cells that survive the acute bacterial infection with pks+ E. coli display hallmarks of cellular senescence: chronic DSB, prolonged cell-cycle arrest, enhanced senescence-associated β-galactosidase (SA-β-Gal activity, expansion of promyelocytic leukemia nuclear foci and senescence-associated heterochromatin foci. This was accompanied by reactive oxygen species production and pro-inflammatory cytokines, chemokines and proteases secretion. These mediators were able to trigger DSB and enhanced SA-β-Gal activity in bystander recipient cells treated with conditioned medium from senescent cells. Furthermore, these senescent cells promoted the growth of human tumor cells. In conclusion, the present data demonstrated that the E. coli genotoxin colibactin induces cellular senescence and subsequently propel bystander genotoxic and oncogenic effects.

  4. PPARgamma Deficiency Counteracts Thymic Senescence

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    David Ernszt

    2017-11-01

    Full Text Available Thymic senescence contributes to increased incidence of infection, cancer and autoimmunity at senior ages. This process manifests as adipose involution. As with other adipose tissues, thymic adipose involution is also controlled by PPARgamma. This is supported by observations reporting that systemic PPARgamma activation accelerates thymic adipose involution. Therefore, we hypothesized that decreased PPARgamma activity could prevent thymic adipose involution, although it may trigger metabolic adverse effects. We have confirmed that both human and murine thymic sections show marked staining for PPARgamma at senior ages. We have also tested the thymic lobes of PPARgamma haplo-insufficient and null mice. Supporting our working hypothesis both adult PPARgamma haplo-insufficient and null mice show delayed thymic senescence by thymus histology, thymocyte mouse T-cell recombination excision circle qPCR and peripheral blood naive T-cell ratio by flow-cytometry. Delayed senescence showed dose–response with respect to PPARgamma deficiency. Functional immune parameters were also evaluated at senior ages in PPARgamma haplo-insufficient mice (null mice do not reach senior ages due to metabolic adverse affects. As expected, sustained and elevated T-cell production conferred oral tolerance and enhanced vaccination efficiency in senior PPARgamma haplo-insufficient, but not in senior wild-type littermates according to ELISA IgG measurements. Of note, humans also show increased oral intolerance issues and decreased protection by vaccines at senior ages. Moreover, PPARgamma haplo-insufficiency also exists in human known as a rare disease (FPLD3 causing metabolic adverse effects, similar to the mouse. When compared to age- and metabolic disorder-matched other patient samples (FPLD2 not affecting PPARgamma activity, FPLD3 patients showed increased human Trec (hTrec values by qPCR (within healthy human range suggesting delayed thymic senescence, in accordance with

  5. Photo-induced hydrophilicity of TiO2-xNx thin films on PET plates

    International Nuclear Information System (INIS)

    Chou, H.-Y.; Lee, E.-K.; You, J.-W.; Yu, S.-S.

    2007-01-01

    TiO 2-x N x thin films were deposited on PET (polyethylene terephthalate) plates by sputtering a TiN target in a N 2 /O 2 plasma and without heating. X-ray photoemission spectroscopy (XPS) was used to investigate the N 1s, Ti 2p core levels and the nitrogen composition in the TiO 2-x N x films. The results indicate that Ti-O-N bonds are formed in the thin films. Two nitrogen states, substitution and interstitial nitrogen atoms, were attributed to peaks at 396 and 399 eV, respectively. It was observed that the nitrogen atoms occupy both the substitutive and interstitial sites in respective of the nitrogen content in the thin films. UV-VIS absorption spectroscopy of PET coated thin films shows a significant shift of the absorption edge to lower energy in the visible-light region. UV and visible-light irradiation are used to activate PET coated thin films for the development of hydrophilicity. The photo-induced surface wettability conversion reaction of the thin films has been investigated by means of water contact angle measurement. PET plates coated with TiO 2-x N x thin films are found to exhibit lower water contact angle than non-coated plates when the surface is illuminated with UV and visible light. The effects of nitrogen doping on photo-generated hydrophilicity of the thin films are investigated in this work

  6. Senescence induction; a possible cancer therapy

    Directory of Open Access Journals (Sweden)

    Kondoh Hiroshi

    2009-01-01

    Full Text Available Abstract Cellular immortalization is a crucial step during the development of human cancer. Primary mammalian cells reach replicative exhaustion after several passages in vitro, a process called replicative senescence. During such a state of permanent growth arrest, senescent cells are refractory to physiological proliferation stimuli: they have altered cell morphology and gene expression patterns, although they remain viable with preserved metabolic activity. Interestingly, senescent cells have also been detected in vivo in human tumors, particularly in benign lesions. Senescence is a mechanism that limits cellular lifespan and constitutes a barrier against cellular immortalization. During immortalization, cells acquire genetic alterations that override senescence. Tumor suppressor genes and oncogenes are closely involved in senescence, as their knockdown and ectopic expression confer immortality and senescence induction, respectively. By using high throughput genetic screening to search for genes involved in senescence, several candidate oncogenes and putative tumor suppressor genes have been recently isolated, including subtypes of micro-RNAs. These findings offer new perspectives in the modulation of senescence and open new approaches for cancer therapy.

  7. HIV and drug abuse mediate astrocyte senescence in a β-catenin-dependent manner leading to neuronal toxicity.

    Science.gov (United States)

    Yu, Chunjiang; Narasipura, Srinivas D; Richards, Maureen H; Hu, Xiu-Ti; Yamamoto, Bryan; Al-Harthi, Lena

    2017-10-01

    Emerging evidence suggests that cell senescence plays an important role in aging-associated diseases including neurodegenerative diseases. HIV leads to a spectrum of neurologic diseases collectively termed HIV-associated neurocognitive disorders (HAND). Drug abuse, particularly methamphetamine (meth), is a frequently abused psychostimulant among HIV+ individuals and its abuse exacerbates HAND. The mechanism by which HIV and meth lead to brain cell dysregulation is not entirely clear. In this study, we evaluated the impact of HIV and meth on astrocyte senescence using in vitro and several animal models. Astrocytes constitute up to 50% of brain cells and play a pivotal role in marinating brain homeostasis. We show here that HIV and meth induce significant senescence of primary human fetal astrocytes, as evaluated by induction of senescence markers (β-galactosidase and p16 INK 4A ), senescence-associated morphologic changes, and cell cycle arrest. HIV- and meth-mediated astrocyte senescence was also demonstrated in three small animal models (humanized mouse model of HIV/NSG-huPBMCs, HIV-transgenic rats, and in a meth administration rat model). Senescent astrocytes in turn mediated neuronal toxicity. Further, we show that β-catenin, a pro-survival/proliferation transcriptional co-activator, is downregulated by HIV and meth in human astrocytes and this downregulation promotes astrocyte senescence while induction of β-catenin blocks HIV- and meth-mediated astrocyte senescence. These studies, for the first time, demonstrate that HIV and meth induce astrocyte senescence and implicate the β-catenin pathway as potential therapeutic target to overcome astrocyte senescence. © 2017 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

  8. Drag Induced by Flat-Plate Imperfections in Compressible Turbulent Flow Regimes

    OpenAIRE

    Molton , Pascal; Hue , David; Bur , Reynald

    2014-01-01

    International audience; This paper presents the results of a coupled experimental and numerical study aimed at evaluating the influence of typical aircraft surface imperfections on the flat-plate drag production in fully turbulent conditions. A test campaign involving high-level measurement techniques, such as microdrag evaluation, near-wall laser Doppler velocimetry, and oil-film interferometry, has been carried out at several Mach numbers from 0.5 to 1.3 to quantify the impact of a large ra...

  9. Regulation of respiration and the oxygen diffusion barrier in soybean protect symbiotic nitrogen fixation from chilling-induced inhibition and shoots from premature senescence.

    Science.gov (United States)

    van Heerden, Philippus D R; Kiddle, Guy; Pellny, Till K; Mokwala, Phatlane W; Jordaan, Anine; Strauss, Abram J; de Beer, Misha; Schlüter, Urte; Kunert, Karl J; Foyer, Christine H

    2008-09-01

    Symbiotic nitrogen fixation is sensitive to dark chilling (7 degrees C-15 degrees C)-induced inhibition in soybean (Glycine max). To characterize the mechanisms that cause the stress-induced loss of nodule function, we examined nodule structure, carbon-nitrogen interactions, and respiration in two soybean genotypes that differ in chilling sensitivity: PAN809 (PAN), which is chilling sensitive, and Highveld Top (HT), which is more chilling resistant. Nodule numbers were unaffected by dark chilling, as was the abundance of the nitrogenase and leghemoglobin proteins. However, dark chilling decreased nodule respiration rates, nitrogenase activities, and NifH and NifK mRNAs and increased nodule starch, sucrose, and glucose in both genotypes. Ureide and fructose contents decreased only in PAN nodules. While the chilling-induced decreases in nodule respiration persisted in PAN even after return to optimal temperatures, respiration started to recover in HT by the end of the chilling period. The area of the intercellular spaces in the nodule cortex and infected zone was greatly decreased in HT after three nights of chilling, an acclimatory response that was absent from PAN. These data show that HT nodules are able to regulate both respiration and the area of the intercellular spaces during chilling and in this way control the oxygen diffusion barrier, which is a key component of the nodule stress response. We conclude that chilling-induced loss of symbiotic nitrogen fixation in PAN is caused by the inhibition of respiration coupled to the failure to regulate the oxygen diffusion barrier effectively. The resultant limitations on nitrogen availability contribute to the greater chilling-induced inhibition of photosynthesis in PAN than in HT.

  10. Cellular Senescence Promotes Adverse Effects of Chemotherapy and Cancer Relapse

    NARCIS (Netherlands)

    Demaria, Marco; O'Leary, Monique N.; Chang, Jianhui; Shao, Lijian; Liu, Su; Alimirah, Fatouma; Koenig, Kristin; Le, Catherine; Mitin, Natalia; Deal, Allison M.; Alston, Shani; Academia, Emmeline C.; Kilmarx, Sumner; Valdovinos, Alexis; Wang, Boshi; de Bruin, Alain; Kennedy, Brian K.; Melov, Simon; Zhou, Daohong; Sharpless, Norman E.; Muss, Hyman; Campisi, Judith

    Cellular senescence suppresses cancer by irreversibly arresting cell proliferation. Senescent cells acquire a proinfl ammatory senescence-associated secretory phenotype. Many genotoxic chemotherapies target proliferating cells nonspecifi cally, often with adverse reactions. In accord with prior

  11. Betacyanins from Portulaca oleracea L. ameliorate cognition deficits and attenuate oxidative damage induced by D-galactose in the brains of senescent mice.

    Science.gov (United States)

    Wang, Chang-Quan; Yang, Gui-Qin

    2010-06-01

    This experiment was designed to assess the protective effect of betacyanins from Portulaca oleracea L. against the D-galactose (D-gal)-induced neurotoxicity in mice. Betacyanins from Portulaca oleracea markedly reversed the D-gal-induced learning and memory impairments, as measured by behavioral tests. The activities of superoxide dismutases (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione reductase (GR) in D-gal-treated mice were enhanced, while the content of the lipid peroxidation product malondialdehyde (MDA) was decreased by betacyanin administration. Furthermore, significant negative correlations were found between mouse latency in finding the platform and the activities of SOD, CAT GR and GPx in the mouse brain, but the level of MDA correlated positively with the latency. These results suggest that the neuroprotective effect of betacyanins against D-gal-induced neurotoxicity might be caused, at least in part, by an increase in the activities of antioxidant enzymes with a reduction in lipid peroxidation. In comparison with vitamin C (VC), the betacyanins had a more pronounced effect on ameliorating cognition deficits in mice.

  12. A Nampt inhibitor FK866 mimics vitamin B3 deficiency by causing senescence of human fibroblastic Hs68 cells via attenuation of NAD(+)-SIRT1 signaling.

    Science.gov (United States)

    Song, Tuzz-Ying; Yeh, Shu-Lan; Hu, Miao-Lin; Chen, Mei-Yau; Yang, Nae-Cherng

    2015-12-01

    Vitamin B3 (niacin) deficiency can cause pellagra with symptoms of dermatitis, diarrhea and dementia. However, it is unclear whether the vitamin B3 deficiency causes human aging. FK866 (a Nampt inhibitor) can reduce intracellular NAD(+) level and induce senescence of human Hs68 cells. However, the mechanisms underlying FK866-induced senescence of Hs68 cells are unclear. In this study, we used FK866 to mimic the effects of vitamin B3 deficiency to reduce the NAD(+) level and investigated the mechanisms of FK866-induced senescence of Hs68 cells. We hypothesized that FK866 induced the senescence of Hs68 cells via an attenuation of NAD(+)-silent information regulator T1 (SIRT1) signaling. We found that FK866 induced cell senescence and diminished cellular NAD(+) levels and SIRT1 activity (detected by acetylation of p53), and these effects were dramatically antagonized by co-treatment with nicotinic acid, nicotinamide, or NAD(+). In contrast, the protein expression of SIRT1, AMP-activated protein kinase, mammalian target of rapamycin, and nicotinamide phosphoribosyltransferase (Nampt) was not affected by FK866. In addition, the role of GSH in the FK866-induced cells senescence may be limited, as N-acetylcysteine did not antagonize FK866-induced cell senescence. These results suggest that FK866 induces cell senescence via attenuation of NAD(+)-SIRT1 signaling. The effects of vitamin B3 deficiency on human aging warrant further investigation.

  13. Implication of p53-dependent cellular senescence related gene, TARSH in tumor suppression

    International Nuclear Information System (INIS)

    Wakoh, Takeshi; Uekawa, Natsuko; Terauchi, Kunihiko; Sugimoto, Masataka; Ishigami, Akihito; Shimada, Jun-ichi; Maruyama, Mitsuo

    2009-01-01

    A novel target of NESH-SH3 (TARSH) was identified as a cellular senescence related gene in mouse embryonic fibroblasts (MEFs) replicative senescence, the expression of which has been suppressed in primary clinical lung cancer specimens. However, the molecular mechanism underlying the regulation of TARSH involved in pulmonary tumorigenesis remains unclear. Here we demonstrate that the reduction of TARSH gene expression by short hairpin RNA (shRNA) system robustly inhibited the MEFs proliferation with increase in senescence-associated β-galactosidase (SA-β-gal) activity. Using p53 -/- MEFs, we further suggest that this growth arrest by loss of TARSH is evoked by p53-dependent p21 Cip1 accumulation. Moreover, we also reveal that TARSH reduction induces multicentrosome in MEFs, which is linked in chromosome instability and tumor development. These results suggest that TARSH plays an important role in proliferation of replicative senescence and may serve as a trigger of tumor development.

  14. NS1 of H7N9 Influenza A Virus Induces NO-Mediated Cellular Senescence in Neuro2a Cells

    OpenAIRE

    Yinxia Yan; Yongming Du; Huali Zheng; Gefei Wang; Rui Li; Jieling Chen; Kangsheng Li

    2017-01-01

    Background/Aims: The novel avian H7N9 influenza A virus has been detected in brain tissues and associated with central nervous system (CNS) symptoms in infected human and mice. Roles of its virulence factor, NS1 protein in influenza virus infected neuron has yet to be explored. Methods: Nitric oxide (NO) release and inducible nitric oxide synthase (iNOS) expression in H7N9/NS1-expressed Neuro2a cells were detected by Griess test and western blotting. Cell proliferation rate of H7N9/NS1-expres...

  15. Proteomic and Biochemical Changes during Senescence of Phalaenopsis 'Red Dragon' Petals.

    Science.gov (United States)

    Chen, Cong; Zeng, Lanting; Ye, Qingsheng

    2018-04-28

    Phalaenopsis flowers are some of the most popular ornamental flowers in the world. For most ornamental plants, petal longevity determines postharvest quality and garden performance. Therefore, it is important to have insight into the senescence mechanism of Phalaenopsis . In the present study, a proteomic approach combined with ultrastructural observation and activity analysis of antioxidant enzymes was used to profile the molecular and biochemical changes during pollination-induced petal senescence in Phalaenopsis “Red Dragon”. Petals appeared to be visibly wilting at 24 h after pollination, accompanied by the mass degradation of macromolecules and organelles during senescence. In addition, 48 protein spots with significant differences in abundance were found by two-dimensional electrophoresis (2-DE) and subjected to matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF/TOF-MS). There were 42 protein spots successfully identified and homologous to known functional protein species involved in key biological processes, including antioxidant pathways, stress response, protein metabolism, cell wall component metabolism, energy metabolism, cell structure, and signal transduction. The activity of all reactive oxygen species (ROS)-scavenging enzymes was increased, keeping the content of ROS at a low level at the early stage of senescence. These results suggest that two processes, a counteraction against increased levels of ROS and the degradation of cellular constituents for maintaining nutrient recycling, are activated during pollination-induced petal senescence in Phalaenopsis . The information provides a basis for understanding the mechanism regulating petal senescence and prolonging the florescence of Phalaenopsis .

  16. Senescence-Associated Secretory Phenotypes Reveal Cell-Nonautonomous Functions of Oncogenic RAS and the p53 Tumor Suppressor

    Energy Technology Data Exchange (ETDEWEB)

    Copp& #233; , Jean-Philippe; Patil, Christopher; Rodier, Francis; Sun, Yu; Munoz, Denise; Goldstein, Joshua; Nelson, Peter; Desprez, Pierre-Yves; Campisi, Judith

    2008-10-24

    Cellular senescence suppresses cancer by arresting cell proliferation, essentially permanently, in response to oncogenic stimuli, including genotoxic stress. We modified the use of antibody arrays to provide a quantitative assessment of factors secreted by senescent cells. We show that human cells induced to senesce by genotoxic stress secrete myriad factors associated with inflammation and malignancy. This senescence-associated secretory phenotype (SASP) developed slowly over several days and only after DNA damage of sufficient magnitude to induce senescence. Remarkably similar SASPs developed in normal fibroblasts, normal epithelial cells, and epithelial tumor cells after genotoxic stress in culture, and in epithelial tumor cells in vivo after treatment of prostate cancer patients with DNA-damaging chemotherapy. In cultured premalignant epithelial cells, SASPs induced an epithelial-mesenchyme transition and invasiveness, hallmarks of malignancy, by a paracrine mechanism that depended largely on the SASP factors interleukin (IL)-6 and IL-8. Strikingly, two manipulations markedly amplified, and accelerated development of, the SASPs: oncogenic RAS expression, which causes genotoxic stress and senescence in normal cells, and functional loss of the p53 tumor suppressor protein. Both loss of p53 and gain of oncogenic RAS also exacerbated the promalignant paracrine activities of the SASPs. Our findings define a central feature of genotoxic stress-induced senescence. Moreover, they suggest a cell-nonautonomous mechanism by which p53 can restrain, and oncogenic RAS can promote, the development of age-related cancer by altering the tissue microenvironment.

  17. Physiology and molecular biology of petal senescence

    NARCIS (Netherlands)

    Doorn, van W.G.; Woltering, E.J.

    2008-01-01

    Petal senescence is reviewed, with the main emphasis on gene expression in relation to physiological functions. Autophagy seems to be the major mechanism for large-scale degradation of macromolecules, but it is still unclear if it contributes to cell death. Depending on the species, petal senescence

  18. Targeting senescence cells in pancreatic cancer | IDRC ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    Targeting senescence cells in pancreatic cancer. Cellular senescence is a programmed response to oncogenic (tumour-causing) stress that aims to halt the expansion of cells with malignant potential. It does this by stopping the proliferation of pre-cancerous lesions and recruitment of the immune system for their elimination.

  19. Oncogenic senescence: a multi-functional perspective

    NARCIS (Netherlands)

    Baker, D.J.; Alimirah, F.; Deursen, J.M.A. van; Campisi, J.; Hildesheim, J.

    2017-01-01

    Cellular senescence is defined as an irreversible growth arrest with the acquisition of a distinctive secretome. The growth arrest is a potent anticancer mechanism whereas the secretome facilitates wound healing, tissue repair, and development. The senescence response has also become increasingly

  20. Potential roles of DNA methylation in the initiation and establishment of replicative senescence revealed by array-based methylome and transcriptome analyses.

    Directory of Open Access Journals (Sweden)

    Mizuho Sakaki

    Full Text Available Cellular senescence is classified into two groups: replicative and premature senescence. Gene expression and epigenetic changes are reported to differ between these two groups and cell types. Normal human diploid fibroblast TIG-3 cells have often been used in cellular senescence research; however, their epigenetic profiles are still not fully understood. To elucidate how cellular senescence is epigenetically regulated in TIG-3 cells, we analyzed the gene expression and DNA methylation profiles of three types of senescent cells, namely, replicatively senescent, ras-induced senescent (RIS, and non-permissive temperature-induced senescent SVts8 cells, using gene expression and DNA methylation microarrays. The expression of genes involved in the cell cycle and immune response was commonly either down- or up-regulated in the three types of senescent cells, respectively. The altered DNA methylation patterns were observed in replicatively senescent cells, but not in prematurely senescent cells. Interestingly, hypomethylated CpG sites detected on non-CpG island regions ("open sea" were enriched in immune response-related genes that had non-CpG island promoters. The integrated analysis of gene expression and methylation in replicatively senescent cells demonstrated that differentially expressed 867 genes, including cell cycle- and immune response-related genes, were associated with DNA methylation changes in CpG sites close to the transcription start sites (TSSs. Furthermore, several miRNAs regulated in part through DNA methylation were found to affect the expression of their targeted genes. Taken together, these results indicate that the epigenetic changes of DNA methylation regulate the expression of a certain portion of genes and partly contribute to the introduction and establishment of replicative senescence.

  1. The Generation of Human Induced Pluripotent Stem Cells from Blood Cells: An Efficient Protocol Using Serial Plating of Reprogrammed Cells by Centrifugation

    OpenAIRE

    Youngkyun Kim; Yeri Alice Rim; Hyoju Yi; Narae Park; Sung-Hwan Park; Ji Hyeon Ju

    2016-01-01

    Human induced pluripotent stem cells (hiPSCs) have demonstrated great potential for differentiation into diverse tissues. We report a straightforward and highly efficient method for the generation of iPSCs from PBMCs. By plating the cells serially to a newly coated plate by centrifugation, this protocol provides multiple healthy iPSC colonies even from a small number of PBMCs. The generated iPSCs expressed pluripotent markers and differentiated into all three germ layer lineages. The protocol...

  2. Increased storage and secretion of phosphatidylcholines by senescent human peritoneal mesothelial cells.

    Science.gov (United States)

    Bartosova, Maria; Rudolf, Andras; Pichl, Sebastian; Schmidt, Kathrin; Okun, Jürgen G; Straub, Beate K; Rutkowski, Rafael; Witowski, Janusz; Schmitt, Claus P

    2016-08-01

    Human peritoneal mesothelial cells (HPMC) secrete phosphatidylcholines (PC) which form a lipid bilayer lining the peritoneum. They prevent frictions and adhesions and act as a barrier to the transport of water-soluble solutes while permitting water flux. PC may play an essential role in peritoneal integrity and function, the role of PD induced HPMC senescence on PC homeostasis, however, is unknown. HPMC cell lines were isolated from four non-uremic patients. Expression of the three PC synthesis genes (rt-PCR), and cellular storage and secretion of PC (ESI-mass-spectrometry) were analyzed in young and senescent HPMC (>Hayflick-limit). Senescent cells displayed significantly altered morphology; flow cytometry demonstrated extensive staining for senescence-associated beta galactosidase. Nine different PC were detected in HPMC with palmitoyl-myristoyl phosphatidylcholine (PMPC) being most abundant. In senescent HPMC mRNA expression of the three key PC synthesis genes was 1.5-, 2.4- and 6-fold increased as compared to young HPMC, with the latter, phosphatidylcholine cytidylyltransferase, being rate limiting. Intracellular storage of the nine PC was 75-450 % higher in senescent vs. young HPMC, PC secretion rates were 100-300 % higher. Intracellular PC concentrations were not correlated with the PC secretion rates. Electron microscopy demonstrated lamellar bodies, the primary storage site of PC, in senescent but not in young cells. Senescent HPMC store and secrete substantially more PC than young cells. Our findings indicate a novel protective mechanism, which should counteract peritoneal damage induced by chronic exposure to PD fluids.

  3. Octopus senescence: the beginning of the end.

    Science.gov (United States)

    Anderson, Roland C; Wood, James B; Byrne, Ruth A

    2002-01-01

    Senescence is a normal stage of an octopus's life cycle that often occurs before death. Some of the following symptoms typify it: lack of feeding, retraction of skin around the eyes, uncoordinated movement, increased undirected activity, and white unhealing lesions on the body. There is inter- and intraspecific variability. Senescence is not a disease or a result of disease, although diseases can also be a symptom of it. Both males and females go through a senescent stage before dying-the males after mating, the females while brooding eggs and after the eggs hatch. There are many aspects of octopus senescence that have not yet been studied. This study discusses the ecological implications of senescence.

