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senescence-associated secretory phenotype

Fei Chen, Qilai Long, Da Fu, Dexiang Zhu, Yan Ji, Liu Han, Boyi Zhang, Qixia Xu, Bingjie Liu, Yan Li, Shanshan Wu, Chen Yang, Min Qian, Jianmin Xu, Suling Liu, Liu Cao, Y Eugene Chin, Eric W-F Lam, Jean-Philippe Coppé, Yu Sun
Chemotherapy and radiation not only trigger cancer cell apoptosis but also damage stromal cells in the tumour microenvironment (TME), inducing a senescence-associated secretory phenotype (SASP) characterized by chronic secretion of diverse soluble factors. Here we report serine protease inhibitor Kazal type I (SPINK1), a SASP factor produced in human stromal cells after genotoxic treatment. DNA damage causes SPINK1 expression by engaging NF-κB and C/EBP, while paracrine SPINK1 promotes cancer cell aggressiveness particularly chemoresistance...
October 17, 2018: Nature Communications
Philipp Velicky, Gudrun Meinhardt, Kerstin Plessl, Sigrid Vondra, Tamara Weiss, Peter Haslinger, Thomas Lendl, Karin Aumayr, Mario Mairhofer, Xiaowei Zhu, Birgit Schütz, Roberta L Hannibal, Robert Lindau, Beatrix Weil, Jan Ernerudh, Jürgen Neesen, Gerda Egger, Mario Mikula, Clemens Röhrl, Alexander E Urban, Julie Baker, Martin Knöfler, Jürgen Pollheimer
Genome amplification and cellular senescence are commonly associated with pathological processes. While physiological roles for polyploidization and senescence have been described in mouse development, controversy exists over their significance in humans. Here, we describe tetraploidization and senescence as phenomena of normal human placenta development. During pregnancy, placental extravillous trophoblasts (EVTs) invade the pregnant endometrium, termed decidua, to establish an adapted microenvironment required for the developing embryo...
October 12, 2018: PLoS Genetics
Jin-Ran Chen, Oxana P Lazarenko, Haijun Zhao, Alexander W Alund, Kartik Shankar
Intrauterine or early postnatal high-fat diet (HFD) has substantial influences on adult offspring health; however, studies of HFD-induced maternal obesity on regulation of adult offspring bone formation are sparse. Here, we investigated the effects of HFD-induced maternal obesity on both fetal and adult offspring skeletal development. We found that HFD-induced maternal obesity significantly decreased fetal skeletal development, but enhanced fetal osteoblastic cell senescence signaling and significantly increased the expression of inflammatory factors of the senescence-associated secretory phenotype (SASP) in osteo-progenitors...
October 1, 2018: Journal of Endocrinology
Sandra Muñoz-Galván, Antonio Lucena-Cacace, Marco Perez, Daniel Otero-Albiol, Julian Gomez-Cambronero, Amancio Carnero
Cancer cells are in continuous communication with the surrounding microenvironment and this communication can affect tumor evolution. In this work, we show that phospholipase D2 (PLD2) was overexpressed in colon tumors and is secreted by cancer cells, inducing senescence in neighboring fibroblasts. This occurs through its lipase domain. Senescence induced by its product, phosphatidic acid, leads to a senescence-associated secretory phenotype (SASP) able to increase the stem properties of cancer cells. This increase in stemness occurs by Wnt pathway activacion...
October 10, 2018: Oncogene
Kunihiro Saga, Yukio Iwashita, Shinya Hidano, Yuiko Aso, Kenji Isaka, Yasutoshi Kido, Kazuhiro Tada, Hiroomi Takayama, Takashi Masuda, Teijiro Hirashita, Yuichi Endo, Masayuki Ohta, Takashi Kobayashi, Masafumi Inomata
Hepatic stellate cells (HSCs) are key players in liver fibrosis, cellular senescence, and hepatic carcinogenesis. Bile acids (BAs) are involved in the activation of HSCs, but the detailed mechanism of this process remains unclear. We conducted a comprehensive DNA microarray study of the human HSC line LX-2 treated with deoxycholic acid (DCA), a secondary unconjugated BA. Additionally, LX-2 cells were exposed to nine BAs and studied using immunofluorescence staining, enzyme-linked immunosorbent assay, and flow cytometry to examine the mechanisms of HSC activation...
October 5, 2018: International Journal of Molecular Sciences
Selene Glück, Andrea Ablasser
Senescence is a multistep cellular program featuring a stable cell cycle arrest, which occurs upon exposure to various stressors. Senescent cells exhibit metabolic activity and hypertrophy and produce a multitude of factors with both cell intrinsic as well as non-cell autonomous functions. These factors are collectively referred to as the senescence-associated secretory phenotype (SASP). Recently, the DNA sensor cyclic GMP AMP synthase (cGAS) and the adaptor stimulator of interferon genes (STING) have been reported to be critically involved in the regulation of senescence...
