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Sample records for premature senescence sips

  1. Copper ability to induce premature senescence in human fibroblasts.

    PubMed

    Matos, Liliana; Gouveia, Alexandra; Almeida, Henrique

    2012-08-01

    Human diploid fibroblasts (HDFs) exposed to subcytotoxic concentrations of oxidative or stressful agents, such as hydrogen peroxide, tert-butylhydroperoxide, or ethanol, undergo stress-induced premature senescence (SIPS). This condition is characterized by the appearance of replicative senescence biomarkers such as irreversible growth arrest, increase in senescence-associated β-galactosidase (SA β-gal) activity, altered cell morphology, and overexpression of several senescence-associated genes. Copper is an essential trace element known to accumulate with ageing and to be involved in the pathogenesis of some age-related disorders. Past studies using either yeast or human cellular models of ageing provided evidence in favor of the role of intracellular copper as a longevity modulator. In the present study, copper ability to cause the appearance of senescent features in HDFs was assessed. WI-38 fibroblasts exposed to a subcytotoxic concentration of copper sulfate presented inhibition of cell proliferation, cell enlargement, increased SA β-gal activity, and mRNA overexpression of several senescence-associated genes such as p21, apolipoprotein J (ApoJ), fibronectin, transforming growth factor β-1 (TGF β1), insulin growth factor binding protein 3, and heme oxygenase 1. Western blotting results confirmed enhanced intracellular p21, ApoJ, and TGF β1 in copper-treated cells. Thus, similar to other SIPS-inducing agents, HDF exposure to subcytotoxic concentration of copper results in premature senescence. Further studies will unravel molecular mechanisms and the biological meaning of copper-associated senescence and lead to a better understanding of copper-related disorder establishment and progression.

  2. HEREDITARY PREMATURE SENESCENCE OF THE RABBIT

    PubMed Central

    Pearce, Louise; Brown, Wade H.

    1960-01-01

    The acute form of hereditary premature senescence in 79 rabbits, among which the 20th generation of the condition was represented, has been described. The manifestations did not differ in kind from those previously described in connection with the chronic form (1) of the complex but their degree and, in particular, the severity and the rate of progression of systemic degeneration were much greater. The rabbits either did not survive to 2 years 6 months, of age or their physical condition had become critical by this time. A senile appearance, largely due to deteriorative changes of the coat, was frequently observed. The essential nature of the senescence condition was obviously a degeneration and one in which vital mechanisms essential to the maintenance of health were involved. PMID:13733753

  3. HEREDITARY PREMATURE SENESCENCE OF THE RABBIT

    PubMed Central

    Pearce, Louise; Brown, Wade H.

    1960-01-01

    The occurrence of hereditary premature senescence in a family of pure bred Belgian hares belonging to a rabbit-breeding colony organized for the investigation of constitutional problems, has been described. Representatives of 20 generations of the complex have been studied. The condition was a degeneration of variable degrees of severity and two principal forms were recognized, the acute and the chronic, the chronic being the more frequent. The chronic form has now been described in terms of the principal local or external manifestations; that is, degeneration of the coat and skin, lesions of the eyes and feet, and reproductive abnormalities, and of the general deterioration which in severe cases pursued a progressive course characterized by muscle wasting, fat reduction, emaciation, weakness, and death. The acute form will be described in the next paper (2). PMID:13733754

  4. Gadd45b deficiency promotes premature senescence and skin aging

    PubMed Central

    Magimaidas, Andrew; Madireddi, Priyanka; Maifrede, Silvia; Mukherjee, Kaushiki; Hoffman, Barbara; Liebermann, Dan A.

    2016-01-01

    The GADD45 family of proteins functions as stress sensors in response to various physiological and environmental stressors. Here we show that primary mouse embryo fibroblasts (MEFs) from Gadd45b null mice proliferate slowly, accumulate increased levels of DNA damage, and senesce prematurely. The impaired proliferation and increased senescence in Gadd45b null MEFs is partially reversed by culturing at physiological oxygen levels, indicating that Gadd45b deficiency leads to decreased ability to cope with oxidative stress. Interestingly, Gadd45b null MEFs arrest at the G2/M phase of cell cycle, in contrast to other senescent MEFs, which arrest at G1. FACS analysis of phospho-histone H3 staining showed that Gadd45b null MEFs are arrested in G2 phase rather than M phase. H2O2 and UV irradiation, known to increase oxidative stress, also triggered increased senescence in Gadd45b null MEFs compared to wild type MEFs. In vivo evidence for increased senescence in Gadd45b null mice includes the observation that embryos from Gadd45b null mice exhibit increased senescence staining compared to wild type embryos. Furthermore, it is shown that Gadd45b deficiency promotes senescence and aging phenotypes in mouse skin. Together, these results highlight a novel role for Gadd45b in stress-induced senescence and in tissue aging. PMID:27105496

  5. Gadd45b deficiency promotes premature senescence and skin aging.

    PubMed

    Magimaidas, Andrew; Madireddi, Priyanka; Maifrede, Silvia; Mukherjee, Kaushiki; Hoffman, Barbara; Liebermann, Dan A

    2016-05-10

    The GADD45 family of proteins functions as stress sensors in response to various physiological and environmental stressors. Here we show that primary mouse embryo fibroblasts (MEFs) from Gadd45b null mice proliferate slowly, accumulate increased levels of DNA damage, and senesce prematurely. The impaired proliferation and increased senescence in Gadd45b null MEFs is partially reversed by culturing at physiological oxygen levels, indicating that Gadd45b deficiency leads to decreased ability to cope with oxidative stress. Interestingly, Gadd45b null MEFs arrest at the G2/M phase of cell cycle, in contrast to other senescent MEFs, which arrest at G1. FACS analysis of phospho-histone H3 staining showed that Gadd45b null MEFs are arrested in G2 phase rather than M phase. H2O2 and UV irradiation, known to increase oxidative stress, also triggered increased senescence in Gadd45b null MEFs compared to wild type MEFs. In vivo evidence for increased senescence in Gadd45b null mice includes the observation that embryos from Gadd45b null mice exhibit increased senescence staining compared to wild type embryos. Furthermore, it is shown that Gadd45b deficiency promotes senescence and aging phenotypes in mouse skin. Together, these results highlight a novel role for Gadd45b in stress-induced senescence and in tissue aging.

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

    PubMed

    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.

  7. Malvidin Protects WI-38 Human Fibroblast Cells Against Stress-induced Premature Senescence

    PubMed Central

    Seo, Hye Rin; Choi, Mi Jin; Choi, Ji Myung; Ko, Jong Cheol; Ko, Jee Yeon; Cho, Eun Ju

    2016-01-01

    Background: Malvidin is one of the most abundant components in red wines and black rice. The effects of malvidin on aging and lifespan under oxidative stress have not been fully understood. This study focused on the anti-aging effect of malvidin on stress-induced premature senescence (SIPS) in WI-38 human lung-derived diploid fibroblasts. Methods: In order to determine the viability of WI-38 cells, MTT assay was conducted, and malondialdehyde level was determined using thiobarbituric acid-reactive substance assay. Protein expression of inflammation-related factors was also evaluated by Western blot analysis. Results: Acute and chronic oxidative stress via hydrogen peroxide (H2O2) treatment led to SIPS in WI-38 cells, which showed decreased cell viability, increased lipid peroxidation, and a shortened lifespan in comparison with non-H2O2-treated WI-38 cells. However, malvidin treatment significantly attenuated H2O2-induced oxidative stress by inhibiting lipid peroxidation and increasing cell viability. Furthermore, the lifespan of WI-38 cells was prolonged by malvidin treatment. In addition, malvidin downregulated the expression of oxidative stress-related proteins, including NF-κB, COX-2, and inducible nitric oxide synthase. Furthermore, protein expression levels of p53, p21, and Bax were also regulated by malvidin treatment in WI-38 cells undergoing SIPS. Conclusions: Malvidin may potentially inhibit the aging process by controlling oxidative stress. PMID:27051647

  8. Premature T Cell Senescence in Pediatric CKD.

    PubMed

    George, Roshan P; Mehta, Aneesh K; Perez, Sebastian D; Winterberg, Pamela; Cheeseman, Jennifer; Johnson, Brandi; Kwun, Jean; Monday, Stephanie; Stempora, Linda; Warshaw, Barry; Kirk, Allan D

    2017-01-01

    An individual's immune function, susceptibility to infection, and response to immunosuppressive therapy are influenced in part by his/her T cell maturation state. Although childhood is the most dynamic period of immune maturation, scant information regarding the variability of T cell maturation in children with renal disease is available. In this study, we compared the T cell phenotype in children with renal failure (n=80) with that in healthy children (n=20) using multiparameter flow cytometry to detect markers of T cell maturation, exhaustion, and senescence known to influence immune function. We correlated data with the degree of renal failure (dialysis or nondialysis), prior immunosuppression use, and markers of inflammation (C-reactive protein and inflammatory cytokines) to assess the influence of these factors on T cell phenotype. Children with renal disease had highly variable and often markedly skewed maturation phenotypes, including CD4/CD8 ratio reversal, increased terminal effector differentiation in CD8(+) T cells, reduction in the proportion of naïve T cells, evidence of T cell exhaustion and senescence, and variable loss of T cell CD28 expression. These findings were most significant in patients who had experienced major immune insults, particularly prior immunosuppressive drug exposure. In conclusion, children with renal disease have exceptional heterogeneity in the T cell repertoire. Cognizance of this heterogeneity might inform risk stratification with regard to the balance between infectious risk and response to immunosuppressive therapy, such as that required for autoimmune disease and transplantation.

  9. Premature aging and immune senescence in HIV-infected children

    PubMed Central

    Gianesin, Ketty; Noguera-Julian, Antoni; Zanchetta, Marisa; Del Bianco, Paola; Petrara, Maria Raffaella; Freguja, Riccardo; Rampon, Osvalda; Fortuny, Clàudia; Camós, Mireia; Mozzo, Elena; Giaquinto, Carlo; De Rossi, Anita

    2016-01-01

    Objective: Several pieces of evidence indicate that HIV-infected adults undergo premature aging. The effect of HIV and antiretroviral therapy (ART) exposure on the aging process of HIV-infected children may be more deleterious since their immune system coevolves from birth with HIV. Design: Seventy-one HIV-infected (HIV+), 65 HIV-exposed-uninfected (HEU), and 56 HIV-unexposed-uninfected (HUU) children, all aged 0–5 years, were studied for biological aging and immune senescence. Methods: Telomere length and T-cell receptor rearrangement excision circle levels were quantified in peripheral blood cells by real-time PCR. CD4+ and CD8+ cells were analysed for differentiation, senescence, and activation/exhaustion markers by flow cytometry. Results: Telomere lengths were significantly shorter in HIV+ than in HEU and HUU children (overall, P < 0.001 adjusted for age); HIV+ ART-naive (42%) children had shorter telomere length compared with children on ART (P = 0.003 adjusted for age). T-cell receptor rearrangement excision circle levels and CD8+ recent thymic emigrant cells (CD45RA+CD31+) were significantly lower in the HIV+ than in control groups (overall, P = 0.025 and P = 0.005, respectively). Percentages of senescent (CD28−CD57+), activated (CD38+HLA-DR+), and exhausted (PD1+) CD8+ cells were significantly higher in HIV+ than in HEU and HUU children (P = 0.004, P < 0.001, and P < 0.001, respectively). Within the CD4+ cell subset, the percentage of senescent cells did not differ between HIV+ and controls, but programmed cell death receptor-1 expression was upregulated in the former. Conclusions: HIV-infected children exhibit premature biological aging with accelerated immune senescence, which particularly affects the CD8+ cell subset. HIV infection per se seems to influence the aging process, rather than exposure to ART for prophylaxis or treatment. PMID:26990630

  10. Initiation of premature senescence by Bcl-2 in hypoxic condition.

    PubMed

    Wang, Wei; Wang, Desheng; Li, Hong

    2014-01-01

    Senescence, a state of cell cycle arrest, has been regarded as an intrinsic barrier to malignance. Although being repressed in most immortal tumors, the genetic program of senescence can be reactivated by critical regulators, including the apoptosis regulator Bcl-2. We showed here that hypoxic condition resulted in an irreversible senescence-like phenotype with increased expression of Bcl-2 in mouse melanoma B16 cells. In CoCl2-simulating hypoxic condition, characteristic morphological alterations and increased activity of senescence-associated β-galactosidase (SA-β-gal) can be detected with high level of Bcl-2, which was confirmed by western blot and co-staining of SA-β-gal and Bcl-2 by immunocytochemistry. Accordingly, Bcl-2 silence by specific siRNA ahead of hypoxia treatment interrupted the senescent development. Moreover Bcl-2 overexpression led to early onset of senescence. We propose that Bcl-2 is required to initiate and maintain the senescent phenotype. In addition, p53 and p16 were not involved in hypoxia-induced senescence according to the expression levels during senescent process. These results suggest that when encountering harmful stress (hypoxia), melanoma cells overexpress Bcl-2 and turn to senescence, a permanent cell-cycle arrest, for prolonged survival.

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

    PubMed

    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

  12. Molecular basis for premature senescence induced by surfactants in normal human cells.

    PubMed

    Yamakami, Yoshimi; Miki, Kensuke; Yonekura, Ryuzo; Kudo, Ikuru; Fujii, Michihiko; Ayusawa, Dai

    2014-01-01

    Sublethal doses of surfactants as exemplified by NP-40 clearly induce premature senescence in normal human cells. To understand molecular basis for this phenomenon, we tried to suppress it with use of various inhibitors. An inhibitor of p38 of the MAPK family almost completely suppressed growth arrest and morphological changes induced by surfactants; however, other inhibitors tested had no effect. Oleic acid, a weak inducer of premature senescence, was found to suppress the effect of NP-40. Fluorescein-labeled oleic acid rapidly bound to the cell surface, and this binding was clearly blocked by pre-treatment with surfactants, suggesting that surfactants and oleic acid compete for binding to the cell surface. Moderate concentrations of cycloheximide, an inhibitor of protein synthesis, also suppressed the senescent features induced by NP-40. These results suggest that surfactants activate p38 signaling pathway by binding to the cell surface, and induce cellular senescence.

  13. Inonotus obliquus Protects against Oxidative Stress-Induced Apoptosis and Premature Senescence

    PubMed Central

    Yun, Jong Seok; Pahk, Jung Woon; Lee, Jong Seok; Shin, Won Cheol; Lee, Shin Young; Hong, Eock Kee

    2011-01-01

    In this study, we investigated the cytoprotective effects of Inonotus obliquus against oxidative stress-induced apoptosis and premature senescence. Pretreatment with I. obliquus scavenged intracellular ROS and prevented lipid peroxidation in hydrogen peroxide-treated human fibroblasts. As a result, I. obliquus exerted protective effects against hydrogen peroxide-induced apoptosis and premature senescence in human fibroblasts. In addition, I. obliquus suppressed UV-induced morphologic skin changes, such as skin thickening and wrinkle formation, in hairless mice in vivo and increased collagen synthesis through inhibition of MMP-1 and MMP-9 activities in hydrogen peroxide- treated human fibroblasts. Taken together, these results demonstrate that I. obliquus can prevent the aging process by attenuating oxidative stress in a model of stress-induced premature senescence. PMID:21359681

  14. Stress-Induced Premature Senescence of Endothelial and Endothelial Progenitor Cells

    PubMed Central

    Goligorsky, M.S.; Hirschi, K.

    2016-01-01

    This brief overview of premature senescence of dysfunctional endothelial and endothelial progenitor cells provides information on endothelial cell differentiation and specialization, their ontogeny, and controversies related to endothelial stem and progenitor cells. Stressors responsible for the dysfunction of endothelial and endothelial progenitor cells, as well as cellular mechanisms and consequences of endothelial cell dysfunction are presented. Metabolic signatures of dysfunctional endothelial cells and senescence pathways are described. Emerging strategies to rejuvenate endothelial and endothelial progenitor cells conclude the review. PMID:27451101

  15. Adiponectin Suppresses UVB-Induced Premature Senescence and hBD2 Overexpression in Human Keratinocytes

    PubMed Central

    Kim, MinJeong; Park, Kui Young; Lee, Mi-Kyung; Jin, Taewon; Seo, Seong Jun

    2016-01-01

    Recent studies have revealed that adiponectin can suppress cellular inflammatory signaling pathways. This study aimed to elucidate the effect of adiponectin on the unregulated production of hBD2 in UVB-induced premature senescent keratinocytes. We constructed an in vitro model of premature senescent keratinocytes through repeated exposure to low energy UVB. After repeated low energy UVB exposure, there was significant generation of reactive oxygen species (ROS) and induction of senescence-associated markers, including senescence associated beta-galactosidase activity and expression of p16INK4a and histone H2AX. In addition, the present clinical study showed higher expression of hBD2 in sun-exposed skin of elderly group, and the overexpression of hBD2 was observed by c-Fos activation in vitro. Adiponectin has the ability to scavenge ROS and consequently inhibit MAPKs and SA-markers in UVB-exposed keratinocytes. An inhibitor study demonstrated that adiponectin downregulated hBD2 mRNA expression through suppression of the AP-1 transcription factor components c-Fos via inactivation of p38 MAPK. Collectively, the dysregulated production of hBD2 by the induction of oxidative stress was attenuated by adiponectin through the suppression of p38 and JNK/SAPK MAPK signaling in UVB-mediated premature senescent inducible conditions. These results suggest the feasibility of adiponectin as an anti-photoaging and anti-inflammatory agent in the skin. PMID:27526049

  16. Dominant gene cpls(r)1 corresponding to premature leaf senescence resistance in cotton (Gossypium hirsutum L.).

    PubMed

    Zhao, Jingqing; Jiang, Tengfei; Liu, Zhi; Zhang, Wenwei; Jian, Guiliang; Qi, Fangjun

    2012-08-01

    Cotton (Gossypium hirsutum L.) premature leaf senescence-resistant inbred XLZ33 and senescence-susceptible inbred lines XLZ13 were selected and crossed to produce F(1), F(1)-reciprocal, F(2) and BC(1) generations for evaluation of leaf senescence process and inheritance. The results showed that leaf senescence processes for XLZ13 and XLZ33 were obviously different and leaf senescence traits could be distinguished between the two parents at particular periods of cotton growth. Inheritance anlysis for the cotton premature leaf senescence resistant trait further showed that the segregation in the F(2) fit a 3:1 ratio inheritance pattern, with resistance being dominant. The backcross of F(1) to the susceptible parent produced a 1:1 ratio, confirming that cotton premature leaf senescence resistant trait was from a single gene. The single dominant gene controlling cotton premature leaf senescence resistance in XLZ33 was named as cotton premature leaf senescence resistance 1, with the symbol cpls(r)1.

  17. Attenuation of replication stress-induced premature cellular senescence to assess anti-aging modalities.

    PubMed

    Zhao, Hong; Darzynkiewicz, Zbigniew

    2014-07-01

    Described is an in vitro model of premature senescence in pulmonary adenocarcinoma A549 cells induced by persistent DNA replication stress in response to treatment with the DNA damaging drug mitoxantrone (Mxt). The degree of cellular senescence, based on characteristic changes in cell morphology, is measured by laser scanning cytometry. Specifically, the flattening of cells grown on slides (considered the hallmark of cellular senescence) is measured as the decline in local intensity of DNA-associated DAPI fluorescence (represented by maximal pixels). This change is paralleled by an increase in nuclear area. Thus, the ratio of mean intensity of maximal pixels to nuclear area provides a very sensitive morphometric biomarker for the degree of senescence. This analysis is combined with immunocytochemical detection of senescence markers, such as overexpression of cyclin kinase inhibitors (e.g., p21(WAF1) ) and phosphorylation of ribosomal protein S6 (rpS6), a key marker associated with aging/senescence that is detected using a phospho-specific antibody. These biomarker indices are presented in quantitative terms defined as a senescence index (SI), which is the fraction of the marker in test cultures relative to the same marker in exponentially growing control cultures. This system can be used to evaluate the anti-aging potential of test agents by assessing attenuation of maximal senescence. As an example, the inclusion of berberine, a natural alkaloid with reported anti-aging properties and a long history of use in traditional Chinese medicine, is shown to markedly attenuate the Mxt-induced SI and phosphorylation of rpS6. The multivariate analysis of senescence markers by laser scanning cytometry offers a promising tool to explore the potential anti-aging properties of a variety agents.

  18. Attenuation of Replication Stress–Induced Premature Cellular Senescence to Assess Anti-Aging Modalities

    PubMed Central

    Zhao, Hong; Darzynkiewicz, Zbigniew

    2014-01-01

    Described is an in vitro model of premature senescence in pulmonary adenocarcinoma A549 cells induced by persistent DNA replication stress in response to treatment with the DNA damaging drug mitoxantrone (Mxt). The degree of cellular senescence, based on characteristic changes in cell morphology, is measured by laser scanning cytometry. Specifically, the flattening of cells grown on slides (considered the hallmark of cellular senescence) is measured as the decline in local intensity of DNA-associated DAPI fluorescence (represented by maximal pixels). This change is paralleled by an increase in nuclear area. Thus, the ratio of mean intensity of maximal pixels to nuclear area provides a very sensitive morphometric biomarker for the degree of senescence. This analysis is combined with immunocytochemical detection of senescence markers, such as overexpression of cyclin kinase inhibitors (e.g., p21WAF1) and phosphorylation of ribosomal protein S6 (rpS6), a key marker associated with aging/senescence that is detected using a phospho-specific antibody. These biomarker indices are presented in quantitative terms defined as a senescence index (SI), which is the fraction of the marker in test cultures relative to the same marker in exponentially growing control cultures. This system can be used to evaluate the anti-aging potential of test agents by assessing attenuation of maximal senescence. As an example, the inclusion of berberine, a natural alkaloid with reported anti-aging properties and a long history of use in traditional Chinese medicine, is shown to markedly attenuate the Mxt-induced SI and phosphorylation of rpS6. The multivariate analysis of senescence markers by laser scanning cytometry offers a promising tool to explore the potential anti-aging properties of a variety agents. PMID:24984966

  19. Mussel oligopeptides protect human fibroblasts from hydrogen peroxide (H2O2)-induced premature senescence.

    PubMed

    Zhou, Yue; Dong, Ying; Xu, Qing-Gang; Zhu, Shu-Yun; Tian, Shi-Lei; Huo, Jing-jing; Hao, Ting-Ting; Zhu, Bei-Wei

    2014-01-01

    Mussel bioactive peptides have been viewed as mediators to maximize the high quality of life. In this study, the anti-aging activities of mussel oligopeptides were evaluated using H2O2-induced prematurely senescent MRC-5 fibroblasts. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and flow cytometry displayed that exposure to H2O2 led to the loss of cell viability and cell cycle arrest. In addition, H2O2 caused the elevation of senescence-associated-β-galactosidase (SA-β-gal) activity and formation of senescence-associated heterochromatin foci (SAHF). It was found that pretreatment with mussel oligopeptides could significantly attenuate these properties associated with cellular senescence. Mussel oligopeptides also led to the increase of glutathione (GSH) level and mitochondrial transmembrane potential (Δψm) recovery. In addition, mussel oligopeptides resulted in an improvement in transcriptional activity of peroxiredoxin 1 (Prx1), nicotinamide phosphoribosyltransferase (NAMPT) and sirtuin 1 (SIRT1). This study revealed that mussel oligopeptides could protect against cellular senescence induced by H2O2, and the effects were closely associated with redox cycle modulating and potentiating the SIRT1 pathway. These findings provide new insights into the beneficial role of mussel bioactive peptides on retarding senescence process.

  20. Role of progerin-induced telomere dysfunction in HGPS premature cellular senescence.

    PubMed

    Benson, Erica K; Lee, Sam W; Aaronson, Stuart A

    2010-08-01

    Hutchinson-Gilford Progeria Syndrome (HGPS) is a premature-aging syndrome caused by a dominant mutation in the gene encoding lamin A, which leads to an aberrantly spliced and processed protein termed progerin. Previous studies have shown that progerin induces early senescence associated with increased DNA-damage signaling and that telomerase extends HGPS cellular lifespan. We demonstrate that telomerase extends HGPS cellular lifespan by decreasing progerin-induced DNA-damage signaling and activation of p53 and Rb pathways that otherwise mediate the onset of premature senescence. We show further that progerin-induced DNA-damage signaling is localized to telomeres and is associated with telomere aggregates and chromosomal aberrations. Telomerase amelioration of DNA-damage signaling is relatively rapid, requires both its catalytic and DNA-binding functions, and correlates in time with the acquisition by HGPS cells of the ability to proliferate. All of these findings establish that HGPS premature cellular senescence results from progerin-induced telomere dysfunction.

  1. RB maintains quiescence and prevents premature senescence through upregulation of DNMT1 in mesenchymal stromal cells.

    PubMed

    Lin, Shih-Pei; Chiu, Fang-Yao; Wang, Yu; Yen, Men-Luh; Kao, Shou-Yen; Hung, Shih-Chieh

    2014-12-09

    Many cell therapies currently being tested are based on mesenchymal stromal cells (MSCs). However, MSCs start to enter the senescent state upon long-term expansion. The role of retinoblastoma (RB) protein in regulating MSC properties is not well studied. Here, we show that RB levels are higher in early-passage MSCs compared with late-passage MSCs. RB knockdown induces premature senescence and reduced differentiation potentials in early-passage MSCs. RB overexpression inhibits senescence and increases differentiation potentials in late-passage MSCs. Expression of DNMT1, but not DNMT3A or DNMT3B, is also higher in early-passage MSCs than in late-passage MSCs. Furthermore, DNMT1 knockdown in early-passage MSCs induces senescence and reduces differentiation potentials, whereas DNMT1 overexpression in late-passage MSCs has the opposite effect. These results demonstrate that RB expressed in early-passage MSCs upregulates DNMT1 expression and inhibits senescence in MSCs. Therefore, genetic modification of RB could be a way to improve the efficiency of MSCs in clinical use.

  2. Curcumin Attenuates Hydrogen Peroxide-Induced Premature Senescence via the Activation of SIRT1 in Human Umbilical Vein Endothelial Cells.

    PubMed

    Sun, Yueliu; Hu, Xiaorong; Hu, Gangying; Xu, Changwu; Jiang, Hong

    2015-01-01

    Endothelial senescence has been proposed to be involved in endothelial dysfunction and atherogenesis. Curcumin, a natural phenol, possesses antioxidant and anti-inflammatory properties. However, the effect of curcumin on endothelial senescence is unclear. This study explores the effect of curcumin on hydrogen peroxide (H2O2)-induced endothelial premature senescence and the mechanisms involved. Human umbilical vein endothelial cells (HUVECs) were cultured, and premature senescence was induced with 100 µM H2O2. Results showed that pretreatment with curcumin significantly attenuated the H2O2-induced HUVECs' premature senescence, which was evidenced by a decreased percentage of senescence-associated β-galactosidase positive cells, improved cell division and decreased expression of senescence-associated protein p21 (all p<0.05). Pretreatment with curcumin decreased oxidative stress and apoptosis in H2O2-treated HUVECs. Treatment of HUVECs with H2O2 also down-regulated the phosphorylation of endothelial nitric oxide synthase (eNOS), decreased the level of nitric oxide in the culture medium, and inhibited the protein expression and enzymatic activity of silent information regulator 1 (SIRT1), while pretreatment with curcumin partly reversed these effects (all p<0.05). Treatment with curcumin alone enhanced the enzymatic activity of SIRT1, but didn't affect cellular senescence, cell growth or apoptosis compared to the Control. The inhibition of SIRT1 using SIRT1 short interfering RNA (siRNA) could decrease the expression and phosphorylation of eNOS and abrogate the protective effect of curcumin on H2O2-induced premature senescence. These findings suggest that curcumin could attenuate oxidative stress-induced HUVECs' premature senescence via the activation of SIRT1.

  3. Melatonin reverses H2 O2 -induced premature senescence in mesenchymal stem cells via the SIRT1-dependent pathway.

    PubMed

    Zhou, Long; Chen, Xi; Liu, Tao; Gong, Yihong; Chen, Sijin; Pan, Guoqing; Cui, Wenguo; Luo, Zong-Ping; Pei, Ming; Yang, Huilin; He, Fan

    2015-09-01

    Mesenchymal stem cells (MSCs) represent an attractive source for stem cell-based regenerative therapy, but they are vulnerable to oxidative stress-induced premature senescence in pathological conditions. We previously reported antioxidant and antiarthritic effects of melatonin on MSCs against proinflammatory cytokines. In this study, we hypothesized that melatonin could protect MSCs from premature senescence induced by hydrogen peroxide (H2 O2 ) via the silent information regulator type 1 (SIRT1)-dependent pathway. In response to H2 O2 at a sublethal concentration of 200 μm, human bone marrow-derived MSCs (BM-MSCs) underwent growth arrest and cellular senescence. Treatment with melatonin before H2 O2 exposure cannot significantly prevent premature senescence; however, treatment with melatonin subsequent to H2 O2 exposure successfully reversed the senescent phenotypes of BM-MSCs in a dose-dependent manner. This result was made evident by improved cell proliferation, decreased senescence-associated β-galactosidase activity, and the improved entry of proliferating cells into the S phase. In addition, treatment with 100 μm melatonin restored the osteogenic differentiation potential of BM-MSCs that was inhibited by H2 O2 -induced premature senescence. We also found that melatonin attenuated the H2 O2 -stimulated phosphorylation of p38 mitogen-activated protein kinase, decreased expression of the senescence-associated protein p16(INK) (4α) , and increased SIRT1. Further molecular experiments revealed that luzindole, a nonselective antagonist of melatonin receptors, blocked melatonin-mediated antisenescence effects. Inhibition of SIRT1 by sirtinol counteracted the protective effects of melatonin, suggesting that melatonin reversed the senescence in cells through the SIRT1-dependent pathway. Together, these findings lay new ground for understanding oxidative stress-induced premature senescence and open perspectives for therapeutic applications of melatonin in stem cell

  4. Effect of lipopolysaccharides on adipogenic potential and premature senescence of adipocyte progenitors.

    PubMed

    Zhao, Ming; Chen, Xiaoli

    2015-08-15

    The elevation of circulating LPS has been associated with obesity and aging. However, whether and how LPS contributes to adipose tissue dysfunction is unclear. In this study, we investigated the effect of LPS on the adipogenic capacity and cellular senescence of adipocyte progenitors. Stromal-vascular cells were isolated from inguinal adipose tissue of C57BL/6 mice and treated with LPS during the different time periods of adipocyte differentiation. We found that LPS treatment for 24 h prior to the induction of differentiation led to the most profound effect on the inhibition of adipogenesis, as evidenced by the morphological changes and the decreased mRNA expression of adipocyte marker genes. In addition, LPS induced features of premature senescence of SV cells, including the activation of p53, the elevation of SA-β-gal activity, and increased hydrogen peroxide production, but not telomere length. Upon LPS treatment, SV cells also developed senescence-associated secretory phenotype (SASP), as demonstrated by the increased expression of TNFα, IL-1β, IL-6, MCP-1, and VEGFα. Blocking LPS-induced NF-κB activation and cytokine production by Bay 11-7082 failed to rescue the impaired adipogenesis and the reduction in PPARγ and Zfp423 expression. On the contrary, rosiglitazone had little effect on cytokine production but corrected the defective adipogenic potential. In conclusion, we demonstrate that LPS inhibits adipogenesis by disrupting the differentiation of adipocyte progenitors in a NF-κB-independent manner; LPS also induces premature senescence of adipocyte progenitors. Our data suggest that LPS could be a potential contributor to the defective adipogenesis and the development of cellular senescence in adipose tissue during obesity and aging.

  5. Gardenia jasminoides extract-capped gold nanoparticles reverse hydrogen peroxide-induced premature senescence.

    PubMed

    Chae, Seon Yeong; Park, Sun Young; Park, Jin Oh; Lee, Kyu Jin; Park, Geuntae

    2016-11-01

    This study reports a green approach for synthesis of gold nanoparticles using Gardenia jasminoides extract, and specifically, can potentially enhance anti senescence activity. Biological synthesis of gold nanoparticles is ecofriendly and effective for the development of environmentally sustainable nanoparticles compared with existing methods. Here, we developed a simple, fast, efficient, and ecofriendly approach to the synthesis of gold nanoparticles by means of a Gardenia jasminoides extract. These G. jasminoides extract-capped gold nanoparticles (GJ-GNPs) were characterized by UV-vis, high resolution transmission electron microscopy (HR-TEM), X-ray diffraction (XRD), and Furrier transform infrared spectroscopy (FT-IR). The synthesized GJ-GNPs turned red and showed maximal absorbance at 540nm. Thus, GJ-GNPs were synthesized successfully. We hypothesized that GJ-GNPs would protect ARPE19 cells from hydrogen peroxide-induced premature senescence. SA-β-gal activity was elevated in hydrogen peroxide-treated cells, however, this effect was attenuated by GJ-GNP treatment. Moreover, compared with the normal control, hydrogen peroxide treatment significantly increased lysosome content of the cells and production of reactive oxygen species (ROS). GJ-GNPs effectively attenuated the increase in lysosome content and ROS production in these senescent cells. According to cell cycle analysis, G2/M arrest was promoted by hydrogen peroxide treatment in ARPE19 cells, however, this change was reversed by GJ-GNPs. Western blot analysis showed that treatment with GJ-GNPs increased the expression of p53, p21, SIRT3, HO-1, and NQO1 in senescent cells. Our findings should advance the understanding of premature senescence and may lead to therapeutic use of GJ-GNPs in retina-related regenerative medicine.

  6. Cordyceps militaris Extract Protects Human Dermal Fibroblasts against Oxidative Stress-Induced Apoptosis and Premature Senescence

    PubMed Central

    Park, Jun Myoung; Lee, Jong Seok; Lee, Ki Rim; Ha, Suk-Jin; Hong, Eock Kee

    2014-01-01

    Oxidative stress induced by reactive oxygen species (ROS) is the major cause of degenerative disorders including aging and disease. In this study, we investigated whether Cordyceps militaris extract (CME) has in vitro protective effects on hydrogen peroxide-induced oxidative stress in human dermal fibroblasts (HDFs). Our results showed that the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity of CME was increased in a dose-dependent manner. We found that hydrogen peroxide treatment in HDFs increased ROS generation and cell death as compared with the control. However, CME improved the survival of HDFs against hydrogen peroxide-induced oxidative stress via inhibition of intracellular ROS production. CME treatment inhibited hydrogen peroxide-induced apoptotic cell death and apoptotic nuclear condensation in HDFs. In addition, CME prevented hydrogen peroxide-induced SA-β-gal-positive cells suggesting CME could inhibit oxidative stress-induced premature senescence. Therefore, these results suggest that CME might have protective effects against oxidative stress-induced premature senescence via scavenging ROS. PMID:25230212

  7. Autophagy inhibition switches low-dose camptothecin-induced premature senescence to apoptosis in human colorectal cancer cells.

    PubMed

    Zhang, Jian-wei; Zhang, Shan-shan; Song, Jian-rui; Sun, Kai; Zong, Chen; Zhao, Qiu-dong; Liu, Wen-ting; Li, Rong; Wu, Meng-chao; Wei, Li-xin

    2014-08-01

    Recently, several studies indicated that senescent tumor cells are resistant to apoptosis in chemotherapy. They may return to cell cycle, thus act as stumbling blocks in anticancer treatments. In the present study, we found that, in human colorectal cancer cells, low-dose camptothecin (CPT) simultaneously induced autophagy and premature senescence through AMPK-TSC2-mTOR pathway and ATM-Chk2-p53-p21 pathway respectively. What's important is the suppression of autophagy substantially increased apoptosis and greatly attenuated senescence possibly by blocking p53/p21 pathway, which suggests that autophagy plays an indispensable role in sustaining cell senescence caused by low-dose CPT. The combination of low-dose CPT and autophagy inhibitor, a way to lead senescent cells to die, would be potentially valuable in cancer therapy.

  8. Cr(VI) induces premature senescence through ROS-mediated p53 pathway in L-02 hepatocytes

    PubMed Central

    Zhang, Yujing; Zhang, Yiyuan; Zhong, Caigao; Xiao, Fang

    2016-01-01

    Hexavalent Chromium [Cr(VI)], which can be found of various uses in industries such as metallurgy and textile dying, can cause a number of human disease including inflammation and cancer. Unlike previous research that focused on Cr(VI)-induced oxidative damage and apoptosis, this study placed emphasis on premature senescence that can be induced by low-dose and long-term Cr(VI) exposure. We found Cr(VI) induced premature senescence in L-02 hepatocytes, as confirmed by increase in senescence associated-β-galactosidase (SA-β-Gal) activity. Cr(VI) stabilized p53 through phosphorylation at Ser15 and increased expression of p53-transcriptional target p21. Mechanism study revealed Cr(VI) targeted and inhibited mitochondrial respiratory chain complex (MRCC) I and II to enhance reactive oxygen species (ROS) production. By applying antioxidant Trolox, we also confirmed that ROS mediated p53 activation. A tetracycline-inducible lentiviral expression system containing shRNA to p53 was used to knockout p53. We found p53 could inhibit pro-survival genes B-cell lymphoma-2 (Bcl-2), myeloid leukemia-1 (Mcl-1) and S phase related cell cycle proteins cyclin-dependent kinase 2 (CDK2), Cyclin E to induce premature senescence, and the functional role of ROS in Cr(VI)-induced premature senescence is depend on p53. The results suggest that Cr(VI) has a role in premature senescence by promoting ROS-dependent p53 activation in L-02 hepatocytes. PMID:27698449

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

    SciTech Connect

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

    2009-06-05

    Akt/PKB plays a pivotal role in cell survival and proliferation. Previously, we reported that UV-irradiation induces extensive cell death in Akt2{sup -/-} mouse embryonic fibroblasts (MEFs) while Akt1{sup -/-} MEFs show cell cycle arrest. Here, we find that Akt1{sup -/-} MEFs exhibit phenotypic changes characteristics of senescence upon UV-irradiation. An enlarged and flattened morphology, a reduced cell proliferation and an increased senescence-associated {beta}-galactosidase (SA {beta}-gal) staining indicate that Akt1{sup -/-} MEFs undergo premature senescence after UV-irradiation. Restoring Akt1 expression in Akt1{sup -/-} MEFs suppressed SA {beta}-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{sup -/-} MEFs, suggesting that UV light induces premature senescence in Akt1{sup -/-} 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. Premature senescence of endothelial cells upon chronic exposure to TNFα can be prevented by N-acetyl cysteine and plumericin

    PubMed Central

    Khan, Shafaat Y.; Awad, Ezzat M.; Oszwald, Andre; Mayr, Manuel; Yin, Xiaoke; Waltenberger, Birgit; Stuppner, Hermann; Lipovac, Markus; Uhrin, Pavel; Breuss, Johannes M.

    2017-01-01

    Cellular senescence is characterized by a permanent cell-cycle arrest and a pro-inflammatory secretory phenotype, and can be induced by a variety of stimuli, including ionizing radiation, oxidative stress, and inflammation. In endothelial cells, this phenomenon might contribute to vascular disease. Plasma levels of the inflammatory cytokine tumor necrosis factor alpha (TNFα) are increased in age-related and chronic conditions such as atherosclerosis, rheumatoid arthritis, psoriasis, and Crohn’s disease. Although TNFα is a known activator of the central inflammatory mediator NF-κB, and can induce the intracellular generation of reactive oxygen species (ROS), the question whether TNFα can induce senescence has not been answered conclusively. Here, we investigated the effect of prolonged TNFα exposure on the fate of endothelial cells and found that such treatment induced premature senescence. Induction of endothelial senescence was prevented by the anti-oxidant N-acetyl cysteine, as well as by plumericin and PHA-408, inhibitors of the NF-κB pathway. Our results indicated that prolonged TNFα exposure could have detrimental consequences to endothelial cells by causing senescence and, therefore, chronically increased TNFα levels might possibly contribute to the pathology of chronic inflammatory diseases by driving premature endothelial senescence. PMID:28045034

  11. Redox status impairment in liver and kidney of prematurely senescent mice: effectiveness of DTS phytotherapeutic compound.

    PubMed

    Marotta, F; Lorenzetti, F; Harada, M; Ono-Nita, S K; Minelli, E; Marandola, P

    2006-05-01

    T-maze test-selected prematurely senescent mice (PSM) were allocated into two groups: (A) those given DTS (150 mg/kg) orally for 30 days and (B) untreated PSM with age-matched fast T-maze performers as control. After sacrifice, the liver and kidney were analyzed for catalase (CAT) activity, glutathione peroxidase (GPx), superoxide dismutase (SOD), malondyaldehyde (MDA), and plasma thiols. Untreated PSM showed decreased plasma thiols and tissue level of CAT, SOD, GPx, with higher MDA (P < 0.01 vs. fast performers), while DTS (Denshichi-Tochiu-Sen) significantly improved glutathione and cysteine (P < 0.05) and tissue concentration of the above parameters (P < 0.05). Such preliminary data suggest that DTS mitigated oxidative damage in PSM, with likely action on the cytoplasm and mitochondrial matrix.

  12. Induction of Premature Senescence by Hsp90 Inhibition in Small Cell Lung Cancer

    PubMed Central

    Restall, Ian J.; Lorimer, Ian A. J.

    2010-01-01

    Background The molecular chaperone Hsp90 is a promising new target in cancer therapy and selective Hsp90 inhibitors are currently in clinical trials. Previously these inhibitors have been reported to induce either cell cycle arrest or cell death in cancer cells. Whether the cell cycle arrest is reversible or irreversible has not generally been assessed. Here we have examined in detail the cell cycle arrest and cell death responses of human small cell lung cancer cell lines to Hsp90 inhibition. Methodology/Principal Findings In MTT assays, small cell lung cancer cells showed a biphasic response to the Hsp90 inhibitors geldanamycin and radicicol, with low concentrations causing proliferation arrest and high concentrations causing cell death. Assessment of Hsp90 intracellular activity using loss of client protein expression showed that geldanamycin concentrations that inhibited Hsp90 correlated closely with those causing proliferation arrest but not cell death. The proliferation arrest induced by low concentrations of geldanamycin was not reversed for a period of over thirty days following drug removal and showed features of senescence. Rare populations of variant small cell lung cancer cells could be isolated that had additional genetic alterations and no longer underwent irreversible proliferation arrest in response to Hsp90 inhibitors. Conclusions/Significance We conclude that: (1) Hsp90 inhibition primarily induces premature senescence, rather than cell death, in small cell lung cancer cells; (2) small cell lung cancer cells can bypass this senescence through further genetic alterations; (3) Hsp90 inhibitor-induced cell death in small cell lung cancer cells is due to inhibition of a target other than cytosolic Hsp90. These results have implications with regard to how these inhibitors will behave in clinical trials and for the design of future inhibitors in this class. PMID:20552022

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

    PubMed Central

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

    2014-01-01

    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. PMID:24395638

  14. Bisdemethoxycurcumin Increases Sirt1 to Antagonize t-BHP-Induced Premature Senescence in WI38 Fibroblast Cells.

    PubMed

    Li, Ying-Bo; Zhong, Zhang-Feng; Chen, Mei-Wan; Bao, Jiao-Lin; Wu, Guo-Sheng; Zhang, Qing-Wen; Lee, Simon Ming-Yuen; Hoi, Pui-Man; Wang, Yi-Tao

    2013-01-01

    Curcuminoids are well known for their capabilities to combat risk factors that are associated with ageing and cellular senescence. Recent reports have demonstrated that curcuminoids can extend the lifespan of model organisms. However, the underlying mechanisms by which these polyphenic compounds exert these beneficial effects remain unknown. In this study, t-BHP-induced premature senescence model in human fibroblasts was chosen to explore the protective effects of a curcuminoid, bisdemethoxycurcumin (BDMC), on cellular senescence. The results demonstrated that BDMC attenuated oxidative stress-induced senescence-like features which include the induction of an enlarged cellular appearance, higher frequency of senescence-associated β -galactosidase staining activity, appearance of senescence-associated heterochromatic foci in nuclei, decrease in proliferation capability, and alteration in related molecules such as p16 and retinoblastoma protein. Notably, we found that BDMC treatment activated Sirt1/AMPK signaling pathway. Moreover, downregulating Sirt1 by the pharmacological inhibitor nicotianamine or small interfering RNA blocked BDMC-mediated protection against t-BHP-mediated decrease in proliferation. These results suggested that BDMC prevented t-BHP-induced cellular senescence, and BDMC-induced Sirt1 may be a mechanism mediating its beneficial effects.

  15. Premature Senescence in Primary Muscle Cultures of Myotonic Dystrophy Type 2 is not Associated with p16 Induction

    PubMed Central

    Renna, L.V.; Cardani, R.; Botta, A.; Rossi, G.; Fossati, B.; Costa, E.; Meola, G.

    2014-01-01

    Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are multisystemic disorders linked to two different genetic loci and characterized by several features including myotonia, muscle weakness and atrophy, cardiac dysfunctions, cataracts and insulin-resistance. In both forms, expanded nucleotide sequences cause the accumulation of mutant transcripts in the nucleus deregulating the activity of some RNA-binding proteins and providing an explanation for the multisystemic phenotype of DM patients. However this pathogenetic mechanism does not explain some histopathological features of DM skeletal muscle like muscle atrophy. It has been observed that DM muscle shares similarities with the ageing muscle, where the progressive muscle weakness and atrophy is accompanied by a lower regenerative capacity possibly due to the failure in satellite cells activation. The aim of our study is to investigate if DM2 satellite cell derived myoblasts exhibit a premature senescence as reported for DM1 and if alterations in their proliferation potential and differentiation capabilities might contribute to some of the histopathological features observed in DM2 muscles. Our results indicate that DM myoblasts have lower proliferative capability than control myoblasts and reach in vitro senescence earlier than controls. Differentely from DM1, the p16 pathway is not responsible for the premature growth arrest observed in DM2 myoblasts which stop dividing with telomeres shorter than controls. During in vitro senescence, a progressive decrease in fusion index is observable in both DM and control myotubes with no significant differences between groups. Moreover, myotubes obtained from senescent myoblasts appear to be smaller than those from young myoblasts. Taken together, our data indicate a possible role of DM2 premature myoblast senescence in skeletal muscle histopathological alterations i.e., dystrophic changes and type 2 fibre atrophy. PMID:25578974

  16. SU5416 induces premature senescence in endothelial progenitor cells from patients with age-related macular degeneration

    PubMed Central

    Berna, Marc J.; Kunst, Frank; Wege, Henning; Strunnikova, Natalya V.; Gordiyenko, Natalya; Grierson, Rebecca; Richard, Gisbert; Csaky, Karl G.

    2011-01-01

    Purpose We recently demonstrated increased frequency and growth potential of late outgrowth endothelial progenitor cells (OECs) in patients with neovascular age-related macular degeneration (nvAMD). This study investigated the effects of short- and long-term in vitro inhibition of vascular endothelial growth factor (VEGF) Receptor-2 (VEGFR-2) signaling by SU5416 and other inhibitors of the VEGF signaling pathway in OECs. Methods OECs, from the peripheral blood of patients with nvAMD, and human umbilical vein endothelial cells were grown in the presence of SU5416, other VEGFR-2 tyrosine kinase inhibitors (TKIs), and inhibitors of phosphatidylinositol 3′-Kinase (PI3K)/protein kinase B (Akt) and protein kinase C (PKC) in complete angiogenic medium. Apotosis was assessed after 48 h using the fluorescein isothiocyanate Annexin V method. Cell counts were performed for 10 days, and features of senescence were analyzed using senescence-associated β-galactosidase staining, the telomeric repeat amplification protocol for telomerase activity, Southern blot analysis for mean telomere length, flow cytometric analysis for cell-cycle arrest, and western blot for p53 and p21. Control OECs, cells treated for 7 days with inhibitors, as well as naturally senescent OECs were analyzed for expression of different endothelial antigens, including VEGFR-2 and the receptor for stromal cell-derived factor 1, chemokine receptor 4 (CXCR-4). Migration in vitro to VEGF and stromal cell-derived factor 1 of OECs was assessed. Results SU5416, other VEGFR-2 TKIs, and inhibitors of PI3K, Akt, and PKC induced apoptosis, inhibited long-term proliferation, reduced telomerase activity, and induced premature senescence and cell-cycle arrest in OECs as well as in human umbilical vein endothelial cells. Naturally senescent cells and cells rendered senescent by VEGFR-2 TKIs had reduced VEGFR-2 and CXCR-4 expression and demonstrated reduced migratory ability to VEGF. Conclusions This study demonstrates

  17. Oxidative stress-induced inhibition of Sirt1 by caveolin-1 promotes p53-dependent premature senescence and stimulates the secretion of interleukin 6 (IL-6).

    PubMed

    Volonte, Daniela; Zou, Huafei; Bartholomew, Janine N; Liu, Zhongmin; Morel, Penelope A; Galbiati, Ferruccio

    2015-02-13

    Oxidative stress can induce premature cellular senescence. Senescent cells secrete various growth factors and cytokines, such as IL-6, that can signal to the tumor microenvironment and promote cancer cell growth. Sirtuin 1 (Sirt1) is a class III histone deacetylase that regulates a variety of physiological processes, including senescence. We found that caveolin-1, a structural protein component of caveolar membranes, is a direct binding partner of Sirt1, as shown by the binding of the scaffolding domain of caveolin-1 (amino acids 82-101) to the caveolin-binding domain of Sirt1 (amino acids 310-317). Our data show that oxidative stress promotes the sequestration of Sirt1 into caveolar membranes and the interaction of Sirt1 with caveolin-1, which lead to inhibition of Sirt1 activity. Reactive oxygen species stimulation promotes acetylation of p53 and premature senescence in wild-type but not caveolin-1 null mouse embryonic fibroblasts (MEFs). Either down-regulation of Sirt1 expression or re-expression of caveolin-1 in caveolin-1 null MEFs restores reactive oxygen species-induced acetylation of p53 and premature senescence. In addition, overexpression of caveolin-1 induces stress induced premature senescence in p53 wild-type but not p53 knockout MEFs. Phosphorylation of caveolin-1 on tyrosine 14 promotes the sequestration of Sirt1 into caveolar membranes and activates p53/senescence signaling. We also identified IL-6 as a caveolin-1-specific cytokine that is secreted by senescent fibroblasts following the caveolin-1-mediated inhibition of Sirt1. The caveolin-1-mediated secretion of IL-6 by senescent fibroblasts stimulates the growth of cancer cells. Therefore, by inhibiting Sirt1, caveolin-1 links free radicals to the activation of the p53/senescence pathway and the protumorigenic properties of IL-6.

  18. Persistent DNA damage-induced premature senescence alters the functional features of human bone marrow mesenchymal stem cells.

    PubMed

    Minieri, Valentina; Saviozzi, Silvia; Gambarotta, Giovanna; Lo Iacono, Marco; Accomasso, Lisa; Cibrario Rocchietti, Elisa; Gallina, Clara; Turinetto, Valentina; Giachino, Claudia

    2015-04-01

    Human mesenchymal stem cells (hMSCs) are adult multipotent stem cells located in various tissues, including the bone marrow. In contrast to terminally differentiated somatic cells, adult stem cells must persist and function throughout life to ensure tissue homeostasis and repair. For this reason, they must be equipped with DNA damage responses able to maintain genomic integrity while ensuring their lifelong persistence. Evaluation of hMSC response to genotoxic insults is of great interest considering both their therapeutic potential and their physiological functions. This study aimed to investigate the response of human bone marrow MSCs to the genotoxic agent Actinomycin D (ActD), a well-known anti-tumour drug. We report that hMSCs react by undergoing premature senescence driven by a persistent DNA damage response activation, as hallmarked by inhibition of DNA synthesis, p21 and p16 protein expression, marked Senescent Associated β-galactosidase activity and enlarged γH2AX foci co-localizing with 53BP1 protein. Senescent hMSCs overexpress several senescence-associated secretory phenotype (SASP) genes and promote motility of lung tumour and osteosarcoma cell lines in vitro. Our findings disclose a multifaceted consequence of ActD treatment on hMSCs that on the one hand helps to preserve this stem cell pool and prevents damaged cells from undergoing neoplastic transformation, and on the other hand alters their functional effects on the surrounding tissue microenvironment in a way that might worsen their tumour-promoting behaviour.

  19. The inflammatory cytokine TNF-α promotes the premature senescence of rat nucleus pulposus cells via the PI3K/Akt signaling pathway

    PubMed Central

    Li, Pei; Gan, Yibo; Xu, Yuan; Song, Lei; Wang, Liyuan; Ouyang, Bin; Zhang, Chengmin; Zhou, Qiang

    2017-01-01

    Premature senescence of nucleus pulposus (NP) cells and inflammation are two common features of degenerated discs. This study investigated the effects of the inflammatory cytokine TNF-α on the premature senescence of NP cells and the molecular mechanism behind this process. Rat NP cells were cultured with or without different concentrations of TNF-α for 1 and 3 days. The inhibitor LY294002 was used to determine the role of the PI3K/Akt pathway. NP cells that were incubated with TNF-α for 3 days followed by 3 days of recovery in the control medium were used to analyze cellular senescence. Results showed that TNF-α promoted premature senescence of NP cells, as indicated by decreased cell proliferation, decreased telomerase activity, increased SA-β-gal staining, the fraction of cells arrested in the G1 phase of the cell cycle, the attenuated ability to synthesize matrix proteins and the up-regulated expression of the senescence marker p16 and p53. Moreover, a high TNF-α concentration produced greater effects than a low TNF-α concentration on day 3 of the experiment. Further analysis indicated that the inhibition of the PI3K/Akt pathway attenuated the TNF-α-induced premature senescence of NP cells. Additionally, TNF-α-induced NP cell senescence did not recover after TNF-α was withdrawn. In conclusion, TNF-α promotes the premature senescence of NP cells, and activation of the PI3K/Akt pathway is involved in this process. PMID:28211497

  20. 2, 3, 7, 8-Tetrachlorodibenzo-p-dioxin induces premature senescence of astrocytes via WNT/β-catenin signaling and ROS production.

    PubMed

    Nie, Xiaoke; Liang, Lingwei; Xi, Hanqing; Jiang, Shengyang; Jiang, Junkang; Tang, Cuiying; Liu, Xipeng; Liu, Suyi; Wan, Chunhua; Zhao, Jianya; Yang, Jianbin

    2015-07-01

    2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) is a ubiquitous environmental contaminant that could exert significant neurotoxicity in the human nervous system. Nevertheless, the molecular mechanism underlying TCDD-mediated neurotoxicity has not been clarified clearly. Herein, we investigated the potential role of TCDD in facilitating premature senescence in astrocytes and the underlying molecular mechanisms. Using the senescence-associated β-galactosidase (SA-β-Gal) assay, we demonstrated that TCDD exposure triggered significant premature senescence of astrocyte cells, which was accompanied by a marked activation of the Wingless and int (WNT)/β-catenin signaling pathway. In addition, TCDD altered the expression of senescence marker proteins, such as p16, p21 and GFAP, which together have been reported to be upregulated in aging astrocytes, in both dose- and time-dependent manners. Further, TCDD led to cell-cycle arrest, F-actin reorganization and the accumulation of cellular reactive oxygen species (ROS). Moreover, the ROS scavenger N-acetylcysteine (NAC) markedly attenuated TCDD-induced ROS production, cellular oxidative damage and astrocyte senescence. Notably, the application of XAV939, an inhibitor of WNT/β-catenin signaling pathway, ameliorated the effect of TCDD on cellular β-catenin level, ROS production, cellular oxidative damage and premature senescence in astrocytes. In summary, our findings indicated that TCDD might induce astrocyte senescence via WNT/β-catenin and ROS-dependent mechanisms.

  1. 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

    PubMed Central

    Loseva, Olga; Shubbar, Emman; Haghdoost, Siamak; Evers, Bastiaan; Helleday, Thomas; Harms-Ringdahl, Mats

    2014-01-01

    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. PMID:28250385

  2. 2, 3, 7, 8-Tetrachlorodibenzo-P-dioxin (TCDD) induces premature senescence in human and rodent neuronal cells via ROS-dependent mechanisms.

    PubMed

    Wan, Chunhua; Liu, Jiao; Nie, Xiaoke; Zhao, Jianya; Zhou, Songlin; Duan, Zhiqing; Tang, Cuiying; Liang, Lingwei; Xu, Guangfei

    2014-01-01

    The widespread environmental pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a potent toxicant that causes significant neurotoxicity. However, the biological events that participate in this process remain largely elusive. In the present study, we demonstrated that TCDD exposure triggered apparent premature senescence in rat pheochromocytoma (PC12) and human neuroblastoma SH-SY5Y cells. Senescence-associated β-galactosidase (SA-β-Gal) assay revealed that TCDD induced senescence in PC12 neuronal cells at doses as low as 10 nM. TCDD led to F-actin reorganization and the appearance of an alternative senescence marker, γ-H2AX foci, both of which are important features of cellular senescence. In addition, TCDD exposure altered the expression of senescence marker proteins, such as p16, p21 and p-Rb, in both dose- and time-dependent manners. Furthermore, we demonstrated that TCDD promotes mitochondrial dysfunction and the accumulation of cellular reactive oxygen species (ROS) in PC12 cells, leading to the activation of signaling pathways that are involved in ROS metabolism and senescence. TCDD-induced ROS generation promoted significant oxidative DNA damage and lipid peroxidation. Notably, treatment with the ROS scavenger N-acetylcysteine (NAC) markedly attenuated TCDD-induced ROS production, cellular oxidative damage and neuronal senescence. Moreover, we found that TCDD induced a similar ROS-mediated senescence response in human neuroblastoma SH-SY5Y cells. In sum, these results demonstrate for the first time that TCDD induces premature senescence in neuronal cells by promoting intracellular ROS production, supporting the idea that accelerating the onset of neuronal senescence may be an important mechanism underlying TCDD-induced neurotoxic effects.

  3. Premature lung aging and cellular senescence in the pathogenesis of idiopathic pulmonary fibrosis and COPD/emphysema.

    PubMed

    Chilosi, Marco; Carloni, Angelo; Rossi, Andrea; Poletti, Venerino

    2013-09-01

    Different anatomic and physiological changes occur in the lung of aging people that can affect pulmonary functions, and different pulmonary diseases, including deadly diseases such as chronic obstructive pulmonary disease (COPD)/emphysema and idiopathic pulmonary fibrosis (IPF), can be related to an acceleration of the aging process. The individual genetic background, as well as exposure to a variety of toxic substances (cigarette smoke in primis) can contribute significantly to accelerating pulmonary senescence. Premature aging can impair lung function by different ways: by interfering specifically with tissue repair mechanisms after damage, thus perturbing the correct crosstalk between mesenchymal and epithelial components; by inducing systemic and/or local alteration of the immune system, thus impairing the complex mechanisms of lung defense against infections; and by stimulating a local and/or systemic inflammatory condition (inflammaging). According to recently proposed pathogenic models in COPD and IPF, premature cellular senescence likely affects distinct progenitors cells (mesenchymal stem cells in COPD, alveolar epithelial precursors in IPF), leading to stem cell exhaustion. In this review, the large amount of data supporting this pathogenic view are discussed, with emphasis on the possible molecular and cellular mechanisms leading to the severe parenchymal remodeling that characterizes, in different ways, these deadly diseases.

  4. Loss of p53-mediated cell-cycle arrest, senescence and apoptosis promotes genomic instability and premature aging.

    PubMed

    Li, Tongyuan; Liu, Xiangyu; Jiang, Le; Manfredi, James; Zha, Shan; Gu, Wei

    2016-03-15

    Although p53-mediated cell cycle arrest, senescence and apoptosis are well accepted as major tumor suppression mechanisms, the loss of these functions does not directly lead to tumorigenesis, suggesting that the precise roles of these canonical activities of p53 need to be redefined. Here, we report that the cells derived from the mutant mice expressing p533KR, an acetylation-defective mutant that fails to induce cell-cycle arrest, senescence and apoptosis, exhibit high levels of aneuploidy upon DNA damage. Moreover, the embryonic lethality caused by the deficiency of XRCC4, a key DNA double strand break repair factor, can be fully rescued in the p533KR/3KR background. Notably, despite high levels of genomic instability, p533KR/3KRXRCC4-/- mice, unlike p53-/- XRCC4-/- mice, are not succumbed to pro-B-cell lymphomas. Nevertheless, p533KR/3KR XRCC4-/- mice display aging-like phenotypes including testicular atrophy, kyphosis, and premature death. Further analyses demonstrate that SLC7A11 is downregulated and that p53-mediated ferroptosis is significantly induced in spleens and testis of p533KR/3KRXRCC4-/- mice. These results demonstrate that the direct role of p53-mediated cell cycle arrest, senescence and apoptosis is to control genomic stability in vivo. Our study not only validates the importance of ferroptosis in p53-mediated tumor suppression in vivo but also reveals that the combination of genomic instability and activation of ferroptosis may promote aging-associated phenotypes.

  5. Transcriptional up-regulation of antioxidant genes by PPAR{delta} inhibits angiotensin II-induced premature senescence in vascular smooth muscle cells

    SciTech Connect

    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

    2011-03-25

    Research highlights: {yields} Activation of PPAR{delta} by GW501516 significantly inhibited Ang II-induced premature senescence in hVSMCs. {yields} Agonist-activated PPAR{delta} suppressed generation of Ang II-triggered ROS with a concomitant reduction in DNA damage. {yields} GW501516 up-regulated expression of antioxidant genes, such as GPx1, Trx1, Mn-SOD and HO-1. {yields} 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) {delta} as a potential target for therapeutic intervention in Ang II-induced senescence in human vascular smooth muscle cells (hVSMCs). Activation of PPAR{delta} by GW501516, a specific agonist of PPAR{delta}, significantly inhibited the Ang II-induced premature senescence of hVSMCs. Agonist-activated PPAR{delta} 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 PPAR{delta}-mediated inhibition of premature senescence through sequestration of ROS in hVSMCs treated with Ang II.