  4. A Petunia Homeodomain-Leucine Zipper Protein, PhHD-Zip, Plays an Important Role in Flower Senescence

    Science.gov (United States)

    Chang, Xiaoxiao; Donnelly, Linda; Sun, Daoyang; Rao, Jingping; Reid, Michael S.; Jiang, Cai-Zhong

    2014-01-01

    Flower senescence is initiated by developmental and environmental signals, and regulated by gene transcription. A homeodomain-leucine zipper transcription factor, PhHD-Zip, is up-regulated during petunia flower senescence. Virus-induced gene silencing of PhHD-Zip extended flower life by 20% both in unpollinated and pollinated flowers. Silencing PhHD-Zip also dramatically reduced ethylene production and the abundance of transcripts of genes involved in ethylene (ACS, ACO), and ABA (NCED) biosynthesis. Abundance of transcripts of senescence-related genes (SAG12, SAG29) was also dramatically reduced in the silenced flowers. Over-expression of PhHD-Zip accelerated petunia flower senescence. Furthermore, PhHD-Zip transcript abundance in petunia flowers was increased by application of hormones (ethylene, ABA) and abiotic stresses (dehydration, NaCl and cold). Our results suggest that PhHD-Zip plays an important role in regulating petunia flower senescence. PMID:24551088

  5. A Petunia homeodomain-leucine zipper protein, PhHD-Zip, plays an important role in flower senescence.

    Science.gov (United States)

    Chang, Xiaoxiao; Donnelly, Linda; Sun, Daoyang; Rao, Jingping; Reid, Michael S; Jiang, Cai-Zhong

    2014-01-01

    Flower senescence is initiated by developmental and environmental signals, and regulated by gene transcription. A homeodomain-leucine zipper transcription factor, PhHD-Zip, is up-regulated during petunia flower senescence. Virus-induced gene silencing of PhHD-Zip extended flower life by 20% both in unpollinated and pollinated flowers. Silencing PhHD-Zip also dramatically reduced ethylene production and the abundance of transcripts of genes involved in ethylene (ACS, ACO), and ABA (NCED) biosynthesis. Abundance of transcripts of senescence-related genes (SAG12, SAG29) was also dramatically reduced in the silenced flowers. Over-expression of PhHD-Zip accelerated petunia flower senescence. Furthermore, PhHD-Zip transcript abundance in petunia flowers was increased by application of hormones (ethylene, ABA) and abiotic stresses (dehydration, NaCl and cold). Our results suggest that PhHD-Zip plays an important role in regulating petunia flower senescence.

  6. A Petunia homeodomain-leucine zipper protein, PhHD-Zip, plays an important role in flower senescence.

    Directory of Open Access Journals (Sweden)

    Xiaoxiao Chang

    Full Text Available Flower senescence is initiated by developmental and environmental signals, and regulated by gene transcription. A homeodomain-leucine zipper transcription factor, PhHD-Zip, is up-regulated during petunia flower senescence. Virus-induced gene silencing of PhHD-Zip extended flower life by 20% both in unpollinated and pollinated flowers. Silencing PhHD-Zip also dramatically reduced ethylene production and the abundance of transcripts of genes involved in ethylene (ACS, ACO, and ABA (NCED biosynthesis. Abundance of transcripts of senescence-related genes (SAG12, SAG29 was also dramatically reduced in the silenced flowers. Over-expression of PhHD-Zip accelerated petunia flower senescence. Furthermore, PhHD-Zip transcript abundance in petunia flowers was increased by application of hormones (ethylene, ABA and abiotic stresses (dehydration, NaCl and cold. Our results suggest that PhHD-Zip plays an important role in regulating petunia flower senescence.

  7. High energy muon induced radioactive nuclides in nickel plate and its use for 2-D muon-beam image profile

    International Nuclear Information System (INIS)

    Kurebayashi, Y.; Sakurai, H.; Takahashi, Y.; Doshita, N.; Kikuchi, S.; Tokanai, F.; Horiuchi, K.; Tajima, Y.; Oe, T.; Sato, T.; Gunji, S.; Inui, E.; Kondo, K.; Iwata, N.; Sasaki, N.; Matsuzaki, H.; Kunieda, S.

    2015-01-01

    Target materials were exposed to a muon beam with an energy of 160 GeV/c at the COMPASS experiment line in CERN-SPS to measure the production cross-sections for muon-induced radionuclides. A muon imager containing four nickel plates, each measuring 100 mm×100 mm, exposed to the IP plate successfully detected the muon beam image during an irradiation period of 33 days. The contrasting density rate of the nickel plate was (5.2±0.7)×10 –9 PSL/muon per one-day exposure to IP. The image measured 122 mm and 174 mm in horizontal and vertical lengths, respectively, in relation to the surface of the base, indicating that 50±6% of the muon beam flux is confined to an area of 18% of the whole muon beam. The number of muons estimated from the PSL value in the total beam image area (0.81±0.1)×10 13 was comparable to the total muon counts of the ion-chamber at the M2 beam line in the CERN-SPS. The production cross-sections of Cr-51, Mn-54, Co-56, Co-57, and Co-58 in nickel were 0.19±0.08, 0.34±0.06, 0.5±0.05, 3.44±0.07, 0.4±0.03 in the unit of mb, respectively, reducing muon associated particles effects. They are approximately 10 times smaller than that a proceeding study by Heisinger et al

  8. Experiments of dike-induced deformation: Insights on the long-term evolution of divergent plate boundaries

    KAUST Repository

    Trippanera, D.

    2015-10-22

    The shallow transport of magma occurs through dikes causing surface deformation. Our understanding of the effects of diking at the surface is limited, especially on the long term, for repeated intrusive episodes. We use analogue models to study the upper crustal deformation induced by dikes. We insert metal plates within cohesive sand with three setups: in setup A, the intrusion rises upward with constant thickness and in setups B and C, the intrusion thickens at a fixed depth, with final rectangular (setup B) or triangular (setup C) shape in section. Setup A creates a doming delimited by reverse faults, with secondary apical graben, without close correspondence in nature. In setups B and C, a depression flanked by two uplifted areas is bordered by inward dipping normal faults propagating downward and, for deeper intrusions in setup B, also by inner faults, reverse at the surface; this deformation is similar to what is observed in nature, suggesting a consistent physical behavior. Dikes in nature initially propagate developing a mode I fracture at the tip, subsequently thickened by magma intrusion, without any host rock translation in the propagation direction (as in setup A). The deformation pattern in setups B and C depends on the intrusion depth and thickness, consistently to what is observed along divergent plate boundaries. The early deformation in setups B and C is similar to that from a single rifting episode (i.e., Lakagigar, Iceland, and Dabbahu, Afar), whereas the late stages resemble the structure of mature rifts (i.e., Krafla, Iceland), confirming diking as a major process in shaping divergent plate boundaries.

  9. Intermediate Crack Induced Debonding in Concrete Beams Strengthened with CFRP Plates - An Experimental Study

    DEFF Research Database (Denmark)

    Rusinowski, Piotr Michal; Täljsten, Björn

    2009-01-01

    , ductility and even durability. Design of structural strengthening applications using externally bonded FRP composites is usually based on conventional design approaches with improvement to account for the presence and characteristics of the FRP material. Non-conventional design issues that are specific...... of the strengthening method. End-peeling has governed a large interest and several debonding models have been presented. However, interfacial peeling at flexural cracks has not attained the same focus – even though this debonding failure is most likely more common. This paper presents laboratory tests of concrete...... beams strengthened in flexure with CFRP epoxy bonded plates. Wrapping with CFRP sheets was applied in order to try to localize the failure initiation. Concrete cracking as well as debonding initiation and propagation was possible to observe with help of advanced optical measuring system and high speed...

  10. RhHB1 mediates the antagonism of gibberellins to ABA and ethylene during rose (Rosa hybrida) petal senescence.

    Science.gov (United States)

    Lü, Peitao; Zhang, Changqing; Liu, Jitao; Liu, Xiaowei; Jiang, Guimei; Jiang, Xinqiang; Khan, Muhammad Ali; Wang, Liangsheng; Hong, Bo; Gao, Junping

    2014-05-01

    Rose (Rosa hybrida) is one of the most important ornamental plants worldwide; however, senescence of its petals terminates the ornamental value of the flower, resulting in major economic loss. It is known that the hormones abscisic acid (ABA) and ethylene promote petal senescence, while gibberellins (GAs) delay the process. However, the molecular mechanisms underlying the antagonistic effects amongst plant hormones during petal senescence are still unclear. Here we isolated RhHB1, a homeodomain-leucine zipper I transcription factor gene, from rose flowers. Quantitative RT-PCR and GUS reporter analyses showed that RhHB1 was strongly expressed in senescing petals, and its expression was induced by ABA or ethylene in petals. ABA or ethylene treatment clearly accelerated rose petal senescence, while application of the gibberellin GA3 delayed the process. However, silencing of RhHB1 delayed the ABA- or ethylene-mediated senescence, and resulted in higher petal anthocyanin levels and lower expression of RhSAG12. Moreover, treatment with paclobutrazol, an inhibitor of GA biosynthesis, repressed these delays. In addition, silencing of RhHB1 blocked the ABA- or ethylene-induced reduction in expression of the GA20 oxidase encoded by RhGA20ox1, a gene in the GA biosynthetic pathway. Furthermore, RhHB1 directly binds to the RhGA20ox1 promoter, and silencing of RhGA20ox1 promoted petal senescence. Eight senescence-related genes showed substantial differences in expression in petals after treatment with GA3 or paclobutrazol. These results suggest that RhHB1 mediates the antagonistic effect of GAs on ABA and ethylene during rose petal senescence, and that the promotion of petal senescence by ABA or ethylene operates through an RhHB1-RhGA20ox1 regulatory checkpoint. © 2014 The Authors The Plant Journal © 2014 John Wiley & Sons Ltd.

  11. Piper betle L. Modulates Senescence-Associated Genes Expression in Replicative Senescent Human Diploid Fibroblasts

    Directory of Open Access Journals (Sweden)

    Lina Wati Durani

    2017-01-01

    Full Text Available Piper betle (PB is a traditional medicine that is widely used to treat different diseases around Asian region. The leaf extracts contain various bioactive compounds, which were reported to have antidiabetic, antibacterial, anti-inflammatory, antioxidant, and anticancer effects. In this study, the effect of PB aqueous extracts on replicative senescent human diploid fibroblasts (HDFs was investigated by determining the expressions of senescence-associated genes using quantitative PCR. Our results showed that PB extracts at 0.4 mg/ml can improve cell proliferation of young (143%, presenescent (127.3%, and senescent (157.3% HDFs. Increased expressions of PRDX6, TP53, CDKN2A, PAK2, and MAPK14 were observed in senescent HDFs compared to young and/or presenescent HDFs. Treatment with PB extracts modulates the transcriptional profile changes in senescent HDFs. By contrast, expressions of SOD1 increased, whereas GPX1, PRDX6, TP53, CDKN2A, PAK2, and MAPK14 were decreased in PB-treated senescent HDFs compared to untreated senescent HDFs. In conclusion, this study indicates the modulation of PB extracts on senescence-associated genes expression of replicative senescent HDFs. Further studies warrant determining the mechanism of PB in modulating replicative senescence of HDFs through these signaling pathways.

  12. Piper betle L. Modulates Senescence-Associated Genes Expression in Replicative Senescent Human Diploid Fibroblasts.

    Science.gov (United States)

    Durani, Lina Wati; Khor, Shy Cian; Tan, Jen Kit; Chua, Kien Hui; Mohd Yusof, Yasmin Anum; Makpol, Suzana

    2017-01-01

    Piper betle (PB) is a traditional medicine that is widely used to treat different diseases around Asian region. The leaf extracts contain various bioactive compounds, which were reported to have antidiabetic, antibacterial, anti-inflammatory, antioxidant, and anticancer effects. In this study, the effect of PB aqueous extracts on replicative senescent human diploid fibroblasts (HDFs) was investigated by determining the expressions of senescence-associated genes using quantitative PCR. Our results showed that PB extracts at 0.4 mg/ml can improve cell proliferation of young (143%), presenescent (127.3%), and senescent (157.3%) HDFs. Increased expressions of PRDX6 , TP53 , CDKN2A , PAK2 , and MAPK14 were observed in senescent HDFs compared to young and/or presenescent HDFs. Treatment with PB extracts modulates the transcriptional profile changes in senescent HDFs. By contrast, expressions of SOD1 increased, whereas GPX1 , PRDX6 , TP53 , CDKN2A , PAK2 , and MAPK14 were decreased in PB-treated senescent HDFs compared to untreated senescent HDFs. In conclusion, this study indicates the modulation of PB extracts on senescence-associated genes expression of replicative senescent HDFs. Further studies warrant determining the mechanism of PB in modulating replicative senescence of HDFs through these signaling pathways.

  13. A crucial role for CDC42 in senescence-associated inflammation and atherosclerosis.

    Directory of Open Access Journals (Sweden)

    Takashi K Ito

    Full Text Available Risk factors for atherosclerosis accelerate the senescence of vascular endothelial cells and promote atherogenesis by inducing vascular inflammation. A hallmark of endothelial senescence is the persistent up-regulation of pro-inflammatory genes. We identified CDC42 signaling as a mediator of chronic inflammation associated with endothelial senescence. Inhibition of CDC42 or NF-κB signaling attenuated the sustained up-regulation of pro-inflammatory genes in senescent human endothelial cells. Endothelium-specific activation of the p53/p21 pathway, a key mediator of senescence, also resulted in up-regulation of pro-inflammatory molecules in mice, which was reversed by Cdc42 deletion in endothelial cells. Likewise, endothelial-specific deletion of Cdc42 significantly attenuated chronic inflammation and plaque formation in atherosclerotic mice. While inhibition of NF-κB suppressed the pro-inflammatory responses in acute inflammation, the influence of Cdc42 deletion was less marked. Knockdown of cdc-42 significantly down-regulated pro-inflammatory gene expression and restored the shortened lifespan to normal in mutant worms with enhanced inflammation. These findings indicate that the CDC42 pathway is critically involved in senescence-associated inflammation and could be a therapeutic target for chronic inflammation in patients with age-related diseases without compromising host defenses.

  14. Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging.

    Science.gov (United States)

    Baar, Marjolein P; Brandt, Renata M C; Putavet, Diana A; Klein, Julian D D; Derks, Kasper W J; Bourgeois, Benjamin R M; Stryeck, Sarah; Rijksen, Yvonne; van Willigenburg, Hester; Feijtel, Danny A; van der Pluijm, Ingrid; Essers, Jeroen; van Cappellen, Wiggert A; van IJcken, Wilfred F; Houtsmuller, Adriaan B; Pothof, Joris; de Bruin, Ron W F; Madl, Tobias; Hoeijmakers, Jan H J; Campisi, Judith; de Keizer, Peter L J

    2017-03-23

    The accumulation of irreparable cellular damage restricts healthspan after acute stress or natural aging. Senescent cells are thought to impair tissue function, and their genetic clearance can delay features of aging. Identifying how senescent cells avoid apoptosis allows for the prospective design of anti-senescence compounds to address whether homeostasis can also be restored. Here, we identify FOXO4 as a pivot in senescent cell viability. We designed a FOXO4 peptide that perturbs the FOXO4 interaction with p53. In senescent cells, this selectively causes p53 nuclear exclusion and cell-intrinsic apoptosis. Under conditions where it was well tolerated in vivo, this FOXO4 peptide neutralized doxorubicin-induced chemotoxicity. Moreover, it restored fitness, fur density, and renal function in both fast aging Xpd TTD/TTD and naturally aged mice. Thus, therapeutic targeting of senescent cells is feasible under conditions where loss of health has already occurred, and in doing so tissue homeostasis can effectively be restored. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. ROS, Cell Senescence, and Novel Molecular Mechanisms in Aging and Age-Related Diseases

    Directory of Open Access Journals (Sweden)

    Pierpaola Davalli

    2016-01-01

    Full Text Available The aging process worsens the human body functions at multiple levels, thus causing its gradual decrease to resist stress, damage, and disease. Besides changes in gene expression and metabolic control, the aging rate has been associated with the production of high levels of Reactive Oxygen Species (ROS and/or Reactive Nitrosative Species (RNS. Specific increases of ROS level have been demonstrated as potentially critical for induction and maintenance of cell senescence process. Causal connection between ROS, aging, age-related pathologies, and cell senescence is studied intensely. Senescent cells have been proposed as a target for interventions to delay the aging and its related diseases or to improve the diseases treatment. Therapeutic interventions towards senescent cells might allow restoring the health and curing the diseases that share basal processes, rather than curing each disease in separate and symptomatic way. Here, we review observations on ROS ability of inducing cell senescence through novel mechanisms that underpin aging processes. Particular emphasis is addressed to the novel mechanisms of ROS involvement in epigenetic regulation of cell senescence and aging, with the aim to individuate specific pathways, which might promote healthy lifespan and improve aging.

  16. Non-Cell Autonomous Effects of the Senescence-Associated Secretory Phenotype in Cancer Therapy

    Directory of Open Access Journals (Sweden)

    Tareq Saleh

    2018-05-01

    Full Text Available In addition to promoting various forms of cell death, most conventional anti-tumor therapies also promote senescence. There is now extensive evidence that therapy-induced senescence (TIS might be transient, raising the concern that TIS could represent an undesirable outcome of therapy by providing a mechanism for tumor dormancy and eventual disease recurrence. The senescence-associated secretory phenotype (SASP is a hallmark of TIS and may contribute to aberrant effects of cancer therapy. Here, we propose that the SASP may also serve as a major driver of escape from senescence and the re-emergence of proliferating tumor cells, wherein factors secreted from the senescent cells contribute to the restoration of tumor growth in a non-cell autonomous fashion. Accordingly, anti-SASP therapies might serve to mitigate the deleterious outcomes of TIS. In addition to providing an overview of the putative actions of the SASP, we discuss recent efforts to identify and eliminate senescent tumor cells.

  17. YUCCA6 over-expression demonstrates auxin function in delaying leaf senescence in Arabidopsis thaliana

    KAUST Repository

    Kim, Jeong Im

    2011-04-21

    The Arabidopsis thaliana YUCCA family of flavin monooxygenase proteins catalyses a rate-limiting step in de novo auxin biosynthesis. A YUCCA6 activation mutant, yuc6-1D, has been shown to contain an elevated free IAA level and to display typical high-auxin phenotypes. It is reported here that Arabidopsis plants over-expressing YUCCA6, such as the yuc6-1D activation mutant and 35S:YUC6 transgenic plants, displayed dramatic longevity. In addition, plants over-expressing YUCCA6 exhibited classical, delayed dark-induced and hormone-induced senescence in assays using detached rosette leaves. However, plants over-expressing an allele of YUCCA6, that carries mutations in the NADPH cofactor binding site, exhibited neither delayed leaf senescence phenotypes nor phenotypes typical of auxin overproduction. When the level of free IAA was reduced in yuc6-1D by conjugation to lysine, yuc6-1D leaves senesced at a rate similar to the wild-type leaves. Dark-induced senescence in detached leaves was accompanied by a decrease in their free IAA content, by the reduced expression of auxin biosynthesis enzymes such as YUCCA1 and YUCCA6 that increase cellular free IAA levels, and by the increased expression of auxin-conjugating enzymes encoded by the GH3 genes that reduce the cellular free auxin levels. Reduced transcript abundances of SAG12, NAC1, and NAC6 during senescence in yuc6-1D compared with the wild type suggested that auxin delays senescence by directly or indirectly regulating the expression of senescence-associated genes. 2011 The Author(s).

  18. Slit shaped microwave induced atmospheric pressure plasma based on a parallel plate transmission line resonator

    Science.gov (United States)

    Kang, S. K.; Seo, Y. S.; Lee, H. Wk; Aman-ur-Rehman; Kim, G. C.; Lee, J. K.

    2011-11-01

    A new type of microwave-excited atmospheric pressure plasma source, based on the principle of parallel plate transmission line resonator, is developed for the treatment of large areas in biomedical applications such as skin treatment and wound healing. A stable plasma of 20 mm width is sustained by a small microwave power source operated at a frequency of 700 MHz and a gas flow rate of 0.9 slm. Plasma impedance and plasma density of this plasma source are estimated by fitting the calculated reflection coefficient to the measured one. The estimated plasma impedance shows a decreasing trend while estimated plasma density shows an increasing trend with the increase in the input power. Plasma uniformity is confirmed by temperature and optical emission distribution measurements. Plasma temperature is sustained at less than 40 °C and abundant amounts of reactive species, which are important agents for bacteria inactivation, are detected over the entire plasma region. Large area treatment ability of this newly developed device is verified through bacteria inactivation experiment using E. coli. Sterilization experiment shows a large bacterial killing mark of 25 mm for a plasma treatment time of 10 s.

  19. Glucocorticoid-induced effects on the growth plate and the IGF system

    NARCIS (Netherlands)

    Smink, Jeske Johanna

    2003-01-01

    Glucocorticoids (GCs) are widely used as anti-inflammatory and immunosuppressive drugs. The use of these potent drugs, however, often results in side-effects, such as growth retardation in children. For already many years, this GC-induced growth retardation is suggested to involve impaired action of

  20. Downregulation of B-myb promotes senescence via the ROS-mediated p53/p21 pathway, in vascular endothelial cells.

    Science.gov (United States)

    Zhou, Zhihui; Yin, Yanlin; Chang, Qun; Sun, Guanqun; Lin, Jiahui; Dai, Yalei

    2017-04-01

    To reveal whether B-myb is involved in preventing senescence of vascular endothelial cells, and if so, to identify possible mechanisms for it. C57/BL6 male mice and primary human aortic endothelial cells (HAECs) were used. Bleomycin was applied to induce stress-related premature senescence. B-myb knockdown was achieved using an siRNA technique and cell senescence was assessed using the senescence-associated β-galactosidase (SA-β-gal) assay. Intracellular reactive oxygen species (ROS) production was analysed using an ROS assay kit and cell proliferation was evaluated using KFluor488 EdU kit. Capillary tube network formation was determined by Matrigel assay. Expressions of mRNA and protein levels were detected by real-time PCR and western blotting. B-myb expression significantly decreased, while p53 and p21 expressions increased in the aortas of aged mice. This expression pattern was also found in replicative senescent HAECs and senescent HAECs induced by bleomycin. B-myb knockdown resulted in upregulation of p22 phox , ROS accumulation and cell senescence of HAECs. Downregulation of B-myb significantly inhibited cell proliferation and capillary tube network formation and activated the p53/p21 signalling pathway. Blocking ROS production or inhibiting p53 activation remarkably attenuated SA-β-gal activity and delayed cell senescence induced by B-myb-silencing. Downregulation of B-myb induced senescence by upregulation of p22 phox and activation of the ROS/p53/p21 pathway, in our vascular endothelial cells, suggesting that B-myb may be a novel candidate for regulating cell senescence to protect against endothelial senescence-related cardiovascular diseases. © 2016 John Wiley & Sons Ltd.

