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senescence-associated secretory phenotype

Pavan Parikh, Sarah Wicher, Karl Khandalavala, Christina M Pabelick, Rodney D Britt, Y S Prakash
Cellular senescence results in cell cycle arrest with secretion of cytokines, chemokines, growth factors and remodeling proteins (senescence associated secretory phenotype; SASP) that have autocrine and paracrine effects on the tissue microenvironment. SASP can promote remodeling, inflammation, infectious susceptibility, angiogenesis and proliferation, while hindering tissue repair and regeneration. While the role of senescence and contributions of senescent cells are increasingly recognized in the context of aging and a variety of disease states, relatively less is known regarding the portfolio and influences of senescent cells in normal lung growth and aging per se, or in the induction or progression of lung diseases across the age spectrum such as bronchopulmonary dysplasia, asthma, COPD, or pulmonary fibrosis...
February 20, 2019: American Journal of Physiology. Lung Cellular and Molecular Physiology
Fanchao Feng, Zhichao Wang, Ruofei Li, Qi Wu, Cheng Gu, Yong Xu, Wenpan Peng, Di Han, Xianmei Zhou, Jing Wu, Hailang He
Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal lung disease with a poor prognosis and limited treatment options. The incidence of IPF increases with age, and the mechanisms related to aging such as cellular senescence have been strongly implicated in disease pathology. Therefore, a better understanding of fibroblasts senescence might provide a new therapeutic strategy to prevent and treat pulmonary fibrosis. In this study, we aimed to explore the effects of citrus alkaline extracts (CAE) on the fibroblasts senescence, and elucidate the underlying mechanism to ameliorate pulmonary fibrosis...
February 19, 2019: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Timothy Nacarelli, Lena Lau, Takeshi Fukumoto, Joseph Zundell, Nail Fatkhutdinov, Shuai Wu, Katherine M Aird, Osamu Iwasaki, Andrew V Kossenkov, David Schultz, Ken-Ichi Noma, Joseph A Baur, Zachary Schug, Hsin-Yao Tang, David W Speicher, Gregory David, Rugang Zhang
Cellular senescence is a stable growth arrest that is implicated in tissue ageing and cancer. Senescent cells are characterized by an upregulation of proinflammatory cytokines, which is termed the senescence-associated secretory phenotype (SASP). NAD+ metabolism influences both tissue ageing and cancer. However, the role of NAD+ metabolism in regulating the SASP is poorly understood. Here, we show that nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of the NAD+ salvage pathway, governs the proinflammatory SASP independent of senescence-associated growth arrest...
February 18, 2019: Nature Cell Biology
Stéphane Lopes-Paciencia, Emmanuelle Saint-Germain, Marie-Camille Rowell, Ana Fernández Ruiz, Paloma Kalegari, Gerardo Ferbeyre
The senescence-associated secretory phenotype (SASP) defines the ability of senescent cells to express and secrete a variety of extracellular modulators that includes cytokines, chemokines, proteases, growth factors and bioactive lipids. The role of the SASP depends on the context. The SASP reinforces the senescent cell cycle arrest, stimulates the immune-mediated clearance of potentially tumorigenic cells, limits fibrosis and promotes wound healing and tissue regeneration. On the other hand, the SASP can mediate chronic inflammation and stimulate the growth and survival of tumor cells...
February 15, 2019: Cytokine
Sulin Zeng, Wen H Shen, Li Liu
Senescence is a double-edged sword that can function in opposite directions. It is a potential mechanism for a cell to avoid malignant transformation. However, senescence can also promote cancer development by altering the cellular microenvironment through a senescence-associated secretory phenotype (SASP). At least, three types of cellular stress such as activation of oncogenes, loss of tumor suppressor genes, and chemo/radiotherapy can induce cell senescence. Oncogene-induced senescence can be intertwiningly associated with the replicative senescence...