  6. Resveratrol Attenuates Copper-Induced Senescence by Improving Cellular Proteostasis

    PubMed Central

    2017-01-01

    Copper sulfate-induced premature senescence (CuSO4-SIPS) consistently mimetized molecular mechanisms of replicative senescence, particularly at the endoplasmic reticulum proteostasis level. In fact, disruption of protein homeostasis has been associated to age-related cell/tissue dysfunction and human disorders susceptibility. Resveratrol is a polyphenolic compound with proved antiaging properties under particular conditions. In this setting, we aimed to evaluate resveratrol ability to attenuate cellular senescence induction and to unravel related molecular mechanisms. Using CuSO4-SIPS WI-38 fibroblasts, resveratrol is shown to attenuate typical senescence alterations on cell morphology, senescence-associated beta-galactosidase activity, and cell proliferation. The mechanisms implicated in this antisenescence effect seem to be independent of senescence-associated genes and proteins regulation but are reliant on cellular proteostasis improvement. In fact, resveratrol supplementation restores copper-induced increased protein content, attenuates BiP level, and reduces carbonylated and polyubiquitinated proteins by autophagy induction. Our data provide compelling evidence for the beneficial effects of resveratrol by mitigating CuSO4-SIPS stressful consequences by the modulation of protein quality control systems. These findings highlight the importance of a balanced cellular proteostasis and add further knowledge on molecular mechanisms mediating resveratrol antisenescence effects. Moreover, they contribute to identifying specific molecular targets whose modulation will prevent age-associated cell dysfunction and improve human healthspan. PMID:28280523

  7. Involvement of Abscisic Acid in PSII Photodamage and D1 Protein Turnover for Light-Induced Premature Senescence of Rice Flag Leaves

    PubMed Central

    Wang, Fubiao; Liu, Jianchao; Chen, Minxue; Zhou, Lujian; Li, Zhaowei; Zhao, Qian; Pan, Gang; Zaidi, Syed-Hassan-Raza; Cheng, Fangmin

    2016-01-01

    D1 protein in the PSII reaction center is the major target of photodamage, and it exhibits the highest turnover rate among all the thylakoid proteins. In this paper, rice psf (premature senescence of flag leaves) mutant and its wild type were used to investigate the genotype-dependent alteration in PSII photo-damage and D1 protein turnover during leaf senescence and its relation to ABA accumulation in senescent leaves. The symptom and extent of leaf senescence of the psf mutant appeared to be sunlight-dependent under natural field condition. The psf also displayed significantly higher levels of ABA accumulation in senescent leaves than the wild type. However, the premature senescence lesion of psf leaves could be alleviated by shaded treatment, concomitantly with the strikingly suppressed ABA level in the shaded areas of flag leaves. The change in ABA concentration contributed to the regulation of shade-delayed leaf senescence. The participation of ABA in the timing of senescence initiation and in the subsequent rate of leaf senescence was closely associated with PSII photodamage and D1 protein turnover during leaf senescence, in which the transcriptional expression of several key genes (psbA, psbB, psbC and OsFtsH2) involved in D1 protein biosynthesis and PSII repair cycle was seriously suppressed by the significantly increased ABA level. This response resulted in the low rate of D1 protein synthesis and impaired repair recovery in the presence of ABA. The psf showed evidently decreased D1 protein amount in the senescent leaves. Both the inhibition of de novo synthesized D1 protein and the slow rate of proteolytic removal for the photodamaged D1 protein was among the most crucial steps for the linkage between light-dependent leaf senescence and the varying ABA concentration in psf mutant leaves. OsFtsH2 transcriptional expression possibly played an important role in the regulation of D1 protein turnover and PSII repair cycle in relation to ABA mediated leaf

  8. 17beta-estradiol Attenuates TNF-α-Induced Premature Senescence of Nucleus Pulposus Cells through Regulating the ROS/NF-κB Pathway

    PubMed Central

    Li, Pei; Gan, Yibo; Xu, Yuan; Wang, Liyuan; Ouyang, Bin; Zhang, Chengmin; Luo, Lei; Zhao, Chen; Zhou, Qiang

    2017-01-01

    Background: Accelerated cellular senescence within the nucleus pulposus (NP) region is a common feature of disc degeneration. Our previous work indicated that TNF-α promoted NP cell senescence. Although the intervertebral disc has been reported to be an estrogen-sensitive tissue, it is unclear whether estrogen can inhibit premature senescence of NP cells. Objective: To investigate whether 17beta-estradiol (E2) can attenuate TNF-α-induced premature senescence of NP cells and the potential mechanism behind this regulatory process. Methods: Isolated NP cells and intact intervertebral discs from healthy rats were cultured with or without TNF-α, E2 or their combination. The pan estrogen receptor (ER) antagonist ICI 182780 was used to investigate the role of ER. Direct and indirect indicators including cell proliferation, SA-β-Gal activity, telomerase activity, cell cycle, and the expression of matrix macromolecules (aggrecan and collagen II) and senescence markers (p16 and p53) were used to evaluate the premature senescence of NP cells. Additionally, intracellular reactive oxygen species (ROS) and NF-κB/p65 activity were also detected in the NP cell cultures. Results: In the NP cell cultures, E2 significantly increased cell proliferation potency, telomerase activity and the expression of matrix macromolecules but attenuated SA-β-Gal activity, senescence marker (p53 and p16) expression and G1 cycle arrest in TNF-α-treated NP cells. Furthermore, E2 inhibited ROS generation and phospho-NF-κB/p65 expression in the TNF-α-treated NP cells. However, the ER antagonist ICI 182780 abolished the effects of E2 on TNF-α-treated NP cells. In the disc organ cultures, E2 also significantly increased matrix synthesis, whereas it decreased senescence marker (p53 and p16) expression, which could be abolished by the ER antagonist ICI 182780. Conclusion: The interaction between E2 and ER can attenuate TNF-α-induced premature senescence of rat NP cells through interfering with the

  9. NaDC3 Induces Premature Cellular Senescence by Promoting Transport of Krebs Cycle Intermediates, Increasing NADH, and Exacerbating Oxidative Damage.

    PubMed

    Ma, Yuxiang; Bai, Xue-Yuan; Du, Xuan; Fu, Bo; Chen, Xiangmei

    2016-01-01

    High-affinity sodium-dependent dicarboxylate cotransporter 3 (NaDC3) is a key metabolism-regulating membrane protein responsible for transport of Krebs cycle intermediates. NaDC3 is upregulated as organs age, but knowledge regarding the underlying mechanisms by which NaDC3 modulates mammalian aging is limited. In this study, we showed that NaDC3 overexpression accelerated cellular senescence in young human diploid cells (MRC-5 and WI-38) and primary renal tubular cells, leading to cell cycle arrest in G1 phase and increased expression of senescent biomarkers, senescence-associated β-galactosidase and p16. Intracellular levels of reactive oxygen species, 8-hydroxy-2'-deoxyguanosine, malondialdehyde, and carbonyl were significantly enhanced, and activities of respiratory complexes I and III and ATP level were significantly decreased in NaDC3-infected cells. Stressful premature senescent phenotypes induced by NaDC3 were markedly ameliorated via treatment with the antioxidants Tiron and Tempol. High expression of NaDC3 caused a prominent increase in intracellular levels of Krebs cycle intermediates and NADH. Exogenous NADH and NAD(+) may aggravate and attenuate the aging phenotypes induced by NaDC3, respectively. These results suggest that NaDC3 can induce premature cellular senescence by promoting the transport of Krebs cycle intermediates, increasing generation of NADH and reactive oxygen species and leading to oxidative damage. Our results clarify the aging signaling pathway regulated by NaDC3.

  10. Real space flight travel is associated with ultrastructural changes, cytoskeletal disruption and premature senescence of HUVEC.

    PubMed

    Kapitonova, M Y; Muid, S; Froemming, G R A; Yusoff, W N W; Othman, S; Ali, A M; Nawawi, H M

    2012-12-01

    Microgravity, hypergravity, vibration, ionizing radiation and temperature fluctuations are major factors of outer space flight affecting human organs and tissues. There are several reports on the effect of space flight on different human cell types of mesenchymal origin while information regarding changes to vascular endothelial cells is scarce. Ultrastructural and cytophysiological features of macrovascular endothelial cells in outer space flight and their persistence during subsequent culturing were demonstrated in the present investigation. At the end of the space flight, endothelial cells displayed profound changes indicating cytoskeletal lesions and increased cell membrane permeability. Readapted cells of subsequent passages exhibited persisting cytoskeletal changes, decreased metabolism and cell growth indicating cellular senescence.

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

    SciTech Connect

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

    2013-01-04

    Highlights: Black-Right-Pointing-Pointer A-T cells were not hypersensitive to low levels of DNA DSBs. Black-Right-Pointing-Pointer A-T cells have enhanced Akt but defect in activation of p53 and apoptotic proteins. Black-Right-Pointing-Pointer A-T cells underwent premature senescence after DNA damage accumulated. Black-Right-Pointing-Pointer 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-{beta}-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.

  12. Haploinsufficiency for BRCA1 leads to cell-type-specific genomic instability and premature senescence.

    PubMed

    Sedic, Maja; Skibinski, Adam; Brown, Nelson; Gallardo, Mercedes; Mulligan, Peter; Martinez, Paula; Keller, Patricia J; Glover, Eugene; Richardson, Andrea L; Cowan, Janet; Toland, Amanda E; Ravichandran, Krithika; Riethman, Harold; Naber, Stephen P; Näär, Anders M; Blasco, Maria A; Hinds, Philip W; Kuperwasser, Charlotte

    2015-06-24

    Although BRCA1 function is essential for maintaining genomic integrity in all cell types, it is unclear why increased risk of cancer in individuals harbouring deleterious mutations in BRCA1 is restricted to only a select few tissues. Here we show that human mammary epithelial cells (HMECs) from BRCA1-mutation carriers (BRCA1(mut/+)) exhibit increased genomic instability and rapid telomere erosion in the absence of tumour-suppressor loss. Furthermore, we uncover a novel form of haploinsufficiency-induced senescence (HIS) specific to epithelial cells, which is triggered by pRb pathway activation rather than p53 induction. HIS and telomere erosion in HMECs correlate with misregulation of SIRT1 leading to increased levels of acetylated pRb as well as acetylated H4K16 both globally and at telomeric regions. These results identify a novel form of cellular senescence and provide a potential molecular basis for the rapid cell- and tissue- specific predisposition of breast cancer development associated with BRCA1 haploinsufficiency.

  13. Diverse gene sequences are overexpressed in werner syndrome fibroblasts undergoing premature replicative senescence.

    PubMed

    Murano, S; Thweatt, R; Shmookler Reis, R J; Jones, R A; Moerman, E J; Goldstein, S

    1991-08-01

    Genes that play a role in the senescent arrest of cellular replication are likely to be overexpressed in human diploid fibroblasts (HDF) derived from subjects with Werner syndrome (WS) because these cells have a severely curtailed replicative life span. To identify some of these genes, a cDNA library was constructed from WS HDF after they had been serum depleted and repleted (5 days in medium containing 1% serum followed by 24 h in medium containing 20% serum). Differential screening of 7,500 colonies revealed 102 clones that hybridized preferentially with [32P]cDNA derived from RNA of WS cells compared with [32P]cDNA derived from normal HDF. Cross-hybridization and partial DNA sequence determination identified 18 independent gene sequences, 9 of them known and 9 unknown. The known genes included alpha 1(I) procollagen, alpha 2(I) procollagen, fibronectin, ferritin heavy chain, insulinlike growth factor-binding protein-3 (IGFBP-3), osteonectin, human tissue plasminogen activator inhibitor type I, thrombospondin, and alpha B-crystallin. The nine unknown clones included two novel gene sequences and seven additional sequences that contained both novel segments and the Alu class of repetitive short interspersed nuclear elements; five of these seven Alu+ clones also contained the long interpersed nuclear element I (KpnI) family of repetitive elements. Northern (RNA) analysis, using the 18 sequences as probes, showed higher levels of these mRNAs in WS HDF than in normal HDF. Five selected mRNAs studied in greater detail [alpha 1(I) procollagen, fibronectin, insulinlike growth factor-binding protein-3, WS3-10, and WS9-14] showed higher mRNA levels in both WS and late-passage normal HDF than in early-passage normal HDF at various intervals following serum depletion/repletion and after subculture and growth from sparse to high-density confluent arrest. These results indicate that senescence of both WS and normal HDF is accompanied by overexpression of similar sets of

  14. Maternal characteristics versus egg size and energy density: do stocked lake trout in Lake Ontario experience premature reproductive senescence?

    USGS Publications Warehouse

    Lantry, B.F.; O'Gorman, R.; Machut, L.S.

    2008-01-01

    Observations from September 1994 and 1997 collections of hatchery-origin, mature female lake trout (Salvelinus namaycush) from Lake Ontario indicated that egg mass decreased with age, fueling the notion that stocked fish experienced premature reproductive senescence. Supplemental collections during September 2002 and November 2002-2004 were combined with the 1994 and 1997 samples to examine whether sample date or maternal age, body mass, condition (K), egg count, or strain were related to egg mass or energy content (percentage dry mass [%DM]). Body mass was correlated with egg mass for age ≥ 8 lake trout sampled in September, and egg count was correlated with egg mass for September age-6 lake trout only. Within each month, egg mass was not related to K or egg %DM, however, egg %DM was 1.52% greater (P ≤ 0.0247) in November than in September which is equivalent to a 110 cal/g difference. Samples were grouped for the three most abundant strains (Seneca, Superior, and Ontario) after finding no strain or year effects from our 1994 and 1997 samples and based on life history data from the literature and our assessment sampling. Further analysis indicated that September egg masses were greater for fish ages ≤ 6 than for fish ages ≥ 8. The age effect disappeared in November when mean egg mass across all ages (0.078 g) was greater than September means (P < 0.0005) for ages -5 (0.054 g), -6 (0.057 g) and ≥ 8 (0.041 g). Our results indicate that the decrease in egg mass with female age in September was not due to senescence, but to oogenesis being closer to completion in young age-5 and -6 fish than in older individuals.

  15. Mapping of post-flowering drought resistance traits in grain sorghum: association between QTLs influencing premature senescence and maturity.

    PubMed

    Crasta, O R; Xu, W W; Rosenow, D T; Mullet, J; Nguyen, H T

    1999-10-01

    The identification of genetic factors underlying the complex responses of plants to drought stress provides a solid basis for improving drought resistance. The staygreen character in sorghum (Sorghum bicolor L. Moench) is a post-flowering drought resistance trait, which makes plants resistant to premature senescence under drought stress during the grainfilling stage. The objective of this study was to identify quantitative trait loci (QTLs) that control premature senescence and maturity traits, and to investigate their association under post-flowering drought stress in grain sorghum. A genetic linkage map was developed using a set of recombinant inbred lines (RILs) obtained from the cross B35 x Tx430, which were scored for 142 restriction fragment length polymorphism (RFLP) markers. The RILs and their parental lines were evaluated for post-flowering drought resistance and maturity in four environments. Simple interval mapping identified seven stay-green QTLs and two maturity QTLs. Three major stay-green QTLs (SGA, SGD and SGG) contributed to 42% of the phenotypic variability (LOD 9.0) and four minor QTLs (SGB, SGI. 1, SGI.2, and SGJ) significantly contributed to an additional 25% of the phenotypic variability in stay-green ratings. One maturity QTL (DFB) alone contributed to 40% of the phenotypic variability (LOD 10.0), while the second QTL (DFG) significantly contributed to an additional 17% of the phenotypic variability (LOD 4.9). Composite interval mapping confirmed the above results with an additional analysis of the QTL x Environment interaction. With heritability estimates of 0.72 for stay-green and 0.90 for maturity, the identified QTLs explained about 90% and 63% of genetic variability for stay-green and maturity traits, respectively. Although stay-green ratings were significantly correlated (r = 0.22, P< or =0.05) with maturity, six of the seven stay-green QTLs were independent of the QTLs influencing maturity. Similarly, one maturity QTL (DFB) was

  16. Total body irradiation causes long-term mouse BM injury via induction of HSC premature senescence in an Ink4a- and Arf-independent manner.

    PubMed

    Shao, Lijian; Feng, Wei; Li, Hongliang; Gardner, David; Luo, Yi; Wang, Yong; Liu, Lingbo; Meng, Aimin; Sharpless, Norman E; Zhou, Daohong

    2014-05-15

    Exposure to total body irradiation (TBI) induces not only acute hematopoietic radiation syndrome but also long-term or residual bone marrow (BM) injury. This residual BM injury is mainly attributed to permanent damage to hematopoietic stem cells (HSCs), including impaired self-renewal, decreased long-term repopulating capacity, and myeloid skewing. These HSC defects were associated with significant increases in production of reactive oxygen species (ROS), expression of p16(Ink4a) (p16) and Arf mRNA, and senescence-associated β-galacotosidase (SA-β-gal) activity, but not with telomere shortening or increased apoptosis, suggesting that TBI induces residual BM injury via induction of HSC premature senescence. This suggestion is supported by the finding that SA-β-gal(+) HSC-enriched LSK cells showed more pronounced defects in clonogenic activity in vitro and long-term engraftment after transplantation than SA-β-gal(-) LSK cells isolated from irradiated mice. However, genetic deletion of p16 and/or Arf had no effect on TBI-induced residual BM suppression and HSC senescence, because HSCs from irradiated p16 and/or Arf knockout (KO) mice exhibited changes similar to those seen in HSCs from wild-type mice after exposure to TBI. These findings provide important new insights into the mechanism by which TBI causes long-term BM suppression (eg, via induction of premature senescence of HSCs in a p16-Arf-independent manner).

  17. Suppression of autophagy dysregulates the antioxidant response and causes premature senescence of melanocytes.

    PubMed

    Zhang, Cheng-Feng; Gruber, Florian; Ni, Chunya; Mildner, Michael; Koenig, Ulrich; Karner, Susanne; Barresi, Caterina; Rossiter, Heidemarie; Narzt, Marie-Sophie; Nagelreiter, Ionela M; Larue, Lionel; Tobin, Desmond J; Eckhart, Leopold; Tschachler, Erwin

    2015-05-01

    Autophagy is the central cellular mechanism for delivering organelles and cytoplasm to lysosomes for degradation and recycling of their molecular components. To determine the contribution of autophagy to melanocyte (MC) biology, we inactivated the essential autophagy gene Atg7 specifically in MCs using the Cre-loxP system. This gene deletion efficiently suppressed a key step in autophagy, lipidation of microtubule-associated protein 1 light chain 3 beta (LC3), in MCs and induced slight hypopigmentation of the epidermis in mice. The melanin content of hair was decreased by 10-15% in mice with autophagy-deficient MC as compared with control animals. When cultured in vitro, MCs from mutant and control mice produced equal amounts of melanin per cell. However, Atg7-deficient MCs entered into premature growth arrest and accumulated reactive oxygen species (ROS) damage, ubiquitinated proteins, and the multi-functional adapter protein SQSTM1/p62. Moreover, nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent expression of NAD(P)H dehydrogenase, quinone 1, and glutathione S-transferase Mu 1 was increased, indicating a contribution of autophagy to redox homeostasis in MCs. In summary, the results of our study suggest that Atg7-dependent autophagy is dispensable for melanogenesis but necessary for achieving the full proliferative capacity of MCs.

  18. Mapping QTL for drought stress-induced premature senescence and maturity in cowpea [Vigna unguiculata (L.) Walp.].

    PubMed

    Muchero, Wellington; Ehlers, Jeffrey D; Close, Timothy J; Roberts, Philip A

    2009-03-01

    Cowpea is an important crop for subsistence farmers in arid regions of Africa, Asia, and South America. Efforts to develop cultivars with improved productivity under drought conditions are constrained by lack of molecular markers associated with drought tolerance. Here, we report the mapping of 12 quantitative trait loci (QTL) associated with seedling drought tolerance and maturity in a cowpea recombinant inbred (RIL) population. One hundred and twenty-seven F(8) RILs developed from a cross between IT93K503-1 and CB46 were screened with 62 EcoR1 and Mse1 primer combinations to generate 306 amplified fragment length polymorphisms for use in genetic linkage mapping. The same population was phenotyped for maintenance of stem greenness (stg) and recovery dry weight (rdw) after drought stress in six greenhouse experiments. In field experiments conducted over 3 years, visual ratings and dry weights were used to phenotype drought stress-induced premature senescence in the RIL population. Kruskall-Wallis and multiple-QTL model mapping analysis were used to identify QTL associated with drought response phenotypes. Observed QTL were highly reproducible between stg and rdw under greenhouse conditions. Field studies confirmed all ten drought-response QTL observed under greenhouse conditions. Regions harboring drought-related QTL were observed on linkage groups 1, 2, 3, 5, 6, 7, 9, and 10 accounting for between 4.7 and 24.2% of the phenotypic variance (R(2)). Further, two QTL for maturity (R(2) = 14.4-28.9% and R(2) = 11.7-25.2%) mapped on linkage groups 7 and 8 separately from drought-related QTL. These results provide a platform for identification of genetic determinants of seedling drought tolerance in cowpea.

  19. Premature cardiac senescence in DahlS.Z-Lepr(fa)/Lepr(fa) rats as a new animal model of metabolic syndrome.

    PubMed

    Takahashi, Keiji; Takatsu, Miwa; Hattori, Takuya; Murase, Tamayo; Ohura, Sae; Takeshita, Yuuri; Watanabe, Shogo; Murohara, Toyoaki; Nagata, Kohzo

    2014-02-01

    Aging is accelerated by metabolic and cardiovascular diseases, and the risk of these diseases increases with age. Obesity is an important risk factor for many age-related diseases and is linked to reduced telomere length in white blood cells. We investigated whether cardiac senescence might be enhanced in DahlS.Z-Lepr(fa)/Lepr(fa) (DS/obese) rats, which we recently established as a new animal model of metabolic syndrome. The heart of DS/obese rats was compared with that of homozygous lean littermates (DahlS.Z-Lepr+/Lepr+, or DS/lean, rats). DS/obese rats manifested hypertension as well as left ventricular hypertrophy, fibrosis, and diastolic dysfunction at 18 weeks of age. Myocardial oxidative stress and inflammation were increased in DS/obese rats compared with DS/lean rats. Telomere length in myocardial cells did not differ between the two rat strains, whereas telomerase activity and expression of the telomerase reverse transcriptase gene were increased in DS/obese rats. Expression of the senescence-associated genes for checkpoint kinase 2 (Chk2), p53, and p21 as well as that of genes related to the renin-angiotensin-aldosterone system were also up-regulated in the DS/obese rat heart. Our results indicate that DS/obese rats undergo premature cardiac senescence as well as cardiac remodeling in association with the development of diastolic dysfunction in these animals.

  20. Reduction of exportin 6 activity leads to actin accumulation via failure of RanGTP restoration and NTF2 sequestration in the nuclei of senescent cells.

    PubMed

    Park, Su Hyun; Park, Tae Jun; Lim, In Kyoung

    2011-04-15

    We have previously reported that G-actin accumulation in nuclei is a universal phenomenon of cellular senescence. By employing primary culture of human diploid fibroblast (HDF) and stress-induced premature senescence (SIPS), we explored whether the failure of actin export to cytoplasm is responsible for actin accumulation in nuclei of senescent cells. Expression of exportin 6 (Exp6) and small G-protein, Ran, was significantly reduced in the replicative senescence, but not yet in SIPS, whereas nuclear import of actin by cofilin was already increased in SIPS. After treatment of young HDF cells with H(2)O(2), rapid reduction of nuclear RanGTP was observed along with cytoplasmic increase of RanGDP. Furthermore, significantly reduced interaction of Exp6 with RanGTP was found by GST-Exp6 pull-down analysis. Failure of RanGTP restoration was accompanied with inhibition of ATP synthesis and NTF2 sequestration in the nuclei along with accordant change of senescence morphology. Indeed, knockdown of Exp6 expression significantly increased actin molecule in the nuclei of young HDF cells. Therefore, actin accumulation in nuclei of senescent cells is most likely due to the failure of RanGTP restoration with ATP deficiency and NTF2 accumulation in nuclei, which result in the decrease of actin export via Exp6 inactivation, in addition to actin import by cofilin activation.

  1. Reduction of exportin 6 activity leads to actin accumulation via failure of RanGTP restoration and NTF2 sequestration in the nuclei of senescent cells

    SciTech Connect

    Park, Su Hyun; Park, Tae Jun; Lim, In Kyoung

    2011-04-15

    We have previously reported that G-actin accumulation in nuclei is a universal phenomenon of cellular senescence. By employing primary culture of human diploid fibroblast (HDF) and stress-induced premature senescence (SIPS), we explored whether the failure of actin export to cytoplasm is responsible for actin accumulation in nuclei of senescent cells. Expression of exportin 6 (Exp6) and small G-protein, Ran, was significantly reduced in the replicative senescence, but not yet in SIPS, whereas nuclear import of actin by cofilin was already increased in SIPS. After treatment of young HDF cells with H{sub 2}O{sub 2}, rapid reduction of nuclear RanGTP was observed along with cytoplasmic increase of RanGDP. Furthermore, significantly reduced interaction of Exp6 with RanGTP was found by GST-Exp6 pull-down analysis. Failure of RanGTP restoration was accompanied with inhibition of ATP synthesis and NTF2 sequestration in the nuclei along with accordant change of senescence morphology. Indeed, knockdown of Exp6 expression significantly increased actin molecule in the nuclei of young HDF cells. Therefore, actin accumulation in nuclei of senescent cells is most likely due to the failure of RanGTP restoration with ATP deficiency and NTF2 accumulation in nuclei, which result in the decrease of actin export via Exp6 inactivation, in addition to actin import by cofilin activation.

  2. Ionizing radiation-mediated premature senescence and paracrine interactions with cancer cells enhance the expression of syndecan 1 in human breast stromal fibroblasts: the role of TGF-β

    PubMed Central

    Liakou, Eleni; Mavrogonatou, Eleni; Pratsinis, Harris; Rizou, Sophia; Evangelou, Konstantinos; Panagiotou, Petros N.; Karamanos, Nikos K.; Gorgoulis, Vassilis G.; Kletsas, Dimitris

    2016-01-01

    The cell surface proteoglycan syndecan 1 (SDC1) is overexpressed in the malignant breast stromal fibroblasts, creating a favorable milieu for tumor cell growth. In the present study, we found that ionizing radiation, a well-established treatment in human breast cancer, provokes premature senescence of human breast stromal fibroblasts in vitro, as well as in the breast tissue in vivo. These senescent cells were found to overexpress SDC1 both in vitro and in vivo. By using a series of specific inhibitors and siRNA approaches, we showed that this SDC1 overexpression in senescent cells is the result of an autocrine action of Transforming Growth Factor-β (TGF-β) through the Smad pathway and the transcription factor Sp1, while the classical senescence pathways of p53 or p38 MAPK - NF-kB are not involved. In addition, the highly invasive human breast cancer cells MDA-MB-231 (in contrast to the low-invasive MCF-7) can also enhance SDC1 expression, both in early-passage and senescent fibroblasts via a paracrine action of TGF-β. The above suggest that radiation-mediated premature senescence and invasive tumor cells, alone or in combination, enhance SDC1 expression in breast stromal fibroblasts, a poor prognostic factor for cancer growth, and that TGF-β plays a crucial role in this process. PMID:27434331

  3. Alterations in microRNA Expression in Stress-induced Cellular Senescence

    PubMed Central

    Li, Guorong; Luna, Coralia; Qiu, Jianming; Epstein, David L.; Gonzalez, Pedro

    2009-01-01

    Summary We investigated miRNA expression changes associated with stress-induced premature senescence (SIPS) in primary cultures of human diploid fibroblasts (HDF) and human trabecular meshwork (HTM) cells. Twenty-five miRNAs were identified by miRNA microarray analysis and their changes in expression were validated by TaqMan realtime RT-PCR in three independent cell lines of HTM and HDF. SIPS in both HTM and HDF cell types was associated with significant down-regulation of four members of the miR-15 family and five miRNAs of the miR-106b family located in the oncogenic clusters miR-17–92, miR-106a-363, and miR-106b-25. SIPS was also associated with up-regulation of two miRNAs (182 and 183) from the miR-183-96-182 cluster. Transfection with miR-106a agomir inhibited the up-regulation of p21CDKN1A associated with SIPS while transfection with miR-106a antagomir led to increased p21CDKN1A expression in senescent cells. In addition, we identified retinoic acid receptor gamma (RARG) as a target of miR-182 and showed that this protein was down-regulated during SIPS in HDF and HTM cells. These results suggest that changes in miRNA expression might contribute to phenotypic alterations of senescent cells by modulating the expression of key regulatory proteins such as p21CDKN1A as well as by targeting genes that are down-regulated in senescent cells such as RARG. PMID:19782699

  4. SCID Dogs: Similar Transplant Potential but Distinct Intra-Uterine Growth Defects and Premature Replicative Senescence Compared with SCID Mice1

    PubMed Central

    Meek, Katheryn; Jutkowitz, Ari; Allen, Lisa; Glover, Jillian; Convery, Erin; Massa, Alisha; Mullaney, Tom; Stanley, Bryden; Rosenstein, Diana; Bailey, Susan M.; Johnson, Cheri; Georges, George

    2014-01-01

    We have previously described DNA-dependent protein kinase (DNA-PKcs) mutations in horses and dogs that result in deficits in V(D)J recombination, DNA repair, and SCID. In this paper, we document substantial developmental growth defects in DNA-PKcs-deficient dogs that are not apparent in SCID mice. Fibroblast cell strains derived from either fetal or adult SCID dogs proliferate poorly in culture and undergo premature replicative senescence, somewhat reminiscent of cells derived from Ku-deficient mice. A limited number of animals have been immune reconstituted (by bone marrow transplantation) so that they can be maintained in a normal environment for long periods. Several of these animals have developed conditions associated with premature ageing at 2–3 years of age, roughly 20% of their expected lifespan. These conditions include intestinal malabsorption and primary neural cell neoplasia. These results suggest that DNA-PKcs deficiency is not tolerated equally in all species, perhaps providing insight into why DNA-PKcs deficiency has not been observed in humans. Finally, this study demonstrates the feasibility of maintaining SCID dogs for extended periods of time and documents their utility for bone marrow transplantation studies and as hosts for the propagation of xenografts. In sum, SCID dogs may present researchers with new possibilities for the development of animal models of human disease. PMID:19635917

  5. The effect of 648 nm diode laser irradiation on second messengers in senescent human keratinocytes

    NASA Astrophysics Data System (ADS)

    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

  6. Obesity-induced hypogonadism in the male: premature reproductive neuroendocrine senescence and contribution of Kiss1-mediated mechanisms.

    PubMed

    Sánchez-Garrido, Miguel Angel; Ruiz-Pino, Francisco; Manfredi-Lozano, Maria; Leon, Silvia; Garcia-Galiano, David; Castaño, Justo P; Luque, Raul M; Romero-Ruiz, Antonio; Castellano, Juan M; Diéguez, Carlos; Pinilla, Leonor; Tena-Sempere, Manuel

    2014-03-01

    Reproduction is sensitive to insufficient body energy reserves, especially in females. Metabolic regulation of the male reproductive axis is less obvious, and the impact of conditions of persistent energy excess has received moderate attention. Yet, the escalating prevalence of obesity and the clinical evidence of its deleterious effects on male fertility have raised considerable concerns. We report here phenotypic and mechanistic studies of the reproductive impact of postnatal nutritional manipulations (mainly overnutrition) coupled to a high-fat diet (HFD) after weaning. Metabolic and hormonal analyses in young (4 months old) and middle-aged (10 months old) animals revealed that HFD caused profound metabolic perturbations, including glucose intolerance, which were worsened by precedent postnatal overfeeding; these were detectable already in young males but aggravated in 10-month-old rats. Impairment of reproductive parameters took place progressively, and HFD alone was sufficient to explain most of these alterations, regardless of postnatal under- or overnutrition. In young males, testosterone (T) levels and steroidogenic enzyme expression were suppressed by HFD, without compensatory increases of LH levels, which were in fact partially inhibited in heavier males. In addition, obese males displayed suppressed hypothalamic Kiss1 expression despite low T, and HFD inhibited LH responses to kisspeptin. Overweight anticipated some of the neuroendocrine effects of aging, such as the suppression of hypothalamic Kiss1 expression and the decline in serum T and LH levels. Nonetheless, HFD per se caused a detectable worsening of key reproductive indices in middle-aged males, such as basal LH and FSH levels as well as LH responses to kisspeptin. Our study demonstrates that nutritional stress, especially HFD, has a profound deleterious impact on metabolic and gonadotropic function as well as on the Kiss1 system and precipitates neuroendocrine reproductive senescence in the

  7. NOX4 downregulation leads to senescence of human vascular smooth muscle cells

    PubMed Central

    Przybylska, Dorota; Janiszewska, Dorota; Goździk, Aleksandra; Bielak-Zmijewska, Anna; Sunderland, Piotr; Sikora, Ewa; Mosieniak, Grażyna

    2016-01-01

    Senescence is a stress response characterized by an irreversible growth arrest and alterations in certain cell functions. It is believed that both double-strand DNA breaks (DSB) and increased ROS level are the main culprit of senescence. Excessive ROS production is also particularly important in the development of a number of cardiovascular disorders. In this context the involvement of professional ROS-producing enzymes, NADPH oxidases (NOX), was postulated. In contrary to the common knowledge, we have shown that not only increased ROS production but also diminished ROS level could be involved in the induction of senescence. Accordingly, our studies revealed that stress-induced premature senescence (SIPS) of vascular smooth muscle cells (VSMCs) induced by doxorubicin or H2O2, correlates with increased level of DSB and ROS. On the other hand, both SIPS and replicative senescence were accompanied by diminished expression of NOX4. Moreover, inhibition of NOX activity or decrease of NOX4 expression led to permanent growth arrest of VSMCs and secretion of interleukins and VEGF. Interestingly, cells undergoing senescence due to NOX4 depletion neither acquired DSB nor activated DNA damage response. Instead, transient induction of the p27, upregulation of HIF-1alpha, decreased expression of cyclin D1 and hypophosphorylated Rb was observed. Our results showed that lowering the level of ROS-producing enzyme - NOX4 oxidase below physiological level leads to cellular senescence of VSMCs which is correlated with secretion of pro-inflammatory cytokines. Thus the use of specific NOX4 inhibitors for pharmacotherapy of vascular diseases should be carefully considered. PMID:27655718

  8. Markers of cellular senescence. Telomere shortening as a marker of cellular senescence

    PubMed Central

    2016-01-01

    The cellular senescence definition comes to the fact of cells irreversible proliferation disability. Besides the cell cycle arrest, senescent cells go through some morphological, biochemical, and functional changes which are the signs of cellular senescence. The senescent cells (including replicative senescence and stress-induced premature senescence) of all the tissues look alike. They are metabolically active and possess the set of characteristics in vitro and in vivo, which are known as biomarkers of aging and cellular senescence. Among biomarkers of cellular senescence telomere shortening is a rather elegant frequently used biomarker. Validity of telomere shortening as a marker for cellular senescence is based on theoretical and experimental data. PMID:26805432

  9. Markers of cellular senescence. Telomere shortening as a marker of cellular senescence.

    PubMed

    Bernadotte, Alexandra; Mikhelson, Victor M; Spivak, Irina M

    2016-01-01

    The cellular senescence definition comes to the fact of cells irreversible proliferation disability. Besides the cell cycle arrest, senescent cells go through some morphological, biochemical, and functional changes which are the signs of cellular senescence. The senescent cells (including replicative senescence and stress-induced premature senescence) of all the tissues look alike. They are metabolically active and possess the set of characteristics in vitro and in vivo, which are known as biomarkers of aging and cellular senescence. Among biomarkers of cellular senescence telomere shortening is a rather elegant frequently used biomarker. Validity of telomere shortening as a marker for cellular senescence is based on theoretical and experimental data.

  10. The matrikine N-acetylated proline-glycine-proline induces premature senescence of nucleus pulposus cells via CXCR1-dependent ROS accumulation and DNA damage and reinforces the destructive effect of these cells on homeostasis of intervertebral discs.

    PubMed

    Feng, Chencheng; Zhang, Yang; Yang, Minghui; Lan, Minghong; Liu, Huan; Wang, Jian; Zhou, Yue; Huang, Bo

    2017-01-01

    Intervertebral disc (IVD) cell senescence is a recognized mechanism of intervertebral disc degeneration (IDD). Elucidating the molecular mechanisms underlying disc cell senescence will contribute to understanding the pathogenesis of IDD. We previously reported that N-acetylated proline-glycine-proline (N-Ac-PGP), a matrikine, is involved in the process of IDD. However, its roles in IDD are not well understood. Here, using rat nucleus pulposus (NP) cells, we found that N-Ac-PGP induced premature senescence of NP cells by binding to CXCR1. N-Ac-PGP induced DNA damage and reactive oxygen species accumulation in NP cells, which resulted in activation of the p53-p21-Rb and p16-Rb pathways. Moreover, the RT(2) profiler PCR array showed that N-Ac-PGP down-regulates the expression of antioxidant genes in NP cells, suggesting a decline in the antioxidants of NP cells. On the other hand, N-Ac-PGP up-regulated the expression of matrix catabolic genes and inflammatory genes in NP cells. Concomitantly, N-Ac-PGP reinforced the destructive effects of senescent NP cells on the homeostasis of the IVDs in vivo. Our study suggests that N-Ac-PGP plays critical roles in the pathogenesis of IDD through the induction of premature senescence of disc cells and via the activation of catabolic and inflammatory cascades in disc cells. N-Ac-PGP also deteriorates the redox environment of disc cells. Hence, N-Ac-PGP is a new potential therapeutic target for IDD.

  11. Carcinogen-specific mutational and epigenetic alterations in INK4A, INK4B and p53 tumour-suppressor genes drive induced senescence bypass in normal diploid mammalian cells.

    PubMed

    Yasaei, H; Gilham, E; Pickles, J C; Roberts, T P; O'Donovan, M; Newbold, R F

    2013-01-10

    Immortalization (senescence bypass) is a critical rate-limiting step in the malignant transformation of mammalian somatic cells. Human cells must breach at least two distinct senescence barriers to permit unfettered clonal evolution during cancer development: (1) stress- or oncogene-induced premature senescence (SIPS/OIS), mediated via the p16-Rb and/or ARF-p53-p21 tumour-suppressive pathways, and (2) replicative senescence triggered by telomere shortening. In contrast, because their telomerase is constitutively active, cells from small rodents possess only the SIPS/OIS barrier, and are therefore useful for studying SIPS/OIS bypass in isolation. Dermal fibroblasts from the Syrian hamster (SHD cells) are exceptionally resistant to spontaneous SIPS bypass, but it can be readily induced following exposure to a wide range of chemical and physical carcinogens. Here we show that a spectrum of carcinogen-specific mutational and epigenetic alterations involving the INK4A (p16), p53 and INK4B (p15) genes are associated with induced SIPS bypass. With ionizing radiation, immortalization is invariably accompanied by efficient biallelic deletion of the complete INK4/CDKN2 locus. In comparison, SHD cells immortalized by the powerful polycyclic hydrocarbon carcinogen benzo(a)pyrene display transversion point mutations in the DNA-binding domain of p53 coupled with INK4 alterations such as loss of expression of p15. Epimutational silencing of p16 is the primary event associated with immortalization by nickel, a human non-genotoxic carcinogen. As SIPS/OIS bypass is a prerequisite for the immortalization of normal diploid human epithelial cells, our results with the SHD model will provide a basis for delineating combinations of key molecular changes underpinning this important event in human carcinogenesis.

  12. Streamlining the SIP Process

    EPA Pesticide Factsheets

    EPA collaborated with the The National Association of Clean Air Agencies (NACAA/ECOs) SIP Reform Work Group to minimize federal and state burden in developing SIPs, but ensure the plans effectiveness in complying with the Clean Air Act.

  13. Cooperative role between p21cip1/waf1 and p27kip1 in premature senescence in glandular proliferative lesions in mice.

    PubMed

    García-Fernández, R A; García-Palencia, P; Suarez, C; Sánchez, M A; Gil-Gómez, G; Sánchez, B; Rollán, E; Martín-Caballero, J; Flores, J M

    2014-03-01

    Cellular senescence has been considered a novel target for cancer therapy. It has also been pointed out that p21(cip1/waf1) and p27(kip1) cyclin-dependent kinase inhibitors (CKIs) play a role in cellular senescence in some tumor types. Therefore, in order to address the possibility of a cooperative role between p21 and p27 proteins in senescence in vivo we analyzed cellular senescence in spontaneous glandular proliferative lesions (adrenal, thyroid and pituitary glands) in a double-KO mice model, using γH2AX, p53, p16, PTEN and Ki67 as senescence markers. The results obtained showed that p21p27 double-null mice had the lowest number of γH2AX positive cells in glandular hyperplasias and benign tumors. Also, in this group, Ki67 proliferation index correlated with a lower immunohistochemical expression of γH2AX and p53. The expression of p16 and PTEN do not seem to cause synergism of senescence in the benign lesions analyzed in p21p27 double-KO mice. These observations suggest an intrinsic cooperation between p21 and p27 CKIs in the activation of stress-induced cellular senescence and tumor progression in vivo, which would be a physiological mechanism to prevent tumor cell proliferation.

  14. Instant Messaging by SIP

    NASA Astrophysics Data System (ADS)

    Muhi, Daniel; Dulai, Tibor; Jaskó, Szilárd

    2008-11-01

    SIP is a general-purpose application layer protocol which is able to establish sessions between two or more parties. These sessions are mainly telephone calls and multimedia conferences. However it can be used for other purposes like instant messaging and presence service. SIP has a very important role in mobile communication as more and more communicating applications are going mobile. In this paper we would like to show how SIP can be used for instant messaging purposes.

  15. Senescence Meets Dedifferentiation

    PubMed Central

    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

  16. A steroid like phytochemical Antcin M is an anti-aging reagent that eliminates hyperglycemia-accelerated premature senescence in dermal fibroblasts by direct activation of Nrf2 and SIRT-1

    PubMed Central

    Senthil, Kumar K.J.; Gokila, Vani M.; Mau, Jeng-Leun; Lin, Chin-Chung; Chu, Fang-Hua; Wei, Chia-Cheng; Liao, Vivian Hsiu-Chuan; Wang, Sheng-Yang

    2016-01-01

    The present study revealed the anti-aging properties of antcin M (ANM) and elucidated the molecular mechanism underlying the effects. We found that exposure of human normal dermal fibroblasts (HNDFs) to high-glucose (HG, 30 mM) for 3 days, accelerated G0/G1 phase arrest and senescence. Indeed, co-treatment with ANM (10 μM) significantly attenuated HG-induced growth arrest and promoted cell proliferation. Further molecular analysis revealed that ANM blocked the HG-induced reduction in G1-S transition regulatory proteins such as cyclin D, cyclin E, CDK4, CDK6, CDK2 and protein retinoblastoma (pRb). In addition, treatment with ANM eliminated HG-induced reactive oxygen species (ROS) through the induction of anti-oxidant genes, HO-1 and NQO-1 via transcriptional activation of Nrf2. Moreover, treatment with ANM abolished HG-induced SIPS as evidenced by reduced senescence-associated β-galactosidase (SA-β-gal) activity. This effect was further confirmed by reduction in senescence-associated marker proteins including, p21CIP1, p16INK4A, and p53/FoxO1 acetylation. Also, the HG-induced decline in aging-related marker protein SMP30 was rescued by ANM. Furthermore, treatment with ANM increased SIRT-1 expression, and prevented SIRT-1 depletion. This protection was consistent with inhibition of SIRT-1 phosphorylation at Ser47 followed by blocking its upstream kinases, p38 MAPK and JNK/SAPK. Further analysis revealed that ANM partially protected HG-induced senescence in SIRT-1 silenced cells. A similar effect was also observed in Nrf2 silenced cells. However, a complete loss of protection was observed in both Nrf2 and SIRT-1 knockdown cells suggesting that both induction of Nrf2-mediated anti-oxidant defense and SIRT-1-mediated deacetylation activity contribute to the anti-aging properties of ANM in vitro. Result of in vivo studies shows that ANM-treated C. elegens exhibits an increased survival rate during HG-induced oxidative stress insult. Furthermore, ANM significantly

  17. A steroid like phytochemical Antcin M is an anti-aging reagent that eliminates hyperglycemia-accelerated premature senescence in dermal fibroblasts by direct activation of Nrf2 and SIRT-1.

    PubMed

    Senthil, Kumar K J; Gokila, Vani M; Mau, Jeng-Leun; Lin, Chin-Chung; Chu, Fang-Hua; Wei, Chia-Cheng; Liao, Vivian Hsiu-Chuan; Wang, Sheng-Yang

    2016-09-27

    The present study revealed the anti-aging properties of antcin M (ANM) and elucidated the molecular mechanism underlying the effects. We found that exposure of human normal dermal fibroblasts (HNDFs) to high-glucose (HG, 30 mM) for 3 days, accelerated G0/G1 phase arrest and senescence. Indeed, co-treatment with ANM (10 µM) significantly attenuated HG-induced growth arrest and promoted cell proliferation. Further molecular analysis revealed that ANM blocked the HG-induced reduction in G1-S transition regulatory proteins such as cyclin D, cyclin E, CDK4, CDK6, CDK2 and protein retinoblastoma (pRb). In addition, treatment with ANM eliminated HG-induced reactive oxygen species (ROS) through the induction of anti-oxidant genes, HO-1 and NQO-1 via transcriptional activation of Nrf2. Moreover, treatment with ANM abolished HG-induced SIPS as evidenced by reduced senescence-associated β-galactosidase (SA-β-gal) activity. This effect was further confirmed by reduction in senescence-associated marker proteins including, p21CIP1, p16INK4A, and p53/FoxO1 acetylation. Also, the HG-induced decline in aging-related marker protein SMP30 was rescued by ANM. Furthermore, treatment with ANM increased SIRT-1 expression, and prevented SIRT-1 depletion. This protection was consistent with inhibition of SIRT-1 phosphorylation at Ser47 followed by blocking its upstream kinases, p38 MAPK and JNK/SAPK. Further analysis revealed that ANM partially protected HG-induced senescence in SIRT-1 silenced cells. A similar effect was also observed in Nrf2 silenced cells. However, a complete loss of protection was observed in both Nrf2 and SIRT-1 knockdown cells suggesting that both induction of Nrf2-mediated anti-oxidant defense and SIRT-1-mediated deacetylation activity contribute to the anti-aging properties of ANM in vitro. Result of in vivo studies shows that ANM-treated C. elegens exhibits an increased survival rate during HG-induced oxidative stress insult. Furthermore, ANM significantly

  18. School Inclusion Programmes (SIPS)

    ERIC Educational Resources Information Center

    Drossinou-Korea, Maria; Matousi, Dimitra; Panopoulos, Nikolaos; Paraskevopoulou, Aikaterini

    2016-01-01

    The purpose of this work was to understand the school inclusion programmes (SIPs) for students with special educational needs (SEN). The methodology was conducted in the field of special education (SE) and focuses on three case studies of students who was supported by SIPs. The Targeted, Individual, Structured, Inclusion Programme for students…

  19. Meiotic drive by the Y-linked D gene in Aedes aegypti (L.) (Diptera: Culicidae) is associated with disruption of spermiogenesis, leading to premature senescence of spermatozoa.

    PubMed

    Owusu-Daaku, K O; Butler, R D; Wood, R J

    2007-06-01

    Y chromosome meiotic drive in the mosquito Aedes aegypti, due to the gene D (Distorter) in coupling with M (male determination) [the MD haplotype], is associated with spermiogenic disruption, leading to senescence, at a rate proportionate to male excess. Spermiogenesis was compared between 'Enhanced Mutant' males with a strongly female-depleted sex ratio (8.9% females), 'Mutant' males showing a lesser degree of distortion (38.3% females), and two controls with normal sex ratios (51.2% and 49.2% females). Sections of testes dissected from mature pupae and adults aged 0, 4, 8, 12 and 16 days were examined by transmission electron microscopy. A difference between Mutant and control spermiogenesis was apparent as early as the pupal stage when some Mutant spermatids showed extra tail elements (axonemes and/or mitochondrial derivatives). The same was true of Enhanced Mutant males but to a more extreme degree. Sperm senescence was evident in Enhanced Mutant testes from day 0 of adult life but in Mutant testes not until day 4. Progressive disorganisation was associated with many loose organelles, and disturbance of the anterior-posterior axis of gamete differentiation within the testis. Degenerative changes of a similar kind in the controls did not become apparent until day 8. These findings are discussed with respect to other characteristics of this meiotic drive system, in terms of a theory of inhibition of reduction division in spermatogenesis associated with fragmentation of the X chromosome, leading to the formation of a restitution nucleus as early as metaphase 1.

  20. Relationship of inflammatory profile of elderly patients serum and senescence-associated secretory phenotype with human breast cancer cells proliferation: Role of IL6/IL8 ratio.

    PubMed

    Barajas-Gómez, Bertha Alicia; Rosas-Carrasco, Oscar; Morales-Rosales, Sandra Lisbeth; Pedraza Vázquez, Gibrán; González-Puertos, Viridiana Yazmín; Juárez-Cedillo, Teresa; García-Álvarez, Jorge Antonio; López-Diazguerrero, Norma Edith; Damián-Matsumura, Pablo; Königsberg, Mina; Luna-López, Armando

    2017-03-01

    Aging is considered a systemic, chronic and low-grade inflammatory state, called "inflammaging", which has been contemplated as a risk factor for cancer development and progression in the elderly population. Cellular senescence is a multifactorial phenomenon of growth arrest and distorted function, which has been recognized as a contributor to aging. Senescent cells have an altered secretion pattern called Senescent Associated Secretory Phenotype (SASP), that comprise a complex mix of factors including cytokines, growth factors, chemokines and matrix metalloproteinases among others. The SASP secreted by accumulated senescent cells during old age has been related to local inflammation that leads to cellular transformation and therefore may be supporting the inflammaging process. Here, we evaluated if the pro-inflammatory profile within the serum obtained from elderly patients (EPS) was able to induce cellular proliferation in the breast cancer transformed cell line (MCF-7), in a similar way to the proliferation stimulated by the SASP obtained from WI-38 primary cells prematurely induced to senescence by oxidative stress (SIPS). At the same time, the participation of IL-6/IL-8 ratio was determined. Our results showed that not all the EPS increased MCF-7 proliferation. However, there was an interesting relationship between IL-6 and IL-8 concentrations, when the IL-6 was higher than IL-8. Similar results were found with SASP from SIPS-WI-38 on the MCF-7 proliferation. Although it is known that those cytokines are fundamental factors to induce proliferation; the occurrence of other components in the cellular microenvironment is necessary to carry out this effect.

  1. Heparan sulfation is essential for the prevention of cellular senescence

    PubMed Central

    Jung, S H; Lee, H C; Yu, D-M; Kim, B C; Park, S M; Lee, Y-S; Park, H J; Ko, Y-G; Lee, J-S

    2016-01-01

    Cellular senescence is considered as an important tumor-suppressive mechanism. Here, we demonstrated that heparan sulfate (HS) prevents cellular senescence by fine-tuning of the fibroblast growth factor receptor (FGFR) signaling pathway. We found that depletion of 3′-phosphoadenosine 5′-phosphosulfate synthetase 2 (PAPSS2), a synthetic enzyme of the sulfur donor PAPS, led to premature cell senescence in various cancer cells and in a xenograft tumor mouse model. Sodium chlorate, a metabolic inhibitor of HS sulfation also induced a cellular senescence phenotype. p53 and p21 accumulation was essential for PAPSS2-mediated cellular senescence. Such senescence phenotypes were closely correlated with cell surface HS levels in both cancer cells and human diploid fibroblasts. The determination of the activation of receptors such as FGFR1, Met, and insulin growth factor 1 receptor β indicated that the augmented FGFR1/AKT signaling was specifically involved in premature senescence in a HS-dependent manner. Thus, blockade of either FGFR1 or AKT prohibited p53 and p21 accumulation and cell fate switched from cellular senescence to apoptosis. In particular, desulfation at the 2-O position in the HS chain contributed to the premature senescence via the augmented FGFR1 signaling. Taken together, we reveal, for the first time, that the proper status of HS is essential for the prevention of cellular senescence. These observations allowed us to hypothesize that the FGF/FGFR signaling system could initiate novel tumor defenses through regulating premature senescence. PMID:26250908

  2. Co-Regulation of p16INK4a and Migratory Genes in Culture Conditions that Lead to Premature Senescence in Human Keratinocytes

    PubMed Central

    Darbro, Benjamin W.; Schneider, Galen B.; Klingelhutz, Aloysius J.

    2007-01-01

    Cellular stasis, also known as telomere-independent senescence, prevents many epithelial cells from becoming immortalized by telomerase alone. As human keratinocytes age in culture, protein levels of the tumor suppressor p16INK4a continue to increase, resulting in growth arrest independent of telomere length. Differences in culture conditions have been shown to modulate both p16INK4a expression and replicative capacity of human keratinocytes; however, the mechanism of p16INK4a induction under these conditions is unknown. Using multiple primary keratinocyte cell strains, we verified a delay in p16INK4a induction and an extended lifespan of human keratinocytes when grown in co-culture with post-mitotic fibroblast feeder cells as compared with keratinocytes grown on tissue culture plastic alone. Evaluation of gene expression levels in the two culture conditions by microarray analysis, and subsequent validation, demonstrated that keratinocytes cultured on plastic alone had significantly increased expression of many genes involved in keratinocyte migration and reduced expression levels of genes involved in keratinocyte differentiation. Higher levels of p16INK4a expression were present in cells that also displayed increased amounts of autophosphorylated focal adhesion kinase and urokinase plaminogen activator receptor (uPAR), both markers of keratinocyte migration. Furthermore, when tyrosine phosphorylation or urokinase-type plasminogen activator (uPA)/uPAR function was inhibited, both keratinocyte migration and p16INK4a expression were reduced. Our results indicate that keratinocytes cultured in the absence of feeder cells exhibit a migratory phenotype and suggest that p16INK4a is selectively induced under these conditions by a mechanism involving tyrosine kinase activity and the urokinase plasminogen activation system. PMID:16117791

  3. Attenuation of TGF-β signaling suppresses premature senescence in a p21-dependent manner and promotes oncogenic Ras-mediated metastatic transformation in human mammary epithelial cells.

    PubMed

    Lin, Shu; Yang, Junhua; Elkahloun, Abdel G; Bandyopadhyay, Abhik; Wang, Long; Cornell, John E; Yeh, I-Tien; Agyin, Joseph; Tomlinson, Gail; Sun, Lu-Zhe

    2012-04-01

    The molecular mechanisms that drive triple-negative, basal-like breast cancer progression are elusive. Few molecular targets have been identified for the prevention or treatment of this disease. Here we developed a series of isogenic basal-like human mammary epithelial cells (HMECs) with altered transforming growth factor-β (TGF-β) sensitivity and different malignancy, resembling a full spectrum of basal-like breast carcinogenesis, and determined the molecular mechanisms that contribute to oncogene-induced transformation of basal-like HMECs when TGF-β signaling is attenuated. We found that expression of a dominant-negative type II receptor (DNRII) of TGF-β abrogated autocrine TGF-β signaling in telomerase-immortalized HMECs and suppressed H-Ras-V12-induced senescence-like growth arrest (SLGA). Furthermore, coexpression of DNRII and H-Ras-V12 rendered HMECs highly tumorigenic and metastatic in vivo in comparison with H-Ras-V12-transformed HMECs that spontaneously escaped H-Ras-V12-induced SLGA. Microarray analysis revealed that p21 was the major player mediating Ras-induced SLGA, and attenuated or loss of p21 expression contributed to the escape from SLGA when autocrine TGF-β signaling was blocked in HMECs. Furthermore, knockdown of p21 also suppressed H-Ras-V12-induced SLGA. Our results identify that autocrine TGF-β signaling is an integral part of the cellular anti-transformation network by suppressing the expression of a host of genes, including p21-regulated genes, that mediate oncogene-induced transformation in basal-like breast cancer.

  4. Autoimmune premature ovarian failure

    PubMed Central

    2017-01-01

    Premature ovarian failure (POF), also termed as primary ovarian insufficiency (POI), is a highly heterogenous condition affecting 0.5-3.0% of women in childbearing age. These young women comprise quite a formidable group with unique physical and psychological needs that require special attention. Premature ovarian senescence (POS) in all of its forms evolves insidiously as a basically asymptomatic process, leading to complete loss of ovarian function, and POI/POF diagnoses are currently made at relatively late stages. Well-known and well-documented risk factors exist, and the presence or suspicion of autoimmune disorder should be regarded as an important one. Premature ovarian failure is to some degree predictable in its occurrence and should be considered while encountering young women with loss of menstrual regularity, especially when there is a concomitant dysfunction in the immune system. PMID:28250725

  5. SIP's in the Speech Classroom

    ERIC Educational Resources Information Center

    Solomon, Martha

    1977-01-01

    Looks at the self-instructional packet (SIP) as an effective tool for individualizing instruction through the use of programmed learning sequences to aid student exploration of topics, concepts or skills. (MH)

  6. SIP: Systematics-Insensitive Periodograms

    NASA Astrophysics Data System (ADS)

    Angus, Ruth

    2016-09-01

    SIP (Systematics-Insensitive Periodograms) extends the generative model used to create traditional sine-fitting periodograms for finding the frequency of a sinusoid by including systematic trends based on a set of eigen light curves in the generative model in addition to using a sum of sine and cosine functions over a grid of frequencies, producing periodograms with vastly reduced systematic features. Acoustic oscillations in giant stars and measurement of stellar rotation periods can be recovered from the SIP periodograms without detrending. The code can also be applied to detection other periodic phenomena, including eclipsing binaries and short-period exoplanet candidates.

  7. Guidance on Streamlining the SIP Process

    EPA Pesticide Factsheets

    EPA collaborated with the The National Association of Clean Air Agencies (NACAA/ECOs) SIP Reform Work Group to minimize federal and state burden in developing SIPs, but ensure the plans effectiveness in complying with the Clean Air Act.

  8. Repression of cancer cell senescence by PKCι.

    PubMed

    Paget, J A; Restall, I J; Daneshmand, M; Mersereau, J A; Simard, M A; Parolin, D A E; Lavictoire, S J; Amin, M S; Islam, S; Lorimer, I A J

    2012-08-02

    Senescence is an irreversible growth arrest phenotype adopted by cells that has a key role in protecting organisms from cancer. There is now considerable interest in therapeutic strategies that reactivate this process to control the growth of cancer cells. Protein kinase-Cι (PKCι) is a member of the atypical PKC family and an important downstream mediator in the phosphoinositide-3-kinase (PI-3-kinase) pathway. PKCι expression was found to be upregulated in a subset of breast cancers and breast cancer cell lines. Activation of the PI-3-kinase pathway by introduction of mutant, oncogenic PIK3CA into breast mammary epithelial cells increased both the expression and activation of PKCι. In breast cancer cells lines overexpressing PKCι, depletion of PKCι increased the number of senescent cells, as assessed by senescence-associated β-galactosidase, morphology and bromodeoxyuridine incorporation. This phenomenon was not restricted to breast cancer cells, as it was also seen in glioblastoma cells in which PKCι is activated by loss of PTEN. Senescence occurred in the absence of a detectable DNA-damage response, was dependent on p21 and was enhanced by the aurora kinase inhibitor VX-680, suggesting that senescence is triggered by defects in mitosis. Depletion of PKCι had no effect on senescence in normal mammary epithelial cell lines. We conclude that PKCι is overexpressed in a subset of cancers where it functions to suppress premature senescence. This function appears to be restricted to cancer cells and inhibition of PKCι may therefore be an effective way to selectively activate premature senescence in cancer cells.

  9. SIP qualification and PRA approaches

    NASA Technical Reports Server (NTRS)

    Ghaffarian, R.; Goetz, M.

    2002-01-01

    System in a package (SIP) development is a response to an increasing demand for integration of different functions into one unit to reduce size and cost and improve functionality. Qualification of the newly developed multifunctional electronics are becoming complex at the package level and even more at the second and system levels.

  10. HJURP regulates cellular senescence in human fibroblasts and endothelial cells via a p53-dependent pathway.

    PubMed

    Heo, Jong-Ik; Cho, Jung Hee; Kim, Jae-Ryong

    2013-08-01

    Holliday junction recognition protein (HJURP), a centromere protein-A (CENP-A) histone chaperone, mediates centromere-specific assembly of CENP-A nucleosome, contributing to high-fidelity chromosome segregation during cell division. However, the role of HJURP in cellular senescence of human primary cells remains unclear. We found that the expression levels of HJURP decreased in human dermal fibroblasts and umbilical vein endothelial cells in replicative or premature senescence. Ectopic expression of HJURP in senescent cells partially overcame cell senescence. Conversely, downregulation of HJURP in young cells led to premature senescence. p53 knockdown, but not p16 knockdown, abolished senescence phenotypes caused by HJURP reduction. These data suggest that HJURP plays an important role in the regulation of cellular senescence through a p53-dependent pathway and might contribute to tissue or organismal aging and protection of cellular transformation.

  11. Delayed Senescence

    NASA Technical Reports Server (NTRS)

    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.

  12. Downregulation of Polo-like kinase 1 induces cellular senescence in human primary cells through a p53-dependent pathway.

    PubMed

    Kim, Hee-Jin; Cho, Jung Hee; Kim, Jae-Ryong

    2013-10-01

    Polo-like kinase 1 (PLK1) plays a key role in various stages of mitosis from entry into M phase to exit from mitosis. However, its role in cellular senescence remains to be determined. Therefore, the effects of PLK1 on cellular senescence in human primary cells were investigated. We found that expression of PLK1 decreased in human dermal fibroblasts and human umbilical vein endothelial cells under replicative senescence and premature senescence induced by adriamycin. PLK1 knockdown with PLK1 small interfering RNAs in young cells induced premature senescence. In contrast, upregulation of PLK1 in old cells partially reversed senescence phenotypes. Cellular senescence by PLK1 inhibition was observed in p16 knockdown cells but not in p53 knockdown cells. Our data suggest that PLK1 repression might result in cellular senescence in human primary cells via a p53-dependent pathway.

  13. Premature infant

    MedlinePlus

    ... the mother, such as diabetes, heart disease, and kidney disease, may contribute to preterm labor. Often, the cause of preterm labor is unknown. 15% of all premature births are multiple pregnancies, such as twins or triplets. Different pregnancy-related ...

