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Hassanpour H, Javdani M, Changaniyan-Khorasgani Z, Rezazadeh E, Jalali R, Mojtahed M. Is castration leading to biological aging in dogs? Assessment of lipid peroxidation, inflammation, telomere length, mitochondrial DNA copy number, and expression of telomerase and age-related genes. BMC Vet Res 2024; 20:485. [PMID: 39448973 PMCID: PMC11515513 DOI: 10.1186/s12917-024-04337-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Accepted: 10/18/2024] [Indexed: 10/26/2024] Open
Abstract
BACKGROUND Biological aging is a complex process influenced by various factors, including reproductive status and castration. This study aimed to evaluate the impact of castration on biological aging in dogs. METHOD Fifteen male crossbred dogs were randomly divided into a sham-operation control group (n = 5) and a castrated group (n = 10). Blood samples were collected at weeks 0, 4, 8, 12, 16, and 18 post-surgery. Malondialdehyde (MDA as indicator of Lipid peroxidation), C-reactive protein (as an indicator of inflammation), telomere length, mitochondrial DNA (mtDNA) copy number, and the expression of age-related (P16, P21, TBX2) and telomerase-related (TERT) genes were assessed in blood samples. RESULTS Plasma MDA levels were higher in the control group at weeks 16 and 18, while CRP levels were higher only at week 18. Telomere length and mtDNA copy number were lower in the control group at week 18. Gene expression analysis showed that P16 was lower in the control group at weeks 8 and 12, P21 and TERT were lower at weeks 16 and 18, and TBX2 was lower at weeks 16 and 18. The TBX2/P16 ratio was lower in the control group at weeks 16 and 18 but higher at week 12, while the TBX2/P21 ratio did not differ between groups. CONCLUSION Castration appears to have a protective effect against biological aging in dogs, as evidenced by lower lipid peroxidation, inflammation, and age-related changes in telomere length, mtDNA copy number, and gene expression.
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Affiliation(s)
- Hossein Hassanpour
- Department of Basic Sciences, Faculty of Veterinary Medicine, Shahrekord University, Shahrekord, Iran.
- Department of Health Equity, Immunoregulation Research Center, Shahed University, Tehran, Iran.
| | - Moosa Javdani
- Department of Clinical Sciences, Faculty of Veterinary Medicine, Shahrekord University, Shahrekord, Iran
| | | | - Elnaz Rezazadeh
- Department of Basic Sciences, Faculty of Veterinary Medicine, Shahrekord University, Shahrekord, Iran
| | - Reza Jalali
- Department of Basic Sciences, Faculty of Veterinary Medicine, Shahrekord University, Shahrekord, Iran
| | - Marzieh Mojtahed
- Department of Cellular and Molecular Biology, Faculty of Advanced Sciences and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
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Sharma S, Ghufran SM, Aftab M, Bihari C, Ghose S, Biswas S. Survivin inhibition ameliorates liver fibrosis by inducing hepatic stellate cell senescence and depleting hepatic macrophage population. J Cell Commun Signal 2024; 18:e12015. [PMID: 38545255 PMCID: PMC10964939 DOI: 10.1002/ccs3.12015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2023] [Accepted: 12/28/2023] [Indexed: 01/29/2025] Open
Abstract
Persistent activation of hepatic stellate cells (HSCs) in the injured liver leads to the progression of liver injury from fibrosis to detrimental cirrhosis. In a previous study, we have shown that survivin protein is upregulated during the early activation of HSCs, which triggers the onset of liver fibrosis. However, the therapeutic potential of targeting survivin in a fully established fibrotic liver needs to be investigated. In this study, we chemically induced hepatic fibrosis in mice using carbon tetrachloride (CCl4) for 6 weeks, which was followed by treatment with a survivin suppressant (YM155). We also evaluated survivin expression in fibrotic human liver tissues, primary HSCs, and HSC cell line by histological analysis. αSMA+ HSCs in human and mice fibrotic liver tissues showed enhanced survivin expression, whereas the hepatocytes and quiescent (qHSCs) displayed minimal expression. Alternatively, activated M2 macrophage subtype induced survivin expression in HSCs through the TGF-β-TGF-β receptor-I/II signaling. Inhibition of survivin in HSCs promoted cell cycle arrest and senescence, which eventually suppressed their activation. In vivo, YM155 treatment increased the expression of cell senescence makers in HSCs around fibrotic septa such as p53, p21, and β-galactosidase. YM155 treatment in vivo also reduced the hepatic macrophage population and inflammatory cytokine expression in the liver. In conclusion, downregulation of survivin in the fibrotic liver decreases HSC activation by inducing cellular senescence and modulating macrophage cytokine expression that collectively ameliorates liver fibrosis.