  1. Nicotine-induced retardation of chondrogenesis through down-regulation of IGF-1 signaling pathway to inhibit matrix synthesis of growth plate chondrocytes in fetal rats

    International Nuclear Information System (INIS)

    Deng, Yu; Cao, Hong; Cu, Fenglong; Xu, Dan; Lei, Youying; Tan, Yang; Magdalou, Jacques; Wang, Hui; Chen, Liaobin

    2013-01-01

    Previous studies have confirmed that maternal tobacco smoking causes intrauterine growth retardation (IUGR) and skeletal growth retardation. Among a multitude of chemicals associated with cigarette smoking, nicotine is one of the leading candidates for causing low birth weights. However, the possible mechanism of delayed chondrogenesis by prenatal nicotine exposure remains unclear. We investigated the effects of nicotine on fetal growth plate chondrocytes in vivo and in vitro. Rats were given 2.0 mg/kg·d of nicotine subcutaneously from gestational days 11 to 20. Prenatal nicotine exposure increased the levels of fetal blood corticosterone and resulted in fetal skeletal growth retardation. Moreover, nicotine exposure induced the inhibition of matrix synthesis and down-regulation of insulin-like growth factor 1 (IGF-1) signaling in fetal growth plates. The effects of nicotine on growth plates were studied in vitro by exposing fetal growth plate chondrocytes to 0, 1, 10, or 100 μM of nicotine for 10 days. Nicotine inhibited matrix synthesis and down-regulated IGF-1 signaling in chondrocytes in a concentration-dependent manner. These results suggest that prenatal nicotine exposure induces delayed chondrogenesis and that the mechanism may involve the down-regulation of IGF-1 signaling and the inhibition of matrix synthesis by growth plate chondrocytes. The present study aids in the characterization of delayed chondrogenesis caused by prenatal nicotine exposure, which might suggest a candidate mechanism for intrauterine origins of osteoporosis and osteoarthritis. - Highlights: ► Prenatal nicotine-exposure could induce delayed chondrogenesis in fetal rats. ► Nicotine inhibits matrix synthesis of fetal growth plate chondrocytes. ► Nicotine inhibits IGF-1 signaling pathway in fetal growth plate chondrocytes

  2. Nicotine-induced retardation of chondrogenesis through down-regulation of IGF-1 signaling pathway to inhibit matrix synthesis of growth plate chondrocytes in fetal rats

    Energy Technology Data Exchange (ETDEWEB)

    Deng, Yu; Cao, Hong; Cu, Fenglong [Department of Orthopedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071 (China); Xu, Dan [Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 430071 (China); Research Center of Food and Drug Evaluation, Wuhan University, Wuhan 430071 (China); Lei, Youying [Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 430071 (China); Tan, Yang [Department of Orthopedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071 (China); Magdalou, Jacques [UMR 7561 CNRS-Nancy Université, Faculté de Médicine, Vandoeuvre-lès-Nancy (France); Wang, Hui [Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 430071 (China); Research Center of Food and Drug Evaluation, Wuhan University, Wuhan 430071 (China); Chen, Liaobin, E-mail: lbchen@whu.edu.cn [Department of Orthopedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071 (China)

    2013-05-15

    Previous studies have confirmed that maternal tobacco smoking causes intrauterine growth retardation (IUGR) and skeletal growth retardation. Among a multitude of chemicals associated with cigarette smoking, nicotine is one of the leading candidates for causing low birth weights. However, the possible mechanism of delayed chondrogenesis by prenatal nicotine exposure remains unclear. We investigated the effects of nicotine on fetal growth plate chondrocytes in vivo and in vitro. Rats were given 2.0 mg/kg·d of nicotine subcutaneously from gestational days 11 to 20. Prenatal nicotine exposure increased the levels of fetal blood corticosterone and resulted in fetal skeletal growth retardation. Moreover, nicotine exposure induced the inhibition of matrix synthesis and down-regulation of insulin-like growth factor 1 (IGF-1) signaling in fetal growth plates. The effects of nicotine on growth plates were studied in vitro by exposing fetal growth plate chondrocytes to 0, 1, 10, or 100 μM of nicotine for 10 days. Nicotine inhibited matrix synthesis and down-regulated IGF-1 signaling in chondrocytes in a concentration-dependent manner. These results suggest that prenatal nicotine exposure induces delayed chondrogenesis and that the mechanism may involve the down-regulation of IGF-1 signaling and the inhibition of matrix synthesis by growth plate chondrocytes. The present study aids in the characterization of delayed chondrogenesis caused by prenatal nicotine exposure, which might suggest a candidate mechanism for intrauterine origins of osteoporosis and osteoarthritis. - Highlights: ► Prenatal nicotine-exposure could induce delayed chondrogenesis in fetal rats. ► Nicotine inhibits matrix synthesis of fetal growth plate chondrocytes. ► Nicotine inhibits IGF-1 signaling pathway in fetal growth plate chondrocytes.

  3. The SETD8/PR-Set7 Methyltransferase Functions as a Barrier to Prevent Senescence-Associated Metabolic Remodeling

    Directory of Open Access Journals (Sweden)

    Hiroshi Tanaka

    2017-02-01

    Full Text Available Summary: Cellular senescence is an irreversible growth arrest that contributes to development, tumor suppression, and age-related conditions. Senescent cells show active metabolism compared with proliferating cells, but the underlying mechanisms remain unclear. Here we show that the SETD8/PR-Set7 methyltransferase, which catalyzes mono-methylation of histone H4 at lysine 20 (H4K20me1, suppresses nucleolar and mitochondrial activities to prevent cellular senescence. SETD8 protein was selectively downregulated in both oncogene-induced and replicative senescence. Inhibition of SETD8 alone was sufficient to trigger senescence. Under these states, the expression of genes encoding ribosomal proteins (RPs and ribosomal RNAs as well as the cyclin-dependent kinase (CDK inhibitor p16INK4A was increased, with a corresponding reduction of H4K20me1 at each locus. As a result, the loss of SETD8 concurrently stimulated nucleolar function and retinoblastoma protein-mediated mitochondrial metabolism. In conclusion, our data demonstrate that SETD8 acts as a barrier to prevent cellular senescence through chromatin-mediated regulation of senescence-associated metabolic remodeling. : Tanaka et al. show that SETD8/PR-Set7 methyltransferase represses senescence-associated genes including ribosomal proteins, ribosomal RNAs, and p16INK4A by catalyzing mono-methylation of histone H4 at lysine 20. Depletion of SETD8 derepresses these genes, resulting in nucleolar and mitochondrial coactivation characteristic of senescence-associated metabolic remodeling. Keywords: SETD8/PR-Set7, H4K20 methylation, senescence-associated metabolic remodeling, nucleolus, mitochondria

  4. Direct observation of binding stress-induced crystalline orientation change in piezoelectric plate sensors

    Energy Technology Data Exchange (ETDEWEB)

    Wu, Wei; Shih, Wei-Heng [Department of Materials Science and Engineering, Drexel University, Philadelphia, Pennsylvania 19104 (United States); Shih, Wan Y., E-mail: shihwy@drexel.edu [School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, Pennsylvania 19104 (United States)

    2016-03-28

    We have examined the mechanism of the detection resonance frequency shift, Δf/f, of a 1370 μm long and 537 μm wide [Pb(Mg{sub 1/3}Nb{sub 2/3})O{sub 3}]{sub 0.65}[PbTiO{sub 3}]{sub 0.35} (PMN-PT) piezoelectric plate sensor (PEPS) made of a 8-μm thick PMN-PT freestanding film. The Δf/f of the PEPS was monitored in a three-step binding model detections of (1) binding of maleimide-activated biotin to the sulfhydryl on the PEPS surface followed by (2) binding of streptavidin to the bound biotin and (3) subsequent binding of biotinylated probe deoxyribonucleic acid to the bound streptavidin. We used a PMN-PT surrogate made of the same 8-μm thick PMN-PT freestanding film that the PEPS was made of but was about 1 cm in length and width to carry out crystalline orientation study using X-ray diffraction (XRD) scan around the (002)/(200) peaks after each of the binding steps. The result of the XRD studies indicated that each binding step caused the crystalline orientation of the PMN-PT thin layer to switch from the vertical (002) orientation to the horizontal (200) orientation, and most of the PEPS detection Δf/f was due to the change in the lateral Young's modulus of the PMN-PT thin layer as a result of the crystalline orientation change.

  5. Multiple effects of TRAIL in human carcinoma cells: Induction of apoptosis, senescence, proliferation, and cytokine production

    International Nuclear Information System (INIS)

    Levina, Vera; Marrangoni, Adele M.; DeMarco, Richard; Gorelik, Elieser; Lokshin, Anna E.

    2008-01-01

    TRAIL is a death ligand that induces apoptosis in malignant but not normal cells. Recently the ability of TRAIL to induce proliferation in apoptosis-resistant normal and malignant cells was reported. In this study, we analyzed TRAIL effects in apoptosis sensitive MCF7, OVCAR3 and H460 human tumor cell lines. TRAIL at low concentrations preferentially induced cell proliferation. At 100 ng/ml, apoptotic death was readily observed, however surviving cells acquired higher proliferative capacity. TRAIL-stimulated production of several cytokines, IL-8, RANTES, MCP-1 and bFGF, and activation of caspases 1 and 8 was essential for this effect. Antibodies to IL-8, RANTES, and bFGF blocked TRAIL-induced cell proliferation and further stimulated apoptosis. For the first time, we report that high TRAIL concentrations induced cell senescence as determined by the altered morphology and expression of several senescence markers: SA-β-gal, p21 Waf1/Cip1 , p16 INK4a , and HMGA. Caspase 9 inhibition protected TRAIL-treated cells from senescence, whereas inhibition of caspases 1 and 8 increased the yield of SLP cells. In conclusion, in cultured human carcinoma cells, TRAIL therapy results in three functional outcomes, apoptosis, proliferation and senescence. TRAIL-induced proapoptotic and prosurvival responses correlate with the strength of signaling. TRAIL-induced cytokine production is responsible for its proliferative and prosurvival effects

  6. Quantitative identification of senescent cells in aging and disease.

    Science.gov (United States)

    Biran, Anat; Zada, Lior; Abou Karam, Paula; Vadai, Ezra; Roitman, Lior; Ovadya, Yossi; Porat, Ziv; Krizhanovsky, Valery

    2017-08-01

    Senescent cells are present in premalignant lesions and sites of tissue damage and accumulate in tissues with age. In vivo identification, quantification and characterization of senescent cells are challenging tasks that limit our understanding of the role of senescent cells in diseases and aging. Here, we present a new way to precisely quantify and identify senescent cells in tissues on a single-cell basis. The method combines a senescence-associated beta-galactosidase assay with staining of molecular markers for cellular senescence and of cellular identity. By utilizing technology that combines flow cytometry with high-content image analysis, we were able to quantify senescent cells in tumors, fibrotic tissues, and tissues of aged mice. Our approach also yielded the finding that senescent cells in tissues of aged mice are larger than nonsenescent cells. Thus, this method provides a basis for quantitative assessment of senescent cells and it offers proof of principle for combination of different markers of senescence. It paves the way for screening of senescent cells for identification of new senescence biomarkers, genes that bypass senescence or senolytic compounds that eliminate senescent cells, thus enabling a deeper understanding of the senescent state in vivo. © 2017 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

  7. Herbivore-induced callose deposition on the sieve plates of rice: an important mechanism for host resistance.

    Science.gov (United States)

    Hao, Peiying; Liu, Caixiang; Wang, Yuanyuan; Chen, Rongzhi; Tang, Ming; Du, Bo; Zhu, Lili; He, Guangcun

    2008-04-01

    The brown planthopper (Nilaparvata lugens Stål; BPH) is a specialist herbivore on rice (Oryza sativa) that ingests phloem sap from the plant through its stylet mouthparts. Electronic penetration graphs revealed that BPH insects spent more time wandering over plants carrying the resistance genes Bph14 and Bph15, but less time ingesting phloem than they did on susceptible plants. They also showed that their feeding was frequently interrupted. Tests with [(14)C]sucrose showed that insects ingested much less phloem sap from the resistant than the susceptible plants. BPH feeding up-regulated callose synthase genes and induced callose deposition in the sieve tubes at the point where the stylet was inserted. The compact callose remained intact in the resistant plants, but genes encoding beta-1,3-glucanases were activated, causing unplugging of the sieve tube occlusions in susceptible plants. Continuing ingestion led to a remarkable reduction in the susceptible plants' sucrose content and activation of the RAmy3D gene, leading to starch hydrolysis and ultimately carbohydrate deprivation in the plants. Our results demonstrate that BPH feeding induces the deposition of callose on sieve plates in rice and that this is an important defense mechanism that prevents insects from ingesting phloem sap. In response, however, the BPH can unplug sieve tube occlusions by activating beta-1,3-glucanase genes in rice plants.

  8. The H3K27me3 demethylase JMJD3 contributes to the activation of the INK4A-ARF locus in response to oncogene- and stress-induced senescence

    DEFF Research Database (Denmark)

    Agger, Karl; Cloos, Paul A C; Rudkjaer, Lise

    2009-01-01

    The tumor suppressor proteins p16INK4A and p14ARF, encoded by the INK4A-ARF locus, are key regulators of cellular senescence. The locus is epigenetically silenced by the repressive H3K27me3 mark in normally growing cells, but becomes activated in response to oncogenic stress. Here, we show that e...... in mouse embryonic fibroblasts results in suppression of p16Ink4a and p19Arf expression and in their immortalization....

  9. Establishing a cellular FRET-based fluorescence plate reader assay to monitor proNGF-induced cross-linking of sortilin and the neurotrophin receptor p75(NTR)

    DEFF Research Database (Denmark)

    Skeldal, Sune; Kjaergaard, Maj M; Alwasel, Saleh

    2015-01-01

    the vps10p domain receptor sortilin and the neurotrophin receptor p75(NTR). However, proNGF-induced receptor complex formation has been difficult to directly assess other than by western blotting. We here describe a fluorescence resonance energy transfer (FRET) based fluorescence plate reader assay...

  10. Air bubble-induced detachment of positively and negatively charged polystyrene particles from collector surfaces in a parallel-plate flow chamber

    NARCIS (Netherlands)

    Gomez-Suarez, C; Van der Mei, HC; Busscher, HJ

    2000-01-01

    Electrostatic interactions between colloidal particles and collector surfaces were found tcr be important in particle detachment as induced by the passage of air bubbles in a parallel-plate Row chamber. Electrostatic interactions between adhering particles and passing air bubbles, however, a-ere

  11. Experimental observations of the coupling between induced currents and mechanical motion in torsionally supported square loops and plates. Part 2. Data inventory

    International Nuclear Information System (INIS)

    Weissenburger, D.W.; Bialek, J.M.; Cargulia, G.J.; Ulrickson, M.; Knott, M.J.; Turner, L.R.; Wehrle, R.B.

    1984-12-01

    A series of experiments was successfully conducted to investigate the coupling between induced currents and rigid body rotation in square loops and plates. The experiments were performed with the Fusion Electromagnetic Induction Experiment (FELIX) facility at the Argonne National Laboratory. The observed data exhibited the magnetic damping and magnetic stiffness effects ehich arise in coupled systems and agreed very well with previous analytic calculations

  12. Induction of senescence and identification of differentially expressed genes in tomato in response to monoterpene.

    Directory of Open Access Journals (Sweden)

    Sumit Ghosh

    Full Text Available Monoterpenes, which are among the major components of plant essential oils, are known for their ecological roles as well for pharmaceutical properties. Geraniol, an acyclic monoterpene induces cell cycle arrest and apoptosis/senescence in various cancer cells and plants; however, the genes involved in the process and the underlying molecular mechanisms are not well understood. In this study, we demonstrate that treatment of tomato plants with geraniol results in induction of senescence due to a substantial alteration in transcriptome. We have identified several geraniol-responsive protein encoding genes in tomato using suppression subtractive hybridization (SSH approach. These genes comprise of various components of signal transduction, cellular metabolism, reactive oxygen species (ROS, ethylene signalling, apoptosis and DNA damage response. Upregulation of NADPH oxidase and antioxidant genes, and increase in ROS level after geraniol treatment point towards the involvement of ROS in geraniol-mediated senescence. The delayed onset of seedling death and induced expression of geraniol-responsive genes in geraniol-treated ethylene receptor mutant (Nr suggest that geraniol-mediated senescence involves both ethylene dependent and independent pathways. Moreover, expression analysis during tomato ripening revealed that geraniol-responsive genes are also associated with the natural organ senescence process.

  13. Induction of Senescence and Identification of Differentially Expressed Genes in Tomato in Response to Monoterpene

    Science.gov (United States)

    Kumar, Vinay; Kumar, Anil; Irfan, Mohammad; Chakraborty, Niranjan; Chakraborty, Subhra; Datta, Asis

    2013-01-01

    Monoterpenes, which are among the major components of plant essential oils, are known for their ecological roles as well for pharmaceutical properties. Geraniol, an acyclic monoterpene induces cell cycle arrest and apoptosis/senescence in various cancer cells and plants; however, the genes involved in the process and the underlying molecular mechanisms are not well understood. In this study, we demonstrate that treatment of tomato plants with geraniol results in induction of senescence due to a substantial alteration in transcriptome. We have identified several geraniol-responsive protein encoding genes in tomato using suppression subtractive hybridization (SSH) approach. These genes comprise of various components of signal transduction, cellular metabolism, reactive oxygen species (ROS), ethylene signalling, apoptosis and DNA damage response. Upregulation of NADPH oxidase and antioxidant genes, and increase in ROS level after geraniol treatment point towards the involvement of ROS in geraniol-mediated senescence. The delayed onset of seedling death and induced expression of geraniol-responsive genes in geraniol-treated ethylene receptor mutant (Nr) suggest that geraniol-mediated senescence involves both ethylene dependent and independent pathways. Moreover, expression analysis during tomato ripening revealed that geraniol-responsive genes are also associated with the natural organ senescence process. PMID:24098759

  14. Preventive Effects of Epigallocatechin-3-O-Gallate against Replicative Senescence Associated with p53 Acetylation in Human Dermal Fibroblasts

    Directory of Open Access Journals (Sweden)

    Dong-Wook Han

    2012-01-01

    Full Text Available Considering the various pharmacological activities of epigallocatechin-3-O-gallate (EGCG including anticancer, and anti-inflammatory, antidiabetic, and so forth, relatively less attention has been paid to the antiaging effect of EGCG on primary cells. In this study, the preventive effects of EGCG against serial passage-induced senescence were investigated in primary cells including rat vascular smooth muscle cells (RVSMCs, human dermal fibroblasts (HDFs, and human articular chondrocytes (HACs. The involvement of Sirt1 and acetylated p53 was examined as an underlying mechanism for the senescence preventive activity of EGCG in HDFs. All cells were employed with the initial passage number (PN between 3 and 7. For inducing senescence, the cells were serially passaged at the predetermined times and intervals in the absence or presence of EGCG (50 or 100 μM. Serial passage-induced senescence in RVSMCs and HACs was able to be significantly prevented at 50 μM EGCG, while in HDFs, 100 μM EGCG could significantly prevent senescence and recover their cell cycle progression close to the normal level. Furthermore, EGCG was found to prevent serial passage- and H2O2-induced senescence in HDFs by suppressing p53 acetylation, but the Sirt1 activity was unaffected. In addition, proliferating HDFs showed similar cellular uptake of FITC-conjugated EGCG into the cytoplasm with their senescent counterparts but different nuclear translocation of it from them, which would partly account for the differential responses to EGCG in proliferating versus senescent cells. Taking these results into consideration, it is suggested that EGCG may be exploited to craft strategies for the development of an antiaging or age-delaying agent.

  15. Involvement of NADPH oxidase isoforms in the production of O2- manipulated by ABA in the senescing leaves of early-senescence-leaf (esl) mutant rice (Oryza sativa).

    Science.gov (United States)

    Li, Zhaowei; Wang, Fubiao; Zhao, Qian; Liu, Jianchao; Cheng, Fangmin

    2018-01-01

    In this study, the differences in reactive oxygen species (ROS) generation and abscisic acid (ABA) accumulation in senescing leaves were investigated by early-senescence-leaf (esl) mutant and its wild type, to clarify the relationship among ABA levels, ROS generation, and NADPH oxidase (Nox) in senescing leaves of rice (Oryza sativa). The temporal expression levels of OsNox isoforms in senescing leaves and their expression patterns in response to ABA treatment were determined through quantitative real-time reverse transcription PCR (qRT-PCR). Results showed that the flag leaf of the esl mutant generated more O2- concentrations and accumulated higher ABA levels than the wild-type cultivar did in the grain-filling stage. Exogenous ABA treatment induced O2- generation; however, it was depressed by diphenyleneiodonium chloride (DPI) pretreatment in the detached leaf segments. This finding suggested the involvement of NADPH oxidase in ABA-induced O2- generation. The esl mutant exhibited significantly higher expression of OsNox2, OsNox5, OsNox6, and OsNox7 in the initial of grain-filling stage, followed by sharply decrease. The transcriptional levels of OsNox1, OsNox3, and OsFR07 in the flag leaf of the esl mutant were significantly lower than those in the wild-type cultivar. The expression levels of OsNox2, OsNox5, OsNox6, and OsNox7 were significantly enhanced by exogenous ABA treatments. The enhanced expression levels of OsNox2 and OsNox6 were dependent on the duration of ABA treatment. The inducible expression levels of OsNox5 and OsNox7 were dependent on ABA concentrations. By contrast, exogenous ABA treatment severely repressed the transcripts of OsNox1, OsNox3, and OsFR07 in the detached leaf segments. Therefore, OsNox2, OsNox5, OsNox6, and OsNox7 were probably involved in the ABA-induced O2- generation in the initial stage of leaf senescence. Subsequently, other oxidases activated in deteriorating cells were associated with ROS generation and accumulation in the

  16. Urea retranslocation from senescing Arabidopsis leaves is promoted by DUR3-mediated urea retrieval from leaf apoplast

    Science.gov (United States)

    Bohner, Anne; Kojima, Soichi; Hajirezaei, Mohammad; Melzer, Michael; von Wirén, Nicolaus

    2015-01-01

    In plants, urea derives either from root uptake or protein degradation. Although large quantities of urea are released during senescence, urea is mainly seen as a short-lived nitrogen (N) catabolite serving urease-mediated hydrolysis to ammonium. Here, we investigated the roles of DUR3 and of urea in N remobilization. During natural leaf senescence urea concentrations and DUR3 transcript levels showed a parallel increase with senescence markers like ORE1 in a plant age- and leaf age-dependent manner. Deletion of DUR3 decreased urea accumulation in leaves, whereas the fraction of urea lost to the leaf apoplast was enhanced. Under natural and N deficiency-induced senescence DUR3 promoter activity was highest in the vasculature, but was also found in surrounding bundle sheath and mesophyll cells. An analysis of petiole exudates from wild-type leaves revealed that N from urea accounted for >13% of amino acid N. Urea export from senescent leaves further increased in ureG-2 deletion mutants lacking urease activity. In the dur3 ureG double insertion line the absence of DUR3 reduced urea export from leaf petioles. These results indicate that urea can serve as an early metabolic marker for leaf senescence, and that DUR3-mediated urea retrieval contributes to the retranslocation of N from urea during leaf senescence. PMID:25440717

  17. Functional characterization of PhGR and PhGRL1 during flower senescence in the petunia.

    Science.gov (United States)

    Yang, Weiyuan; Liu, Juanxu; Tan, Yinyan; Zhong, Shan; Tang, Na; Chen, Guoju; Yu, Yixun

    2015-09-01

    Petunia PhGRL1 suppression accelerated flower senescence and increased the expression of the genes downstream of ethylene signaling, whereas PhGR suppression did not. Ethylene plays an important role in flowers senescence. Homologous proteins Green-Ripe and Reversion to Ethylene sensitivity1 are positive regulators of ethylene responses in tomato and Arabidopsis, respectively. The petunia flower has served as a model for the study of ethylene response during senescence. In this study, petunia PhGR and PhGRL1 expression was analyzed in different organs, throughout floral senescence, and after exogenous ethylene treatment; and the roles of PhGR and PhGRL1 during petunia flower senescence were investigated. PhGRL1 suppression mediated by virus-induced gene silencing accelerated flower senescence and increased ethylene production; however, the suppression of PhGR did not. Taken together, these data suggest that PhGRL1 is involved in negative regulation of flower senescence, possibly via ethylene production inhibition and consequently reduced ethylene signaling activation.

  18. Interaction of plant growth regulators and reactive oxygen species to regulate petal senescence in wallflowers (Erysimum linifolium).

    Science.gov (United States)

    Salleh, Faezah Mohd; Mariotti, Lorenzo; Spadafora, Natasha D; Price, Anna M; Picciarelli, Piero; Wagstaff, Carol; Lombardi, Lara; Rogers, Hilary

    2016-04-02

    transcript abundance of WPS46, an auxin-induced gene. A model for the interaction between cytokinins, ethylene, reactive oxygen species and auxin in the regulation of floral senescence in wallflowers is proposed. The combined increase in ethylene and reduction in cytokinin triggers the initiation of senescence and these two plant growth regulators directly or indirectly result in increased reactive oxygen species levels. A fall in conjugated auxin and/or the total auxin pool eventually triggers abscission.

  19. A Simplified Model for the Effect of Weld-Induced Residual Stresses on the Axial Ultimate Strength of Stiffened Plates

    Science.gov (United States)

    Chen, Bai-Qiao; Guedes Soares, C.

    2018-03-01

    The present work investigates the compressive axial ultimate strength of fillet-welded steel-plated ship structures subjected to uniaxial compression, in which the residual stresses in the welded plates are calculated by a thermo-elasto-plastic finite element analysis that is used to fit an idealized model of residual stress distribution. The numerical results of ultimate strength based on the simplified model of residual stress show good agreement with those of various methods including the International Association of Classification Societies (IACS) Common Structural Rules (CSR), leading to the conclusion that the simplified model can be effectively used to represent the distribution of residual stresses in steel-plated structures in a wide range of engineering applications. It is concluded that the widths of the tension zones in the welded plates have a quasi-linear behavior with respect to the plate slenderness. The effect of residual stress on the axial strength of the stiffened plate is analyzed and discussed.