  14. PKCι depletion initiates mitotic slippage-induced senescence in glioblastoma

    PubMed Central

    Restall, Ian J; Parolin, Doris A E; Daneshmand, Manijeh; Hanson, Jennifer E L; Simard, Manon A; Fitzpatrick, Megan E; Kumar, Ritesh; Lavictoire, Sylvie J; Lorimer, Ian A J

    2015-01-01

    Cellular senescence is a tumor suppressor mechanism where cells enter a permanent growth arrest following cellular stress. Oncogene-induced senescence (OIS) is induced in non-malignant cells following the expression of an oncogene or inactivation of a tumor suppressor. Previously, we have shown that protein kinase C iota (PKCι) depletion induces cellular senescence in glioblastoma cells in the absence of a detectable DNA damage response. Here we demonstrate that senescent glioblastoma cells exhibit an aberrant centrosome morphology. This was observed in basal levels of senescence, in p21-induced senescence, and in PKCι depletion-induced senescence. In addition, senescent glioblastoma cells are polyploid, Ki-67 negative and arrest at the G1/S checkpoint, as determined by expression of cell cycle regulatory proteins. These markers are all consistent with cells that have undergone mitotic slippage. Failure of the spindle assembly checkpoint to function properly can lead to mitotic slippage, resulting in the premature exit of mitotic cells into the G1 phase of the cell cycle. Although in G1, these cells have the replicated DNA and centrosomal phenotype of a cell that has entered mitosis and failed to divide. Overall, we demonstrate that PKCι depletion initiates mitotic slippage-induced senescence in glioblastoma cells. To our knowledge, this is the first evidence of markers of mitotic slippage directly in senescent cells by co-staining for senescence-associated β-galactosidase and immunofluorescence markers in the same cell population. We suggest that markers of mitotic slippage be assessed in future studies of senescence to determine the extent of mitotic slippage in the induction of cellular senescence. PMID:26208522

  15. PKCι depletion initiates mitotic slippage-induced senescence in glioblastoma.

    PubMed

    Restall, Ian J; Parolin, Doris A E; Daneshmand, Manijeh; Hanson, Jennifer E L; Simard, Manon A; Fitzpatrick, Megan E; Kumar, Ritesh; Lavictoire, Sylvie J; Lorimer, Ian A J

    2015-01-01

    Cellular senescence is a tumor suppressor mechanism where cells enter a permanent growth arrest following cellular stress. Oncogene-induced senescence (OIS) is induced in non-malignant cells following the expression of an oncogene or inactivation of a tumor suppressor. Previously, we have shown that protein kinase C iota (PKCι) depletion induces cellular senescence in glioblastoma cells in the absence of a detectable DNA damage response. Here we demonstrate that senescent glioblastoma cells exhibit an aberrant centrosome morphology. This was observed in basal levels of senescence, in p21-induced senescence, and in PKCι depletion-induced senescence. In addition, senescent glioblastoma cells are polyploid, Ki-67 negative and arrest at the G1/S checkpoint, as determined by expression of cell cycle regulatory proteins. These markers are all consistent with cells that have undergone mitotic slippage. Failure of the spindle assembly checkpoint to function properly can lead to mitotic slippage, resulting in the premature exit of mitotic cells into the G1 phase of the cell cycle. Although in G1, these cells have the replicated DNA and centrosomal phenotype of a cell that has entered mitosis and failed to divide. Overall, we demonstrate that PKCι depletion initiates mitotic slippage-induced senescence in glioblastoma cells. To our knowledge, this is the first evidence of markers of mitotic slippage directly in senescent cells by co-staining for senescence-associated β-galactosidase and immunofluorescence markers in the same cell population. We suggest that markers of mitotic slippage be assessed in future studies of senescence to determine the extent of mitotic slippage in the induction of cellular senescence.

  16. Modified apolipoprotein (apo) A-I by artificial sweetener causes severe premature cellular senescence and atherosclerosis with impairment of functional and structural properties of apoA-I in lipid-free and lipid-bound state.

    PubMed

    Jang, Wookju; Jeoung, Nam Ho; Cho, Kyung-Hyun

    2011-05-01

    Long-term consumption of artificial sweeteners (AS) has been the recent focus of safety concerns. However, the potential risk of the AS in cardiovascular disease and lipoprotein metabolism has not been investigated sufficiently. We compared the influence of AS (aspartame, acesulfame K, and saccharin) and fructose in terms of functional and structural correlations of apolipoprotein (apo) A-I and high-density lipoproteins (HDL), which have atheroprotective effects. Long-term treatment of apoA-I with the sweetener at physiological concentration (3 mM for 168 h) resulted in loss of antioxidant and phospholipid binding activities with modification of secondary structure. The AS treated apoA-I exhibited proteolytic cleavage to produce 26 kDa-fragment. They showed pro-atherogenic properties in acetylated LDL phagocytosis of macrophages. Each sweetener alone or sweetener-treated apoA-I caused accelerated senescence in human dermal fibroblasts. These results suggest that long-term consumption of AS might accelerate atherosclerosis and senescence via impairment of function and structure of apoA-I and HDL.

  17. 75 FR 28626 - Disease, Disability, and Injury Prevention and Control Special Interest Projects (SIPs): SIP 10...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-05-21

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF HEALTH AND HUMAN SERVICES Centers for Disease Control and Prevention Disease, Disability, and Injury Prevention and Control Special Interest Projects (SIPs): SIP 10-029, Pilot Study--Cancer Survivorship Care Planning & SIP 10-030, Evaluating Special Events as...

  18. Cardiac Hegemony of Senescence

    PubMed Central

    Siddiqi, Sailay; Sussman, Mark A.

    2013-01-01

    Cardiac senescence and age-related disease development have gained general attention and recognition in the past decades due to increased accessibility and quality of health care. The advancement in global civilization is complementary to concerns regarding population aging and development of chronic degenerative diseases. Cardiac degeneration has been rigorously studied. The molecular mechanisms of cardiac senescence are on multiple cellular levels and hold a multilayer complexity level, thereby hampering development of unambiguous treatment protocols. In particular, the synergistic exchange of the senescence phenotype through a senescence secretome between myocytes and stem cells appears complicated and is of great future therapeutic value. The current review article will highlight hallmarks of senescence, cardiac myocyte and stem cell senescence, and the mutual exchange of senescent secretome. Future cardiac cell therapy approaches require a comprehensive understanding of myocardial senescence to improve therapeutic efficiency as well as efficacy. PMID:24349878

  19. Jasmonates during senescence

    PubMed Central

    Seltmann, Martin A; Hussels, Wiebke

    2010-01-01

    Jasmonic acid and derivatives are oxylipin signaling compounds derived from linolenic acid. Jasmonates accumulate during natural and dark-induced senescence but the increase in these compounds is not essential for the initiation or progression of these senescence processes. Here we report that during natural and dark-induced senescence the increase in jasmonate levels does not trigger jasmonate signaling. Furthermore we provide evidence that jasmonate production might result from membrane turnover during dark-induced senescence. PMID:21057217

  20. Senescence responsive transcriptional element

    DOEpatents

    Campisi, Judith; Testori, Alessandro

    1999-01-01

    Recombinant polynucleotides have expression control sequences that have a senescence responsive element and a minimal promoter, and which are operatively linked to a heterologous nucleotide sequence. The molecules are useful for achieving high levels of expression of genes in senescent cells. Methods of inhibiting expression of genes in senescent cells also are provided.

  1. Lightweight SIP/SDP compression scheme (LSSCS)

    NASA Astrophysics Data System (ADS)

    Wu, Jian J.; Demetrescu, Cristian

    2001-10-01

    In UMTS new IP based services with tight delay constraints will be deployed over the W-CDMA air interface such as IP multimedia and interactive services. To integrate the wireline and wireless IP services, 3GPP standard forum adopted the Session Initiation Protocol (SIP) as the call control protocol for the UMTS Release 5, which will implement next generation, all IP networks for real-time QoS services. In the current form the SIP protocol is not suitable for wireless transmission due to its large message size which will need either a big radio pipe for transmission or it will take far much longer to transmit than the current GSM Call Control (CC) message sequence. In this paper we present a novel compression algorithm called Lightweight SIP/SDP Compression Scheme (LSSCS), which acts at the SIP application layer and therefore removes the information redundancy before it is sent to the network and transport layer. A binary octet-aligned header is added to the compressed SIP/SDP message before sending it to the network layer. The receiver uses this binary header as well as the pre-cached information to regenerate the original SIP/SDP message. The key features of the LSSCS compression scheme are presented in this paper along with implementation examples. It is shown that this compression algorithm makes SIP transmission efficient over the radio interface without losing the SIP generality and flexibility.

  2. Premature ejaculation

    MedlinePlus

    ... is no way to prevent this disorder. Images Male reproductive system References Cooper K, Martyn-St James M, Kaltenthaler E, et al. Behavioral therapies for management of premature ejaculation: a systematic ... CG. Disorders of male orgasm and ejaculation. In: Wein AJ, ed. Campbell- ...

  3. Anti-tumor activity and the mechanism of SIP-S: A sulfated polysaccharide with anti-metastatic effect.

    PubMed

    Zong, Aizhen; Liu, Yuhong; Zhang, Yan; Song, Xinlei; Shi, Yikang; Cao, Hongzhi; Liu, Chunhui; Cheng, Yanna; Jiang, Wenjie; Du, Fangling; Wang, Fengshan

    2015-09-20

    Our previous studies demonstrated that SIP-S had anti-metastatic activity and inhibited the growth of metastatic foci. Here we report the anti-tumor and immunoregulatory potential of SIP-S. SIP-S could significantly inhibit tumor growth in S180-bearing mice, and the inhibition rates was 43.7% at 30 mg/kg d. Besides, SIP-S could improve the thymus and spleen indices of S180-bearing mice and the mice treated with CTX. The combination of SIP-S (15 mg/kg d) with CTX (12.5 mg/kg d) showed higher anti-tumor potency than CTX (25 mg/kg d) alone. These results indicated that SIP-S had immunoenhancing and anticancer activity, and the immunoenhancing activity might be one mechanism for its anti-tumor activity. Flow cytometry results showed that SIP-S could induce tumor cells apoptosis. Western blot analysis indicated that SIP-S could upregulate the expression of pro-apoptotic proteins, caspase-3, -8, -9 and Bax, and downregulate the expression of anti-apoptotic protein PARP-1 in tumor cells in a dose-dependent manner. In summary, SIP-S has anti-tumor activity, which may be associated with its immunostimulating and pro-apoptotic activity.

  4. c-JUN Dimerization Protein 2 (JDP2) Is a Transcriptional Repressor of Follicle-stimulating Hormone β (FSHβ) and Is Required for Preventing Premature Reproductive Senescence in Female Mice.

    PubMed

    Jonak, Carrie R; Lainez, Nancy M; Roybal, Lacey L; Williamson, Alexa D; Coss, Djurdjica

    2017-02-17

    Follicle-stimulating hormone (FSH) regulates follicular growth and stimulates estrogen synthesis in the ovaries. FSH is a heterodimer consisting of an α subunit, also present in luteinizing hormone, and a unique β subunit, which is transcriptionally regulated by gonadotropin-releasing hormone 1 (GNRH). Because most FSH is constitutively secreted, tight transcriptional regulation is critical for maintaining FSH levels within a narrow physiological range. Previously, we reported that GNRH induces FSHβ (Fshb) transcription via induction of the AP-1 transcription factor, a heterodimer of c-FOS and c-JUN. Herein, we identify c-JUN-dimerization protein 2 (JDP2) as a novel repressor of GNRH-mediated Fshb induction. JDP2 exhibited high basal expression and bound the Fshb promoter at an AP-1-binding site in a complex with c-JUN. GNRH treatment induced c-FOS to replace JDP2 as a c-JUN binding partner, forming transcriptionally active AP-1. Subsequently, rapid c-FOS degradation enabled reformation of the JDP2 complex. In vivo studies revealed that JDP2 null male mice have normal reproductive function, as expected from a negative regulator of the FSH hormone. Female JDP2 null mice, however, exhibited early puberty, observed as early vaginal opening, larger litters, and early reproductive senescence. JDP2 null females had increased levels of circulating FSH and higher expression of the Fshb subunit in the pituitary, resulting in elevated serum estrogen and higher numbers of large ovarian follicles. Disruption of JDP2 function therefore appears to cause early cessation of reproductive function, a condition that has been associated with elevated FSH in women.

  5. [Senescence and cellular immortality].

    PubMed

    Trentesaux, C; Riou, J-F

    2010-11-01

    Senescence was originally described from the observation of the limited ability of normal cells to grow in culture, and may be generated by telomere erosion, accumulation of DNA damages, oxidative stress and modulation of oncogenes or tumor suppressor genes. Senescence corresponds to a cellular response aiming to control tumor progression by limiting cell proliferation and thus constitutes an anticancer barrier. Senescence is observed in pre-malignant tumor stages and disappears from malignant tumors. Agents used in standard chemotherapy also have the potential to induce senescence, which may partly explain their therapeutic activities. It is possible to restore senescence in tumors using targeted therapies that triggers telomere dysfunction or reactivates suppressor genes functions, which are essential for the onset of senescence.

  6. Fragrance volatiles of developing and senescing carnation flowers.

    PubMed

    Schade, F; Legge, R L; Thompson, J E

    2001-04-01

    Thirteen major volatiles of the carnation flower fragrance signature have been identified by GC/MS. Of these, ten, hexanal, (2E)-hexenal, 1-hexanol, 2-hexanol, 3-hexen-1-ol, nonanal, benzaldehyde, benzyl alcohol, benzyl benzoate and caryophyllene, were quantified. The steady-state levels of these ten volatiles change independently as the flowers develop and senesce, suggesting that their synthesis is developmentally regulated. In addition, the chemical composition of the fragrance signature in naturally senesced flowers proved to be very different from that for flowers that had been induced to senesce prematurely by treatment with ethylene. Thus, senescence-related changes in carnation floral scent appear not to be directly regulated by ethylene. From cellular fractionation studies, it is evident that all of the volatiles, except 2-hexanol, are present in both membranous and cytosolic compartments, suggesting that their synthesis is membrane-associated and that they subsequently partition into the cytosol in accordance with partition coefficients.

  7. Glioma-associated endothelial cells show evidence of replicative senescence

    SciTech Connect

    Charalambous, Christiana; Virrey, Jenilyn; Kardosh, Adel; Jabbour, Mark N.; Qazi-Abdullah, Lubna; Pen, Ligaya; Zidovetzki, Raphael; Schoenthal, Axel H.; Chen, Thomas C.; Hofman, Florence M. . E-mail: hofman@usc.edu

    2007-04-01

    The innately programmed process of replicative senescence has been studied extensively with respect to cancer, but primarily from the perspective of tumor cells overcoming this stringent innate barrier and acquiring the capacity for unlimited proliferation. In this study, we focus on the potential role of replicative senescence affecting the non-transformed endothelial cells of the blood vessels within the tumor microenvironment. Based on the well-documented aberrant structural and functional features of blood vessels within solid tumors, we hypothesized that tumor-derived factors may lead to premature replicative senescence in tumor-associated brain endothelial cells (TuBEC). We show here that glioma tissue, but not normal brain tissue, contains cells that express the signature of replicative senescence, senescence-associated {beta}-galactosidase (SA-{beta}-gal), on CD31-positive endothelial cells. Primary cultures of human TuBEC stain for SA-{beta}-gal and exhibit characteristics of replicative senescence, including increased levels of the cell cycle inhibitors p21 and p27, increased resistance to cytotoxic drugs, increased growth factor production, and inability to proliferate. These data provide the first demonstration that tumor-derived brain endothelial cells may have reached an end-stage of differentiation known as replicative senescence and underscore the need for anti-angiogenic therapies to target this unique tumor-associated endothelial cell population.

  8. Biomarkers of cell senescence

    DOEpatents

    Dirmi, G.P.; Campisi, J.; Peacocke, M.

    1996-02-13

    The present invention provides a biomarker system for the in vivo and in vitro assessment of cell senescence. In the method of the present invention, {beta}-galactosidase activity is utilized as a means by which cell senescence may be assessed either in in vitro cell cultures or in vivo. 1 fig.

  9. Biomarkers of cell senescence

    DOEpatents

    Dimri, G.P.; Campisi, J.; Peacocke, M.

    1998-08-18

    The present invention provides a biomarker system for the in vivo and in vitro assessment of cell senescence. In the method of the present invention, {beta}-galactosidase activity is utilized as a means by which cell senescence may be assessed either in vitro cell cultures or in vivo. 1 fig.

  10. Biomarkers of cell senescence

    DOEpatents

    Dirmi, Goberdhan P.; Campisi, Judith; Peacocke, Monica

    1996-01-01

    The present invention provides a biomarker system for the in vivo and in vitro assessment of cell senescence. In the method of the present invention, .beta.-galactosidase activity is utilized as a means by which cell senescence may be assessed either in in vitro cell cultures or in vivo.

  11. Biomarkers of cell senescence

    DOEpatents

    Dimri, Goberdhan P.; Campisi, Judith; Peacocke, Monica

    1998-01-01

    The present invention provides a biomarker system for the in vivo and in vitro assessment of cell senescence. In the method of the present invention, .beta.-galactosidase activity is utilized as a means by which cell senescence may be assessed either in vitro cell cultures or in vivo.

  12. Evolution of plant senescence

    PubMed Central

    Thomas, Howard; Huang, Lin; Young, Mike; Ougham, Helen

    2009-01-01

    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 characteristics of senescence

  13. Photobiomodulation on senescence

    NASA Astrophysics Data System (ADS)

    Liu, Timon Cheng-Yi; Cheng, Lei; Rong, Dong-Liang; Xu, Xiao-Yang; Cui, Li-Ping; Lu, Jian; Deng, Xiao-Yuan; Liu, Song-Hao

    2006-09-01

    Photobiomodulation (PBM) is an effect oflow intensity monochromatic light or laser irradiation (LIL) on biological systems. which stimulates or inhibits biological functions but does not result in irreducible damage. It has been observed that PBM can suppress cellular senescence, reverse skin photoageing and improve fibromyalgia. In this paper, the biological information model of photobiomodulation (BIMP) is used to discuss its mechanism. Cellular senescence can result from short, dysfunctional telomeres, oxidative stress, or oncogene expression, and may contribute to aging so that it can be seen as a decline of cellular function in which cAMP plays an important role, which provide a foundation for PBM on senescence since cellular senescence is a reasonable model of senescence and PBM is a cellular rehabilitation in which cAMP also plays an important role according to BIMP. The PBM in reversing skin photoageing and improving fibromyalgia are then discussed in detail.

  14. Osteopenia - premature infants

    MedlinePlus

    Neonatal rickets; Brittle bones - premature infants; Weak bones - premature infants; Osteopenia of prematurity ... of calcium and phosphorus needed to form strong bones. While in the womb, fetal activity increases during ...

  15. Glycerophospholipid profile in oncogene-induced senescence.

    PubMed

    Cadenas, Cristina; Vosbeck, Sonja; Hein, Eva-Maria; Hellwig, Birte; Langer, Alice; Hayen, Heiko; Franckenstein, Dennis; Büttner, Bettina; Hammad, Seddik; Marchan, Rosemarie; Hermes, Matthias; Selinski, Silvia; Rahnenführer, Jörg; Peksel, Begüm; Török, Zsolt; Vígh, László; Hengstler, Jan G

    2012-09-01

    Alterations in lipid metabolism and in the lipid composition of cellular membranes are linked to the pathology of numerous diseases including cancer. However, the influence of oncogene expression on cellular lipid profile is currently unknown. In this work we analyzed changes in lipid profiles that are induced in the course of ERBB2-expression mediated premature senescence. As a model system we used MCF-7 breast cancer cells with doxycycline-inducible expression of NeuT, an oncogenic ERBB2 variant. Affymetrix gene array data showed NeuT-induced alterations in the transcription of many enzymes involved in lipid metabolism, several of which (ACSL3, CHPT1, PLD1, LIPG, MGLL, LDL and NPC1) could be confirmed by quantitative realtime PCR. A study of the glycerophospholipid and lyso-glycerophospholipid profiles, obtained by high performance liquid chromatography coupled to Fourier-transform ion cyclotron resonance-mass spectrometry revealed senescence-associated changes in numerous lipid species, including mitochondrial lipids. The most prominent changes were found in PG(34:1), PG(36:1) (increased) and LPE(18:1), PG(40:7) and PI(36:1) (decreased). Statistical analysis revealed a general trend towards shortened phospholipid acyl chains in senescence and a significant trend to more saturated acyl chains in the class of phosphatidylglycerol. Additionally, the cellular cholesterol content was elevated and accumulated in vacuoles in senescent cells. These changes were accompanied by increased membrane fluidity. In mitochondria, loss of membrane potential along with altered intracellular distribution was observed. In conclusion, we present a comprehensive overview of altered cholesterol and glycerophospholipid patterns in senescence, showing that predominantly mitochondrial lipids are affected and lipid species less susceptible to peroxidation are increased.

  16. Strategies to ameliorate abiotic stress-induced plant senescence.

    PubMed

    Gepstein, Shimon; Glick, Bernard R

    2013-08-01

    The plant senescence syndrome resembles, in many molecular and phenotypic aspects, plant responses to abiotic stresses. Both processes have an enormous negative global agro-economic impact and endanger food security worldwide. Premature plant senescence is the main cause of losses in grain filling and biomass yield due to leaf yellowing and deteriorated photosynthesis, and is also responsible for the losses resulting from the short shelf life of many vegetables and fruits. Under abiotic stress conditions the yield losses are often even greater. The primary challenge in agricultural sciences today is to develop technologies that will increase food production and sustainability of agriculture especially under environmentally limiting conditions. In this chapter, some of the mechanisms involved in abiotic stress-induced plant senescence are discussed. Recent studies have shown that crop yield and nutritional values can be altered as well as plant stress tolerance through manipulating the timing of senescence. It is often difficult to separate the effects of age-dependent senescence from stress-induced senescence since both share many biochemical processes and ultimately result in plant death. The focus of this review is on abiotic stress-induced senescence. Here, a number of the major approaches that have been developed to ameliorate some of the effects of abiotic stress-induced plant senescence are considered and discussed. Some approaches mimic the mechanisms already used by some plants and soil bacteria whereas others are based on development of new improved transgenic plants. While there may not be one simple strategy that can effectively decrease all losses of crop yield that accrue as a consequence of abiotic stress-induced plant senescence, some of the strategies that are discussed already show great promise.

  17. Heterotypic paracrine signaling drives fibroblast senescence and tumor progression of large cell carcinoma of the lung

    PubMed Central

    Lugo, Roberto; Gabasa, Marta; Andriani, Francesca; Puig, Marta; Facchinetti, Federica; Ramírez, Josep; Gómez-Caro, Abel; Pastorino, Ugo; Fuster, Gemma; Almendros, Isaac; Gascón, Pere; Davalos, Albert; Reguart, Noemí; Roz, Luca; Alcaraz, Jordi

    2016-01-01

    Senescence in cancer cells acts as a tumor suppressor, whereas in fibroblasts enhances tumor growth. Senescence has been reported in tumor associated fibroblasts (TAFs) from a growing list of cancer subtypes. However, the presence of senescent TAFs in lung cancer remains undefined. We examined senescence in TAFs from primary lung cancer and paired control fibroblasts from unaffected tissue in three major histologic subtypes: adenocarcinoma (ADC), squamous cell carcinoma (SCC) and large cell carcinoma (LCC). Three independent senescence markers (senescence-associated beta-galactosidase, permanent growth arrest and spreading) were consistently observed in cultured LCC-TAFs only, revealing a selective premature senescence. Intriguingly, SCC-TAFs exhibited a poor growth response in the absence of senescence markers, indicating a dysfunctional phenotype rather than senescence. Co-culturing normal fibroblasts with LCC (but not ADC or SCC) cancer cells was sufficient to render fibroblasts senescent through oxidative stress, indicating that senescence in LCC-TAFs is driven by heterotypic signaling. In addition, senescent fibroblasts provided selective growth and invasive advantages to LCC cells in culture compared to normal fibroblasts. Likewise, senescent fibroblasts enhanced tumor growth and lung dissemination of tumor cells when co-injected with LCC cells in nude mice beyond the effects induced by control fibroblasts. These results define the subtype-specific aberrant phenotypes of lung TAFs, thereby challenging the common assumption that lung TAFs are a heterogeneous myofibroblast-like cell population regardless of their subtype. Importantly, because LCC often distinguishes itself in the clinic by its aggressive nature, we argue that senescent TAFs may contribute to the selective aggressive behavior of LCC tumors. PMID:27384989

  18. Heterotypic paracrine signaling drives fibroblast senescence and tumor progression of large cell carcinoma of the lung.

    PubMed

    Lugo, Roberto; Gabasa, Marta; Andriani, Francesca; Puig, Marta; Facchinetti, Federica; Ramírez, Josep; Gómez-Caro, Abel; Pastorino, Ugo; Fuster, Gemma; Almendros, Isaac; Gascón, Pere; Davalos, Albert; Reguart, Noemí; Roz, Luca; Alcaraz, Jordi

    2016-12-13

    Senescence in cancer cells acts as a tumor suppressor, whereas in fibroblasts enhances tumor growth. Senescence has been reported in tumor associated fibroblasts (TAFs) from a growing list of cancer subtypes. However, the presence of senescent TAFs in lung cancer remains undefined. We examined senescence in TAFs from primary lung cancer and paired control fibroblasts from unaffected tissue in three major histologic subtypes: adenocarcinoma (ADC), squamous cell carcinoma (SCC) and large cell carcinoma (LCC). Three independent senescence markers (senescence-associated beta-galactosidase, permanent growth arrest and spreading) were consistently observed in cultured LCC-TAFs only, revealing a selective premature senescence. Intriguingly, SCC-TAFs exhibited a poor growth response in the absence of senescence markers, indicating a dysfunctional phenotype rather than senescence. Co-culturing normal fibroblasts with LCC (but not ADC or SCC) cancer cells was sufficient to render fibroblasts senescent through oxidative stress, indicating that senescence in LCC-TAFs is driven by heterotypic signaling. In addition, senescent fibroblasts provided selective growth and invasive advantages to LCC cells in culture compared to normal fibroblasts. Likewise, senescent fibroblasts enhanced tumor growth and lung dissemination of tumor cells when co-injected with LCC cells in nude mice beyond the effects induced by control fibroblasts. These results define the subtype-specific aberrant phenotypes of lung TAFs, thereby challenging the common assumption that lung TAFs are a heterogeneous myofibroblast-like cell population regardless of their subtype. Importantly, because LCC often distinguishes itself in the clinic by its aggressive nature, we argue that senescent TAFs may contribute to the selective aggressive behavior of LCC tumors.

  19. Protein-SIP in environmental studies.

    PubMed

    Jehmlich, Nico; Vogt, Carsten; Lünsmann, Vanessa; Richnow, Hans Hermann; von Bergen, Martin

    2016-10-01

    Metaproteomics coupled to stable isotope probing (SIP) was established to detect metabolically active key players in microbial communities. Here, we discuss the current state of protein-based stable isotope probing (protein-SIP) and the perspectives of using different stable isotope atoms (i.e. (13)C, (15)N, (18)O, (34/36)S), multiple isotope labelling, the utilisation of substrates of major abundance and micro-pollutants [pesticides, herbicides and pharmaceuticals present in the environment at very low concentrations (ngμg/L)], and applications in complex model systems and in situ studies in the environment.

  20. Infrastructure State Implementation Plan (SIP) Requirements and Guidance

    EPA Pesticide Factsheets

    The Clean Air Act requires states to submit SIPs that implement, maintain, and enforce a new or revised national ambient air quality standard (NAAQS) within 3 years of EPA issuing the standard. The Infrastructure SIP is required for all states.

  1. 46 CFR 8.540 - Enrollment in SIP.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 46 Shipping 1 2010-10-01 2010-10-01 false Enrollment in SIP. 8.540 Section 8.540 Shipping COAST... ALTERNATIVES Streamlined Inspection Program § 8.540 Enrollment in SIP. Upon successful completion of the training and evaluation phase, the Coast Guard SIP Advisor will recommend to the OCMI that the company...

  2. 40 CFR 93.151 - State implementation plan (SIP) revision.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 21 2012-07-01 2012-07-01 false State implementation plan (SIP... implementation plan (SIP) revision. The provisions and requirements of this subpart to demonstrate conformity... nonattainment and maintenance areas where EPA has not approved the General Conformity SIP revision allowed...

  3. 40 CFR 93.151 - State implementation plan (SIP) revision.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 21 2013-07-01 2013-07-01 false State implementation plan (SIP... implementation plan (SIP) revision. The provisions and requirements of this subpart to demonstrate conformity... nonattainment and maintenance areas where EPA has not approved the General Conformity SIP revision allowed...

  4. 40 CFR 57.108 - Comparable existing SIP provisions.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 6 2012-07-01 2012-07-01 false Comparable existing SIP provisions. 57... (CONTINUED) PRIMARY NONFERROUS SMELTER ORDERS General § 57.108 Comparable existing SIP provisions... subject under the applicable EPA-approved State Implementation Plan (SIP) for sulfur dioxide in lieu...

  5. 40 CFR 52.2182 - PM10 Committal SIP.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 5 2013-07-01 2013-07-01 false PM10 Committal SIP. 52.2182 Section 52...) APPROVAL AND PROMULGATION OF IMPLEMENTATION PLANS (CONTINUED) South Dakota § 52.2182 PM10 Committal SIP. On July 12 1988, the State submitted a Committal SIP for the Rapid City Group II PM10 area, as required...

  6. 40 CFR 52.2182 - PM10 Committal SIP.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 4 2011-07-01 2011-07-01 false PM10 Committal SIP. 52.2182 Section 52...) APPROVAL AND PROMULGATION OF IMPLEMENTATION PLANS (CONTINUED) South Dakota § 52.2182 PM10 Committal SIP. On July 12 1988, the State submitted a Committal SIP for the Rapid City Group II PM10 area, as required...

  7. 40 CFR 52.2182 - PM10 Committal SIP.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 5 2014-07-01 2014-07-01 false PM10 Committal SIP. 52.2182 Section 52...) APPROVAL AND PROMULGATION OF IMPLEMENTATION PLANS (CONTINUED) South Dakota § 52.2182 PM10 Committal SIP. On July 12 1988, the State submitted a Committal SIP for the Rapid City Group II PM10 area, as required...

  8. 46 CFR 8.540 - Enrollment in SIP.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 46 Shipping 1 2011-10-01 2011-10-01 false Enrollment in SIP. 8.540 Section 8.540 Shipping COAST... ALTERNATIVES Streamlined Inspection Program § 8.540 Enrollment in SIP. Upon successful completion of the training and evaluation phase, the Coast Guard SIP Advisor will recommend to the OCMI that the company...

  9. 40 CFR 93.151 - State implementation plan (SIP) revision.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 20 2010-07-01 2010-07-01 false State implementation plan (SIP... implementation plan (SIP) revision. The Federal conformity rules under this subpart, in addition to any existing... requirements until such time as the required conformity SIP revision is approved by EPA. A State's...

  10. 40 CFR 51.851 - State Implementation Plan (SIP) revision.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 2 2010-07-01 2010-07-01 false State Implementation Plan (SIP... Plan (SIP) revision. Link to an amendment published at 75 FR 17272, April 5, 2010. (a) Each State must... to meet the Act requirements until such time as the required conformity SIP revision is approved...

  11. 46 CFR 8.540 - Enrollment in SIP.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 46 Shipping 1 2014-10-01 2014-10-01 false Enrollment in SIP. 8.540 Section 8.540 Shipping COAST... ALTERNATIVES Streamlined Inspection Program § 8.540 Enrollment in SIP. Upon successful completion of the training and evaluation phase, the Coast Guard SIP Advisor will recommend to the OCMI that the company...

  12. 40 CFR 93.151 - State implementation plan (SIP) revision.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 20 2011-07-01 2011-07-01 false State implementation plan (SIP... implementation plan (SIP) revision. The provisions and requirements of this subpart to demonstrate conformity... nonattainment and maintenance areas where EPA has not approved the General Conformity SIP revision allowed...

  13. 46 CFR 8.540 - Enrollment in SIP.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 46 Shipping 1 2012-10-01 2012-10-01 false Enrollment in SIP. 8.540 Section 8.540 Shipping COAST... ALTERNATIVES Streamlined Inspection Program § 8.540 Enrollment in SIP. Upon successful completion of the training and evaluation phase, the Coast Guard SIP Advisor will recommend to the OCMI that the company...

  14. 46 CFR 8.540 - Enrollment in SIP.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 46 Shipping 1 2013-10-01 2013-10-01 false Enrollment in SIP. 8.540 Section 8.540 Shipping COAST... ALTERNATIVES Streamlined Inspection Program § 8.540 Enrollment in SIP. Upon successful completion of the training and evaluation phase, the Coast Guard SIP Advisor will recommend to the OCMI that the company...

  15. 40 CFR 93.151 - State implementation plan (SIP) revision.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 20 2014-07-01 2013-07-01 true State implementation plan (SIP... implementation plan (SIP) revision. The provisions and requirements of this subpart to demonstrate conformity... nonattainment and maintenance areas where EPA has not approved the General Conformity SIP revision allowed...

  16. 40 CFR 57.108 - Comparable existing SIP provisions.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 6 2013-07-01 2013-07-01 false Comparable existing SIP provisions. 57... (CONTINUED) PRIMARY NONFERROUS SMELTER ORDERS General § 57.108 Comparable existing SIP provisions... subject under the applicable EPA-approved State Implementation Plan (SIP) for sulfur dioxide in lieu...

  17. 40 CFR 57.108 - Comparable existing SIP provisions.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 5 2011-07-01 2011-07-01 false Comparable existing SIP provisions. 57... (CONTINUED) PRIMARY NONFERROUS SMELTER ORDERS General § 57.108 Comparable existing SIP provisions... subject under the applicable EPA-approved State Implementation Plan (SIP) for sulfur dioxide in lieu...

  18. 40 CFR 52.2182 - PM10 Committal SIP.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 4 2010-07-01 2010-07-01 false PM10 Committal SIP. 52.2182 Section 52...) APPROVAL AND PROMULGATION OF IMPLEMENTATION PLANS (CONTINUED) South Dakota § 52.2182 PM10 Committal SIP. On July 12 1988, the State submitted a Committal SIP for the Rapid City Group II PM10 area, as required...

  19. 40 CFR 57.108 - Comparable existing SIP provisions.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 5 2010-07-01 2010-07-01 false Comparable existing SIP provisions. 57... (CONTINUED) PRIMARY NONFERROUS SMELTER ORDERS General § 57.108 Comparable existing SIP provisions... subject under the applicable EPA-approved State Implementation Plan (SIP) for sulfur dioxide in lieu...

  20. 40 CFR 57.108 - Comparable existing SIP provisions.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 6 2014-07-01 2014-07-01 false Comparable existing SIP provisions. 57... (CONTINUED) PRIMARY NONFERROUS SMELTER ORDERS General § 57.108 Comparable existing SIP provisions... subject under the applicable EPA-approved State Implementation Plan (SIP) for sulfur dioxide in lieu...

  1. 40 CFR 52.2182 - PM10 Committal SIP.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 5 2012-07-01 2012-07-01 false PM10 Committal SIP. 52.2182 Section 52...) APPROVAL AND PROMULGATION OF IMPLEMENTATION PLANS (CONTINUED) South Dakota § 52.2182 PM10 Committal SIP. On July 12 1988, the State submitted a Committal SIP for the Rapid City Group II PM10 area, as required...

  2. Transcriptional networks in leaf senescence.

    PubMed

    Schippers, Jos H M

    2015-10-01

    Plant senescence is a natural phenomenon known for the appearance of beautiful autumn colors and the ripening of cereals in the field. Senescence is a controlled process that plants utilize to remobilize nutrients from source leaves to developing tissues. While during the past decades, molecular components underlying the onset of senescence have been intensively studied, knowledge remains scarce on the age-dependent mechanisms that control the onset of senescence. Recent advances have uncovered transcriptional networks regulating the competence to senesce. Here, gene regulatory networks acting as internal timing mechanisms for the onset of senescence are highlighted, illustrating that early and late leaf developmental phases are highly connected.

  3. Senescence, aging, and disease.

    PubMed

    Crews, Douglas E

    2007-05-01

    All over the world people are surviving into their seventh and later decades of life more frequently today than ever before in human history. Some remain in good health, while others show chronic degenerative conditions (CDCs), frailty, and relatively rapid mortality. Thereafter, multiple factors promoting health and well-being become ever more complex as we age. After attainment of reproductive maturation, many physiological decrements occurring in concert with age reflect both senescent and disease processes, not simply the passage of time. Senescence is a process that begins with DNA, molecules and cells and ultimately terminates in cellular death, loss of organ function, and somatic frailty. These changes are different from benign changes with age that do not alter function. Both differ from the pathological processes represented by disease. Either disease or senescence may be age-related, but neither is age-determined. Disease results from pathological alterations and it affects all age groups. Diseases need not be related to senescence, which includes alterations due to inherent aspects of organismal biology. Distinctions among senescence, aging, and disease blur for the late-life CDCs because, in addition to disease processes, many CDCs are phenotypic manifestations of senescing DNA, organelles, cells, and organs. During earlier epochs of human evolution, greater environmental exposures and fewer cultural buffers likely lead to greater frailty and mortality before senescence progressed greatly, as they still do for most animals. In modern-day settings, culturally patterned behaviors have allowed human frailty to become disconnected somewhat from mortality, unlike non-human species.

  4. The role of nuclear lamin B1 in cell proliferation and senescence

    PubMed Central

    Shimi, Takeshi; Butin-Israeli, Veronika; Adam, Stephen A.; Hamanaka, Robert B.; Goldman, Anne E.; Lucas, Catherine A.; Shumaker, Dale K.; Kosak, Steven T.; Chandel, Navdeep S.; Goldman, Robert D.

    2011-01-01

    Nuclear lamin B1 (LB1) is a major structural component of the nucleus that appears to be involved in the regulation of many nuclear functions. The results of this study demonstrate that LB1 expression in WI-38 cells decreases during cellular senescence. Premature senescence induced by oncogenic Ras also decreases LB1 expression through a retinoblastoma protein (pRb)-dependent mechanism. Silencing the expression of LB1 slows cell proliferation and induces premature senescence in WI-38 cells. The effects of LB1 silencing on proliferation require the activation of p53, but not pRb. However, the induction of premature senescence requires both p53 and pRb. The proliferation defects induced by silencing LB1 are accompanied by a p53-dependent reduction in mitochondrial reactive oxygen species (ROS), which can be rescued by growth under hypoxic conditions. In contrast to the effects of LB1 silencing, overexpression of LB1 increases the proliferation rate and delays the onset of senescence of WI-38 cells. This overexpression eventually leads to cell cycle arrest at the G1/S boundary. These results demonstrate the importance of LB1 in regulating the proliferation and senescence of human diploid cells through a ROS signaling pathway. PMID:22155925

  5. The basics of prematurity.

    PubMed

    Kelly, Michelle M

    2006-01-01

    Prematurity is the greatest single risk factor for death within the first year of life. The March of Dimes and Centers for Disease Control and Prevention define prematurity as birth before the completion of 37 weeks' gestation. In 2002, one in eight babies were delivered prematurely. This manuscript is Part I of a three-part series on premature infants. The overall goal of this series is to educate pediatric primary care providers regarding topics specific to delivering care to premature infants after discharge. Part I addresses the incidence of prematurity and the terminology used in neonatal literature and provides an overview of common comorbidities associated with prematurity. Part II will focus on the primary care management of uncomplicated premature infants. Part III will highlight issues of primary care for medically complex premature infants.

  6. A small molecule inhibitor of PAI-1 protects against doxorubicin-induced cellular senescence

    PubMed Central

    Ghosh, Asish K.; Rai, Rahul; Park, Kitae E.; Eren, Mesut; Miyata, Toshio; Wilsbacher, Lisa D.; Vaughan, Douglas E.

    2016-01-01

    Doxorubicin, an anthracycline antibiotic, is a commonly used anticancer drug. In spite of its widespread usage, its therapeutic effect is limited by its cardiotoxicity. On the cellular level, Doxorubicin-induced cardiotoxicity manifests as stress induced premature senescence. Previously, we demonstrated that plasminogen activator inhibitor-1 (PAI-1), a potent inhibitor of serine proteases, is an important biomarker and regulator of cellular senescence and aging. Here, we tested the hypothesis that pharmacological inhibition of cellular PAI-1 protects against stress- and aging-induced cellular senescence and delineated the molecular basis of protective action of PAI-1 inhibition. Results show that TM5441, a potent small molecule inhibitor of PAI-1, effectively prevents Doxorubicin-induced senescence in cardiomyocytes, fibroblasts and endothelial cells. TM5441 exerts its inhibitory effect on Doxorubicin-induced cellular senescence by decreasing reactive oxygen species generation, induction of antioxidants like catalase and suppression of stress-induced senescence cadre p53, p21, p16, PAI-1 and IGFBP3. Importantly, TM5441 also reduces replicative senescence of fibroblasts. Together these results for the first time demonstrate the efficacy of PAI-1 inhibitor in prevention of Doxorubicin-induced and replicative senescence in normal cells. Thus PAI-1 inhibitor may form an important adjuvant component of chemotherapy regimens, limiting not only Doxorubicin-induced cardiac senescence but also ameliorating the prothrombotic profile. PMID:27736799

  7. Caring for Your Premature Baby

    MedlinePlus

    ... hearing problems, immunization, immunizations, low birth weight, neonatal intensive care unit, newborn, NICU, patient education, patient information, pediatric, preemie, premature, premature babies, prematurity, premie, respiratory syncytial ...

  8. Your Premature Baby

    MedlinePlus

    ... Search Our mission Fighting premature birth About us Annual report Our work Community impact Global programs Research Need ... Cause Our mission Fighting premature birth About us Annual report Our work Community impact Global programs Research Need ...

  9. Whole Chromosome Instability induces senescence and promotes SASP

    PubMed Central

    Andriani, Grasiella Angelina; Almeida, Vinnycius Pereira; Faggioli, Francesca; Mauro, Maurizio; Tsai, Wanxia Li; Santambrogio, Laura; Maslov, Alexander; Gadina, Massimo; Campisi, Judith; Vijg, Jan; Montagna, Cristina

    2016-01-01

    Age-related accumulation of ploidy changes is associated with decreased expression of genes controlling chromosome segregation and cohesin functions. To determine the consequences of whole chromosome instability (W-CIN) we down-regulated the spindle assembly checkpoint component BUB1 and the mitotic cohesin SMC1A, and used four-color-interphase-FISH coupled with BrdU incorporation and analyses of senescence features to reveal the fate of W-CIN cells. We observed significant correlations between levels of not-diploid cells and senescence-associated features (SAFs). W-CIN induced DNA double strand breaks and elevated oxidative stress, but caused low apoptosis. SAFs of W-CIN cells were remarkably similar to those induced by replicative senescence but occurred in only 13 days versus 4 months. Cultures enriched with not-diploid cells acquired a senescence-associated secretory phenotype (SASP) characterized by IL1B, CXCL8, CCL2, TNF, CCL27 and other pro-inflammatory factors including a novel SASP component CLEC11A. These findings suggest that W-CIN triggers premature senescence, presumably to prevent the propagation of cells with an abnormal DNA content. Cells deviating from diploidy have the ability to communicate with their microenvironment by secretion of an array of signaling factors. Our results suggest that aneuploid cells that accumulate during aging in some mammalian tissues potentially contribute to age-related pathologies and inflammation through SASP secretion. PMID:27731420

  10. Retinopathy of Prematurity

    ERIC Educational Resources Information Center

    Steinweg, Sue Byrd; Griffin, Harold C.; Griffin, Linda W.; Gingras, Happy

    2005-01-01

    The eyes of premature infants are especially vulnerable to injury after birth. A serious complication is called retinopathy of prematurity (ROP), which is abnormal growth of the blood vessels in an infant's eye. Retinopathy of prematurity develops when abnormal blood vessels grow and spread throughout the retina, which is the nerve tissue at the…

  11. Application of Borehole SIP Technique to Sulfide Mineral Exploration

    NASA Astrophysics Data System (ADS)

    Kim, Changryol; Park, Mi Kyung; Park, Samgyu; Sung, Nak Hoon; Shin, Seung Wook

    2016-04-01

    In the study, SIP (Spectral Induced Polarization) well logging probe system was developed to rapidly locate the metal ore bodies with sulfide minerals in the boreholes. The newly developed SIP logging probe employed the non-polarizable electrodes, consisting of zinc chloride (ZnCl2), sodium chloride (NaCl), gypsum (CaSO4·2H2O), and water (H2O), instead of existing copper electrodes, leading to eliminating the EM coupling effect in the IP surveys as much as possible. In addition, the SIP logging system is designed to make measurements down to maximum 500 meters in depth in the boreholes. The SIP well logging was conducted to examine the applicability of the SIP probe system to the boreholes at the ore mine in Jecheon area, Korea. The boreholes used in the SIP logging are known to have penetrated the metal ore bodies with sulfide minerals from the drilling investigations. The ore mine of the study area is the scarn deposits surrounded by the limestone or lime-silicate rocks in Ordovician period. The results of the SIP well logging have shown that the borehole segments with limestone or lime-silicate rocks yielded the insignificant SIP responses while the borehole segments with sulfide minerals (e.g. pyrite) provided the significant phase shifts of the SIP responses. The borehole segments penetrating the metal ore body, so-called cupola, have shown very high response of the phase shift, due to the high contents of the sulfide mineral pyrite. The phase shifts of the SIP response could be used to estimate the grade of the ore bodies since the higher contents of the sulfide minerals, the higher magnitudes of the phase shifts in the SIP responses. It is, therefore, believed that the borehole SIP technique can be applied to investigate the metal ore bodies with sulfide minerals, and that could be used to estimate the ore grades as a supplementary tool in the future.

  12. Prematurity and potential predictors.

    PubMed

    Field, Tiffany; Diego, Miguel; Hernandez-Reif, Maria

    2008-02-01

    Prematurity continues to be the leading cause of neonatal death and developmental disability, highlighting the importance of identifying potential predictors of prematurity as well as interventions that can be linked to the predictors. This review covers recent research on potential psychological, physiological, and biochemical predictors. Among the psychological stressors are depression, anxiety, difficult relationships, and lack of social support. Biochemical predictors include corticotropin-releasing hormone, cortisol, and fetal fibronectin. A program of research that links an intervention for prematurity with a predictor for prematurity, that is, massage therapy to reduce cortisol and, in turn, reduce prematurity, is then presented.

  13. Induction of Nuclear Enlargement and Senescence by Sirtuin Inhibitors in Glioblastoma Cells.

    PubMed

    Yoon, Kyoung B; Park, Kyeong R; Kim, Soo Y; Han, Sun-Young

    2016-06-01

    Sirtuin family members with lysine deacetylase activity are known to play an important role in anti-aging and longevity. Cellular senescence is one of the hallmarks of aging, and downregulation of sirtuin is reported to induce premature senescence. In this study, we investigated the effects of small-molecule sirtuin inhibitors on cellular senescence. Various small molecules such as tenovin-1 and EX527 were employed for direct sirtuin activity inhibition. U251, SNB-75, and U87MG glioblastoma cells treated with sirtuin inhibitors exhibited phenotypes with nuclear enlargement. Furthermore, treatment of rat primary astrocytes with tenovin-1 also increased the size of the nucleus. The activity of senescence-associated β-galactosidase, a marker of cellular senescence, was induced by tenovin-1 and EX527 treatment in U87MG glioblastoma cells. Consistent with the senescent phenotype, treatment with tenovin-1 increased p53 expression in U87MG cells. This study demonstrated the senescence-inducing effect of sirtuin inhibitors, which are potentially useful tools for senescence research.

  14. Foam cell-derived 4-hydroxynonenal induces endothelial cell senescence in a TXNIP-dependent manner.

    PubMed

    Riahi, Yael; Kaiser, Nurit; Cohen, Guy; Abd-Elrahman, Ihab; Blum, Galia; Shapira, Oz M; Koler, Tomer; Simionescu, Maya; Sima, Anca V; Zarkovic, Neven; Zarkovic, Kamelija; Orioli, Marica; Aldini, Giancarlo; Cerasi, Erol; Leibowitz, Gil; Sasson, Shlomo

    2015-08-01

    Vascular endothelial cell (VEC) senescence is considered an early event in the development of atherosclerotic lesions. Stressful stimuli, in particular oxidative stress, have been linked to premature senescence in the vasculature. Foam cells are a major source of reactive oxygen species and may play a role in the induction of VEC senescence; hence, we investigated their involvement in the induction of VEC senescence in a co-culture transwell system. Primary bovine aortic endothelial cells, exposed to the secretome of THP-1 monocyte-derived foam cells, were analysed for the induction of senescence. Senescence associated β-galactosidase activity and the expression of p16 and p21 were increased, whereas phosphorylated retinoblastoma protein was reduced. This senescent phenotype was mediated by 4-hydroxnonenal (4-HNE), a lipid peroxidation product secreted from foam cells; scavenging of 4-HNE in the co-culture medium blunted this effect. Furthermore, both foam cells and 4-HNE increased the expression of the pro-oxidant thioredoxin-interacting protein (TXNIP). Molecular manipulation of TXNIP expression confirmed its involvement in foam cell-induced senescence. Previous studies showed that peroxisome proliferator-activated receptor (PPAR)δ was activated by 4-hydroalkenals, such as 4-HNE. Pharmacological interventions supported the involvement of the 4-HNE-PPARδ axis in the induction of TXNIP and VEC senescence. The association of TXNIP with VEC senescence was further supported by immunofluorescent staining of human carotid plaques in which the expression of both TXNIP and p21 was augmented in endothelial cells. Collectively, these findings suggest that foam cell-released 4-HNE activates PPARδ in VEC, leading to increased TXNIP expression and consequently to senescence.

  15. 75 FR 32190 - Disease, Disability, and Injury Prevention and Control Special Interest Projects (SIPs): SIP 10...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-06-07

    ... School Start Times on the Health and Academic Performance of High School Students.'' Contact Person for... Among Underserved Populations and SIP 10-035, Impact of High School Start Times on the Health and Academic Performance of High School Students, Initial Review In accordance with Section 10(a)(2) of...

  16. 75 FR 30410 - Disease, Disability, and Injury Prevention and Control Special Interest Projects (SIPs): Outcomes...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-06-01

    ... Evaluations Within Africa and Asia under the President's Emergency Plan for AIDS Relief (PEPFAR) SIP 10-034... Support for Health Systems Evaluations within Africa and Asia under PEPFAR, SIP 10-034 and SIP...

  17. A structural basis for cellular senescence

    PubMed Central

    Aranda-Anzaldo, Armando

    2009-01-01

    Replicative senescence (RS) that limits the proliferating potential of normal eukaryotic cells occurs either by a cell-division counting mechanism linked to telomere erosion or prematurely through induction by cell stressors such as oncogene hyper-activation. However, there is evidence that RS also occurs by a stochastic process that is independent of number of cell divisions or cellular stress and yet it leads to a highly-stable, non-reversible post-mitotic state that may be long-lasting and that such a process is widely represented among higher eukaryotes. Here I present and discuss evidence that the interactions between DNA and the nuclear substructure, commonly known as the nuclear matrix, define a higher-order structure within the cell nucleus that following thermodynamic constraints, stochastically evolves towards maximum stability, thus becoming limiting for mitosis to occur. It is suggested that this process is responsible for ultimate replicative senescence and yet it is compatible with long-term cell survival. PMID:20157542

  18. Four faces of cellular senescence

    PubMed Central

    Rodier, Francis

    2011-01-01

    Cellular senescence is an important mechanism for preventing the proliferation of potential cancer cells. Recently, however, it has become apparent that this process entails more than a simple cessation of cell growth. In addition to suppressing tumorigenesis, cellular senescence might also promote tissue repair and fuel inflammation associated with aging and cancer progression. Thus, cellular senescence might participate in four complex biological processes (tumor suppression, tumor promotion, aging, and tissue repair), some of which have apparently opposing effects. The challenge now is to understand the senescence response well enough to harness its benefits while suppressing its drawbacks. PMID:21321098

  19. Effects of substrate deformation and sip thickness on tile/sip interface stresses for shuttle thermal protection

    NASA Technical Reports Server (NTRS)

    Shore, C. P.; Garcia, R.

    1980-01-01

    A nonlinear analysis was used to study the effects of substrate deformation characteristics and strain isolator pad (SIP) thickness on TILE/SIP interface stresses for the space shuttle thermal protection system. The configuration analyzed consisted of a 5.08 cm thick, 15.24 cm square tile with a 12.7 cm square SIP footprint bordered by a 1.27 cm wide filler bar and was subjected to forces and moments representative of a 20.7 kPa aerodynamic shock passing over the tile. The SIP stress deflection curves were obtained after a 69 kPa proof load and 100 cycles conditioning at 55 kPa. The TILE/SIP interface stresses increase over flat substrate values for zero to peak substrate deformation amplitudes up to 0.191 cm by up to a factor of nearly five depending on deformation amplitude, half wave length, and location. Stresses for a 0.23 cm thick SIP found to be up to 60 percent greater than for a 0.41 cm thick SIP for identical loads and substrate deformation characteristics. A simplified method was developed for approximating the substrate location which produces maximum TILE/SIP interface stresses.

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

    PubMed Central

    Sakaki, Mizuho; Ebihara, Yukiko; Okamura, Kohji; Nakabayashi, Kazuhiko; Igarashi, Arisa; Matsumoto, Kenji; Hata, Kenichiro; Kobayashi, Yoshiro

    2017-01-01

    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. PMID:28158250

  1. Alteration of the phenology of leaf senescence and fall in winter deciduous species by climate change: effects on nutrient proficiency.

    PubMed

    Estiarte, Marc; Peñuelas, Josep

    2015-03-01

    Leaf senescence in winter deciduous species signals the transition from the active to the dormant stage. The purpose of leaf senescence is the recovery of nutrients before the leaves fall. Photoperiod and temperature are the main cues controlling leaf senescence in winter deciduous species, with water stress imposing an additional influence. Photoperiod exerts a strict control on leaf senescence at latitudes where winters are severe and temperature gains importance in the regulation as winters become less severe. On average, climatic warming will delay and drought will advance leaf senescence, but at varying degrees depending on the species. Warming and drought thus have opposite effects on the phenology of leaf senescence, and the impact of climate change will therefore depend on the relative importance of each factor in specific regions. Warming is not expected to have a strong impact on nutrient proficiency although a slower speed of leaf senescence induced by warming could facilitate a more efficient nutrient resorption. Nutrient resorption is less efficient when the leaves senesce prematurely as a consequence of water stress. The overall effects of climate change on nutrient resorption will depend on the contrasting effects of warming and drought. Changes in nutrient resorption and proficiency will impact production in the following year, at least in early spring, because the construction of new foliage relies almost exclusively on nutrients resorbed from foliage during the preceding leaf fall. Changes in the phenology of leaf senescence will thus impact carbon uptake, but also ecosystem nutrient cycling, especially if the changes are consequence of water stress.

  2. Senescence induced by RECQL4 dysfunction contributes to Rothmund–Thomson syndrome features in mice

    PubMed Central

    Lu, H; Fang, E F; Sykora, P; Kulikowicz, T; Zhang, Y; Becker, K G; Croteau, D L; Bohr, V A

    2014-01-01

    Cellular senescence refers to irreversible growth arrest of primary eukaryotic cells, a process thought to contribute to aging-related degeneration and disease. Deficiency of RecQ helicase RECQL4 leads to Rothmund–Thomson syndrome (RTS), and we have investigated whether senescence is involved using cellular approaches and a mouse model. We first systematically investigated whether depletion of RECQL4 and the other four human RecQ helicases, BLM, WRN, RECQL1 and RECQL5, impacts the proliferative potential of human primary fibroblasts. BLM-, WRN- and RECQL4-depleted cells display increased staining of senescence-associated β-galactosidase (SA-β-gal), higher expression of p16INK4a or/and p21WAF1 and accumulated persistent DNA damage foci. These features were less frequent in RECQL1- and RECQL5-depleted cells. We have mapped the region in RECQL4 that prevents cellular senescence to its N-terminal region and helicase domain. We further investigated senescence features in an RTS mouse model, Recql4-deficient mice (Recql4HD). Tail fibroblasts from Recql4HD showed increased SA-β-gal staining and increased DNA damage foci. We also identified sparser tail hair and fewer blood cells in Recql4HD mice accompanied with increased senescence in tail hair follicles and in bone marrow cells. In conclusion, dysfunction of RECQL4 increases DNA damage and triggers premature senescence in both human and mouse cells, which may contribute to symptoms in RTS patients. PMID:24832598

  3. Copper induces cellular senescence in human glioblastoma multiforme cells through downregulation of Bmi-1.

    PubMed

    Li, Yuan; Hu, Jifan; Guan, Fangxia; Song, Laijun; Fan, Ruitai; Zhu, Huaijie; Hu, Xiang; Shen, Eileen; Yang, Bo

    2013-05-01

    Most human tumor cells, including glioblastoma multiforme (GBM) cells, have aberrant control of cell aging and apoptosis. Subcytotoxic concentrations of oxidative or stress‑causing agents, such as hydrogen peroxide, may induce human cell senescence. Thus, induction of tumor cells into premature senescence may provide a useful in vitro model for developing novel therapeutic strategy to combat tumors. In the present study, we assessed the molecular mechanism(s) underlying senescence in GBM cells induced by copper sulfate. Following pretreatment with subcytotoxic concentrations of copper sulfate, U87-MG tumor cells showed typical aging characteristics, including reduced cell proliferation, cell enlargement, increased level of senescence-associated β-galactosidase (SA β-gal) activity, and overexpression of several senescence-associated genes, p16, p21, transforming growth factor β-1 (TGF-β1), insulin growth factor binding protein 3 (IGFBP3) and apolipoprotein J (ApoJ). We further demonstrated that the Bmi-1 pathway was downregulated in GBM cells in parallel with the induced senescence. The present study for the first time demonstrates the ability of copper to induce GBM cell senescence by downregulating Bmi-1.

  4. Retinopathy of Prematurity.

    ERIC Educational Resources Information Center

    Trief, E.; And Others

    1989-01-01

    Retinopathy of prematurity (ROP) has increased due to a high incidence of premature, low birthweight infants. Stages of severity range from no visual damage to total blindness, and educational problems of ROP children parallel those of other visually impaired children, early intervention being crucial. Treatments are either pharmacological or…

  5. Family Perspectives on Prematurity

    ERIC Educational Resources Information Center

    Zero to Three (J), 2003

    2003-01-01

    In this article, seven families describe their experiences giving birth to and raising a premature baby. Their perspectives vary, one from another, and shift over time, depending on each family's circumstances and the baby's developmental course. Experiences discussed include premature labor, medical interventions and the NICU, bringing the baby…

  6. Lamin B1 depletion in senescent cells triggers large-scale changes in gene expression and the chromatin landscape

    PubMed Central

    Shah, Parisha P.; Donahue, Greg; Otte, Gabriel L.; Capell, Brian C.; Nelson, David M.; Cao, Kajia; Aggarwala, Varun; Cruickshanks, Hazel A.; Rai, Taranjit Singh; McBryan, Tony; Gregory, Brian D.; Adams, Peter D.; Berger, Shelley L.

    2013-01-01

    Senescence is a stable proliferation arrest, associated with an altered secretory pathway, thought to promote tumor suppression and tissue aging. While chromatin regulation and lamin B1 down-regulation have been implicated as senescence effectors, functional interactions between them are poorly understood. We compared genome-wide Lys4 trimethylation on histone H3 (H3K4me3) and H3K27me3 distributions between proliferating and senescent human cells and found dramatic differences in senescence, including large-scale domains of H3K4me3- and H3K27me3-enriched “mesas” and H3K27me3-depleted “canyons.” Mesas form at lamin B1-associated domains (LADs) in replicative senescence and oncogene-induced senescence and overlap DNA hypomethylation regions in cancer, suggesting that pre-malignant senescent chromatin changes foreshadow epigenetic cancer changes. Hutchinson-Gilford progeria syndrome fibroblasts (mutant lamin A) also show evidence of H3K4me3 mesas, suggesting a link between premature chromatin changes and accelerated cell senescence. Canyons mostly form between LADs and are enriched in genes and enhancers. H3K27me3 loss is correlated with up-regulation of key senescence genes, indicating a link between global chromatin changes and local gene expression regulation. Lamin B1 reduction in proliferating cells triggers senescence and formation of mesas and canyons. Our data illustrate profound chromatin reorganization during senescence and suggest that lamin B1 down-regulation in senescence is a key trigger of global and local chromatin changes that impact gene expression, aging, and cancer. PMID:23934658

  7. Intracellular oxidant activity, antioxidant enzyme defense system, and cell senescence in fibroblasts with trisomy 21.

    PubMed

    Rodríguez-Sureda, Víctor; Vilches, Ángel; Sánchez, Olga; Audí, Laura; Domínguez, Carmen

    2015-01-01

    Down's syndrome (DS) is characterized by a complex phenotype associated with chronic oxidative stress and mitochondrial dysfunction. Overexpression of genes on chromosome-21 is thought to underlie the pathogenesis of the major phenotypic features of DS, such as premature aging. Using cultured fibroblasts with trisomy 21 (T21F), this study aimed to ascertain whether an imbalance exists in activities, mRNA, and protein expression of the antioxidant enzymes SOD1, SOD2, glutathione-peroxidase, and catalase during the cell replication process in vitro. T21F had high SOD1 expression and activity which led to an interenzymatic imbalance in the antioxidant defense system, accentuated with replicative senescence. Intracellular ROS production and oxidized protein levels were significantly higher in T21F compared with control cells; furthermore, a significant decline in intracellular ATP content was detected in T21F. Cell senescence was found to appear prematurely in DS cells as shown by SA-β-Gal assay and p21 assessment, though not apoptosis, as neither p53 nor the proapoptotic proteins cytochrome c and caspase 9 were altered in T21F. These novel findings would point to a deleterious role of oxidatively modified molecules in early cell senescence of T21F, thereby linking replicative and stress-induced senescence in cultured cells to premature aging in DS.

  8. Premature ovarian failure.

    PubMed

    Kalantaridou, S N; Davis, S R; Nelson, L M

    1998-12-01

    In 1% of women, premature ovarian failure develops by 40 years of age, a condition causing amenorrhea, infertility, sex steroid deficiency, and elevated gonadotropins. Early loss of ovarian function has significant psychosocial sequelae and major health implications. These young women have a nearly two-fold age-specific increase in mortality rate. Among women with spontaneous premature ovarian failure who have a normal karyotype, half have ovarian follicles remaining in the ovary that function intermittently. Indeed, pregnancies have occurred after the diagnosis of premature ovarian failure. Thus, premature ovarian failure should not be considered as a premature menopause. Young women with this disorder have a 5% to 10% chance for spontaneous pregnancy. Attempts at ovulation induction using various regimens fail to induce ovulation rates greater than those seen in untreated patients; however, oocyte donation for women desiring fertility is an option. Young women with premature ovarian failure need a thorough assessment, sex steroid replacement, and long-term surveillance to monitor therapy. Estrogen-progestin replacement therapy should be instituted as soon as the diagnosis is made. Androgen replacement should also be considered for women with low libido, persistent fatigue, and poor well-being despite taking adequate estrogen replacement. Women with premature ovarian failure should be followed up for the presence of associated autoimmune endocrine disorders such as hypothyroidism, adrenal insufficiency, and diabetes mellitus.

  9. 40 CFR 52.331 - Committal SIP for the Colorado Group II PM10 areas.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 3 2014-07-01 2014-07-01 false Committal SIP for the Colorado Group II... SIP for the Colorado Group II PM10 areas. On April 14, 1989, the Governor submitted a Committal SIP for the Colorado Group II PM10 areas. The SIP commits the State to continue to monitor for...