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Affiliation(s)
- Sachin Sharma
- Amity Institute of Molecular Medicine and Stem Cell Research (AIMMSCR)Amity UniversityNoidaUttar PradeshIndia
- Department of MedicineUniversity of CaliforniaSan FranciscoCaliforniaUSA
| | - Shaikh Maryam Ghufran
- Amity Institute of Molecular Medicine and Stem Cell Research (AIMMSCR)Amity UniversityNoidaUttar PradeshIndia
- Heersink School of MedicineUniversity of AlabamaBirminghamUSA
| | - Mehreen Aftab
- Division of Cellular and Molecular OncologyNational Institute of Cancer Prevention and Research (NICPR)NoidaUttar PradeshIndia
| | - Chhagan Bihari
- Department of PathologyInstitute of Liver and Biliary Sciences (ILBS)New DelhiIndia
| | - Sampa Ghose
- Department of Medical OncologyAll India Institute of Medical Sciences (AIIMS)New DelhiIndia
| | - Subhrajit Biswas
- Amity Institute of Molecular Medicine and Stem Cell Research (AIMMSCR)Amity UniversityNoidaUttar PradeshIndia
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Gulej R, Nyúl-Tóth Á, Ahire C, DelFavero J, Balasubramanian P, Kiss T, Tarantini S, Benyo Z, Pacher P, Csik B, Yabluchanskiy A, Mukli P, Kuan-Celarier A, Krizbai IA, Campisi J, Sonntag WE, Csiszar A, Ungvari Z. Elimination of senescent cells by treatment with Navitoclax/ABT263 reverses whole brain irradiation-induced blood-brain barrier disruption in the mouse brain. GeroScience 2023; 45:2983-3002. [PMID: 37642933 PMCID: PMC10643778 DOI: 10.1007/s11357-023-00870-x] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2023] [Accepted: 07/06/2023] [Indexed: 08/31/2023] Open
Abstract
Whole brain irradiation (WBI), a commonly employed therapy for multiple brain metastases and as a prophylactic measure after cerebral metastasis resection, is associated with a progressive decline in neurocognitive function, significantly impacting the quality of life for approximately half of the surviving patients. Recent preclinical investigations have shed light on the multifaceted cerebrovascular injury mechanisms underlying this side effect of WBI. In this study, we aimed to test the hypothesis that WBI induces endothelial senescence, contributing to chronic disruption of the blood-brain barrier (BBB) and microvascular rarefaction. To accomplish this, we utilized transgenic p16-3MR mice, which enable the identification and selective elimination of senescent cells. These mice were subjected to a clinically relevant fractionated WBI protocol (5 Gy twice weekly for 4 weeks), and cranial windows were applied to both WBI-treated and control mice. Quantitative assessment of BBB permeability and capillary density was performed using two-photon microscopy at the 6-month post-irradiation time point. The presence of senescent microvascular endothelial cells was assessed by imaging flow cytometry, immunolabeling, and single-cell RNA-sequencing (scRNA-seq). WBI induced endothelial senescence, which associated with chronic BBB disruption and a trend for decreased microvascular density in the mouse cortex. In order to investigate the cause-and-effect relationship between WBI-induced senescence and microvascular injury, senescent cells were selectively removed from animals subjected to WBI treatment using Navitoclax/ABT263, a well-known senolytic drug. This intervention was carried out at the 3-month post-WBI time point. In WBI-treated mice, Navitoclax/ABT263 effectively eliminated senescent endothelial cells, which was associated with decreased BBB permeability and a trend for increased cortical capillarization. Our findings provide additional preclinical evidence that senolytic treatment approaches may be developed for prevention of the side effects of WBI.