October 5, 2018: Current Opinion in Immunology
Rosa Fernandes, Sofia D Viana, Sara Nunes, Flávio Reis
The increased prevalence of type 2 diabetes mellitus (T2DM) and life expectancy of diabetic patients fosters the worldwide prevalence of retinopathy and nephropathy, two major microvascular complications that have been difficult to treat with contemporary glucose-lowering medications. The gut microbiota (GM) has become a lively field research in the last years; there is a growing recognition that altered intestinal microbiota composition and function can directly impact the phenomenon of ageing and age-related disorders...
October 1, 2018: Biochimica et biophysica acta. Molecular basis of disease
Santosh Kumar, Shubhankar Suman, Albert J Fornace, Kamal Datta
Proliferative gastrointestinal (GI) tissue is radiation-sensitive, and heavy-ion space radiation with its high-linear energy transfer (high-LET) and higher damaging potential than low-LET γ-rays is predicted to compromise astronauts' GI function. However, much uncertainty remains in our understanding of how heavy ions affect coordinated epithelial cell migration and extrusion, which are essential for GI homeostasis. Here we show using mouse small intestine as a model and BrdU pulse labeling that cell migration along the crypt-villus axis is persistently decreased after a low dose of heavy-ion 56 Fe radiation relative to control and γ-rays...
October 1, 2018: Proceedings of the National Academy of Sciences of the United States of America
Maciel Alencar Bruxel, Angela Maria Vicente Tavares, Luiz Domingues Zavarize Neto, Victor de Souza Borges, Helena Trevisan Schroeder, Patricia Martins Bock, Maria Inês Lavina Rodrigues, Adriane Belló-Klein, Paulo Ivo Homem de Bittencourt
Unhealthy lifestyle persistently feeds forward inflammation in metabolic organs thus imposing senescence-associated secretory phenotype (SASP), as observed in obesity and type 2 diabetes. However, SASP blocks physiological resolution of inflammation by suppressing the anti-inflammatory and anti-senescent heat shock (HS) response, i.e., the gene program centered in heat shock factor-1 (HSF1)-dependent expression heat shock proteins (HSPs). As SASP-inducing factors are not removed, leading to the perpetuation of inflammation, we argued that SIRT1-HSF1-HSP axis might also be suppressed in atherosclerosis, which could be reversible by heat treatment (HT), the most powerful HS response trigger...
September 28, 2018: Biochimie
Zsofia Budai, Laszlo Balogh, Zsolt Sarang
BACKGROUND: During aging, muscle tissue undergoes profound changes which lead to a decline in its functional and regenerative capacity. We utilized global gene expression analysis and gene set enrichment analysis to characterize gene expression changes in aging muscle satellite cells. METHOD: Gene expression data; obtained from Affymetrix Mouse Genome 430 2.0 Array, for 14 mouse muscle satellite cell samples (5 young, 4 middle-aged, and 5 aged), were retrieved from public Gene Expression Omnibus repository...
September 24, 2018: Current Aging Science
Neetu Razdan, Themistoklis Vasilopoulos, Utz Herbig
Cells that had undergone telomere dysfunction-induced senescence secrete numerous cytokines and other molecules, collectively called the senescence-associated secretory phenotype (SASP). Although certain SASP factors have been demonstrated to promote cellular senescence in neighboring cells in a paracrine manner, the mechanisms leading to bystander senescence and the functional significance of these effects are currently unclear. Here, we demonstrate that TGF-β1, a component of the SASP, causes telomere dysfunction in normal somatic human fibroblasts in a Smad3/NOX4/ROS-dependent manner...
September 22, 2018: Aging Cell
Olena Sapega, Romana Mikyšková, Jana Bieblová, Blanka Mrázková, Zdeněk Hodný, Milan Reiniš
Cellular senescence is the process of the permanent proliferative arrest of cells in response to various inducers. It is accompanied by typical morphological changes, in addition to the secretion of bioactive molecules, including proinflammatory cytokines and chemokines [known as the senescence-associated secretory phenotype (SASP)]. Thus, senescent cells may affect their local environment and induce a so-called 'bystander' senescence through the state of SASP. The phenotypes of senescent cells are determined by the type of agent inducing cellular stress and the cell lineages...
November 2018: International Journal of Oncology
Xinnan Bao, Xinyu Hu
BACKGROUND: Cartilage degradation would result in osteoarthritis (OA). p16INK4awas found in some age-related diseases. In this study, we aimed to determine the role of p16INK4a during OA and to investigate the underlying mechanisms. METHODS: Enzyme-linked immunosorbent assay (ELISA) was performed to test the activity of senescence-associated secretory phenotype (SASP). Real-time PCR (RT-PCR) and Western blot were used to determine the expressions of target genes...