  10. 40 CFR 52.331 - Committal SIP for the Colorado Group II PM10 areas.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 3 2010-07-01 2010-07-01 false Committal SIP for the Colorado Group II... SIP for the Colorado Group II PM10 areas. On April 14, 1989, the Governor submitted a Committal SIP for the Colorado Group II PM10 areas. The SIP commits the State to continue to monitor for...

  11. 40 CFR 52.331 - Committal SIP for the Colorado Group II PM10 areas.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 3 2013-07-01 2013-07-01 false Committal SIP for the Colorado Group II... SIP for the Colorado Group II PM10 areas. On April 14, 1989, the Governor submitted a Committal SIP for the Colorado Group II PM10 areas. The SIP commits the State to continue to monitor for...

  12. 76 FR 39797 - Approval and Promulgation of Implementation Plans; Connecticut; Infrastructure SIP for the 1997 8...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-07-07

    ... AGENCY 40 CFR Part 52 Approval and Promulgation of Implementation Plans; Connecticut; Infrastructure SIP... and submit a SIP for the implementation, maintenance and enforcement of each NAAQS promulgated by the EPA. This SIP is commonly referred to as an infrastructure SIP. The one element of the submittal...

  13. 46 CFR 8.570 - Interim approval of prototype SIP company or vessel plans.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 46 Shipping 1 2013-10-01 2013-10-01 false Interim approval of prototype SIP company or vessel... of prototype SIP company or vessel plans. (a) A company operating under an approved prototype SIP... continue operating under the plans while revisions are developed to bring the prototype SIP company...

  14. 46 CFR 8.570 - Interim approval of prototype SIP company or vessel plans.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 46 Shipping 1 2010-10-01 2010-10-01 false Interim approval of prototype SIP company or vessel... of prototype SIP company or vessel plans. (a) A company operating under an approved prototype SIP... continue operating under the plans while revisions are developed to bring the prototype SIP company...

  15. 46 CFR 8.570 - Interim approval of prototype SIP company or vessel plans.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 46 Shipping 1 2012-10-01 2012-10-01 false Interim approval of prototype SIP company or vessel... of prototype SIP company or vessel plans. (a) A company operating under an approved prototype SIP... continue operating under the plans while revisions are developed to bring the prototype SIP company...

  16. 40 CFR 52.331 - Committal SIP for the Colorado Group II PM10 areas.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 3 2011-07-01 2011-07-01 false Committal SIP for the Colorado Group II... SIP for the Colorado Group II PM10 areas. On April 14, 1989, the Governor submitted a Committal SIP for the Colorado Group II PM10 areas. The SIP commits the State to continue to monitor for...

  17. 46 CFR 8.570 - Interim approval of prototype SIP company or vessel plans.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 46 Shipping 1 2011-10-01 2011-10-01 false Interim approval of prototype SIP company or vessel... of prototype SIP company or vessel plans. (a) A company operating under an approved prototype SIP... continue operating under the plans while revisions are developed to bring the prototype SIP company...

  18. 40 CFR 52.331 - Committal SIP for the Colorado Group II PM10 areas.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 3 2012-07-01 2012-07-01 false Committal SIP for the Colorado Group II... SIP for the Colorado Group II PM10 areas. On April 14, 1989, the Governor submitted a Committal SIP for the Colorado Group II PM10 areas. The SIP commits the State to continue to monitor for...

  19. 46 CFR 8.570 - Interim approval of prototype SIP company or vessel plans.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 46 Shipping 1 2014-10-01 2014-10-01 false Interim approval of prototype SIP company or vessel... of prototype SIP company or vessel plans. (a) A company operating under an approved prototype SIP... continue operating under the plans while revisions are developed to bring the prototype SIP company...

  20. Flower senescence: some molecular aspects.

    PubMed

    Shahri, Waseem; Tahir, Inayatullah

    2014-02-01

    Some molecular aspects of flower senescence have been reviewed. The isolation, identification and characterization of different genes from various flowers (mainly from petals) associated with senescence have been discussed. The isolated genes were divided into different groups. A large proportion of genes have been found to be upregulated during flower senescence while some genes were also found to be downregulated indicating that there exists a complex interplay between the expression patterns of various genes. The genes involved in petal expansion are found to be upregulated during normal flower development from anthesis to open flower stage, but XTH (Xyloglucan endotransglucosylase hydrolase) is found to be involved in petal expansion as well as abscission. Cysteine proteases or the genes encoding cysteine proteases (assigned a central role in protein degradation) have been identified from various flower systems, but no cysteine protease has been identified from senescing Mirabilis jalapa flowers. In addition to proteases, the genes encoding ubiquitin (exhibiting proteasomal degradation by 26S proteasomes) have also been identified suggesting the two alternate pathways for protein degradation. Genes encoding specific nucleases have also been identified, but they displayed an early increase in transcript abundance before the senescence symptoms become evident and characterize the involvement of PCD during flower senescence. A range of transcription factors are described and their possible role in flower senescence has been discussed. A detailed description of genes involved in ethylene synthesis and the components involved in ethylene signaling have been presented.

  1. Cytokinin inhibition of leaf senescence

    PubMed Central

    Zwack, Paul J.; Rashotte, Aaron M.

    2013-01-01

    The senescence delaying effect of cytokinin is well known, however, the details behind how this process occurs remain unclear. Efforts to improve understanding of this phenomenon have led to the identification in Arabidopsis of specific cytokinin signaling components through which senescence signal responses are regulated. These include the cytokinin receptor (AHK3), the type-B response regulator (ARR2) and the recently identified cytokinin response factor (CRF6). At the mechanistic end of this process, it was found that increased cell-wall invertase activity which occurs in response to cytokinin is both necessary and sufficient for the inhibition of senescence. Yet, a direct link between the signaling and mechanistic steps of a cytokinin regulated senescence process has yet to be demonstrated. This may be in part because the relationship between senescence and primary metabolism implied by the key role of cell-wall invertase is the subject of two apparently opposing bodies of evidence. Here we briefly summarize and propose a model in which cytokinin mediated changes in sink/source relationships leads to delayed senescence which is consistent with existing evidence both for and against sugars as a trigger for developmental senescence. PMID:23656876

  2. Energy Efficiency and Renewable Energy in SIPs and TIPs

    EPA Pesticide Factsheets

    Tools and guides to encourage state, tribal and local agencies to consider incorporating Energy Efficiency (EE) and Renewable Energy (RE) policies and programs in their State and Tribal Implementation Plans (SIPs/TIPs).

  3. The potential role of CacyBP/SIP in tumorigenesis.

    PubMed

    Ning, Xiaoxuan; Chen, Yang; Wang, Xiaosu; Li, Qiaoneng; Sun, Shiren

    2016-08-01

    Calcyclin-binding protein/Siah-1-interacting protein (CacyBP/SIP) was initially described as a binding partner of S100A6 in the Ehrlich ascites tumor cells and later as a Siah-1-interacting protein. This 30 kDa protein includes three domains and is involved in cell proliferation, differentiation, cytoskeletal rearrangement, and transcriptional regulation via binding to various proteins. Studies have also shown that the CacyBP/SIP is a critical protein in tumorigenesis. But, its promotion or suppression of cancer progression may depend on the cell type. In this review, the biological characteristics and target proteins of CacyBP/SIP have been described. Moreover, the exact role of CacyBP/SIP in various cancers is discussed.

  4. Apnea of prematurity

    MedlinePlus

    Apnea - newborns; AOP; As and Bs; A/B/D; Blue spell - newborns; Dusky spell - newborns; Spell - newborns; Apnea - neonatal ... the airway open are weak Other stresses in a sick or premature baby may worsen apnea, including: ...

  5. Premature Ventricular Contractions (PVCs)

    MedlinePlus

    ... in the body that may be caused by caffeine, tobacco, exercise or anxiety Injury to the heart ... may increase your risk of premature ventricular contractions: Caffeine, tobacco and alcohol Exercise High blood pressure (hypertension) ...

  6. Prevention of premature birth.

    PubMed

    Fuchs, F

    1980-03-01

    With six different groups of pharmacologic agents that potentially can inhibit undesirable uterine contractions, prevention of premature births should be increasingly successful. The rationale for the use of each of these agents and their advantages and disadvantages are discussed.

  7. Correcting electrode impedance effects in broadband SIP measurements

    NASA Astrophysics Data System (ADS)

    Huisman, Johan Alexander; Zimmermann, Egon; Esser, Odilia; Haegel, Franz-Hubert; Vereecken, Harry

    2016-04-01

    Broadband spectral induced polarization (SIP) measurements of the complex electrical resistivity can be affected by the contact impedance of the potential electrodes above 100 Hz. In this study, we present a correction procedure to remove electrode impedance effects from SIP measurements. The first step in this correction procedure is to estimate the electrode impedance using a measurement with reversed current and potential electrodes. In a second step, this estimated electrode impedance is used to correct SIP measurements based on a simplified electrical model of the SIP measurement system. We evaluated this new correction procedure using SIP measurements on water because of the well-defined dielectric properties. It was found that the difference between the corrected and expected phase of the complex electrical resistivity of water was below 0.1 mrad at 1 kHz for a wide range of electrode impedances. In addition, SIP measurements on a saturated unconsolidated sediment sample with two types of potential electrodes showed that the measured phase of the electrical resistivity was very similar (difference <0.2 mrad) up to a frequency of 10 kHz after the effect of the different electrode impedances was removed. Finally, SIP measurements on variably saturated unconsolidated sand were made. Here, the plausibility of the phase of the electrical resistivity was improved for frequencies up to 1 kHz, but errors remained for higher frequencies due to the approximate nature of the electrode impedance estimates and some remaining unknown parasitic capacitances that led to current leakage. It was concluded that the proposed correction procedure for SIP measurements improved the accuracy of the phase measurements by an order of magnitude in the kHz frequency range. Further improvement of this accuracy requires a method to accurately estimate parasitic capacitances in situ.

  8. Chronic treatment with N-acetyl-cystein delays cellular senescence in endothelial cells isolated from a subgroup of atherosclerotic patients.

    PubMed

    Voghel, Guillaume; Thorin-Trescases, Nathalie; Farhat, Nada; Mamarbachi, Aida M; Villeneuve, Louis; Fortier, Annik; Perrault, Louis P; Carrier, Michel; Thorin, Eric

    2008-05-01

    Endothelial senescence may contribute to the pathogenesis of age-related vascular disorders. Furthermore, chronic exposure to risk factors for cardiovascular disease (CVD) accelerates the effects of chronological aging by generating stress-dependent damages, including oxidative stress, therefore promoting stress-induced premature senescence. Our objective was to determine whether a chronic treatment with an antioxidant (N-acetyl-cystein, NAC) could delay senescence of endothelial cells (EC) isolated and cultured from arterial segments of patients with severe coronary artery disease. If EC were considered as one population (n=26), chronic NAC treatment slightly shortened telomere attrition rate associated with senescence but did not significantly delay the onset of endothelial senescence. However, in a subgroup of NAC-treated EC (n=15) cellular senescence was significantly delayed, NAC decreased lipid peroxidation (HNE), activated the catalytic subunit of telomerase (hTERT) and inhibited telomere attrition. In contrast, in another subgroup of EC (n=11) characterized by initial short telomeres, no effect of NAC on HNE and high levels of DNA damages, the antioxidant was not beneficial on senescence, suggesting an irreversible stress-dependent damage. In conclusion, chronic exposure to NAC can delay senescence of diseased EC via hTERT activation and transient telomere stabilization, unless oxidative stress-associated cell damage has become irreversible.

  9. Nitric oxide induces cotyledon senescence involving co-operation of the NES1/MAD1 and EIN2-associated ORE1 signalling pathways in Arabidopsis

    PubMed Central

    Du, Jing; Li, Manli; Kong, Dongdong; Wang, Lei; Lv, Qiang; Wang, Jinzheng; Bao, Fang; Gong, Qingqiu; Xia, Jinchan; He, Yikun

    2014-01-01

    After germination, cotyledons undertake the major role in supplying nutrients to the pre-photoautorophy angiosperm seedlings until they senesce. Like other senescence processes, cotyledon senescence is a programmed degenerative process. Nitric oxide can induce premature cotyledon senescence in Arabidopsis thaliana, yet the underlying mechanism remains elusive. A screen for genetic mutants identified the nes1 mutant, in which cotyledon senescence was accelerated by nitric oxide. Map-based cloning revealed that NES1 is allelic to a previously reported mitotic checkpoint family gene, MAD1. The nes1/mad1 mutants were restored to the wild type, in response to nitric oxide, by transforming them with pNES1::NES1. Ectopic expression of NES1 in the wild type delayed nitric oxide-mediated cotyledon senescence, confirming the repressive role of NES1. Moreover, two positive regulators of leaf senescence, the ethylene signalling component EIN2 and the transcription factor ORE1/AtNAC2/ANAC092, were found to function during nitric oxide-induced senescence in cotyledons. The block of ORE1 function delayed senescence and ectopic expression induced the process, revealing the positive role of ORE1. EIN2 was required to induce ORE1. Furthermore, the genetic interaction analysis between NES1 and ORE1 showed that the ore1 loss-of-function mutants were epistatic to nes1, suggesting the dominant role of ORE1 and the antagonistic role of NES1 during nitric oxide-induced cotyledon senescence in Arabidopsis. PMID:24336389

  10. Screening of a kinase library reveals novel pro-senescence kinases and their common NF-κB-dependent transcriptional program

    PubMed Central

    Ferrand, Mylène; Kirsh, Olivier; Griveau, Audrey; Vindrieux, David; Martin, Nadine; Defossez, Pierre-Antoine; Bernard, David

    2015-01-01

    Cellular senescence results in proliferation arrest and acquisition of hallmarks such as the Senescence-Associated Secretory Phenotype (SASP). Senescence is involved in regulating numerous physio-pathological responses, including embryonic development, cancer, and several aging-related diseases. Only a few kinases, centered on the RAS signaling pathway, have been identified as inducing premature senescence. About possible other senescence-regulating kinases and signaling pathways, practically little is known. By screening a library of activated kinases, we identified 33 kinases whose constitutive expression decreases cell proliferation and induces expression of senescence markers; p16 and SASP components. Focusing on some kinases showing the strongest pro-senescence effects, we observed that they all induce expression of SASP-component genes through activation of an NF-κB-dependent transcriptional program. Furthermore, inhibition of the p53 or Rb pathway failed to prevent the SASP-inducing effect of pro-senescence kinases. Inhibition of the NF-κB, p53, or Rb pathway proved insufficient to prevent kinase-triggered cell cycle arrest. We have thus identified a repertoire of novel pro-senescence kinases and pathways. These results will open new perspectives in the understanding on the role of cellular senescence in various physio-pathological responses. PMID:26583757

  11. WNT16B is a new marker of cellular senescence that regulates p53 activity and the phosphoinositide 3-kinase/AKT pathway.

    PubMed

    Binet, Romuald; Ythier, Damien; Robles, Ana I; Collado, Manuel; Larrieu, Delphine; Fonti, Claire; Brambilla, Elisabeth; Brambilla, Christian; Serrano, Manuel; Harris, Curtis C; Pedeux, Rémy

    2009-12-15

    Senescence is a tumor suppression mechanism that is induced by several stimuli, including oncogenic signaling and telomere shortening, and controlled by the p53/p21(WAF1) signaling pathway. Recently, a critical role for secreted factors has emerged, suggesting that extracellular signals are necessary for the onset and maintenance of senescence. Conversely, factors secreted by senescent cells may promote tumor growth. By using expression profiling techniques, we searched for secreted factors that were overexpressed in fibroblasts undergoing replicative senescence. We identified WNT16B, a member of the WNT family of secreted proteins. We found that WNT16B is overexpressed in cells undergoing stress-induced premature senescence and oncogene-induced senescence in both MRC5 cell line and the in vivo murine model of K-Ras(V12)-induced senescence. By small interfering RNA experiments, we observed that both p53 and WNT16B are necessary for the onset of replicative senescence. WNT16B expression is required for the full transcriptional activation of p21(WAF1). Moreover, WNT16B regulates activation of the phosphoinositide 3-kinase (PI3K)/AKT pathway. Overall, we identified WNT16B as a new marker of senescence that regulates p53 activity and the PI3K/AKT pathway and is necessary for the onset of replicative senescence.

  12. Tumor Suppressor and Aging Biomarker p16INK4a Induces Cellular Senescence without the Associated Inflammatory Secretory Phenotype*

    PubMed Central

    Coppé, Jean-Philippe; Rodier, Francis; Patil, Christopher K.; Freund, Adam; Desprez, Pierre-Yves; Campisi, Judith

    2011-01-01

    Cellular senescence suppresses cancer by preventing the proliferation of cells that experience potentially oncogenic stimuli. Senescent cells often express p16INK4a, a cyclin-dependent kinase inhibitor, tumor suppressor, and biomarker of aging, which renders the senescence growth arrest irreversible. Senescent cells also acquire a complex phenotype that includes the secretion of many cytokines, growth factors, and proteases, termed a senescence-associated secretory phenotype (SASP). The SASP is proposed to underlie age-related pathologies, including, ironically, late life cancer. Here, we show that ectopic expression of p16INK4a and another cyclin-dependent kinase inhibitor, p21CIP1/WAF1, induces senescence without a SASP, even though they induced other features of senescence, including a stable growth arrest. Additionally, human fibroblasts induced to senesce by ionizing radiation or oncogenic RAS developed a SASP regardless of whether they expressed p16INK4a. Cells induced to senesce by ectopic p16INK4a expression lacked paracrine activity on epithelial cells, consistent with the absence of a functional SASP. Nonetheless, expression of p16INK4a by cells undergoing replicative senescence limited the accumulation of DNA damage and premature cytokine secretion, suggesting an indirect role for p16INK4a in suppressing the SASP. These findings suggest that p16INK4a-positive cells may not always harbor a SASP in vivo and, furthermore, that the SASP is not a consequence of p16INK4a activation or senescence per se, but rather is a damage response that is separable from the growth arrest. PMID:21880712

  13. Phenotyping jasmonate regulation of senescence.

    PubMed

    Seltmann, Martin A; Berger, Susanne

    2013-01-01

    Osmotic stress induces several senescence-like processes in leaves, such as specific changes in gene expression and yellowing. These processes are dependent on the accumulation of jasmonates and on intact jasmonate signaling. This chapter describes the treatment of Arabidopsis thaliana leaves with sorbitol as an osmotic stress agent and the determination of the elicited phenotypes encompassing chlorophyll loss, degradation of plastidial membrane lipids, and induction of genes regulated by senescence and jasmonate.

  14. CD9 monoclonal antibody-conjugated PEGylated liposomes for targeted delivery of rapamycin in the treatment of cellular senescence.

    PubMed

    Nguyen, Hanh Thuy; Thapa, Raj Kumar; Shin, Beom Soo; Jeong, Jee-Heon; Kim, Jae-Ryong; Yong, Chul Soon; Kim, Jong Oh

    2017-03-03

    Premature cellular senescence refers to the state of irreversible cell cycle arrest due to DNA damage or other stresses. In this study, CD9 monoclonal antibody (CD9mAb) was successfully conjugated to the surface of PEGylated liposomes for targeted delivery of rapamycin (LR-CD9mAb) to overcome senescence of CD9 receptor-overexpressing cells. LR-CD9mAb has a small particle size (143.3 ± 2.4 nm), narrow size distribution (polydispersity index: 0.220 ± 0.036), and negative zeta potential (-14.6 ± 1.2 mV). The uptake of CD9-targeted liposomes by premature senescent human dermal fibroblasts (HDFs) was higher than that by young HDFs, as displayed by confocal microscopic images. The senescence might not be reversed by treatment with rapamycin; however, the drug promoted cell proliferation and reduced the number of cells that expressed the senescence-associated-β-galactosidase (SA-β-gal). These effects were further confirmed by cell viability, cell cycle, and Western blotting analyses. Moreover, CD9-targeted liposomes showed better anti-senescence activity, in comparison with free rapamycin or the conventional liposomal formulation, suggesting the potential application of this system in further in vivo studies.

  15. CD9 monoclonal antibody-conjugated PEGylated liposomes for targeted delivery of rapamycin in the treatment of cellular senescence

    NASA Astrophysics Data System (ADS)

    Thuy Nguyen, Hanh; Thapa, Raj Kumar; Shin, Beom Soo; Jeong, Jee-Heon; Kim, Jae-Ryong; Yong, Chul Soon; Kim, Jong Oh

    2017-03-01

    Premature cellular senescence refers to the state of irreversible cell cycle arrest due to DNA damage or other stresses. In this study, CD9 monoclonal antibody (CD9mAb) was successfully conjugated to the surface of PEGylated liposomes for targeted delivery of rapamycin (LR-CD9mAb) to overcome senescence of CD9 receptor-overexpressing cells. LR-CD9mAb has a small particle size (143.3 ± 2.4 nm), narrow size distribution (polydispersity index: 0.220 ± 0.036), and negative zeta potential (‑14.6 ± 1.2 mV). The uptake of CD9-targeted liposomes by premature senescent human dermal fibroblasts (HDFs) was higher than that by young HDFs, as displayed by confocal microscopic images. The senescence might not be reversed by treatment with rapamycin; however, the drug promoted cell proliferation and reduced the number of cells that expressed the senescence-associated-β-galactosidase (SA-β-gal). These effects were further confirmed by cell viability, cell cycle, and Western blotting analyses. Moreover, CD9-targeted liposomes showed better anti-senescence activity, in comparison with free rapamycin or the conventional liposomal formulation, suggesting the potential application of this system in further in vivo studies.

  16. Noncoding RNA Control of Cellular Senescence

    PubMed Central

    Abdelmohsen, Kotb; Gorospe, Myriam

    2015-01-01

    Senescent cells accumulate in normal tissues with advancing age and arise by long-term culture of primary cells. Senescence develops following exposure to a range of stress-causing agents and broadly influences the physiology and pathology of tissues, organs, and systems in the body. While many proteins are known to control senescence, numerous noncoding (nc)RNAs are also found to promote or repress the senescent phenotype. Here, we review the regulatory ncRNAs (primarily microRNAs and lncRNAs) identified to-date as key modulators of senescence. We highlight the major senescent pathways (p53/p21 and pRB/p16), as well as the senescence-associated secretory phenotype (SASP) and other senescence-associated events governed by ncRNAs, and discuss the importance of understanding comprehensively the ncRNAs implicated in cell senescence. PMID:26331977

  17. Hormonal regulation of leaf senescence in Lilium.

    PubMed

    Arrom, Laia; Munné-Bosch, Sergi

    2012-10-15

    In addition to floral senescence and longevity, the control of leaf senescence is a major factor determining the quality of several cut flowers, including Lilium, in the commercial market. To better understand the physiological process underlying leaf senescence in this species, we evaluated: (i) endogenous variation in the levels of phytohormones during leaf senescence, (ii) the effects of leaf darkening in senescence and associated changes in phytohormones, and (iii) the effects of spray applications of abscisic acid (ABA) and pyrabactin on leaf senescence. Results showed that while gibberellin 4 (GA(4)) and salicylic acid (SA) contents decreased, that of ABA increased during the progression of leaf senescence. However, dark-induced senescence increased ABA levels, but did not affect GA(4) and SA levels, which appeared to correlate more with changes in air temperature and/or photoperiod than with the induction of leaf senescence. Furthermore, spray applications of pyrabactin delayed the progression of leaf senescence in cut flowers. Thus, we conclude that (i) ABA plays a major role in the regulation of leaf senescence in Lilium, (ii) darkness promotes leaf senescence and increases ABA levels, and (iii) exogenous applications of pyrabactin inhibit leaf senescence in Lilium, therefore suggesting that it acts as an antagonist of ABA in senescing leaves of cut lily flowers.

  18. Prematurity: present and future

    PubMed Central

    Tsimis, M. E.; Al-Hamayel, N. Abu; Germaine, H.; Burd, I.

    2014-01-01

    The study of preterm labor and prematurity, as with any medical science, has undergone a major transformation in its approach from an inevitable part of obstetrics with few answers to one in which science has led to knowledge and clinical intervention. Despite these advancements, understanding of preterm labor and prevention of prematurity is still limited. In the current review, we begin the discussion with fetal viability, first from a historical perspective and then from the understanding of this issue from a prospective of various professional organizations. We then present the scope of the problem of preterm birth from various countries including the discrepancy between the US and Europe. We continue with updates on extreme prematurity and outcomes with two longitudinal studies from the past 2 years. We further review available interventions for prematurity and discuss the use of antenatal corticosteroids. First, we examine their use in the context of professional recommendations and then examine the trajectory of their continued use in the late preterm period. We focus on a European-based trial with preliminary results and an ongoing American counterpart. The current knowledge of molecular mechanisms behind preterm labor is presented with a focus on the multiple etiologies of preterm labor, both known and presumed, with updates in the basic science realm. Furthermore, up-to-date studies on prediction of preterm birth and prematurity-related morbidity are presented. PMID:25300768

  19. Dapoxetine: in premature ejaculation.

    PubMed

    Hoy, Sheridan M; Scott, Lesley J

    2010-07-30

    Dapoxetine, a selective serotonin reuptake inhibitor, is the first oral pharmacological agent indicated for the treatment of men aged 18-64 years with premature ejaculation. In four randomized, double-blind, placebo-controlled, multicentre studies of 12-24 weeks' duration, oral dapoxetine 30 or 60 mg (administered as needed) was effective in the treatment of men with premature ejaculation, inducing significantly (p < 0.001) greater improvements from baseline than placebo in the primary efficacy endpoint (mean intravaginal ejaculatory latency time [IELT] or mean average IELT [defined as the average of IELT values over the previous 4 weeks], as measured by the female partner utilizing a stopwatch). For the most part, dapoxetine recipients achieved significantly better outcomes than placebo recipients with regard to the secondary endpoints, including the Premature Ejaculation Profile (PEP) domains and the Clinical Global Impression or Patient Global Impression ratings of change in premature ejaculation, across these clinical studies. The beneficial effects of dapoxetine therapy on the perceived control over ejaculation and satisfaction with sexual intercourse PEP domains were sustained in a 9-month noncomparative extension phase of two identical 12-week, double-blind studies. Oral dapoxetine therapy for up to 12 months was generally well tolerated in men with premature ejaculation, with the nature of treatment-emergent adverse events generally similar across the clinical studies and between dapoxetine and placebo.

  20. SIP: A Web-Based Astronomical Image Processing Program

    NASA Astrophysics Data System (ADS)

    Simonetti, J. H.

    1999-12-01

    I have written an astronomical image processing and analysis program designed to run over the internet in a Java-compatible web browser. The program, Sky Image Processor (SIP), is accessible at the SIP webpage (http://www.phys.vt.edu/SIP). Since nothing is installed on the user's machine, there is no need to download upgrades; the latest version of the program is always instantly available. Furthermore, the Java programming language is designed to work on any computer platform (any machine and operating system). The program could be used with students in web-based instruction or in a computer laboratory setting; it may also be of use in some research or outreach applications. While SIP is similar to other image processing programs, it is unique in some important respects. For example, SIP can load images from the user's machine or from the Web. An instructor can put images on a web server for students to load and analyze on their own personal computer. Or, the instructor can inform the students of images to load from any other web server. Furthermore, since SIP was written with students in mind, the philosophy is to present the user with the most basic tools necessary to process and analyze astronomical images. Images can be combined (by addition, subtraction, multiplication, or division), multiplied by a constant, smoothed, cropped, flipped, rotated, and so on. Statistics can be gathered for pixels within a box drawn by the user. Basic tools are available for gathering data from an image which can be used for performing simple differential photometry, or astrometry. Therefore, students can learn how astronomical image processing works. Since SIP is not part of a commercial CCD camera package, the program is written to handle the most common denominator image file, the FITS format.

  1. Redox regulation of SIRT1 in inflammation and cellular senescence.

    PubMed

    Hwang, Jae-woong; Yao, Hongwei; Caito, Samuel; Sundar, Isaac K; Rahman, Irfan

    2013-08-01

    Sirtuin 1 (SIRT1) regulates inflammation, aging (life span and health span), calorie restriction/energetics, mitochondrial biogenesis, stress resistance, cellular senescence, endothelial functions, apoptosis/autophagy, and circadian rhythms through deacetylation of transcription factors and histones. SIRT1 level and activity are decreased in chronic inflammatory conditions and aging, in which oxidative stress occurs. SIRT1 is regulated by a NAD(+)-dependent DNA repair enzyme, poly(ADP-ribose) polymerase-1 (PARP1), and subsequent NAD(+) depletion by oxidative stress may have consequent effects on inflammatory and stress responses as well as cellular senescence. SIRT1 has been shown to undergo covalent oxidative modifications by cigarette smoke-derived oxidants/aldehydes, leading to posttranslational modifications, inactivation, and protein degradation. Furthermore, oxidant/carbonyl stress-mediated reduction of SIRT1 leads to the loss of its control on acetylation of target proteins including p53, RelA/p65, and FOXO3, thereby enhancing the inflammatory, prosenescent, and apoptotic responses, as well as endothelial dysfunction. In this review, the mechanisms of cigarette smoke/oxidant-mediated redox posttranslational modifications of SIRT1 and its roles in PARP1 and NF-κB activation, and FOXO3 and eNOS regulation, as well as chromatin remodeling/histone modifications during inflammaging, are discussed. Furthermore, we have also discussed various novel ways to activate SIRT1 either directly or indirectly, which may have therapeutic potential in attenuating inflammation and premature senescence involved in chronic lung diseases.

  2. Rejuvenating the senescent heart

    PubMed Central

    Nguyen, Nathalie; Sussman, Mark A.

    2015-01-01

    Purpose of review The purpose of this review is to provide an update on the cardiac stem cell field with an emphasis on aging and to suggest some relevant strategies directed toward rejuvenation of the senescent heart. Recent findings Stem cells were long considered as a fountain of youth and were assumed to be equipped against any form of aging effect. However, it is now clear that stem cells suffer the consequences of aging as well. With the discovery that cardiac stem cells reside in the heart comes the question whether these cells are also impaired upon aging. As cardiac stem cell properties are also altered with age, autologous stem cell-based therapy to treat heart failure will benefit from new improved strategies. Summary With the goal to improve stem cell properties that are impaired upon aging, some strategies are highlighted. Genetic modification of adult human cardiac progenitor cells prior to autologous stem cell-based therapy, delivery of the next generation of stem cells such as CardioChimeras and CardioClusters, and improvement of the myocardial environment with rejuvenating factors constitute some of the possibilities and are discussed in more detail in this review. PMID:25760821

  3. Early-onset Evans syndrome, immunodeficiency, and premature immunosenescence associated with tripeptidyl-peptidase II deficiency

    PubMed Central

    Stepensky, Polina; Rensing-Ehl, Anne; Gather, Ruth; Revel-Vilk, Shoshana; Fischer, Ute; Nabhani, Schafiq; Beier, Fabian; Brümmendorf, Tim H.; Fuchs, Sebastian; Zenke, Simon; Firat, Elke; Pessach, Vered Molho; Borkhardt, Arndt; Rakhmanov, Mirzokhid; Keller, Bärbel; Warnatz, Klaus; Eibel, Hermann; Niedermann, Gabriele; Elpeleg, Orly

    2015-01-01

    Autoimmune cytopenia is a frequent manifestation of primary immunodeficiencies. Two siblings presented with Evans syndrome, viral infections, and progressive leukopenia. DNA available from one patient showed a homozygous frameshift mutation in tripeptidyl peptidase II (TPP2) abolishing protein expression. TPP2 is a serine exopeptidase involved in extralysosomal peptide degradation. Its deficiency in mice activates cell death programs and premature senescence. Similar to cells from naïve, uninfected TPP2-deficient mice, patient cells showed increased major histocompatibility complex I expression and most CD8+ T-cells had a senescent CCR7-CD127−CD28−CD57+ phenotype with poor proliferative responses and enhanced staurosporine-induced apoptosis. T-cells showed increased expression of the effector molecules perforin and interferon-γ with high expression of the transcription factor T-bet. Age-associated B-cells with a CD21− CD11c+ phenotype expressing T-bet were increased in humans and mice, combined with antinuclear antibodies. Moreover, markers of senescence were also present in human and murine TPP2-deficient fibroblasts. Telomere lengths were normal in patient fibroblasts and granulocytes, and low normal in lymphocytes, which were compatible with activation of stress-induced rather than replicative senescence programs. TPP2 deficiency is the first primary immunodeficiency linking premature immunosenescence to severe autoimmunity. Determination of senescent lymphocytes should be part of the diagnostic evaluation of children with refractory multilineage cytopenias. PMID:25414442

  4. Early-onset Evans syndrome, immunodeficiency, and premature immunosenescence associated with tripeptidyl-peptidase II deficiency.

    PubMed

    Stepensky, Polina; Rensing-Ehl, Anne; Gather, Ruth; Revel-Vilk, Shoshana; Fischer, Ute; Nabhani, Schafiq; Beier, Fabian; Brümmendorf, Tim H; Fuchs, Sebastian; Zenke, Simon; Firat, Elke; Pessach, Vered Molho; Borkhardt, Arndt; Rakhmanov, Mirzokhid; Keller, Bärbel; Warnatz, Klaus; Eibel, Hermann; Niedermann, Gabriele; Elpeleg, Orly; Ehl, Stephan

    2015-01-29

    Autoimmune cytopenia is a frequent manifestation of primary immunodeficiencies. Two siblings presented with Evans syndrome, viral infections, and progressive leukopenia. DNA available from one patient showed a homozygous frameshift mutation in tripeptidyl peptidase II (TPP2) abolishing protein expression. TPP2 is a serine exopeptidase involved in extralysosomal peptide degradation. Its deficiency in mice activates cell death programs and premature senescence. Similar to cells from naïve, uninfected TPP2-deficient mice, patient cells showed increased major histocompatibility complex I expression and most CD8(+) T-cells had a senescent CCR7-CD127(-)CD28(-)CD57(+) phenotype with poor proliferative responses and enhanced staurosporine-induced apoptosis. T-cells showed increased expression of the effector molecules perforin and interferon-γ with high expression of the transcription factor T-bet. Age-associated B-cells with a CD21(-) CD11c(+) phenotype expressing T-bet were increased in humans and mice, combined with antinuclear antibodies. Moreover, markers of senescence were also present in human and murine TPP2-deficient fibroblasts. Telomere lengths were normal in patient fibroblasts and granulocytes, and low normal in lymphocytes, which were compatible with activation of stress-induced rather than replicative senescence programs. TPP2 deficiency is the first primary immunodeficiency linking premature immunosenescence to severe autoimmunity. Determination of senescent lymphocytes should be part of the diagnostic evaluation of children with refractory multilineage cytopenias.

  5. Growth hormone is a cellular senescence target in pituitary and nonpituitary cells.

    PubMed

    Chesnokova, Vera; Zhou, Cuiqi; Ben-Shlomo, Anat; Zonis, Svetlana; Tani, Yuji; Ren, Song-Guang; Melmed, Shlomo

    2013-08-27

    Premature proliferative arrest in benign or early-stage tumors induced by oncoproteins, chromosomal instability, or DNA damage is associated with p53/p21 activation, culminating in either senescence or apoptosis, depending on cell context. Growth hormone (GH) elicits direct peripheral metabolic actions as well as growth effects mediated by insulin-like growth factor 1 (IGF1). Locally produced peripheral tissue GH, in contrast to circulating pituitary-derived endocrine GH, has been proposed to be both proapoptotic and prooncogenic. Pituitary adenomas expressing and secreting GH are invariably benign and exhibit DNA damage and a senescent phenotype. We therefore tested effects of nutlin-induced p53-mediated senescence in rat and human pituitary cells. We show that DNA damage senescence induced by nutlin triggers the p53/p21 senescent pathway, with subsequent marked induction of intracellular pituitary GH in vitro. In contrast, GH is not induced in cells devoid of p53. Furthermore we show that p53 binds specific GH promoter motifs and enhances GH transcription and secretion in senescent pituitary adenoma cells and also in nonpituitary (human breast and colon) cells. In vivo, treatment with nutlin results in up-regulation of both p53 and GH in the pituitary gland, as well as increased GH expression in nonpituitary tissues (lung and liver). Intracrine GH acts in pituitary cells as an apoptosis switch for p53-mediated senescence, likely protecting the pituitary adenoma from progression to malignancy. Unlike in the pituitary, in nonpituitary cells GH exerts antiapoptotic properties. Thus, the results show that GH is a direct p53 transcriptional target and fulfills criteria as a p53 target gene. Induced GH is a readily measurable cell marker for p53-mediated cellular senescence.

  6. Chilling stress--the key predisposing factor for causing Alternaria alternata infection and leading to cotton (Gossypium hirsutum L.) leaf senescence.

    PubMed

    Zhao, Jingqing; Li, Sha; Jiang, Tengfei; Liu, Zhi; Zhang, Wenwei; Jian, Guiliang; Qi, Fangjun

    2012-01-01

    Leaf senescence plays a vital role in nutrient recycling and overall capacity to assimilate carbon dioxide. Cotton premature leaf senescence, often accompanied with unexpected short-term low temperature, has been occurring with an increasing frequency in many cotton-growing areas and causes serious reduction in yield and quality of cotton. The key factors for causing and promoting cotton premature leaf senescence are still unclear. In this case, the relationship between the pre-chilling stress and Alternaria alternata infection for causing cotton leaf senescence was investigated under precisely controlled laboratory conditions with four to five leaves stage cotton plants. The results showed short-term chilling stress could cause a certain degree of physiological impairment to cotton leaves, which could be recovered to normal levels in 2-4 days when the chilling stresses were removed. When these chilling stress injured leaves were further inoculated with A. alternata, the pronounced appearance and development of leaf spot disease, and eventually the pronounced symptoms of leaf senescence, occurred on these cotton leaves. The onset of cotton leaf senescence at this condition was also reflected in various physiological indexes such as irreversible increase in malondialdehyde (MDA) content and electrolyte leakage, irreversible decrease in soluble protein content and chlorophyll content, and irreversible damage in leaves' photosynthesis ability. The presented results demonstrated that chilling stress acted as the key predisposing factor for causing A. alternata infection and leading to cotton leaf senescence. It could be expected that the understanding of the key factors causing and promoting cotton leaf senescence would be helpful for taking appropriate management steps to prevent cotton premature leaf senescence.

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

    PubMed

    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.

  8. Evolution of maternal effect senescence

    PubMed Central

    Moorad, Jacob A.; Nussey, Daniel H.

    2016-01-01

    Increased maternal age at reproduction is often associated with decreased offspring performance in numerous species of plants and animals (including humans). Current evolutionary theory considers such maternal effect senescence as part of a unified process of reproductive senescence, which is under identical age-specific selective pressures to fertility. We offer a novel theoretical perspective by combining William Hamilton’s evolutionary model for aging with a quantitative genetic model of indirect genetic effects. We demonstrate that fertility and maternal effect senescence are likely to experience different patterns of age-specific selection and thus can evolve to take divergent forms. Applied to neonatal survival, we find that selection for maternal effects is the product of age-specific fertility and Hamilton’s age-specific force of selection for fertility. Population genetic models show that senescence for these maternal effects can evolve in the absence of reproductive or actuarial senescence; this implies that maternal effect aging is a fundamentally distinct demographic manifestation of the evolution of aging. However, brief periods of increasingly beneficial maternal effects can evolve when fertility increases with age faster than cumulative survival declines. This is most likely to occur early in life. Our integration of theory provides a general framework with which to model, measure, and compare the evolutionary determinants of the social manifestations of aging. Extension of our maternal effects model to other ecological and social contexts could provide important insights into the drivers of the astonishing diversity of lifespans and aging patterns observed among species. PMID:26715745

  9. SNEV(Prp19/PSO4) deficiency increases PUVA-induced senescence in mouse skin.

    PubMed

    Monteforte, Rossella; Beilhack, Georg F; Grausenburger, Reinhard; Mayerhofer, Benjamin; Bittner, Reginald; Grillari-Voglauer, Regina; Sibilia, Maria; Dellago, Hanna; Tschachler, Erwin; Gruber, Florian; Grillari, Johannes

    2016-03-01

    Senescent cells accumulate during ageing in various tissues and contribute to organismal ageing. However, factors that are involved in the induction of senescence in vivo are still not well understood. SNEV(P) (rp19/) (PSO) (4) is a multifaceted protein, known to be involved in DNA damage repair and senescence, albeit only in vitro. In this study, we used heterozygous SNEV(+/-) mice (SNEV-knockout results in early embryonic lethality) and wild-type littermate controls as a model to elucidate the role of SNEV(P) (rp19/) (PSO) (4) in DNA damage repair and senescence in vivo. We performed PUVA treatment as model system for potently inducing cellular senescence, consisting of 8-methoxypsoralen in combination with UVA on mouse skin to induce DNA damage and premature skin ageing. We show that SNEV(P) (rp19/) (PSO) (4) expression decreases during organismal ageing, while p16, a marker of ageing in vivo, increases. In response to PUVA treatment, we observed in the skin of both SNEV(P) (rp19/) (PSO) (4) and wild-type mice an increase in γ-H2AX levels, a DNA damage marker. In old SNEV(P) (rp19/) (PSO) (4) mice, this increase is accompanied by reduced epidermis thickening and increase in p16 and collagenase levels. Thus, the DNA damage response occurring in the mouse skin upon PUVA treatment is dependent on SNEV(P) (rp19/) (PSO) (4) expression and lower levels of SNEV(P) (rp19/) (PSO) (4) , as in old SNEV(+/-) mice, result in increase in cellular senescence and acceleration of premature skin ageing.

  10. Microvesicles from the plasma of elderly subjects and from senescent endothelial cells promote vascular calcification.

    PubMed

    Alique, Matilde; Ruíz-Torres, María Piedad; Bodega, Guillermo; Noci, María Victoria; Troyano, Nuria; Bohórquez, Lourdes; Luna, Carlos; Luque, Rafael; Carmona, Andrés; Carracedo, Julia; Ramírez, Rafael

    2017-03-08

    Vascular calcification is commonly seen in elderly people, though it can also appear in middle-aged subjects affected by premature vascular aging. The aim of this work is to test the involvement of microvesicles (MVs) produced by senescent endothelial cells (EC) and from plasma of elderly people in vascular calcification. The present work shows that MVs produced by senescent cultured ECs, plus those found in the plasma of elderly subjects, promote calcification in vascular smooth muscle cells. Only MVs from senescent ECs, and from elderly subjects' plasma, induced calcification. This ability correlated with these types of MVs' carriage of: a) increased quantities of annexins (which might act as nucleation sites for calcification), b) increased quantities of bone-morphogenic protein, and c) larger Ca contents. The MVs of senescent, cultured ECs, and those present in the plasma of elderly subjects, promote vascular calcification. The present results provide mechanistic insights into the observed increase in vascular calcification-related diseases in the elderly, and in younger patients with premature vascular aging, paving the way towards novel therapeutic strategies.

  11. Role of galactose in cellular senescence.

    PubMed

    Elzi, David J; Song, Meihua; Shiio, Yuzuru

    2016-01-01

    Cellular senescence has been proposed to play critical roles in tumor suppression and organismal aging, but the molecular mechanism of senescence remains incompletely understood. Here we report that a putative lysosomal carbohydrate efflux transporter, Spinster, induces cellular senescence in human primary fibroblasts. Administration of d-galactose synergistically enhanced Spinster-induced senescence and this synergism required the transporter activity of Spinster. Intracellular d-galactose is metabolized to galactose-1-phosphate by galactokinase. Galactokinase-deficient fibroblasts, which accumulate intracellular d-galactose, displayed increased baseline senescence. Senescence of galactokinase-deficient fibroblasts was further enhanced by d-galactose administration and was diminished by restoration of wild-type galactokinase expression. Silencing galactokinase in normal fibroblasts also induced senescence. These results suggest a role for intracellular galactose in the induction of cellular senescence.

  12. A Secured Authentication Protocol for SIP Using Elliptic Curves Cryptography

    NASA Astrophysics Data System (ADS)

    Chen, Tien-Ho; Yeh, Hsiu-Lien; Liu, Pin-Chuan; Hsiang, Han-Chen; Shih, Wei-Kuan

    Session initiation protocol (SIP) is a technology regularly performed in Internet Telephony, and Hyper Text Transport Protocol (HTTP) as digest authentication is one of the major methods for SIP authentication mechanism. In 2005, Yang et al. pointed out that HTTP could not resist server spoofing attack and off-line guessing attack and proposed a secret authentication with Diffie-Hellman concept. In 2009, Tsai proposed a nonce based authentication protocol for SIP. In this paper, we demonstrate that their protocol could not resist the password guessing attack and insider attack. Furthermore, we propose an ECC-based authentication mechanism to solve their issues and present security analysis of our protocol to show that ours is suitable for applications with higher security requirement.

  13. Predatory senescence in ageing wolves

    USGS Publications Warehouse

    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.

  14. Predatory senescence in aging wolves

    USGS Publications Warehouse

    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.

  15. Predatory senescence in ageing wolves.

    PubMed

    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.

  16. Transgenic plants with altered senescence characteristics

    DOEpatents

    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. Selective insulin resistance in hepatocyte senescence

    SciTech Connect

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

    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.

  18. 40 CFR 52.146 - Particulate matter (PM-10) Group II SIP commitments.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... submitted a revision to the State Implementation Plan (SIP) for Casa Grande, Show Low, Safford, Flagstaff... Implementation Plan (SIP) requirements for Casa Grande, Show Low, Safford, Flagstaff and Joseph City as...

  19. Impact of 50% Synthesized Iso-Paraffins (SIP) on F-76 Fuel Coalescence

    DTIC Science & Technology

    2013-12-16

    time required to flow the entire volume of fluid in a container, also known as residence time (volume of fuel ÷ volumetric flow rate ) NF...petroleum JP-5 and Synthesized Iso-Paraffins (SIP). SIP fuels are made from direct fermentation of sugar into olefinic hydrocarbons. The olefinic...5 and Synthesized Iso-Paraffins (SIP). SIP fuels are made from direct fermentation of sugar into olefinic hydrocarbons. The olefinic hydrocarbons

  20. Testing Dialog-Verification of SIP Phones with Single-Message Denial-of-Service Attacks

    NASA Astrophysics Data System (ADS)

    Seedorf, Jan; Beckers, Kristian; Huici, Felipe

    The Session Initiation Protocol (SIP) is widely used for signaling in multimedia communications. However, many SIP implementations are still in their infancy and vulnerable to malicious messages. We investigate flaws in the SIP implementations of eight phones, showing that the deficient verification of SIP dialogs further aggravates the problem by making it easier for attacks to succeed. Our results show that the majority of the phones we tested are susceptible to these attacks.

  1. 40 CFR 52.2306 - Particulate Matter (PM10) Group II SIP commitments.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 5 2014-07-01 2014-07-01 false Particulate Matter (PM10) Group II SIP... Particulate Matter (PM10) Group II SIP commitments. On July 18, 1988, the Governor of Texas submitted a revision to the State Implementation Plan (SIP) that contained commitments for implementing all of...

  2. 40 CFR 51.851 - State implementation plan (SIP) or Tribal implementation plan (TIP) revision.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 2 2012-07-01 2012-07-01 false State implementation plan (SIP) or... § 51.851 State implementation plan (SIP) or Tribal implementation plan (TIP) revision. (a) A State or... requirements, to demonstrate conformity with the applicable SIP or TIP as required by section 176(c) of the...

  3. 40 CFR 52.2306 - Particulate Matter (PM10) Group II SIP commitments.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 4 2011-07-01 2011-07-01 false Particulate Matter (PM10) Group II SIP... Particulate Matter (PM10) Group II SIP commitments. On July 18, 1988, the Governor of Texas submitted a revision to the State Implementation Plan (SIP) that contained commitments for implementing all of...

  4. 40 CFR 52.1489 - Particulate matter (PM-10) Group II SIP commitments.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 4 2014-07-01 2014-07-01 false Particulate matter (PM-10) Group II SIP... Particulate matter (PM-10) Group II SIP commitments. (a) On March 29, 1989, the Air Quality Officer for the... inventory, and other tasks that may be necessary to satisfy the requirements of the PM-10 Group II SIPs....

  5. 40 CFR 52.146 - Particulate matter (PM-10) Group II SIP commitments.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 3 2013-07-01 2013-07-01 false Particulate matter (PM-10) Group II SIP... (PM-10) Group II SIP commitments. (a) On December 28, 1988, the Governor's designee for Arizona submitted a revision to the State Implementation Plan (SIP) for Casa Grande, Show Low, Safford,...

  6. 40 CFR 52.1489 - Particulate matter (PM-10) Group II SIP commitments.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 4 2013-07-01 2013-07-01 false Particulate matter (PM-10) Group II SIP... Particulate matter (PM-10) Group II SIP commitments. (a) On March 29, 1989, the Air Quality Officer for the... inventory, and other tasks that may be necessary to satisfy the requirements of the PM-10 Group II SIPs....

  7. 40 CFR 93.162 - Emissions beyond the time period covered by the SIP.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... covered by the SIP. 93.162 Section 93.162 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY... § 93.162 Emissions beyond the time period covered by the SIP. If a Federal action would result in total... period covered by the SIP, the Federal agency can: (a) Demonstrate conformity with the last...

  8. 40 CFR 52.634 - Particulate matter (PM-10) Group III SIP.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... SIP. 52.634 Section 52.634 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR... (PM-10) Group III SIP. (a) On September 14, 1988, the Governor of Hawaii submitted a revision to the State Implementation Plan (SIP) for implementing the required monitoring activities and other...

  9. 40 CFR 52.32 - Sanctions following findings of SIP inadequacy.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 3 2012-07-01 2012-07-01 false Sanctions following findings of SIP inadequacy. 52.32 Section 52.32 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR... following findings of SIP inadequacy. For purposes of the SIP revisions required by § 51.120, EPA may make...

  10. 40 CFR 93.162 - Emissions beyond the time period covered by the SIP.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... covered by the SIP. 93.162 Section 93.162 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY... § 93.162 Emissions beyond the time period covered by the SIP. If a Federal action would result in total... period covered by the SIP, the Federal agency can: (a) Demonstrate conformity with the last...

  11. 40 CFR 51.851 - State implementation plan (SIP) or Tribal implementation plan (TIP) revision.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 2 2013-07-01 2013-07-01 false State implementation plan (SIP) or... § 51.851 State implementation plan (SIP) or Tribal implementation plan (TIP) revision. (a) A State or... requirements, to demonstrate conformity with the applicable SIP or TIP as required by section 176(c) of the...

  12. 40 CFR 52.1637 - Particulate Matter (PM10) Group II SIP commitments.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 4 2013-07-01 2013-07-01 false Particulate Matter (PM10) Group II SIP... Particulate Matter (PM10) Group II SIP commitments. (a) On August 19, 1988, the Governor of New Mexico submitted a revision to the State Implementation Plan (SIP) that contained commitments, from the Director...

  13. 40 CFR 52.1637 - Particulate Matter (PM10) Group II SIP commitments.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 4 2010-07-01 2010-07-01 false Particulate Matter (PM10) Group II SIP... Particulate Matter (PM10) Group II SIP commitments. (a) On August 19, 1988, the Governor of New Mexico submitted a revision to the State Implementation Plan (SIP) that contained commitments, from the Director...

  14. 40 CFR 52.1489 - Particulate matter (PM-10) Group II SIP commitments.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 4 2011-07-01 2011-07-01 false Particulate matter (PM-10) Group II SIP... Particulate matter (PM-10) Group II SIP commitments. (a) On March 29, 1989, the Air Quality Officer for the... inventory, and other tasks that may be necessary to satisfy the requirements of the PM-10 Group II SIPs....

  15. 40 CFR 52.146 - Particulate matter (PM-10) Group II SIP commitments.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 3 2014-07-01 2014-07-01 false Particulate matter (PM-10) Group II SIP... (PM-10) Group II SIP commitments. (a) On December 28, 1988, the Governor's designee for Arizona submitted a revision to the State Implementation Plan (SIP) for Casa Grande, Show Low, Safford,...

  16. 40 CFR 52.32 - Sanctions following findings of SIP inadequacy.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 3 2011-07-01 2011-07-01 false Sanctions following findings of SIP inadequacy. 52.32 Section 52.32 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR... following findings of SIP inadequacy. For purposes of the SIP revisions required by § 51.120, EPA may make...

  17. 40 CFR 52.2306 - Particulate Matter (PM10) Group II SIP commitments.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 4 2010-07-01 2010-07-01 false Particulate Matter (PM10) Group II SIP... Particulate Matter (PM10) Group II SIP commitments. On July 18, 1988, the Governor of Texas submitted a revision to the State Implementation Plan (SIP) that contained commitments for implementing all of...

  18. 40 CFR 52.634 - Particulate matter (PM-10) Group III SIP.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... SIP. 52.634 Section 52.634 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR... (PM-10) Group III SIP. (a) On September 14, 1988, the Governor of Hawaii submitted a revision to the State Implementation Plan (SIP) for implementing the required monitoring activities and other...

  19. 40 CFR 52.2306 - Particulate Matter (PM10) Group II SIP commitments.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 5 2013-07-01 2013-07-01 false Particulate Matter (PM10) Group II SIP... Particulate Matter (PM10) Group II SIP commitments. On July 18, 1988, the Governor of Texas submitted a revision to the State Implementation Plan (SIP) that contained commitments for implementing all of...

  20. 40 CFR 51.851 - State implementation plan (SIP) or Tribal implementation plan (TIP) revision.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 2 2014-07-01 2014-07-01 false State implementation plan (SIP) or... § 51.851 State implementation plan (SIP) or Tribal implementation plan (TIP) revision. (a) A State or... requirements, to demonstrate conformity with the applicable SIP or TIP as required by section 176(c) of the...

  1. 40 CFR 52.634 - Particulate matter (PM-10) Group III SIP.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... SIP. 52.634 Section 52.634 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR... (PM-10) Group III SIP. (a) On September 14, 1988, the Governor of Hawaii submitted a revision to the State Implementation Plan (SIP) for implementing the required monitoring activities and other...

  2. 40 CFR 52.634 - Particulate matter (PM-10) Group III SIP.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... SIP. 52.634 Section 52.634 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR... (PM-10) Group III SIP. (a) On September 14, 1988, the Governor of Hawaii submitted a revision to the State Implementation Plan (SIP) for implementing the required monitoring activities and other...

  3. 40 CFR 93.162 - Emissions beyond the time period covered by the SIP.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... covered by the SIP. 93.162 Section 93.162 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY... § 93.162 Emissions beyond the time period covered by the SIP. If a Federal action would result in total... period covered by the SIP, the Federal agency can: (a) Demonstrate conformity with the last...

  4. 40 CFR 52.32 - Sanctions following findings of SIP inadequacy.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 3 2014-07-01 2014-07-01 false Sanctions following findings of SIP inadequacy. 52.32 Section 52.32 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR... following findings of SIP inadequacy. For purposes of the SIP revisions required by § 51.120, EPA may make...

  5. 40 CFR 52.1489 - Particulate matter (PM-10) Group II SIP commitments.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 4 2010-07-01 2010-07-01 false Particulate matter (PM-10) Group II SIP... Particulate matter (PM-10) Group II SIP commitments. (a) On March 29, 1989, the Air Quality Officer for the... inventory, and other tasks that may be necessary to satisfy the requirements of the PM-10 Group II SIPs....

  6. 40 CFR 52.2306 - Particulate Matter (PM10) Group II SIP commitments.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 5 2012-07-01 2012-07-01 false Particulate Matter (PM10) Group II SIP... Particulate Matter (PM10) Group II SIP commitments. On July 18, 1988, the Governor of Texas submitted a revision to the State Implementation Plan (SIP) that contained commitments for implementing all of...

  7. 40 CFR 52.146 - Particulate matter (PM-10) Group II SIP commitments.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 3 2012-07-01 2012-07-01 false Particulate matter (PM-10) Group II SIP... (PM-10) Group II SIP commitments. (a) On December 28, 1988, the Governor's designee for Arizona submitted a revision to the State Implementation Plan (SIP) for Casa Grande, Show Low, Safford,...

  8. 40 CFR 93.162 - Emissions beyond the time period covered by the SIP.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... covered by the SIP. 93.162 Section 93.162 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY... § 93.162 Emissions beyond the time period covered by the SIP. If a Federal action would result in total... period covered by the SIP, the Federal agency can: (a) Demonstrate conformity with the last...

  9. 40 CFR 52.1637 - Particulate Matter (PM10) Group II SIP commitments.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 4 2011-07-01 2011-07-01 false Particulate Matter (PM10) Group II SIP... Particulate Matter (PM10) Group II SIP commitments. (a) On August 19, 1988, the Governor of New Mexico submitted a revision to the State Implementation Plan (SIP) that contained commitments, from the Director...

  10. 40 CFR 52.634 - Particulate matter (PM-10) Group III SIP.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... SIP. 52.634 Section 52.634 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR... (PM-10) Group III SIP. (a) On September 14, 1988, the Governor of Hawaii submitted a revision to the State Implementation Plan (SIP) for implementing the required monitoring activities and other...

  11. 40 CFR 52.1637 - Particulate Matter (PM10) Group II SIP commitments.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 4 2012-07-01 2012-07-01 false Particulate Matter (PM10) Group II SIP... Particulate Matter (PM10) Group II SIP commitments. (a) On August 19, 1988, the Governor of New Mexico submitted a revision to the State Implementation Plan (SIP) that contained commitments, from the Director...

  12. 40 CFR 51.851 - State implementation plan (SIP) or Tribal implementation plan (TIP) revision.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 2 2011-07-01 2011-07-01 false State implementation plan (SIP) or... § 51.851 State implementation plan (SIP) or Tribal implementation plan (TIP) revision. (a) A State or... requirements, to demonstrate conformity with the applicable SIP or TIP as required by section 176(c) of the...

  13. 40 CFR 52.32 - Sanctions following findings of SIP inadequacy.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 3 2013-07-01 2013-07-01 false Sanctions following findings of SIP inadequacy. 52.32 Section 52.32 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR... following findings of SIP inadequacy. For purposes of the SIP revisions required by § 51.120, EPA may make...

  14. 40 CFR 52.1489 - Particulate matter (PM-10) Group II SIP commitments.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 4 2012-07-01 2012-07-01 false Particulate matter (PM-10) Group II SIP... Particulate matter (PM-10) Group II SIP commitments. (a) On March 29, 1989, the Air Quality Officer for the... inventory, and other tasks that may be necessary to satisfy the requirements of the PM-10 Group II SIPs....

  15. 40 CFR 52.32 - Sanctions following findings of SIP inadequacy.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 3 2010-07-01 2010-07-01 false Sanctions following findings of SIP inadequacy. 52.32 Section 52.32 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR... following findings of SIP inadequacy. For purposes of the SIP revisions required by § 51.120, EPA may make...

  16. 40 CFR 52.1637 - Particulate Matter (PM10) Group II SIP commitments.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 4 2014-07-01 2014-07-01 false Particulate Matter (PM10) Group II SIP... Particulate Matter (PM10) Group II SIP commitments. (a) On August 19, 1988, the Governor of New Mexico submitted a revision to the State Implementation Plan (SIP) that contained commitments, from the Director...

  17. Cellular senescence and protein degradation

    PubMed Central

    Deschênes-Simard, Xavier; Lessard, Frédéric; Gaumont-Leclerc, Marie-France; Bardeesy, Nabeel; Ferbeyre, Gerardo

    2014-01-01

    Autophagy and the ubiquitin–proteasome pathway (UPP) are the major protein degradation systems in eukaryotic cells. Whereas the former mediate a bulk nonspecific degradation, the UPP allows a rapid degradation of specific proteins. Both systems have been shown to play a role in tumorigenesis, and the interest in developing therapeutic agents inhibiting protein degradation is steadily growing. However, emerging data point to a critical role for autophagy in cellular senescence, an established tumor suppressor mechanism. Recently, a selective protein degradation process mediated by the UPP was also shown to contribute to the senescence phenotype. This process is tightly regulated by E3 ubiquitin ligases, deubiquitinases, and several post-translational modifications of target proteins. Illustrating the complexity of UPP, more than 600 human genes have been shown to encode E3 ubiquitin ligases, a number which exceeds that of the protein kinases. Nevertheless, our knowledge of proteasome-dependent protein degradation as a regulated process in cellular contexts such as cancer and senescence remains very limited. Here we discuss the implications of protein degradation in senescence and attempt to relate this function to the protein degradation pattern observed in cancer cells. PMID:24866342

  18. Premature Aging in Fibromyalgia.

    PubMed

    Hassett, Afton L; Clauw, Daniel J; Williams, David A

    2015-01-01

    Chronic pain is highly prevalent in older adults, and until recently, was considered to be common but relatively "benign." Mounting evidence, however, suggests that some of the 116 million US adults who suffer from chronic pain are also at an increased risk for developing age-related diseases prematurely, suffering earlier cognitive and physical decline, and experiencing earlier mortality. Given the aging US population and the prevalence of chronic pain along with related healthcare consequences, there is a critical need to better understand the relationship between aging and chronic pain. Herein, we focus on one chronic pain state, fibromyalgia, and provide an overview of the evidence suggesting that individuals with this chronic pain condition show signs of premature aging.

  19. Lifestyle influences on prematurity.

    PubMed

    Creasy, R K

    1991-01-01

    It is apparent from this review that the lifestyle of an individual gravida can potentially lead to a premature delivery. Some of these adverse behavioral characteristics may be dealt with by education and motivation, and some with actual medical treatment. However, there also appears to be significant need for public policy reorientation if we are to make a significant impact on the problem of preterm delivery.

  20. Rapamycin inhibits the secretory phenotype of senescent cells by a Nrf2-independent mechanism.

    PubMed

    Wang, Rong; Yu, Zhen; Sunchu, Bharath; Shoaf, James; Dang, Ivana; Zhao, Stephanie; Caples, Kelsey; Bradley, Lynda; Beaver, Laura M; Ho, Emily; Löhr, Christiane V; Perez, Viviana I

    2017-03-31

    Senescent cells contribute to age-related pathology and loss of function, and their selective removal improves physiological function and extends longevity. Rapamycin, an inhibitor of mTOR, inhibits cell senescence in vitro and increases longevity in several species. Nrf2 levels have been shown to decrease with aging and silencing Nrf2 gene induces premature senescence. Therefore, we explored whether Nrf2 is involved in the mechanism by which rapamycin delays cell senescence. In wild-type (WT) mouse fibroblasts, rapamycin increased the levels of Nrf2, and this correlates with the activation of autophagy and a reduction in the induction of cell senescence, as measured by SA-β-galactosidase (β-gal) staining, senescence-associated secretory phenotype (SASP), and p16 and p21 molecular markers. In Nrf2KO fibroblasts, however, rapamycin still decreased β-gal staining and the SASP, but rapamycin did not activate the autophagy pathway or decrease p16 and p21 levels. These observations were further confirmed in vivo using Nrf2KO mice, where rapamycin treatment led to a decrease in β-gal staining and pro-inflammatory cytokines in serum and fat tissue; however, p16 levels were not significantly decreased in fat tissue. Consistent with literature demonstrating that the Stat3 pathway is linked to the production of SASP, we found that rapamycin decreased activation of the Stat3 pathway in cells or tissue samples from both WT and Nrf2KO mice. Our data thus suggest that cell senescence is a complex process that involves at least two arms, and rapamycin uses Nrf2 to regulate cell cycle arrest, but not the production of SASP.