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Affiliation(s)
- Rafal Gulej
- Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Department of Public Health, Semmelweis University, Budapest, Hungary
| | - Ádám Nyúl-Tóth
- Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Department of Public Health, Semmelweis University, Budapest, Hungary
- International Training Program in Geroscience, Institute of Biophysics, Biological Research Centre, Eötvös Loránd Research Network, Szeged, Hungary
| | - Chetan Ahire
- Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Jordan DelFavero
- Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Priya Balasubramanian
- Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Stephenson Cancer Center, University of Oklahoma, Oklahoma City, OK, USA
| | - Tamas Kiss
- Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- International Training Program in Geroscience, First Department of Pediatrics, Semmelweis University, Budapest, Hungary
- Eötvös Loránd Research Network and Semmelweis University (ELKH-SE) Cerebrovascular and Neurocognitive Disorders Research Group, Budapest, Hungary
- International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Department of Translational Medicine, Semmelweis University, Budapest, Hungary
- Graduate School, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Stefano Tarantini
- Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Department of Public Health, Semmelweis University, Budapest, Hungary
- Stephenson Cancer Center, University of Oklahoma, Oklahoma City, OK, USA
| | - Zoltan Benyo
- Eötvös Loránd Research Network and Semmelweis University (ELKH-SE) Cerebrovascular and Neurocognitive Disorders Research Group, Budapest, Hungary
- International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Department of Translational Medicine, Semmelweis University, Budapest, Hungary
- Graduate School, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Pal Pacher
- Laboratory of Cardiovascular Physiology and Tissue Injury, National Institute On Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
| | - Boglarka Csik
- Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Department of Public Health, Semmelweis University, Budapest, Hungary
| | - Andriy Yabluchanskiy
- Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Department of Public Health, Semmelweis University, Budapest, Hungary
| | - Peter Mukli
- Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Department of Public Health, Semmelweis University, Budapest, Hungary
| | - Anna Kuan-Celarier
- Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - István A Krizbai
- International Training Program in Geroscience, Institute of Biophysics, Biological Research Centre, Eötvös Loránd Research Network, Szeged, Hungary
- Institute of Life Sciences, Vasile Goldiş Western University of Arad, Arad, Romania
| | | | - William E Sonntag
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Anna Csiszar
- Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Stephenson Cancer Center, University of Oklahoma, Oklahoma City, OK, USA
- International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Department of Translational Medicine, Semmelweis University, Budapest, Hungary
| | - Zoltan Ungvari
- Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
- International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Department of Public Health, Semmelweis University, Budapest, Hungary.
- Stephenson Cancer Center, University of Oklahoma, Oklahoma City, OK, USA.