  20. Accelerated cellular senescence phenotype of GAPDH-depleted human lung carcinoma cells

    Energy Technology Data Exchange (ETDEWEB)

    Phadke, Manali; Krynetskaia, Natalia [Temple University School of Pharmacy, Philadelphia, PA 19140 (United States); Mishra, Anurag [Jayne Haines Center for Pharmacogenomics, Temple University School of Pharmacy, Philadelphia, PA 19140 (United States); Krynetskiy, Evgeny, E-mail: ekrynets@temple.edu [Temple University School of Pharmacy, Philadelphia, PA 19140 (United States); Jayne Haines Center for Pharmacogenomics, Temple University School of Pharmacy, Philadelphia, PA 19140 (United States)

    2011-07-29

    Highlights: {yields} We examined the effect of glyceraldehyde 3-phosphate (GAPDH) depletion on proliferation of human carcinoma A549 cells. {yields} GAPDH depletion induces accelerated senescence in tumor cells via AMPK network, in the absence of DNA damage. {yields} Metabolic and genetic rescue experiments indicate that GAPDH has regulatory functions linking energy metabolism and cell cycle. {yields} Induction of senescence in LKB1-deficient lung cancer cells via GAPDH depletion suggests a novel strategy to control tumor cell proliferation. -- Abstract: Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) is a pivotal glycolytic enzyme, and a signaling molecule which acts at the interface between stress factors and the cellular apoptotic machinery. Earlier, we found that knockdown of GAPDH in human carcinoma cell lines resulted in cell proliferation arrest and chemoresistance to S phase-specific cytotoxic agents. To elucidate the mechanism by which GAPDH depletion arrests cell proliferation, we examined the effect of GAPDH knockdown on human carcinoma cells A549. Our results show that GAPDH-depleted cells establish senescence phenotype, as revealed by proliferation arrest, changes in morphology, SA-{beta}-galactosidase staining, and more than 2-fold up-regulation of senescence-associated genes DEC1 and GLB1. Accelerated senescence following GAPDH depletion results from compromised glycolysis and energy crisis leading to the sustained AMPK activation via phosphorylation of {alpha} subunit at Thr172. Our findings demonstrate that GAPDH depletion switches human tumor cells to senescent phenotype via AMPK network, in the absence of DNA damage. Rescue experiments using metabolic and genetic models confirmed that GAPDH has important regulatory functions linking the energy metabolism and the cell cycle networks. Induction of senescence in LKB1-deficient non-small cell lung cancer cells via GAPDH depletion suggests a novel strategy to control tumor cell proliferation.

  1. Possible role of ginsenoside Rb1 in skin wound healing via regulating senescent skin dermal fibroblast.

    Science.gov (United States)

    Hou, Jingang; Kim, Sunchang

    2018-05-05

    Cellular senescence suppresses cancer by inducing irreversible cell growth arrest. Nevertheless, senescent cells is proposed as causal link with aging and aging-related pathologies. The physiological beneficial functions of senescent cells are still of paucity. Here we show that senescent human dermal fibroblast accelerates keratinocytes scratch wound healing and stimulates differentiation of fibroblast. Using oxidative stress (100 μM H 2 O 2 exposure for 1 h) induction, we successfully triggered fibroblast senescence and developed senescence associated secretory phenotype (SASP). The induction of SASP was regulated by p38MAPK/MSK2/NF-κB pathway. Interestingly, inhibition of p38MAPK activation only partially suppressed SASP. However, SASP was significantly inhibited by SB747651A, a specific MSK inhibitor. Additionally, we demonstrate that SASP stimulates migration of keratinocytes and myofibroblast transition of fibroblast, through fold-increased secretion of growth factors, platelet-derived growth factor AA (PDGF-AA) and AB (PDGF-AB), transforming growth factor beta 1 (TGF-β1) and beta 2 (TGF-β2), vascular endothelial growth factor A (VEGF-A) and D (VEGF-D), vascular endothelial growth factor receptor 2 (VEGFR2) and 3 (VEGFR3). Importantly, we also confirmed ginsenoside Rb1 promoted SASP-mediated healing process via p38MAPK/MSK2/NF-κB pathway. The results pointed to senescent fibroblast as a potential mechanism of wound healing control in human skin. Further, it provided a candidate targeted for wound therapy. Copyright © 2018 Elsevier Inc. All rights reserved.

  2. A Study on Characterization of Light-Induced Electroless Plated Ni Seed Layer and Silicide Formation for Solar Cell Application

    Science.gov (United States)

    Takaloo, Ashkan Vakilipour; Joo, Seung Ki; Es, Firat; Turan, Rasit; Lee, Doo Won

    2018-03-01

    Light-induced electroless plating (LIEP) is an easy and inexpensive method that has been widely used for seed layer deposition of Nickel/Copper (Ni/Cu)-based metallization in the solar cell. In this study, material characterization aspects of the Ni seed layer and Ni silicide formation at different bath conditions and annealing temperatures on the n-side of a silicon diode structure have been examined to achieve the optimum cell contacts. The effects of morphology and chemical composition of Ni film on its electrical conductivity were evaluated and described by a quantum mechanical model. It has been found that correlation exists between the theoretical and experimental conductivity of Ni film. Residual stress and phase transformation of Ni silicide as a function of annealing temperature were evaluated using Raman and XRD techniques. Finally, transmission line measurement (TLM) technique was employed to determine the contact resistance of Ni/Si stack after thermal treatment and to understand its correlation with the chemical-structural properties. Results indicated that low electrical resistive mono-silicide (NiSi) phase as low as 5 mΩ.cm2 was obtained.

  3. AMP-activated protein kinase reduces inflammatory responses and cellular senescence in pulmonary emphysema.

    Science.gov (United States)

    Cheng, Xiao-Yu; Li, Yang-Yang; Huang, Cheng; Li, Jun; Yao, Hong-Wei

    2017-04-04

    Current drug therapy fails to reduce lung destruction of chronic obstructive pulmonary disease (COPD). AMP-activated protein kinase (AMPK) has emerged as an important integrator of signals that control energy balance and lipid metabolism. However, there are no studies regarding the role of AMPK in reducing inflammatory responses and cellular senescence during the development of emphysema. Therefore, we hypothesize that AMPK reduces inflammatroy responses, senescence, and lung injury. To test this hypothesis, human bronchial epithelial cells (BEAS-2B) and small airway epithelial cells (SAECs) were treated with cigarette smoke extract (CSE) in the presence of a specific AMPK activator (AICAR, 1 mM) and inhibitor (Compound C, 5 μM). Elastase injection was performed to induce mouse emphysema, and these mice were treated with a specific AMPK activator metformin as well as Compound C. AICAR reduced, whereas Compound C increased CSE-induced increase in IL-8 and IL-6 release and expression of genes involved in cellular senescence. Knockdown of AMPKα1/α2 increased expression of pro-senescent genes (e.g., p16, p21, and p66shc) in BEAS-2B cells. Prophylactic administration of an AMPK activator metformin (50 and 250 mg/kg) reduced while Compound C (4 and 20 mg/kg) aggravated elastase-induced airspace enlargement, inflammatory responses and cellular senescence in mice. This is in agreement with therapeutic effect of metformin (50 mg/kg) on airspace enlargement. Furthermore, metformin prophylactically protected against but Compound C further reduced mitochondrial proteins SOD2 and SIRT3 in emphysematous lungs. In conclusion, AMPK reduces abnormal inflammatory responses and cellular senescence, which implicates as a potential therapeutic target for COPD/emphysema.

  4. Oxygen effects on senescence in chondrocytes and mesenchymal stem cells: consequences for tissue engineering.

    Science.gov (United States)

    Moussavi-Harami, Farid; Duwayri, Yazan; Martin, James A; Moussavi-Harami, Farshid; Buckwalter, Joseph A

    2004-01-01

    Primary isolates of chondrocytes and mesenchymal stem cells are often insufficient for cell-based autologous grafting procedures, necessitating in vitro expansion of cell populations. However, the potential for expansion is limited by cellular senescence, a form of irreversible cell cycle arrest regulated by intrinsic and extrinsic factors. Intrinsic mechanisms common to most somatic cells enforce senescence at the so-called "Hayflick limit" of 60 population doublings. Termed "replicative senescence", this mechanism prevents cellular immortalization and suppresses oncogenesis. Although it is possible to overcome the Hayflick limit by genetically modifying cells, such manipulations are regarded as prohibitively dangerous in the context of tissue engineering. On the other hand, senescence associated with extrinsic factors, often called "stress-induced" senescence, can be avoided simply by modifying culture conditions. Because stress-induced senescence is "premature" in the sense that it can halt growth well before the Hayflick limit is reached, growth potential can be significantly enhanced by minimizing culture related stress. Standard culture techniques were originally developed to optimize the growth of fibroblasts but these conditions are inherently stressful to many other cell types. In particular, the 21% oxygen levels used in standard incubators, though well tolerated by fibroblasts, appear to induce oxidative stress in other cells. We reasoned that chondrocytes and MSCs, which are adapted to relatively low oxygen levels in vivo, might be sensitive to this form of stress. To test this hypothesis we compared the growth of MSC and chondrocyte strains in 21% and 5% oxygen. We found that incubation in 21% oxygen significantly attenuated growth and was associated with increased oxidant production. These findings indicated that sub-optimal standard culture conditions sharply limited the expansion of MSC and chondrocyte populations and suggest that cultures for

  5. The Generation of Human Induced Pluripotent Stem Cells from Blood Cells: An Efficient Protocol Using Serial Plating of Reprogrammed Cells by Centrifugation

    Directory of Open Access Journals (Sweden)

    Youngkyun Kim

    2016-01-01

    Full Text Available Human induced pluripotent stem cells (hiPSCs have demonstrated great potential for differentiation into diverse tissues. We report a straightforward and highly efficient method for the generation of iPSCs from PBMCs. By plating the cells serially to a newly coated plate by centrifugation, this protocol provides multiple healthy iPSC colonies even from a small number of PBMCs. The generated iPSCs expressed pluripotent markers and differentiated into all three germ layer lineages. The protocol can also be used with umbilical cord blood mononuclear cells (CBMCs. In this study, we present a simple and efficient protocol that improved the yield of iPSCs from floating cells such as PBMCs and CBMCs by serial plating and centrifugation.

  6. Ultraviolet-light-induced multi-physics behaviors of 0–3 polarized transparent PLZT plates: II. Finite element analysis and validation

    International Nuclear Information System (INIS)

    Luo, Quantian; Tong, Liyong

    2011-01-01

    This paper presents a novel finite element formulation for 0–3 polarized PbLaZrTi (PLZT) plates and a comparison of the predicted and measured bending displacements. The coupled multi-physics fields and Hamilton's principle for piezoelectric (PZT) materials are first extended to PLZT ceramics by including the anomalous photovoltaic and photo-thermal effects. The photo-induced non-uniform electrical field and mechanical strains across the thickness are modeled in the present finite element formulation for 0–3 polarized PLZT plates, and the associated actuator and sensor equations are derived. The transverse displacements of a 0–3 polarized PLZT plate are predicted using the present finite element formulation and compared with the measured data given in part I. A reasonably good correlation is noted for the transverse displacements at the ten measurement points

  7. The matricellular protein TSP1 promotes human and mouse endothelial cell senescence through CD47 and Nox1.

    Science.gov (United States)

    Meijles, Daniel N; Sahoo, Sanghamitra; Al Ghouleh, Imad; Amaral, Jefferson H; Bienes-Martinez, Raquel; Knupp, Heather E; Attaran, Shireen; Sembrat, John C; Nouraie, Seyed M; Rojas, Mauricio M; Novelli, Enrico M; Gladwin, Mark T; Isenberg, Jeffrey S; Cifuentes-Pagano, Eugenia; Pagano, Patrick J

    2017-10-17

    Senescent cells withdraw from the cell cycle and do not proliferate. The prevalence of senescent compared to normally functioning parenchymal cells increases with age, impairing tissue and organ homeostasis. A contentious principle governing this process has been the redox theory of aging. We linked matricellular protein thrombospondin 1 (TSP1) and its receptor CD47 to the activation of NADPH oxidase 1 (Nox1), but not of the other closely related Nox isoforms, and associated oxidative stress, and to senescence in human cells and aged tissue. In human endothelial cells, TSP1 promoted senescence and attenuated cell cycle progression and proliferation. At the molecular level, TSP1 increased Nox1-dependent generation of reactive oxygen species (ROS), leading to the increased abundance of the transcription factor p53. p53 mediated a DNA damage response that led to senescence through Rb and p21 cip , both of which inhibit cell cycle progression. Nox1 inhibition blocked the ability of TSP1 to increase p53 nuclear localization and p21 cip abundance and its ability to promote senescence. Mice lacking TSP1 showed decreases in ROS production, p21 cip expression, p53 activity, and aging-induced senescence. Conversely, lung tissue from aging humans displayed increases in the abundance of vascular TSP1, Nox1, p53, and p21 cip Finally, genetic ablation or pharmacological blockade of Nox1 in human endothelial cells attenuated TSP1-mediated ROS generation, restored cell cycle progression, and protected against senescence. Together, our results provide insights into the functional interplay between TSP1 and Nox1 in the regulation of endothelial senescence and suggest potential targets for controlling the aging process at the molecular level. Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

  8. Senescence from glioma stem cell differentiation promotes tumor growth

    International Nuclear Information System (INIS)

    Ouchi, Rie; Okabe, Sachiko; Migita, Toshiro; Nakano, Ichiro; Seimiya, Hiroyuki

    2016-01-01

    Glioblastoma (GBM) is a lethal brain tumor composed of heterogeneous cellular populations including glioma stem cells (GSCs) and differentiated non-stem glioma cells (NSGCs). While GSCs are involved in tumor initiation and propagation, NSGCs' role remains elusive. Here, we demonstrate that NSGCs undergo senescence and secrete pro-angiogenic proteins, boosting the GSC-derived tumor formation in vivo. We used a GSC model that maintains stemness in neurospheres, but loses the stemness and differentiates into NSGCs upon serum stimulation. These NSGCs downregulated telomerase, shortened telomeres, and eventually became senescent. The senescent NSGCs released pro-angiogenic proteins, including vascular endothelial growth factors and senescence-associated interleukins, such as IL-6 and IL-8. Conditioned medium from senescent NSGCs promoted proliferation of brain microvascular endothelial cells, and mixed implantation of GSCs and senescent NSGCs into mice enhanced the tumorigenic potential of GSCs. The senescent NSGCs seem to be clinically relevant, because both clinical samples and xenografts of GBM contained tumor cells that expressed the senescence markers. Our data suggest that senescent NSGCs promote malignant progression of GBM in part via paracrine effects of the secreted proteins. - Highlights: • Non-stem glioma cells (NSGCs) lose telomerase and eventually become senescent. • Senescent NSGCs secrete pro-angiogenic proteins, such as VEGFs, IL-6, and IL-8. • Senescent NSGCs enhance the growth of brain microvascular endothelial cells. • Senescent NSGCs enhance the tumorigenic potential of glioma stem cells in vivo.

  9. Senescence from glioma stem cell differentiation promotes tumor growth

    Energy Technology Data Exchange (ETDEWEB)

    Ouchi, Rie [Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550 (Japan); Laboratory of Molecular Target Therapy of Cancer, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550 (Japan); Okabe, Sachiko; Migita, Toshiro [Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550 (Japan); Nakano, Ichiro [Department of Neurosurgery, Comprehensive Cancer Center, University of Alabama at Birmingham, 1824 6th Avenue South, Birmingham, AL 35233 (United States); Seimiya, Hiroyuki, E-mail: hseimiya@jfcr.or.jp [Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550 (Japan); Laboratory of Molecular Target Therapy of Cancer, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550 (Japan)

    2016-02-05

    Glioblastoma (GBM) is a lethal brain tumor composed of heterogeneous cellular populations including glioma stem cells (GSCs) and differentiated non-stem glioma cells (NSGCs). While GSCs are involved in tumor initiation and propagation, NSGCs' role remains elusive. Here, we demonstrate that NSGCs undergo senescence and secrete pro-angiogenic proteins, boosting the GSC-derived tumor formation in vivo. We used a GSC model that maintains stemness in neurospheres, but loses the stemness and differentiates into NSGCs upon serum stimulation. These NSGCs downregulated telomerase, shortened telomeres, and eventually became senescent. The senescent NSGCs released pro-angiogenic proteins, including vascular endothelial growth factors and senescence-associated interleukins, such as IL-6 and IL-8. Conditioned medium from senescent NSGCs promoted proliferation of brain microvascular endothelial cells, and mixed implantation of GSCs and senescent NSGCs into mice enhanced the tumorigenic potential of GSCs. The senescent NSGCs seem to be clinically relevant, because both clinical samples and xenografts of GBM contained tumor cells that expressed the senescence markers. Our data suggest that senescent NSGCs promote malignant progression of GBM in part via paracrine effects of the secreted proteins. - Highlights: • Non-stem glioma cells (NSGCs) lose telomerase and eventually become senescent. • Senescent NSGCs secrete pro-angiogenic proteins, such as VEGFs, IL-6, and IL-8. • Senescent NSGCs enhance the growth of brain microvascular endothelial cells. • Senescent NSGCs enhance the tumorigenic potential of glioma stem cells in vivo.

  10. Cold plate

    Energy Technology Data Exchange (ETDEWEB)

    Marroquin, Christopher M.; O' Connell, Kevin M.; Schultz, Mark D.; Tian, Shurong

    2018-02-13

    A cold plate, an electronic assembly including a cold plate, and a method for forming a cold plate are provided. The cold plate includes an interface plate and an opposing plate that form a plenum. The cold plate includes a plurality of active areas arranged for alignment over respective heat generating portions of an electronic assembly, and non-active areas between the active areas. A cooling fluid flows through the plenum. The plenum, at the non-active areas, has a reduced width and/or reduced height relative to the plenum at the active areas. The reduced width and/or height of the plenum, and exterior dimensions of cold plate, at the non-active areas allow the non-active areas to flex to accommodate surface variations of the electronics assembly. The reduced width and/or height non-active areas can be specifically shaped to fit between physical features of the electronics assembly.

  11. The Antioxidant Machinery of Young and Senescent Human Umbilical Vein Endothelial Cells and Their Microvesicles

    Directory of Open Access Journals (Sweden)

    Guillermo Bodega

    2017-01-01

    Full Text Available We examine the antioxidant role of young and senescent human umbilical vein endothelial cells (HUVECs and their microvesicles (MVs. Proteomic and Western blot studies have shown young HUVECs to have a complete and well-developed antioxidant system. Their MVs also contain antioxidant molecules, though of a smaller and more specific range, specialized in the degradation of hydrogen peroxide and the superoxide anion via the thioredoxin-peroxiredoxin system. Senescence was shown to be associated with a large increase in the size of the antioxidant machinery in both HUVECs and their MVs. These responses might help HUVECs and their MVs deal with the more oxidising conditions found in older cells. Functional analysis confirmed the antioxidant machinery of the MVs to be active and to increase in size with senescence. No glutathione or nonpeptide antioxidant (ascorbic acid and vitamin E activity was detected in the MVs. Endothelial cells and MVs seem to adapt to higher ROS concentrations in senescence by increasing their antioxidant machinery, although this is not enough to recover completely from the senescence-induced ROS increase. Moreover, MVs could be involved in the regulation of the blood plasma redox status by functioning as ROS scavengers.

  12. The senescent microenvironment promotes the emergence of heterogeneous cancer stem-like cells.

    Science.gov (United States)

    Castro-Vega, Luis Jaime; Jouravleva, Karina; Ortiz-Montero, Paola; Liu, Win-Yan; Galeano, Jorge Luis; Romero, Martha; Popova, Tatiana; Bacchetti, Silvia; Vernot, Jean Paul; Londoño-Vallejo, Arturo

    2015-10-01

    There is a well-established association between aging and the onset of metastasis. Although the mechanisms through which age impinges upon the malignant phenotype remain uncharacterized, the role of a senescent microenvironment has been emphasized. We reported previously that human epithelial cells that undergo telomere-driven chromosome instability (T-CIN) display global microRNA (miR) deregulation and develop migration and invasion capacities. Here, we show that post-crisis cells are not able to form tumors unless a senescent microenvironment is provided. The characterization of cell lines established from such tumors revealed that these cells have acquired cell autonomous tumorigenicity, giving rise to heterogeneous tumors. Further experiments demonstrate that explanted cells, while displaying differences in cell differentiation markers, are all endowed of enhanced stem cell properties including self-renewal and multilineage differentiation capacity. Treatments of T-CIN+ cells with senescence-conditioned media induce sphere formation exclusively in cells with senescence-associated tumorigenicity, a capacity that depends on miR-145 repression. These results indicate that the senescent microenvironment, while promoting further transdifferentiations in cells with genome instability, is able to propel the progression of premalignant cells towards a malignant, cell stem-like state. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  13. Plating laboratory

    International Nuclear Information System (INIS)

    Seamster, A.G.; Weitkamp, W.G.

    1984-01-01

    The lead plating of the prototype resonator has been conducted entirely in the plating laboratory at SUNY Stony Brook. Because of the considerable cost and inconvenience in transporting personnel and materials to and from Stony Brook, it is clearly impractical to plate all the resonators there. Furthermore, the high-beta resonator cannot be accommodated at Stony Brook without modifying the set up there. Consequently the authors are constructing a plating lab in-house

  14. CIRCADIAN CLOCK-ASSOCIATED 1 Inhibits Leaf Senescence in Arabidopsis

    Directory of Open Access Journals (Sweden)

    Yi Song

    2018-03-01

    Full Text Available Leaf senescence is an integral part of plant development, and the timing and progressing rate of senescence could substantially affect the yield and quality of crops. It has been known that a circadian rhythm synchronized with external environmental cues is critical for the optimal coordination of various physiological and metabolic processes. However, the reciprocal interactions between the circadian clock and leaf senescence in plants remain unknown. Here, through measuring the physiological and molecular senescence related markers of several circadian components mutants, we found that CIRCADIAN CLOCK-ASSOCIATED 1 inhibits leaf senescence. Further molecular and genetic studies revealed that CCA1 directly activates GLK2 and suppresses ORE1 expression to counteract leaf senescence. As plants age, the expression and periodic amplitude of CCA1 declines and thus weakens the inhibition of senescence. Our findings reveal an age-dependent circadian clock component of the process of leaf senescence.

  15. Flow induced deformation and collapse of a thin rectangular plate with application to the Engineering Test Reactor nuclear fuel elements

    International Nuclear Information System (INIS)

    Davis, C.D.

    1981-01-01

    This work examines a single flat fuel plate bounded by two channels and determines static plate deflections, resultant forces and bending stresses due to pressure differential and hydrodynamic loadings. The classical then reactangular plate equations are used to model the fuel plate. These equations contain as an input the hydrodynamic loading function for modeling the fluid-structural interaction. Two models of the channel flow are developed. One assumes the accelerating potential core flow is laminar with developing two-dimensional laminar boundary layers being formed on the channel walls. The Schlichting entry length solution for developing laminar flow is found to be valid the entire length of the channel. The second model assumes the core flow is fully-developed turbulent the entire length of the channel. Hydrodynamic loading functions are developed for both flow models containing parameters for fluid density, fluid velocity, Reynolds number and channel and plate dimensions. Hence the effects of each parameter can be examined independently. A criterion is developed for predicting ETR fuel plate collapse at high channel flow velocities, 1067 cm/s (420 in/sec) (R/sub e/ = 60,000). The criterion predicts that in order to prevent ETR plate collapse the inlet velocities between channels must not differ by more than 2%

  16. In vitro senescence of immune cells.

    Science.gov (United States)

    Effros, Rita B; Dagarag, Mirabelle; Valenzuela, Hector F

    2003-01-01

    Immune cells are eminently suitable model systems in which to address the possible role of replicative senescence during in vivo aging. Since there are more than 10(8) unique antigen specificities present within the total T lymphocyte population of each individual, the immune response to any single antigen requires massive clonal expansion of the small proportion of T cells whose receptors recognize that antigen. The Hayflick Limit may, therefore, constitute a barrier to effective immune function, at least for those T cells that encounter their specific antigen more than once over the life course. Application of the fibroblast replicative senescence model to the so-called cytotoxic or CD8 T cell, the class of T cells that controls viral infection and cancer, has revealed certain features in common with other cell types as well as several characteristics that are unique to T cells. One senescence-associated change that is T cell-specific is the complete loss of expression of the activation signaling surface molecule, CD28, an alteration that enabled the documentation of high proportions of senescent T cells in vivo. The T cell model has also provided the unique opportunity to analyze telomere dynamics in a cell type that has the ability to upregulate telomerase yet nevertheless undergoes senescence. The intimate involvement of the immune system in the control of pathogens and cancer as well as in modulation of bone homeostasis suggests that more extensive analysis of the full range of characteristics of senescent T cells may help elucidate a broad spectrum of age-associated physiological changes.

  17. The flow of a non-Newtonian fluid induced due to the oscillations of a porous plate

    Directory of Open Access Journals (Sweden)

    S. Asghar

    2004-01-01

    Full Text Available An analytic solution of the flow of a third-grade fluid on a porous plate is constructed. The porous plate is executing oscillations in its own plane with superimposed injection or suction. An increasing or decreasing velocity amplitude of the oscillating porous plate is also examined. It is also shown that in case of third-grade fluid, a combination of suction/injection and decreasing/increasing velocity amplitude is possible as well. Several limiting situations with their implications are given and discussed.

  18. Thin-plate spline analysis of mandibular morphological changes induced by early class III treatment: a long-term evaluation.