  1. Long-Term Treatment of Native LDL Induces Senescence of Cultured Human Endothelial Cells

    PubMed Central

    Oh, Sung-Tack; Park, Hoon; Yoon, Hyun Joong

    2017-01-01

    The study aimed to evaluate whether the treatment of primary cultured human endothelial cells with native low-density lipoprotein (nLDL) could induce their senescence and to uncover some of the putative mechanisms involved. For this purpose, human umbilical vein endothelial cells (HUVECs) were subcultured and/or continuously cultured with nLDL (0, 2, 5, and 10 μg protein/mL), for up to 9 days. The results indicated that nLDL inhibited the proliferation of HUVECs by arresting the cell cycle at G1 phase. The G1-arrested cells showed increase in cytosolic senescence-associated-β-galactosidase (SA-β-Gal) activity, a biomarker of cellular senescence. The causative factor of the cellular senescence was nLDL itself and not oxidized LDL (oxLDL), since blocking LDL receptor (LDLR) with the anti-LDLR antibody opposed the nLDL-induced increase of SA-β-Gal activity and decrease of cellular proliferation. In addition, nLDL-induced cellular senescence by inhibiting the phosphorylation of pRb (G1 arrest) via p53 as well as p16 signal transduction pathways. G1 phase arrest of the senescent cells was not overcome by nLDL removal from the culture medium. Moreover, the nLDL-treated cells produced reactive oxygen species (ROS) dose- and time-dependently. These results suggested, for the first time, that long-term treatment of nLDL could induce the premature senescence of endothelial cells. PMID:28197300

  2. Cell senescence is an antiviral defense mechanism

    PubMed Central

    Baz-Martínez, Maite; Da Silva-Álvarez, Sabela; Rodríguez, Estefanía; Guerra, Jorge; El Motiam, Ahmed; Vidal, Anxo; García-Caballero, Tomás; González-Barcia, Miguel; Sánchez, Laura; Muñoz-Fontela, César; Collado, Manuel; Rivas, Carmen

    2016-01-01

    Cellular senescence is often considered a protection mechanism triggered by conditions that impose cellular stress. Continuous proliferation, DNA damaging agents or activated oncogenes are well-known activators of cell senescence. Apart from a characteristic stable cell cycle arrest, this response also involves a proinflammatory phenotype known as senescence-associated secretory phenotype (SASP). This, together with the widely known interference with senescence pathways by some oncoviruses, had led to the hypothesis that senescence may also be part of the host cell response to fight virus. Here, we evaluate this hypothesis using vesicular stomatitis virus (VSV) as a model. Our results show that VSV replication is significantly impaired in both primary and tumor senescent cells in comparison with non-senescent cells, and independently of the stimulus used to trigger senescence. Importantly, we also demonstrate a protective effect of senescence against VSV in vivo. Finally, our results identify the SASP as the major contributor to the antiviral defense exerted by cell senescence in vitro, and points to a role activating and recruiting the immune system to clear out the infection. Thus, our study indicates that cell senescence has also a role as a natural antiviral defense mechanism. PMID:27849057

  3. Enhanced Viral Replication by Cellular Replicative Senescence

    PubMed Central

    Kim, Ji-Ae; Seong, Rak-Kyun

    2016-01-01

    Cellular replicative senescence is a major contributing factor to aging and to the development and progression of aging-associated diseases. In this study, we sought to determine viral replication efficiency of influenza virus (IFV) and Varicella Zoster Virus (VZV) infection in senescent cells. Primary human bronchial epithelial cells (HBE) or human dermal fibroblasts (HDF) were allowed to undergo numbers of passages to induce replicative senescence. Induction of replicative senescence in cells was validated by positive senescence-associated β-galactosidase staining. Increased susceptibility to both IFV and VZV infection was observed in senescent HBE and HDF cells, respectively, resulting in higher numbers of plaque formation, along with the upregulation of major viral antigen expression than that in the non-senescent cells. Interestingly, mRNA fold induction level of virus-induced type I interferon (IFN) was attenuated by senescence, whereas IFN-mediated antiviral effect remained robust and potent in virus-infected senescent cells. Additionally, we show that a longevity-promoting gene, sirtuin 1 (SIRT1), has antiviral role against influenza virus infection. In conclusion, our data indicate that enhanced viral replication by cellular senescence could be due to senescence-mediated reduction of virus-induced type I IFN expression. PMID:27799874

  4. Prematurely terminated slug tests

    SciTech Connect

    Karasaki, K. )

    1990-07-01

    A solution of the well response to a prematurely terminated slug test (PTST) is presented. The advantages of a PTST over conventional slug tests are discussed. A systematized procedure of a PTST is proposed, where a slug test is terminated in the midpoint of the flow point, and the subsequent shut-in data is recorded and analyzed. This method requires a downhole shut-in device and a pressure transducer, which is no more than the conventional deep-well slug testing. As opposed to slug tests, which are ineffective when a skin is present, more accurate estimate of formation permeability can be made using a PTST. Premature termination also shortens the test duration considerably. Because in most cases no more information is gained by completing a slug test to the end, the author recommends that conventional slug tests be replaced by the premature termination technique. This study is part of an investigation of the feasibility of geologic isolation of nuclear wastes being carried out by the US Department of Energy and the National Cooperative for the Storage of Radioactive Waste of Switzerland.

  5. Scientific Instrument Package for the large space telescope (SIP)

    NASA Technical Reports Server (NTRS)

    1972-01-01

    The feasibility of a scientific instrument package (SIP) that will satisfy the requirements of the large space telescope was established. A reference configuration serving as a study model and data which will aid in the trade-off studies leading to the final design configuration are reported.

  6. Cooper Screening of Information Processing (C-SIP). Administrator's Manual.

    ERIC Educational Resources Information Center

    Cooper, Richard

    This document is designed to assist individuals administering the Cooper Screening of Information Processing (C-SIP), which is intended as a diagnostic teaching tool that allows teachers or others to determine, in a conversational setting, whether a person manifests any common characteristics of learning problems. After a brief introduction, a…

  7. Covert Channels in SIP for VoIP Signalling

    NASA Astrophysics Data System (ADS)

    Mazurczyk, Wojciech; Szczypiorski, Krzysztof

    In this paper, we evaluate available steganographic techniques for SIP (Session Initiation Protocol) that can be used for creating covert channels during signaling phase of VoIP (Voice over IP) call. Apart from characterizing existing steganographic methods we provide new insights by introducing new techniques. We also estimate amount of data that can be transferred in signalling messages for typical IP telephony call.

  8. Nonattainment and Ozone Transport Region (OTR) SIP Requirements

    EPA Pesticide Factsheets

    The Clean Air Act (CAA) requires a group of northeast states, which make up the Ozone Transport Region (OTR), to submit a SIP and install a certain level of controls for the pollutants that form ozone, even if they meet ozone standards.

  9. Cellular senescence mediates fibrotic pulmonary disease

    PubMed Central

    Schafer, Marissa J.; White, Thomas A.; Iijima, Koji; Haak, Andrew J.; Ligresti, Giovanni; Atkinson, Elizabeth J.; Oberg, Ann L.; Birch, Jodie; Salmonowicz, Hanna; Zhu, Yi; Mazula, Daniel L.; Brooks, Robert W.; Fuhrmann-Stroissnigg, Heike; Pirtskhalava, Tamar; Prakash, Y. S.; Tchkonia, Tamara; Robbins, Paul D.; Aubry, Marie Christine; Passos, João F.; Kirkland, James L.; Tschumperlin, Daniel J.; Kita, Hirohito; LeBrasseur, Nathan K.

    2017-01-01

    Idiopathic pulmonary fibrosis (IPF) is a fatal disease characterized by interstitial remodelling, leading to compromised lung function. Cellular senescence markers are detectable within IPF lung tissue and senescent cell deletion rejuvenates pulmonary health in aged mice. Whether and how senescent cells regulate IPF or if their removal may be an efficacious intervention strategy is unknown. Here we demonstrate elevated abundance of senescence biomarkers in IPF lung, with p16 expression increasing with disease severity. We show that the secretome of senescent fibroblasts, which are selectively killed by a senolytic cocktail, dasatinib plus quercetin (DQ), is fibrogenic. Leveraging the bleomycin-injury IPF model, we demonstrate that early-intervention suicide-gene-mediated senescent cell ablation improves pulmonary function and physical health, although lung fibrosis is visibly unaltered. DQ treatment replicates benefits of transgenic clearance. Thus, our findings establish that fibrotic lung disease is mediated, in part, by senescent cells, which can be targeted to improve health and function. PMID:28230051

  10. Cellular senescence mediates fibrotic pulmonary disease.

    PubMed

    Schafer, Marissa J; White, Thomas A; Iijima, Koji; Haak, Andrew J; Ligresti, Giovanni; Atkinson, Elizabeth J; Oberg, Ann L; Birch, Jodie; Salmonowicz, Hanna; Zhu, Yi; Mazula, Daniel L; Brooks, Robert W; Fuhrmann-Stroissnigg, Heike; Pirtskhalava, Tamar; Prakash, Y S; Tchkonia, Tamara; Robbins, Paul D; Aubry, Marie Christine; Passos, João F; Kirkland, James L; Tschumperlin, Daniel J; Kita, Hirohito; LeBrasseur, Nathan K

    2017-02-23

    Idiopathic pulmonary fibrosis (IPF) is a fatal disease characterized by interstitial remodelling, leading to compromised lung function. Cellular senescence markers are detectable within IPF lung tissue and senescent cell deletion rejuvenates pulmonary health in aged mice. Whether and how senescent cells regulate IPF or if their removal may be an efficacious intervention strategy is unknown. Here we demonstrate elevated abundance of senescence biomarkers in IPF lung, with p16 expression increasing with disease severity. We show that the secretome of senescent fibroblasts, which are selectively killed by a senolytic cocktail, dasatinib plus quercetin (DQ), is fibrogenic. Leveraging the bleomycin-injury IPF model, we demonstrate that early-intervention suicide-gene-mediated senescent cell ablation improves pulmonary function and physical health, although lung fibrosis is visibly unaltered. DQ treatment replicates benefits of transgenic clearance. Thus, our findings establish that fibrotic lung disease is mediated, in part, by senescent cells, which can be targeted to improve health and function.

  11. Comparison of H.323 and SIP for IP telephony signaling

    NASA Astrophysics Data System (ADS)

    Dalgic, Ismail; Fang, Hanlin

    1999-11-01

    Two standards currently compete for the dominance of IP telephony signaling: the H.323 protocol suite by ITU-T, and the Session Initiation Protocol (SIP) by IETF. Both of these signaling protocols provide mechanisms for call establishment and teardown, call control and supplementary services, and capability exchange. We investigate and compare these two protocols in terms of Functionality, Quality of Service (QoS), Scalability, Flexibility, Interoperability, and Ease of Implementation. For fairness of comparison, we consider similar scenarios for both protocols. In particular, we focus on scenarios that involve a gatekeeper for H.323, and a Proxy/Redirect server for SIP. The reason is that medium-to-large IP Telephony systems are not manageable without a gatekeeper or proxy server. We consider all three versions of H.323. In terms of functionality and services that can be supported, H.323 version 2 and SIP are very similar. However, supplementary services in H.323 are more rigorously defined, and therefore fewer interoperability issues are expected among its implementations. Furthermore, H.323 has taken more steps to ensure compatibility among its different versions, and to interoperate with PSTN. The two protocols are comparable in their QoS support [similar call setup delays, no support for resource reservation or class of service (CoS) setting], but H.323 version 3 will allow signaling of the requested CoS. SIP's primary advantages are (1) flexibility to add new features, and (2) relative ease of implementation and debugging. Finally, we note that H.323 and SIP are improving themselves by learning from each other, and the differences between them are diminishing with each new version.

  12. Defective ATM-Kap-1-mediated chromatin remodeling impairs DNA repair and accelerates senescence in progeria mouse model.

    PubMed

    Liu, Baohua; Wang, Zimei; Ghosh, Shrestha; Zhou, Zhongjun

    2013-04-01

    ATM-mediated phosphorylation of KAP-1 triggers chromatin remodeling and facilitates the loading and retention of repair proteins at DNA lesions. Mouse embryonic fibroblasts (MEFs) derived from Zmpste24(-/-) mice undergo early senescence, attributable to delayed recruitment of DNA repair proteins. Here, we show that ATM-Kap-1 signaling is compromised in Zmpste24(-/-) MEFs, leading to defective DNA damage-induced chromatin remodeling. Knocking down Kap-1 rescues impaired chromatin remodeling, defective DNA repair and early senescence in Zmpste24(-/-) MEFs. Thus, ATM-Kap-1-mediated chromatin remodeling plays a critical role in premature aging, carrying significant implications for progeria therapy.

  13. Dephosphorylation of Tyrosine 393 in Argonaute 2 by Protein Tyrosine Phosphatase 1B Regulates Gene Silencing in Oncogenic RAS-Induced Senescence

    PubMed Central

    Yang, Ming; Haase, Astrid D.; Huang, Fang-Ke; Coulis, Gérald; Rivera, Keith D.; Dickinson, Bryan C.; Chang, Christopher J.; Pappin, Darryl J.; Neubert, Thomas A.; Hannon, Gregory J.; Boivin, Benoit; Tonks, Nicholas K.

    2014-01-01

    SUMMARY Oncogenic RAS (H-RASV12) induces premature senescence in primary cells by triggering production of reactive oxygen species (ROS), but the molecular role of ROS in senescence remains elusive. We investigated whether inhibition of protein tyrosine phosphatases by ROS contributed to H-RASV12-induced senescence. We identified protein tyrosine phosphatase 1B (PTP1B) as a major target of H-RASV12-induced ROS. Inactivation of PTP1B was necessary and sufficient to induce premature senescence in H-RASV12-expressing IMR90 fibroblasts. We identified phospho-Tyr 393 of argonaute 2 (AGO2) as a direct substrate of PTP1B. Phosphorylation of AGO2 at Tyr 393 inhibited loading with microRNAs (miRNA) and thus miRNA-mediated gene silencing, which counteracted the function of H-RASV12-induced oncogenic miRNAs. Overall, our data illustrate that premature senescence in H-RASV12-transformed primary cells is a consequence of oxidative inactivation of PTP1B and inhibition of miRNA-mediated gene silencing. PMID:25175024

  14. Senescence-like Phenotypes in Human Nevi

    PubMed Central

    Joselow, Andrew; Lynn, Darren; Terzian, Tamara; Box, Neil F.

    2016-01-01

    Summary Cellular senescence is an irreversible arrest of cell proliferation at the G1 stage of the cell cycle in which cells become refractory to growth stimuli. Senescence is a critical and potent defense mechanism that mammalian cells have to suppress tumors. While there are many ways to induce a senescence response, oncogene-induced senescence (OIS) remains key to inhibiting progression of cells that have acquired oncogenic mutations. In primary cells in culture, OIS induces a set of measurable phenotypic and behavioral changes, in addition to cell cycle exit. Senescence-associated β-Galactosidase (SA-β-Gal) activity is a main hallmark of senescent cells, along with morphological changes that may depend on the oncogene that is activated, or on the primary cell type. Characteristic cellular changes of senescence include increased size, flattening, multi-nucleation, and extensive vacuolation. At the molecular level, tumor suppressor genes such as p53 and p16INK4a may play a role in initiation or maintenance of OIS. Activation of a DNA damage response and a senescence-associated secretory phenotype could delineate the onset of senescence. Despite advances in our understanding of how OIS suppresses some tumor types, the in vivo role of OIS in melanocytic nevi and melanoma remains poorly understood and not validated. In an effort to stimulate research in this field, we review in this chapter the known markers of senescence and provide experimental protocols for their identification by immunofluorescent staining in melanocytic nevi and malignant melanoma. PMID:27812879

  15. The Submergence Tolerance Gene SUB1A Delays Leaf Senescence under Prolonged Darkness through Hormonal Regulation in Rice1[W][OA

    PubMed Central

    Fukao, Takeshi; Yeung, Elaine; Bailey-Serres, Julia

    2012-01-01

    Leaf senescence is a natural age-dependent process that is induced prematurely by various environmental stresses. Typical alterations during leaf senescence include breakdown of chlorophyll, a shift to catabolism of energy reserves, and induction of senescence-associated genes, all of which can occur during submergence, drought, and constant darkness. Here, we evaluated the influence of the submergence tolerance regulator, SUBMERGENCE1A (SUB1A), in the acclimation responses during leaf senescence caused by prolonged darkness in rice (Oryza sativa). SUB1A messenger RNA was highly induced by prolonged darkness in a near-isogenic line containing SUB1A. Genotypes with conditional and ectopic overexpression of SUB1A significantly delayed loss of leaf color and enhanced recovery from dark stress. Physiological analysis revealed that SUB1A postpones dark-induced senescence through the maintenance of chlorophyll and carbohydrate reserves in photosynthetic tissue. This delay allowed leaves of SUB1A genotypes to recover photosynthetic activity more quickly upon reexposure to light. SUB1A also restricted the transcript accumulation of representative senescence-associated genes. Jasmonate and salicylic acid are positive regulators of leaf senescence, but ectopic overexpression of SUB1A dampened responsiveness to both hormones in the context of senescence. We found that ethylene accelerated senescence stimulated by darkness and jasmonate, although SUB1A significantly restrained dark-induced ethylene accumulation. Overall, SUB1A genotypes displayed altered responses to prolonged darkness by limiting ethylene production and responsiveness to jasmonate and salicylic acid, thereby dampening the breakdown of chlorophyll, carbohydrates, and the accumulation of senescence-associated messenger RNAs. A delay of leaf senescence conferred by SUB1A can contribute to the enhancement of tolerance to submergence, drought, and oxidative stress. PMID:23073696

  16. Premature ovarian failure

    PubMed Central

    Beck-Peccoz, Paolo; Persani, Luca

    2006-01-01

    Premature ovarian failure (POF) is a primary ovarian defect characterized by absent menarche (primary amenorrhea) or premature depletion of ovarian follicles before the age of 40 years (secondary amenorrhea). It is a heterogeneous disorder affecting approximately 1% of women <40 years, 1:10,000 women by age 20 and 1:1,000 women by age 30. The most severe forms present with absent pubertal development and primary amenorrhea (50% of these cases due to ovarian dysgenesis), whereas forms with post-pubertal onset are characterized by disappearance of menstrual cycles (secondary amenorrhea) associated with premature follicular depletion. As in the case of physiological menopause, POF presents by typical manifestations of climacterium: infertility associated with palpitations, heat intolerance, flushes, anxiety, depression, fatigue. POF is biochemically characterized by low levels of gonadal hormones (estrogens and inhibins) and high levels of gonadotropins (LH and FSH) (hypergonadotropic amenorrhea). Beyond infertility, hormone defects may cause severe neurological, metabolic or cardiovascular consequences and lead to the early onset of osteoporosis. Heterogeneity of POF is also reflected by the variety of possible causes, including autoimmunity, toxics, drugs, as well as genetic defects. POF has a strong genetic component. X chromosome abnormalities (e.g. Turner syndrome) represent the major cause of primary amenorrhea associated with ovarian dysgenesis. Despite the description of several candidate genes, the cause of POF remains undetermined in the vast majority of the cases. Management includes substitution of the hormone defect by estrogen/progestin preparations. The only solution presently available for the fertility defect in women with absent follicular reserve is ovum donation. PMID:16722528

  17. 40 CFR 51.125 - Emissions reporting requirements for SIP revisions relating to budgets for SO2 and NOX emissions.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... SIP revisions relating to budgets for SO2 and NOX emissions. 51.125 Section 51.125 Protection of... SIP revisions relating to budgets for SO2 and NOX emissions. (a) For its transport SIP revision under... projections contained in its approved SIP submission. (1) Every-year reporting cycle. As applicable,...

  18. Abruption-associated prematurity

    PubMed Central

    Han, Christina S.; Schatz, Frederick; Lockwood, Charles J.

    2011-01-01

    SYNOPSIS Chronic, subacute decidual hemorrhage (i.e., abruptio placenta and retrochorionic hematoma formation) is an important contributor to preterm parturition. Such hemorrhage induces thrombin from decidual tissue factor, which play a pivotal role in the development of preterm premature rupture of membranes and preterm delivery by acting through protease-activated receptors to promote the production of pro-inflammatory cytokines, and matrix-degrading metalloproteinases. Severe, acute abruption can lead to maternal and fetal mortality. Current management of abruption is individualized based on severity of disease, underlying etiology, and gestational age. PMID:21890016

  19. Volatile organic chemical emissions from structural insulated panel (SIP) materials and implications for indoor air quality

    SciTech Connect

    Hodgson, Alfred T.

    2003-09-01

    The emissions of volatile organic compounds (VOCs) from structural insulated panel (SIP) materials were investigated. Specimens of newly produced SIPs and associated panel adhesives were obtained from two relatively large manufacturers. Additionally, specimens of the oriented strand board (OSB) used as the inner and outer sheathing and the extruded polystyrene core for the SIP were obtained from one manufacturer. Using small-scale chambers, emissions of formaldehyde, acetaldehyde, acetic acid and other VOCs from SIPs, OSB and polystyrene were measured over a period of four months and from the adhesives over two months. SIP specimens overlaid by gypsum board panels were also tested over four months. The predominant VOCs emitted by the SIPs included acetic acid, pentanal, hexanal and styrene. The emissions of formaldehyde and acetaldehyde were relatively low. Acetic acid and the aldehydes derived from the OSB, while styrene derived from the polystyrene. One of the SIPs emitted toluene and methyl acetate. The adhesives primarily emitted a mixture of hydrocarbons. The emission rates of most VOCs from the SIP/gypsum board assemblies were approximately the same or higher than their respective emission rates from the unfinished SIPs. Modeling using VOC emission factors obtained for the SIP/gypsum board assemblies demonstrated the potential for SIP materials to degrade indoor air quality in houses. A field study to investigate VOC concentrations and emission rates in SIP houses relative to closely matched conventionally constructed houses is necessary to determine the actual impacts of SIPs. If significant impacts are observed, to it may be desirable to develop control measures to reduce the emissions of VOCs from SIPs, such as the substitution of lower emitting materials or the use of vapor diffusion barriers.

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

    SciTech Connect

    Zhai, Yingying; Chen, Xi; Yu, Dehai; Li, Tao; Cui, Jiuwei; Wang, Guanjun; Hu, Ji-Fan; Li, Wei

    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.

  1. Leaf Senescence by Magnesium Deficiency

    PubMed Central

    Tanoi, Keitaro; Kobayashi, Natsuko I.

    2015-01-01

    Magnesium ions (Mg2+) are the second most abundant cations in living plant cells, and they are involved in various functions, including photosynthesis, enzyme catalysis, and nucleic acid synthesis. Low availability of Mg2+ in an agricultural field leads to a decrease in yield, which follows the appearance of Mg-deficient symptoms such as chlorosis, necrotic spots on the leaves, and droop. During the last decade, a variety of physiological and molecular responses to Mg2+ deficiency that potentially link to leaf senescence have been recognized, allowing us to reconsider the mechanisms of Mg2+ deficiency. This review focuses on the current knowledge about the physiological responses to Mg2+ deficiency including a decline in transpiration, accumulation of sugars and starch in source leaves, change in redox states, increased oxidative stress, metabolite alterations, and a decline in photosynthetic activity. In addition, we refer to the molecular responses that are thought to be related to leaf senescence. With these current data, we give an overview of leaf senescence induced by Mg deficiency. PMID:27135350

  2. Premature rupture of membranes.

    PubMed Central

    Poma, P. A.

    1996-01-01

    The management of patients with premature rupture of membranes has changed markedly in the past several years. The basis for this is a combination of a better understanding of newborn physiology, improved neonatal care, refinements in antibiotic therapy, and the widespread use of maternal and fetal monitoring. The best outcome for both mother and infant undoubtedly reflects data based on a combination of factors, among which are gestational age survival, evidence of fetal distress, presence or absence of labor and sepsis, and of course, the cervical condition as it is related to labor-readiness. An important recent advance is the recognition that an active observation management program is associated with less morbidity and mortality than the classic management course of delivery within 12 hours of membrane rupture. The fact that preterm premature rupture of membranes tends to recur in subsequent pregnancies offers an opportunity for prevention. Moreover, advances in perinatal and neonatal care will continue to improve the outcomes of these women and their children. PMID:8583489

  3. Cellular senescence and the aging brain

    PubMed Central

    Chinta, Shankar J.; Woods, Georgia; Rane, Anand; Demaria, Marco; Campisi, Judith; Andersen, Julie K

    2014-01-01

    Cellular senescence is a potent anti-cancer mechanism that arrests the proliferation of mitotically competent cells to prevent malignant transformation. Senescent cells accumulate with age in a variety of human and mouse tissues where they express a complex ‘senescence-associated secretory phenotype’ (SASP). The SASP includes many pro-inflammatory cytokines, chemokines, growth factors and proteases that have the potential to cause or exacerbate age-related pathology, both degenerative and hyperplastic. While cellular senescence in peripheral tissues has recently been linked to a number of age-related pathologies, its involvement in brain aging is just beginning to be explored. Recent data generated by several laboratories suggest both aging and age-related neurodegenerative diseases are accompanied by an increase in SASP-expressing senescent cells of non-neuronal origin in the brain. Moreover, this increase correlates with neurodegeneration. Senescent cells in the brain could therefore constitute novel therapeutic targets for treating age-related neuropathologies. PMID:25281806

  4. Preparing for a storm: the MOPITT SIPS experience

    NASA Astrophysics Data System (ADS)

    Ziskin, Daniel C.; Chen, Jarmei S.; Cavanaugh, Charles

    2002-01-01

    MOPITT is an instrument aboard NASA's Terra spacecraft. To process the data from raw instrument counts to observations of Carbon Monoxide and Methane a system was established at the National Center for Atmospheric Research (NCAR). This Science Investigator-led Processing System (SIPS) was quickly deployed prior to launch as an alternative to data processing within the Earth Observing System (EOS) Data and Information System (EOSDIS) Core System (ECS). The system was tested a few months before launch and soon became operational. During testing and after launch many lessons were learned due to the divergence between assumptions and reality. The main points to be aware of in order to avoid the worst SIPS problems are: *Don't believe everything you read. *Be flexible. *Test everything. *Build teamwork. *Be consistent. This presentation will provide examples of these principles.

  5. Milwaukee Laboratory System Improvement Program (L-SIP).

    PubMed

    Gradus, M Stephen; Bhattacharyya, Sanjib; Murphy, Amy; Becker, Julie N; Baker, Bevan K

    2013-01-01

    The Laboratory System Improvement Program (L-SIP) of the Association of Public Health Laboratories aims to improve state public health laboratory (PHL) system performance through continuous quality improvement. We successfully applied this state assessment tool to a local PHL (LPHL) system by tailoring it to reflect local system needs and created an LPHL system definition explaining how a local system differs from, yet complements, a state system. On November 18, 2010, 75 stakeholders from 40 agencies assessed the Milwaukee, Wisconsin, PHL system, capturing themes, strengths and weaknesses of the system, and scores for each of the 10 Essential Public Health Services. A Laboratory Advisory Committee analyzed assessment results to identify a strategic focus of research and workforce development and define an action plan, which is now being carried out. Milwaukee's L-SIP process is effectively improving LPHL system research and workforce development while raising community awareness of the system.

  6. Spectral induced polarization (SIP) response of mine tailings.

    PubMed

    Placencia-Gómez, Edmundo; Parviainen, Annika; Slater, Lee; Leveinen, Jussi

    2015-02-01

    Mine tailings impoundments are a source of leachates known as acid mine drainage (AMD) which can pose a contamination risk for surrounding surface and groundwater. Methodologies which can help management of this environmental issue are needed. We carried out a laboratory study of the spectral induced polarization (SIP) response of tailings from the Haveri Au-Cu mine, SW Finland. The primary objectives were, (1) to determine possible correlations between SIP parameters and textural properties associated with oxidative-weathering mechanisms, mineralogical composition and metallic content, and (2) to evaluate the effects of the pore water chemistry on SIP parameters associated with redox-inactive and redox-active electrolytes varying in molar concentration, conductivity and pH. The Haveri tailings exhibit well defined relaxation spectra between 100 and 10,000Hz. The relaxation magnitudes are governed by the in-situ oxidative-weathering conditions on sulphide mineral surfaces contained in the tailings, and decrease with the oxidation degree. The oxidation-driven textural variation in the tailings results in changes to the frequency peak of the phase angle, the imaginary conductivity and chargeability, when plotted versus the pore water conductivity. In contrast, the real and the formation electrical conductivity components show a single linear dependence on the pore water conductivity. The increase of the pore water conductivity (dominated by the increase of ions concentration in solution) along with a transition to acidic conditions shifts the polarization peak towards higher frequencies. These findings show the unique sensitivity of the SIP method to potentially discriminate AMD discharges from reactive oxidation zones in tailings, suggesting a significant advantage for monitoring threatened aquifers.

  7. Comparison of artificial intelligence classifiers for SIP attack data

    NASA Astrophysics Data System (ADS)

    Safarik, Jakub; Slachta, Jiri

    2016-05-01

    Honeypot application is a source of valuable data about attacks on the network. We run several SIP honeypots in various computer networks, which are separated geographically and logically. Each honeypot runs on public IP address and uses standard SIP PBX ports. All information gathered via honeypot is periodically sent to the centralized server. This server classifies all attack data by neural network algorithm. The paper describes optimizations of a neural network classifier, which lower the classification error. The article contains the comparison of two neural network algorithm used for the classification of validation data. The first is the original implementation of the neural network described in recent work; the second neural network uses further optimizations like input normalization or cross-entropy cost function. We also use other implementations of neural networks and machine learning classification algorithms. The comparison test their capabilities on validation data to find the optimal classifier. The article result shows promise for further development of an accurate SIP attack classification engine.

  8. The SHIP: A SIP to HTTP Interaction Protocol

    NASA Astrophysics Data System (ADS)

    Zeiß, Joachim; Gabner, Rene; Bessler, Sandford; Happenhofer, Marco

    IMS is capable of providing a wide range of services. As a result, terminal software becomes more and more complex to deliver network intelligence to user applications. Currently mobile terminal software needs to be permanently updated so that the latest network services and functionality can be delivered to the user. In the Internet, browser based user interfaces assure that an interface is made available to the user which offers the latest services in the net immediately. Our approach combines the benefits of the Session Initiation Protocol (SIP) and those of the HTTP protocol to bring the same type of user interfacing to IMS. SIP (IMS) realizes authentication, session management, charging and Quality of Service (QoS), HTTP provides access to Internet services and allows the user interface of an application to run on a mobile terminal while processing and orchestration is done on the server. A SHIP enabled IMS client only needs to handle data transport and session management via SIP, HTTP and RTP and render streaming media, HTML and Javascript. SHIP allows new kinds of applications, which combine audio, video and data within a single multimedia session.

  9. Design of SIP transformation server for efficient media negotiation

    NASA Astrophysics Data System (ADS)

    Pack, Sangheon; Paik, Eun Kyoung; Choi, Yanghee

    2001-07-01

    Voice over IP (VoIP) is one of the advanced services supported by the next generation mobile communication. VoIP should support various media formats and terminals existing together. This heterogeneous environment may prevent diverse users from establishing VoIP sessions among them. To solve the problem an efficient media negotiation mechanism is required. In this paper, we propose the efficient media negotiation architecture using the transformation server and the Intelligent Location Server (ILS). The transformation server is an extended Session Initiation Protocol (SIP) proxy server. It can modify an unacceptable session INVITE message into an acceptable one using the ILS. The ILS is a directory server based on the Lightweight Directory Access Protocol (LDAP) that keeps userí*s location information and available media information. The proposed architecture can eliminate an unnecessary response and re-INVITE messages of the standard SIP architecture. It takes only 1.5 round trip times to negotiate two different media types while the standard media negotiation mechanism takes 2.5 round trip times. The extra processing time in message handling is negligible in comparison to the reduced round trip time. The experimental results show that the session setup time in the proposed architecture is less than the setup time in the standard SIP. These results verify that the proposed media negotiation mechanism is more efficient in solving diversity problems.

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

    SciTech Connect

    Zhu, Liang; Dong, Chuanming; Sun, Chenxi; Ma, Rongjie; Yang, Danjing; Zhu, Hongwen; Xu, Jun

    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.

  11. Prevalence and Correlates of Sipping Alcohol in a Prospective Middle School Sample

    PubMed Central

    Jackson, Kristina M.; Colby, Suzanne M.; Barnett, Nancy P.; Abar, Caitlin C.

    2015-01-01

    Research documents an association between early use of alcohol and adverse outcomes. Most studies on drinking initiation exclude sipping or confound sips with consumption of a full drink. Yet, even a few sips of alcohol can constitute a meaningful experience for naïve drinkers. Prior research with this project indicated that sipping prior to middle school predicted subsequent adverse outcomes (at high-school entry), even controlling for child externalizing and sensation seeking and parent alcohol use. The present study extends our prior work by examining the correlates of early sipping and sipping onset. The sample was comprised of 1,023 6th, 7th, and 8th graders (52% female; 24% non-White, 12% Hispanic). Participants completed web-based surveys on five occasions over the course of two years. The prevalence of sipping at Wave 1 was 37%, with 29% of never-sippers initiating sipping within two years. Sipping was associated with stronger alcohol-related cognitions and low school engagement as well as contextual influences in the peer, sibling, and parent domains. Sipping onset among never-sippers was prospectively predicted by sensation seeking and problem behavior as well as parental and sibling influences. Importantly, mere availability of alcohol was a strong correlate both concurrently and prospectively. Further analyses demonstrated that youth who sipped alcohol with parental permission had a lower profile of risk and healthier relationships with parents as compared to youth who reported unsanctioned sipping. Findings point to the importance of considering fine-grained early drinking behavior and call for further attention to sipping in research on initiation of alcohol use. PMID:25938631

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

    SciTech Connect

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

    2014-04-18

    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.

  13. Premature ejaculation: A review

    PubMed Central

    Gajjala, Sukumar Reddy; Khalidi, Azheel

    2014-01-01

    Premature ejaculation (PE) is a common male sexual disorder. It is defined by the Diagnostic and statistical manual of mental disorders as “ejaculation occurring, without control, on or shortly after penetration and before the person wishes it, causing marked distress or interpersonal difficulty.[1] Although the timing of intravaginal ejaculatory latency time (IELT) (i.e., time from penetration to ejaculation) is not included in this definition, an IELT of <2 min, or ejaculation occurring before penetration, has been considered consistent with PE.[2] Management involves both the patient and his partner. Therapeutic options should suit both partners and be appropriate to their habit in planning and frequency of intercourse. Follow-up at appropriate intervals to judge efficacy, titrate dosage of pharmacological treatments and ascertain side effects is mandatory. PMID:26396440

  14. Apnea of Prematurity (For Parents)

    MedlinePlus

    ... other babies. The apnea of prematurity does not cause brain damage. A healthy baby who is apnea free for a week will probably never have AOP again. Although sudden infant death syndrome (SIDS) does happen more often in premature infants, no relationship between AOP and SIDS has ...

  15. Silica-Induced Protein (Sip) in Thermophilic Bacterium Thermus thermophilus Responds to Low Iron Availability

    PubMed Central

    Fujino, Yasuhiro; Nagayoshi, Yuko; Iwase, Makoto; Yokoyama, Takushi; Ohshima, Toshihisa

    2016-01-01

    ABSTRACT Thermus thermophilus HB8 expresses silica-induced protein (Sip) when cultured in medium containing supersaturated silicic acids. Using genomic information, Sip was identified as a Fe3+-binding ABC transporter. Detection of a 1-kb hybridized band in Northern analysis revealed that sip transcription is monocistronic and that sip has its own terminator and promoter. The sequence of the sip promoter showed homology with that of the σA-dependent promoter, which is known as a housekeeping promoter in HB8. Considering that sip is transcribed when supersaturated silicic acids are added, the existence of a repressor is presumed. DNA microarray analysis suggested that supersaturated silicic acids and iron deficiency affect Thermus cells similarly, and enhanced sip transcription was detected under both conditions. This suggested that sip transcription was initiated by iron deficiency and that the ferric uptake regulator (Fur) controlled the transcription. Three Fur gene homologues (TTHA0255, TTHA0344, and TTHA1292) have been annotated in the HB8 genome, and electrophoretic mobility shift assays revealed that the TTHA0344 product interacts with the sip promoter region. In medium containing supersaturated silicic acids, free Fe3+ levels were decreased due to Fe3+ immobilization on colloidal silica. This suggests that, because Fe3+ ions are captured by colloidal silica in geothermal water, Thermus cells are continuously exposed to the risk of iron deficiency. Considering that Sip is involved in iron acquisition, Sip production may be a strategy to survive under conditions of low iron availability in geothermal water. IMPORTANCE The thermophilic bacterium Thermus thermophilus HB8 produces silica-induced protein (Sip) in the presence of supersaturated silicic acids. Sip has homology with iron-binding ABC transporter; however, the mechanism by which Sip expression is induced by silicic acids remains unexplained. We demonstrate that Sip captures iron and its transcription

  16. Oxidative stress-associated senescence in dermal papilla cells of men with androgenetic alopecia.

    PubMed

    Upton, James H; Hannen, Rosalind F; Bahta, Adiam W; Farjo, Nilofer; Farjo, Bessam; Philpott, Michael P

    2015-05-01

    Dermal papilla cells (DPCs) taken from male androgenetic alopecia (AGA) patients undergo premature senescence in vitro in association with the expression of p16(INK4a), suggesting that DPCs from balding scalp are more sensitive to environmental stress than nonbalding cells. As one of the major triggers of senescence in vitro stems from the cell "culture shock" owing to oxidative stress, we have further investigated the effects of oxidative stress on balding and occipital scalp DPCs. Patient-matched DPCs from balding and occipital scalp were cultured at atmospheric (21%) or physiologically normal (2%) O2. At 21% O2, DPCs showed flattened morphology and a significant reduction in mobility, population doubling, increased levels of reactive oxygen species and senescence-associated β-Gal activity, and increased expression of p16(INK4a) and pRB. Balding DPCs secreted higher levels of the negative hair growth regulators transforming growth factor beta 1 and 2 in response to H2O2 but not cell culture-associated oxidative stress. Balding DPCs had higher levels of catalase and total glutathione but appear to be less able to handle oxidative stress compared with occipital DPCs. These in vitro findings suggest that there may be a role for oxidative stress in the pathogenesis of AGA both in relation to cell senescence and migration but also secretion of known hair follicle inhibitory factors.

  17. Sip-sizing behaviors in natural drinking conditions compared to instructed experimental conditions.

    PubMed

    Bennett, Janice W; Van Lieshout, Pascal H H M; Pelletier, Cathy A; Steele, Catriona M

    2009-06-01

    To understand disordered physiology, it is first necessary to determine what constitutes normal function. Liquid sip size during swallowing in healthy individuals has been investigated with varied results. Bolus size is a variable that is manipulated in both research studies and clinical swallowing assessments, so defining normal sip size has relevance in both domains. This study looked at sip size under instruction in experimental tasks and compared it to sip size in free drinking while participants were unaware that drinking was being observed. A statistically significant difference was found in water sip volume between natural drinking (mean = 16 ml) and instructed experimental drinking tasks (mean = 6.6-6.8 ml). This difference far exceeded the magnitude of sip-size variation observed between instructed drinking tasks using different stimuli and as a function of participant's gender or age group.

  18. Senescent cells communicate via intercellular protein transfer

    PubMed Central

    Biran, Anat; Perelmutter, Meirav; Gal, Hilah; Burton, Dominick G.A.; Ovadya, Yossi; Vadai, Ezra; Geiger, Tamar

    2015-01-01

    Mammalian cells mostly rely on extracellular molecules to transfer signals to other cells. However, in stress conditions, more robust mechanisms might be necessary to facilitate cell–cell communications. Cellular senescence, a stress response associated with permanent exit from the cell cycle and the development of an immunogenic phenotype, limits both tumorigenesis and tissue damage. Paradoxically, the long-term presence of senescent cells can promote tissue damage and aging within their microenvironment. Soluble factors secreted from senescent cells mediate some of these cell-nonautonomous effects. However, it is unknown whether senescent cells impact neighboring cells by other mechanisms. Here we show that senescent cells directly transfer proteins to neighboring cells and that this process facilitates immune surveillance of senescent cells by natural killer (NK) cells. We found that transfer of proteins to NK and T cells is increased in the murine preneoplastic pancreas, a site where senescent cells are present in vivo. Proteomic analysis and functional studies of the transferred proteins revealed that the transfer is strictly dependent on cell–cell contact and CDC42-regulated actin polymerization and is mediated at least partially by cytoplasmic bridges. These findings reveal a novel mode of intercellular communication by which senescent cells regulate their immune surveillance and might impact tumorigenesis and tissue aging. PMID:25854920

  19. Relationship between CacyBP/SIP expression and prognosis in astrocytoma.

    PubMed

    Zhao, Wei; Wang, Chunlin; Wang, Junyu; Ge, Aiqing; Li, Yiming; Li, Weiqing; Lu, Yicheng

    2011-09-01

    The aim of this study was to investigate the expression of calcyclin-binding protein (also known as Siah-1-interacting protein [CacyBP/SIP]) in astrocytoma and to determine its prognostic value in overall survival of patients with glioblastoma multiforme (GBM). Tissue specimens were obtained from 77 Chinese patients who had undergone surgery for astrocytoma. The expression of CacyBP/SIP was examined by immunohistochemistry. The relationship between CacyBP/SIP and proliferating cell nuclear antigen index (PCNA) expression was investigated, and the prognostic value of CacyBP/SIP expression in patients with astrocytomas was analyzed. Of 77 tumors, 49 (63.6%) were negative for CacyBP/SIP expression. Loss of CacyBP/SIP expression was significantly associated with a high histological grade and with poor survival in univariate and multivariate analyses. Cox multivariable analysis showed that loss of CacyBP/SIP expression correlated with poor prognosis in patients with astrocytomas and was an independent prognostic factor (p<0.05). The mean survival time of patients with tumors that had lost expression of CacyBP/SIP was 25.58months (95% confidence interval [CI], 15.36-25.81months), compared to a mean survival time of 36.37months (95% CI, 27.90-44.84months) for patients with CacyBP/SIP-expressing tumors. CacyBP/SIP expression was also negatively correlated with PCNA expression in astrocytoma tissue (p<0.05). Our findings suggest that CacyBP/SIP may have an important role as a negative regulator of astrocytoma development and progression, and that CacyBP/SIP might be a useful molecular marker for predicting the prognosis of astrocytoma.

  20. Impact of 50% Synthesized Iso-Paraffins (SIP) on Middle Distillate Fuel Filtration and Coalescence

    DTIC Science & Technology

    2014-10-30

    Impact of 50% Synthesized Iso -Paraffins (SIP) on Middle Distillate Fuel Filtration and Coalescence NF&LCFT REPORT 441/15-003 30 October 2014...negative structural impacts. An alternative sourced F-76 currently under-going qualification testing is Synthesized Iso -Paraffins (SIP). SIP fuels...are made from direct fermentation of sugar into olefinic hydrocarbons. The olefinic hydrocarbons are hydroprocessed to produce an iso -paraffinic

  1. Recapitulation of premature ageing with iPSCs from Hutchinson-Gilford progeria syndrome.

    PubMed

    Liu, Guang-Hui; Barkho, Basam Z; Ruiz, Sergio; Diep, Dinh; Qu, Jing; Yang, Sheng-Lian; Panopoulos, Athanasia D; Suzuki, Keiichiro; Kurian, Leo; Walsh, Christopher; Thompson, James; Boue, Stephanie; Fung, Ho Lim; Sancho-Martinez, Ignacio; Zhang, Kun; Yates, John; Izpisua Belmonte, Juan Carlos

    2011-04-14

    Hutchinson-Gilford progeria syndrome (HGPS) is a rare and fatal human premature ageing disease, characterized by premature arteriosclerosis and degeneration of vascular smooth muscle cells (SMCs). HGPS is caused by a single point mutation in the lamin A (LMNA) gene, resulting in the generation of progerin, a truncated splicing mutant of lamin A. Accumulation of progerin leads to various ageing-associated nuclear defects including disorganization of nuclear lamina and loss of heterochromatin. Here we report the generation of induced pluripotent stem cells (iPSCs) from fibroblasts obtained from patients with HGPS. HGPS-iPSCs show absence of progerin, and more importantly, lack the nuclear envelope and epigenetic alterations normally associated with premature ageing. Upon differentiation of HGPS-iPSCs, progerin and its ageing-associated phenotypic consequences are restored. Specifically, directed differentiation of HGPS-iPSCs to SMCs leads to the appearance of premature senescence phenotypes associated with vascular ageing. Additionally, our studies identify DNA-dependent protein kinase catalytic subunit (DNAPKcs, also known as PRKDC) as a downstream target of progerin. The absence of nuclear DNAPK holoenzyme correlates with premature as well as physiological ageing. Because progerin also accumulates during physiological ageing, our results provide an in vitro iPSC-based model to study the pathogenesis of human premature and physiological vascular ageing.

  2. Possible Roles of Strigolactones during Leaf Senescence.

    PubMed

    Yamada, Yusuke; Umehara, Mikihisa

    2015-09-11

    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.

  3. 75 FR 81555 - Approval and Promulgation of Air Quality Implementation Plans; Minnesota; Sulfur Dioxide SIP...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-12-28

    ... Dioxide SIP Revision for Marathon Petroleum St. Paul Park AGENCY: Environmental Protection Agency (EPA... revision request for Marathon Petroleum in St. Paul Park, Minnesota. This submittal updates the...

  4. The Spectral Image Processing System (SIPS): Software for integrated analysis of AVIRIS data

    NASA Technical Reports Server (NTRS)

    Kruse, F. A.; Lefkoff, A. B.; Boardman, J. W.; Heidebrecht, K. B.; Shapiro, A. T.; Barloon, P. J.; Goetz, A. F. H.

    1992-01-01

    The Spectral Image Processing System (SIPS) is a software package developed by the Center for the Study of Earth from Space (CSES) at the University of Colorado, Boulder, in response to a perceived need to provide integrated tools for analysis of imaging spectrometer data both spectrally and spatially. SIPS was specifically designed to deal with data from the Airborne Visible/Infrared Imaging Spectrometer (AVIRIS) and the High Resolution Imaging Spectrometer (HIRIS), but was tested with other datasets including the Geophysical and Environmental Research Imaging Spectrometer (GERIS), GEOSCAN images, and Landsat TM. SIPS was developed using the 'Interactive Data Language' (IDL). It takes advantage of high speed disk access and fast processors running under the UNIX operating system to provide rapid analysis of entire imaging spectrometer datasets. SIPS allows analysis of single or multiple imaging spectrometer data segments at full spatial and spectral resolution. It also allows visualization and interactive analysis of image cubes derived from quantitative analysis procedures such as absorption band characterization and spectral unmixing. SIPS consists of three modules: SIPS Utilities, SIPS_View, and SIPS Analysis. SIPS version 1.1 is described below.

  5. BAF180 regulates cellular senescence and hematopoietic stem cell homeostasis through p21

    PubMed Central

    Lee, Hyemin; Dai, Fangyan; Zhuang, Li; Xiao, Zhen-Dong; Kim, Jongchan; Zhang, Yilei; Ma, Li; You, M. James; Wang, Zhong; Gan, Boyi

    2016-01-01

    BAF180 (also called PBRM1), a subunit of the SWI/SNF complex, plays critical roles in the regulation of chromatin remodeling and gene transcription, and is frequently mutated in several human cancers. However, the role of mammalian BAF180 in tumor suppression and tissue maintenance in vivo remains largely unknown. Here, using a conditional somatic knockout approach, we explored the cellular and organismal functions of BAF180 in mouse. BAF180 deletion in primary mouse embryonic fibroblasts (MEFs) triggers profound cell cycle arrest, premature cellular senescence, without affecting DNA damage response or chromosomal integrity. While somatic deletion of BAF180 in adult mice does not provoke tumor development, BAF180 deficient mice exhibit defects in hematopoietic system characterized by progressive reduction of hematopoietic stem cells (HSCs), defective long-term repopulating potential, and hematopoietic lineage developmental aberrations. BAF180 deletion results in elevated p21 expression in both MEFs and HSCs. Mechanistically, we showed that BAF180 binds to p21 promoter, and BAF180 deletion enhances the binding of modified histones associated with transcriptional activation on p21 promoter. Deletion of p21 rescues cell cycle arrest and premature senescence in BAF180 deficient MEFs, and partially rescues hematopoietic defects in BAF180 deficient mice. Together, our study identifies BAF180 as a critical regulator of cellular senescence and HSC homeostasis, which is at least partially regulated through BAF180-mediated suppression of p21 expression. Our results also suggest that senescence triggered by BAF180 inactivation may serve as a failsafe mechanism to restrain BAF180 deficiency-associated tumor development, providing a conceptual framework to further understand BAF180 function in tumor biology. PMID:26992241

  6. Advances in treating premature ejaculation

    PubMed Central

    Şerefoğlu, Ege Can

    2014-01-01

    In spite of its high prevalence and long history, the ambiguity regarding the definition, epidemiology and management of premature ejaculation continues. Topical anesthetic creams and daily or on-demand selective serotonin reuptake inhibitor (SSRI) treatment forms the basis of pharmacotherapy for premature ejaculation today, in spite of low adherence by patients. Psychotherapy may improve the outcomes when combined with these treatment modalities. Tramadol and phosphodiesterase type 5 inhibitors have a limited role in the management of premature ejaculation. Further research is required to develop better options for the treatment of this common sexual disorder. PMID:25184045

  7. Outcome of retinopathy of prematurity.

    PubMed

    Holmström, Gerd; Larsson, Eva

    2013-06-01

    In prematurely born children, various visual and ophthalmologic sequelae occur because of both retinopathy of prematurity (ROP) and preterm birth per se. Several long-term follow-up studies have described the outcome of ROP. Visual impairment and blindness are well-known consequences, but the prevalence varies globally because of differing neonatal and ophthalmologic care. Improving treatment options and criteria for the treatment of ROP are continuously changing the ophthalmologic outcome. The anatomic outcome has improved with treatment, but good anatomic outcome in treated severe ROP does not always reflect the functional outcome. There is no consensus regarding long-term follow-up of prematurely born children.

  8. Genome-Wide Analysis of MicroRNAs and Their Target Genes Related to Leaf Senescence of Rice

    PubMed Central

    Liu, Chaoping; Chen, Eryong; Chen, Qifeng; Zhuang, Jieyun; Shen, Bo

    2014-01-01

    Grain production of rice (Oryza sativa L.) is a top priority in ensuring food security for human beings. One of the approaches to increase yield is to delay leaf senescence and to extend the available time for photosynthesis. MicroRNAs (miRNAs) are key regulators of aging and cellular senescence in eukaryotes. Here, to help understand their biological role in rice leaf senescence, we report identification of miRNAs and their putative target genes by deep sequencing of six small RNA libraries, six RNA-seq libraries and two degradome libraries from the leaves of two super hybrid rice, Nei-2-You 6 (N2Y6, age-resistant rice) and Liang-You-Pei 9 (LYP9, age-sensitive rice). In total 372 known miRNAs, 162 miRNA candidates and 1145 targets were identified. Compared with the expression of miRNAs in the leaves of LYP9, the numbers of miRNAs up-regulated and down-regulated in the leaves of N2Y6 were 47 and 30 at early stage of grain-filling, 21 and 17 at the middle stage, and 11 and 37 at the late stage, respectively. Six miRNA families, osa-miR159, osa-miR160 osa-miR164, osa-miR167, osa-miR172 and osa-miR1848, targeting the genes encoding APETALA2 (AP2), zinc finger proteins, salicylic acid-induced protein 19 (SIP19), auxin response factors (ARF) and NAC transcription factors, respectively, were found to be involved in leaf senescence through phytohormone signaling pathways. These results provided valuable information for understanding the miRNA-mediated leaf senescence of rice, and offered an important foundation for rice breeding. PMID:25479006

  9. Naturally occurring antibodies for the group B streptococcal surface immunogenic protein (Sip) in pregnant women and newborn babies.

    PubMed

    Manning, Shannon D; Wood, Stephen; Kasha, Katherine; Martin, Denis; Rioux, Stéphane; Brodeur, Bernard; Davies, H Dele

    2006-11-17

    Sip is a surface-exposed protein of GBS, which causes severe neonatal disease. Because Sip elicits a protective immune response in mice, we assessed whether pregnant women and newborns have Sip antibodies. Sera were collected from 644 pregnant women and 176 of their healthy newborns, and 10 newborns with GBS disease and their mothers. Using ELISA, most (99%) women and newborns (97%) had serum Sip antibodies, as did most newborns followed through 6 months. This suggests that naturally occurring Sip antibodies cross the placenta and persist into infancy, which underscores the need to study Sip further as a potential vaccine candidate.

  10. Laboratory SIP signatures associated with oxidation of disseminated metal sulfides.

    PubMed

    Placencia-Gómez, Edmundo; Slater, Lee; Ntarlagiannis, Dimitrios; Binley, Andrew

    2013-05-01

    Oxidation of metal sulfide minerals is responsible for the generation of acidic waters rich in sulfate and metals. When associated with the oxidation of sulfide ore mine waste deposits the resulting pore water is called acid mine drainage (AMD); AMD is a known environmental problem that affects surface and ground waters. Characterization of oxidation processes in-situ is challenging, particularly at the field scale. Geophysical techniques, spectral induced polarization (SIP) in particular, may provide a means of such investigation. We performed laboratory experiments to assess the sensitivity of the SIP method to the oxidation mechanisms of common sulfide minerals found in mine waste deposits, i.e., pyrite and pyrrhotite, when the primary oxidant agent is dissolved oxygen. We found that SIP parameters, e.g., phase shift, the imaginary component of electrical conductivity and total chargeability, decrease as the time of exposure to oxidation and oxidation degree increase. This observation suggests that dissolution-depletion of the mineral surface reduces the capacitive properties and polarizability of the sulfide minerals. However, small increases in the phase shift and imaginary conductivity do occur during oxidation. These transient increases appear to correlate with increases of soluble oxidizing products, e.g., Fe(2+) and Fe(3+) in solution; precipitation of secondary minerals and the formation of a passivating layer to oxidation coating the mineral surface may also contribute to these increases. In contrast, the real component of electrical conductivity associated with electrolytic, electronic and interfacial conductance is sensitive to changes in the pore fluid chemistry as a result of the soluble oxidation products released (Fe(2+) and Fe(3+)), particularly for the case of pyrrhotite minerals.

  11. Failed MTR Fuel Element Detect in a Sipping Tests

    SciTech Connect

    Zeituni, C.A.; Terremoto, L.A.A.; da Silva, J.E.R.

    2004-10-06

    This work describes sipping tests performed on Material Testing Reactor (MTR) fuel elements of the IEA-R1 research reactor, in order to find out which one failed in the core during a routine operation. Radioactive iodine isotopes {sup 131}I and {sup 133}I, employed as failure monitors, were detected in samples corresponding to the failed fuel element. The specific activity of each sample, as well as the average leaking rate, were measured for {sup 137}Cs. The nuclear fuels U{sub 3}O{sub 8} - Al dispersion and U - Al alloy were compared concerning their measured average leaking rates of {sup 137}Cs.

  12. Paracrine effects of human adipose-derived mesenchymal stem cells in inflammatory stress-induced senescence features of osteoarthritic chondrocytes

    PubMed Central

    Platas, Julia; Guillén, Maria Isabel; del Caz, Maria Dolores Pérez; Gomar, Francisco; Castejón, Miguel Angel; Mirabet, Vicente; Alcaraz, Maria José

    2016-01-01

    Aging and exposure to stress would determine the chondrocyte phenotype in osteoarthritis (OA). In particular, chronic inflammation may contribute to stress-induced senescence of chondrocytes and cartilage degeneration during OA progression. Recent studies have shown that adipose-derived mesenchymal stem cells exert paracrine effects protecting against degenerative changes in chondrocytes. We have investigated whether the conditioned medium (CM) from adipose-derived mesenchymal stem cells may regulate senescence features induced by inflammatory stress in OA chondrocytes. Our results indicate that CM down-regulated senescence markers induced by interleukin-1β including senescence-associated β-galactosidase activity, accumulation of γH2AX foci and morphological changes with enhanced formation of actin stress fibers. Treatment of chondrocytes with CM also decreased the production of oxidative stress, the activation of mitogen-activated protein kinases, and the expression of caveolin-1 and p21. The effects of CM were related to the reduction in p53 acetylation which would be dependent on the enhancement of Sirtuin 1 expression. Therefore, CM may exert protective effects in degenerative joint conditions by countering the premature senescence of OA chondrocytes induced by inflammatory stress. PMID:27490266

  13. Loss of MT1-MMP causes cell senescence and nuclear defects which can be reversed by retinoic acid.

    PubMed

    Gutiérrez-Fernández, Ana; Soria-Valles, Clara; Osorio, Fernando G; Gutiérrez-Abril, Jesús; Garabaya, Cecilia; Aguirre, Alina; Fueyo, Antonio; Fernández-García, María Soledad; Puente, Xose S; López-Otín, Carlos

    2015-07-14

    MT1-MMP (MMP14) is a collagenolytic enzyme located at the cell surface and implicated in extracellular matrix (ECM) remodeling. Mmp14(-/-) mice present dwarfism, bone abnormalities, and premature death. We demonstrate herein that the loss of MT1-MMP also causes cardiac defects and severe metabolic changes, and alters the cytoskeleton and the nuclear lamina structure. Moreover, the absence of MT1-MMP induces a senescent phenotype characterized by up-regulation of p16(INK4a) and p21(CIP1/WAF) (1), increased activity of senescence-associated β-galactosidase, generation of a senescence-associated secretory phenotype, and somatotroph axis alterations. Consistent with the role of retinoic acid signaling in nuclear lamina stabilization, treatment of Mmp14(-/-) mice with all-trans retinoic acid reversed the nuclear lamina alterations, partially rescued the cell senescence phenotypes, ameliorated the pathological defects in bone, skin, and heart, and extended their life span. These results demonstrate that nuclear architecture and cell senescence can be modulated by a membrane protease, in a process involving the ECM as a key regulator of nuclear stiffness under cell stress conditions.

  14. Loss of MT1-MMP causes cell senescence and nuclear defects which can be reversed by retinoic acid

    PubMed Central

    Gutiérrez-Fernández, Ana; Soria-Valles, Clara; Osorio, Fernando G; Gutiérrez-Abril, Jesús; Garabaya, Cecilia; Aguirre, Alina; Fueyo, Antonio; Fernández-García, María Soledad; Puente, Xose S; López-Otín, Carlos

    2015-01-01

    MT1-MMP (MMP14) is a collagenolytic enzyme located at the cell surface and implicated in extracellular matrix (ECM) remodeling. Mmp14−/− mice present dwarfism, bone abnormalities, and premature death. We demonstrate herein that the loss of MT1-MMP also causes cardiac defects and severe metabolic changes, and alters the cytoskeleton and the nuclear lamina structure. Moreover, the absence of MT1-MMP induces a senescent phenotype characterized by up-regulation of p16INK4a and p21CIP1/WAF1, increased activity of senescence-associated β-galactosidase, generation of a senescence-associated secretory phenotype, and somatotroph axis alterations. Consistent with the role of retinoic acid signaling in nuclear lamina stabilization, treatment of Mmp14−/− mice with all-trans retinoic acid reversed the nuclear lamina alterations, partially rescued the cell senescence phenotypes, ameliorated the pathological defects in bone, skin, and heart, and extended their life span. These results demonstrate that nuclear architecture and cell senescence can be modulated by a membrane protease, in a process involving the ECM as a key regulator of nuclear stiffness under cell stress conditions. PMID:25991604

  15. Early senescence induced by 2-3H-benzoxazolinone (BOA) in Arabidopsis thaliana.

    PubMed

    Sánchez-Moreiras, Adela M; Martínez-Peñalver, Ana; Reigosa, Manuel J

    2011-06-15

    Measurements of chlorophyll a fluorescence, nutrient and trace elements, total protein content and malonyldialdehyde in leaves of Arabidopsis thaliana between 1 and 192 h after treatment with 0, 1 or 3 mM 2-3H-benzoxazolinone (BOA), together with imaging of chlorophyll a fluorescence and of the distributions of hydrogen peroxide and superoxide anion, suggested that the primary phytotoxic action of BOA is the induction of premature senescence, and that oxidative stress is a secondary effect that sets in a day or two later.

  16. [Premature ovarian failure: present aspects].

    PubMed

    Vilodre, Luiz Cesar; Moretto, Marcelo; Kohek, Maria Beatriz da Fonte; Spritzer, Poli Mara

    2007-08-01

    Premature ovarian failure occurs in approximately 1:1000 women before 30 years, 1:250 by 35 years and 1:100 by the age of 40. It is characterized by primary or secondary amenorrhea and cannot be considered as definitive because spontaneous conception may occur in 5 to 10% of cases. In 95% of cases, premature ovarian failure is sporadic. The known causes of premature ovarian failure include chromosomal defects, autoimmune diseases, exposure to radiation or chemotherapy, surgical procedures, and certain drugs. Frequently, however, the etiology is not clear and these cases are considered to be idiopathic. Premature ovarian failure is defined by gonadal failure and high serum follicle-stimulating hormone (FSH) levels. Clinical approach includes emotional support, hormonal therapy with estrogens and progesterone or progestogens, infertility treatment, and prevention of osteoporosis and potential cardiovascular risk.