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4
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Senescent cells and SASP in cancer microenvironment: New approaches in cancer therapy. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2023; 133:115-158. [PMID: 36707199 DOI: 10.1016/bs.apcsb.2022.10.002] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Cellular senescence was first described as a state characterized by telomere shortening, resulting in limiting cell proliferation in aging. Apart from this type of senescence, which is called replicative senescence, other senescence types occur after exposure to different stress factors. One of these types of senescence induced after adjuvant therapy (chemotherapy and radiotherapy) is called therapy-induced senescence. The treatment with chemotherapeutics induces cellular senescence in normal and cancer cells in the tumor microenvironment. Thus therapy-induced senescence in the cancer microenvironment is accepted one of the drivers of tumor progression. Recent studies have revealed that senescence-associated secretory phenotype induction has roles in pathological processes such as inducing epithelial-mesenchymal transition and promoting tumor vascularization. Thus senolytic drugs that specifically kill senescent cells and senomorphic drugs that inhibit the secretory activity of senescent cells are seen as a new approach in cancer treatment. Developing and discovering new senotherapeutic agents targeting senescent cells is also gaining importance. In this review, we attempt to summarize the signaling pathways regarding the metabolism, cell morphology, and organelles of the senescent cell. Furthermore, we also reviewed the effects of SASP in the cancer microenvironment and the senotherapeutics that have the potential to be used as adjuvant therapy in cancer treatment.
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5
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Frediani E, Scavone F, Laurenzana A, Chillà A, Tortora K, Cimmino I, Leri M, Bucciantini M, Mangoni M, Fibbi G, Del Rosso M, Mocali A, Giovannelli L, Margheri F. Olive phenols preserve lamin B1 expression reducing cGAS/STING/NFκB-mediated SASP in ionizing radiation-induced senescence. J Cell Mol Med 2022; 26:2337-2350. [PMID: 35278036 PMCID: PMC8995441 DOI: 10.1111/jcmm.17255] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Revised: 02/04/2022] [Accepted: 02/11/2022] [Indexed: 12/25/2022] Open
Abstract
Senescence occurs upon critical telomere shortening, or following DNA damage, oncogenic activation, hypoxia and oxidative stress, overall referred to stress-induced premature senescence (SIPS). In response to DNA damage, senescent cells release cytoplasmic chromatin fragments (CCFs), and express an altered secretome, the senescence-associated secretory phenotype (SASP), which contributes to generate a pro-inflammatory and pro-tumoral extracellular milieu. Polyphenols have gained significant attention owing to their anti-inflammatory and anti-tumour activities. Here, we studied the effect of oleuropein aglycone (OLE) and hydroxytyrosol (HT) on DNA damage, CCF appearance and SASP in a model of irradiation-induced senescence. Neonatal human dermal fibroblasts (NHDFs) were γ-irradiated and incubated with OLE, 5 µM and HT, 1 µM. Cell growth and senescence-associated (SA)-β-Gal-staining were used as senescence markers. DNA damage was evaluated by Comet assay, lamin B1 expression, release of CCFs, cyclic GMP-AMP Synthase (cGAS) activation. IL-6, IL-8, MCP-1 and RANTES were measured by ELISA assay. Our results showed that OLE and HT exerted a protective effect on 8 Gy irradiation-induced senescence, preserving lamin B1 expression and reducing cGAS/STING/NFκB-mediated SASP. The ability of OLE and HT to mitigate DNA damage, senescence status and the related SASP in normal cells can be exploited to improve the efficacy and safety of cancer radiotherapy.