    Science.gov (United States)

    Franchi, Lorenzo; Pavoni, Chiara; Cerroni, Silvia; Cozza, Paola

    2014-08-01

    To evaluate the long-term mandibular morphological changes induced by early treatment of class III malocclusion with rapid maxillary expansion (RME) and facial mask (FM). Twenty-five subjects [10 boys, 15 girls; mean age at T1 (start of treatment) 9.3±1.6 years] with class III disharmony were treated with RME and FM therapy followed by fixed appliances. The patients were re-evaluated at the end of growth (T2), about 8.5 years after the end of the treatment (mean age, 18.6±2.0 years). Sixteen subjects with untreated class III malocclusion comprised the control group. Mandibular shape changes were analysed on the lateral cephalograms of the subjects of both groups by means of thin-plate spline (TPS) analysis. Procrustes average mandibular configurations were subjected to TPS analysis by means of both cross-sectional between-group comparisons at T1 and at T2 and longitudinal within-group comparisons. Statistical analysis of shape differences was performed using a generalized Goodall F test. In the long term, the treated group exhibited a significant upward and forward direction of condylar growth. On the contrary, untreated class III subjects showed an upward and backward direction of condylar growth associated with a downward and forward deformation of the mandibular symphysis. Limitations are related to the small sample size of both treated and control groups and to the retrospective nature of the study. Early treatment of class III malocclusion with RME and FM is able to produce significant and favourable long-term mandibular shape changes characterized by an anterior morphogenetic rotation. © The Author 2013. Published by Oxford University Press on behalf of the European Orthodontic Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  19. Senescence rates in patients with end-stage renal disease

    DEFF Research Database (Denmark)

    Koopman, J J E; Rozing, M P; Kramer, Ada

    2011-01-01

    function of the Gompertz equation as a superior descriptor of senescence rate. Here, we tested both measures of the rate of senescence in a population of patients with end-stage renal disease. It is clinical dogma that patients on dialysis experience accelerated senescence, whereas those with a functional...

  20. A multi-component parallel-plate flow chamber system for studying the effect of exercise-induced wall shear stress on endothelial cells.

    Science.gov (United States)

    Wang, Yan-Xia; Xiang, Cheng; Liu, Bo; Zhu, Yong; Luan, Yong; Liu, Shu-Tian; Qin, Kai-Rong

    2016-12-28

    In vivo studies have demonstrated that reasonable exercise training can improve endothelial function. To confirm the key role of wall shear stress induced by exercise on endothelial cells, and to understand how wall shear stress affects the structure and the function of endothelial cells, it is crucial to design and fabricate an in vitro multi-component parallel-plate flow chamber system which can closely replicate exercise-induced wall shear stress waveforms in artery. The in vivo wall shear stress waveforms from the common carotid artery of a healthy volunteer in resting and immediately after 30 min acute aerobic cycling exercise were first calculated by measuring the inner diameter and the center-line blood flow velocity with a color Doppler ultrasound. According to the above in vivo wall shear stress waveforms, we designed and fabricated a parallel-plate flow chamber system with appropriate components based on a lumped parameter hemodynamics model. To validate the feasibility of this system, human umbilical vein endothelial cells (HUVECs) line were cultured within the parallel-plate flow chamber under abovementioned two types of wall shear stress waveforms and the intracellular actin microfilaments and nitric oxide (NO) production level were evaluated using fluorescence microscope. Our results show that the trends of resting and exercise-induced wall shear stress waveforms, especially the maximal, minimal and mean wall shear stress as well as oscillatory shear index, generated by the parallel-plate flow chamber system are similar to those acquired from the common carotid artery. In addition, the cellular experiments demonstrate that the actin microfilaments and the production of NO within cells exposed to the two different wall shear stress waveforms exhibit different dynamic behaviors; there are larger numbers of actin microfilaments and higher level NO in cells exposed in exercise-induced wall shear stress condition than resting wall shear stress condition

  1. Senescence and the pro-tumorigenic stroma.

    Science.gov (United States)

    Alspach, Elise; Fu, Yujie; Stewart, Sheila A

    2013-01-01

    Hayflick and Moorhead first described senescence in the late 1960's as a permanent growth arrest that primary cells underwent after a defined number of cellular divisions in culture. This observation gave rise to the hypothesis that cells contained an internal counting mechanism that limited cellular division and that this limit was an important barrier to cellular transformation. What began as an in vitro observation has led to an immense body of work that reaches into all fields of biology and is of particular interest in the areas of aging, tissue regeneration, and tumorigenesis. The initially simplistic view that senescence limits cellular division and contributes to aging while stymying tumorigenesis has now evolved into an important and complex biological process that has numerous caveats and often opposing effects on tumorigenesis. In this review, we limit our discussion to the complex role senescence plays in tumorigenesis. Throughout the review we attempt to draw many parallels to other systems including the role senescent cells play in the tumor microenvironment and their significant molecular and phenotypic similarities to cancer associated fibroblasts (CAFs).

  2. biomedical challenges of human senescence: a review

    African Journals Online (AJOL)

    2002-12-12

    Dec 12, 2002 ... generation per mitochondrion. Understanding the role of cellular ageing in vivo is another major challenge for integrative study. The in vitro model of cell replicative senescence pioneered by. Sith and Pereira has elucidated the mechanisms limiting cell proliferation(30). Until recently the link between in.

  3. Senescence in the aging process [version 1; referees: 3 approved

    Directory of Open Access Journals (Sweden)

    Richard GA Faragher

    2017-07-01

    Full Text Available The accumulation of ‘senescent’ cells has long been proposed to act as an ageing mechanism. These cells display a radically altered transcriptome and degenerative phenotype compared with their growing counterparts. Tremendous progress has been made in recent years both in understanding the molecular mechanisms controlling entry into the senescent state and in the direct demonstration that senescent cells act as causal agents of mammalian ageing. The challenges now are to gain a better understanding of how the senescent cell phenotype varies between different individuals and tissues, discover how senescence predisposes to organismal frailty, and develop mechanisms by which the deleterious effects of senescent cells can be ameliorated.

  4. Abscisic acid as an internal integrator of multiple physiological processes modulates leaf senescence onset in Arabidopsis thaliana

    Directory of Open Access Journals (Sweden)

    Yuwei eSong

    2016-02-01

    Full Text Available Many studies have shown that exogenous abscisic acid (ABA promotes leaf abscission and senescence. However, owing to a lack of genetic evidence, ABA function in plant senescence has not been clearly defined. Here, two-leaf early-senescence mutants (eas that were screened by chlorophyll fluorescence imaging and named eas1-1 and eas1-2 showed high photosynthetic capacity in the early stage of plant growth compared with the wild type. Gene mapping showed that eas1-1 and eas1-2 are two novel ABA2 allelic mutants. Under unstressed conditions, the eas1 mutations caused plant dwarf, early germination, larger stomatal apertures, and early leaf senescence compared with those of the wild type. Flow cytometry assays showed that the cell apoptosis rate in eas1 mutant leaves was higher than that of the wild type after day 30. A significant increase in the transcript levels of several senescence-associated genes, especially SAG12, was observed in eas1 mutant plants in the early stage of plant growth. More importantly, ABA-activated calcium channel activity in plasma membrane and induced the increase of cytoplasmic calcium concentration in guard cells are suppressed due to the mutation of EAS1. In contrast, the eas1 mutants lost chlorophyll and ion leakage significant faster than in the wild type under treatment with calcium channel blocker. Hence, our results indicate that endogenous ABA level is an important factor controlling the onset of leaf senescence through Ca2+ signaling.

  5. A human-like senescence-associated secretory phenotype is conserved in mouse cells dependent on physiological oxygen.

    Directory of Open Access Journals (Sweden)

    Jean-Philippe Coppé

    2010-02-01

    Full Text Available Cellular senescence irreversibly arrests cell proliferation in response to oncogenic stimuli. Human cells develop a senescence-associated secretory phenotype (SASP, which increases the secretion of cytokines and other factors that alter the behavior of neighboring cells. We show here that "senescent" mouse fibroblasts, which arrested growth after repeated passage under standard culture conditions (20% oxygen, do not express a human-like SASP, and differ from similarly cultured human cells in other respects. However, when cultured in physiological (3% oxygen and induced to senesce by radiation, mouse cells more closely resemble human cells, including expression of a robust SASP. We describe two new aspects of the human and mouse SASPs. First, cells from both species upregulated the expression and secretion of several matrix metalloproteinases, which comprise a conserved genomic cluster. Second, for both species, the ability to promote the growth of premalignant epithelial cells was due primarily to the conserved SASP factor CXCL-1/KC/GRO-alpha. Further, mouse fibroblasts made senescent in 3%, but not 20%, oxygen promoted epithelial tumorigenesis in mouse xenographs. Our findings underscore critical mouse-human differences in oxygen sensitivity, identify conditions to use mouse cells to model human cellular senescence, and reveal novel conserved features of the SASP.

  6. New agents that target senescent cells: the flavone, fisetin, and the BCL-XL inhibitors, A1331852 and A1155463.

    Science.gov (United States)

    Zhu, Yi; Doornebal, Ewald J; Pirtskhalava, Tamar; Giorgadze, Nino; Wentworth, Mark; Fuhrmann-Stroissnigg, Heike; Niedernhofer, Laura J; Robbins, Paul D; Tchkonia, Tamara; Kirkland, James L

    2017-03-08

    Senescent cells accumulate with aging and at sites of pathology in multiple chronic diseases. Senolytics are drugs that selectively promote apoptosis of senescent cells by temporarily disabling the pro-survival pathways that enable senescent cells to resist the pro-apoptotic, pro-inflammatory factors that they themselves secrete. Reducing senescent cell burden by genetic approaches or by administering senolytics delays or alleviates multiple age- and disease-related adverse phenotypes in preclinical models. Reported senolytics include dasatinib, quercetin, navitoclax (ABT263), and piperlongumine. Here we report that fisetin, a naturally-occurring flavone with low toxicity, and A1331852 and A1155463, selective BCL-X L inhibitors that may have less hematological toxicity than the less specific BCL-2 family inhibitor navitoclax, are senolytic. Fisetin selectively induces apoptosis in senescent but not proliferating human umbilical vein endothelial cells (HUVECs). It is not senolytic in senescent IMR90 cells, a human lung fibroblast strain, or primary human preadipocytes. A1331852 and A1155463 are senolytic in HUVECs and IMR90 cells, but not preadipocytes. These agents may be better candidates for eventual translation into clinical interventions than some existing senolytics, such as navitoclax, which is associated with hematological toxicity.

  7. Correlation of epiphyllous bud differentiation with foliar senescence in crassulacean succulent Kalanchoe pinnata as revealed by thidiazuron and ethrel application.

    Science.gov (United States)

    Jaiswal, Sarita; Sawhney, Sudhir

    2006-05-01

    Leaves of Kalanchoe pinnata have crenate margins with each notch bearing a dormant bud competent to develop into a healthy plantlet. Leaf detachment is a common signal for inducing two contrastingly different leaf-based processes, i.e. epiphyllous bud development into plantlet and foliar senescence. To investigate differentiation of bud and its correlation, if any, with foliar senescence, thidiazuron (TDZ), having cytokinin activity and ethrel (ETH), an ethylene releasing compound, were employed. The experimental system was comprised of marginal leaf discs, each harbouring an epiphyllous bud. Most of the growth characteristics of plantlet developing from the epiphyllous bud were significantly inhibited by TDZ but promoted by ETH. The two regulators modulated senescence in a manner different for leaf discs and plantlet leaves. Thus, TDZ caused a complete retention whereas ETH a complete loss of chlorophyll in the leaf discs. In contrast, the former resulted in a complete depletion of chlorophyll from the plantlet leaves producing an albino effect, while the latter reduced it by 50% only. In combined dispensation of the two regulators, the effect of TDZ was expressed in majority of responses studied. The results presented in this investigation clearly show that the foliar processes of epiphyllous bud differentiation and senescence are interlinked as TDZ that delayed senescence inhibited epiphyllous bud differentiation and ETH that hastened senescence promoted it. A working hypothesis to interpret responsiveness of the disc-bud composite on lines of a source-sink duo, has been proposed.

  8. Acrolein-Exposed Normal Human Lung Fibroblasts in Vitro: Cellular Senescence, Enhanced Telomere Erosion, and Degradation of Werner’s Syndrome Protein

    Science.gov (United States)

    Jang, Jun-Ho; Bruse, Shannon; Huneidi, Salam; Schrader, Ronald M.; Monick, Martha M.; Lin, Yong; Carter, A. Brent; Klingelhutz, Aloysius J.

    2014-01-01

    Background: Acrolein is a ubiquitous environmental hazard to human health. Acrolein has been reported to activate the DNA damage response and induce apoptosis. However, little is known about the effects of acrolein on cellular senescence. Objectives: We examined whether acrolein induces cellular senescence in cultured normal human lung fibroblasts (NHLF). Methods: We cultured NHLF in the presence or absence of acrolein and determined the effects of acrolein on cell proliferative capacity, senescence-associated β-galactosidase activity, the known senescence-inducing pathways (e.g., p53, p21), and telomere length. Results: We found that acrolein induced cellular senescence by increasing both p53 and p21. The knockdown of p53 mediated by small interfering RNA (siRNA) attenuated acrolein-induced cellular senescence. Acrolein decreased Werner’s syndrome protein (WRN), a member of the RecQ helicase family involved in DNA repair and telomere maintenance. Acrolein-induced down-regulation of WRN protein was rescued by p53 knockdown or proteasome inhibition. Finally, we found that acrolein accelerated p53-mediated telomere shortening. Conclusions: These results suggest that acrolein induces p53-mediated cellular senescence accompanied by enhanced telomere attrition and WRN protein down-regulation. Citation: Jang JH, Bruse S, Huneidi S, Schrader RM, Monick MM, Lin Y, Carter AB, Klingelhutz AJ, Nyunoya T. 2014. Acrolein-exposed normal human lung fibroblasts in vitro: cellular senescence, enhanced telomere erosion, and degradation of Werner’s syndrome protein. Environ Health Perspect 122:955–962; http://dx.doi.org/10.1289/ehp.1306911 PMID:24747221

  9. MNK1 expression increases during cellular senescence and modulates the subcellular localization of hnRNP A1

    International Nuclear Information System (INIS)

    Ziaei, Samira; Shimada, Naoko; Kucharavy, Herman; Hubbard, Karen

    2012-01-01

    Heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) is an RNA-binding protein that modulates splice site usage, polyadenylation, and cleavage efficiency. This protein has also been implicated in mRNA stability and transport from the nucleus. We have previously demonstrated that hnRNP A1 had diminished protein levels and showed cytoplasmic accumulation in senescent human diploid fibroblasts. Furthermore, we have shown that inhibition of p38 MAPK, a key regulator of cellular senescence, elevated hnRNP A1 protein levels and inhibited hnRNP A1 cytoplasmic localization. In this study, we have explored the possible involvement of MNK1, one of the downstream effector of p38 MAPK, in the regulation of hnRNP A1. We have demonstrated that pharmacological inhibition of MNK1 by CGP 57380 decreased the phosphorylation levels of hnRNP A1 in young and senescent fibroblast cells and blocked the cytoplasmic accumulation of hnRNP A1 in senescent cells. In addition, MNK1 formed a complex with hnRNP A1 in vivo. The expression levels of MNK1, phospho-MNK1, and phospho-eIF4E proteins were found to be elevated in senescent cells. These data suggest that MNK1 regulates the phosphorylation and the subcellular distribution of hnRNP A1 and that MNK1 may play a role in the induction of senescence. -- Highlights: ► MNK1 and not MAPKAPK2 phosphorylates hnRNP A1. ► MNK1 has elevated levels in senescent cells, this has not been reported previously. ► MNK1 activity induces cytoplasmic accumulation of hnRNP A1 in senescent cells. ► Altered cytoplasmic localization of hnRNP A1 may alter gene expression patterns. ► Our studies may increase our understanding of RNA metabolism during cellular aging.

  10. Astrocyte Senescence and Metabolic Changes in Response to HIV Antiretroviral Therapy Drugs

    Directory of Open Access Journals (Sweden)

    Justin Cohen

    2017-08-01

    Full Text Available With the advent of highly active antiretroviral therapy (HAART survival rates among patients infected by HIV have increased. However, even though survival has increased HIV-associated neurocognitive disorders (HAND still persist, suggesting that HAART-drugs may play a role in the neurocognitive impairment observed in HIV-infected patients. Given previous data demonstrating that astrocyte senescence plays a role in neurocognitive disorders such as Alzheimer’s disease (AD, we examined the role of HAART on markers of senescence in primary cultures of human astrocytes (HAs. Our results indicate HAART treatment induces cell cycle arrest, senescence-associated beta-galactosidase, and the cell cycle inhibitor p21. Highly active antiretroviral therapy treatment is also associated with the induction of reactive oxygen species and upregulation of mitochondrial oxygen consumption. These changes in mitochondria correlate with increased glycolysis in HAART drug treated astrocytes. Taken together these results indicate that HAART drugs induce the senescence program in HAs, which is associated with oxidative and metabolic changes that could play a role in the development of HAND.

  11. Molecular bases of cellular senescence: Hayflick phenomenon 50 years later

    Directory of Open Access Journals (Sweden)

    Patrycja Sosińska

    2016-03-01

    Full Text Available Normal human somatic cells have strictly limited proliferative capacity and reach a state of senescence when it becomes exhausted. It is believed that senescence is a response to extensive and irreparable DNA injury, localized in telomeric and/or non-telomeric regions of the genome. Main cause of this damage is oxidative stress, increasing due to deteriorated function of mitochondria. Senescent cells accumulate in tissues during aging, which is causatively linked with the development of various pathologies in elderly individuals, including cancer. This paper, prepared exactly 50 years after Leonard Hayflick’s discovery of the relationship between cellular senescence and organismal aging is aimed at presenting the current knowledge about molecular determinants of senescence, with particular emphasis paid to the role of oxidative stress, effectors of senescence at the level of cell cycle, markers of this phenomenon, and the effect of senescent cells on the development of certain age-related diseases.

  12. Use of NAP gene to manipulate leaf senescence in plants

    Science.gov (United States)

    Gan, Susheng; Guo, Yongfeng

    2013-04-16

    The present invention discloses transgenic plants having an altered level of NAP protein compared to that of a non-transgenic plant, where the transgenic plants display an altered leaf senescence phenotype relative to a non-transgenic plant, as well as mutant plants comprising an inactivated NAP gene, where mutant plants display a delayed leaf senescence phenotype compared to that of a non-mutant plant. The present invention also discloses methods for delaying leaf senescence in a plant, as well as methods of making a mutant plant having a decreased level of NAP protein compared to that of a non-mutant plant, where the mutant plant displays a delayed leaf senescence phenotype relative to a non-mutant plant. Methods for causing precocious leaf senescence or promoting leaf senescence in a plant are also disclosed. Also disclosed are methods of identifying a candidate plant suitable for breeding that displays a delayed leaf senescence and/or enhanced yield phenotype.

  13. Acceleration of leaf senescence is slowed down in transgenic barley plants deficient in the DNA/RNA-binding protein WHIRLY1.

    Science.gov (United States)

    Kucharewicz, Weronika; Distelfeld, Assaf; Bilger, Wolfgang; Müller, Maren; Munné-Bosch, Sergi; Hensel, Götz; Krupinska, Karin

    2017-02-01

    WHIRLY1 in barley was isolated as a potential regulator of the senescence-associated gene HvS40. In order to investigate whether the plastid-nucleus-located DNA/RNA-binding protein WHIRLY1 plays a role in regulation of leaf senescence, primary foliage leaves from transgenic barley plants with an RNAi-mediated knockdown of the WHIRLY1 gene were characterized by typical senescence parameters, namely pigment contents, function and composition of the photosynthetic apparatus, as well as expression of selected genes known to be either down- or up-regulated during leaf senescence. When the plants were grown at low light intensity, senescence progression was similar between wild-type and RNAi-W1 plants. Likewise, dark-induced senescence of detached leaves was not affected by reduction of WHIRLY1. When plants were grown at high light intensity, however, senescence was induced prematurely in wild-type plants but was delayed in RNAi-W1 plants. This result suggests that WHIRLY1 plays a role in light sensing and/or stress communication between chloroplasts and the nucleus. © The Author 2017. Published by Oxford University Press on behalf of the Society for Experimental Biology.

  14. Neurotrophin-3 Induces BMP-2 and VEGF Activities and Promotes the Bony Repair of Injured Growth Plate Cartilage and Bone in Rats.

    Science.gov (United States)

    Su, Yu-Wen; Chung, Rosa; Ruan, Chun-Sheng; Chim, Shek Man; Kuek, Vincent; Dwivedi, Prem P; Hassanshahi, Mohammadhossein; Chen, Ke-Ming; Xie, Yangli; Chen, Lin; Foster, Bruce K; Rosen, Vicki; Zhou, Xin-Fu; Xu, Jiake; Xian, Cory J

    2016-06-01

    Injured growth plate is often repaired by bony tissue causing bone growth defects, for which the mechanisms remain unclear. Because neurotrophins have been implicated in bone fracture repair, here we investigated their potential roles in growth plate bony repair in rats. After a drill-hole injury was made in the tibial growth plate and bone, increased injury site mRNA expression was observed for neurotrophins NGF, BDNF, NT-3, and NT-4 and their Trk receptors. NT-3 and its receptor TrkC showed the highest induction. NT-3 was localized to repairing cells, whereas TrkC was observed in stromal cells, osteoblasts, and blood vessel cells at the injury site. Moreover, systemic NT-3 immunoneutralization reduced bone volume at injury sites and also reduced vascularization at the injured growth plate, whereas recombinant NT-3 treatment promoted bony repair with elevated levels of mRNA for osteogenic markers and bone morphogenetic protein (BMP-2) and increased vascularization and mRNA for vascular endothelial growth factor (VEGF) and endothelial cell marker CD31 at the injured growth plate. When examined in vitro, NT-3 promoted osteogenesis in rat bone marrow stromal cells, induced Erk1/2 and Akt phosphorylation, and enhanced expression of BMPs (particularly BMP-2) and VEGF in the mineralizing cells. It also induced CD31 and VEGF mRNA in rat primary endothelial cell culture. BMP activity appears critical for NT-3 osteogenic effect in vitro because it can be almost completely abrogated by co-addition of the BMP inhibitor noggin. Consistent with its angiogenic effect in vivo, NT-3 promoted angiogenesis in metatarsal bone explants, an effect abolished by co-treatment with anti-VEGF. This study suggests that NT-3 may be an osteogenic and angiogenic factor upstream of BMP-2 and VEGF in bony repair, and further studies are required to investigate whether NT-3 may be a potential target for preventing growth plate faulty bony repair or for promoting bone fracture healing. © 2016

  15. The effect of 648 nm diode laser irradiation on second messengers in senescent human keratinocytes

    Science.gov (United States)

    Hawkins Evans, D.; Abrahamse, H.

    2009-02-01

    Background/purpose: Stress induced premature senescence (SIPS) is defined as the long-term effect of subcytotoxic stress on proliferative cell types. Cells in SIPS display differences at the level of protein expression which affect energy metabolism, defense systems, redox potential, cell morphology and transduction pathways. This study aimed to determine the effect of laser irradiation on second messengers in senescent cells and to establish if that effect can be directly linked to changes in cellular function such as cell viability or proliferation. Materials and Methods: Human keratinocyte cell cultures were modified to induce premature senescence using repeated sub-lethal stresses of 200 uM H2O2 or 5% OH every day for four days with two days recovery. SIPS was confirmed by senescence-associated β-galactosidase staining. Control conditions included normal, repeated stress of 500 uM H2O2 to induce apoptosis and 200 uM PBN as an anti-oxidant or free radical scavenger. Cells were irradiated with 1.5 J/cm2 on day 1 and 4 using a 648 nm diode laser (3.3 mW/cm2) and cellular responses were measured 1 h post irradiation. The affect on second messengers was assessed by measuring cAMP, cGMP, nitric oxide and intracellular calcium (Ca2+) while functional changes were assessed using cell morphology, ATP cell viability, LDH membrane integrity and WST-1 cell proliferation. Results: Results indicate an increase in NO and a decrease in cGMP and Ca2+ in 200 uM H2O2 irradiated cells while PBN irradiated cells showed a decrease in cAMP and an increase in ATP viability and cell proliferation. Conclusion: Laser irradiation influences cell signaling which ultimately changes the biological function of senescent cells. If laser therapy can stimulate the biological function of senescent cells it may be beneficial to conditions such as immune senescence, skin ageing, muscle atrophy, premature ageing of arteries in patients with advanced heart disease, neurodegenerative disorders and

  16. Application of a novel bone osteotomy plate leads to reduction in heat-induced bone tissue necrosis in sheep.

    Science.gov (United States)

    Bekić, Marijo; Davila, Slavko; Hrskanović, Mato; Bekić, Marijana; Seiwerth, Sven; Erdeljić, Viktorija; Capak, Darko; Butković, Vladimir

    2008-12-01

    Previous studies have shown substantial effect thermal damage can have on new bone formation following osteotomy. In this study we evaluated the extent of thermal damage which occurs in four different methods of osteotomy and the effects it can have on bone healing. We further wanted to test whether a special osteotomy plate we constructed can lead to diminished heat generation during osteotomy and enhanced bone healing. The four methods evaluated included osteotomy performed by chisel, a newly constructed osteotomy plate, Gigly and oscillating saw. Twelve adult sheep underwent osteotomy performed on both tibiae. Bone fragments were stabilized using a fixation plate. Callus size was assessed using standard radiographs. Densitometry and histological evaluation were performed at 8 weeks following osteotomy. Temperature measurements were performed both in vivo during the operation, and ex vivo on explanted tibiae. The defects healed without complications and showed typical course of secondary fracture healing with callus ingrowth into the osteotomy gap. Radiographic examination of bone healing showed a tendency towards more callus formation in bones osteotomized using Gigly and oscillating saw, but this difference lacked significance. Use of Gigly and oscillating saw elicited much higher temperatures at the bone cortex surface, which subsequently lead to slightly impaired bone healing according to histological analysis. BMD was equal among all bones. In conclusion, the time required for complete healing of the defect differed depended greatly on the instruments used. The newly constructed osteotomy plate showed best results based on histological findings of capillary and osteoblast density.