September 15, 2018: BMC Musculoskeletal Disorders
Ana Peropadre, Paloma Fernández Freire, María José Hazen
Perfluorooctanoic acid has been used widespread, during the last decades, in a number of consumer and industrial products. Although this compound has been subjected to extensive epidemiological and toxicological studies, limited data are available concerning its potential dermal toxicity in mammalian cells. In this study, we used a two-stage approach with relevant cytotoxicity endpoints including cell viability and proliferation, oxidative stress, DNA damage and cell senescence to assess the immediate and the long-lasting or delayed cytotoxicity caused by the compound in HaCaT keratinocytes...
September 12, 2018: Food and Chemical Toxicology
Lukáš Lacina, Jan Brábek, Vladimír Král, Ondřej Kodet, Karel Smetana
Interleukin-6 is a multifaceted cytokine, usually reported as a pro-inflammatory molecule. However, certain anti-inflammatory activities were also attributed to IL-6. The levels of IL-6 in serum as well as in other biological fluids are elevated in an age-dependent manner. Notably, it is consistently reported also as a key feature of the senescence-associated secretory phenotype. In the elderly, this cytokine participates in the initiation of catabolism resulting in, e.g. sarcopenia. It can cross the blood-brain barrier, and so it is in causal association with, e...
September 4, 2018: Histology and Histopathology
Breno S Diniz
Major depressive disorder in the elderly-or late-life depression (LLD)-is one of the most common mental illnesses in the aging population. LLD has several negative effects on health and well-being. Individuals with LLD have an elevated risk of chronic and persistent depressive symptoms as well as high rates of treatment resistance. They also have a higher risk of developing cognitive impairment with progression to dementia and higher rates of medical comorbidity, frailty, and mortality. The mechanisms linking LLD to these adverse health outcomes are not well understood...
July 24, 2018: American Journal of Geriatric Psychiatry
Young Yeon Kim, Jee-Hyun Um, Jeanho Yun
Cellular senescence has been considered a state of irreversible growth arrest upon exhaustion of proliferative capacity or exposure to various stresses. Recent studies have extended the role of cellular senescence to various physiological processes, including development, wound healing, immune surveillance, and age-related tissue dysfunction. Although cell cycle arrest is a critical hallmark of cellular senescence, an increased intracellular reactive oxygen species (ROS) production has also been demonstrated to play an important role in the induction of cellular senescence...
August 12, 2018: Journal of Visualized Experiments: JoVE
Jingwen Xu, Nipa H Patel, Tareq Saleh, Emmanuel K Cudjoe, Moureq Alotaibi, Yingliang Wu, Santiago Lima, Adam M Hawkridge, David A Gewirtz
Studies of radiation interaction with tumor cells often focus on apoptosis as an end point; however, clinically relevant doses of radiation also promote autophagy and senescence. Moreover, functional p53 has frequently been implicated in contributing to radiation sensitivity through the facilitation of apoptosis. To address the involvement of apoptosis, autophagy, senescence and p53 status in the response to radiation, the current studies utilized isogenic H460 non-small cell lung cancer cells that were either p53-wild type (H460wt) or null (H460crp53)...
August 22, 2018: Radiation Research
Jia Huo, Zhe Xu, Kazunori Hosoe, Hiroshi Kubo, Hiroki Miyahara, Jian Dai, Masayuki Mori, Jinko Sawashita, Keiichi Higuchi
Oxidative damage in endothelial cells is proposed to play an important role in endothelial dysfunction and atherogenesis. We previously reported that the reduced form of coenzyme Q10 (CoQ10 H2 ) effectively inhibits oxidative stress and decelerates senescence in senescence-accelerated mice. Here, we treated human umbilical vein endothelial cells (HUVECs) with H2 O2 and investigated the protective effect of CoQ10 H2 against senescence, oxidative damage, and reduction in cellular functions. We found that CoQ10 H2 markedly reduced the number of senescence-associated β -galactosidase-positive cells and suppressed the expression of senescence-associated secretory phenotype-associated genes in H2 O2 -treated HUVECs...
2018: Oxidative Medicine and Cellular Longevity
Miriam S Hohmann, David M Habiel, Ana L Coelho, Waldiceu A Verri, Cory M Hogaboam
While cellular senescence may be a protective mechanism in modulating proliferative capacity, fibroblast senescence is now recognized as a key pathogenic mechanism in Idiopathic Pulmonary Fibrosis (IPF). In aged mice, abundance and persistence of apoptosis-resistant senescent fibroblasts play a central role in non-resolving lung fibrosis after bleomycin challenge. Therefore, we investigated whether quercetin can restore the susceptibility of senescent IPF fibroblasts to pro-apoptotic stimuli and mitigate bleomycin-induced pulmonary fibrosis in aged mice...
August 15, 2018: American Journal of Respiratory Cell and Molecular Biology
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