  17. Sip size of orangeade: effects on intake and sensory-specific satiation.

    PubMed

    Weijzen, Pascalle L G; Smeets, Paul A M; de Graaf, Cees

    2009-10-01

    Sensory-specific satiation (SSS) drives food selection and contributes to meal termination. We hypothesised that smaller sips would increase SSS due to increased oro-sensory exposure, irrespective of energy content. The objective was to determine the effects of sip size and energy content on ad libitum intake of orangeade and subjective SSS for orangeade. Orangeade intake and ratings of wanting and liking were measured before and after ad libitum orangeade consumption in a 2 x 2 cross-over design (n 53). Conditions differed in energy content (no-energy v. regular-energy orangeade) and in sip size (large, 20 g/sip v. small, 5 g/sip). The mean intake of both orangeades was lower when consumed with small sips than when consumed with large sips (regular-energy, 352 v. 493 g; no-energy, 338 v. 405 g; both P < 0.001). When consumed with large sips, the mean intake of no-energy orangeade was lower than that of regular-energy orangeade (P = 0.02). When consumed with small sips, subjective SSS (based on the desire to drink) was higher for no-energy orangeade than for regular-energy orangeade (P = 0.01), while mean intake was comparable. We concluded that smaller sip size, i.e. increased oro-sensory exposure per unit of consumption, can lower intake of sweet drinks. Only with low oro-sensory exposure (large sip size) was intake higher for an energy-containing sweet drink than for a no-energy sweet drink. This suggests that intake of sweet drinks is stimulated by (metabolic) reward value and inhibited by sensory satiation. This underpins the importance of SSS for meal termination.

  18. Aldehyde Oxidase 4 Plays a Critical Role in Delaying Silique Senescence by Catalyzing Aldehyde Detoxification1[OPEN

    PubMed Central

    Yarmolinsky, Dmitry; Soltabayeva, Aigerim; Samani, Talya

    2017-01-01

    The Arabidopsis (Arabidopsis thaliana) aldehyde oxidases are a multigene family of four oxidases (AAO1–AAO4) that oxidize a variety of aldehydes, among them abscisic aldehyde, which is oxidized to the phytohormone abscisic acid. Toxic aldehydes are generated in plants both under normal conditions and in response to stress. The detoxification of such aldehydes by oxidation is attributed to aldehyde dehydrogenases but never to aldehyde oxidases. The feasibility of the detoxification of aldehydes in siliques via oxidation by AAO4 was demonstrated, first, by its ability to efficiently oxidize an array of aromatic and aliphatic aldehydes, including the reactive carbonyl species (RCS) acrolein, hydroxyl-2-nonenal, and malondialdehyde. Next, exogenous application of several aldehydes to siliques in AAO4 knockout (KO) Arabidopsis plants induced severe tissue damage and enhanced malondialdehyde levels and senescence symptoms, but not in wild-type siliques. Furthermore, abiotic stresses such as dark and ultraviolet C irradiation caused an increase in endogenous RCS and higher expression levels of senescence marker genes, leading to premature senescence of KO siliques, whereas RCS and senescence marker levels in wild-type siliques were hardly affected. Finally, in naturally senesced KO siliques, higher endogenous RCS levels were associated with enhanced senescence molecular markers, chlorophyll degradation, and earlier seed shattering compared with the wild type. The aldehyde-dependent differential generation of superoxide and hydrogen peroxide by AAO4 and the induction of AAO4 expression by hydrogen peroxide shown here suggest a self-amplification mechanism for detoxifying additional reactive aldehydes produced during stress. Taken together, our results indicate that AAO4 plays a critical role in delaying senescence in siliques by catalyzing aldehyde detoxification. PMID:28188272

  19. Plant senescence: Its biochemistry and physiology

    SciTech Connect

    Thomson, W.W.; Nothnagel, E.A.; Huffaker, R.C. )

    1987-01-01

    Considering the early phylogenetic appearance of functional xylem and phloem elements and the range of senescent processes expressed onto genetically, it becomes apparent that such processes are inextricably linked to the evolution, development, reproduction, form, and function of higher plants. The importance of these senescent processes to man are patently obvious since, in one form or another, these processes provide major sources of wood, fiber, and fuel, and are involved in seed development and grain and fruit ripening. To many, the results of senescent processes also have esthetic value including, for example, the grandeur of a Sequoia, the blaze of colors across a desert landscape covered in the spring by ephermal flowers, or the rich tones and panoramic splendor of a deciduous forest in autumn. Senescent processes are widespread, but varied in kind and degree, ranging from whole plants to individual tissues and cells. This symposium was organized primarily around cellular and biochemical aspects of senescence. A major emphasis was the view that senescent processes, and those which developmentally lead to senescence, are highly regulated with an underlying genetic component. Individual papers were processed separately for the database.

  20. Autocrine IL-6 mediates pituitary tumor senescence.

    PubMed

    Sapochnik, Melanie; Haedo, Mariana R; Fuertes, Mariana; Ajler, Pablo; Carrizo, Guillermo; Cervio, Andrés; Sevlever, Gustavo; Stalla, Günter K; Arzt, Eduardo

    2017-01-17

    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.

  1. Calcium alterations signal either to senescence or to autophagy induction in stem cells upon oxidative stress

    PubMed Central

    Borodkina, Aleksandra V.; Shatrova, Alla N.; Deryabin, Pavel I.; Griukova, Anastasiia A.; Abushik, Polina A.; Antonov, Sergei M.; Nikolsky, Nikolay N.; Burova, Elena B.

    2016-01-01

    Intracellular calcium ([Ca2+]i) has been reported to play an important role in autophagy, apoptosis and necrosis, however, a little is known about its impact in senescence. Here we investigated [Ca2+]i contribution to oxidative stress-induced senescence of human endometrium-derived stem cells (hMESCs). In hMESCs sublethal H2O2-treatment resulted in a rapid calcium release from intracellular stores mediated by the activation of PLC/IP3/IP3R pathway. Notably, further senescence development was accompanied by persistently elevated [Ca2+]i levels. In H2O2-treated hMESCs, [Ca2+]i chelation by BAPTA-AM (BAPTA) was sufficient to prevent the expansion of the senescence phenotype, to decrease endogenous reactive oxygen species levels, to avoid G0/G1 cell cycle arrest, and finally to retain proliferation. Particularly, loading with BAPTA attenuated phosphorylation of the main DNA damage response members, including ATM, 53BP1 and H2A.X and reduced activation of the p53/p21/Rb pathway in H2O2-stimulated cells. Next, we revealed that BAPTA induced an early onset of AMPK-dependent autophagy in H2O2-treated cells as confirmed by both the phosphorylation status of AMPK/mTORC1 pathway and the dynamics of the LC3 lipidization. Summarizing the obtained data we can assume that calcium chelation is able to trigger short-term autophagy and to prevent the premature senescence of hMESCs under oxidative stress. PMID:27941214

  2. Identification of microRNAs dysregulated in cellular senescence driven by endogenous genotoxic stress

    PubMed Central

    Nidadavolu, Lolita S.; Niedernhofer, Laura J.; Khan, Saleem A.

    2013-01-01

    XFE progeroid syndrome, a disease of accelerated aging caused by deficiency in the DNA repair endonuclease XPF-ERCC1, is modeled by Ercc1 knockout and hypomorphic mice. Tissues and primary cells from these mice senesce prematurely, offering a unique opportunity to identify factors that regulate senescence and aging. We compared microRNA (miRNA) expression in Ercc1−/− primary mouse embryonic fibroblasts (MEFs) and wild-type (WT) MEFs in different growth conditions to identify miRNAs that drive cellular senescence. Microarray analysis showed three differentially expressed miRNAs in passage 7 (P7) Ercc1−/− MEFs grown at 20% O2 compared to Ercc1−/− MEFs grown at 3% O2. Thirty-six differentially expressed miRNAs were identified in Ercc1−/− MEFs at P7 compared to early passage (P3) in 3% O2. Eight of these miRNAs (miR-449a, miR-455*, miR-128, miR-497, miR-543, miR-450b-3p, miR-872 and miR-10b) were similarly downregulated in the liver of progeroid Ercc1−/Δ and old WT mice compared to adult WT mice, a tissue that senesces with aging. Three miRNAs (miR-449a, miR-455* and miR-128) were also downregulated in Ercc1−/Δ and WT old mice kidneys compared to young WT mice. We also discovered that the miRNA expression regulator Dicer is significantly downregulated in tissues of old mice and late passage cells compared to young controls. Collectively these results support the conclusion that the miRNAs identified may play an important role in staving off cellular senescence and their altered expression could be indicative of aging. PMID:23852002

  3. 75 FR 81471 - Approval and Promulgation of Air Quality Implementation Plans; Minnesota; Sulfur Dioxide SIP...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-12-28

    ... Dioxide SIP Revision for Marathon Petroleum St. Paul Park AGENCY: Environmental Protection Agency (EPA... dioxide State Implementation Plan revision for Marathon Petroleum in St. Paul Park. This submittal updates... (SO 2 ) State Implementation Plan (SIP) revision request for Marathon Petroleum Co, LLC, (Marathon)...

  4. 75 FR 30410 - Disease, Disability, and Injury Prevention and Control Special Interest Project (SIP): Provider...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-06-01

    ... Control Special Interest Project (SIP): Provider and Public Health Input for Vaccine Policy Decisions SIP..., discussion, and evaluation of applications received in response to ``Provider and Public Health Input for... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF HEALTH...

  5. Overexpressed CacyBP/SIP leads to the suppression of growth in renal cell carcinoma

    SciTech Connect

    Sun, Shiren; Ning, Xiaoxuan; Liu, Jie; Liu, Lili; Chen, Yu; Han, Shuang; Zhang, Yanqi; Liang, Jie; Wu, Kaichun; Fan, Daiming . E-mail: fandaim@fmmu.edu.cn

    2007-05-18

    Calcyclin-binding protein/Siah-1-interacting protein (CacyBP/SIP), a target protein of S100, has been identified as a component of a novel ubiquitinylation complex leading to {beta}-catenin degradation, which was found to be related to the malignant phenotypes of gastric cancer. However, the roles of CacyBP/SIP in renal cell carcinoma still remain unclear. In the present study, we had analyzed the expression of the CacyBP/SIP protein in human renal cancer cells and clinical tissue samples. The possible roles of CacyBP/SIP in regulating the malignant phenotype of renal cancer cells were also investigated. The results demonstrated that the expression of CacyBP/SIP was markedly down-regulated in renal cell carcinoma tissues and cell lines. Ectopic overexpression of CacyBP/SIP in A498 cells inhibited the proliferation of this cell and delayed cell cycle progression significantly, which might be related to the down-regulation of Cyclin D1 through reducing {beta}-catenin protein. CacyBP/SIP also suppressed colony formation in soft agar and its tumorigenicity in nude mice. Taken together, our work showed that CacyBP/SIP, as a novel down-regulated gene in renal cell carcinoma, suppressed proliferation and tumorigenesis of renal cancer cells.

  6. 75 FR 32190 - Disease, Disability, and Injury Prevention and Control Special Interest Projects (SIPs...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-06-07

    ...: Michelle Mathieson, Public Health Analyst, National Center for Chronic Disease and Health Promotion, Office... HUMAN SERVICES Centers for Disease Control and Prevention Disease, Disability, and Injury Prevention and... Chronic Conditions SIP 10-037 and Epidemiologic Follow- Up Study of Newly Diagnosed Epilepsy SIP...

  7. 78 FR 21281 - Approval and Promulgation of Implementation Plans; State of Missouri; Infrastructure SIP...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-04-10

    ...EPA is proposing action on four Missouri State Implementation Plan (SIP) submissions. First, EPA is proposing to approve portions of two SIP submissions from the State of Missouri addressing the applicable requirements of Clean Air Act (CAA) for the 1997 and 2006 National Ambient Air Quality Standards (NAAQS) for fine particulate matter (PM2.5). The CAA requires that each state......

  8. 40 CFR 52.1638 - Bernalillo County particulate matter (PM10) Group II SIP commitments.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... (PM10) Group II SIP commitments. 52.1638 Section 52.1638 Protection of Environment ENVIRONMENTAL... (CONTINUED) New Mexico § 52.1638 Bernalillo County particulate matter (PM10) Group II SIP commitments. (a) On December 7, 1988, the Governor of New Mexico submitted a revision to the State Implementation Plan...

  9. 40 CFR 52.1638 - Bernalillo County particulate matter (PM10) Group II SIP commitments.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... (PM10) Group II SIP commitments. 52.1638 Section 52.1638 Protection of Environment ENVIRONMENTAL... (CONTINUED) New Mexico § 52.1638 Bernalillo County particulate matter (PM10) Group II SIP commitments. (a) On December 7, 1988, the Governor of New Mexico submitted a revision to the State Implementation Plan...

  10. 40 CFR 52.1638 - Bernalillo County particulate matter (PM10) Group II SIP commitments.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... (PM10) Group II SIP commitments. 52.1638 Section 52.1638 Protection of Environment ENVIRONMENTAL... (CONTINUED) New Mexico § 52.1638 Bernalillo County particulate matter (PM10) Group II SIP commitments. (a) On December 7, 1988, the Governor of New Mexico submitted a revision to the State Implementation Plan...

  11. Overexpressed CacyBP/SIP leads to the suppression of growth in renal cell carcinoma.

    PubMed

    Sun, Shiren; Ning, Xiaoxuan; Liu, Jie; Liu, Lili; Chen, Yu; Han, Shuang; Zhang, Yanqi; Liang, Jie; Wu, Kaichun; Fan, Daiming

    2007-05-18

    Calcyclin-binding protein/Siah-1-interacting protein (CacyBP/SIP), a target protein of S100, has been identified as a component of a novel ubiquitinylation complex leading to beta-catenin degradation, which was found to be related to the malignant phenotypes of gastric cancer. However, the roles of CacyBP/SIP in renal cell carcinoma still remain unclear. In the present study, we had analyzed the expression of the CacyBP/SIP protein in human renal cancer cells and clinical tissue samples. The possible roles of CacyBP/SIP in regulating the malignant phenotype of renal cancer cells were also investigated. The results demonstrated that the expression of CacyBP/SIP was markedly down-regulated in renal cell carcinoma tissues and cell lines. Ectopic overexpression of CacyBP/SIP in A498 cells inhibited the proliferation of this cell and delayed cell cycle progression significantly, which might be related to the down-regulation of Cyclin D1 through reducing beta-catenin protein. CacyBP/SIP also suppressed colony formation in soft agar and its tumorigenicity in nude mice. Taken together, our work showed that CacyBP/SIP, as a novel down-regulated gene in renal cell carcinoma, suppressed proliferation and tumorigenesis of renal cancer cells.

  12. 40 CFR 52.1638 - Bernalillo County particulate matter (PM10) Group II SIP commitments.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... (PM10) Group II SIP commitments. 52.1638 Section 52.1638 Protection of Environment ENVIRONMENTAL... (CONTINUED) New Mexico § 52.1638 Bernalillo County particulate matter (PM10) Group II SIP commitments. (a) On December 7, 1988, the Governor of New Mexico submitted a revision to the State Implementation Plan...

  13. CacyBP/SIP as a novel modulator of the thin filament.

    PubMed

    Jurewicz, Ewelina; Ostrowska, Zofia; Jozwiak, Jolanta; Redowicz, Maria Jolanta; Lesniak, Wieslawa; Moraczewska, Joanna; Filipek, Anna

    2013-03-01

    The CacyBP/SIP protein interacts with several targets, including actin. Since the majority of actin filaments are associated with tropomyosin, in this work we characterized binding of CacyBP/SIP to the actin-tropomyosin complex and examined the effects of CacyBP/SIP on actin filament functions. By using reconstituted filaments composed of actin and AEDANS-labeled tropomyosin, we observed that binding of CacyBP/SIP caused an increase in tropomyosin fluorescence intensity indicating the occurrence of conformational changes within the filament. We also found that CacyBP/SIP bound directly to tropomyosin and that these proteins did not compete with each other for binding to actin. Electron microscopy showed that in the absence of tropomyosin CacyBP/SIP destabilized actin filaments, but tropomyosin reversed this effect. Actin-activated myosin S1 ATPase activity assays, performed using a colorimetric method, indicated that CacyBP/SIP reduced ATPase activity and that the presence of tropomyosin enhanced this inhibitory effect. Thus, our results suggest that CacyBP/SIP, through its interaction with both actin and tropomyosin, regulates the organization and functional properties of the thin filament.

  14. Demonstrating the Benefits of Staff Development: Assessment When Beginning a SIP Process.

    ERIC Educational Resources Information Center

    Todnem, Guy R.; Warner, Michael P.

    1995-01-01

    Assessment can assist key steps in the development of effective school improvement planning (SIP) programs. The article refers to an SIP Action Guide, highlighting four occasions during use of the Action Guide when assessment processes are key (assessment within action plans and assessment to identify strengths, concerns, and possible causes). (SM)

  15. CacyBP/SIP promotes the proliferation of colon cancer cells.

    PubMed

    Zhai, Huihong; Shi, Yongquan; Chen, Xiong; Wang, Jun; Lu, Yuanyuan; Zhang, Faming; Liu, Zhengxiong; Lei, Ting; Fan, Daiming

    2017-01-01

    CacyBP/SIP is a component of the ubiquitin pathway and is overexpressed in several transformed tumor tissues, including colon cancer, which is one of the most common cancers worldwide. It is unknown whether CacyBP/SIP promotes the proliferation of colon cancer cells. This study examined the expression level, subcellular localization, and binding activity of CacyBP/SIP in human colon cancer cells in the presence and absence of the hormone gastrin. We found that CacyBP/SIP was expressed in a high percentage of colon cancer cells, but not in normal colonic surface epithelium. CacyBP/SIP promoted the cell proliferation of colon cancer cells under both basal and gastrin stimulated conditions as shown by knockdown studies. Gastrin stimulation triggered the translocation of CacyBP/SIP to the nucleus, and enhanced interaction between CacyBP/SIP and SKP1, a key component of ubiquitination pathway which further mediated the proteasome-dependent degradation of p27kip1 protein. The gastrin induced reduction in p27kip1 was prevented when cells were treated with the proteasome inhibitor MG132. These results suggest that CacyBP/SIP may be promoting growth of colon cancer cells by enhancing ubiquitin-mediated degradation of p27kip1.

  16. MAP kinase p38 is a novel target of CacyBP/SIP phosphatase.

    PubMed

    Topolska-Woś, Agnieszka M; Rosińska, Sara; Filipek, Anna

    2017-03-10

    Mitogen-activated protein (MAP) kinases are important players in cellular signaling pathways. Recently, it has been shown that CacyBP/SIP serves as a phosphatase for one of the MAP kinases, ERK1/2. Through dephosphorylation of this kinase CacyBP/SIP modulates the transcriptional activity of Elk-1 and the activity of the CREB-BDNF pathway. In this work, using NB2a cell lysate and recombinant proteins, we show that CacyBP/SIP binds and dephosphorylates another member of the MAP kinase family, p38. Analysis of recombinant full-length CacyBP/SIP and its three major domains, N-terminal, middle CS and C-terminal SGS, indicates that the middle CS domain is responsible for p38 dephosphorylation. Moreover, we show that CacyBP/SIP might be implicated in response to oxidative stress. Dephosphorylation of phospho-p38 by CacyBP/SIP in NB2a cells treated with hydrogen peroxide is much more effective than in control ones. In conclusion, involvement of CacyBP/SIP in the regulation of p38 kinase activity, in addition to that of ERK1/2, might point to the function of CacyBP/SIP in pro-survival and pro-apoptotic pathways.

  17. School Improvement through School/University Collaboration: The C-SIP Model.

    ERIC Educational Resources Information Center

    Hackmann, Donald G.; Schmitt, Donna M.

    1995-01-01

    The Collaborative School Improvement Program (C-SIP) is a successful school-university partnership that encourages collaborative relationships between Eastern Michigan University and area schools through building-level shared decision making. The article describes C-SIP's six-step process, typical school improvement activities, and implications…

  18. 40 CFR 52.1638 - Bernalillo County particulate matter (PM10) Group II SIP commitments.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... (PM10) Group II SIP commitments. 52.1638 Section 52.1638 Protection of Environment ENVIRONMENTAL... (CONTINUED) New Mexico § 52.1638 Bernalillo County particulate matter (PM10) Group II SIP commitments. (a) On December 7, 1988, the Governor of New Mexico submitted a revision to the State Implementation Plan...

  19. Design of a SIP device cooperation system on OSGi service platforms

    NASA Astrophysics Data System (ADS)

    Takayama, Youji; Koita, Takahiro; Sato, Kenya

    2007-12-01

    Home networks feature such various technologies as protocols, specifications, and middleware, including HTTP, UPnP, and Jini. A service platform is required to handle such technologies to enable them to cooperate with different devices. The OSGi service platform, which meets the requirements based on service-oriented architecture, is designed and standardized by OSGi Alliance and consists of two parts: one OSGi Framework and bundles. On the OSGi service platform, APIs are defined as services that can handle these technologies and are implemented in the bundle. By using the OSGi Framework with bundles, various technologies can cooperate with each other. On the other hand, in IP networks, Session Initiation Protocol (SIP) is often used in device cooperation services to resolve an IP address, control a session between two or more devices, and easily exchange the statuses of devices. However, since many existing devices do not correspond to SIP, it cannot be used for device cooperation services. A device that does not correspond to SIP is called an unSIP device. This paper proposes and implements a prototype system that enables unSIP devices to correspond to SIP. For unSIP devices, the proposed system provides device cooperation services with SIP.

  20. 77 FR 31358 - Disease, Disability, and Injury Prevention and Control Special Interest Projects (SIPs): Initial...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-05-25

    ... Center for the Managing Epilepsy Well (MEW) Prevention Research Centers Network, SIP12-056, and Managing Epilepsy Well (MEW) Collaborating Center for Epilepsy Self-Management Intervention Research, SIP12-057..., discussion, and evaluation of ``Coordinating Center for the Managing Epilepsy Well (MEW)...

  1. CacyBP/SIP promotes the proliferation of colon cancer cells

    PubMed Central

    Chen, Xiong; Wang, Jun; Lu, Yuanyuan; Zhang, Faming; Liu, Zhengxiong; Lei, Ting; Fan, Daiming

    2017-01-01

    CacyBP/SIP is a component of the ubiquitin pathway and is overexpressed in several transformed tumor tissues, including colon cancer, which is one of the most common cancers worldwide. It is unknown whether CacyBP/SIP promotes the proliferation of colon cancer cells. This study examined the expression level, subcellular localization, and binding activity of CacyBP/SIP in human colon cancer cells in the presence and absence of the hormone gastrin. We found that CacyBP/SIP was expressed in a high percentage of colon cancer cells, but not in normal colonic surface epithelium. CacyBP/SIP promoted the cell proliferation of colon cancer cells under both basal and gastrin stimulated conditions as shown by knockdown studies. Gastrin stimulation triggered the translocation of CacyBP/SIP to the nucleus, and enhanced interaction between CacyBP/SIP and SKP1, a key component of ubiquitination pathway which further mediated the proteasome-dependent degradation of p27kip1 protein. The gastrin induced reduction in p27kip1 was prevented when cells were treated with the proteasome inhibitor MG132. These results suggest that CacyBP/SIP may be promoting growth of colon cancer cells by enhancing ubiquitin-mediated degradation of p27kip1. PMID:28196083

  2. Two-dimensional SiP: an unexplored direct band-gap semiconductor

    NASA Astrophysics Data System (ADS)

    Zhang, Shengli; Guo, Shiying; Huang, Yaxin; Zhu, Zhen; Cai, Bo; Xie, Meiqiu; Zhou, Wenhan; Zeng, Haibo

    2017-03-01

    Inspired by successful synthesis of layered SiP single crystals in experiments, we explore their structures, electronic properties, and stability using first-principles calculations. The interlayer interaction in layered SiP crystal is weak, thus mechanical exfoliation is viable. We find that SiP undergoes a transition from an indirect band gap to a direct band gap of 2.59 eV when thinned from bulk to a monolayer. Our calculations also show that SiP monolayers are both dynamically and thermodynamically stable even at elevated temperatures. Monolayer SiP, with simultaneously high stability and a large direct band gap, is a promising candidate for two-dimensional blue light emitting diodes.

  3. SIP30 Is Regulated by ERK in Peripheral Nerve Injury-induced Neuropathic Pain*

    PubMed Central

    Peng, Guangdun; Han, Mei; Du, Yimin; Lin, Anning; Yu, Lei; Zhang, Yuqiu; Jing, Naihe

    2009-01-01

    ERK plays an important role in chronic neuropathic pain. However, the underlying mechanism is largely unknown. Here we show that in chronic constriction injury-treated rat spinal cords, up-regulation of SIP30 (SNAP25-interacting protein 30), which is involved in the development and maintenance of chronic constriction injury-induced neuropathic pain, correlates with ERK activation and that the up-regulation of SIP30 is suppressed by intrathecal delivery of the MEK inhibitor U0126. In PC12 cells, up-regulation of SIP30 by nerve growth factor is also dependent on ERK activation. We found that there is an ERK-responsive region in the rat sip30 promoter. Activation of ERK promotes the recruitment of the transcription factor cyclic AMP-response element-binding protein to the sip30 gene promoter. Taken together, our results provide a potential downstream target of ERK activation-mediated neuropathic pain. PMID:19723624

  4. Prenatal stress, prematurity and asthma

    PubMed Central

    Medsker, Brock; Forno, Erick; Simhan, Hyagriv; Celedón, Juan C.

    2016-01-01

    Asthma is the most common chronic disease of childhood, affecting millions of children in the U.S. and worldwide. Prematurity is a risk factor for asthma, and certain ethnic or racial minorities such as Puerto Ricans and non-Hispanic Blacks are disproportionately affected by both prematurity and asthma. In this review, we examine current evidence to support maternal psychosocial stress as a putative link between prematurity and asthma, while also focusing on disruption of the hypothalamic-pituitary-adrenal (HPA) axis and immune responses as potential underlying mechanisms for stress-induced “premature asthma”. Prenatal stress may not only cause abnormalities in the HPA axis but also epigenetic changes in the fetal glucocorticoid receptor gene (NR3C1), leading to impaired glucocorticoid metabolism. Moreover, maternal stress can alter fetal cytokine balance, favoring Th2 (allergic) immune responses characteristic of atopic asthma: IL-6, which has been associated with premature labor, can promote Th2 responses by stimulating production of IL-4 and IL-13. Given a link among stress, prematurity, and asthma, future research should include birth cohorts aimed at confirming and better characterizing “premature asthma”. If confirmed, clinical trials of prenatal maternal stress reduction would be warranted to reduce the burden of these common co-morbidities. While awaiting the results of such studies, sound policies to prevent domestic and community violence (e.g. from firearms) are justified, not only by public safety but also by growing evidence of detrimental effects of violence-induced stress on psychiatric and somatic health. PMID:26676148

  5. Modelling transcriptional networks in leaf senescence.

    PubMed

    Penfold, Christopher A; Buchanan-Wollaston, Vicky

    2014-07-01

    The process of leaf senescence is induced by an extensive range of developmental and environmental signals and controlled by multiple, cross-linking pathways, many of which overlap with plant stress-response signals. Elucidation of this complex regulation requires a step beyond a traditional one-gene-at-a-time analysis. Application of a more global analysis using statistical and mathematical tools of systems biology is an approach that is being applied to address this problem. A variety of modelling methods applicable to the analysis of current and future senescence data are reviewed and discussed using some senescence-specific examples. Network modelling with a senescence transcriptome time course followed by testing predictions with gene-expression data illustrates the application of systems biology tools.

  6. The female reproduction and senescence nexus.

    PubMed

    Marquez, Cielo Mae D; Ibana, Joyce A; Velarde, Michael C

    2017-02-10

    Successful pregnancy is regulated by several soluble factors that are differentially expressed throughout gestation. These factors are important to initiate and establish embryo implantation and parturition. Senescent cells, which undergo permanent cell proliferation arrest in response to stress, also produce several secreted factors, referred to as the senescence-associated secretory phenotype (SASP). Here, we review some of the secreted factors found during early and late pregnancy and compare their expression profile with those of the SASP. Because senescent cells are found in the uterus and embryo during pregnancy, we hypothesize that SASP factors contribute to successful pregnancy. We discuss how senescent cells may support embryo development and signal parturition. We provide evidences for potential contribution of SASP to the physiology and pathophysiology of pregnancy.

  7. Geroconversion: irreversible step to cellular senescence

    PubMed Central

    Blagosklonny, Mikhail V

    2014-01-01

    Cellular senescence happens in 2 steps: cell cycle arrest followed, or sometimes preceded, by gerogenic conversion (geroconversion). Geroconvesrion is a form of growth, a futile growth during cell cycle arrest. It converts reversible arrest to irreversible senescence. Geroconversion is driven by growth-promoting, mitogen-/nutrient-sensing pathways such as mTOR. Geroconversion leads to hyper-secretory, hypertrophic and pro-inflammatory cellular phenotypes, hyperfunctions and malfunctions. On organismal level, geroconversion leads to age-related diseases and death. Rapamycin, a gerosuppressant, extends life span in diverse species from yeast to mammals. Stress–and oncogene-induced accelerated senescence, replicative senescence in vitro and life-long cellular aging in vivo all can be described by 2-step model. PMID:25483060

  8. Polyamines and regulation of ripening and senescence

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Polyamines (PAs) are small polycationic, biogenic amines that influence many biochemical and physiological processes such as cell division, cell elongation, flowering, fruit set and development, fruit ripening and senescence. Significant information about PA action has emerged from indirect studies ...

  9. The Prospective Association Between Sipping Alcohol by the Sixth Grade and Later Substance Use

    PubMed Central

    Jackson, Kristina M.; Barnett, Nancy P.; Colby, Suzanne M.; Rogers, Michelle L.

    2015-01-01

    Objective: Although there is a clear association between early use of alcohol and short- and long-term adverse outcomes, it is unclear whether consumption of minor amounts of alcohol (less than a full drink) at a young age is prognostic of risk behaviors in later adolescence. Method: Data were taken from 561 students enrolled in an ongoing prospective web-based study on alcohol initiation and progression (55% female; 25% White non-Hispanic). Based on a combination of monthly and semiannual surveys, we coded whether participants sipped alcohol before sixth grade and examined associations between early sipping and alcohol consumption by fall of ninth grade, as well as other indices of problem behavior. Participants also reported on the context of the first sipping event. Results: The prevalence of sipping alcohol by fall of sixth grade was 29.5%. Most participants indicated that their first sip took place at their own home, and the primary source of alcohol was an adult, usually a parent. Youth who sipped alcohol by sixth grade had significantly greater odds of consuming a full drink, getting drunk, and drinking heavily by ninth grade than nonsippers. These associations held even when we controlled for temperamental, behavioral, and environmental factors that contribute to proneness for problem behavior, which suggests that sipping is not simply a marker of underlying risk. Conclusions: Our findings that early sipping is associated with elevated odds of risky behaviors at high school entry dispute the idea of sipping as a protective factor. Offering even just a sip of alcohol may undermine messages about the unacceptability of alcohol consumption for youth. PMID:25785796

  10. Post senescent grass canopy remote sensing

    NASA Technical Reports Server (NTRS)

    Tucker, C. J.

    1978-01-01

    Analysis of in situ collected spectral reflectance data from a dormant or senescent grass canopy showed a direct relationship existed between spectral reflectance and biomass for the 0.50-0.80 micron spectral region. The data, collected four weeks after the end of the growing season, indicated that post senescent remote sensing of grass canopy biomass is possible and helps to elucidate the spectral contribution of recently dead vegetation in mixed live/dead canopy situations.

  11. 40 CFR 51.122 - Emissions reporting requirements for SIP revisions relating to budgets for NOX emissions.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... SIP revisions relating to budgets for NOX emissions. 51.122 Section 51.122 Protection of Environment... OF IMPLEMENTATION PLANS Control Strategy § 51.122 Emissions reporting requirements for SIP revisions... set forth in § 51.50. (b) For its transport SIP revision under § 51.121, each state must submit to...

  12. 17 CFR 249.1001 - Form SIP, for application for registration as a securities information processor or to amend such...

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 17 Commodity and Securities Exchanges 3 2012-04-01 2012-04-01 false Form SIP, for application for... § 249.1001 Form SIP, for application for registration as a securities information processor or to amend... Note: For Federal Register citations affecting Form SIP, see the List of CFR Sections Affected,...

  13. 40 CFR 51.122 - Emissions reporting requirements for SIP revisions relating to budgets for NOX emissions.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... SIP revisions relating to budgets for NOX emissions. 51.122 Section 51.122 Protection of Environment... OF IMPLEMENTATION PLANS Control Strategy § 51.122 Emissions reporting requirements for SIP revisions... set forth in § 51.50. (b) For its transport SIP revision under § 51.121, each state must submit to...

  14. 40 CFR 57.705 - Contents of SIP Compliance Schedule required by § 57.201(d) (2) and (3).

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 6 2013-07-01 2013-07-01 false Contents of SIP Compliance Schedule... Requirements § 57.705 Contents of SIP Compliance Schedule required by § 57.201(d) (2) and (3). This section applies to smelters which are required to submit a SIP Compliance Schedule as discussed below. (a)...

  15. 40 CFR 51.10 - How does my state report emissions that are required by the NOX SIP Call?

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... are required by the NOX SIP Call? 51.10 Section 51.10 Protection of Environment ENVIRONMENTAL... does my state report emissions that are required by the NOX SIP Call? The District of Columbia and states that are subject to the NOX SIP Call § 51.121) are subject to the emissions reporting...

  16. 40 CFR 51.10 - How does my state report emissions that are required by the NOX SIP Call?

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... are required by the NOX SIP Call? 51.10 Section 51.10 Protection of Environment ENVIRONMENTAL... does my state report emissions that are required by the NOX SIP Call? The District of Columbia and states that are subject to the NOX SIP Call § 51.121) are subject to the emissions reporting...

  17. 40 CFR 57.705 - Contents of SIP Compliance Schedule required by § 57.201(d) (2) and (3).

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 6 2014-07-01 2014-07-01 false Contents of SIP Compliance Schedule... Requirements § 57.705 Contents of SIP Compliance Schedule required by § 57.201(d) (2) and (3). This section applies to smelters which are required to submit a SIP Compliance Schedule as discussed below. (a)...

  18. 40 CFR 51.10 - How does my state report emissions that are required by the NOX SIP Call?

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... are required by the NOX SIP Call? 51.10 Section 51.10 Protection of Environment ENVIRONMENTAL... does my state report emissions that are required by the NOX SIP Call? The District of Columbia and states that are subject to the NOX SIP Call § 51.121) are subject to the emissions reporting...

  19. 40 CFR 57.205 - Submission of supplementary information upon relaxation of an SO2 SIP emission limitation.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... upon relaxation of an SO2 SIP emission limitation. 57.205 Section 57.205 Protection of Environment... Application and the NSO Process § 57.205 Submission of supplementary information upon relaxation of an SO2 SIP emission limitation. (a) In the event an SO2 SIP limit is relaxed subsequent to EPA approval or issuance...

  20. 17 CFR 249.1001 - Form SIP, for application for registration as a securities information processor or to amend such...

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 17 Commodity and Securities Exchanges 3 2013-04-01 2013-04-01 false Form SIP, for application for... § 249.1001 Form SIP, for application for registration as a securities information processor or to amend... Note: For Federal Register citations affecting Form SIP, see the List of CFR Sections Affected,...

  1. 17 CFR 249.1001 - Form SIP, for application for registration as a securities information processor or to amend such...

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 17 Commodity and Securities Exchanges 4 2014-04-01 2014-04-01 false Form SIP, for application for... § 249.1001 Form SIP, for application for registration as a securities information processor or to amend... Note: For Federal Register citations affecting Form SIP, see the List of CFR Sections Affected,...

  2. 40 CFR 57.705 - Contents of SIP Compliance Schedule required by § 57.201(d) (2) and (3).

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 6 2012-07-01 2012-07-01 false Contents of SIP Compliance Schedule... Requirements § 57.705 Contents of SIP Compliance Schedule required by § 57.201(d) (2) and (3). This section applies to smelters which are required to submit a SIP Compliance Schedule as discussed below. (a)...

  3. 40 CFR 57.205 - Submission of supplementary information upon relaxation of an SO2 SIP emission limitation.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... upon relaxation of an SO2 SIP emission limitation. 57.205 Section 57.205 Protection of Environment... Application and the NSO Process § 57.205 Submission of supplementary information upon relaxation of an SO2 SIP emission limitation. (a) In the event an SO2 SIP limit is relaxed subsequent to EPA approval or issuance...

  4. 40 CFR 51.10 - How does my state report emissions that are required by the NOX SIP Call?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... are required by the NOX SIP Call? 51.10 Section 51.10 Protection of Environment ENVIRONMENTAL... does my state report emissions that are required by the NOX SIP Call? The District of Columbia and states that are subject to the NOX SIP Call § 51.121) are subject to the emissions reporting...

  5. 40 CFR 57.205 - Submission of supplementary information upon relaxation of an SO2 SIP emission limitation.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... upon relaxation of an SO2 SIP emission limitation. 57.205 Section 57.205 Protection of Environment... Application and the NSO Process § 57.205 Submission of supplementary information upon relaxation of an SO2 SIP emission limitation. (a) In the event an SO2 SIP limit is relaxed subsequent to EPA approval or issuance...

  6. 40 CFR 57.705 - Contents of SIP Compliance Schedule required by § 57.201(d) (2) and (3).

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 5 2011-07-01 2011-07-01 false Contents of SIP Compliance Schedule... Requirements § 57.705 Contents of SIP Compliance Schedule required by § 57.201(d) (2) and (3). This section applies to smelters which are required to submit a SIP Compliance Schedule as discussed below. (a)...

  7. 40 CFR 51.122 - Emissions reporting requirements for SIP revisions relating to budgets for NOX emissions.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... SIP revisions relating to budgets for NOX emissions. 51.122 Section 51.122 Protection of Environment... OF IMPLEMENTATION PLANS Control Strategy § 51.122 Emissions reporting requirements for SIP revisions... set forth in § 51.50. (b) For its transport SIP revision under § 51.121, each state must submit to...

  8. 40 CFR 57.205 - Submission of supplementary information upon relaxation of an SO2 SIP emission limitation.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... upon relaxation of an SO2 SIP emission limitation. 57.205 Section 57.205 Protection of Environment... Application and the NSO Process § 57.205 Submission of supplementary information upon relaxation of an SO2 SIP emission limitation. (a) In the event an SO2 SIP limit is relaxed subsequent to EPA approval or issuance...

  9. 40 CFR 57.705 - Contents of SIP Compliance Schedule required by § 57.201(d) (2) and (3).

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 5 2010-07-01 2010-07-01 false Contents of SIP Compliance Schedule... Requirements § 57.705 Contents of SIP Compliance Schedule required by § 57.201(d) (2) and (3). This section applies to smelters which are required to submit a SIP Compliance Schedule as discussed below. (a)...

  10. 40 CFR 51.10 - How does my state report emissions that are required by the NOX SIP Call?

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... are required by the NOX SIP Call? 51.10 Section 51.10 Protection of Environment ENVIRONMENTAL... does my state report emissions that are required by the NOX SIP Call? The District of Columbia and states that are subject to the NOX SIP Call § 51.121) are subject to the emissions reporting...

  11. 17 CFR 249.1001 - Form SIP, for application for registration as a securities information processor or to amend such...

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 17 Commodity and Securities Exchanges 3 2011-04-01 2011-04-01 false Form SIP, for application for... § 249.1001 Form SIP, for application for registration as a securities information processor or to amend... Note: For Federal Register citations affecting Form SIP, see the List of CFR Sections Affected,...

  12. 40 CFR 57.205 - Submission of supplementary information upon relaxation of an SO2 SIP emission limitation.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... upon relaxation of an SO2 SIP emission limitation. 57.205 Section 57.205 Protection of Environment... Application and the NSO Process § 57.205 Submission of supplementary information upon relaxation of an SO2 SIP emission limitation. (a) In the event an SO2 SIP limit is relaxed subsequent to EPA approval or issuance...

  13. 17 CFR 249.1001 - Form SIP, for application for registration as a securities information processor or to amend such...

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 17 Commodity and Securities Exchanges 3 2010-04-01 2010-04-01 false Form SIP, for application for... § 249.1001 Form SIP, for application for registration as a securities information processor or to amend... Note: For Federal Register citations affecting Form SIP, see the List of CFR Sections Affected,...

  14. Risk Factors for Retinopathy of Prematurity in Premature Born Children

    PubMed Central

    Alajbegovic-Halimic, Jasmina; Zvizdic, Denisa; Alimanovic-Halilovic, Emina; Dodik, Irena; Duvnjak, Sanela

    2015-01-01

    Introduction: Retinopathy of Prematurity (ROP) represent disease of the eye in premature born children which affects immature blood vessels of the retina during their development. The emergence of retinopathy of prematurity depends on the interaction of multiple factors, such as: gestational age, low birth weight, hypoxia, duration of oxygen supplementation, respiratory distress syndrome, twin pregnancy, anemia, blood transfusions, sepsis, intraventricular hemorrhage, hypotension, hypothermia, etc. If remain unrecognized and untreated it can cause severe visual impairment and blindness in children, but can also be prevented with timely screening. Goals: To establish the number of patients with development of retinopathy of prematurity active forms in the observed time period and examine which risk factors have most significant impact on its origin. Material and methods: In a clinical, retrospective study we observed a total of 80 premature born children in the period from January to May 2015 with regard to listed risk factors identified for eye examination. Results: From a total of 80 premature newborns sample included 48.8% male and 51.2% female children. The active form of ROP developed in 6.2% of cases, while in 93.8% of cases there was a spontaneous resolution. Patients who developed active form of ROP have significantly younger gestational age (26.4±1.5 weeks) and lower birth weight (874±181 grams), lower Apgar score in the first and fifth minute and were longer on oxygen therapy (20±3.4 days). Conclusion: Of the potential risk factors that could affect the development of ROP active form following factors have a statistically significant influence: early gestational age, low birth weight, lower Apgar score and prolonged oxygen therapy (p <0.05). PMID:26843736

  15. [Inhibition of premature uterine contractions].

    PubMed

    Troszyński, M; Leibschang, J; Chazan, B; Adamowicz, R; Brankowska, J

    1979-01-01

    Various drugs used to stop premature uterine contractions are discussed in the paper. Particular attention is paid to beta-mimetic drugs. The results of ming Partusisten, one of beta-mimetic drugs, is presented on the material of 104 patients with threatening immature and premature labour. Partusisten was administered in the form of intravenous drip infusion or tablets. During treatment monitoring of the uterine contractility and of foetal heart rate took place. Inhibition of the uterine contraction activity was successful in 100 per cent of cases. In 60,9 per cent in the group of threatening immature labour and in 38,1 per cent in the group threatening premature labour, the delay of delivery was more then 28 days. The delay of delivery by 48 hours was 87 per cent and 84 per cent in both groups respectively. Tachycardia was one of the first side effects observed in 15,2 per cent of cases. There is also presented an example of pregnancy when delivery was delayed by 21 days in spite of premature outflow of amniotic fluid (at a high rupture of membrane). The authors are of the opinion that Partusisten is very effective and gives little side effects, preventing premature uterine contractions. Dosage should be individualized according to the case and labour advancement, and should be based on topographic evaluation of uterine contraction. Negative influence of the drug on foetuses was not observed.

  16. T CELL REPLICATIVE SENESCENCE IN HUMAN AGING

    PubMed Central

    Chou, Jennifer P.; Effros, Rita B.

    2013-01-01

    The decline of the immune system appears to be an intractable consequence of aging, leading to increased susceptibility to infections, reduced effectiveness of vaccination and higher incidences of many diseases including osteoporosis and cancer in the elderly. These outcomes can be attributed, at least in part, to a phenomenon known as T cell replicative senescence, a terminal state characterized by dysregulated immune function, loss of the CD28 costimulatory molecule, shortened telomeres and elevated production of pro-inflammatory cytokines. Senescent CD8 T cells, which accumulate in the elderly, have been shown to frequently bear antigen specificity against cytomegalovirus (CMV), suggesting that this common and persistent infection may drive immune senescence and result in functional and phenotypic changes to the T cell repertoire. Senescent T cells have also been identified in patients with certain cancers, autoimmune diseases and chronic infections, such as HIV. This review discusses the in vivo and in vitro evidence for the contribution of CD8 T cell replicative senescence to a plethora of age-related pathologies and a few possible therapeutic avenues to delay or prevent this differentiative end-state in T cells. The age-associated remodeling of the immune system, through accumulation of senescent T cells has far-reaching consequences on the individual and society alike, for the current healthcare system needs to meet the urgent demands of the increasing proportions of the elderly in the US and abroad. PMID:23061726

  17. Proteasome Modulates Mitochondrial Function During Cellular Senescence

    PubMed Central

    Torres, Claudio A.; Perez, Viviana I.

    2009-01-01

    Proteasome plays fundamental roles in the removal of oxidized proteins and in the normal degradation of short-lived proteins. Previously we have provided evidences that the impairment in proteasome observed during the replicative senescence of human fibroblasts has significant effects on MAPK signaling, proliferation, life span, senescent phenotype and protein oxidative status. These studies have demonstrated that proteasome inhibition and replicative senescence caused accumulation of intracellular protein carbonyl content. In this study, we have investigated the mechanisms by which proteasome dysfunction modulates protein oxidation during cellular senescence. The results indicate that proteasome inhibition during replicative senescence have significant effects on the intra and extracellular ROS production in vitro. The data also show that ROS impaired the proteasome function, which is partially reversible by antioxidants. Increases in ROS after proteasome inhibition correlated with a significant negative effect on the activity of most mitochondrial electron transporters. We propose that failures in proteasome during cellular senescence lead to mitochondrial dysfunction, ROS production and oxidative stress. Furthermore, it is likely that changes in proteasome dynamics could generate a pro-oxidative condition at the immediate extracellular microenvironment that could cause tissue injury during aging, in vivo. PMID:17976388

  18. Pirin Inhibits Cellular Senescence in Melanocytic Cells

    PubMed Central

    Licciulli, Silvia; Luise, Chiara; Scafetta, Gaia; Capra, Maria; Giardina, Giuseppina; Nuciforo, Paolo; Bosari, Silvano; Viale, Giuseppe; Mazzarol, Giovanni; Tonelli, Chiara; Lanfrancone, Luisa; Alcalay, Myriam

    2011-01-01

    Cellular senescence has been widely recognized as a tumor suppressing mechanism that acts as a barrier to cancer development after oncogenic stimuli. A prominent in vivo model of the senescence barrier is represented by nevi, which are composed of melanocytes that, after an initial phase of proliferation induced by activated oncogenes (most commonly BRAF), are blocked in a state of cellular senescence. Transformation to melanoma occurs when genes involved in controlling senescence are mutated or silenced and cells reacquire the capacity to proliferate. Pirin (PIR) is a highly conserved nuclear protein that likely functions as a transcriptional regulator whose expression levels are altered in different types of tumors. We analyzed the expression pattern of PIR in adult human tissues and found that it is expressed in melanocytes and has a complex pattern of regulation in nevi and melanoma: it is rarely detected in mature nevi, but is expressed at high levels in a subset of melanomas. Loss of function and overexpression experiments in normal and transformed melanocytic cells revealed that PIR is involved in the negative control of cellular senescence and that its expression is necessary to overcome the senescence barrier. Our results suggest that PIR may have a relevant role in melanoma progression. PMID:21514450

  19. Anti-aging Effect of Transplanted Amniotic Membrane Mesenchymal Stem Cells in a Premature Aging Model of Bmi-1 Deficiency

    PubMed Central

    Xie, Chunfeng; Jin, Jianliang; Lv, Xianhui; Tao, Jianguo; Wang, Rong; Miao, Dengshun

    2015-01-01

    To determine whether transplanted amniotic membrane mesenchymal stem cells (AMSCs) ameliorated the premature senescent phenotype of Bmi-1-deficient mice, postnatal 2-day-old Bmi-1−/− mice were injected intraperitoneally with the second-passage AMSCs from amniotic membranes of β-galactosidase (β-gal) transgenic mice or wild-type (WT) mice labeled with DiI. Three reinjections were given, once every seven days. Phenotypes of 5-week-old β-gal+ AMSC-transplanted or 6-week-old DiI+ AMSC-transplanted Bmi-1−/− mice were compared with vehicle-transplanted Bmi-1−/− and WT mice. Vehicle-transplanted Bmi-1−/− mice displayed growth retardation and premature aging with decreased cell proliferation and increased cell apoptosis; a decreased ratio and dysmaturity of lymphocytic series; premature osteoporosis with reduced osteogenesis and increased adipogenesis; redox imbalance and DNA damage in multiple organs. Transplanted AMSCs carried Bmi-1 migrated into multiple organs, proliferated and differentiated into multiple tissue cells, promoted growth and delayed senescence in Bmi-1−/− transplant recipients. The dysmaturity of lymphocytic series were ameliorated, premature osteoporosis were rescued by promoting osteogenesis and inhibiting adipogenesis, the oxidative stress and DNA damage in multiple organs were inhibited by the AMSC transplantation in Bmi-1−/− mice. These findings indicate that AMSC transplantation ameliorated the premature senescent phenotype of Bmi-1-deficient mice and could be a novel therapy to delay aging and prevent aging-associated degenerative diseases. PMID:26370922

  20. Molecular insights into the premature aging disease progeria.

    PubMed

    Vidak, Sandra; Foisner, Roland

    2016-04-01

    Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare premature aging disease presenting many features resembling the normal aging process. HGPS patients die before the age of 20 years due to cardiovascular problems and heart failure. HGPS is linked to mutations in the LMNA gene encoding the intermediate filament protein lamin A. Lamin A is a major component of the nuclear lamina, a scaffold structure at the nuclear envelope that defines mechanochemical properties of the nucleus and is involved in chromatin organization and epigenetic regulation. Lamin A is also present in the nuclear interior where it fulfills lamina-independent functions in cell signaling and gene regulation. The most common LMNA mutation linked to HGPS leads to mis-splicing of the LMNA mRNA and produces a mutant lamin A protein called progerin that tightly associates with the inner nuclear membrane and affects the dynamic properties of lamins. Progerin expression impairs many important cellular processes providing insight into potential disease mechanisms. These include changes in mechanosignaling, altered chromatin organization and impaired genome stability, and changes in signaling pathways, leading to impaired regulation of adult stem cells, defective extracellular matrix production and premature cell senescence. In this review, we discuss these pathways and their potential contribution to the disease pathologies as well as therapeutic approaches used in preclinical and clinical tests.

  1. Extended Password Recovery Attacks against APOP, SIP, and Digest Authentication

    NASA Astrophysics Data System (ADS)

    Sasaki, Yu; Wang, Lei; Ohta, Kazuo; Kunihiro, Noboru

    In this paper, we propose password recovery attacks against challenge-response authentication protocols. Our attacks use a message difference for a MD5 collision attack proposed in IEICE 2008. First, we show how to efficiently find a message pair that collides with the above message difference. Second, we show that a password used in authenticated post office protocol (APOP) can be recovered practically. We also show that the password recovery attack can be applied to a session initiation protocol (SIP) and digest authentication. Our attack can recover up to the first 31 password characters in a short time and up to the first 60 characters faster than the naive search method. We have implemented our attack and confirmed that 31 characters can be successfully recovered.

  2. Audio CAPTCHA for SIP-Based VoIP

    NASA Astrophysics Data System (ADS)

    Soupionis, Yannis; Tountas, George; Gritzalis, Dimitris

    Voice over IP (VoIP) introduces new ways of communication, while utilizing existing data networks to provide inexpensive voice communications worldwide as a promising alternative to the traditional PSTN telephony. SPam over Internet Telephony (SPIT) is one potential source of future annoyance in VoIP. A common way to launch a SPIT attack is the use of an automated procedure (bot), which generates calls and produces audio advertisements. In this paper, our goal is to design appropriate CAPTCHA to fight such bots. We focus on and develop audio CAPTCHA, as the audio format is more suitable for VoIP environments and we implement it in a SIP-based VoIP environment. Furthermore, we suggest and evaluate the specific attributes that audio CAPTCHA should incorporate in order to be effective, and test it against an open source bot implementation.

  3. Is senescence-associated β-galactosidase a marker of neuronal senescence?

    PubMed Central

    Wysocka, Adrianna; Nalberczak, Maria; Sliwinska, Malgorzata A.; Radwanska, Kasia; Sikora, Ewa

    2016-01-01

    One of the features of cellular senescence is the activity of senescence-associated- β-galactosidase (SA-β-gal). The main purpose of this study was to evaluate this marker of senescence in aging neurons. We found that cortical neurons exhibited noticeable SA-β-gal activity quite early in culture. Many SA-β-gal-positive neurons were negative for another canonical marker of senescence, namely, double-strand DNA breaks (DSBs). Moreover, DDR signalling triggered by low doses of doxorubicin did not accelerate the appearance of neuronal SA-β-gal. In vivo, we observed pronounced induction of SA-β-gal activity in the hippocampus of 24-month-old mice, which is consistent with previous findings and supports the view that at this advanced age neurons developed a senescence-like phenotype. Surprisingly however, relatively high SA-β-gal activity, probably unrelated to the senescence process, was also observed in much younger, 3-month-old mice. In conclusion, we propose that SA-β-gal activity in neurons cannot be attributed uniquely to cell senescence either in vitro or in vivo. Additionally, we showed induction of REST protein in aging neurons in long-term culture and we propose that REST could be a marker of neuronal senescence in vitro. PMID:27768595

  4. QTL analysis for sugar-regulated leaf senescence supports flowering-dependent and -independent senescence pathways.

    PubMed

    Wingler, Astrid; Purdy, Sarah Jane; Edwards, Sally-Anne; Chardon, Fabien; Masclaux-Daubresse, Céline

    2010-01-01

    *The aim of this work was to determine the genetic basis of sugar-regulated senescence and to explore the relationship with other traits, including flowering and nitrogen-use efficiency. *Quantitative trait loci (QTLs) for senescence were mapped in the Arabidopsis Bay-0 x Shahdara recombinant-inbred line (RIL) population after growth on glucose-containing medium, which accelerates senescence. The extent of whole-rosette senescence was determined by imaging the maximum quantum yield of photosystem II (F(v)/F(m)). *A major QTL on the top of chromosome 4 colocalized with FRI, a major determinant of flowering. This QTL interacted epistatically with a QTL on chromosome 5, where the floral repressor FLC localizes. Vernalization accelerated senescence in late-flowering lines with functional FRI and FLC alleles. Comparison with previous results using the Bay-0 x Shahdara population showed that rapid rosette senescence on glucose-containing medium was correlated with early flowering and high sugar content in compost-grown plants. In addition, correlation was found between the expression of flowering and senescence-associated genes in Arabidopsis accessions. However, an additional QTL on chromosome 3 was not linked to flowering, but to nitrogen-use efficiency. *The results show that whole-rosette senescence is genetically linked to the vernalization-dependent control of flowering, but is also controlled by flowering-independent pathways.

  5. Pituitary gene expression differs in D-galactose-induced cell senescence and steroid-induced prolactinomas.

    PubMed

    Zhang, Tiehui; Zhao, Binhai; Li, Jia; Zhang, Chunlei; Li, Hongzhi; Wu, Jiang; Zhang, Shiming; Hui, Guozhen

    2015-04-01

    In general, pituitary tumors are benign with low mitotic activity. Premature senescence has been considered to be a significant mechanism underlying this uniquely benign pituitary tumor. The present study aims to compare the expression of the associated proteins involved in premature senescence pathways among normal, aging and pituitary adenoma cells. We successfully induced the aging pituitary using continuous D‑galactose (D‑gal) injection as well as a prolactin‑secreting pituitary tumor via diethylstilbestrol implants. Compared with normal pituitary cells, the aging pituitary tissues revealed increased expression of IL‑6, C/EBPβ, p53, p21 and p16 and decreased expression of pituitary tumor transforming gene. In contrast, the expression of IL‑6, p21 and p16 was decreased in pituitary tumor cells compared with normal pituitary tissues. Taken together, multiple pathways including IL‑6/C/EBPβ, p53/p21 and p16 were activated in aging pituitary cells in response to D‑gal treatment. However, all these pathways were immune to pituitary tumors treated by chronic estrogen. The findings and the involvement of cytokines in a highly prevalent natural disease model (pituitary adenomas) indicate a potential use of this pathway as a target for effective therapy for tumor silencing and prevention of adenoma progression towards malignancy.

  6. NASA SNPP SIPS - Following in the Path of EOS

    NASA Technical Reports Server (NTRS)

    Behnke, Jeanne; Hall, Alfreda; Ho, Evelyn

    2016-01-01

    NASA's Earth Science Data Information System (ESDIS) Project has been operating NASA's Suomi National Polar-Orbiting Partnership (SNPP) Science Data Segment (SDS) since the launch in October 2011. At launch, the SDS focused primarily on the evaluation of Sensor Data Records (SDRs) and Environmental Data Records (EDRs) produced by the Joint Polar Satellite System (JPSS), a National Oceanic and Atmosphere Administration (NOAA) Program, as to their suitability for Earth system science. During the summer of 2014, NASA transitioned to the production of standard Earth Observing System (EOS)-like science products for all instruments aboard Suomi NPP. The five Science Investigator-led Processing Systems (SIPS): Land, Ocean, Atmosphere, Ozone, and Sounder were established to produce the NASA SNPP standard Level 1, Level 2, and global Level 3 products developed by the SNPP Science Teams and to provide the products to NASA's Distributed Active Archive Centers (DAACs) for archive and distribution to the user community. The processing, archiving and distribution of data from NASA's Clouds and the Earth's Radiant Energy System (CERES) and Ozone Mapper/Profiler Suite (OMPS) Limb instruments will continue. With the implementation of the JPSS Block 2 architecture and the launch of JPSS-1, the SDS will receive SNPP data in near real-time via the JPSS Stored Mission Data Hub (JSH), as well as JPSS-1 and future JPSS-2 data. The SNPP SIPS will ingest EOS compatible Level 0 data from the EOS Data Operations System (EDOS) element for their data processing, enabling the continuous EOS-SNPP-JPSS Satellite Data Record.

  7. FOXP1 controls mesenchymal stem cell commitment and senescence during skeletal aging.

    PubMed

    Li, Hanjun; Liu, Pei; Xu, Shuqin; Li, Yinghua; Dekker, Joseph D; Li, Baojie; Fan, Ying; Zhang, Zhenlin; Hong, Yang; Yang, Gong; Tang, Tingting; Ren, Yongxin; Tucker, Haley O; Yao, Zhengju; Guo, Xizhi

    2017-04-03

    A hallmark of aged mesenchymal stem/progenitor cells (MSCs) in bone marrow is the pivot of differentiation potency from osteoblast to adipocyte coupled with a decrease in self-renewal capacity. However, how these cellular events are orchestrated in the aging progress is not fully understood. In this study, we have used molecular and genetic approaches to investigate the role of forkhead box P1 (FOXP1) in transcriptional control of MSC senescence. In bone marrow MSCs, FOXP1 expression levels declined with age in an inverse manner with those of the senescence marker p16INK4A. Conditional depletion of Foxp1 in bone marrow MSCs led to premature aging characteristics, including increased bone marrow adiposity, decreased bone mass, and impaired MSC self-renewal capacity in mice. At the molecular level, FOXP1 regulated cell-fate choice of MSCs through interactions with the CEBPβ/δ complex and recombination signal binding protein for immunoglobulin κ J region (RBPjκ), key modulators of adipogenesis and osteogenesis, respectively. Loss of p16INK4A in Foxp1-deficient MSCs partially rescued the defects in replication capacity and bone mass accrual. Promoter occupancy analyses revealed that FOXP1 directly represses transcription of p16INK4A. These results indicate that FOXP1 attenuates MSC senescence by orchestrating their cell-fate switch while maintaining their replicative capacity in a dose- and age-dependent manner.

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

    PubMed Central

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

    2016-01-01

    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. DOI: http://dx.doi.org/10.7554/eLife.13768.001 PMID:27697148

  9. Radiation-induced senescence-like terminal growth arrest in thyroid cells.

    PubMed

    Podtcheko, Alexei; Namba, Hiroyuki; Saenko, Vladimir; Ohtsuru, Akira; Starenki, Dmitriy; Meirmanov, Serik; Polona, Iryna; Rogounovitch, Tatiana; Yamashita, Shunichi

    2005-04-01

    Premature senescence may play an important role as an acute, drug-, or ionizing radiation (IR)-inducible growth arrest program along with interphase apoptosis and mitotic catastrophe. The aim of the study was to evaluate whether IR can induce senescence-like phenotype (SLP) associated with terminal growth arrest in the thyroid cells, and if so, to evaluate impact of terminal growth arrest associated with SLP in intrinsic radiosensitivity of various thyroid carcinomas. The induction of SLP in thyroid cells were identified by: (1) senescence associated beta-galactosidase (SA-beta-Gal) staining method, (2) dual-flow cytometric analysis of cell proliferation and side light scatter using vital staining with PKH-2 fluorescent dye, (3) double labeling for 5-bromodeoxyuridine and SA- beta-Gal, (4) Staining for SA-beta-Gal with consequent antithyroglobulin immunohistochemistry. IR induced SLP associated with terminal growth arrest in four thyroid cancer cells lines and in primary thyrocytes in time- and dose-dependent manner. Analysis of relationship between induction of SLP and radiosensitivity revealed a trend in which more radioresistant cell lines strongly tended to show lower specific SLP yields (r = -0.93, p = 0.068). We find out that SA-beta-Gal staining is detectable in irradiated ARO xenotransplants, but not in control tumors. We, therefore, conclude that induction of SLP with terminal growth arrest contribute to the elimination of clonogenic populations after IR.

  10. Fibroblast growth factor-23 induces cellular senescence in human mesenchymal stem cells from skeletal muscle.

    PubMed

    Sato, Chisato; Iso, Yoshitaka; Mizukami, Takuya; Otabe, Koji; Sasai, Masahiro; Kurata, Masaaki; Sanbe, Takeyuki; Sekiya, Ichiro; Miyazaki, Akira; Suzuki, Hiroshi

    2016-02-12

    Although muscle wasting and/or degeneration are prevalent in patients with chronic kidney disease, it remains unknown whether FGF-23 influences muscle homeostasis and regeneration. Mesenchymal stem cells (MSCs) in skeletal muscle are distinct from satellite cells and have a known association with muscle degeneration. In this study we sought to investigate the effects of FGF-23 on MSCs isolated from human skeletal muscle in vitro. The MSCs expressed FGF receptors (1 through 4) and angiotensin-II type 1 receptor, but no traces of the Klotho gene were detected. MSCs and satellite cells were treated with FGF-23 and angiotensin-II for 48 h. Treatment with FGF-23 significantly decreased the number of MSCs compared to controls, while treatment with angiotensin-II did not. FGF-23 and angiotensin-II both left the cell counts of the satellite cells unchanged. The FGF-23-treated MSCs exhibited the senescent phenotype, as judged by senescence-associated β-galactosidase assay, cell morphology, and increased expression of p53 and p21 in western blot analysis. FGF-23 also significantly altered the gene expression of oxidative stress regulators in the cells. In conclusion, FGF-23 induced premature senescence in MSCs from skeletal muscle via the p53/p21/oxidative-stress pathway. The interaction between the MSCs and FGF-23 may play a key role in the impaired muscle reparative mechanisms of chronic kidney disease.