May 2018: Cancer Translational Medicine
Qiang He, Shuyin Xue, Yiqing Tan, Ling Zhang, Qing Shao, Lei Xing, Yunhai Li, Tingxiu Xiang, Xinrong Luo, Guosheng Ren
Activated Akt and ERK signaling pathways are closely related to breast cancer progression, and Akt or ERK inhibition induces cell senescence. However, the crosstalk between the Akt and ERK signaling pathways in cell senescence and how to simultaneously suppress Akt and ERK signaling in triple-negative breast cancer (TNBC) are undefined. In this study, we found that norcantharidin (NCTD) effectively induced cell senescence and cell cycle arrest in TNBC in vitro, which was accompanied by a decline in phosphorylated Akt and ERK and a rise in p21 and p16...
February 8, 2019: Cancer Letters
Adam Rolt, Anitha Nair, Lynne S Cox
Cellular senescence has been shown to be sufficient for the development of multiple age-related pathologies. Senescent cells adopt a secretory phenotype (the SASP) which comprises a large number of pro-inflammatory cytokines, chemokines and proteases. The SASP itself is thought to be causative in many pathologies of age-related diseases, and there is growing interest in developing seno-modifying agents that can suppress the SASP. However, in order to identify new agents, it is necessary to conduct moderate to high throughput screening with robust assays for the required outcome...
February 11, 2019: Biogerontology
Zehua Wang, Jianwen Gao, Jiabing Zhou, Haiou Liu, Congjian Xu
OBJECTIVE: Poly (ADP-ribose) polymerase (PARP) is an important molecule in the early stress response of DNA damage, which is involved in DNA damage repair and cellular senescence. Olaparib, as PARP inhibitor, has an anti-tumor effect on high grade serous ovarian cancer, but its effects on cellular senescence have not been reported. This study intends to explore the role of olaparib in the regulation of senescence in ovarian cancer cells. METHODS: The effects of olaparib on the senescence of ovarian cancer cells were detected by using the senescence-associated β-galactosidase (SA-β-Gal) and senescence-associated heterochromatin aggregation (SAHF)...
November 22, 2018: Journal of Gynecologic Oncology
Rhys Anderson, Anthony Lagnado, Damien Maggiorani, Anna Walaszczyk, Emily Dookun, James Chapman, Jodie Birch, Hanna Salmonowicz, Mikolaj Ogrodnik, Diana Jurk, Carole Proctor, Clara Correia-Melo, Stella Victorelli, Edward Fielder, Rolando Berlinguer-Palmini, Andrew Owens, Laura C Greaves, Kathy L Kolsky, Angelo Parini, Victorine Douin-Echinard, Nathan K LeBrasseur, Helen M Arthur, Simon Tual-Chalot, Marissa J Schafer, Carolyn M Roos, Jordan D Miller, Neil Robertson, Jelena Mann, Peter D Adams, Tamara Tchkonia, James L Kirkland, Jeanne Mialet-Perez, Gavin D Richardson, João F Passos
Ageing is the biggest risk factor for cardiovascular disease. Cellular senescence, a process driven in part by telomere shortening, has been implicated in age-related tissue dysfunction. Here, we address the question of how senescence is induced in rarely dividing/post-mitotic cardiomyocytes and investigate whether clearance of senescent cells attenuates age-related cardiac dysfunction. During ageing, human and murine cardiomyocytes acquire a senescent-like phenotype characterised by persistent DNA damage at telomere regions that can be driven by mitochondrial dysfunction and crucially can occur independently of cell division and telomere length...
February 8, 2019: EMBO Journal
Sam Hobson, Samsul Arefin, Karolina Kublickiene, Paul G Shiels, Peter Stenvinkel
Together with bone-mineral disorders, premature vascular ageing is a common feature of the uremic phenotype. A detailed understanding of mechanisms involved remains unclear and warrants further research. Available treatment options for end stage renal disease are principally dialysis and organ transplantation, as other treatment alternatives have proven insufficient. Chronic kidney disease (CKD) has been proposed as a model of early vascular and bone ageing, with accumulating evidence supporting the contribution of cellular senescence and the senescence-associated secretory phenotype (SASP) to cardiovascular pathology in CKD...