  17. Surface stress-induced change in overall elastic behavior and self-bending of ultrathin cantilever plates

    NARCIS (Netherlands)

    Sadeghian, H.; Goosen, J.F.L.; Bossche, A.; Van Keulen, F.

    2009-01-01

    In this letter, the dominant role of surface stress and surface elasticity on the overall elastic behavior of ultrathin cantilever plates is studied. A general framework based on two-dimensional plane-stress analysis is presented. Because of either surface reconstruction or molecular adsorption,

  18. Experiments of dike-induced deformation: Insights on the long-term evolution of divergent plate boundaries

    KAUST Repository

    Trippanera, D.; Ruch, Joel; Acocella, V.; Rivalta, E.

    2015-01-01

    on the intrusion depth and thickness, consistently to what is observed along divergent plate boundaries. The early deformation in setups B and C is similar to that from a single rifting episode (i.e., Lakagigar, Iceland, and Dabbahu, Afar), whereas the late stages

  19. Molecular genetic approaches to the study of cellular senescence.

    Science.gov (United States)

    Goletz, T J; Smith, J R; Pereira-Smith, O M

    1994-01-01

    Cellular senescence is an inability of cells to synthesize DNA and divide, which results in a terminal loss of proliferation despite the maintenance of basic metabolic processes. Senescence has been proposed as a model for the study of aging at the cellular level, and the basis for this model system and its features have been summarized. Although strong experimental evidence exists to support the hypothesis that cellular senescence is a dominant active process, the mechanisms responsible for this phenomenon remain a mystery. Investigators have taken several approaches to gain a better understanding of senescence. Several groups have documented the differences between young and senescent cells, and others have identified changes that occur during the course of a cell's in vitro life span. Using molecular and biochemical approaches, important changes in gene expression and function of cell-cycle-associated products have been identified. The active production of an inhibitor of DNA synthesis has been demonstrated. This may represent the final step in a cascade of events governing senescence. The study of immortal cells which have escaped senescence has also provided useful information, particularly with regard to the genes governing the senescence program. These studies have identified four complementation groups for indefinite division, which suggests that there are at least four genes or gene pathways in the senescence program. Through the use of microcell-mediated chromosome transfer, chromosomes encoding senescence genes have been identified; efforts to clone these genes are ongoing.(ABSTRACT TRUNCATED AT 250 WORDS)

  20. Senescence-associated β-galactosidase activity in the in vitro ovarian stromal fibroblasts

    Directory of Open Access Journals (Sweden)

    Lilian Chuaire-Noack

    2011-04-01

    Full Text Available A growing biological research field is the cellular senescence, a mechanism that has been associated, under certain circumstances, withmalignant transformation. Given the high incidence of ovarian cancerand its main origin from the ovarian surface epithelium, as well asthe possibility that an epithelial-mesenchymal transition occurs, weevaluated both the in vitro growth of stromal fibroblasts from the ovarian cortex and their β-galactosidase activity at pH 6,enzyme whose expression is considered as a marker of replicativesenescence. Methods: 48 samples of ovarian cortical fibroblasts fromdonors without a history of cancer were serially cultured untilthe end of their replicative life. β-galactosidase activity at pH 6was quantified in each passage by the chemiluminiscent method. Ascontrol, we used ovarian epithelial cell cultures from the samedonors. The enzyme activity was also evaluated in fibroblastspreviously induced to senescence by exposure to hydrogen peroxide.Results: The analysis of the enzyme activity and the replicativecapacity taken together showed that the fibroblast cultures reachedthe senescent state at passages 4-5, as what happened with the control epithelial cells. Fibroblasts induced to senescence showed high variability in the values of enzymatic activity. Conclusions:The similarity between both types of cells in reaching the senescent state deserves to be taken into account in relation to theepithelialmesenchymal transition that has been proposed to explaintheir behavior in the genesis of cancer arising from ovarian surfaceepithelium. Low β-galactosidase activity values at pH 6 would suggestpossible inactivation of the response pathways to oxidative stress.

  1. Protein oxidation and degradation during proliferative senescence of human MRC-5 fibroblasts.

    Science.gov (United States)

    Sitte, N; Merker, K; von Zglinicki, T; Grune, T

    2000-03-01

    One of the highlights of age-related changes of cellular metabolism is the accumulation of oxidized proteins. The aging process on a cellular level can be treated either as the ongoing proliferation until a certain number of cell divisions is reached (the Hayflick limit) or as the aging of nondividing cells, that is, the age-related changes in cells without proliferation. The present investigation was undertaken to reveal the changes in protein turnover, proteasome activity, and protein oxidation status during proliferative senescence. We were able to demonstrate that the activity of the cytosolic proteasomal system declines dramatically during the proliferative senescence of human MRC-5 fibroblasts. Regardless of the loss in activity, it could be demonstrated that there are no changes in the transcription and translation of proteasomal subunits. This decline in proteasome activity was accompanied by an increased concentration of oxidized proteins. Cells at higher proliferation stages were no longer able to respond with increased degradation of endogenous [(35)S]-Met-radiolabeled proteins after hydrogen peroxide- or quinone-induced oxidative stress. It could be demonstrated that oxidized proteins in senescent human MRC-5 fibroblasts are not as quickly removed as they are in young cells. Therefore, our study demonstrates that the accumulation of oxidized proteins and decline in protein turnover and activity of the proteasomal system are not only a process of postmitotic aging but also occur during proliferative senescence and result in an increased half-life of oxidized proteins.

  2. Effect of visible light treatments on postharvest senescence of broccoli (Brassica oleracea L.).

    Science.gov (United States)

    Büchert, Agustin M; Gómez Lobato, Maria E; Villarreal, Natalia M; Civello, Pedro M; Martínez, Gustavo A

    2011-01-30

    Broccoli (Brassica oleracea L.) is a rapidly perishable vegetable crop. Several postharvest treatments have been applied in order to delay de-greening. Since light has been shown to have an effect on pigment accumulation during development and darkness is known to induce senescence, the effect of continuous and periodic exposure to low-intensity white light at 22 °C on postharvest senescence of broccoli heads was assayed. Exposure to a constant dose of 12 micromol m(-2) s(-1) was selected as the most suitable treatment and was employed for subsequent experiments. During the course of the treatments, hue and L* values as well as chlorophyll content and visual observation of florets indicated an evident delay in yellowing in treated samples compared with controls. No statistically significant differences in total protein content were found, but soluble protein content was higher in treated samples. Total and reducing sugar as well as starch levels decreased during postharvest senescence, with lower values in control samples. The results of this study indicate that storage under continuous low-intensity light is an efficient and low-cost treatment that delays postharvest senescence while maintaining the quality of harvested broccoli florets. 2010 Society of Chemical Industry.

  3. Qualitative and quantitative modifications of root mitochondria during senescence of above-ground parts of Arabidopis thaliana.

    Science.gov (United States)

    Fanello, Diego Darío; Bartoli, Carlos Guillermo; Guiamet, Juan José

    2017-05-01

    This work studied modifications experienced by root mitochondria during whole plant senescence or under light deprivation, using Arabidopsis thaliana plants with YFP tagged to mitochondria. During post-bolting development, root respiratory activity started to decline after aboveground organs (i.e., rosette leaves) had senesced. This suggests that carbohydrate starvation may induce root senescence. Similarly, darkening the whole plant induced a decrease in respiration of roots. This was partially due to a decrease in the number of total mitochondria (YFP-labelled mitochondria) and most probably to a decrease in the quantity of mitochondria with a developed inner membrane potential (ΔΨm, i.e., Mitotracker red- labelled mitochondria). Also, the lower amount of mitochondria with ΔΨm compared to YFP-labelled mitochondria at 10d of whole darkened plant, suggests the presence of mitochondria in a "standby state". The experiments also suggest that small mitochondria made the main contribution to the respiratory activity that was lost during root senescence. Sugar supplementation partially restored the respiration of mitochondria after 10d of whole plant dark treatment. These results suggest that root senescence is triggered by carbohydrate starvation, with loss of ΔΨm mitochondria and changes in mitochondrial size distribution. Copyright © 2017 Elsevier B.V. All rights reserved.

  4. Simulation of the irradiation-induced thermo-mechanical behaviors evolution in monolithic U–Mo/Zr fuel plates under a heterogeneous irradiation condition

    Energy Technology Data Exchange (ETDEWEB)

    Zhao, Yunmei; Gong, Xin; Ding, Shurong, E-mail: dsr1971@163.com

    2015-04-15

    Highlights: • The three-dimensional stress update algorithms in a co-rotational framework are developed for U–Mo and Zircalloy with the irradiation effects. • An effective method for three-dimensional modeling of the in-pile behaviors in heterogeneously irradiated monolithic fuel plates is established and validated. • The effects of the fission-induced creep effects in the U–Mo foil are investigated in detail. • A deformation phenomenon similar to the irradiation experimental results is obtained. - Abstract: For monolithic fuel plates with U–Mo foil and Zircalloy cladding, the three-dimensional large deformation incremental constitutive relations and stress update algorithms in the co-rotational coordinate framework are developed for the fuel and cladding with their respective irradiation effects involved. Three-dimensional finite element simulation of their in-pile thermo-mechanical coupling behaviors under a location-dependent irradiation condition is implemented via the validated user-defined subroutines UMATHT and UMAT in ABAQUS. Comparison of the simulation results for two cases with or without creep considered in the U–Mo foil indicates that with the irradiation creep included (1) considerable stress-relaxation appears in the U–Mo foil, and the mechanical interaction between fuel and cladding is weakened; (2) approximately identical thickness increments in the plate and fuel foil exist and become comparably larger; (3) plastic deformation in the cladding is significantly diminished.

  5. Markers of T Cell Senescence in Humans

    Directory of Open Access Journals (Sweden)

    Weili Xu

    2017-08-01

    Full Text Available Many countries are facing the aging of their population, and many more will face a similar obstacle in the near future, which could be a burden to many healthcare systems. Increased susceptibility to infections, cardiovascular and neurodegenerative disease, cancer as well as reduced efficacy of vaccination are important matters for researchers in the field of aging. As older adults show higher prevalence for a variety of diseases, this also implies higher risk of complications, including nosocomial infections, slower recovery and sequels that may reduce the autonomy and overall quality of life of older adults. The age-related effects on the immune system termed as “immunosenescence” can be exemplified by the reported hypo-responsiveness to influenza vaccination of the elderly. T cells, which belong to the adaptive arm of the immune system, have been extensively studied and the knowledge gathered enables a better understanding of how the immune system may be affected after acute/chronic infections and how this matters in the long run. In this review, we will focus on T cells and discuss the surface and molecular markers that are associated with T cell senescence. We will also look at the implications that senescent T cells could have on human health and diseases. Finally, we will discuss the benefits of having these markers for investigators and the future work that is needed to advance the field of T cell senescence markers.

  6. Leaf senescence and nutrient remobilisation in barley and wheat

    DEFF Research Database (Denmark)

    Gregersen, P L; Holm, P B; Krupinska, K

    2008-01-01

    Extensive studies have been undertaken on senescence processes in barley and wheat and their importance for the nitrogen use efficiency of these crop plants. During the senescence processes, proteins are degraded and nutrients are re-mobilised from senescing leaves to other organs, especially...... of chloroplasts is summarised. Rubisco is thought to be released from chloroplasts into vesicles containing stroma material (RCB = Rubisco-containing bodies). These vesicles may then take different routes for their degradation. Transcriptome analyses on barley and wheat senescence have identified genes involved...... in degradative, metabolic and regulatory processes that could be used in future strategies aimed at modifying the senescence process. The breeding of crops for characters related to senescence processes, e.g. higher yields and better nutrient use efficiency, is complex. Such breeding has to cope with the dilemma...

  7. Global transcriptome analysis of the maize (Zea mays L.) inbred line 08LF during leaf senescence initiated by pollination-prevention.

    Science.gov (United States)

    Wu, Liancheng; Li, Mingna; Tian, Lei; Wang, Shunxi; Wu, Liuji; Ku, Lixia; Zhang, Jun; Song, Xiaoheng; Liu, Haiping; Chen, Yanhui

    2017-01-01

    In maize (Zea mays), leaf senescence acts as a nutrient recycling process involved in proteins, lipids, and nucleic acids degradation and transport to the developing sink. However, the molecular mechanisms of pre-maturation associated with pollination-prevention remain unclear in maize. To explore global gene expression changes during the onset and progression of senescence in maize, the inbred line 08LF, with severe early senescence caused by pollination prevention, was selected. Phenotypic observation showed that the onset of leaf senescence of 08LF plants occurred approximately 14 days after silking (DAS) by pollination prevention. Transcriptional profiling analysis of the leaf at six developmental stages during induced senescence revealed that a total of 5,432 differentially expressed genes (DEGs) were identified, including 2314 up-regulated genes and 1925 down-regulated genes. Functional annotation showed that the up-regulated genes were mainly enriched in multi-organism process and nitrogen compound transport, whereas down-regulated genes were involved in photosynthesis. Expression patterns and pathway enrichment analyses of early-senescence related genes indicated that these DEGs are involved in complex regulatory networks, especially in the jasmonic acid pathway. In addition, transcription factors from several families were detected, particularly the CO-like, NAC, ERF, GRAS, WRKY and ZF-HD families, suggesting that these transcription factors might play important roles in driving leaf senescence in maize as a result of pollination-prevention.

  8. The WRKY transcription factor family and senescence in switchgrass.

    Science.gov (United States)

    Rinerson, Charles I; Scully, Erin D; Palmer, Nathan A; Donze-Reiner, Teresa; Rabara, Roel C; Tripathi, Prateek; Shen, Qingxi J; Sattler, Scott E; Rohila, Jai S; Sarath, Gautam; Rushton, Paul J

    2015-11-09

    Early aerial senescence in switchgrass (Panicum virgatum) can significantly limit biomass yields. WRKY transcription factors that can regulate senescence could be used to reprogram senescence and enhance biomass yields. All potential WRKY genes present in the version 1.0 of the switchgrass genome were identified and curated using manual and bioinformatic methods. Expression profiles of WRKY genes in switchgrass flag leaf RNA-Seq datasets were analyzed using clustering and network analyses tools to identify both WRKY and WRKY-associated gene co-expression networks during leaf development and senescence onset. We identified 240 switchgrass WRKY genes including members of the RW5 and RW6 families of resistance proteins. Weighted gene co-expression network analysis of the flag leaf transcriptomes across development readily separated clusters of co-expressed genes into thirteen modules. A visualization highlighted separation of modules associated with the early and senescence-onset phases of flag leaf growth. The senescence-associated module contained 3000 genes including 23 WRKYs. Putative promoter regions of senescence-associated WRKY genes contained several cis-element-like sequences suggestive of responsiveness to both senescence and stress signaling pathways. A phylogenetic comparison of senescence-associated WRKY genes from switchgrass flag leaf with senescence-associated WRKY genes from other plants revealed notable hotspots in Group I, IIb, and IIe of the phylogenetic tree. We have identified and named 240 WRKY genes in the switchgrass genome. Twenty three of these genes show elevated mRNA levels during the onset of flag leaf senescence. Eleven of the WRKY genes were found in hotspots of related senescence-associated genes from multiple species and thus represent promising targets for future switchgrass genetic improvement. Overall, individual WRKY gene expression profiles could be readily linked to developmental stages of flag leaves.

  9. Protective role of klotho protein on epithelial cells upon co-culture with activated or senescent monocytes

    Energy Technology Data Exchange (ETDEWEB)

    Mytych, Jennifer, E-mail: jennifermytych@gmail.com [Institute of Applied Biotechnology and Basic Sciences, University of Rzeszow, Werynia 502, 36-100 Kolbuszowa (Poland); Centre of Applied Biotechnology and Basic Sciences, University of Rzeszow, Werynia 502, 36-100 Kolbuszowa (Poland); Wos, Izabela; Solek, Przemyslaw; Koziorowski, Marek [Institute of Applied Biotechnology and Basic Sciences, University of Rzeszow, Werynia 502, 36-100 Kolbuszowa (Poland); Centre of Applied Biotechnology and Basic Sciences, University of Rzeszow, Werynia 502, 36-100 Kolbuszowa (Poland)

    2017-01-15

    Monocytes ensure proper functioning and maintenance of epithelial cells, while good condition of monocytes is a key factor of these interactions. Although, it was shown that in some circumstances, a population of altered monocytes may appear, there is no data regarding their effect on epithelial cells. In this study, using direct co-culture model with LPS-activated and Dox-induced senescent THP-1 monocytes, we reported for the first time ROS-induced DNA damage, reduced metabolic activity, proliferation inhibition and cell cycle arrest followed by p16-, p21- and p27-mediated DNA damage response pathways activation, premature senescence and apoptosis induction in HeLa cells. Also, we show that klotho protein possessing anti-aging and anti-inflammatory characteristics reduced cytotoxic and genotoxic events by inhibition of insulin/IGF-IR and downregulation of TRF1 and TRF2 proteins. Therefore, klotho protein could be considered as a protective factor against changes caused by altered monocytes in epithelial cells. - Highlights: • Activated and senescent THP-1 monocytes induced cyto- and genotoxicity in HeLa cells. • Altered monocytes provoked oxidative and nitrosative stress-induced DNA damage. • DNA damage activated DDR pathways and lead to premature senescence and apoptosis. • Klotho reduced ROS/RNS-mediated toxicity through insulin/IGF-IR pathway inhibition. • Klotho protects HeLa cells from cyto- and genotoxicity induced by altered monocytes.

  10. Protective role of klotho protein on epithelial cells upon co-culture with activated or senescent monocytes

    International Nuclear Information System (INIS)

    Mytych, Jennifer; Wos, Izabela; Solek, Przemyslaw; Koziorowski, Marek

    2017-01-01

    Monocytes ensure proper functioning and maintenance of epithelial cells, while good condition of monocytes is a key factor of these interactions. Although, it was shown that in some circumstances, a population of altered monocytes may appear, there is no data regarding their effect on epithelial cells. In this study, using direct co-culture model with LPS-activated and Dox-induced senescent THP-1 monocytes, we reported for the first time ROS-induced DNA damage, reduced metabolic activity, proliferation inhibition and cell cycle arrest followed by p16-, p21- and p27-mediated DNA damage response pathways activation, premature senescence and apoptosis induction in HeLa cells. Also, we show that klotho protein possessing anti-aging and anti-inflammatory characteristics reduced cytotoxic and genotoxic events by inhibition of insulin/IGF-IR and downregulation of TRF1 and TRF2 proteins. Therefore, klotho protein could be considered as a protective factor against changes caused by altered monocytes in epithelial cells. - Highlights: • Activated and senescent THP-1 monocytes induced cyto- and genotoxicity in HeLa cells. • Altered monocytes provoked oxidative and nitrosative stress-induced DNA damage. • DNA damage activated DDR pathways and lead to premature senescence and apoptosis. • Klotho reduced ROS/RNS-mediated toxicity through insulin/IGF-IR pathway inhibition. • Klotho protects HeLa cells from cyto- and genotoxicity induced by altered monocytes.

  11. Photochemical Production and Behavior of Hydroperoxyacids in Heterotrophic Bacteria Attached to Senescent Phytoplanktonic Cells

    Directory of Open Access Journals (Sweden)

    Frédéric Vaultier

    2013-06-01

    Full Text Available The photooxidation of cellular monounsaturated fatty acids was investigated in senescent phytoplanktonic cells (Emiliania huxleyi and in their attached bacteria under laboratory controlled conditions. Our results indicated that UV-visible irradiation of phytodetritus induced the photooxidation of oleic (produced by phytoplankton and bacteria and cis-vaccenic (specifically produced by bacteria acids. These experiments confirmed the involvement of a substantial singlet oxygen transfer from senescent phytoplanktonic cells to attached bacteria, and revealed a significant correlation between the concentration of chlorophyll, a photosensitizer, in the phytodetritus and the photodegradation state of bacteria. Hydroperoxyacids (fatty acid photoproducts appeared to be quickly degraded to ketoacids and hydroxyacids in bacteria and in phytoplanktonic cells. This degradation involves homolytic cleavage (most likely induced by UV and/or transition metal ions and peroxygenase activity (yielding epoxy acids.

  12. The evolution of senescence in the tree of life

    DEFF Research Database (Denmark)

    Salguero-Gómez, Roberto

    The existing theories on the evolution of senescence assume that senescence is inevitable in all organisms. However, recent studies have shown that this is not necessarily true. A better understanding of senescence and its underlying mechanisms could have far-reaching consequences for conservation...... and eco-evolutionary research. This book is the first to offer interdisciplinary perspectives on the evolution of senescence in many species, setting the stage for further developments. It brings together new insights from a wide range of scientific fields and cutting-edge research done on a multitude...

  13. Downregulation of Melanoma Cell Adhesion Molecule (MCAM/CD146) Accelerates Cellular Senescence in Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells.

    Science.gov (United States)

    Jin, Hye Jin; Kwon, Ji Hye; Kim, Miyeon; Bae, Yun Kyung; Choi, Soo Jin; Oh, Wonil; Yang, Yoon Sun; Jeon, Hong Bae

    2016-04-01

    . However, long-term growth inevitably induces cellular senescence, which potentially causes poor clinical outcomes by inducing growth arrest and the loss of stem cell properties. Thus, the identification of markers for evaluating the status of MSC senescence during long-term culture may enhance the success of MSC-based therapy. This study provides strong evidence that CD146 is a novel and useful marker for predicting senescence in human umbilical cord blood-derived MSCs (hUCB-MSCs), and CD146 can potentially be applied in quality-control assessments of hUCB-MSC-based therapy. ©AlphaMed Press.

  14. Snail regulates cell survival and inhibits cellular senescence in human metastatic prostate cancer cell lines.

    Science.gov (United States)

    Emadi Baygi, Modjtaba; Soheili, Zahra Soheila; Schmitz, Ingo; Sameie, Shahram; Schulz, Wolfgang A

    2010-12-01

    The epithelial-mesenchymal transition (EMT) is regarded as an important step in cancer metastasis. Snail, a master regulator of EMT, has been recently proposed to act additionally as a cell survival factor and inducer of motility. We have investigated the function of Snail (SNAI1) in prostate cancer cells by downregulating its expression via short (21-mer) interfering RNA (siRNA) and measuring the consequences on EMT markers, cell viability, death, cell cycle, senescence, attachment, and invasivity. Of eight carcinoma cell lines, the prostate carcinoma cell lines LNCaP and PC-3 showed the highest and moderate expression of SNAI1 mRNA, respectively, as measured by quantitative RT-PCR. Long-term knockdown of Snail induced a severe decline in cell numbers in LNCaP and PC-3 and caspase activity was accordingly enhanced in both cell lines. In addition, suppression of Snail expression induced senescence in LNCaP cells. SNAI1-siRNA-treated cells did not tolerate detachment from the extracellular matrix, probably due to downregulation of integrin α6. Expression of E-cadherin, vimentin, and fibronectin was also affected. Invasiveness of PC-3 cells was not significantly diminished by Snail knockdown. Our data suggest that Snail acts primarily as a survival factor and inhibitor of cellular senescence in prostate cancer cell lines. We therefore propose that Snail can act as early driver of prostate cancer progression.

  15. Stem cell senescence drives age-attenuated induction of pituitary tumours in mouse models of paediatric craniopharyngioma.

    Science.gov (United States)

    Mario Gonzalez-Meljem, Jose; Haston, Scott; Carreno, Gabriela; Apps, John R; Pozzi, Sara; Stache, Christina; Kaushal, Grace; Virasami, Alex; Panousopoulos, Leonidas; Neda Mousavy-Gharavy, Seyedeh; Guerrero, Ana; Rashid, Mamunur; Jani, Nital; Goding, Colin R; Jacques, Thomas S; Adams, David J; Gil, Jesus; Andoniadou, Cynthia L; Martinez-Barbera, Juan Pedro

    2017-11-28

    Senescent cells may promote tumour progression through the activation of a senescence-associated secretory phenotype (SASP), whether these cells are capable of initiating tumourigenesis in vivo is not known. Expression of oncogenic β-catenin in Sox2+ young adult pituitary stem cells leads to formation of clusters of stem cells and induction of tumours resembling human adamantinomatous craniopharyngioma (ACP), derived from Sox2- cells in a paracrine manner. Here, we uncover the mechanisms underlying this paracrine tumourigenesis. We show that expression of oncogenic β-catenin in Hesx1+ embryonic precursors also results in stem cell clusters and paracrine tumours. We reveal that human and mouse clusters are analogous and share a common signature of senescence and SASP. Finally, we show that mice with reduced senescence and SASP responses exhibit decreased tumour-inducing potential. Together, we provide evidence that senescence and a stem cell-associated SASP drive cell transformation and tumour initiation in vivo in an age-dependent fashion.

