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https://www.readbyqxmd.com/read/28533436/metformin-synergizes-with-bcl-xl-bcl-2-inhibitor-abt-263-to-induce-apoptosis-specifically-in-p53-defective-cancer-cells
#1
Xinzhe Li, Bo Li, Zhenhong Ni, Peng Zhou, Bin Wang, Jintao He, Haojun Xiong, Fan Yang, Yaran Wu, Xilin Lyu, Yan Zhang, Yijun Zeng, Jiqin Lian, Fengtian He
p53 deficiency, a frequent event in multiple kinds of malignancies, decreases the sensitivity of diverse targeted chemotherapeutics including the BCL-XL/BCL-2 inhibitor ABT-263. Loss of p53 function can activate mTOR complex 1 (mTORC1), which may make it a vulnerable target. Metformin has shown anti-neoplastic efficiency partially through suppressing mTORC1. However, it remains unknown whether mTORC1 activation confers ABT-263 resistance and whether metformin can overcome it in the p53-defective contexts. In this study, we for the first time demonstrated that metformin and ABT-263 synergistically elicited remarkable apoptosis through orchestrating the pro-apoptotic machineries in various p53-defective cancer cells...
May 22, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28533362/cgas-is-essential-for-cellular-senescence
#2
Hui Yang, Hanze Wang, Junyao Ren, Qi Chen, Zhijian J Chen
Cellular senescence is a natural barrier to tumorigenesis and it contributes to the antitumor effects of several therapies, including radiation and chemotherapeutic drugs. Senescence also plays an important role in aging, fibrosis, and tissue repair. The DNA damage response is a key event leading to senescence, which is characterized by the senescence-associated secretory phenotype (SASP) that includes expression of inflammatory cytokines. Here we show that cGMP-AMP (cGAMP) synthase (cGAS), a cytosolic DNA sensor that activates innate immunity, is essential for senescence...
May 22, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28518126/techniques-to-induce-and-quantify-cellular-senescence
#3
Nicole Noren Hooten, Michele K Evans
In response to cellular stress or damage, proliferating cells can induce a specific program that initiates a state of long-term cell-cycle arrest, termed cellular senescence. Accumulation of senescent cells occurs with organismal aging and through continual culturing in vitro. Senescent cells influence many biological processes, including embryonic development, tissue repair and regeneration, tumor suppression, and aging. Hallmarks of senescent cells include, but are not limited to, increased senescence-associated β-galactosidase activity (SA-β-gal); p16(INK4A), p53, and p21 levels; higher levels of DNA damage, including γ-H2AX; the formation of Senescence-associated Heterochromatin Foci (SAHF); and the acquisition of a Senescence-associated Secretory Phenotype (SASP), a phenomenon characterized by the secretion of a number of pro-inflammatory cytokines and signaling molecules...
May 1, 2017: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/28502821/sasp-regulation-by-noncoding-rna
#4
REVIEW
Amaresh C Panda, Kotb Abdelmohsen, Myriam Gorospe
Noncoding RNAs (ncRNAs), including micro (mi)RNAs, long noncoding (lnc)RNAs, and circular (circ)RNAs, control specific gene expression programs by regulating transcriptional, post-transcriptional, and post-translational processes. Through their broad influence on protein expression and function, ncRNAs have been implicated in virtually all cellular processes such as proliferation, senescence, quiescence, differentiation, apoptosis, and the stress and immune responses. Senescence is a cellular phenotype associated with the physiologic decline of aging and with age-related pathologies...
May 11, 2017: Mechanisms of Ageing and Development
https://www.readbyqxmd.com/read/28489601/cellular-senescence-senescence-associated-secretory-phenotype-and-chronic-kidney-disease
#5
REVIEW
Wen-Juan Wang, Guang-Yan Cai, Xiang-Mei Chen
Chronic kidney disease (CKD) is increasingly being accepted as a type of renal ageing. The kidney undergoes age-related alterations in both structure and function. To date, a comprehensive analysis of cellular senescence and senescence-associated secretory phenotype (SASP) in CKD is lacking. Hence, this review mainly discusses the relationship between the two phenomena to show the striking similarities between SASP and CKD-associated secretory phenotype (CASP). It has been reported that replicative senescence, stress-induced premature ageing, and epigenetic abnormalities participate in the occurrence and development of CKD...