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Affiliation(s)
- Elena Frediani
- Department of Experimental and Clinical Biomedical SciencesUniversity of FlorenceFlorenceItaly
| | - Francesca Scavone
- Department of Experimental and Clinical Biomedical SciencesUniversity of FlorenceFlorenceItaly
| | - Anna Laurenzana
- Department of Experimental and Clinical Biomedical SciencesUniversity of FlorenceFlorenceItaly
| | - Anastasia Chillà
- Department of Experimental and Clinical Biomedical SciencesUniversity of FlorenceFlorenceItaly
| | | | - Ilaria Cimmino
- Department of Translational MedicineResearch Unit (URT) Genomic of DiabetesInstitute of Experimental Endocrinology and OncologyNational Council of Research (CNR)University of Naples Federico IINaplesItaly
| | - Manuela Leri
- Department of Experimental and Clinical Biomedical SciencesUniversity of FlorenceFlorenceItaly
| | - Monica Bucciantini
- Department of Experimental and Clinical Biomedical SciencesUniversity of FlorenceFlorenceItaly
| | - Monica Mangoni
- Department of Experimental and Clinical Biomedical SciencesUniversity of FlorenceFlorenceItaly
- Radiation Oncology Unit ‐ Oncology DepartmentAzienda Ospedaliero Universitaria CareggiFlorenceItaly
| | - Gabriella Fibbi
- Department of Experimental and Clinical Biomedical SciencesUniversity of FlorenceFlorenceItaly
| | - Mario Del Rosso
- Department of Experimental and Clinical Biomedical SciencesUniversity of FlorenceFlorenceItaly
| | - Alessandra Mocali
- Department of Experimental and Clinical Biomedical SciencesUniversity of FlorenceFlorenceItaly
| | - Lisa Giovannelli
- Department of Neurofarba (Department of Neurosciences, Psychology, Drug Research and Child Health)University of FlorenceFlorenceItaly
| | - Francesca Margheri
- Department of Experimental and Clinical Biomedical SciencesUniversity of FlorenceFlorenceItaly
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Gupta S, Panda PK, Hashimoto RF, Samal SK, Mishra S, Verma SK, Mishra YK, Ahuja R. Dynamical modeling of miR-34a, miR-449a, and miR-16 reveals numerous DDR signaling pathways regulating senescence, autophagy, and apoptosis in HeLa cells. Sci Rep 2022; 12:4911. [PMID: 35318393 PMCID: PMC8941124 DOI: 10.1038/s41598-022-08900-y] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Accepted: 03/02/2022] [Indexed: 12/31/2022] Open
Abstract
Transfection of tumor suppressor miRNAs such as miR-34a, miR-449a, and miR-16 with DNA damage can regulate apoptosis and senescence in cancer cells. miR-16 has been shown to influence autophagy in cervical cancer. However, the function of miR-34a and miR-449a in autophagy remains unknown. The functional and persistent G1/S checkpoint signaling pathways in HeLa cells via these three miRNAs, either synergistically or separately, remain a mystery. As a result, we present a synthetic Boolean network of the functional G1/S checkpoint regulation, illustrating the regulatory effects of these three miRNAs. To our knowledge, this is the first synthetic Boolean network that demonstrates the advanced role of these miRNAs in cervical cancer signaling pathways reliant on or independent of p53, such as MAPK or AMPK. We compared our estimated probability to the experimental data and found reasonable agreement. Our findings indicate that miR-34a or miR-16 may control senescence, autophagy, apoptosis, and the functional G1/S checkpoint. Additionally, miR-449a can regulate just senescence and apoptosis on an individual basis. MiR-449a can coordinate autophagy in HeLa cells in a synergistic manner with miR-16 and/or miR-34a.
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Affiliation(s)
- Shantanu Gupta
- Instituto de Matemática e Estatística, Departamento de Ciência da Computação, Universidade de São Paulo, Rua do Matão 1010, São Paulo, SP, 05508-090, Brazil.
| | - Pritam Kumar Panda
- Condensed Matter Theory Group, Materials Theory Division, Department of Physics and Astronomy, Uppsala University, Box 516, 751 20, Uppsala, Sweden
| | - Ronaldo F Hashimoto
- Instituto de Matemática e Estatística, Departamento de Ciência da Computação, Universidade de São Paulo, Rua do Matão 1010, São Paulo, SP, 05508-090, Brazil
| | - Shailesh Kumar Samal
- Unit of Immunology and Chronic Disease, Institute of Environmental Medicine, Karolinska Institutet, 17177, Stockholm, Sweden
| | - Suman Mishra
- School of Biotechnology, KIIT University, Bhubaneswar, 751024, India
| | - Suresh Kr Verma
- Condensed Matter Theory Group, Materials Theory Division, Department of Physics and Astronomy, Uppsala University, Box 516, 751 20, Uppsala, Sweden
| | - Yogendra Kumar Mishra
- Mads Clausen Institute, NanoSYD, University of Southern Denmark, Alsion 2, 6400, Sønderborg, Denmark
| | - Rajeev Ahuja
- Condensed Matter Theory Group, Materials Theory Division, Department of Physics and Astronomy, Uppsala University, Box 516, 751 20, Uppsala, Sweden.