  16. Histological evidence of oxidative stress and premature senescence in preterm premature rupture of the human fetal membranes recapitulated in vitro.

    Science.gov (United States)

    Menon, Ramkumar; Boldogh, Istvan; Hawkins, Hal K; Woodson, Michael; Polettini, Jossimara; Syed, Tariq Ali; Fortunato, Stephen J; Saade, George R; Papaconstantinou, John; Taylor, Robert N

    2014-06-01

    Preterm prelabor rupture of the membranes (pPROM) may lead to preterm births (PTBs). We investigated premature senescence of fetal membranes in women with pPROM and spontaneous PTB with intact membranes (PTBs, and term births. Term fetal membranes were exposed to cigarette smoke extract to induce oxidative stress. Western blots documented p-p53 and p-p38 MAPK. Transmission electron microscopy assessed cellular morphologic features in clinical and cigarette smoke extract-treated membranes. A total of 80% of pPROM cells and >60% of term cells were positive for all three senescence phenotype markers, and concentrations were higher than in PTBs (P PTBs. Histologic and biochemical resemblance of pPROM and term membranes suggests premature senescence of the membranes is a mechanistic feature in pPROM, and this can be phenocopied in an in vitro model. Copyright © 2014 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  17. Polyamines, peroxidase and proteins involved in the senescence ...

    African Journals Online (AJOL)

    Senescence is the natural aging process at the cellular level or range of phenomena associated with this process. The objective of this review was to show the involvement of substances that may be related to senescence in plants, such as polyamines, peroxidase and proteins. These substances were related with the ...

  18. Cellular and molecular aspects of quinoa leaf senescence.

    Science.gov (United States)

    López-Fernández, María Paula; Burrieza, Hernán Pablo; Rizzo, Axel Joel; Martínez-Tosar, Leandro Julián; Maldonado, Sara

    2015-09-01

    During leaf senescence, degradation of chloroplasts precede to changes in nuclei and other cytoplasmic organelles, RuBisCO stability is progressively lost, grana lose their structure, plastidial DNA becomes distorted and degraded, the number of plastoglobuli increases and abundant senescence-associated vesicles containing electronically dense particles emerge from chloroplasts pouring their content into the central vacuole. This study examines quinoa leaf tissues during development and senescence using a range of well-established markers of programmed cell death (PCD), including: morphological changes in nuclei and chloroplasts, degradation of RuBisCO, changes in chlorophyll content, DNA degradation, variations in ploidy levels, and changes in nuclease profiles. TUNEL reaction and DNA electrophoresis demonstrated that DNA fragmentation in nuclei occurs at early senescence, which correlates with induction of specific nucleases. During senescence, metabolic activity is high and nuclei endoreduplicate, peaking at 4C. At this time, TEM images showed some healthy nuclei with condensed chromatin and nucleoli. We have found that DNA fragmentation, induction of senescence-associated nucleases and endoreduplication take place during leaf senescence. This provides a starting point for further research aiming to identify key genes involved in the senescence of quinoa leaves. Published by Elsevier Ireland Ltd.

  19. Delay of Iris flower senescence by protease inhibitors

    NARCIS (Netherlands)

    Pak, C.; Doorn, van W.G.

    2005-01-01

    asterisk inside a circle sign Visible senescence of the flag tepals in Iris x hollandica (cv. Blue Magic) was preceded by a large increase in endoprotease activity. Just before visible senescence about half of total endoprotease activity was apparently due to cysteine proteases, somewhat less than

  20. Shock-induced thermal wave propagation and response analysis of a viscoelastic thin plate under transient heating loads

    Science.gov (United States)

    Li, Chenlin; Guo, Huili; Tian, Xiaogeng

    2018-04-01

    This paper is devoted to the thermal shock analysis for viscoelastic materials under transient heating loads. The governing coupled equations with time-delay parameter and nonlocal scale parameter are derived based on the generalized thermo-viscoelasticity theory. The problem of a thin plate composed of viscoelastic material, subjected to a sudden temperature rise at the boundary plane, is solved by employing Laplace transformation techniques. The transient responses, i.e. temperature, displacement, stresses, heat flux as well as strain, are obtained and discussed. The effects of time-delay and nonlocal scale parameter on the transient responses are analyzed and discussed. It can be observed that: the propagation of thermal wave is dynamically smoothed and changed with the variation of time-delay; while the displacement, strain, and stress can be rapidly reduced by nonlocal scale parameter, which can be viewed as an important indicator for predicting the stiffness softening behavior for viscoelastic materials.

  1. Life History Trade-Offs Modulate the Speed of Senescence

    DEFF Research Database (Denmark)

    Salguero-Gómez, Roberto; Jones, Owen

    2017-01-01

    that the speed of senescence varies dramatically across the Tree of Life and that it has a moderate phylogenetic signal when considering both plants and animals but that this signal is stronger in animals than in plants, indicating that the strength of selection on the trait may differ between kingdoms. We next...... examined the speed of senescence at two taxonomic levels: comparing kingdoms, with plants more likely to postpone senescence than animals, and, when the data allowed for it, comparing taxonomic classes, where we found that pine trees are particularly slow to senesce, followed by reptiles and sponges. Most...... puzzling and worthy of investigation in itself. We used two open-data repositories of high-quality demographic information for animals and plants to present a novel overview of the degree of variation in life-history strategies and their component life-history traits, including the speed of senescence...

  2. Senescence gives insights into the morphogenetic evolution of anamniotes

    Directory of Open Access Journals (Sweden)

    Éric Villiard

    2017-06-01

    Full Text Available Senescence represents a mechanism to avoid undesired cell proliferation that plays a role in tumor suppression, wound healing and embryonic development. In order to gain insight on the evolution of senescence, we looked at its presence in developing axolotls (urodele amphibians and in zebrafish (teleost fish, which are both anamniotes. Our data indicate that cellular senescence is present in various developing structures in axolotls (pronephros, olfactory epithelium of nerve fascicles, lateral organs, gums and in zebrafish (epithelium of the yolk sac and in the lower part of the gut. Senescence was particularly associated with transient structures (pronephros in axolotls and yolk sac in zebrafish suggesting that it may play a role in the elimination of these tissues. Our data supports the notion that cellular senescence evolved early in vertebrate evolution to influence embryonic development.

  3. Evasion of Cell Senescence Leads to Medulloblastoma Progression

    Directory of Open Access Journals (Sweden)

    Lukas Tamayo-Orrego

    2016-03-01

    Full Text Available How brain tumors progress from precancerous lesions to advanced cancers is not well understood. Using Ptch1+/− mice to study medulloblastoma progression, we found that Ptch1 loss of heterozygosity (LOH is an early event that is associated with high levels of cell senescence in preneoplasia. In contrast, advanced tumors have evaded senescence. Remarkably, we discovered that the majority of advanced medulloblastomas display either spontaneous, somatic p53 mutations or Cdkn2a locus inactivation. Consistent with senescence evasion, these p53 mutations are always subsequent to Ptch1 LOH. Introduction of a p53 mutation prevents senescence, accelerates tumor formation, and increases medulloblastoma incidence. Altogether, our results show that evasion of senescence associated with Ptch1 LOH allows progression to advanced tumors.

  4. Functional loss of GABA transaminase (GABA-T expressed early leaf senescence under various stress conditions in Arabidopsis thaliana

    Directory of Open Access Journals (Sweden)

    Syed Uzma Jalil

    2017-06-01

    Full Text Available GABA-transaminase (GABA-T involved in carbon and nitrogen metabolism during the plant development process via GABA shunt and GABA-T mutant, which is defective in GABA catabolism, is ideal model to examine the role of GABA-T in plant development and leaf senescence of plant. We have characterized GABA transaminase knock out mutant pop2-1 that is transition and pop2-3 which is T-DNA insertion mutant of Arabidopsis thaliana during various stress conditions.The GABA-T knockout mutant plants displayed precocious leaf senescence, which was accompanied by the assays of physiological parameters of leaf senescence during various stress conditions. Furthermore, our physiological evidence indicates that pop2-1 and pop2-3 mutations rapidly decreased the efficiency of leaf photosynthesis, chlorophyll content, GABA content, GABA-T, and glutamate decarboxylase (GAD activity and on the other hand increases membrane ion leakage, malondialdehyde (MDA level in stress induced leaves. However, cell viability assay by trypan blue and insitu Hydrogen peroxidation assay by 3,3-diaminobenzidine (DAB in stress induced leaves also display that pop2-1 and pop2-3 mutant leaves show oversensitivity in response to different stress conditions as compared to wild type. These results strongly indicate that the loss-of-function of GABA transaminase gene induces early leaf senescence in Arabidopsis thaliana during various stress conditions.

  5. A crucial role of ROCK for alleviation of senescence-associated phenotype.

    Science.gov (United States)

    Park, Joon Tae; Kang, Hyun Tae; Park, Chi Hyun; Lee, Young-Sam; Cho, Kyung A; Park, Sang Chul

    2018-06-01

    In our previous study, we uncovered a novel mechanism in which amelioration of Hutchinson-Gilford progeria syndrome (HGPS) phenotype is mediated by mitochondrial functional recovery upon rho-associated protein kinase (ROCK) inhibition. However, it remains elusive whether this mechanism is also applied to the amelioration of normal aging cells. In this study, we used Y-27632 and fasudil as effective ROCK inhibitors, and examined their role in senescence. We found that ROCK inhibition induced the functional recovery of the mitochondria as well as the metabolic reprogramming, which are two salient features that are altered in normal aging cells. Moreover, microarray analysis revealed that the up-regulated pathway upon ROCK inhibition is enriched for chromatin remodeling genes, which may play an important role in the alleviation of senescence-associated cell cycle arrest. Indeed, ROCK inhibition induced cellular proliferation, concomitant with the amelioration of senescent phenotype. Furthermore, the restorative effect by ROCK inhibition was observed in vivo as evidenced by the facilitated cutaneous wound healing. Taken together, our data indicate that ROCK inhibition might be utilized to ameliorate normal aging process and to treat age-related disease. Copyright © 2018 Elsevier Inc. All rights reserved.

  6. Involvement of NADPH oxidase isoforms in the production of O2− manipulated by ABA in the senescing leaves of early-senescence-leaf (esl) mutant rice (Oryza sativa)

    Science.gov (United States)

    Wang, Fubiao; Zhao, Qian; Liu, Jianchao; Cheng, Fangmin

    2018-01-01

    In this study, the differences in reactive oxygen species (ROS) generation and abscisic acid (ABA) accumulation in senescing leaves were investigated by early-senescence-leaf (esl) mutant and its wild type, to clarify the relationship among ABA levels, ROS generation, and NADPH oxidase (Nox) in senescing leaves of rice (Oryza sativa). The temporal expression levels of OsNox isoforms in senescing leaves and their expression patterns in response to ABA treatment were determined through quantitative real-time reverse transcription PCR (qRT-PCR). Results showed that the flag leaf of the esl mutant generated more O2- concentrations and accumulated higher ABA levels than the wild-type cultivar did in the grain-filling stage. Exogenous ABA treatment induced O2- generation; however, it was depressed by diphenyleneiodonium chloride (DPI) pretreatment in the detached leaf segments. This finding suggested the involvement of NADPH oxidase in ABA-induced O2- generation. The esl mutant exhibited significantly higher expression of OsNox2, OsNox5, OsNox6, and OsNox7 in the initial of grain-filling stage, followed by sharply decrease. The transcriptional levels of OsNox1, OsNox3, and OsFR07 in the flag leaf of the esl mutant were significantly lower than those in the wild-type cultivar. The expression levels of OsNox2, OsNox5, OsNox6, and OsNox7 were significantly enhanced by exogenous ABA treatments. The enhanced expression levels of OsNox2 and OsNox6 were dependent on the duration of ABA treatment. The inducible expression levels of OsNox5 and OsNox7 were dependent on ABA concentrations. By contrast, exogenous ABA treatment severely repressed the transcripts of OsNox1, OsNox3, and OsFR07 in the detached leaf segments. Therefore, OsNox2, OsNox5, OsNox6, and OsNox7 were probably involved in the ABA-induced O2- generation in the initial stage of leaf senescence. Subsequently, other oxidases activated in deteriorating cells were associated with ROS generation and accumulation in the

  7. Arabidopsis CPR5 is a senescence-regulatory gene with pleiotropic functions as predicted by the evolutionary theory of senescence

    NARCIS (Netherlands)

    Jing, Hai-Chun; Anderson, Lisa; Sturre, Marcel J. G.; Hille, Jacques; Dijkwel, Paul P.

    2007-01-01

    Arabidopsis CPR5 is a senescence-regulatory gene with pleiotropic functions as predicted by the evolutionary theory of senescence Hai-Chun Jing1,2, Lisa Anderson3, Marcel J.G. Sturre1, Jacques Hille1 and Paul P. Dijkwel1,* 1Molecular Biology of Plants, Groningen Biomolecular Sciences and

  8. p38 MAPK and JNK antagonistically control senescence and cytoplasmic p16INK4A expression in doxorubicin-treated endothelial progenitor cells.

    Directory of Open Access Journals (Sweden)

    Paolo Spallarossa

    Full Text Available Patients treated with low-dose anthracyclines often show late onset cardiotoxicity. Recent studies suggest that this form of cardiotoxicity is the result of a progenitor cell disease. In this study we demonstrate that Cord Blood Endothelial Progenitor Cells (EPCs exposed to low, sub-apoptotic doses of doxorubicin show a senescence phenotype characterized by increased SA-b-gal activity, decreased TRF2 and chromosomal abnormalities, enlarged cell shape, and disarrangement of F-actin stress fibers accompanied by impaired migratory ability. P16( INK4A localizes in the cytoplasm of doxorubicin-induced senescent EPCs and not in the nucleus as is the case in EPCs rendered senescent by different stimuli. This localization together with the presence of an arrest in G2, and not at the G1 phase boundary, which is what usually occurs in response to the cell cycle regulatory activity of p16(INK4A, suggests that doxorubicin-induced p16( INK4A does not regulate the cell cycle, even though its increase is closely associated with senescence. The effects of doxorubicin are the result of the activation of MAPKs p38 and JNK which act antagonistically. JNK attenuates the senescence, p16( INK4A expression and cytoskeleton remodeling that are induced by activated p38. We also found that conditioned medium from doxorubicin-induced senescent cardiomyocytes does not attract untreated EPCs, unlike conditioned medium from apoptotic cardiomyocytes which has a strong chemoattractant capacity. In conclusion, this study provides a better understanding of the senescence of doxorubicin-treated EPCs, which may be helpful in preventing and treating late onset cardiotoxicity.

  9. Use of the gapped bead-on-plate test to investigate hydrogen induced cracking of flux cored arc welds of a quenched and tempered steel

    International Nuclear Information System (INIS)

    Chen, Liang; Dunne, Druce; Davidson, Len

    2014-01-01

    Gapped bead-on-plate (G-BOP) testing of flux cored arc welds was conducted to assess the susceptibility to hydrogen induced cold cracking (HICC) of weld metal deposited on a high strength quenched and tempered steel. For preheat temperatures higher than 40°C, no weld metal cracking was observed using a shielding gas consisting of argon with 20% carbon dioxide. In contrast, the no-crack condition was not achieved for a shielding gas consisting of argon-5% carbon dioxide for preheat temperatures lower than 100°C. This extraordinary difference in weld metal HICC resistance indicates that, in general, the shielding gas mixture can exert a major influence on weld metal transverse cold cracking behaviour

  10. Flavonoids and darkness lower PCD in senescing Vitis vinifera suspension cell cultures.

    Science.gov (United States)

    Bertolini, Alberto; Petrussa, Elisa; Patui, Sonia; Zancani, Marco; Peresson, Carlo; Casolo, Valentino; Vianello, Angelo; Braidot, Enrico

    2016-10-26

    Senescence is a key developmental process occurring during the life cycle of plants that can be induced also by environmental conditions, such as starvation and/or darkness. During senescence, strict control of genes regulates ordered degradation and dismantling events, the most remarkable of which are genetically programmed cell death (PCD) and, in most cases, an upregulation of flavonoid biosynthesis in the presence of light. Flavonoids are secondary metabolites that play multiple essential roles in development, reproduction and defence of plants, partly due to their well-known antioxidant properties, which could affect also the same cell death machinery. To understand further the effect of endogenously-produced flavonoids and their interplay with different environment (light or dark) conditions, two portions (red and green) of a senescing grapevine callus were used to obtain suspension cell cultures. Red Suspension cell Cultures (RSC) and Green Suspension cell Cultures (GSC) were finally grown under either dark or light conditions for 6 days. Darkness enhanced cell death (mainly necrosis) in suspension cell culture, when compared to those grown under light condition. Furthermore, RSC with high flavonoid content showed a higher viability compared to GSC and were more protected toward PCD, in accordance to their high content in flavonoids, which might quench ROS, thus limiting the relative signalling cascade. Conversely, PCD was mainly occurring in GSC and further increased by light, as it was shown by cytochrome c release and TUNEL assays. Endogenous flavonoids were shown to be good candidates for exploiting an efficient protection against oxidative stress and PCD induction. Light seemed to be an important environmental factor able to induce PCD, especially in GSC, which lacking of flavonoids were not capable of preventing oxidative damage and signalling leading to senescence.

  11. MiR-495 Promotes Senescence of Mesenchymal Stem Cells by Targeting Bmi-1

    Directory of Open Access Journals (Sweden)

    Xiujun Li

    2017-06-01

    Full Text Available Background/Aims: Mesenchymal stem cells (MSCs play an important role in regulating angiogenesis and immune balance. Abnormal proliferation and function of MSCs were reported at maternal fetal interface in patients with pre-eclampsia (PE. Micro-RNA-495 was known to be upregulated in the MSCs derived from patients with PE. However, it is not clear whether the up-regulated miR-495 is related to the pathogenesis of PE. Methods: We analyzed the expression of miR-495 in MSCs and umbilical cords derived from healthy pregnancies (NC and PE, then we upregulated or downregulated the expression of miR-495 in MSCs derived from NC and tested the proliferation, apoptosis, migration, invasion, tube formation and senescence. Results: In the current study, we found that the expression of miR-495 was significantly increased in both umbilical cord tissues and MSCs in patients with severe PE. Overexpressing miR-495 arrested cell cycle in S phase and promoted cell apoptosis. The supernatants from miR-495-overexpressed-MSCs inhibited the migration of MSCs and HTR-8/SVneo, invasion of HTR-8/SVneo and tube formation of HUVEC, while si-miR-495 had the opposite effects. Furthermore, we analyzed the senescence related β-galactosidase activity and CD146 and found that miR-495 induced the senescence of MSCs. Molecular mechanism studies confirmed that Bmi-1 mediated these effects of miR-495 on MSCs. Conclusion: Taken together, our data demonstrated that miR-495 induced senescence of MSCs may be involved in the pathogenesis of PE.

  12. In situ measurement using FBGs of process-induced strains during curing of thick glass/epoxy laminate plate

    DEFF Research Database (Denmark)

    Nielsen, Michael Wenani; Schmidt, Jacob Wittrup; Hattel, Jesper Henri

    2012-01-01

    For large composite structures, such as wind turbine blades, thick laminates are required to withstand large in-service loads. During the manufacture of thick laminates, one of the challenges met is avoiding process-induced shape distortions and residual stresses. In this paper, embedded fibre...... Bragg grating sensors are used to monitor process-induced strains during vacuum infusion of a thick glass/epoxy laminate. The measured strains are compared with predictions from a cure hardening instantaneous linear elastic (CHILE) thermomechanical numerical model where different mechanical boundary...... conditions are employed. The accuracy of the CHILE model in predicting process-induced internal strains, in what is essentially a viscoelastic boundary value problem, is investigated. A parametric study is furthermore performed to reveal the effect of increasing the laminate thickness. The numerical model...

  13. Substance P increases liver fibrosis by differential changes in senescence of cholangiocytes and hepatic stellate cells.

    Science.gov (United States)

    Wan, Ying; Meng, Fanyin; Wu, Nan; Zhou, Tianhao; Venter, Julie; Francis, Heather; Kennedy, Lindsey; Glaser, Trenton; Bernuzzi, Francesca; Invernizzi, Pietro; Glaser, Shannon; Huang, Qiaobing; Alpini, Gianfranco

    2017-08-01

    Substance P (SP) is involved in the proliferation of cholangiocytes in bile duct-ligated (BDL) mice and human cholangiocarcinoma growth by interacting with the neurokinin-1 receptor (NK-1R). To identify whether SP regulates liver fibrosis during cholestasis, wild-type or NK-1R knockout (NK-1R -/- ) mice that received BDL or sham surgery and multidrug resistance protein 2 knockout (Mdr2 -/- ) mice treated with either an NK-1R antagonist (L-733,060) or saline were used. Additionally, wild-type mice were treated with SP or saline intraperitoneally. In vivo, there was increased expression of tachykinin precursor 1 (coding SP) and NK-1R in both BDL and Mdr2 -/- mice compared to wild-type mice. Expression of tachykinin precursor 1 and NK-1R was significantly higher in liver samples from primary sclerosing cholangitis patients compared to healthy controls. Knockout of NK-1R decreased BDL-induced liver fibrosis, and treatment with L-733,060 resulted in decreased liver fibrosis in Mdr2 -/- mice, which was shown by decreased sirius red staining, fibrosis gene and protein expression, and reduced transforming growth factor-β1 levels in serum and cholangiocyte supernatants. Furthermore, we observed that reduced liver fibrosis in NK-1R -/- mice with BDL surgery or Mdr2 -/- mice treated with L-733,060 was associated with enhanced cellular senescence of hepatic stellate cells and decreased senescence of cholangiocytes. In vitro, L-733,060 inhibited SP-induced expression of fibrotic genes in hepatic stellate cells and cholangiocytes; treatment with L-733,060 partially reversed the SP-induced decrease of senescence gene expression in cultured hepatic stellate cells and the SP-induced increase of senescence-related gene expression in cultured cholangiocytes. Collectively, our results demonstrate the regulatory effects of the SP/NK-1R axis on liver fibrosis through changes in cellular senescence during cholestatic liver injury. (Hepatology 2017;66:528-541). © 2017 by the American

  14. Senescent mouse cells fail to overtly regulate the HIRA histone chaperone and do not form robust Senescence Associated Heterochromatin Foci

    Directory of Open Access Journals (Sweden)

    Enders Greg H

    2010-06-01

    Full Text Available Abstract Background Cellular senescence is a permanent growth arrest that occurs in response to cellular stressors, such as telomere shortening or activation of oncogenes. Although the process of senescence growth arrest is somewhat conserved between mouse and human cells, there are some critical differences in the molecular pathways of senescence between these two species. Recent studies in human fibroblasts have defined a cell signaling pathway that is initiated by repression of a specific Wnt ligand, Wnt2. This, in turn, activates a histone chaperone HIRA, and culminates in formation of specialized punctate domains of facultative heterochromatin, called Senescence-Associated Heterochromatin Foci (SAHF, that are enriched in the histone variant, macroH2A. SAHF are thought to repress expression of proliferation-promoting genes, thereby contributing to senescence-associated proliferation arrest. We asked whether this Wnt2-HIRA-SAHF pathway is conserved in mouse fibroblasts. Results We show that mouse embryo fibroblasts (MEFs and mouse skin fibroblasts, do not form robust punctate SAHF in response to an activated Ras oncogene or shortened telomeres. However, senescent MEFs do exhibit elevated levels of macroH2A staining throughout the nucleus as a whole. Consistent with their failure to fully activate the SAHF assembly pathway, the Wnt2-HIRA signaling axis is not overtly regulated between proliferating and senescent mouse cells. Conclusions In addition to the previously defined differences between mouse and human cells in the mechanisms and phenotypes associated with senescence, we conclude that senescent mouse and human fibroblasts also differ at the level of chromatin and the signaling pathways used to regulate chromatin. These differences between human and mouse senescence may contribute to the increased propensity of mouse fibroblasts (and perhaps other mouse cell types to become immortalized and transformed, compared to human cells.