April 21, 2017: Oncotarget
https://www.readbyqxmd.com/read/28489070/senescent-tumor-cells-lead-the-collective-invasion-in-thyroid-cancer
#6
Young Hwa Kim, Yong Won Choi, Jeonghun Lee, Euy Young Soh, Jang-Hee Kim, Tae Jun Park
Cellular senescence has been perceived as a barrier against carcinogenesis. However, the senescence-associated secretory phenotype (SASP) of senescent cells can promote tumorigenesis. Here, we show senescent tumour cells are frequently present in the front region of collective invasion of papillary thyroid carcinoma (PTC), as well as lymphatic channels and metastatic foci of lymph nodes. In in vitro invasion analysis, senescent tumour cells exhibit high invasion ability as compared with non-senescent tumour cells through SASP expression...
May 10, 2017: Nature Communications
https://www.readbyqxmd.com/read/28489069/histone-variant-h2a-j-accumulates-in-senescent-cells-and-promotes-inflammatory-gene-expression
#7
Kévin Contrepois, Clément Coudereau, Bérénice A Benayoun, Nadine Schuler, Pierre-François Roux, Oliver Bischof, Régis Courbeyrette, Cyril Carvalho, Jean-Yves Thuret, Zhihai Ma, Céline Derbois, Marie-Claire Nevers, Hervé Volland, Christophe E Redon, William M Bonner, Jean-François Deleuze, Clotilde Wiel, David Bernard, Michael P Snyder, Claudia E Rübe, Robert Olaso, François Fenaille, Carl Mann
The senescence of mammalian cells is characterized by a proliferative arrest in response to stress and the expression of an inflammatory phenotype. Here we show that histone H2A.J, a poorly studied H2A variant found only in mammals, accumulates in human fibroblasts in senescence with persistent DNA damage. H2A.J also accumulates in mice with aging in a tissue-specific manner and in human skin. Knock-down of H2A.J inhibits the expression of inflammatory genes that contribute to the senescent-associated secretory phenotype (SASP), and over expression of H2A...
May 10, 2017: Nature Communications
https://www.readbyqxmd.com/read/28472950/senescence-associated-il-6-and-il-8-cytokines-induce-a-self-and-cross-reinforced-senescence-inflammatory-milieu-strengthening-tumorigenic-capabilities-in-the-mcf-7-breast-cancer-cell-line
#8
Paola Ortiz-Montero, Arturo Londoño-Vallejo, Jean-Paul Vernot
BACKGROUND: There is compelling evidence associating senescent cells with the malignant progression of tumours. Of all senescence-related mechanisms, the so-called senescence-associated secretory phenotype (SASP) has attracted much attention. Since the pro-inflammatory cytokines IL-6 and IL-8 are consistently present in the SASP, and secreted by highly aggressive breast cancer cell lines, we aimed at elucidating their role on the less aggressive breast cancer cell line MCF-7, which does not secret these cytokines...
May 4, 2017: Cell Communication and Signaling: CCS
https://www.readbyqxmd.com/read/28471483/human-sle-bone-marrow-mesenchymal-stem-cells-bmscs-have-a-senescence-associated-secretory-phenotype-sasp-mediated-by-a-mavs-ifn%C3%AE-feedback-loop
#9
Lin Gao, Anna K Bird, Nida Meednu, Kristin Dauenhauer, Jane Liesveld, Jennifer Anolik, R John Looney
Objective - BMSCs create a special microenvironment for hematopoiesis and immunity and also display robust immunomodulatory properties which are impaired in SLE. This study was undertaken to define the mechanisms of defects in human SLE BMSCs. Methods - Patients fulfilling SLE classification criteria and healthy controls were recruited under an Institutional Review Board approved protocol (n=6 each). BMSCs were isolated with low density Ficoll/Hypaque. BMSCs were verified by flow cytometry and studied using immunocytochemistry, real-time PCR, western blotting, comet assay, beta-galactosidase assay, and RNA interference...
May 4, 2017: Arthritis & Rheumatology
https://www.readbyqxmd.com/read/28456683/patchouli-alcohol-ameliorates-dextran-sodium-sulfate-induced-experimental-colitis-and-suppresses-tryptophan-catabolism
#10
Chang Qu, Zhong-Wen Yuan, Xiu-Ting Yu, Yan-Feng Huang, Guang-Hua Yang, Jian-Nan Chen, Xiao-Ping Lai, Zi-Ren Su, Hui-Fang Zeng, Ying Xie, Xiao-Jun Zhang
Despite the increased morbidity of ulcerative colitis (UC) in recent years, available treatments remain unsatisfactory. Pogostemon cablin has been widely applied to treat a variety of gastrointestinal disorders in clinic for centuries, in which patchouli alcohol (PA, C15H26O) has been identified as the major active component. This study attempted to determine the bioactivity of PA on dextran sulfate sodium (DSS)-induced mice colitis and clarify the mechanism of action. Acute colitis was induced in mice by 3% DSS for 7 days...