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Palmer A, Epton S, Crawley E, Straface M, Gammon L, Edgar MM, Xu Y, Elahi S, Chin-Aleong J, Martin JE, Bishop CL, Knowles CH, Sanger GJ. Expression of p16 Within Myenteric Neurons of the Aged Colon: A Potential Marker of Declining Function. Front Neurosci 2021; 15:747067. [PMID: 34690683 PMCID: PMC8529329 DOI: 10.3389/fnins.2021.747067] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Accepted: 09/14/2021] [Indexed: 01/31/2023] Open
Abstract
Human colonic neuromuscular functions decline among the elderly. The aim was to explore the involvement of senescence. A preliminary PCR study looked for age-dependent differences in expression of CDKN1A (encoding the senescence-related p21 protein) and CDKN2A (encoding p16 and p14) in human ascending and descending colon (without mucosa) from 39 (approximately 50: 50 male: female) adult (aged 27–60 years) and elderly donors (70–89 years). Other genes from different aging pathways (e.g., inflammation, oxidative stress, autophagy) and cell-types (e.g., neurons, neuron axonal transport) were also examined. Unlike CDKN1A, CDKN2A (using primers for p16 and p14 but not when using p14-specific primers) was upregulated in both regions of colon. Compared with the number of genes appearing to upregulate in association with temporal age, more genes positively associated with increased CDKN2A expression (respectively, 16 and five of 44 genes studied for ascending and descending colon). Confirmation of increased expression of CDKN2A was sought by immunostaining for p16 in the myenteric plexus of colon from 52 patients, using a semi-automated software protocol. The results showed increased staining not within the glial cells (S100 stained), but in the cytoplasm of myenteric nerve cell bodies (MAP2 stained, with identified nucleus) of ascending, but not descending colon of the elderly, and not in the cell nucleus of either region or age group (5,710 neurons analyzed: n = 12–14 for each group). It was concluded that increased p16 staining within the cytoplasm of myenteric nerve cell bodies of elderly ascending (but not descending) colon, suggests a region-dependent, post-mitotic cellular senescence-like activity, perhaps involved with aging of enteric neurons within the colon.
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Affiliation(s)
- Alexandra Palmer
- Center for Neuroscience, Surgery and Trauma, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Sarah Epton
- Barts Health NHS Trust, Department of Colorectal Surgery and Pathology, The Royal London Hospital, London, United Kingdom
| | - Ellie Crawley
- Center for Neuroscience, Surgery and Trauma, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Marilisa Straface
- Center for Neuroscience, Surgery and Trauma, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Luke Gammon
- Center for Cell Biology and Cutaneous Research, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Meghan M Edgar
- Gastroenterology Drug Discovery Unit, Takeda Pharmaceuticals, San Diego, CA, United States
| | - Yichen Xu
- Center for Neuroscience, Surgery and Trauma, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Shezan Elahi
- Center for Neuroscience, Surgery and Trauma, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Joanne Chin-Aleong
- Barts Health NHS Trust, Department of Colorectal Surgery and Pathology, The Royal London Hospital, London, United Kingdom
| | - Joanne E Martin
- Center for Neuroscience, Surgery and Trauma, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.,Barts Health NHS Trust, Department of Colorectal Surgery and Pathology, The Royal London Hospital, London, United Kingdom
| | - Cleo L Bishop
- Center for Cell Biology and Cutaneous Research, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.,Center for Inflammation and Therapeutic Innovation Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Charles H Knowles
- Center for Neuroscience, Surgery and Trauma, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.,Barts Health NHS Trust, Department of Colorectal Surgery and Pathology, The Royal London Hospital, London, United Kingdom
| | - Gareth J Sanger
- Center for Neuroscience, Surgery and Trauma, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
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8