  15. Investigation of trapped thickness-twist waves induced by functionally graded piezoelectric material in an inhomogeneous plate

    International Nuclear Information System (INIS)

    Li, Peng; Jin, Feng; Cao, Xiao-Shan

    2013-01-01

    The effect of functional graded piezoelectric materials on the propagation of thickness-twist waves is investigated through equations of the linear theory of piezoelectricity. The elastic and piezoelectric coefficients, dielectric permittivity, and mass density are assumed to change in a linear form but with different graded parameters along the wave propagation direction. We employ the power-series technique to solve the governing differential equations with variable coefficients attributed to the different graded parameters and prove the correction and convergence of this method. As a special case, the functional graded middle layer resulting from piezoelectric damage and material bonding is investigated. Piezoelectric damaged material can facilitate energy trapping, which is impossible in perfect materials. The increase in the damaged length and the reduction in the piezoelectric coefficient decrease the resonance frequency but increase the number of modes. Higher modes of thickness-twist waves appear periodically along the damaged length. Moreover, the displacement of the center of the damaged portion is neither symmetric nor anti-symmetric, unlike the non-graded plate. The conclusions are theoretically and practically significant for wave devices. (paper)

  16. The Impacts of Cellular Senescence in Elderly Pneumonia and in Age-Related Lung Diseases That Increase the Risk of Respiratory Infections.

    Science.gov (United States)

    Yanagi, Shigehisa; Tsubouchi, Hironobu; Miura, Ayako; Matsuo, Ayako; Matsumoto, Nobuhiro; Nakazato, Masamitsu

    2017-02-25

    Pneumonia generates considerable negative impacts on the elderly. Despite the widespread uses of vaccines and appropriate antibiotics, the morbidity and mortality of elderly pneumonia are significantly higher compared to the counterparts of young populations. The definitive mechanisms of high vulnerability in the elderly against pathogen threats are unclear. Age-associated, chronic low-grade inflammation augments the susceptibility and severity of pneumonia in the elderly. Cellular senescence, one of the hallmarks of aging, has its own characteristics, cell growth arrest and senescence-associated secretory phenotype (SASP). These properties are beneficial if the sequence of senescence-clearance-regeneration is transient in manner. However, persisting senescent cell accumulation and excessive SASP might induce sustained low-grade inflammation and disruption of normal tissue microenvironments in aged tissue. Emerging evidence indicates that cellular senescence is a key component in the pathogenesis of chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF), which are known to be age-related and increase the risk of pneumonia. In addition to their structural collapses, COPD and IPF might increase the vulnerability to pathogen insults through SASP. Here, we discuss the current advances in understanding of the impacts of cellular senescence in elderly pneumonia and in these chronic lung disorders that heighten the risk of respiratory infections.

  17. Senescent phenotypes of skin fibroblasts from patients with Tangier disease

    International Nuclear Information System (INIS)

    Matsuura, Fumihiko; Hirano, Ken-ichi; Ikegami, Chiaki; Sandoval, Jose C.; Oku, Hiroyuki; Yuasa-Kawase, Miyako; Tsubakio-Yamamoto, Kazumi; Koseki, Masahiro; Masuda, Daisaku; Tsujii, Ken-ichi; Ishigami, Masato; Nishida, Makoto; Shimomura, Iichiro; Hori, Masatsugu; Yamashita, Shizuya

    2007-01-01

    Tangier disease (TD) is characterized by a deficiency of high density lipoprotein (HDL) in plasma and patients with TD have an increased risk for coronary artery disease (CAD). Recently, we reported that fibroblasts from TD exhibited large and flattened morphology, which is often observed in senescent cells. On the other hand, data have accumulated to show the relationship between cellular senescence and development of atherosclerotic CAD. The aim of the present study was to investigate whether TD fibroblasts exhibited cellular senescence. The proliferation of TD fibroblasts was gradually decreased at population doubling level (PDL) ∼10 compared with control cells. TD cells practically ceased proliferation at PDL ∼30. DNA synthesis was markedly decreased in TD fibroblasts. TD cells exhibited a higher positive rate for senescence-associated β-galactosidase (SA-β-gal), which is one of the biomarkers of cellular senescence in vitro. These data showed that TD cells reached cellular senescence at an earlier PDL compared with controls. Although, there was no difference in the telomere length of fibroblasts between TD and controls at the earlier passage (PDL 6), the telomere length of TD cells was shorter than that of controls at the late passage (PDL 25). Taken together, the current study demonstrates that the late-passaged TD fibroblasts showed senescent phenotype in vitro, which might be related to the increased cardiovascular manifestations in TD patients

  18. Enhanced NOLC1 promotes cell senescence and represses hepatocellular carcinoma cell proliferation by disturbing the organization of nucleolus.

    Science.gov (United States)

    Yuan, Fuwen; Zhang, Yu; Ma, Liwei; Cheng, Qian; Li, Guodong; Tong, Tanjun

    2017-08-01

    The nucleolus is a key organelle that is responsible for the synthesis of rRNA and assembly of ribosomal subunits, which is also the center of metabolic control because of the critical role of ribosomes in protein synthesis. Perturbations of rRNA biogenesis are closely related to cell senescence and tumor progression; however, the underlying molecular mechanisms are not well understood. Here, we report that cellular senescence-inhibited gene (CSIG) knockdown up-regulated NOLC1 by stabilizing the 5'UTR of NOLC1 mRNA, and elevated NOLC1 induced the retention of NOG1 in the nucleolus, which is responsible for rRNA processing. Besides, the expression of NOLC1 was negatively correlated with CSIG in the aged mouse tissue and replicative senescent 2BS cells, and the down-regulation of NOLC1 could rescue CSIG knockdown-induced 2BS senescence. Additionally, NOLC1 expression was decreased in human hepatocellular carcinoma (HCC) tissue, and the ectopic expression of NOLC1 repressed the proliferation of HCC cells and tumor growth in a HCC xenograft model. © 2017 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

  19. Contrasting patterns of cytokinins between years in senescing aspen leaves

    Czech Academy of Sciences Publication Activity Database

    Edlund, E.; Novák, Ondřej; Karady, M.; Ljung, K.; Jansson, S.

    2017-01-01

    Roč. 40, č. 5 (2017), s. 622-634 ISSN 0140-7791 R&D Projects: GA ČR GA14-34792S; GA MŠk(CZ) LO1204 Institutional support: RVO:61389030 Keywords : leaf senescence * arabidopsis-thaliana * autumn senescence * gene-expression * populus-trichocarpa * mass-spectrometry * tobacco plants * translocation * biosynthesis * identification * autumn senescence * gene expression * metabolism * Populus tremula * profiling Subject RIV: CB - Analytical Chemistry, Separation OBOR OECD: Plant sciences, botany Impact factor: 6.173, year: 2016

  20. The commitment of human cells to senescence.

    Science.gov (United States)

    Holliday, Robin

    2014-01-01

    Fifty years ago, it was demonstrated by Leonard Hayflick that human diploid fibroblasts grown in culture have a finite lifespan. Since that time, innumerable experiments have been published to discover the mechanism(s) that are responsible for this 'Hayflick limit' to continuous growth. Much new information has been gained, but there are certain features of this experimental system which have not been fully understood. One is the fact that different populations of the foetal lung strains WI-38 and MRC-5 have a range in division potential of at least a millionfold. The commitment theory of cellular aging, published more than 30 years ago, is able to explain this, but it has been consistently ignored. The theory predicts that bottlenecks, which are transient reductions in population size, can significantly reduce lifespan, or increase variability of lifespans. Computer simulations specify the effects of bottlenecks on longevity, and these were confirmed in two series of experiments. Commitment to senescence may be the loss of telomerase, which leads to the erosion of telomeres and the inability to grow indefinitely. Many experiments have been done with skin fibroblasts from human donors of different age, and it was originally thought that in vitro lifespan was inversely correlated with donor age. In these experiments, a single skin biopsy produces a population of cells that are grown to senescence. However, there is no reason to believe that skin fibroblasts are less variable in their in vitro lifespan than foetal lung strains, in which case the data points with skin cells are so variable that they may completely obscure any inverse correlation between culture lifespans and donor age.

  1. Plate tectonics

    Digital Repository Service at National Institute of Oceanography (India)

    Chaubey, A.K.

    's continental drift theory was later disproved, it was one of the first times that the idea of crustal movement had been introduced to the scientific community; and it has laid the groundwork for the development of modern plate tectonics. In the early... of the structure of the atom was to physical sciences and the theory of evolution was to the life sciences. Tectonics is the study of the forces within the Earth that give rise to continents, ocean basins, mountain ranges, earthquake belts and other large-scale...

  2. Create Your Plate

    Medline Plus

    Full Text Available ... Plate Share Create Your Plate ! Share: Seven Simple Steps to Create Your Plate It's simple and effective ... foods within each food category. Try these seven steps to get started: Using your dinner plate, put ...

  3. Unscheduled DNA synthesis and elimination of DNA damage in liver cells of. gamma. -irradiated senescent mice

    Energy Technology Data Exchange (ETDEWEB)

    Gaziev, A.I.; Malakhova, L.V. (AN SSSR, Pushchino-na-Oke. Inst. Biologicheskoj Fiziki)

    1982-10-01

    The level of 'spontaneous' and ..gamma..-radiation-induced DNA synthesis which is not inhibited with hydroxyurea (unscheduled synthesis) is considerably lower in hepatocytes of 18-22-month-old mice than that of 1.5-2-month-old mice. The dose-dependent increase (10-300 Gy) of unscheduled DNA synthesis (UDS) in hepatocytes of senescent mice is higher than in young animals. The elimination of damage in DNA of ..gamma..-irradiated hepatocytes (100 Gy) was examined by using an enzyme system (M. luteus extract and DNA-polymerase I of E. coli). It was found that the rate of elimination of the DNA damage in hepatocytes of 20-month-old mice is lower than that of 2-month-old mice although the activities of DNA-polymerase ..beta.. and apurinic endonuclease remain equal in the liver of both senescent and young mice. However, the nucleoids from ..gamma..-irradiated liver nuclei of 2-month-old mice are relaxed to a greater extent (as judged by the criterion of ethidium-binding capacity) than those of 20-month-old mice. The results suggest that there are limitations in the functioning of repair enzymes and in their access to damaged DNA sites in the chromatin of senescent mouse liver cells.

  4. Extracellular Vesicles from Adipose-Derived Mesenchymal Stem Cells Downregulate Senescence Features in Osteoarthritic Osteoblasts

    Directory of Open Access Journals (Sweden)

    Miguel Tofiño-Vian

    2017-01-01

    Full Text Available Osteoarthritis (OA affects all articular tissues leading to pain and disability. The dysregulation of bone metabolism may contribute to the progression of this condition. Adipose-derived mesenchymal stem cells (ASC are attractive candidates in the search of novel strategies for OA treatment and exert anti-inflammatory and cytoprotective effects on cartilage. Chronic inflammation in OA is a relevant factor in the development of cellular senescence and joint degradation. In this study, we extend our previous observations of ASC paracrine effects to study the influence of conditioned medium and extracellular vesicles from ASC on senescence induced by inflammatory stress in OA osteoblasts. Our results in cells stimulated with interleukin- (IL- 1β indicate that conditioned medium, microvesicles, and exosomes from ASC downregulate senescence-associated β-galactosidase activity and the accumulation of γH2AX foci. In addition, they reduced the production of inflammatory mediators, with the highest effect on IL-6 and prostaglandin E2. The control of mitochondrial membrane alterations and oxidative stress may provide a mechanism for the protective effects of ASC in OA osteoblasts. We have also shown that microvesicles and exosomes mediate the paracrine effects of ASC. Our study suggests that correction of abnormal osteoblast metabolism by ASC products may contribute to their protective effects.

  5. The role of N-lauroylethanolamine in the regulation of senescence of cut carnations (Dianthus caryophyllus).

    Science.gov (United States)

    Zhang, Yun; Guo, Wei-ming; Chen, Su-mei; Han, Liang; Li, Zheng-ming

    2007-08-01

    N-acylethanolamines (NAEs) are a group of lipid mediators that play important roles in mammals, but not much is known about their precise function in plants. In this work, we analyzed the possible involvement of N-lauroylethanolamine [NAE(12:0)] in the regulation of cut-flower senescence. In cut carnation flowers of cv. Red Barbara, the pulse treatment with 5 microM NAE(12:0) slowed senescence by delaying the onset of initial wilting. Ion leakage, which is a reliable indicator of membrane integrity, was postponed in NAE(12:0)-treated flowers. The lipid peroxidation increased in carnation petals with time, in parallel to the development in activity of lipoxygenase and superoxide anion production rate, and these increases were both delayed by NAE(12:0) supplementation. The activities of four enzymes (superoxide dismutase, catalase, glutathione reductase and ascorbate peroxidase) that are implicated in antioxidant defense were also upregulated in the cut carnations that had been treated with NAE(12:0). These data indicate that NAE(12:0)-induced delays in cut-carnation senescence involve the protection of the integrity of membranes via suppressing oxidative damage and enhancing antioxidant defense. We propose that the stage from the end of blooming to the onset of wilting is a critical period for NAE(12:0) action.

  6. At the intersection of non-coding transcription, DNA repair, chromatin structure, and cellular senescence

    Directory of Open Access Journals (Sweden)

    Ryosuke eOhsawa

    2013-07-01

    Full Text Available It is well accepted that non-coding RNAs play a critical role in regulating gene expression. Recent paradigm-setting studies are now revealing that non-coding RNAs, other than microRNAs, also play intriguing roles in the maintenance of chromatin structure, in the DNA damage response, and in adult human stem cell aging. In this review, we will discuss the complex inter-dependent relationships among non-coding RNA transcription, maintenance of genomic stability, chromatin structure and adult stem cell senescence. DNA damage-induced non-coding RNAs transcribed in the vicinity of the DNA break regulate recruitment of the DNA damage machinery and DNA repair efficiency. We will discuss the correlation between non-coding RNAs and DNA damage repair efficiency and the potential role of changing chromatin structures around double-strand break sites. On the other hand, induction of non-coding RNA transcription from the repetitive Alu elements occurs during human stem cell aging and hinders efficient DNA repair causing entry into senescence. We will discuss how this fine balance between transcription and genomic instability may be regulated by the dramatic changes to chromatin structure that accompany cellular senescence.

  7. Translational research in immune senescence: Assessing the relevance of current models

    Science.gov (United States)

    High, Kevin P.; Akbar, Arne N.; Nikolich-Zugich, Janko

    2014-01-01

    Advancing age is accompanied by profound changes in immune function; some are induced by the loss of critical niches that support development of naïve cells (e.g. thymic involution), others by the intrinsic physiology of long-lived cells attempting to maintain homeostasis, still others by extrinsic effects such as oxidative stress or long-term exposure to antigen due to persistent viral infections. Once compensatory mechanisms can no longer maintain a youthful phenotype the end result is the immune senescent milieu – one characterized by chronic, low grade, systemic inflammation and impaired responses to immune challenge, particularly when encountering new antigens. This state is associated with progression of chronic illnesses like atherosclerosis and dementia, and an increased risk of acute illness, disability and death in older adults. The complex interaction between immune senescence and chronic illness provides an ideal landscape for translational research with the potential to greatly affect human health. However, current animal models and even human investigative strategies for immune senescence have marked limitations, and the reductionist paradigm itself may be poorly suited to meet these challenges. A new paradigm, one that embraces complexity as a core feature of research in older adults is required to address the critical health issues facing the burgeoning senior population, the group that consumes the majority of healthcare resources. In this review, we outline the major advantages and limitations of current models and offer suggestions for how to move forward. PMID:22633440

  8. Thin-plate spline analysis of mandibular shape changes induced by functional appliances in Class II malocclusion : A long-term evaluation.

    Science.gov (United States)

    Franchi, Lorenzo; Pavoni, Chiara; Faltin, Kurt; Bigliazzi, Renato; Gazzani, Francesca; Cozza, Paola

    2016-09-01

    The purpose of this work was to evaluate the long-term morphological mandibular changes induced by functional treatment of Class II malocclusion with mandibular retrusion. Forty patients (20 females, 20 males) with Class II malocclusion consecutively treated with either a Bionator or an Activator followed by fixed appliances were compared with a control group of 40 subjects (19 females, 21 males) with untreated Class II malocclusion. Lateral cephalograms were available at the start of treatment (T1, mean age 9.9 years), at the end of treatment with functional appliances (T2, mean age 12.2 years), and for long-term follow-up (T3, mean age 18.3 years). Mandibular shape changes were analyzed on lateral cephalograms of the subjects in both groups via thin-plate spline (TPS) analysis. Shape differences were statistically analyzed by conducting permutation tests on Goodall F statistics. In the long term, both the treated and control groups exhibited significant longitudinal mandibular shape changes characterized by upward and forward dislocation of point Co associated with a vertical extension in the gonial region and backward dislocation of point B. Functional appliances induced mandible's significant posterior morphogenetic rotation over the short term. The treated and control groups demonstrated similar mandibular shape over the long term.

  9. Chlorophyll fluorescence, photochemical reflective index and normalized difference vegetative index during plant senescence.

    Science.gov (United States)

    Cordon, Gabriela; Lagorio, M Gabriela; Paruelo, José M

    2016-07-20

    The relationship between the Photochemical Reflectance Index (PRI), Normalized Difference Vegetation Index (NDVI) and chlorophyll fluorescence along senescence was investigated in this work. Reflectance and radiance measurements were performed at canopy level in grass species presenting different photosynthetic metabolism: Avena sativa (C3) and Setaria italica (C4), at different stages of the natural senescence process. Sun induced-chlorophyll fluorescence at 760nm (SIF 760 ) and the apparent fluorescence yield (SIF 760 /a, with a=irradiance at time of measurement) were extracted from the radiance spectra of canopies using the Fraunhofer Line Discrimination-method. The photosynthetic parameters derived from Kautsky kinetics and pigment content were also calculated at leaf level. Whilst stand level NDVI patterns were related to changes in the structure of canopies and not in pigment content, stand level PRI patterns suggested changes both in terms of canopy and of pigment content in leaves. Both SIF 760 /a and Φ PSII decreased progressively along senescence in both species. A strong increment in NPQ was evident in A. sativa while in S. italica NPQ values were lower. Our most important finding was that two chlorophyll fluorescence signals, Φ PSII and SIF 760 /a, correlated with the canopy PRI values in the two grasses assessed, even when tissues at different ontogenic stages were present. Even though significant changes occurred in the Total Chlr/Car ratio along senescence in both studied species, significant correlations between PRI and chlorophyll fluorescence signals might indicate the usefulness of this reflectance index as a proxy of photosynthetic RUE, at least under the conditions of this study. The relationships between stand level PRI and the fluorescence estimators (Φ PSII and SIF 760 /a) were positive in both cases. Therefore, an increase in PRI values as in the fluorescence parameters would indicate higher RUE. Copyright © 2016 Elsevier GmbH. All

  10. c-Myc is essential to prevent endothelial pro-inflammatory senescent phenotype.

    Directory of Open Access Journals (Sweden)

    Victoria Florea

    Full Text Available The proto-oncogene c-Myc is vital for vascular development and promotes tumor angiogenesis, but the mechanisms by which it controls blood vessel growth remain unclear. In the present work we investigated the effects of c-Myc knockdown in endothelial cell functions essential for angiogenesis to define its role in the vasculature. We provide the first evidence that reduction in c-Myc expression in endothelial cells leads to a pro-inflammatory senescent phenotype, features typically observed during vascular aging and pathologies associated with endothelial dysfunction. c-Myc knockdown in human umbilical vein endothelial cells using lentivirus expressing specific anti-c-Myc shRNA reduced proliferation and tube formation. These functional defects were associated with morphological changes, increase in senescence-associated-β-galactosidase activity, upregulation of cell cycle inhibitors and accumulation of c-Myc-deficient cells in G1-phase, indicating that c-Myc knockdown in endothelial cells induces senescence. Gene expression analysis of c-Myc-deficient endothelial cells showed that senescent phenotype was accompanied by significant upregulation of growth factors, adhesion molecules, extracellular-matrix components and remodeling proteins, and a cluster of pro-inflammatory mediators, which include Angptl4, Cxcl12, Mdk, Tgfb2 and Tnfsf15. At the peak of expression of these cytokines, transcription factors known to be involved in growth control (E2f1, Id1 and Myb were downregulated, while those involved in inflammatory responses (RelB, Stat1, Stat2 and Stat4 were upregulated. Our results demonstrate a novel role for c-Myc in the prevention of vascular pro-inflammatory phenotype, supporting an important physiological function as a central regulator of inflammation and endothelial dysfunction.

  11. Effect of cytokinins on delaying petunia flower senescence: a transcriptome study approach.

    Science.gov (United States)

    Trivellini, Alice; Cocetta, Giacomo; Vernieri, Paolo; Mensuali-Sodi, Anna; Ferrante, Antonio

    2015-01-01

    Flower senescence is a fascinating natural process that represents the final developmental stage in the life of a flower. Plant hormones play an important role in regulating the timing of flower senescence. Ethylene is a trigger and usually accelerates the senescence rate, while cytokinins are known to delay it. The aim of this work was to study the effect of 6-benzylaminopurine (BA) on petal senescence by transcript profile comparison after 3 or 6 h using a cross-species method by hybridizing petunia samples to a 4 × 44 K Agilent tomato array. The relative content of ethylene, abscisic acid, anthocyanins, total carotenoids and total phenols that determine the physiological behaviours of the petal tissue were measured. BA treatment prolonged the flower life and increased the concentrations of phenols and anthocyanins, while total carotenoids did not increase and were lower than the control. The ethylene biosynthetic and perception gene expressions were studied immediately after treatment until 24 h and all genes were repressed, while ethylene production was strongly induced after 4 days. The microarray analyses highlighted that BA strongly affected gene regulation after 3 h, but only 14% of genes remained differentially expressed after 6 h. The most affected pathways and genes were those related to stress, such as heat shock proteins, abscisic acid (ABA) catabolism and its signalling pathway, lipid metabolism and antioxidant defence systems. A gene annotation enrichment analysis using DAVID showed that the most important gene clusters were involved in energy generation and conservation processes. In addition to the ethylene pathway, cytokinins seem to be strongly involved the regulation of the ABA response in flower tissues.

  12. Telomeres and replicative senescence: Is it only length that counts?

    Science.gov (United States)

    von Zglinicki, T

    2001-07-26

    Telomeres are well established as a major 'replicometer', counting the population doublings in primary human cell cultures and ultimately triggering replicative senescence. However, neither is the pace of this biological clock inert, nor is there a fixed threshold telomere length acting as the universal trigger of replicative senescence. The available data suggest that opening of the telomeric loop and unscheduled exposure of the single-stranded G-rich telomeric overhang might act like a semaphore to signal senescent cell cycle arrest. Short telomere length, telomeric single-strand breaks, low levels of loop-stabilizing proteins, or other factors may trigger this opening of the loop. Thus, both telomere shortening and the ultimate signalling into senescence are able to integrate different environmental and genetic factors, especially oxidative stress-mediated damage, which might otherwise become a thread to genomic stability.

  13. Interaction Mortality: Senescence May Have Evolved because It Increases Lifespan

    DEFF Research Database (Denmark)

    Wensink, M. J.; Wrycza, T. F.; Baudisch, A.

    2014-01-01

    Given an extrinsic challenge, an organism may die or not depending on how the threat interacts with the organism's physiological state. To date, such interaction mortality has been only a minor factor in theoretical modeling of senescence. We describe a model of interaction mortality that does...... not involve specific functions, making only modest assumptions. Our model distinguishes explicitly between the physiological state of an organism and potential extrinsic, age-independent threats. The resulting mortality may change with age, depending on whether the organism's state changes with age. We find...... that depending on the physiological constraints, any outcome, be it 'no senescence' or 'high rate of senescence', can be found in any environment; that the highest optimal rate of senescence emerges for an intermediate physiological constraint, i.e. intermediate strength of trade-off; and that the optimal rate...

  14. Assessing senescence patterns in populations of large mammals

    Directory of Open Access Journals (Sweden)

    Gaillard, J.-M.

    2004-06-01

    Full Text Available Theoretical models such as those of Gompertz and Weibull are commonly used to study senescence in survival for humans and laboratory or captive animals. For wild populations of vertebrates, senescence in survival has more commonly been assessed by fitting simple linear or quadratic relationships between survival and age. By using appropriate constraints on survival parameters in Capture-Mark-Recapture (CMR models, we propose a first analysis of the suitability of the Gompertz and the two-parameter Weibull models for describing aging-related mortality in free-ranging populations of ungulates. We first show how to handle the Gompertz and the two-parameter Weibull models in the context of CMR analyses. Then we perform a comparative analysis of senescence patterns in both sexes of two ungulate species highly contrasted according to the intensity of sexual selection. Our analyses provide support to the Gompertz model for describing senescence patterns in ungulates. Evolutionary implications of our results are discussed

  15. Branched-chain amino acids enhance premature senescence through mammalian target of rapamycin complex I-mediated upregulation of p21 protein.

    Directory of Open Access Journals (Sweden)

    Masayuki Nakano

    Full Text Available Branched-chain amino acids (BCAAs have been applied as an oral supplementation to patients with liver cirrhosis. BCAAs not only improve nutritional status of patients but also decrease the incidence of liver cancer. Mammalian target of rapamycin (mTOR links cellular metabolism with growth and proliferation in response to nutrients, energy, and growth factors. BCAAs, especially leucine, have been shown to regulate protein synthesis through mTOR activities. On the other hand, cellular senescence is suggested to function as tumor suppressor mechanisms, and induced by a variety of