  11. [Cell senescence and pathophysiology of chronic lung diseases: role in chronic obstructive pulmonary disease].

    PubMed

    Adnot, Serge

    2014-01-01

    Knowledge of the biology of cellular senescence has improved markedly in recent years, helping us to understand the aging process. It is now clear that cellular senescence is involved in the pathogenesis of many age-related diseases, including respiratory diseases such as chronic obstructive pulmonary disease (COPD). COPD occupies a special place among chronic respiratory diseases because of its frequency and socio-economic impact. The high morbidity and mortality associated with COPD are related to multiple systemic manifestations independent of the severity of airway obstruction. COPD, although most often due to smoking, is also an aging-related respiratory disease. According to a newly developed concept, lung-cell senescence could play a key role in the pathophysiology of COPD, including remodeling of blood vessels and lung parenchyma, as well as the characteristic inflammatory process. Systemic manifestations of COPD, including cardiovascular disease, weight loss, bone demineralization and muscle dysfunction, may reflect a general process of premature aging secondary to the pulmonary changes.

  12. Prolonged autophagy by MTOR inhibitor leads radioresistant cancer cells into senescence.

    PubMed

    Nam, Hae Yun; Han, Myung Woul; Chang, Hyo Won; Kim, Sang Yoon; Kim, Seong Who

    2013-10-01

    Radiotherapy is one of the well-established therapeutic modalities for cancer treatment. However, the emergence of cells refractory to radiation is a major obstacle to successful treatment with radiotherapy. Many reports suggest that inhibitors targeting the mechanistic target of rapamycin (MTOR) can sensitize cancer cells to the effect of radiation, although by which mechanism MTOR inhibitors enhance the efficacy of radiation toward cancer cells remains to be elucidated. Our studies indicate that a potent and persistent activation of autophagy via inhibition of the MTOR pathway, even in cancer cells where autophagy is occurring, can trigger premature senescence, cellular proliferation arrest. Combined treatment of MTOR inhibitor and radiation induce heterochromatin formation, an irreversible growth arrest and an increase of senescence-associated GLB1 (β-galactosidase) activity, which appear to result from a constant activation of TP53 and a restoration in the activity of retinoblastoma 1 protein (RB1)-E2F1. Thus, this study provides evidence that promoting cellular senescence via inhibition of the MTOR pathway may serve as an avenue to augment radiosensitivity in cancer cells that initiate an autophagy-survival mode to radiotherapy.

  13. NHERF2/SIP-1 interacts with mouse SRY via a different mechanism than human SRY.

    PubMed

    Thevenet, Laurie; Albrecht, Kenneth H; Malki, Safia; Berta, Philippe; Boizet-Bonhoure, Brigitte; Poulat, Francis

    2005-11-18

    In mammals, male sex determination is controlled by the SRY protein, which drives differentiation of the bipotential embryonic gonads into testes by activating the Sertoli cell differentiation program. The morphological effects of SRY are well documented; however, its molecular mechanism of action remains unknown. Moreover, SRY proteins display high sequence variability among mammalian species, which makes protein motifs difficult to delineate. We previously isolated SIP-1/NHERF2 as a human SRY-interacting protein. SIP-1/NHERF2, a PDZ protein, interacts with the C-terminal extremity of the human SRY protein. Here we showed that the interaction of SIP-1/NHERF2 and SRY via the SIP-1/NHERF2 PDZ1 domain is conserved in mice. However, the interaction occurs via a domain that is internal to the mouse SRY protein and involves a different recognition mechanism than human SRY. Furthermore, we show that mouse and human SRY induce nuclear accumulation of the SIP-1/NHERF2 protein in cultured cells. Finally, a transgenic mouse line expressing green fluorescent protein under the control of the mouse Sry promoter allowed us to show that SRY and SIP-1/NHERF2 are co-expressed in the nucleus of pre-Sertoli cells during testis determination. Taken together, our results suggested that the function of SIP-1/NHERF2 as an SRY cofactor during testis determination is conserved between human and mouse.

  14. The modular structure of SIP facilitates its role in stabilizing multiprotein assemblies.

    PubMed

    Bhattacharya, Shibani; Lee, Young-Tae; Michowski, Wojciech; Jastrzebska, Beata; Filipek, Anna; Kuznicki, Jacek; Chazin, Walter J

    2005-07-12

    Siah-interacting protein (SIP) was identified as a novel adaptor that physically links the E3 ubiquitin ligase activity of Siah-1 with Skp1 and Ebi F-Box protein in the degradation of beta-catenin, a transcriptional activator of TCF/LEF genes. In this study, we have used solution NMR spectroscopy to characterize the domain structure of SIP, which includes a novel helical hairpin domain at the N-terminus flexibly linked to a CS domain and an unstructured carboxy terminal SGS domain. These studies have been complemented by mapping the sites of functionally important protein-protein interactions involving Siah-1 and Skp1 to individual domains of SIP. NMR-based chemical shift perturbation assays show that Siah-1 interacts with the flexible linker between SIP N and CS domains. This site for interaction in the linker does not perturb residues in the structured region at the N-terminus but does appear to restrict the rotational freedom of the SIP CS domain in the context of the full-length protein. In contrast, Skp1 engages the SIP CS domain exclusively through weak interactions that are not coupled to the other domains. The principal role of the modular structure of SIP appears to be in bringing these two proteins into physical proximity and orchestrating the orientation required for polyubiquitination of beta-catenin in the intact SCF-type complex.

  15. Isolation of SIP, a protein that interacts with SPB, a possible transcriptional regulatory factor in Rhodobacter sphaeroides.

    PubMed

    Shimada, Hiroshi; Ishida, Kazuhiro; Machiya, Yasuhiro; Takamiya, Ken-Ichiro

    2007-10-01

    SPB is a transcriptional factor in Rhodobacter sphaeroides that represses expression of the puf operon under aerobic or semi-aerobic light conditions. Here, we identified a 17,500 Da protein designated SIP (SPB interaction protein) that interacts with SPB, as determined by binding to an SPB-His(x6) fusion protein-Ni column. The SPB-SIP interaction in vivo was confirmed by an immunoprecipitation assay. The level of transcripts and protein of SIP did not differ for all growth conditions tested, indicating that regulation of the SIP-SPB interaction, if any, is not through modulation of sip or spb expression but rather by modification of the proteins.

  16. Extracellular Vesicles as New Players in Cellular Senescence

    PubMed Central

    Urbanelli, Lorena; Buratta, Sandra; Sagini, Krizia; Tancini, Brunella; Emiliani, Carla

    2016-01-01

    Cell senescence is associated with the secretion of many factors, the so-called “senescence-associated secretory phenotype”, which may alter tissue microenvironment, stimulating the organism to clean up senescent cells and replace them with newly divided ones. Therefore, although no longer dividing, these cells are still metabolically active and influence the surrounding tissue. Much attention has been recently focused not only on soluble factors released by senescent cells, but also on extracellular vesicles as conveyors of senescence signals outside the cell. Here, we give an overview of the role of extracellular vesicles in biological processes and signaling pathways related to senescence and aging. PMID:27571072

  17. Age, stage and senescence in plants

    PubMed Central

    Caswell, Hal; Salguero-Gómez, Roberto

    2013-01-01

    1. Senescence (an increase in the mortality rate or force of mortality, or a decrease in fertility, with increasing age) is a widespread phenomenon. Theories about the evolution of senescence have long focused on the age trajectories of the selection gradients on mortality and fertility. In purely age-classified models, these selection gradients are non-increasing with age, implying that traits expressed early in life have a greater impact on fitness than traits expressed later in life. This pattern leads inevitably to the evolution of senescence if there are trade-offs between early and late performance. 2. It has long been suspected that the stage- or size-dependent demography typical of plants might change these conclusions. In this paper, we develop a model that includes both stage- and age-dependence and derive the age-dependent, stage-dependent and age×stage-dependent selection gradients on mortality and fertility. 3. We applied this model to stage-classified population projection matrices for 36 species of plants, from a wide variety of growth forms (from mosses to trees) and habitats. 4. We found that the age-specific selection gradients within a life cycle stage can exhibit increases with age (we call these contra-senescent selection gradients). In later stages, often large size classes in plant demography, the duration of these contra-senescent gradients can exceed the life expectancy by several fold. 5. Synthesis. The interaction of age- and stage-dependence in plants leads to selection pressures on senescence fundamentally different from those found in previous, age-classified theories. This result may explain the observation that large plants seem less subject to senescence than most kinds of animals. The methods presented here can lead to improved analysis of both age-dependent and stage-dependent demographic properties of plant populations. PMID:23741075

  18. Mothers' Retrospections of Premature Childbirth.

    ERIC Educational Resources Information Center

    Kalmar, Magda; And Others

    This study examined Hungarian mothers' recollections, 8 years after the birth of their premature baby, of their stress at the time of the baby's birth. Interviews were conducted with 30 mothers whose babies had been born between 30 and 37 weeks gestational age. At the time of the follow-up, all children had normal IQs and were attending normal…

  19. Music Therapy with Premature Infants

    ERIC Educational Resources Information Center

    Standley, Jayne

    2003-01-01

    Over 20 years of research and clinical practice in music therapy with premature infants has been compiled into this text designed for Board Certified Music Therapists specializing in Neonatal Intensive Care clinical services, for NICU medical staff incorporating research-based music therapy into developmental care plans, and for parents of…

  20. SENESCENCE-SUPPRESSED PROTEIN PHOSPHATASE Directly Interacts with the Cytoplasmic Domain of SENESCENCE-ASSOCIATED RECEPTOR-LIKE KINASE and Negatively Regulates Leaf Senescence in Arabidopsis1[OPEN

    PubMed Central

    Xiao, Dong; Cui, Yanjiao; Xu, Fan; Xu, Xinxin; Gao, Guanxiao; Wang, Yaxin; Guo, Zhaoxia; Wang, Dan; Wang, Ning Ning

    2015-01-01

    Reversible protein phosphorylation mediated by protein kinases and phosphatases plays an important role in the regulation of leaf senescence. We previously reported that the leucine-rich repeat receptor-like kinase SENESCENCE-ASSOCIATED RECEPTOR-LIKE KINASE (AtSARK) positively regulates leaf senescence in Arabidopsis (Arabidopsis thaliana). Here, we report the involvement of a protein serine/threonine phosphatase 2C-type protein phosphatase, SENESCENCE-SUPPRESSED PROTEIN PHOSPHATASE (SSPP), in the negative regulation of Arabidopsis leaf senescence. SSPP transcript levels decreased greatly during both natural senescence and SARK-induced precocious senescence. Overexpression of SSPP significantly delayed leaf senescence in Arabidopsis. Protein pull-down and bimolecular fluorescence complementation assays demonstrated that the cytosol-localized SSPP could interact with the cytoplasmic domain of the plasma membrane-localized AtSARK. In vitro assays showed that SSPP has protein phosphatase function and can dephosphorylate the cytosolic domain of AtSARK. Consistent with these observations, overexpression of SSPP effectively rescued AtSARK-induced precocious leaf senescence and changes in hormonal responses. All our results suggested that SSPP functions in sustaining proper leaf longevity and preventing early senescence by suppressing or perturbing SARK-mediated senescence signal transduction. PMID:26304848

  1. Reproductive senescence in a cooperatively breeding mammal.

    PubMed

    Sharp, Stuart P; Clutton-Brock, Tim H

    2010-01-01

    1. Senescence (or 'ageing') is a widespread and important process in wild animal populations, but variation in ageing patterns within and between species is poorly understood. 2. In cooperatively breeding species, the costs of reproduction are shared between breeders and one or more helpers. The effects of ageing in breeders may therefore be moderated by the presence of helpers, but there have been very few studies of senescence patterns in natural populations of cooperative breeders. 3. Here, we use 13 years of data from a long-term study population of wild meerkats (Suricata suricatta) to investigate age-related changes in several traits known to be key components of reproductive success in females of this species. 4. Four of the six traits studied exhibited significant declines with age, indicating senescence. Litter size, the number of litters produced per year and the number of pups that survived to emergence from the natal burrow per year all increased with female age up to a peak at c. 4 years, and declined steeply thereafter; the mean pup weight at emergence in a given litter declined steadily from age zero. 5. These results provide the first evidence of reproductive senescence in a wild population of a cooperatively breeding vertebrate. Breeding success declined with age despite the sharing of reproductive costs in this species, but further study is needed to investigate whether helping affects other aspects of senescence, including survival.

  2. Senescence and immortality in hepatocellular carcinoma.

    PubMed

    Ozturk, Mehmet; Arslan-Ergul, Ayca; Bagislar, Sevgi; Senturk, Serif; Yuzugullu, Haluk

    2009-12-01

    Cellular senescence is a process leading to terminal growth arrest with characteristic morphological features. This process is mediated by telomere-dependent, oncogene-induced and ROS-induced pathways, but persistent DNA damage is the most common cause. Senescence arrest is mediated by p16(INK4a)- and p21(Cip1)-dependent pathways both leading to retinoblastoma protein (pRb) activation. p53 plays a relay role between DNA damage sensing and p21(Cip1) activation. pRb arrests the cell cycle by recruiting proliferation genes to facultative heterochromatin for permanent silencing. Replicative senescence that occurs in hepatocytes in culture and in liver cirrhosis is associated with lack of telomerase activity and results in telomere shortening. Hepatocellular carcinoma (HCC) cells display inactivating mutations of p53 and epigenetic silencing of p16(INK4a). Moreover, they re-express telomerase reverse transcriptase required for telomere maintenance. Thus, senescence bypass and cellular immortality is likely to contribute significantly to HCC development. Oncogene-induced senescence in premalignant lesions and reversible immortality of cancer cells including HCC offer new potentials for tumor prevention and treatment.

  3. Thinking about Pregnancy After Premature Birth

    MedlinePlus

    ... Search Our mission Fighting premature birth About us Annual report Our work Community impact Global programs Research Need ... Cause Our mission Fighting premature birth About us Annual report Our work Community impact Global programs Research Need ...

  4. Shining the Light on Senescence Associated LncRNAs

    PubMed Central

    Ghanam, A.R.; Xu, Qianlan; Ke, Shengwei; Azhar, Muhammad; Cheng, Qingyu; Song, Xiaoyuan

    2017-01-01

    Cellular senescence can be described as a complex stress response that leads to irreversible cell cycle arrest. This process was originally described as an event that primary cells go through after many passages of cells during cell culture. More recently, cellular senescence is viewed as a programmed process by which the cell displays a senescence phenotype when exposed to a variety of stresses. Cellular senescence has been implicated in tumor suppression and aging such that senescence may contribute to both tumor progression and normal tissue repair. Here, we review different forms of cellular senescence, as well as current biomarkers used to identify senescent cells in vitro and in vivo. Additionally, we highlight the role of senescence-associated long noncoding RNAs (lncRNAs).

  5. Keeping the senescence secretome under control: Molecular reins on the senescence-associated secretory phenotype.

    PubMed

    Malaquin, Nicolas; Martinez, Aurélie; Rodier, Francis

    2016-09-01

    Cellular senescence is historically associated with cancer suppression and aging. Recently, the reach of the senescence genetic program has been extended to include the ability of senescent cells to actively participate in tissue remodelling during many physiological processes, including placental biology, embryonic patterning, wound healing, and tissue stress responses caused by cancer therapy. Besides growth arrest, a significant feature of senescent cells is their ability to modify their immediate microenvironment using a senescence-associated (SA) secretome, commonly termed the SA secretory phenotype (SASP). Among others, the SASP contains growth factors, cytokines, and extracellular proteases that modulate the majority of both the beneficial and detrimental microenvironmental phenotypes caused by senescent cells. The SASP is thus becoming an obvious pharmaceutical target to manipulate SA effects. Herein, we review known signalling pathways underlying the SASP, including the DNA damage response (DDR), stress kinases, inflammasome, alarmin, inflammation- and cell survival-related transcription factors, miRNAs, RNA stability, autophagy, chromatin components, and metabolic regulators. We also describe the SASP as a temporally regulated dynamic sub-program of senescence that can be divided into a rapid DDR-associated phase, an early self-amplification phase, and a late "mature" phase, the late phase currently being the most widely studied SASP signature. Finally, we discuss how deciphering the signalling pathways regulating the SASP reveal targets that can be manipulated to harness the SA effects to benefit therapies for cancer and other age-related pathologies.

  6. Guidance for 1-Hour Sulfur Dioxide (SO2) Nonattainment Area State Implementation Plans (SIP) Submissions

    EPA Pesticide Factsheets

    The document is intended to provide guidance and recommendations to state, local and tribal governments for the development of SIPs and tribal implementation plans (TIPs) under the 2010 1-hour primary NAAQS for Sulfur Dioxide (SO2).

  7. The type three secreted effector SipC regulates the trafficking of PERP during Salmonella infection.

    PubMed

    Hallstrom, Kelly N; McCormick, Beth A

    2016-01-01

    Salmonella enterica Typhimurium employs type III secreted effectors to induce cellular invasion and pathogenesis. We previously reported the secreted effector SipA is in part responsible for inducing the apical accumulation of the host membrane protein PERP, a host factor we have shown is key to the inflammatory response induced by Salmonella. We now report that the S. Typhimurium type III secreted effector SipC significantly contributes to PERP redistribution to the apical membrane surface. To our knowledge, this is the first report demonstrating a role for SipC in directing the trafficking of a host membrane protein to the cell surface. In sum, facilitation of PERP trafficking appears to be a result of type III secreted effector-mediated recruitment of vesicles to the apical surface. Our study therefore reveals a new role for SipC, and builds upon previous reports suggesting recruitment of vesicles to the cell surface is important for Salmonella invasion.

  8. Technical Data and Reports on Nitrogen Dioxide Measurements and SIP Status

    EPA Pesticide Factsheets

    EPA collects data from the states and regions on their air quality and state implementation plan (SIP) progress. This information is compiled in a database, and used to create reports, trend charts, and maps.

  9. Technical Data and Reports on Carbon Monoxide Measurements and SIP Status

    EPA Pesticide Factsheets

    EPA collects data from the states and regions on their air quality and state implementation plan (SIP) progress. This information is compiled in a database, and used to create reports, trend charts, and maps.

  10. 78 FR 68005 - Approval and Promulgation of Implementation Plans; Mississippi; Transportation Conformity SIP...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-11-13

    ... Conformity SIP--Memorandum of Agreement AGENCY: Environmental Protection Agency (EPA). ACTION: Proposed rule... establishing transportation conformity criteria and procedures related to interagency consultation and... streamlines the conformity process to allow direct consultation among agencies at the Federal, state and...

  11. 78 FR 67952 - Approval and Promulgation of Implementation Plans; Mississippi; Transportation Conformity SIP...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-11-13

    ... Conformity SIP--Memorandum of Agreement AGENCY: Environmental Protection Agency (EPA). ACTION: Direct final... adopts a memorandum of agreement (MOA) establishing transportation conformity criteria and procedures... and mitigation measures. This action streamlines the conformity process to allow direct...

  12. ERK1/2 is dephosphorylated by a novel phosphatase--CacyBP/SIP.

    PubMed

    Kilanczyk, Ewa; Filipek, Slawomir; Filipek, Anna

    2011-01-07

    Recently, we have reported that the CacyBP/SIP protein binds ERK1/2 (Kilanczyk et al., BBRC, 2009). In this work we show that CacyBP/SIP exhibits a phosphatase activity toward ERK1/2 kinases while its E217K mutant does not. The K(m) and V(max) values established for a standard phosphatase substrate, p-NPP, are 16.9±3.6 mM and 4.3±0.4 μmol/min, respectively. The CacyBP/SIP phosphatase activity is decreased by okadaic acid (IC(50)=45 nM). Our experimental results are supported by a theoretical analysis which revealed important sequence similarities between CacyBP/SIP and the phosphatase-like proteins as well as certain MAP kinase phosphatases.

  13. Nationwide SIP Telephony Network Design to Prevent Congestion Caused by Disaster

    NASA Astrophysics Data System (ADS)

    Satoh, Daisuke; Ashitagawa, Kyoko

    We present a session initiation protocol (SIP) network design for a voice-over-IP network to prevent congestion caused by people calling friends and family after a disaster. The design increases the capacity of SIP servers in a network by using all of the SIP servers equally. It takes advantage of the fact that equipment for voice data packets is different from equipment for signaling packets in SIP networks. Furthermore, the design achieves simple routing on the basis of telephone numbers. We evaluated the performance of our design in preventing congestion through simulation. We showed that the proposed design has roughly 20 times more capacity, which is 57 times the normal load, than the conventional design if a disaster were to occur in Niigata Prefecture struck by the Chuetsu earthquake in 2004.

  14. 76 FR 27649 - Disease, Disability, and Injury Prevention and Control Special Interest Projects (SIPs): Initial...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-05-12

    ..., Feasibility Study to Link Data from the National Breast and Cervical Cancer Early Detection Program (NBCCEDP... Disadvantaged Communities, SIP11-041, Feasibility Study to Link Data from the National Breast and...

  15. Incorporating Voluntary Mobile Source Emission Reduction Programs in State Implementation Plans (SIPs)

    EPA Pesticide Factsheets

    This EPA memorandum provides guidance and sets forth policy and interpretation regarding the granting of explicit State Implementation Plan (SIP) credit for Voluntary Mobile Source Emission Reduction Programs (VMEPs) under section 110 of the Clean Air Act.

  16. Technical Data and Reports on Sulfur Dioxide (SO2) Measurements and SIP Status

    EPA Pesticide Factsheets

    EPA collects data from the states and regions on their air quality and state implementation plan (SIP) progress. This information is compiled in a database, and used to create reports, trend charts, and maps.

  17. Jasmonates during senescence: signals or products of metabolism?

    PubMed

    Seltmann, Martin A; Hussels, Wiebke; Berger, Susanne

    2010-11-01

    Jasmonic acid and derivatives are oxylipin signaling compounds derived from linolenic acid. Jasmonates accumulate during natural and dark-induced senescence but the increase in these compounds is not essential for the initiation or progression of these senescence processes. Here we report that during natural and dark-induced senescence the increase in jasmonate levels does not trigger jasmonate signaling. Furthermore we provide evidence that jasmonate production might result from membrane turnover during dark-induced senescence.

  18. Application of high resolution 2D/3D spectral induced polarization (SIP) in metalliferous ore exploration

    NASA Astrophysics Data System (ADS)

    Chen, R.; Zhao, X.; Yao, H.; He, X.; Zeng, P.; Chang, F.; Yang, Y.; Zhang, X.; Xi, X.; He, L.

    2015-12-01

    Induced polarization (IP) is a powerful tool in metalliferous ore exploration. However, there are many sources, such as clay and graphite, which can generate IP anomaly. Spectral induced polarization (SIP) measures IP response on a wide frequency range. This method provides a way to discriminate IP response generated by metalliferous ore or other objects. The best way to explore metalliferous ore is 3D SIP exploration. However, if we consider the exploration cost and efficiency, we can use SIP profiling to find an anomaly, and then use 2D/3D SIP sounding to characterize the anomaly. Based on above idea, we used a large-scale distributed SIP measurement system which can realize 800 sounding sites in one direction at the same time. This system can be used for SIP profiling, 2D/3D SIP sounding with high efficiency, high resolution, and large depth of investigation (> 1000 m). Qiushuwan copper - molybdenum deposit is located in Nanyang city, Henan province, China. It is only a middle-size deposit although over 100 holes were drilled and over 40 years of exploration were spent because of very complex geological setting. We made SIP measurement over 100 rock and ore samples to discriminate IP responses of ore and rock containing graphite. Then we carried out 7 lines of 2D SIP exploration with the depth of investigation great than 1000 m. The minimum electode spacing for potential difference is only 20 m. And we increase the spacing of current electodes at linear scale. This acquisition setting ensures high density data acquired and high quality data acquisition. Modeling and inversion result proves that we can get underground information with high resolution by our method. Our result shows that there exists a strong SIP response related to ore body in depth > 300 m. Pseudo-3D inversion of five 2D SIP sounding lines shows the location and size of IP anomaly. The new drillings based our result found a big copper-molybdenum ore body in new position with depth > 300 m and

  19. Role of the CacyBP/SIP protein in gastric cancer.

    PubMed

    Zhai, Huihong; Meng, Juan; Jin, Haifeng; Li, Yuanfei; Wang, Jinbo

    2015-05-01

    Various reports indicate that calcyclin binding protein/Siah-1-interacting protein (CacyBP/SIP) is an important protein in tumorigenesis, but whether CacyBP/SIP promotes or suppresses cancer may depend on the cell type. In order to investigate whether CacyBP/SIP is significant in gastric cancerous tumorigenesis, the present study used immunohistochemistry to analyze 181 gastric cancer tissue samples, as well as 181 healthy tissue samples from the same gastric cancer patients. The immunohistochemical results were compared against patient data and pathological analysis of the tissue slices, including gender, age, degree of tumor differentiation and tumor, node, metastasis (TNM) stage. In addition, the level of CacyBP/SIP expression was detected in three frozen tissue samples of gastric adenocarcinoma using western blot analysis. Of the 181 cases analyzed in the present study, 80 cases were identified as non-metastatic gastric cancer and 101 cases were identified as gastric cancer that had metastasized to the lymph nodes. Tissue biopsies from the two sets of patients were examined using immunohistochemistry to identify the level of CacyBP/SIP expression in metastatic and primary gastric cancer tissues. Statistical analyses were performed on all data. The immunohistochemical analysis revealed that CacyBP/SIP was expressed in 31% (56/181) of gastric adenocarcinoma tissue samples and 7% (12/181) of adjacent non-cancerous gastric tissues (P<0.05). Furthermore, the expression levels of CacyBP/SIP were higher in cancerous tissue compared with the adjacent non-cancerous gastric tissue using western blotting. No association was identified between CacyBP/SIP expression and patient age (P=0.975), gender (P=0.185), degree of tumor differentiation (P=0.076) or TNM stage (P=0.979). Among the 101 patients with metastatic gastric cancer, CacyBP/SIP was expressed at primary sites in 31% (31/101) of cases and at metastatic sites in 26% (26/101) of cases (P=0.434). However, among the

  20. Outcomes for extremely premature infants.

    PubMed

    Glass, Hannah C; Costarino, Andrew T; Stayer, Stephen A; Brett, Claire M; Cladis, Franklyn; Davis, Peter J

    2015-06-01

    Premature birth is a significant cause of infant and child morbidity and mortality. In the United States, the premature birth rate, which had steadily increased during the 1990s and early 2000s, has decreased annually for 7 years and is now approximately 11.39%. Human viability, defined as gestational age at which the chance of survival is 50%, is currently approximately 23 to 24 weeks in developed countries. Infant girls, on average, have better outcomes than infant boys. A relatively uncomplicated course in the intensive care nursery for an extremely premature infant results in a discharge date close to the prenatal estimated date of confinement. Despite technological advances and efforts of child health experts during the last generation, the extremely premature infant (less than 28 weeks gestation) and extremely low birth weight infant (<1000 g) remain at high risk for death and disability with 30% to 50% mortality and, in survivors, at least 20% to 50% risk of morbidity. The introduction of continuous positive airway pressure, mechanical ventilation, and exogenous surfactant increased survival and spurred the development of neonatal intensive care in the 1970s through the early 1990s. Routine administration of antenatal steroids during premature labor improved neonatal mortality and morbidity in the late 1990s. The recognition that chronic postnatal administration of steroids to infants should be avoided may have improved outcomes in the early 2000s. Evidence from recent trials attempting to define the appropriate target for oxygen saturation in preterm infants suggests arterial oxygen saturation between 91% and 95% (compared with 85%-89%) avoids excess mortality; however, final analyses of data from these trials have not been published, so definitive recommendations are still pending. The development of neonatal neurocritical intensive care units may improve neurocognitive outcomes in this high-risk group. Long-term follow-up to detect and address

  1. Outcomes for Extremely Premature Infants

    PubMed Central

    Glass, Hannah C.; Costarino, Andrew T.; Stayer, Stephen A.; Brett, Claire; Cladis, Franklyn; Davis, Peter J.

    2015-01-01

    Premature birth is a significant cause of infant and child morbidity and mortality. In the United States, the premature birth rate, which had steadily increased during the 1990s and early 2000s, has decreased annually for four years and is now approximately 11.5%. Human viability, defined as gestational age at which the chance of survival is 50%, is currently approximately 23–24 weeks in developed countries. Infant girls, on average, have better outcomes than infant boys. A relatively uncomplicated course in the intensive care nursery for an extremely premature infant results in a discharge date close to the prenatal EDC. Despite technological advances and efforts of child health experts during the last generation, the extremely premature infant (less than 28 weeks gestation) and extremely low birth weight infant (ELBW) (< 1000 grams) remain at high risk for death and disability with 30–50% mortality and, in survivors, at least 20–50% risk of morbidity. The introduction of CPAP, mechanical ventilation, and exogenous surfactant increased survival and spurred the development of neonatal intensive care in the 1970s through the early 1990s. Routine administration of antenatal steroids during premature labor improved neonatal mortality and morbidity in the late 1990s. The recognition that chronic postnatal administration of steroids to infants should be avoided may have improved outcomes in the early 2000s. Evidence from recent trials attempting to define the appropriate target for oxygen saturation in preterm infants suggests arterial oxygen saturation between 91–95% (compared to 85–89%) avoids excess mortality. However, final analyses of data from these trials have not been published, so definitive recommendations are still pending The development of neonatal neurocognitive care visits may improve neurocognitive outcomes in this high-risk group. Long-term follow up to detect and address developmental, learning, behavioral, and social problems is critical for

  2. Spectral induced polarization (SIP) measurement of NAPL contaminated soils

    NASA Astrophysics Data System (ADS)

    Schwartz, N.; Huisman, J. A.; Furman, A.

    2010-12-01

    The potential applicability of spectral induce polarization (SIP) as a tool to map NAPLs (non aqueous phase liquids) contaminants at the subsurface lead researchers to investigate the electric signature of those contaminant on the spectral response. However, and despite the cumulative efforts, the effect of NAPL on the electrical properties of soil, and the mechanisms that control this effect are largely unknown. In this work a novel experiment is designed to further examine the effect of NAPL on the electrical properties of partially saturated soil. The measurement system that used is the ZEL-SIP04 impedance meter developed at the Forschungszentrum Julich, Germany. The system accurately (nominal phase precision of 0.1 mrad below 1 kHz) measures the phase and the amplitude of a material possessing a very low polarization (such as soil). The sample holder has a dimension of 60 cm long and 4.6 cm in diameter. Current and potential electrodes were made of brass, and while the current electrodes were inserted in full into the soil, the contact between the potential electrode and the soil was made through an Agarose bridge. Two types of soils were used: clean quartz sand, and a mixture of sand with clean Bentonite. Each soil (sandy or clayey) was mixed with water to get saturation degree of 30%. Following the mixture with water, NAPL was added and the composite were mixed again. Packing was done by adding and compressing small portions of the soil to the column. A triplicate of each mixture was made with a good reproducible bulk density. Both for the sandy and clayey soils, the results indicate that additions of NAPL decrease the real part of the complex resistivity. Additionally, for the sandy soil this process is time depended, and that a further decrease in resistivity develops over time. The results are analyzed considering geometrical factors: while the NAPL is electrically insulator, addition of NAPL to the soil is expected to increase the connectivity of the

  3. Sipping at the Straw: Planning for Sustainable Water Supplies for U.S. Army Installations

    DTIC Science & Technology

    2011-05-01

    Thermoelectric power • Geothermal • Biofuels • Solar-hot water • Hydropower • Carbon Capture • “ Fracking ” Regional Water Balance?  Supply  Rivers...Sipping at the Straw: Planning for Sustainable Water Supplies for U.S. Army Installations Marc Kodack Senior Fellow, Army Environmental Policy...00-00-2011 4. TITLE AND SUBTITLE Sipping at the Straw: Planning for Sustainable Water Supplies for U.S. Army Installations 5a. CONTRACT NUMBER 5b

  4. Evaluation of a novel correction procedure to remove electrode impedance effects from broadband SIP measurements

    NASA Astrophysics Data System (ADS)

    Huisman, Johan Alexander; Zimmermann, Egon; Esser, Odilia; Haegel, Franz-Hubert; Treichel, Andrea; Vereecken, Harry

    2016-12-01

    Broadband spectral induced polarization (SIP) measurements of the complex electrical resistivity can be affected by the contact impedance of the potential electrodes above 100 Hz. In this study, we present a correction procedure to remove electrode impedance effects from SIP measurements to improve the accuracy of broadband complex electrical resistivity measurements. The first step in this correction procedure is to estimate the electrode impedance using a measurement with reversed current and potential electrodes. In a second step, this estimated electrode impedance is used to correct SIP measurements based on a simplified electrical model of the SIP measurement system. We evaluated this new correction procedure using SIP measurements on water because of the well-defined dielectric properties. It was found that the difference between the corrected and expected phase of the complex electrical resistivity of water was below 0.1 mrad at 1 kHz for a wide range of electrode impedances. In addition, SIP measurements on a saturated unconsolidated sediment sample with two types of potential electrodes showed that the measured phase of the electrical resistivity was very similar (difference < 0.2 mrad) up to a frequency of 10 kHz after the effect of the different electrode impedances was removed. Finally, SIP measurements on variably saturated unconsolidated sand were made. Here, the plausibility of the phase of the electrical resistivity was improved for frequencies up to 1 kHz, but errors remained for higher frequencies due to the approximate nature of the electrode impedance estimates and some remaining unknown parasitic capacitances that led to current leakage. It was concluded that the proposed correction procedure for SIP measurements improved the accuracy of the phase measurements by an order of magnitude in the kHz frequency range. Further improvement of this accuracy requires a method to accurately estimate parasitic capacitances in situ.

  5. The SETI Interpreter Program (SIP). a Software Package for the SETI Field Tests

    NASA Technical Reports Server (NTRS)

    Olsen, E. T.; Lokshin, A.

    1983-01-01

    The SETI (Search for Extraterrestrial Intelligence) Interpreter Program (SIP) is an interactive software package designed to allow flexible off line processing of the SETI field test data on a PDP 11/44 computer. The user can write and immediately execute complex analysis programs using the compact SIP command language. The software utilized by the SETI Interpreter Program consists of FORTRAN - coded modules that are sequentially installed and executed.

  6. The WRKY transcription factor family and senescence in switchgrass

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Background: 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. Methods: All potential WRKY genes present in the version 1.0 of the...

  7. Biological Impact of Senescence Induction in Prostate Cancer

    DTIC Science & Technology

    2008-01-01

    Coupled with clinical observations, these data suggest that the proliferative effects of senescent cancer cells are negligible and support the further...AD_________________ Award Number: W81XWH-06-1-0207 TITLE: Biological Impact of Senescence ...COVERED (From - To) 15 DEC 2006 - 14 DEC 2007 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Biological Impact of Senescence Induction in Prostate

  8. Mitochondrial DNA damage induces apoptosis in senescent cells

    PubMed Central

    Laberge, R-M; Adler, D; DeMaria, M; Mechtouf, N; Teachenor, R; Cardin, G B; Desprez, P-Y; Campisi, J; Rodier, F

    2013-01-01

    Senescence is a cellular response to damage and stress. The senescence response prevents cancer by suppressing the proliferation of cells with a compromised genome and contributes to optimal wound healing in normal tissues. Persistent senescent cells are also thought to drive aging and age-associated pathologies through their secretion of inflammatory factors that modify the tissue microenvironment and alter the function of nearby normal or transformed cells. Understanding how senescent cells alter the microenvironment would be aided by the ability to induce or eliminate senescent cells at will in vivo. Here, we combine the use of the synthetic nucleoside analog ganciclovir (GCV) with herpes simplex virus thymidine kinase (HSVtk) activity to create or eliminate senescent human cells. We show that low concentrations of GCV induce senescence through the accumulation of nuclear DNA damage while higher concentrations of GCV, similar to those used in vivo, kill non-dividing senescent cells via mitochondrial DNA (mtDNA) damage and caspase-dependent apoptosis. Using this system, we effectively eliminated xenografted normal human senescent fibroblasts or induced senescence in human breast cancer cells in vivo. Thus, cellular senescence and mtDNA damage are outcomes of synthetic nucleoside analog treatment, indicating that the GCV–HSVtk combination can be used effectively to promote the targeted formation or eradication of senescent cells. PMID:23868060

  9. Mitochondrial DNA damage induces apoptosis in senescent cells.

    PubMed

    Laberge, R-M; Adler, D; DeMaria, M; Mechtouf, N; Teachenor, R; Cardin, G B; Desprez, P-Y; Campisi, J; Rodier, F

    2013-07-18

    Senescence is a cellular response to damage and stress. The senescence response prevents cancer by suppressing the proliferation of cells with a compromised genome and contributes to optimal wound healing in normal tissues. Persistent senescent cells are also thought to drive aging and age-associated pathologies through their secretion of inflammatory factors that modify the tissue microenvironment and alter the function of nearby normal or transformed cells. Understanding how senescent cells alter the microenvironment would be aided by the ability to induce or eliminate senescent cells at will in vivo. Here, we combine the use of the synthetic nucleoside analog ganciclovir (GCV) with herpes simplex virus thymidine kinase (HSVtk) activity to create or eliminate senescent human cells. We show that low concentrations of GCV induce senescence through the accumulation of nuclear DNA damage while higher concentrations of GCV, similar to those used in vivo, kill non-dividing senescent cells via mitochondrial DNA (mtDNA) damage and caspase-dependent apoptosis. Using this system, we effectively eliminated xenografted normal human senescent fibroblasts or induced senescence in human breast cancer cells in vivo. Thus, cellular senescence and mtDNA damage are outcomes of synthetic nucleoside analog treatment, indicating that the GCV-HSVtk combination can be used effectively to promote the targeted formation or eradication of senescent cells.

  10. Epigenetic clock analyses of cellular senescence and ageing.

    PubMed

    Lowe, Donna; Horvath, Steve; Raj, Kenneth

    2016-02-23

    A confounding aspect of biological ageing is the nature and role of senescent cells. It is unclear whether the three major types of cellular senescence, namely replicative senescence, oncogene-induced senescence and DNA damage-induced senescence are descriptions of the same phenomenon instigated by different sources, or if each of these is distinct, and how they are associated with ageing. Recently, we devised an epigenetic clock with unprecedented accuracy and precision based on very specific DNA methylation changes that occur in function of age. Using primary cells, telomerase-expressing cells and oncogene-expressing cells of the same genetic background, we show that induction of replicative senescence (RS) and oncogene-induced senescence (OIS) are accompanied by ageing of the cell. However, senescence induced by DNA damage is not, even though RS and OIS activate the cellular DNA damage response pathway, highlighting the independence of senescence from cellular ageing. Consistent with this, we observed that telomerase-immortalised cells aged in culture without having been treated with any senescence inducers or DNA-damaging agents, re-affirming the independence of the process of ageing from telomeres and senescence. Collectively, our results reveal that cellular ageing is distinct from cellular senescence and independent of DNA damage response and telomere length.

  11. Drying without senescence in resurrection plants

    PubMed Central

    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

  12. Drying without senescence in resurrection plants.

    PubMed

    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

  13. CacyBP/SIP inhibits Doxourbicin-induced apoptosis of glioma cells due to activation of ERK1/2.

    PubMed

    Tang, Yuan; Zhan, Wenjian; Cao, Tong; Tang, Tianjin; Gao, Yong; Qiu, Zhichao; Fu, Chunling; Qian, Fengyuan; Yu, Rutong; Shi, Hengliang

    2016-03-01

    Calcyclin-binding protein or Siah-1-interacting protein (CacyBP/SIP) was previously reported to promote the proliferation of glioma cells. However, the effect of CacyBP/SIP on apoptosis of glioma is poorly understood. Here, our study shows that CacyBP/SIP plays a role in inhibiting doxorubicin (DOX) induced apoptosis of glioma cells U251 and U87. Overexpression of CacyBP/SIP obviously suppressed the DOX-induced cell apoptosis. On the contrary, silencing of CacyBP/SIP significantly promoted it. Further investigation indicated that inhibition of apoptosis by CacyBP/SIP was relevant to its nuclear translocation in response to the DOX treatment. Importantly, we found that the level of p-ERK1/2 in nuclei was related to the nuclear accumulation of CacyBP/SIP. Finally, the role of CacyBP/SIP was confirmed in vivo in a mouse model with the cell line stably silencing CacyBP/SIP. Taken together, our results suggest that CacyBP/SIP plays an important role in inhibiting apoptosis of glioma cells which might be mediated by ERK1/2 signaling pathway, which will provide some guidance for the treatment of glioma.

  14. Psychometric validation of the Korean version of Structured Interview for Post-traumatic Stress Disorder (K-SIP).

    PubMed

    Kim, Won; Kim, Daeho; Seo, Ho-Jun; Lee, Sang-Yeol; Ryu, Seung-Ho; Kim, Jung-Bum; Chung, Moon Yong; Koo, Young Jin; Ryu, Seong Gon; Kim, Eui Jung; Kim, Tae-Suk; Lim, Hyun-Kook; Woo, Jong-Min; Chae, Jeong-Ho

    2009-02-01

    For diagnosis and management of post-traumatic stress disorder (PTSD), the easily administered assessment tool is essential. Structured Interview for PTSD (SIP) is a validated, 17-item, simple measurement being used widely. We aimed to develop the Korean version of SIP (K-SIP) and investigated its psychometric properties. Ninety-three subjects with PTSD, 73 subjects with mood disorder or anxiety disorder as a psychiatric control group, and 88 subjects as a healthy control group were enrolled in this study. All subjects completed psychometric assessments that included the K-SIP, the Korean versions of the Clinician-Administered PTSD Scale (CAPS) and other assessment tools. The K-SIP presented good internal consistency (Cronbach's alpha=0.92) and test-retest reliability (r=0.87). K-SIP showed strong correlations with CAPS (r=0.72). Among three groups including PTSD patients, psychiatric controls, and normal controls, there were significant differences in the K-SIP total score. The potential cut-off total score of K-SIP was 20 with highest diagnostic efficiency (91.9%). At this point, the sensitivity and specificity were 95.5% and 88.4%, respectively. Our result showed that K-SIP had good reliability and validity. We expect that K-SIP will be used as a simple but structured instrument for assessment of PTSD.

  15. CacyBP/SIP binds ERK1/2 and affects transcriptional activity of Elk-1.

    PubMed

    Kilanczyk, Ewa; Filipek, Slawomir; Jastrzebska, Beata; Filipek, Anna

    2009-02-27

    In this work we showed for the first time that mouse CacyBP/SIP interacts with extracellular signal regulated kinases 1 and 2 (ERK1/2). We also established that a calcium binding protein, S100A6, competes for this interaction. Moreover, the E217K mutant of CacyBP/SIP does not bind significantly to ERK1/2 although it retains the ability to interact with S100A6. Molecular modeling shows that the E217K mutation in the 189-219 CacyBP/SIP fragment markedly changes its electrostatic potential, suggesting that the binding with ERK1/2 might have an electrostatic character. We also demonstrate that CacyBP/SIP-ERK1/2 interaction inhibits phosphorylation of the Elk-1 transcription factor in vitro and in the nuclear fraction of NB2a cells. Altogether, our data suggest that the binding of CacyBP/SIP with ERK1/2 might regulate Elk-1 phosphorylation/transcriptional activity and that S100A6 might further modulate this effect via Ca(2+)-dependent interaction with CacyBP/SIP and competition with ERK1/2.

  16. The CacyBP/SIP protein is sumoylated in neuroblastoma NB2a cells.

    PubMed

    Wasik, Urszula; Filipek, Anna

    2013-11-01

    The Calcyclin binding protein and Siah-1 interacting protein (CacyBP/SIP) protein is highly expressed in mammalian brain as well as in neuroblastoma NB2a cells and pheochromocytoma PC12 cells. This protein interacts with several targets such as cytoskeletal proteins or ERK1/2 kinase and seems to be involved in many cellular processes. In this work we examined a post-translational modification of CacyBP/SIP which might have an effect on its function. Since theoretical analysis of the amino acid sequence of CacyBP/SIP indicated several lysine residues which could potentially be sumoylated we checked experimentally whether this protein might be modified by SUMO attachment. We have shown that indeed CacyBP/SIP bound the E2 SUMO ligase, Ubc9, in neuroblastoma NB2a cell extract and was sumoylated in these cells. By fractionation of NB2a cell extract we have found that, contrary to the majority of SUMO-modified proteins, sumoylated CacyBP/SIP is present in the cytoplasmic and not in the nuclear fraction. We have also established that lysine 16 is the residue which undergoes sumoylation in the CacyBP/SIP protein.

  17. CacyBP/SIP protein is important for the proliferation of human glioma cells.

    PubMed

    Shi, Hengliang; Gao, Yong; Tang, Yuan; Wu, Yuxuan; Gong, Hui; Du, Jin; Zheng, Bao; Hu, Jinxia; Shi, Qiong; Yu, Rutong

    2014-04-01

    Recently, calcyclin-binding protein or Siah-1-interacting protein (CacyBP/SIP), a component of a novel ubiquitinylation pathway, could regulate the β-catenin degradation (Fukushima et al., Immunity 2006, 24, 29-39). However, the potential role of CacyBP/SIP itself in human glioma cells has not been clarified. Here, we found that CacyBP/SIP was expressed highly in human glioma tissues. Silencing of CacyBP/SIP by short-hairpin RNA severely suppressed the proliferation of human glioma cell U251, which was at least partly mediated by downregulation of phospho-Akt (p-Akt) and phospho-β-catenin (p-β-catenin) as well as upregulation of p53 and p21. Furthermore, overexpression of CacyBP/SIP obviously promoted the proliferation of human glioma U251, which exhibited the exactly contrary trend in the expression of p-Akt, p-β-catenin, p53, and p21. Taken together, these findings suggest that CacyBP/SIP plays important roles in the proliferation of human glioma cell which might be involved in the development of human glioma.

  18. CacyBP/SIP binds ERK1/2 and affects transcriptional activity of Elk-1

    SciTech Connect

    Kilanczyk, Ewa; Filipek, Slawomir; Jastrzebska, Beata; Filipek, Anna

    2009-02-27

    In this work we showed for the first time that mouse CacyBP/SIP interacts with extracellular signal regulated kinases 1 and 2 (ERK1/2). We also established that a calcium binding protein, S100A6, competes for this interaction. Moreover, the E217K mutant of CacyBP/SIP does not bind significantly to ERK1/2 although it retains the ability to interact with S100A6. Molecular modeling shows that the E217K mutation in the 189-219 CacyBP/SIP fragment markedly changes its electrostatic potential, suggesting that the binding with ERK1/2 might have an electrostatic character. We also demonstrate that CacyBP/SIP-ERK1/2 interaction inhibits phosphorylation of the Elk-1 transcription factor in vitro and in the nuclear fraction of NB2a cells. Altogether, our data suggest that the binding of CacyBP/SIP with ERK1/2 might regulate Elk-1 phosphorylation/transcriptional activity and that S100A6 might further modulate this effect via Ca{sup 2+}-dependent interaction with CacyBP/SIP and competition with ERK1/2.

  19. Human milk for the premature infant.

    PubMed

    Underwood, Mark A

    2013-02-01

    Premature infants are at risk for growth failure, developmental delays, necrotizing enterocolitis, and late-onset sepsis. Human milk from women delivering prematurely has more protein and higher levels of bioactive molecules. Human milk must be fortified for premature infants to achieve adequate growth. Mother's own milk improves growth and neurodevelopment, decreases the risk of necrotizing enterocolitis and late-onset sepsis, and should be the primary enteral diet for premature infants. Donor milk is a resource for premature infants whose mothers are unable to provide an adequate supply of milk. Challenges include the need for pasteurization, nutritional and biochemical deficiencies, and limited supply.

  20. Western diet consumption promotes vascular remodeling in non-senescent mice consistent with accelerated senescence, but does not modify vascular morphology in senescent ones.

    PubMed

    Dantas, Ana Paula; Onetti, Yara; Oliveira, María Aparecida; Carvalho, Maria Helena; Heras, Magda; Vila, Elisabet; Jiménez-Altayó, Francesc

    2014-07-01

    Senescence accelerated mice (SAM) are susceptible to developing vascular dysfunction and remodeling. Food intake and type of diet have also been identified as determining factors in vascular remodeling. However, the interplay between senescence and diet in vascular remodeling is largely unknown. We aimed to analyze structure of large (aorta) and small (mesenteric; MA) arteries from seven-month-old SAM prone (SAMP8) and resistant (SAMR1) mice that received a Western-type high-fat diet (WD; 8weeks). Aortic structure was assessed by morphometric analysis of hematoxylin and eosin-stained cross sections, and collagen content by qRT-PCR, immunofluorescence and picrosirius red. In MAs, structural and mechanical properties were measured by pressure myography; elastin and collagen content by qRT-PCR and immunofluorescence; nuclei distribution by confocal microscopy; and apoptosis by qRT-PCR and TUNEL assay. In aorta, wall thickness (WT), but not cross-sectional area (CSA), was increased by senescence, and WD only increased WT in SAMR1. WD intake, but not senescence, was associated with increased collagen deposition. In MAs, senescence diminished WT and CSA, without altering collagen and elastin deposition, reduced the number of MA wall cells, and increased pro apoptotic activation. WD consumption promoted in SAMR1 the same remodeling observed with senescence, while in SAMP8 the senescence-associated changes remained unaffected. The mechanisms involved in WD-induced MA remodeling in SAMR1 mimicked those observed in senescence per se. Our study reveals qualitatively different remodeling in aortas and MAs from senescent mice. Consumption of a WD induced remodeling of the SAMR1 vasculature similar to that induced by senescence, while it did not promote any further alteration in the latter. Therefore, we propose that increased consumption of fat-enriched diets could promote accelerated senescence of the non-senescent vasculature, although it does not exacerbate vascular

  1. [Forensic importance of premature craniosynostosis].

    PubMed

    Fehlow, P

    1991-01-01

    In agreement with Canabis craniosynostosis as a little known organic partial factor of sociopathy is demonstrated. A psychic syndrome of the frontal lobe with increased susceptibility in environmental damages is assumed to be basic disorder. In the criminals of the material sexual offenders were preponderating. Associated craniofacial dysplasias are a risk for psychic maldevelopment. The importance of premature craniosynostocis as a biological risk factor, incidence, diagnostic, indication for an operation, also in the meaning of a neurosurgical "Konflikttherapie" (cosmetical indication) are discussed.

  2. SIP-CCME cooperation in multimedia VoIP network

    NASA Astrophysics Data System (ADS)

    Grądkowska, Magdalena; Popiel, Piotr; Sobańska, Katarzyna

    2006-10-01

    VoIP is a fast-developing technology which allows making telephone calls using a data network like the Internet. VoIP converts the voice signal from the telephone into a digital signal that travels over the Internet and then converts it back at the other end so that speaking to anyone with a regular phone number is possible. VoIP may also enable the direct calls from a computer with the use of a conventional telephone or a microphone. Some services using VoIP may only allow you to call other people using the same VoIP service, but others may allow you to call anyone who has a telephone number. First condition is a broadband Internet connection for VoIP technology to work. There are two major advantages of VOIP: lower cost and increased functionality. In the paper the integration of two networks, one with a CCME based installation and the other with a full Asterisk/SIP voicemail deployment is presented. The goal was to allow dialing between VoIP's telephony from different networks and evaluate a quality of connection with the use of certain codecs.

  3. Progesterone Deficiency and Premature Labour

    PubMed Central

    Csapo, A. I.; Pohanka, O.; Kaihola, H. L.

    1974-01-01

    Plasma oestradiol 17β and progesterone levels in 11 patients admitted to hospital for threatened premature labour of unknown aetiology were compared with those of women at similar stages of gestation whose pregnancy was normal. Oestradiol levels in the study group were slightly higher than in the normal controls but their progesterone levels were significantly lower. This progesterone deficiency increased the oestradiol/progesterone ratio in the study group patients, and it increased still more as the progesterone withdrawal continued during premature labour. Since uterine activity during pregnancy is regulated by a balanced action of several factors a deficiency in progesterone, an opponent of uterine activity, creates a regulatory imbalance which, if uncorrected, provokes premature labour. An increase in uterine volume stimulates uterine activity, and the present study reinforced our previous conclusion that the uterine-volume/plasma-progesterone ratio is a more accurate measure of the state of regulatory balance than the progesterone level alone. The cause of the progesterone deficiency in these cases remains unexplained, but we suggest that placental growth and function are contributory factors. We are investigating ways of correcting the resulting imbalance in the regulatory mechanism. PMID:4812406

  4. Development of 2D SIP Data Processing Software for a Metallic Mineral Deposit Exploration

    NASA Astrophysics Data System (ADS)

    PARK, M.; Kim, K. S.; Seo, H. K.; Son, J.; Park, S.; Kim, C.; Kim, J. H.

    2015-12-01

    In this study, we developed commercially two dimensional SIP (Spectral Induced Polarization) data processing software for measured SIP data, because the end user to comfortably use it. In order to consider the application of the developed technique, two dimensional SIP was tested in the area of hydro-thermal mineral deposit, Haenam in South Korea. We also acquired time-domain IP data for the same profile in order to verify the accuracy of SIP data, and compared both data after data processing and analysis completed. Separation of transmitter and receiver line was used to get more accurate data, and porous pot electrode was also used to remove the polarization effect of receiver electrodes. As results of both survey methods, we knew that resistivity images were nearly same but the chargeability and phase images were slight different. From the previous experience of SIP survey on the close test, phase anomaly was closely related and expected to the mineralized zone also in this survey. The site where the test survey was conducted was a small hills, and on the top of hill silicified alteration zone was identified which were shown as a high-resistivity anomaly on the resistivity mage. Below this high-resistivity anomaly, we identified phase anomaly that showed a consistent trend originated from the deep anomaly directly under the mountain, and it continued from south to north, and deep to shallow. This trend of phase anomaly was not clearly identified on the inverted chargeability images for the averaged chargeability of time-domain IP data. But when we use new inversion algorithm which use all the chargeability data of 20 time windows simultaneously, we got similar inverted results for the middle-time IP data. Through the test survey of SIP and IP, we know that S/N ration of SIP measurements was superior to those of IP measurement because SIP measurement was made during the transmitter on but IP measurement did not. And if we use the newly developed IP inversion

  5. Characteristics of SIP Response for Rock Specimens in the Gagok Skarn Deposit, Korea

    NASA Astrophysics Data System (ADS)

    Kim, C.; Mi Kyung, P.; Park, S.; Shin, S.

    2012-12-01

    Spectral Induced Polarization (SIP) method was conducted to develop mineral exploration technique in the Gagok skarn deposit, Korea. The Gagok mine was once abandoned and recently reopened. The Gagok stratabound skarn deposit is originated from the Cretaceous granite intrusion into the Paleozoic limestone and slate formations. The ore minerals of the Gagok deposit include sulfide minerals such as sphalerite, pyrrhotite, galena, chalcopyrite, pyrite, arsenopyrite, etc. The characteristics of SIP response for the rock specimens were examined to re-evaluate mineral resources. Total 104 rock specimens were obtained from the mine shafts at the various elevations, and were modified in cylindrical shape for the measurement of SIP response, along with other physical properties such as porosity, density, DC electrical resistivity, magnetic susceptibility, and seismic velocity. The SIP measurement system consists of electrical current transmitter and receiver (model GDP-32 system, Zonge Co. USA), and measures amplitude for resistivity, and phase at 14 steps of frequencies ranging from 0.125 to 1,024 Hz. The results of the SIP measurement shows that the rock specimens from ore bodies accompanied with sulfide minerals such as sphalerite and pyrite produce large phase differences with frequencies applied. The results also show that the rock specimens at the lower elevation of the mine shaft have stronger SIP response and mineralization. The rock specimens with large phase differences of strong SIP response were classified into three phase curve types, based on the range of critical frequency from the SIP measurement. (1) Curve type 1: critical frequency of less than 1 Hz with decreasing phase curve (2) Curve type 2: critical frequency of 1 to 10 Hz with bell shape, (3) Curve type 3: critical frequency of larger than 10 Hz with mixture of curve type 1 and 2. It is believed that the graphitic components and sulfide minerals such as sphalerite and pyrite are dominant in the rock

  6. T cell senescence and cardiovascular diseases.

    PubMed

    Yu, Hee Tae; Park, Sungha; Shin, Eui-Cheol; Lee, Won-Woo

    2016-08-01

    Age-related changes in the immune system, commonly termed "immunosenescence," contribute to deterioration of the immune response and fundamentally impact the health and survival of elderly individuals. Immunosenescence affects both the innate and adaptive immune systems; however, the most notable changes are in T cell immunity and include thymic involution, the collapse of T cell receptor (TCR) diversity, an imbalance in T cell populations, and the clonal expansion of senescent T cells. Senescent T cells have the ability to produce large quantities of proinflammatory cytokines and cytotoxic mediators; thus, they have been implicated in the pathogenesis of many chronic inflammatory diseases. Recently, an increasing body of evidence has suggested that senescent T cells also have pathogenic potential in cardiovascular diseases, such as hypertension, atherosclerosis, and myocardial infarction, underscoring the detrimental roles of these cells in various chronic inflammatory responses. Given that cardiovascular disease is the number one cause of death worldwide, there is great interest in understanding the contribution of age-related immunological changes to its pathogenesis. In this review, we discuss general features of age-related alterations in T cell immunity and the possible roles of senescent T cells in the pathogenesis of cardiovascular disease.

  7. Colorimetric detection of senescence-associated β galactosidase.

    PubMed

    Itahana, Koji; Itahana, Yoko; Dimri, Goberdhan P

    2013-01-01

    Most normal human cells have a finite replicative capacity and eventually undergo cellular senescence, whereby cells cease to proliferate. Cellular senescence is also induced by various stress signals, such as those generated by oncogenes, DNA damage, hyperproliferation, and an oxidative environment. Cellular senescence is well established as an intrinsic tumor suppressive mechanism. Recent progress concerning senescence research has revealed that cellular senescence occurs in vivo and that, unexpectedly, it has a very complex role in tissue repair, promoting tumor progression and aging via the secretion of various cytokines, growth factors, and enzymes. Therefore, the importance of biomarkers for cellular senescence has greatly increased. In 1995, we described the "senescence-associated β galactosidase" (SA-βgal) biomarker, which conveniently identifies individual senescent cells in vitro and in vivo. Here, we describe an updated protocol for the detection of cell senescence based on this widely used biomarker, which contributed to recent advances in senescence, aging and cancer research. We provide an example of detecting SA-βgal together with other senescence markers and a proliferation marker, EdU, in single cells.

  8. Quantitative Analysis of Cellular Senescence in Culture and In Vivo.

    PubMed

    Zhao, Jing; Fuhrmann-Stroissnigg, Heike; Gurkar, Aditi U; Flores, Rafael R; Dorronsoro, Akaitz; Stolz, Donna B; St Croix, Claudette M; Niedernhofer, Laura J; Robbins, Paul D

    2017-01-05

    Cellular senescence refers to the irreversible growth arrest of normally dividing cells in response to various types of stress. Cellular senescence is induced by telomere shortening due to repeated cell division, which causes a DNA damage response, as well as genotoxic, oxidative, and inflammatory stress. Strong mitogenic signaling, such as oncogene activation, also drives cells into a senescent state. Senescent cells express a specific subset of genes, termed the senescence-associated secretory phenotype (SASP), including pro-inflammatory factors, growth factors, and matrix metalloproteinases, which together promote non-cell autonomous, secondary senescence. Clearance of senescent cells that accumulate with age improves health span, implicating cellular senescence as a contributing factor to the aging process. Thus, there is a need for methods to identify and quantify cellular senescence, both in cultured cells and in vivo. Here, methods for the most well-characterized and widely used senescent assays are described, from cell morphology and senescence-associated β-galactosidase (SA-βgal) staining to nuclear biomarkers, SASP, and altered levels of tumor suppressors. © 2017 by John Wiley & Sons, Inc.

  9. Mitochondria change dynamics and morphology during grapevine leaf senescence.

    PubMed

    Ruberti, Cristina; Barizza, Elisabetta; Bodner, Martina; La Rocca, Nicoletta; De Michele, Roberto; Carimi, Francesco; Lo Schiavo, Fiorella; Zottini, Michela

    2014-01-01

    Leaf senescence is the last stage of development of an organ and is aimed to its ordered disassembly and nutrient reallocation. Whereas chlorophyll gradually degrades during senescence in leaves, mitochondria need to maintain active to sustain the energy demands of senescing cells. Here we analysed the motility and morphology of mitochondria in different stages of senescence in leaves of grapevine (Vitis vinifera), by stably expressing a GFP (green fluorescent protein) reporter targeted to these organelles. Results show that mitochondria were less dynamic and markedly changed morphology during senescence, passing from the elongated, branched structures found in mature leaves to enlarged and sparse organelles in senescent leaves. Progression of senescence in leaves was not synchronous, since changes in mitochondria from stomata were delayed. Mitochondrial morphology was also analysed in grapevine cell cultures. Mitochondria from cells at the end of their growth curve resembled those from senescing leaves, suggesting that cell cultures might represent a useful model system for senescence. Additionally, senescence-associated mitochondrial changes were observed in plants treated with high concentrations of cytokinins. Overall, morphology and dynamics of mitochondria might represent a reliable senescence marker for plant cells.

  10. Multiple climate drivers accelerate Arctic plant community senescence

    NASA Astrophysics Data System (ADS)

    Livensperger, C.; Steltzer, H.; Wallenstein, M. D.; Weintraub, M. N.

    2015-12-01

    Alteration of seasonal phenology cues due to climate change has led to changes in the onset and duration of the growing season. While photoperiod often acts as an ultimate control on phenological events, recent studies have shown that environmental cues such as temperature and soil water content can modify the direction and rate of senescence processes. Warmer temperatures have resulted in an observed trend towards delayed senescence across temperate latitudes. However, Arctic regions are characterized by extreme seasonality and rapidly decreasing photoperiod, and consequently senescence may not shift as climate warms. We monitored the timing of Arctic plant community senescence for three years under the framework of an experimental manipulation that altered seasonal phenological cues through warming and earlier snowmelt. Alternative models of senescence were tested to determine if microclimate (air temperature, soil temperature, and soil moisture) or start of season phenology affect the timing and rate of community senescence. We found that all three microclimate predictors contributed to explaining variation in timing of senescence, suggesting that photoperiod is not the sole control on timing of senescence in Arctic plant communities. Rather, increased air and soil temperatures along with drier soil conditions, led to acceleration in the onset of senescence at a community level. Our data suggest that (1) multiple climate drivers predict timing of plant community senescence, and (2) climate change could result in a shorter peak season due to earlier onset of senescence, which would decrease the potential carbon uptake in moist acidic tundra.