April 27, 2017: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/28445002/glucose-metabolism-targeting-therapy-and-withaferin-a-are-effective-for-egfr-tki-induced-drug-tolerant-persisters
#11
Kei Kunimasa, Tatsuya Nagano, Yohei Shimono, Ryota Dokuni, Tatsunori Kiriu, Shuntaro Tokunaga, Daisuke Tamura, Masatsugu Yamamoto, Motoko Tachihara, Kazuyuki Kobayashi, Miyako Satouchi, Yoshihiro Nishimura
In pathway-targeted cancer drug therapies, the relatively rapid emergence of drug-tolerant persisters (DTPs) substantially limits the overall therapeutic benefit. However, little is known about the roles of DTPs in drug resistance. In this study, we investigated the features of EGFR-TKI induced DTPs and explored a new treatment strategy to overcome the emergence of these DTPs. We used two EGFR mutated lung adenocarcinoma cell lines, PC9 and II-18. They were treated with 2 μM gefitinib for 6, 12, or 24 days or 6 month...
April 26, 2017: Cancer Science
https://www.readbyqxmd.com/read/28436958/local-clearance-of-senescent-cells-attenuates-the-development-of-post-traumatic-osteoarthritis-and-creates-a-pro-regenerative-environment
#12
Ok Hee Jeon, Chaekyu Kim, Remi-Martin Laberge, Marco Demaria, Sona Rathod, Alain P Vasserot, Jae Wook Chung, Do Hun Kim, Yan Poon, Nathaniel David, Darren J Baker, Jan M van Deursen, Judith Campisi, Jennifer H Elisseeff
Senescent cells (SnCs) accumulate in many vertebrate tissues with age and contribute to age-related pathologies, presumably through their secretion of factors contributing to the senescence-associated secretory phenotype (SASP). Removal of SnCs delays several pathologies and increases healthy lifespan. Aging and trauma are risk factors for the development of osteoarthritis (OA), a chronic disease characterized by degeneration of articular cartilage leading to pain and physical disability. Senescent chondrocytes are found in cartilage tissue isolated from patients undergoing joint replacement surgery, yet their role in disease pathogenesis is unknown...
April 24, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28427150/senoptosis-non-lethal-dna-cleavage-as-a-route-to-deep-senescence
#13
Maja Studencka, Jörg Schaber
DNA-damage-induced apoptosis and cellular senescence are perceived as two distinct cell fates. We found that after ionizing radiation (IR)-induced DNA damage the majority (up to 70 %) of senescent human diploid fibroblasts (HDFs) were subjected to controlled cleavage of DNA, resulting in the establishment of a viable and stable sub-G1 population, i.e. deeply senescent cells. We show that in senescent HDFs this DNA cleavage is triggered by modest loss of the mitochondrial membrane potential, which is not sufficient to activate caspases, but strong enough to release mitochondrial endonuclease G (EndoG)...
May 9, 2017: Oncotarget
https://www.readbyqxmd.com/read/28425040/schiff-base-complexes-of-copper-and-zinc-as-potential-anti-colitic-compounds
#14
Elaine M Conner, John Reglinski, W Ewen Smith, I Jack Zeitlin
The design, synthesis and activity of polymodal compounds for the treatment of inflammatory bowel disease are reported. The compounds, being based on a metal-Schiff base motif, are designed to degrade during intestinal transit to release the bioactive components in the gut. The compounds have been developed sequential with the biomodal compounds combining copper or zinc with a salicylaldehyde adduct. These compounds were tested in a formalin induced colonic inflammation model in BK:A mice. From these studies a trimodal compound based on a zinc Schiff base analogue of sulfasalazine was designed...