February 1, 2019: Toxins
Charlene Boumendil, Priya Hari, Karl C F Olsen, Juan Carlos Acosta, Wendy A Bickmore
During oncogene-induced senescence (OIS), heterochromatin is lost from the nuclear periphery and forms internal senescence-associated heterochromatin foci (SAHFs). We show that an increased nuclear pore density during OIS is responsible for SAHF formation. In particular, the nucleoporin TPR is necessary for both formation and maintenance of SAHFs. Loss of SAHFs does not affect cell cycle arrest but abrogates the senescence-associated secretory phenotype-a program of inflammatory cytokine gene activation. Our results uncover a previously unknown role of nuclear pores in heterochromatin reorganization in mammalian nuclei and demonstrate the importance of heterochromatin organization for a specific gene activation program...
January 28, 2019: Genes & Development
Jie-Yu Liu, George P Souroullas, Brian O Diekman, Janakiraman Krishnamurthy, Brandon M Hall, Jessica A Sorrentino, Joel S Parker, Garrett A Sessions, Andrei V Gudkov, Norman E Sharpless
The activation of cellular senescence throughout the lifespan promotes tumor suppression, whereas the persistence of senescent cells contributes to aspects of aging. This theory has been limited, however, by an inability to identify and isolate individual senescent cells within an intact organism. Toward that end, we generated a murine reporter strain by "knocking-in" a fluorochrome, tandem-dimer Tomato (tdTom), into exon 1α of the p16 INK4a locus. We used this allele ( p16 tdTom ) for the enumeration, isolation, and characterization of individual p16 INK4a -expressing cells (tdTom+ )...
January 25, 2019: Proceedings of the National Academy of Sciences of the United States of America
Guillaume Canaud, Craig R Brooks, Seiji Kishi, Kensei Taguchi, Kenji Nishimura, Sato Magassa, Adam Scott, Li-Li Hsiao, Takaharu Ichimura, Fabiola Terzi, Li Yang, Joseph V Bonventre
Fibrosis contributes to the progression of chronic kidney disease (CKD). Severe acute kidney injury can lead to CKD through proximal tubular cell (PTC) cycle arrest in the G2 -M phase, with secretion of profibrotic factors. Here, we show that epithelial cells in the G2 -M phase form target of rapamycin (TOR)-autophagy spatial coupling compartments (TASCCs), which promote profibrotic secretion similar to the senescence-associated secretory phenotype. Cyclin G1 (CG1), an atypical cyclin, promoted G2 -M arrest in PTCs and up-regulated TASCC formation...
January 23, 2019: Science Translational Medicine
Jia Wang, Xiang Zheng, Zailong Qin, Lingyu Wei, Yuanjun Lu, Qiu Peng, Yingxue Gao, Xuemei Zhang, Xiaoyue Zhang, Zhengshuo Li, Yuxin Fu, Peishan Liu, Can Liu, Qun Yan, Wei Xiong, Guiyuan Li, Jianhong Lu, Jian Ma
Epstein-Barr virus-associated gastric cancer (EBVaGC) accounts for about 10% of all gastric cancer cases and has unique pathological and molecular characteristics. EBV encodes a large number of microRNAs, which actively participate in the development of EBV-related tumors. Here we report EBV-miR-BART3-3p (BART3-3p) promotes gastric cancer cell growth in vitro and in vivo. Moreover, BART3-3p inhibits the senescence of gastric cancer cells induced by oncogene (RASG12V) or chemotherapy (Irinotecan). LMP1 and EBNA3C encoded by EBV had also been reported to have anti-senescence effects, however, in EBVaGC specimens, LMP1 expression is very low and EBNA3C is not expressed...