  11. Mitochondria Change Dynamics and Morphology during Grapevine Leaf Senescence

    PubMed Central

    Bodner, Martina; La Rocca, Nicoletta; De Michele, Roberto; Carimi, Francesco; Schiavo, Fiorella Lo; Zottini, Michela

    2014-01-01

    Leaf senescence is the last stage of development of an organ and is aimed to its ordered disassembly and nutrient reallocation. Whereas chlorophyll gradually degrades during senescence in leaves, mitochondria need to maintain active to sustain the energy demands of senescing cells. Here we analysed the motility and morphology of mitochondria in different stages of senescence in leaves of grapevine (Vitis vinifera), by stably expressing a GFP (green fluorescent protein) reporter targeted to these organelles. Results show that mitochondria were less dynamic and markedly changed morphology during senescence, passing from the elongated, branched structures found in mature leaves to enlarged and sparse organelles in senescent leaves. Progression of senescence in leaves was not synchronous, since changes in mitochondria from stomata were delayed. Mitochondrial morphology was also analysed in grapevine cell cultures. Mitochondria from cells at the end of their growth curve resembled those from senescing leaves, suggesting that cell cultures might represent a useful model system for senescence. Additionally, senescence-associated mitochondrial changes were observed in plants treated with high concentrations of cytokinins. Overall, morphology and dynamics of mitochondria might represent a reliable senescence marker for plant cells. PMID:25009991

  12. Cellular senescence: ex vivo p53-dependent asymmetric cell kinetics

    PubMed Central

    2001-01-01

    Although senescence is a defining property of euploid mammalian cells, its physiologic basis remains obscure. Previously, cell kinetics properties of normal tissue cells have not been considered in models for senescence. We now provide evidence that senescence is in fact the natural consequence of normal in vivo somatic stem cell kinetics extended in culture. This concept of senescence is based on our discovery that cells engineered to conditionally express the well-recognized tumor suppressor protein and senescence factor, p53, exhibit asymmetric cell kinetics. In vivo, asymmetric cell kinetics are essential for maintenance of somatic stem cells; ex vivo, the same cell kinetics yield senescence as a simple kinetic endpoint. This new “asymmetric cell kinetics model” for senescence suggests novel strategies for the isolation and propagation of somatic tissue stem cells in culture. PMID:12488624

  13. A genomics approach identifies senescence-specific gene expression regulation

    PubMed Central

    Lackner, Daniel H; Hayashi, Makoto T; Cesare, Anthony J; Karlseder, Jan

    2014-01-01

    Replicative senescence is a fundamental tumor-suppressive mechanism triggered by telomere erosion that results in a permanent cell cycle arrest. To understand the impact of telomere shortening on gene expression, we analyzed the transcriptome of diploid human fibroblasts as they progressed toward and entered into senescence. We distinguished novel transcription regulation due to replicative senescence by comparing senescence-specific expression profiles to profiles from cells arrested by DNA damage or serum starvation. Only a small specific subset of genes was identified that was truly senescence-regulated and changes in gene expression were exacerbated from presenescent to senescent cells. The majority of gene expression regulation in replicative senescence was shown to occur due to telomere shortening, as exogenous telomerase activity reverted most of these changes. PMID:24863242

  14. Use of NAP gene to manipulate leaf senescence in plants

    DOEpatents

    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.

  15. A genomics approach identifies senescence-specific gene expression regulation.

    PubMed

    Lackner, Daniel H; Hayashi, Makoto T; Cesare, Anthony J; Karlseder, Jan

    2014-10-01

    Replicative senescence is a fundamental tumor-suppressive mechanism triggered by telomere erosion that results in a permanent cell cycle arrest. To understand the impact of telomere shortening on gene expression, we analyzed the transcriptome of diploid human fibroblasts as they progressed toward and entered into senescence. We distinguished novel transcription regulation due to replicative senescence by comparing senescence-specific expression profiles to profiles from cells arrested by DNA damage or serum starvation. Only a small specific subset of genes was identified that was truly senescence-regulated and changes in gene expression were exacerbated from presenescent to senescent cells. The majority of gene expression regulation in replicative senescence was shown to occur due to telomere shortening, as exogenous telomerase activity reverted most of these changes.

  16. A Secretion-Amplification Role for Salmonella enterica Translocon Protein SipD.

    PubMed

    Glasgow, Anum Azam; Wong, Han Teng; Tullman-Ercek, Danielle

    2017-03-16

    The bacterial type III secretion system (T3SS) is an important target for enabling high-titer production of proteins of biotechnological interest as well as for synthetic biology applications that rely on protein delivery to host cells. The T3SS forms a membrane-embedded needle complex that is capped by the translocon proteins and extends into the extracellular space. The needle tip complex in Salmonella enterica consists of three translocon proteins: SipB, SipC, and SipD. It is known that knocking out sipD disrupts T3SS regulation to cause constitutive secretion of native proteins. However, we discovered that complementation of SipD in trans via exogenous addition to T3SS-expressing cultures further improves heterologous protein secretion titers, suggesting a previously unknown but important role for this protein. Building on this knowledge, we have engineered a hyper-secreting strain of S. enterica for a greater than 100-fold improvement in the production of a variety of biotechnologically valuable heterologous proteins that are challenging to produce, such as toxic antimicrobial peptides and proteolysis-prone biopolymer proteins. We determined that transcription by several T3SS promoters is upregulated with the addition of SipD, that the N-terminal domain of SipD is sufficient to observe the increased secretion phenotype, and that the effect is post-transcriptional and post-translational. These results lend support to the use of bacterial secretion as a powerful protein production strategy, and the hypothesis that translocon proteins contribute to type III secretion regulation.

  17. Tubulin binding protein, CacyBP/SIP, induces actin polymerization and may link actin and tubulin cytoskeletons.

    PubMed

    Schneider, Gabriela; Nieznanski, Krzysztof; Jozwiak, Jolanta; Slomnicki, Lukasz P; Redowicz, Maria J; Filipek, Anna

    2010-11-01

    CacyBP/SIP, originally identified as a S100A6 target, was shown to interact with some other S100 proteins as well as with Siah-1, Skp1, tubulin and ERK1/2 kinases (reviewed in Schneider and Filipek, Amino Acids, 2010). Here, we show that CacyBP/SIP interacts and co-localizes with actin in NB2a cells. Using a zero-length cross-linker we found that both proteins bound directly to each other. Co-sedimentation assays revealed that CacyBP/SIP induced G-actin polymerization and formation of unique circular actin filament bundles. The N-terminal fragment of CacyBP/SIP (residues 1-179) had similar effect on actin polymerization as the entire CacyBP/SIP protein, while the C-terminal one (residues 178-229) had not. To check the influence of CacyBP/SIP on cell morphology as well as on cell adhesion and migration, a stable NIH 3T3 cell line with an increased level of CacyBP/SIP was generated. We found that the adhesion and migration rates of the modified cells were changed in comparison with the control ones. Interestingly, the co-sedimentation and proximity ligation assays indicated that CacyBP/SIP could simultaneously interact with tubulin and actin, suggesting that CacyBP/SIP might link actin and tubulin cytoskeletons.

  18. CacyBP/SIP interacts with tubulin in neuroblastoma NB2a cells and induces formation of globular tubulin assemblies.

    PubMed

    Schneider, Gabriela; Nieznanski, Krzysztof; Kilanczyk, Ewa; Bieganowski, Paweł; Kuznicki, Jacek; Filipek, Anna

    2007-11-01

    CacyBP/SIP, originally identified as a S100A6 (calcyclin) target, was later shown to interact with some other members of the S100 family as well as with Siah-1 and Skp1 proteins. Recently, it has been shown that CacyBP/SIP is up-regulated during differentiation of cardiomyocytes. In this work we show that the level of CacyBP/SIP is higher in differentiated neuroblastoma NB2a cells than in undifferentiated ones and that in cells overexpressing CacyBP/SIP the level of GAP-43, a marker of differentiation, was increased. Since the process of differentiation is accompanied by an extensive rearrangement of microtubules, we examined whether CacyBP/SIP interacted with tubulin. By applying cross-linking experiments we found that these two proteins bind directly. The dissociation constant of the tubulin-CacyBP/SIP complex determined by the surface plasmon resonance technique is 1.57 x 10(-7 )M which suggests that the interaction is tight. The interaction and co-localization of CacyBP/SIP and tubulin was also demonstrated by co-immunoprecipitation, affinity chromatography and immunofluorescence methods. Light scattering measurements and electron microscopy studies revealed that CacyBP/SIP, but not its homologue, Sgt1, increased tubulin oligomerization. Altogether, our results suggest that CacyBP/SIP, via its interaction with tubulin, might contribute to the differentiation of neuroblastoma NB2a cells.

  19. CacyBP/SIP enhances multidrug resistance of pancreatic cancer cells by regulation of P-gp and Bcl-2.

    PubMed

    Chen, Xiong; Zheng, Peichan; Xue, Zengfu; Li, Jie; Wang, Wenwu; Chen, Xi; Xie, Fangwei; Yu, Zongyang; Ouyang, Xuenong

    2013-07-01

    Our former report indicates that calcyclin-binding protein or Siah-1-interacting protein (CacyBP/SIP) is over-expressed in the SGC7901/ADR cell line. However, the potential role of CacyBP/SIP in the development of multidrug resistance (MDR) of pancreatic cancer is still uncertain. In this paper, we investigated the role of CacyBP/SIP in MDR of pancreatic cancer cells and its possible underlying mechanisms, and found that CacyBP/SIP was over-expressed in the Gemcitabine induced MDR pancreatic cancer cell PC-3/Gem compared with its parental cell PC-3. Up-regulation of CacyBP/SIP expression could enhance resistance of chemotherapy drugs on PC-3 cells and inhibit Adriamycin-induced apoptosis accompanied by decreased accumulation of intracellular Adriamycin. Furthermore, CacyBP/SIP could significantly up-regulate the expression of P-gp, Bcl-2, and the transcription of the MDR1 gene. In addition, the decrease of CacyBP/SIP expression using RNA interference or P-gp inhibitor could partially reverse CacyBP/SIP-mediated MDR. In brief, our study demonstrated that CacyBP/SIP could enhance the MDR phenotype of pancreatic cancer cells by increasing the expression of P-gp and Bcl-2, thus inhibiting apoptosis of pancreatic cancer cell.

  20. [Skin antisepsis in premature infants].

    PubMed

    Agolini, G; Faldella, G; Janes, E; Raitano, A; Spinelli, M; Vitali, M

    2011-01-01

    In some premature newborns, 7 months old and with less than 1 kg of body wheight, total parenteral nutrition is used for weeks, so that good antiseptics can cooperate to the prevention of nosocomial infections, associating the best biocide effects to the best topical tolerability. Details are reported on the biocide cutaneous properties of some chloro-derivates, as sodium hypochlorite and NaDCC, of ethyl and propyl alcohols, of chlorhexidine, of iodophors and also of triclosan and octenidine (even if these latter biocids are not normally available in Italy as cutaneous antiseptics).

  1. [Premature ejaculation: pills or sexology?].

    PubMed

    Wisard, M; Audette, N

    2008-03-26

    Premature ejaculation (PE) is a frequent male sexual complaint that affects 20 to 30% of men. The exact aetiology is unknown: psychological/behavioristic and biogenic etiologies have been proposed. The introduction of selective serotonin reuptake inhibitors (SSRI) was revolutionary in the medical treatment of PE. However precautions should be taken because of potential adverse side effects. There is no clear consensus as to whether SSRI may represent an eventual cure of PE or will be required for life. The sexocorporal approach is an other treatment of PE, but convincing scientific treatment data are also lacking.

  2. Current therapies for premature ejaculation.

    PubMed

    Gur, Serap; Kadowitz, Philip J; Sikka, Suresh C

    2016-07-01

    Premature ejaculation (PE) subjectively affects 20-30% of men globally. Until recently, understanding of PE was hampered by the absence of a widely accepted definition, paucity of evidence-based clinical studies, and the absence of an appropriate animal model. Here, we elaborate on the current definition of PE, its pathogenesis, currently available therapies, and future treatment prospects. Most treatments for PE are 'off-label' and include selective serotonin reuptake inhibitors (SSRIs), topical anesthetics, tramadol, and phosphodiesterase type 5 (PDE5) inhibitors. Such knowledge of the benefit and limitations of each treatment will help to direct future drug design and formulations.

  3. Gene Expression Profiles Deciphering Leaf Senescence Variation between Early- and Late-Senescence Cotton Lines

    PubMed Central

    Kong, Xiangqiang; Luo, Zhen; Dong, Hezhong; Eneji, A. Egrinya; Li, Weijiang; Lu, Hequan

    2013-01-01

    Leaf senescence varies greatly among genotypes of cotton (Gossypium hirsutium L), possibly due to the different expression of senescence-related genes. To determine genes involved in leaf senescence, we performed genome-wide transcriptional profiling of the main-stem leaves of an early- (K1) and a late-senescence (K2) cotton line at 110 day after planting (DAP) using the Solexa technology. The profiling analysis indicated that 1132 genes were up-regulated and 455 genes down-regulated in K1 compared with K2 at 110 DAP. The Solexa data were highly consistent with, and thus were validated by those from real-time quantitative PCR (RT-PCR). Most of the genes related to photosynthesis, anabolism of carbohydrates and other biomolecules were down-regulated, but those for catabolism of proteins, nucleic acids, lipids and nutrient recycling were mostly up-regulated in K1 compared with K2. Fifty-one differently expressed hormone-related genes were identified, of which 5 ethylene, 3 brassinosteroid (BR), 5 JA, 18 auxin, 8 GA and 1 ABA related genes were up-regulated in K1 compared with K2, indicating that these hormone-related genes might play crucial roles in early senescence of K1 leaves. Many differently expressed transcription factor (TF) genes were identified and 11 NAC and 8 WRKY TF genes were up-regulated in K1 compared with K2, suggesting that TF genes, especially NAC and WRKY genes were involved in early senescence of K1 leaves. Genotypic variation in leaf senescence was attributed to differently expressed genes, particularly hormone-related and TF genes. PMID:23922821

  4. Premature ventricular contractions associated with isotretinoin use*

    PubMed Central

    Alan, Sevil; Ünal, Betül; Yildirim, Aytül

    2016-01-01

    Isotretinoin has been considered a unique drug for acne treatment. However, it is associated with numerous adverse effects. Isotretinoin can trigger premature ventricular contractions. This report describes a 33-year-old-woman who presented with palpitations for 1 week while undergoing 1-month isotretinoin treatment for mild-moderate facial acne. An electrocardiogram and Holter monitoring showed premature ventricular contractions during isotretinoin (Roaccutane, Roche) treatment. Isotretinoin-related premature ventricular contractions were strongly suggested in this case due to the existence of documented premature ventricular contractions on electrocardiograms and the disappearance of these premature ventricular contractions two weeks after termination of the treatment To the authors' knowledge, there has been 1 reported case of premature ventricular contractions linked to isotretinoin use; this report describes a second such case. PMID:28099609

  5. Lithium Ion Mobility in Lithium Phosphidosilicates: Crystal Structure, (7) Li, (29) Si, and (31) P MAS NMR Spectroscopy, and Impedance Spectroscopy of Li8 SiP4 and Li2 SiP2.

    PubMed

    Toffoletti, Lorenzo; Kirchhain, Holger; Landesfeind, Johannes; Klein, Wilhelm; van Wüllen, Leo; Gasteiger, Hubert A; Fässler, Thomas F

    2016-12-05

    The need to improve electrodes and Li-ion conducting materials for rechargeable all-solid-state batteries has drawn enhanced attention to the investigation of lithium-rich compounds. The study of the ternary system Li-Si-P revealed a series of new compounds, two of which, Li8 SiP4 and Li2 SiP2 , are presented. Both phases represent members of a new family of Li ion conductors that display Li ion conductivity in the range from 1.15(7)×10(-6) Scm(-1) at 0 °C to 1.2(2)×10(-4) Scm(-1) at 75 °C (Li8 SiP4 ) and from 6.1(7)×10(-8) Scm(-1) at 0 °C to 6(1)×10(-6) Scm(-1) at 75 °C (Li2 SiP2 ), as determined by impedance measurements. Temperature-dependent solid-state (7) Li NMR spectroscopy revealed low activation energies of about 36 kJ mol(-1) for Li8 SiP4 and about 47 kJ mol(-1) for Li2 SiP2 . Both compounds were structurally characterized by X-ray diffraction analysis (single crystal and powder methods) and by (7) Li, (29) Si, and (31) P MAS NMR spectroscopy. Both phases consist of tetrahedral SiP4 anions and Li counterions. Li8 SiP4 contains isolated SiP4 units surrounded by Li atoms, while Li2 SiP2 comprises a three-dimensional network based on corner-sharing SiP4 tetrahedra, with the Li ions located in cavities and channels.

  6. Heterologous Protein Secretion in Lactobacilli with Modified pSIP Vectors

    PubMed Central

    Karlskås, Ingrid Lea; Maudal, Kristina; Axelsson, Lars; Rud, Ida; Eijsink, Vincent G. H.; Mathiesen, Geir

    2014-01-01

    We describe new variants of the modular pSIP-vectors for inducible gene expression and protein secretion in lactobacilli. The basic functionality of the pSIP system was tested in Lactobacillus strains representing 14 species using pSIP411, which harbors the broad-host-range Lactococcus lactis SH71rep replicon and a β-glucuronidase encoding reporter gene. In 10 species, the inducible gene expression system was functional. Based on these results, three pSIP vectors with different signal peptides were modified by replacing their narrow-host-range L. plantarum 256rep replicon with SH71rep and transformed into strains of five different species of Lactobacillus. All recombinant strains secreted the target protein NucA, albeit with varying production levels and secretion efficiencies. The Lp_3050 derived signal peptide generally resulted in the highest levels of secreted NucA. These modified pSIP vectors are useful tools for engineering a wide variety of Lactobacillus species. PMID:24614815

  7. SIP metagenomics identifies uncultivated Methylophilaceae as dimethylsulphide degrading bacteria in soil and lake sediment.

    PubMed

    Eyice, Özge; Namura, Motonobu; Chen, Yin; Mead, Andrew; Samavedam, Siva; Schäfer, Hendrik

    2015-11-01

    Dimethylsulphide (DMS) has an important role in the global sulphur cycle and atmospheric chemistry. Microorganisms using DMS as sole carbon, sulphur or energy source, contribute to the cycling of DMS in a wide variety of ecosystems. The diversity of microbial populations degrading DMS in terrestrial environments is poorly understood. Based on cultivation studies, a wide range of bacteria isolated from terrestrial ecosystems were shown to be able to degrade DMS, yet it remains unknown whether any of these have important roles in situ. In this study, we identified bacteria using DMS as a carbon and energy source in terrestrial environments, an agricultural soil and a lake sediment, by DNA stable isotope probing (SIP). Microbial communities involved in DMS degradation were analysed by denaturing gradient gel electrophoresis, high-throughput sequencing of SIP gradient fractions and metagenomic sequencing of phi29-amplified community DNA. Labelling patterns of time course SIP experiments identified members of the Methylophilaceae family, not previously implicated in DMS degradation, as dominant DMS-degrading populations in soil and lake sediment. Thiobacillus spp. were also detected in (13)C-DNA from SIP incubations. Metagenomic sequencing also suggested involvement of Methylophilaceae in DMS degradation and further indicated shifts in the functional profile of the DMS-assimilating communities in line with methylotrophy and oxidation of inorganic sulphur compounds. Overall, these data suggest that unlike in the marine environment where gammaproteobacterial populations were identified by SIP as DMS degraders, betaproteobacterial Methylophilaceae may have a key role in DMS cycling in terrestrial environments.

  8. SIP, a novel ankyrin repeat containing protein, sequesters steroid receptor coactivators in the cytoplasm.

    PubMed

    Zhang, Ying; Zhang, Hua; Liang, Jing; Yu, Wenhua; Shang, Yongfeng

    2007-06-06

    Steroid receptor coactivators (SRCs) exert profound effects on animal development and physiology. These coactivators are nuclear proteins and transcription co-regulators that function to facilitate the transcription initiation mediated by nuclear receptors, as well as by other well-known transcription factors. However, how these co-regulators are functionally regulated is poorly understood. During genome-wide screening for SRC-interacting proteins, we identified a novel ankyrin repeat containing protein, SIP (SRC-Interacting Protein), which interacts with SRC coactivators in the cytoplasm. We demonstrated that extracellular stimuli such as the addition of estrogen, induced phosphorylation of SIP in its PEST (Proline, Glutamate, Serine, and Threonine rich) domain by casein kinase II. The phosphorylation of SIP resulted in dissociation of SRC proteins from SIP in the cytoplasm and led to subsequent nuclear translocation of SRC proteins and gene coactivation. Both gain-of-function and loss-of-function experiments indicate that SIP functions to sequester SRC coactivators in the cytoplasm and buffer the availability of these coactivators, thus providing a mechanism for the regulation of the transcription regulators.

  9. Spatial variation in senescence rates in a bird metapopulation.

    PubMed

    Holand, H; Kvalnes, T; Gamelon, M; Tufto, J; Jensen, H; Pärn, H; Ringsby, T H; Sæther, B-E

    2016-07-01

    Investigating factors which affect the decline in survival with age, i.e. actuarial senescence, is important in order to understand how demographic rates vary in wild populations. Although the evidence for the occurrence of actuarial senescence in wild populations is growing, very few studies have compared actuarial senescence rates between wild populations of the same species. We used data from a long-time study of demography of house sparrows (Passer domesticus) to investigate differences in rates of actuarial senescence between habitats and sub-populations. We also investigated whether rates of actuarial senescence differed between males and females. We found that rates of actuarial senescence showed large spatial variation. We also found that the onset of actuarial senescence varied between sub-populations. However, these differences were not significantly explained by a general difference in habitat type. We also found no significant difference in actuarial senescence rates between males and females. This study shows that senescence rates in natural populations may vary significantly between sub-populations and that failing to account for such differences may give a biased estimate of senescence rates of a species.

  10. NKG2D ligands mediate immunosurveillance of senescent cells

    PubMed Central

    Moshayev, Zhana; Vadai, Ezra; Wensveen, Felix; Ben-Dor, Shifra; Golani, Ofra; Polic, Bojan; Krizhanovsky, Valery

    2016-01-01

    Cellular senescence is a stress response mechanism that limits tumorigenesis and tissue damage. Induction of cellular senescence commonly coincides with an immunogenic phenotype that promotes self-elimination by components of the immune system, thereby facilitating tumor suppression and limiting excess fibrosis during wound repair. The mechanisms by which senescent cells regulate their immune surveillance are not completely understood. Here we show that ligands of an activating Natural Killer (NK) cell receptor (NKG2D), MICA and ULBP2 are consistently up-regulated following induction of replicative senescence, oncogene-induced senescence and DNA damage - induced senescence. MICA and ULBP2 proteins are necessary for efficient NK-mediated cytotoxicity towards senescent fibroblasts. The mechanisms regulating the initial expression of NKG2D ligands in senescent cells are dependent on a DNA damage response, whilst continuous expression of these ligands is regulated by the ERK signaling pathway. In liver fibrosis, the accumulation of senescent activated stellate cells is increased in mice lacking NKG2D receptor leading to increased fibrosis. Overall, our results provide new insights into the mechanisms regulating the expression of immune ligands in senescent cells and reveal the importance of NKG2D receptor-ligand interaction in protecting against liver fibrosis. PMID:26878797

  11. PKCη promotes senescence induced by oxidative stress and chemotherapy

    PubMed Central

    Zurgil, U; Ben-Ari, A; Atias, K; Isakov, N; Apte, R; Livneh, E

    2014-01-01

    Senescence is characterized by permanent cell-cycle arrest despite continued viability and metabolic activity, in conjunction with the secretion of a complex mixture of extracellular proteins and soluble factors known as the senescence-associated secretory phenotype (SASP). Cellular senescence has been shown to prevent the proliferation of potentially tumorigenic cells, and is thus generally considered a tumor suppressive process. However, some SASP components may act as pro-tumorigenic mediators on premalignant cells in the microenvironment. A limited number of studies indicated that protein kinase C (PKC) has a role in senescence, with different isoforms having opposing effects. It is therefore important to elucidate the functional role of specific PKCs in senescence. Here we show that PKCη, an epithelial specific and anti-apoptotic kinase, promotes senescence induced by oxidative stress and DNA damage. We further demonstrate that PKCη promotes senescence through its ability to upregulate the expression of the cell cycle inhibitors p21Cip1 and p27Kip1 and enhance transcription and secretion of interleukin-6 (IL-6). Moreover, we demonstrate that PKCη creates a positive loop for reinforcing senescence by increasing the transcription of both IL-6 and IL-6 receptor, whereas the expression of IL-8 is specifically suppressed by PKCη. Thus, the presence/absence of PKCη modulates major components of SASP. Furthermore, we show that the human polymorphic variant of PKCη, 374I, that exhibits higher kinase activity in comparison to WT-374V, is also more effective in IL-6 secretion, p21Cip1 expression and the promotion of senescence, further supporting a role for PKCη in senescence. As there is now considerable interest in senescence activation/elimination to control tumor progression, it is first crucial to reveal the molecular regulators of senescence. This will improve our ability to develop new strategies to harness senescence as a potential cancer therapy in the

  12. Premature ovarian insufficiency - fertility challenge.

    PubMed

    Check, J H

    2014-04-01

    Premature ovarian insufficiency, defined as amenorrhea with estrogen deficiency in a woman younger than 40 associated with a serum follicle stimulating hormone (FSH) >35 mIU/mL, can be temporarily reversed with ovulation achieved resulting in live delivered pregnancies. Though this may occur spontaneously the frequency of ovulation can be considerably increased by various techniques of lowering the elevated serum FSH level and thus up-regulate down-regulated FSH receptors in the granulosa-theca cells. This can be accomplished by either suppressing FSH release from the pituitary by negative feedback through high dose estrogen or by suppressing FSH production by inhibiting the gonadotropin releasing hormone (GnRH) by either using GnRH agonists or antagonists. The estrogen method is the technique of choice because it is much less expensive than GnRH analogues, and helps stimulate cervical mucus and endometrial development. Ethinyl estradiol is the preferred estrogen because it does not contribute to the measurement of serum estradiol and thus allows proper monitoring of follicular maturation. Sometimes exogenous gonadotropins are needed as a boost but the dosage should be low so as not to down-regulate FSH receptors again. The technique is referred to as the FSH receptor restoration technique. Progesterone should be supplemented in the luteal phase. Physicians should be cognizant of trying to help prevent premature ovarian insufficiency by judiciously choosing less gonadotoxic cancer treatment alternatives that are equally efficacious. Also surgery for ovarian endometriomas should be performed only when absolutely necessary.

  13. Characterization of senescence-associated protease activities involved in the efficient protein remobilization during leaf senescence of winter oilseed rape.

    PubMed

    Poret, Marine; Chandrasekar, Balakumaran; van der Hoorn, Renier A L; Avice, Jean-Christophe

    2016-05-01

    Oilseed rape (Brassica napus L.) is a crop plant characterized by a poor nitrogen (N) use efficiency that is mainly due to low N remobilization efficiency during the sequential leaf senescence of the vegetative stage. As a high leaf N remobilization efficiency was strongly linked to a high remobilization of proteins during leaf senescence of rapeseed, our objective was to identify senescence-associated protease activities implicated in the protein degradation. To reach this goal, leaf senescence processes and protease activities were investigated in a mature leaf becoming senescent in plants subjected to ample or low nitrate supply. The characterization of protease activities was performed by using in vitro analysis of RuBisCO degradation with or without inhibitors of specific protease classes followed by a protease activity profiling using activity-dependent probes. As expected, the mature leaf became senescent regardless of the nitrate treatment, and nitrate limitation enhanced the senescence processes associated with an enhanced degradation of soluble proteins. The characterization of protease activities revealed that: (i) aspartic proteases and the proteasome were active during senescence regardless of nitrate supply, and (ii) the activities of serine proteases and particularly cysteine proteases (Papain-like Cys proteases and vacuolar processing enzymes) increased when protein remobilization associated with senescence was accelerated by nitrate limitation. Short statement: Serine and particularly cysteine proteases (both PLCPs and VPEs) seem to play a crucial role in the efficient protein remobilization when leaf senescence of oilseed rape was accelerated by nitrate limitation.

  14. Control of the senescence-associated secretory phenotype by NF-κB promotes senescence and enhances chemosensitivity.

    PubMed

    Chien, Yuchen; Scuoppo, Claudio; Wang, Xiaowo; Fang, Xueping; Balgley, Brian; Bolden, Jessica E; Premsrirut, Prem; Luo, Weijun; Chicas, Agustin; Lee, Cheng S; Kogan, Scott C; Lowe, Scott W

    2011-10-15

    Cellular senescence acts as a potent barrier to tumorigenesis and contributes to the anti-tumor activity of certain chemotherapeutic agents. Senescent cells undergo a stable cell cycle arrest controlled by RB and p53 and, in addition, display a senescence-associated secretory phenotype (SASP) involving the production of factors that reinforce the senescence arrest, alter the microenvironment, and trigger immune surveillance of the senescent cells. Through a proteomics analysis of senescent chromatin, we identified the nuclear factor-κB (NF-κB) subunit p65 as a major transcription factor that accumulates on chromatin of senescent cells. We found that NF-κB acts as a master regulator of the SASP, influencing the expression of more genes than RB and p53 combined. In cultured fibroblasts, NF-κB suppression causes escape from immune recognition by natural killer (NK) cells and cooperates with p53 inactivation to bypass senescence. In a mouse lymphoma model, NF-κB inhibition bypasses treatment-induced senescence, producing drug resistance, early relapse, and reduced survival. Our results demonstrate that NF-κB controls both cell-autonomous and non-cell-autonomous aspects of the senescence program and identify a tumor-suppressive function of NF-κB that contributes to the outcome of cancer therapy.

  15. Control of the senescence-associated secretory phenotype by NF-κB promotes senescence and enhances chemosensitivity

    PubMed Central

    Chien, Yuchen; Scuoppo, Claudio; Wang, Xiaowo; Fang, Xueping; Balgley, Brian; Bolden, Jessica E.; Premsrirut, Prem; Luo, Weijun; Chicas, Agustin; Lee, Cheng S.; Kogan, Scott C.; Lowe, Scott W.

    2011-01-01

    Cellular senescence acts as a potent barrier to tumorigenesis and contributes to the anti-tumor activity of certain chemotherapeutic agents. Senescent cells undergo a stable cell cycle arrest controlled by RB and p53 and, in addition, display a senescence-associated secretory phenotype (SASP) involving the production of factors that reinforce the senescence arrest, alter the microenvironment, and trigger immune surveillance of the senescent cells. Through a proteomics analysis of senescent chromatin, we identified the nuclear factor-κB (NF-κB) subunit p65 as a major transcription factor that accumulates on chromatin of senescent cells. We found that NF-κB acts as a master regulator of the SASP, influencing the expression of more genes than RB and p53 combined. In cultured fibroblasts, NF-κB suppression causes escape from immune recognition by natural killer (NK) cells and cooperates with p53 inactivation to bypass senescence. In a mouse lymphoma model, NF-κB inhibition bypasses treatment-induced senescence, producing drug resistance, early relapse, and reduced survival. Our results demonstrate that NF-κB controls both cell-autonomous and non-cell-autonomous aspects of the senescence program and identify a tumor-suppressive function of NF-κB that contributes to the outcome of cancer therapy. PMID:21979375

  16. Functional aging and gradual senescence in zebrafish.

    PubMed

    Kishi, Shuji

    2004-06-01

    Zebrafish (Danio rerio) has been recognized as a powerful model for genetic studies in developmental biology. Recently, the zebrafish system also has given insights into several human diseases such as neurodegenerative, hematopoietic, and cardiovascular disease, and cancer. Because aging processes affect these and various other human disorders, it is important to compare zebrafish and mammalian senescence. However, the aging process of zebrafish remains largely unexplored, and little is known about functional aging and senescence in zebrafish. In our initial studies to assess aging phenotypes in zebrafish, we have identified several potential aging biomarkers in an ongoing search for suitable ones on zebrafish aging. In aging zebrafish, we detected senescence-associated beta-galactosidase activity in skin and oxidized protein accumulation in muscle. On the other hand, we did not observe lipofuscin granules (aging pigments), which accumulate in postmitotic cells, in muscle of zebrafish with advancing age. Consistently, there were continuously proliferating myocytes that incorporated BrdU in muscle tissues of the aged fish. Moreover, we demonstrated that zebrafish have constitutively abundant telomerase activity in adult somatic tissues implicating unlimited replicative ability of cells throughout their lives. Although some stress-associated markers are upregulated and minor histological changes are observed during the aging process of zebrafish, our studies together with other evidence of remarkable reproductive and regenerative abilities suggest that zebrafish show very gradual senescence. By using those biological and biochemical aging markers already characterized in normal zebrafish, transgenic fish analyses and genetic mutant fish screens can be readily performed. These efforts will help to elucidate the role and molecular mechanisms of common or different pathways of aging among vertebrates from fish to humans and also will contribute to the discovery of

  17. Management of multicellular senescence and oxidative stress

    PubMed Central

    Haines, David D; Juhasz, Bela; Tosaki, Arpad

    2013-01-01

    Progressively sophisticated understanding of cellular and molecular processes that contribute to age-related physical deterioration is being gained from ongoing research into cancer, chronic inflammatory syndromes and other serious disorders that increase with age. Particularly valuable insight has resulted from characterization of how senescent cells affect the tissues in which they form in ways that decrease an organism's overall viability. Increasingly, the underlying pathophysiology of ageing is recognized as a consequence of oxidative damage. This leads to hyperactivity of cell growth pathways, prominently including mTOR (mammalian target of rapamycin), that contribute to a build-up in cells of toxic aggregates such as progerin (a mutant nuclear cytoskeletal protein), lipofuscin and other cellular debris, triggering formation of senescent cellular phenotypes, which interact destructively with surrounding tissue. Indeed, senescent cell ablation dramatically inhibits physical deterioration in progeroid (age-accelerated) mice. This review explores ways in which oxidative stress creates ageing-associated cellular damage and triggers induction of the cell death/survival programs’ apoptosis, necrosis, autophagy and ‘necroapoptophagy’. The concept of ‘necroapoptophagy’ is presented here as a strategy for varying tissue oxidative stress intensity in ways that induce differential activation of death versus survival programs, resulting in enhanced and sustained representation of healthy functional cells. These strategies are discussed in the context of specialized mesenchymal stromal cells with the potential to synergize with telocytes in stabilizing engrafted progenitor cells, thereby extending periods of healthy life. Information and concepts are summarized in a hypothetical approach to suppressing whole-organism senescence, with methods drawn from emerging understandings of ageing, gained from Cnidarians (jellyfish, corals and anemones) that undergo a

  18. [Physiological and pathophysiological meanings of gastrointestinal smooth muscle motor unit SIP syncytium].

    PubMed

    Song, Ni-Na; Xu, Wen-Xie

    2016-10-25

    Gastrointestinal smooth muscle layer contains two kinds of interstitial cells with special differentiation, i.e., interstitial cells of Cajal (ICC) and platelet-derived growth factor receptor α-positive (PDGFRα(+)) cells. The ICC and PDGFRα(+) cells contact with smooth muscle cells (SMCs) by gap junctions and regulate contractive function of the SMCs. Therefore, these three kinds of cells constitute a functional syncytium, i.e., the SMC, ICC and PDGFRα(+) cells syncytium (SIP syncytium). Various neurotransmitters, humoral factors, endogenous bioactive molecules, as well as drugs regulate gastrointestinal motility through the SIP syncytium. In this review, we introduce the concept of SIP syncytium and summarize functions of the syncytium, as well as its physiological and pathological significances.

  19. Siah1/SIP regulates p27(kip1) stability and cell migration under metabolic stress.

    PubMed

    Nagano, Yoshito; Fukushima, Toru; Okemoto, Kazuo; Tanaka, Keiichiro; Bowtell, David D L; Ronai, Ze'ev; Reed, John C; Matsuzawa, Shu-ichi

    2011-08-01

    p27(kip1) has been implicated in cell cycle regulation, functioning as an inhibitor of cyclin-dependent kinase activity. In addition, p27 was also shown to affect cell migration, with accumulation of cytoplasmic p27 associated with tumor invasiveness. However, the mechanism underlying p27 regulation as a cytoplasmic protein is poorly understood. Here we show that glucose starvation induces proteasome-dependent degradation of cytoplasmic p27, accompanied by a decrease in cell motility. We also show that the glucose limitation-induced p27 degradation is regulated through an ubiquitin E3 ligase complex involving Siah1 and SIP/CacyBP. SIP (-/-) embryonic fibroblasts have increased levels of cytosolic p27 and exhibit increased cell motility compared to wild-type cells. These observations suggest that the Siah1/SIP E3 ligase complex regulates cell motility through degradation of p27.

  20. Cell culture and senescence in uterine fibroids.

    PubMed

    Markowski, Dominique Nadine; Bartnitzke, Sabine; Belge, Gazanfer; Drieschner, Norbert; Helmke, Burkhard Maria; Bullerdiek, Jörn

    2010-10-01

    The in vitro growth of cells from uterine fibroids is characterized by an early onset of senescence. Often, an even lower growth potential than that of matching myometrial cells is noted. Also, the tremendous differences in the expression of the high mobility group protein HMGA2 seen when comparing fibroids of different genetic subtypes are surprisingly not reflected by significant differences in their growth potential in vitro. We aimed to evaluate possible changes of the HMGA2 expression level between the native tissue and cell cultures, so we performed quantitative real-time polymerase chain reaction studies that revealed a marked decrease of the HMGA2 mRNA in culture in those cases with overexpression of HMGA2. In the two cases initially showing the highest expression, it decreased by approximately 97%. Associated with the decrease of HMGA2 was a clearly increased expression of the senescence-associated p19(Arf). Together, these findings explain the similar behavior of cell cultures from fibroids of different genetic subgroups and may also offer an explanation for the early onset of in vitro senescence in these cell cultures.

  1. Tristetraprolin: Roles in Cancer and Senescence

    PubMed Central

    Ross, Christina R.; Brennan-Laun, Sarah E.; Wilson, Gerald M.

    2012-01-01

    Cancer and senescence are both complex transformative processes that dramatically alter many features of cell physiology and their interactions with surrounding tissues. Developing the wide range of cellular features characteristic of these conditions requires profound alterations in global gene expression patterns, which can be achieved by suppressing, activating, or uncoupling cellular gene regulatory pathways. Many genes associated with the initiation and development of tumors are regulated at the level of mRNA decay, frequently through the activity of AU-rich mRNA-destabilizing elements (AREs) located in their 3′-untranslated regions. As such, cellular factors that recognize and control the decay of ARE-containing mRNAs can influence tumorigenic or senescent phenotypes mediated by products of these transcripts. In this review, we discuss evidence showing how suppressed expression and/or activity of the ARE-binding protein tristetraprolin (TTP) can contribute to these processes. Next, we outline current findings linking TTP suppression to exacerbation of individual tumorigenic phenotypes, and the roles of specific TTP substrate mRNAs in mediating these effects. Finally, we survey potential mechanisms that cells may employ to suppress TTP expression in cancer, and propose potential diagnostic and therapeutic strategies that may exploit the relationship between TTP expression and tumor progression or senescence. PMID:22387927

  2. Rupatadine Protects against Pulmonary Fibrosis by Attenuating PAF-Mediated Senescence in Rodents

    PubMed Central

    Lv, Xiao-xi; Wang, Xiao-xing; Li, Ke; Wang, Zi-yan; Li, Zhe; Lv, Qi; Fu, Xiao-ming; Hu, Zhuo-Wei

    2013-01-01

    A similar immune response is implicated in the pathogenesis of pulmonary fibrosis and allergic disorders. We investigated the potential therapeutic efficacy and mechanism of rupatadine, a dual antagonist of histamine and platelet-activation factor (PAF), in bleomycin- (BLM-) and silica-induced pulmonary fibrosis. The indicated dosages of rupatadine were administered in rodents with bleomycin or silica-induced pulmonary fibrosis. The tissue injury, fibrosis, inflammatory cells and cytokines, and lung function were examined to evaluate the therapeutic efficacy of rupatadine. The anti-fibrosis effect of rupatadine was compared with an H1 or PAF receptor antagonist, and efforts were made to reveal rupatadine’s anti-fibrotic mechanism. Rupatadine promoted the resolution of pulmonary inflammation and fibrosis in a dose-dependent manner, as indicated by the reductions in inflammation score, collagen deposition and epithelial-mesenchymal transformation, and infiltration or expression of inflammatory cells or cytokines in the fibrotic lung tissue. Thus, rupatadine treatment improved the declined lung function and significantly decreased animal death. Moreover, rupatadine was able not only to attenuate silica-induced silicosis but also to produce a superior therapeutic efficacy compared to pirfenidone, histamine H1 antagonist loratadine, or PAF antagonist CV-3988. The anti-fibrotic action of rupatadine might relate to its attenuation of BLM- or PAF-induced premature senescence because rupatadine treatment protected against the in vivo and in vitro activation of the p53/p21-dependent senescence pathway. Our studies indicate that rupatadine promotes the resolution of pulmonary inflammation and fibrosis by attenuating the PAF-mediated senescence response. Rupatadine holds promise as a novel drug to treat the devastating disease of pulmonary fibrosis. PMID:23869224

  3. Carbamylated low-density lipoprotein induces oxidative stress and accelerated senescence in human endothelial progenitor cells.

    PubMed

    Carracedo, Julia; Merino, Ana; Briceño, Carolina; Soriano, Sagrario; Buendía, Paula; Calleros, Laura; Rodriguez, Mariano; Martín-Malo, Alejandro; Aljama, Pedro; Ramírez, Rafael

    2011-04-01

    Carbamylated low-density lipoprotein (cLDL) plays a role in atherosclerosis. In this study we evaluate the effect of uremia on LDL carbamylation and the effect of cLDL and oxidized LDL (oxLDL; 200 μg/ml) on number, function, and genomic stability of endothelial progenitor cells (EPCs) obtained from healthy volunteers. cLDL was generated after incubation of native LDL (nLDL) with uremic serum from patients with chronic kidney disease (CKD) stages 2-4. Oxidative stress was measured by flow cytometry and fluorescent microscopy, mitochondrial depolarization by flow cytometry, senescence by β-galactosidase activity and telomere length, and DNA damage by phosphorylated histone H2AX (γH2AX). The percentage of cLDL by uremic serum was related to the severity of CKD. Compared with nLDL, cLDL induced an increase in oxidative stress (62±5 vs. 8±3%, P<0.001) and cells with mitochondrial depolarization (73±7 vs. 9±5%, P<0.001), and a decrease in EPC proliferation and angiogenesis. cLDL also induced accelerated senescence (73±16 vs. 12±9%, P<0.001), which was associated with a decrease in the expression of γH2AX (62±9 vs. 5±3%, P<0.001). The degree of injury induced by cLDL was comparable to that observed with oxLDL. This study supports the hypothesis that cLDL triggers genomic damage in EPCs, resulting in premature senescence. We can, therefore, hypothesize that EPCs injury by cLDL contributes to an increase in atherosclerotic disease in CKD.

  4. Context-dependent effects of cellular senescence in cancer development

    PubMed Central

    Lecot, Pacome; Alimirah, Fatouma; Desprez, Pierre-Yves; Campisi, Judith; Wiley, Christopher

    2016-01-01

    Cellular senescence is an established tumour-suppressive mechanism that prevents the proliferation of premalignant cells. However, several lines of evidence show that senescent cells, which often persist in vivo, can also promote tumour progression in addition to other age-related pathologies via the senescence-associated secretory phenotype (SASP). Moreover, new insights suggest the SASP can facilitate tissue repair. Here, we review the beneficial and detrimental roles of senescent cells, highlighting conditions under which the senescence response does and does not promote pathology, particularly cancer. By better understanding the context-dependent effects of cellular senescence, it may be feasible to limit its detrimental properties while preserving its beneficial effects, and develop novel therapeutic strategies to prevent or treat cancer and possibly other age-associated diseases. PMID:27140310

  5. Ultraconserved region-containing Transformer 2β4 controls senescence of colon cancer cells.

    PubMed

    Kajita, K; Kuwano, Y; Satake, Y; Kano, S; Kurokawa, K; Akaike, Y; Masuda, K; Nishida, K; Rokutan, K

    2016-04-04

    Ultraconserved regions (UCRs) are >200 bp genomic segments with perfect human-to-rodent sequence identity. Transcribed UCRs constitute a new category of noncoding RNAs whose functions remain poorly understood. The human transformer 2β (TRA2B) gene contains a 419-bp UCR spanning the 276-bp exon 2 and its neighboring introns. TRA2B exon 2 has premature stop codons, whereas an exon 2-containing splice variant (TRA2β4) was expressed preferentially in the nuclei of human colon cancer cells. TRA2β4 knockdown p53-independently stimulated CDKN1A transcription and increased p21, resulting in the appearance of senescent cells. Biotin pull-down and RNA immunoprecipitation assays revealed that TRA2β4 interacted with Sp1 through a Sp1-binding sequence (485-GGGG-488) in a stem-loop structure of exon 2. Mutation of this sequence (485-AAGG-488) disrupted the stem-loop structure, blocked the interaction with Sp1 and increased CDKN1A transcription. Overexpression of TRA2β4 significantly decreased CDKN1A mRNA levels and accelerated cell growth, but the introduction of the mutation in the Sp1-binding sequence completely canceled these effects. Taken together, TRA2β4 may sequester Sp1 from occupying promoters of target genes including CDKN1A, promoting cell growth by interrupting the senescence-related gene expression program. This novel function of TRA2β4 may uncover an oncogenic function of transcribed UCRs.

  6. Immunosurveillance of senescent cancer cells by natural killer cells

    PubMed Central

    Iannello, Alexandre; Raulet, David H

    2014-01-01

    We recently dissected how senescent tumors can trigger complementing signaling pathways that mobilize natural killer (NK) cells to eliminate malignant cells. In addition to cell-intrinsic effects on proliferation, senescence induces the production of chemokine (C-C motif) ligand 2 (CCL2), which recruits NK cells to mediate direct tumoricidal effects. Hence, senescence activates a cancer cell-extrinsic oncosuppression program. PMID:24800169

  7. A sip-and-puff wireless remote control for the Apple iPod.

    PubMed

    Jones, Michael; Grogg, Kevin; Anschutz, John; Fierman, Ruth

    2008-01-01

    This brief technical note describes the authors' efforts to modify an existing wireless remote control for the Apple iPod so it could be operated using sip-and-puff switches by individuals with limited upper extremity dexterity due to cervical level spinal cord injury. The authors were able to successfully interface the wireless controller with sip-and-puff switches so that users could play, pause, and fast forward through a song list on the iPod. Details of the interface are described, and limitations of the current system are discussed.

  8. [Pathogenesis of retinopathy of prematurity].

    PubMed

    Stahl, A; Lagrèze, W A; Agostini, H T

    2012-12-01

    Retinopathy of prematurity (ROP) is a complex disease with a multifactorial pathogenetic cascade that is still only partially understood. Important pathogenetic factors are gestational age at birth and birth weight. Potent postnatal factors are exposure to supplemental oxygen, slow weight gain and expression of angiogenic growth factors. Some of these crucial aspects of ROP pathogenesis will be discussed in this article and put into clinical context. With the introduction of intravitreal anti-VEGF (vascular endothelial growth factor) treatment into ROP therapy, the pathomechanistic role of VEGF in ROP deserves a special focus. Apart from VEGF, other factors will be discussed that may precede VEGF upregulation and thus may represent targets for an earlier and potentially protective intervention. Among these insulin-like growth factor 1 (IGF-1) appears to be most prominent. Finally, factors such as postnatal weight gain will be discussed in light of their potential role as screening parameters and their ability to predict ROP severity.

  9. [Premature ovarian failure: which protocols?].

    PubMed

    Merviel, P; Lourdel, E; Boulard, V; Cabry, R; Claeys, C; Oliéric, M-F; Sanguinet, P; Brasseur, F; Henri, I; Copin, H

    2008-09-01

    This review shows the results of the various studies concerning the protocols applied to the women presenting a premature ovarian failure. Will be thus analyzed the natural cycles (or semi-natural), the increase in the dose of gonadotrophins, the clomiphene citrate and the anti-aromatases, the protocols with GnRH agonists long, short, stop or microdoses, the protocols with GnRH antagonists and the adjuvant treatments: aspirin, nitric oxyde, recombinant LH recombining, growth hormone and androgens. The interest of several protocols is to collect a sufficient number of oocytes (and thus of embryos to be transferred), making it possible to obtain reasonable rates of pregnancy. However, it arises that the rates of pregnancy observed among these women depend not only on their ovarian reserve and their age, but are also function of the type of infertility, of the cycle number and the uterus.

  10. E-cigarettes and flavorings induce inflammatory and pro-senescence responses in oral epithelial cells and periodontal fibroblasts.

    PubMed

    Sundar, Isaac K; Javed, Fawad; Romanos, Georgios E; Rahman, Irfan

    2016-11-22

    Electronic-cigarettes (e-cigs) represent a significant and increasing proportion of tobacco product consumption, which may pose an oral health concern. Oxidative/carbonyl stress via protein carbonylation is an important factor in causing inflammation and DNA damage. This results in stress-induced premature senescence (a state of irreversible growth arrest which re-enforces chronic inflammation) in gingival epithelium, which may contribute to the pathogenesis of oral diseases. We show that e-cigs with flavorings cause increased oxidative/carbonyl stress and inflammatory cytokine release in human periodontal ligament fibroblasts, Human Gingival Epithelium Progenitors pooled (HGEPp), and epigingival 3D epithelium. We further show increased levels of prostaglandin-E2 and cycloxygenase-2 are associated with upregulation of the receptor for advanced glycation end products (RAGE) by e-cig exposure-mediated carbonyl stress in gingival epithelium/tissue. Further, e-cigs cause increased oxidative/carbonyl and inflammatory responses, and DNA damage along with histone deacetylase 2 (HDAC2) reduction via RAGE-dependent mechanisms in gingival epithelium. A greater response is elicited by flavored e-cigs. Increased oxidative stress, pro-inflammatory and pro-senescence responses (DNA damage and HDAC2 reduction) can result in dysregulated repair due to proinflammatory and pro-senescence responses in periodontal cells. These data highlight the pathologic role of e-cig aerosol and its flavoring to cells and tissues of the oral cavity in compromised oral health.

  11. Rb-dependent cellular senescence, multinucleation and susceptibility to oncogenic transformation through PKC scaffolding by SSeCKS/AKAP12

    PubMed Central

    Akakura, Shin; Nochajski, Peter; Gao, Lingqiu; Sotomayor, Paul; Matsui, Sei-ichi

    2010-01-01

    A subset of AKAPs (A Kinase Anchoring Proteins) regulate signaling and cytoskeletal pathways through the spaciotemporal scaffolding of multiple protein kinases (PK), such as PKC and PKA, and associations with the plasma membrane and the actin-based cytoskeleton. SSeCKS/Gravin/Akap12 expression is severely downregulated in many advanced cancers and exhibits tumor- and metastasis-suppressing activity. akap12-null (KO) mice develop prostatic hyperplasia with focal dysplasia, but the precise mechanism how Akap12 prevents oncogenic progression remains unclear. Here, we show that KO mouse embryonic fibroblasts (MEF) exhibit premature senescence marked by polyploidy and multinucleation, and by increased susceptibility to oncogenic transformation. Although p53 and Rb pathways are activated in the absence of Akap12, senescence is dependent on Rb. Senescence is driven by the activation of PKCα, which induces p16Ink4a/Rb through a MEK-dependent downregulation of Id1, and PKCδ, which downregulates Lats1/Warts, a mitotic exit network kinase required for cytokinesis. Our data strongly suggest that Akap12 controls Rb-mediated cell aging and oncogenic progression by directly scaffolding and attenuating PKCα/δ. PMID:21099353

  12. Nutritional enhancement of leaves by a psyllid through senescence-like processes: insect manipulation or plant defence?

    PubMed

    Steinbauer, M J; Burns, A E; Hall, A; Riegler, M; Taylor, G S

    2014-12-01

    Some herbivores can modify the physiology of plant modules to meet their nutritional requirements. Induction of premature leaf senescence could benefit herbivores since it is associated with the mobilisation of nutrients. We compared the effects of nymphal feeding by Cardiaspina near densitexta on Eucalyptus moluccana with endogenous processes associated with senescence to assess the relative merits of an insect manipulation or plant defence interpretation of responses. Evidence supporting insect manipulation included increased size of fourth and fifth instar nymphs (in the latter the effect was restricted to forewing pad length of females) on leaves supporting high numbers of conspecifics and feeding preventing leaf necrosis. Intra-specific competition negated greater performance at very high densities. High and very high abundances of nymphs were associated with increased concentrations of amino acid N but only very high abundances of nymphs tended to be associated with increased concentrations of six essential amino acids. Contrary to the insect manipulation interpretation, feeding by very high abundances of nymphs was associated with significant reductions in chlorophyll, carotenoids and anthocyanins. Evidence supporting plant defence included the severity of chlorosis increasing with the abundance of nymphs. Leaf reddening did not develop because ambient conditions associated with photoinhibition (high irradiance and low temperature) were not experienced by leaves with chlorotic lesions. Leaf reddening (from anthocyanins) alone is not expected to adversely affect nymphal survival; only leaf necrosis would kill nymphs. For senescence-inducing psyllids, nutritional enhancement does not fit neatly into either an insect manipulation or plant defence interpretation.

  13. E-cigarettes and flavorings induce inflammatory and pro-senescence responses in oral epithelial cells and periodontal fibroblasts

    PubMed Central

    Sundar, Isaac K.; Javed, Fawad; Romanos, Georgios E.; Rahman, Irfan

    2016-01-01

    Electronic-cigarettes (e-cigs) represent a significant and increasing proportion of tobacco product consumption, which may pose an oral health concern. Oxidative/carbonyl stress via protein carbonylation is an important factor in causing inflammation and DNA damage. This results in stress-induced premature senescence (a state of irreversible growth arrest which re-enforces chronic inflammation) in gingival epithelium, which may contribute to the pathogenesis of oral diseases. We show that e-cigs with flavorings cause increased oxidative/carbonyl stress and inflammatory cytokine release in human periodontal ligament fibroblasts, Human Gingival Epithelium Progenitors pooled (HGEPp), and epigingival 3D epithelium. We further show increased levels of prostaglandin-E2 and cycloxygenase-2 are associated with upregulation of the receptor for advanced glycation end products (RAGE) by e-cig exposure-mediated carbonyl stress in gingival epithelium/tissue. Further, e-cigs cause increased oxidative/carbonyl and inflammatory responses, and DNA damage along with histone deacetylase 2 (HDAC2) reduction via RAGE-dependent mechanisms in gingival epithelium. A greater response is elicited by flavored e-cigs. Increased oxidative stress, pro-inflammatory and pro-senescence responses (DNA damage and HDAC2 reduction) can result in dysregulated repair due to proinflammatory and pro-senescence responses in periodontal cells. These data highlight the pathologic role of e-cig aerosol and its flavoring to cells and tissues of the oral cavity in compromised oral health. PMID:27791204

  14. Tetraploidization or autophagy: The ultimate fate of senescent human endometrial stem cells under ATM or p53 inhibition.

    PubMed

    Borodkina, Aleksandra V; Shatrova, Alla N; Deryabin, Pavel I; Grukova, Anastasiya A; Nikolsky, Nikolay N; Burova, Elena B

    2016-01-01

    Previously we demonstrated that endometrium-derived human mesenchymal stem cells (hMESCs) via activation of the ATM/p53/p21/Rb pathway enter the premature senescence in response to oxidative stress. Down regulation effects of the key components of this signaling pathway, particularly ATM and p53, on a fate of stressed hMESCs have not yet been investigated. In the present study by using the specific inhibitors Ku55933 and Pifithrin-α, we confirmed implication of both ATM and p53 in H(2)O(2)-induced senescence of hMESCs. ATM or p53 down regulation was shown to modulate differently the cellular fate of H(2)O(2)-treated hMESCs. ATM inhibition allowed H(2)O(2)-stimulated hMESCs to escape the permanent cell cycle arrest due to loss of the functional ATM/p53/p21/Rb pathway, and induced bypass of mitosis and re-entry into S phase, resulting in tetraploid cells. On the contrary, suppression of the p53 transcriptional activity caused a pronounced cell death of H(2)O(2)-treated hMESCs via autophagy induction. The obtained data clearly demonstrate that down regulation of ATM or p53 shifts senescence of human endometrial stem cells toward tetraploidization or autophagy.

  15. 7 CFR 29.2290 - Premature primings.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 2 2010-01-01 2010-01-01 false Premature primings. 29.2290 Section 29.2290 Agriculture Regulations of the Department of Agriculture AGRICULTURAL MARKETING SERVICE (Standards... 21) § 29.2290 Premature primings. Ground leaves harvested before reaching complete growth...

  16. Stable cellular senescence is associated with persistent DDR activation.

    PubMed

    Fumagalli, Marzia; Rossiello, Francesca; Mondello, Chiara; d'Adda di Fagagna, Fabrizio

    2014-01-01

    The DNA damage response (DDR) is activated upon DNA damage generation to promote DNA repair and inhibit cell cycle progression in the presence of a lesion. Cellular senescence is a permanent cell cycle arrest characterized by persistent DDR activation. However, some reports suggest that DDR activation is a feature only of early cellular senescence that is then lost with time. This challenges the hypothesis that cellular senescence is caused by persistent DDR activation. To address this issue, we studied DDR activation dynamics in senescent cells. Here we show that normal human fibroblasts retain DDR markers months after replicative senescence establishment. Consistently, human fibroblasts from healthy aged donors display markers of DDR activation even three years in culture after entry into replicative cellular senescence. However, by extending our analyses to different human cell strains, we also observed an apparent DDR loss with time following entry into cellular senescence. This though correlates with the inability of these cell strains to survive in culture upon replicative or irradiation-induced cellular senescence. We propose a model to reconcile these results. Cell strains not suffering the prolonged in vitro culture stress retain robust DDR activation that persists for years, indicating that under physiological conditions persistent DDR is causally involved in senescence establishment and maintenance. However, cell strains unable to maintain cell viability in vitro, due to their inability to cope with prolonged cell culture-associated stress, show an only-apparent reduction in DDR foci which is in fact due to selective loss of the most damaged cells.

  17. Simvastatin suppresses breast cancer cell proliferation induced by senescent cells

    PubMed Central

    Liu, Su; Uppal, Harpreet; Demaria, Marco; Desprez, Pierre-Yves; Campisi, Judith; Kapahi, Pankaj

    2015-01-01

    Cellular senescence suppresses cancer by preventing the proliferation of damaged cells, but senescent cells can also promote cancer though the pro-inflammatory senescence-associated secretory phenotype (SASP). Simvastatin, an HMG-coA reductase inhibitor, is known to attenuate inflammation and prevent certain cancers. Here, we show that simvastatin decreases the SASP of senescent human fibroblasts by inhibiting protein prenylation, without affecting the senescent growth arrest. The Rho family GTPases Rac1 and Cdc42 were activated in senescent cells, and simvastatin reduced both activities. Further, geranylgeranyl transferase, Rac1 or Cdc42 depletion reduced IL-6 secretion by senescent cells. We also show that simvastatin mitigates the effects of senescent conditioned media on breast cancer cell proliferation and endocrine resistance. Our findings identify a novel activity of simvastatin and mechanism of SASP regulation. They also suggest that senescent cells, which accumulate after radio/chemo therapy, promote endocrine resistance in breast cancer and that simvastatin might suppress this resistance. PMID:26658759

  18. Senescence from glioma stem cell differentiation promotes tumor growth

    PubMed Central

    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. PMID:26775840

  19. Human milk for the premature infant

    PubMed Central

    Underwood, Mark A.

    2012-01-01

    Synopsis Premature infants are a heterogeneous group with widely differing needs for nutrition and immune protection with risk of growth failure, developmental delays, necrotizing enterocolitis, and late-onset sepsis increasing with decreasing gestational age and birth weight. Human milk from women delivering prematurely has more protein and higher levels of many bioactive molecules compared to milk from women delivering at term. Human milk must be fortified for small premature infants to achieve adequate growth. Mother’s own milk improves growth and neurodevelopment and decreases the risk of necrotizing enterocolitis and late-onset sepsis and should therefore be the primary enteral diet of premature infants. Donor milk is a valuable resource for premature infants whose mothers are unable to provide an adequate supply of milk, but presents significant challenges including the need for pasteurization, nutritional and biochemical deficiencies and a limited supply. PMID:23178065

  20. 17AAG Treatment Accelerates Doxorubicin Induced Cellular Senescence: Hsp90 Interferes with Enforced Senescence of Tumor Cells

    PubMed Central

    Sarangi, Upasana; Paithankar, Khande Rao; Kumar, Jonnala Ujwal; Subramaniam, Vaidyanathan; Sreedhar, Amere Subbarao

    2012-01-01

    Hsp90 chaperone has been identified as an attractive pharmacological target to combat cancer. However, some metastatic tumors either fail to respond to Hsp90 inhibition or show recovery necessitating irreversible therapeutic strategies. In response to this enforced senescence has been proposed as an alternate strategy. Here, we demonstrate that inhibiting Hsp90 with 17AAG sensitizes human neuroblastoma to DNA damage response mediated cellular senescence. Among individual and combination drug treatments, 17AAG pre-treatment followed by doxorubicin treatment exhibited senescence-like characteristics such as increased nucleus to cytoplasm ratio, cell cycle arrest, SA-β-gal staining and the perpetual increase in SAHF. Doxorubicin induced senescence signaling was mediated by p53-p21CIP/WAF-1 and was accelerated in the absence of functional Hsp90. Sustained p16INK4a and H3K4me3 expressions correlating with unaffected telomerase activation annulled replicative senescence and appraised stress induced senescence. Despite increases in [(ROS)i] and [(Ca2+)i], a concomitant increase in cellular antioxidant defense system suggested oxidation independent senescence activation. Sustained activation of survival (Akt) and proliferative (ERK1/2) kinases fosters robustness of cells. Invigorating senescent cells with growth factor or snooping with mTOR or PI3 kinase inhibitors compromised cell survival but not senescence. Intriguingly, senescence-associated secretory factors from the senescence cells manifested established senescence in neuroblastoma, which offers clinical advantage to our approach. Our study discusses tumor selective functions of Hsp90 and discusses irrefutable strategies of Hsp90 inhibition in anticancer treatments. PMID:22915839