June 2017: Biometals: An International Journal on the Role of Metal Ions in Biology, Biochemistry, and Medicine
https://www.readbyqxmd.com/read/28416161/cellular-senescence-a-translational-perspective
#15
REVIEW
James L Kirkland, Tamara Tchkonia
Cellular senescence entails essentially irreversible replicative arrest, apoptosis resistance, and frequently acquisition of a pro-inflammatory, tissue-destructive senescence-associated secretory phenotype (SASP). Senescent cells accumulate in various tissues with aging and at sites of pathogenesis in many chronic diseases and conditions. The SASP can contribute to senescence-related inflammation, metabolic dysregulation, stem cell dysfunction, aging phenotypes, chronic diseases, geriatric syndromes, and loss of resilience...
April 12, 2017: EBioMedicine
https://www.readbyqxmd.com/read/28412724/the-quality-of-the-educational-environment-in-a-medical-college-in-saudi-arabia
#16
Abdullah H Altemani, Tarig H Merghani
Objectives: The study aimed to examine the quality of the educational environment in the Faculty of Medicine, University of Tabuk, Saudi Arabia, and to compare between male and female students using the Dundee Ready Educational Environment Measure (DREEM). Methods: We utilized a cross-sectional survey design.  Participants were 221 medical students (96 males and 125 females) from all classes (1st to 6th year). Each participant responded to a translated version of the DREEM questionnaire that measures five domains: students' perception of learning (SPL), students' perception of teachers (SPT), students' academic self-perception (SASP), students' perception of atmosphere (SPA), and students' social self-perception (SSSP)...
April 14, 2017: International Journal of Medical Education
https://www.readbyqxmd.com/read/28401730/dna-damage-and-senescence-in-osteoprogenitors-expressing-osx1-may-cause-their-decrease-with-age
#17
Ha-Neui Kim, Jianhui Chang, Lijian Shao, Li Han, Srividhya Iyer, Stavros C Manolagas, Charles A O'Brien, Robert L Jilka, Daohong Zhou, Maria Almeida
Age-related bone loss in mice results from a decrease in bone formation and an increase in cortical bone resorption. The former is accounted by a decrease in the number of postmitotic osteoblasts which synthesize the bone matrix and is thought to be the consequence of age-dependent changes in mesenchymal osteoblast progenitors. However, there are no specific markers for these progenitors, and conclusions rely on results from in vitro cultures of mixed cell populations. Moreover, the culprits of such changes remain unknown...
April 12, 2017: Aging Cell
https://www.readbyqxmd.com/read/28384888/perception-of-learning-environment-among-undergraduate-medical-students-in-two-different-medical-schools-through-dreem-and-jhles-questionnaire
#18
Parama Sengupta, Abhishek Sharma, Nina Das
INTRODUCTION: Assessment of learning environment is essential to assess the acceptability of the curriculum among students. Several tools are available to assess undergraduate medical students' perception of learning environment. Dundee Ready Education Environment Measure (DREEM) questionnaire is the most commonly used tool. Here, we have used both the widely used DREEM questionnaire and a relatively new questionnaire Johns Hopkins Learning Environment Scale (JHLES). AIM: Assessment of students' perception of learning environment of two eastern Indian medical schools using DREEM and JHLES questionnaire...
February 2017: Journal of Clinical and Diagnostic Research: JCDR
https://www.readbyqxmd.com/read/28378188/apigenin-suppresses-the-senescence-associated-secretory-phenotype-and-paracrine-effects-on-breast-cancer-cells
#19
Kevin M Perrott, Christopher D Wiley, Pierre-Yves Desprez, Judith Campisi
Apigenin (4',5,7,-trihydroxyflavone) is a flavonoid found in certain herbs, fruits, and vegetables. Apigenin can attenuate inflammation, which is associated with many chronic diseases of aging. Senescent cells-stressed cells that accumulate with age in mammals-display a pro-inflammatory senescence-associated secretory phenotype (SASP) that can drive or exacerbate several age-related pathologies, including cancer. Flavonoids, including apigenin, were recently shown to reduce the SASP of a human fibroblast strain induced to senesce by bleomycin...
April 2017: GeroScience
https://www.readbyqxmd.com/read/28371119/rapamycin-inhibits-the-secretory-phenotype-of-senescent-cells-by-a-nrf2-independent-mechanism
#20
Rong Wang, Zhen Yu, Bharath Sunchu, James Shoaf, Ivana Dang, Stephanie Zhao, Kelsey Caples, Lynda Bradley, Laura M Beaver, Emily Ho, Christiane V Löhr, Viviana I Perez
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...
June 2017: Aging Cell
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