January 23, 2019: Journal of Biological Chemistry
Yuanyuan Su, Chenzhong Xu, Zhaomeng Sun, Yao Liang, Guodong Li, Tanjun Tong, Jun Chen
Senescent cells display the senescence-associated secretory phenotype (SASP) which plays important roles in cancer, aging, etc. Cell surface-bound IL-1α is a crucial SASP factor and acts as an upstream regulator to induce NF-κB activity and subsequent SASP genes transcription. IL-1α exports to cell surface via S100A13 protein-dependent non-classical secretory pathway. However, the status of this secretory pathway during cellular senescence and its role in cellular senescence remain unknown. Here, we show that S100A13 is up-regulated in various types of cellular senescence...
January 23, 2019: Aging
Qinghe Geng, Haiyan Gao, Renlei Yang, Kaijin Guo, Dengshun Miao
Accumulating studies have shown that oxidative stress increases with aging, which is related to the pathophysiology of postmenopausal osteoporosis. Pyrroloquinoline quinone (PQQ) is a natural anti-oxidant with anti-oxidative and anti-aging effects. However, it is unclear whether PQQ has a protective role against estrogen deficiency-induced osteoporosis. Here, we evaluated the efficacy of PQQ on bone mineral density, bone microarchitecture, bone turnover and biomechanical strength in ovariectomy (OVX)-induced osteoporosis mouse model...
2019: International Journal of Biological Sciences
Joshua N Farr, Sundeep Khosla
Cellular senescence refers to a process induced by various types of stress that causes irreversible cell cycle arrest and distinct cellular alterations, including profound changes in gene expression, metabolism, and chromatin organization as well as activation/reinforcement of anti-apoptotic pathways and development of a pro-inflammatory secretome or senescence-associated secretory phenotype (SASP). However, because of challenges and technical limitations in identifying and characterizing senescent cells in living organisms, only recently have some of the diverse in vivo roles of these unique cells been discovered...
January 16, 2019: Bone
Ramesh T Gunaratna, Andres Santos, Linjie Luo, Chandandeep Nagi, Isabel Lambertz, Madison Spier, Claudio J Conti, Robin S Fuchs-Young
Female breast cancer (BrCa) is the most common noncutaneous cancer among women in the United States. Human epidemiological studies reveal that a p53 single-nucleotide polymorphism (SNP) at codon 72, encoding proline (P72) or arginine (R72), is associated with differential risk of several cancers, including BrCa. However, the molecular mechanisms by which these variants affect mammary tumorigenesis remain unresolved. To investigate the effects of this polymorphism on susceptibility to mammary cancer, we used a humanized p53 mouse model, homozygous for either P72 or R72...
January 16, 2019: Oncogene
Chaska C Walton, Julie K Andersen
Oxidative stress has long been considered a key component contributing to pathologies associated with brain aging and age-related neurodegenerative diseases. The proposed mechanisms involved are varied, but recently have been suggested to include induction of cellular senescence, a cellular growth arrest state characterized by the secretion of pre-inflammatory senescence-associated secretory phenotype (SASP) factors. The post-mitotic status of neurons has been traditionally considered to prohibit cellular senescence, however recent studies have provided compelling evidence that neurons may be capable of undergoing senescence in response to oxidative stress and other factors...
January 9, 2019: Free Radical Biology & Medicine
Kelly E Leon, Katherine M Aird
Senescence is a stable cell cycle arrest that is either tumor suppressive or tumor promoting depending on context. Epigenetic changes such as histone methylation are known to affect both the induction and suppression of senescence by altering expression of genes that regulate the cell cycle and the senescence-associated secretory phenotype. A conserved group of proteins containing a Jumonji C (JmjC) domain alter chromatin state, and therefore gene expression, by demethylating histones. Here, we will discuss what is currently known about JmjC demethylases in the induction of senescence, and how these enzymes suppress senescence to contribute to tumorigenesis...
January 9, 2019: Genes
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