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Otero-Albiol D, Carnero A. Cellular senescence or stemness: hypoxia flips the coin. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2021; 40:243. [PMID: 34325734 PMCID: PMC8323321 DOI: 10.1186/s13046-021-02035-0] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Accepted: 07/05/2021] [Indexed: 01/10/2023]
Abstract
Cellular senescence is a complex physiological state whose main feature is proliferative arrest. Cellular senescence can be considered the reverse of cell immortalization and continuous tumor growth. However, cellular senescence has many physiological functions beyond being a putative tumor suppressive trait. It remains unknown whether low levels of oxygen or hypoxia, which is a feature of every tissue in the organism, modulate cellular senescence, altering its capacity to suppress the limitation of proliferation. It has been observed that the lifespan of mammalian primary cells is increased under low oxygen conditions. Additionally, hypoxia promotes self-renewal and pluripotency maintenance in adult and embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs) and cancer stem cells (CSCs). In this study, we discuss the role of hypoxia facilitating senescence bypass during malignant transformation and acquisition of stemness properties, which all contribute to tumor development and cancer disease aggressiveness.
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Affiliation(s)
- Daniel Otero-Albiol
- Instituto de Biomedicina de Sevilla, IBIS, Hospital Universitario Virgen del Rocío, Universidad de Sevilla, Consejo Superior de Investigaciones Científicas, Avda. Manuel Siurot s/n, 41013, Seville, Spain.,CIBER de CANCER, Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | - Amancio Carnero
- Instituto de Biomedicina de Sevilla, IBIS, Hospital Universitario Virgen del Rocío, Universidad de Sevilla, Consejo Superior de Investigaciones Científicas, Avda. Manuel Siurot s/n, 41013, Seville, Spain. .,CIBER de CANCER, Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
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9
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Basu A. The interplay between apoptosis and cellular senescence: Bcl-2 family proteins as targets for cancer therapy. Pharmacol Ther 2021; 230:107943. [PMID: 34182005 DOI: 10.1016/j.pharmthera.2021.107943] [Citation(s) in RCA: 89] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Accepted: 04/30/2021] [Indexed: 02/07/2023]
Abstract
Cell death by apoptosis and permanent cell cycle arrest by senescence serve as barriers to the development of cancer. Chemotherapeutic agents not only induce apoptosis, they can also induce senescence known as therapy-induced senescence (TIS). There are, however, controversies whether TIS improves or worsens therapeutic outcome. Unlike apoptosis, which permanently removes cancer cells, senescent cells are metabolically active, and can contribute to tumor progression and relapse. If senescent cells are not cleared by the immune system or if cancer cells escape senescence, they may acquire resistance to apoptotic stimuli and become highly aggressive. Thus, there have been significant efforts in developing senolytics, drugs that target these pro-survival molecules to eliminate senescent cells. The anti-apoptotic Bcl-2 family proteins not only protect against cell death by apoptosis, but they also allow senescent cells to survive. While combining senolytics with chemotherapeutic drugs is an attractive approach, there are also limitations. Moreover, members of the Bcl-2 family have distinct effects on apoptosis and senescence. The purpose of this review article is to discuss recent literatures on how members of the Bcl-2 family orchestrate the interplay between apoptosis and senescence, and the challenges and progress in targeting these Bcl-2 family proteins for cancer therapy.
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Affiliation(s)
- Alakananda Basu
- Department of Microbiology, Immunology and Genetics, University of North Texas Health Science Center, Fort Worth, TX 76107, USA.
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10
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Hu Y, Fryatt GL, Ghorbani M, Obst J, Menassa DA, Martin-Estebane M, Muntslag TAO, Olmos-Alonso A, Guerrero-Carrasco M, Thomas D, Cragg MS, Gomez-Nicola D. Replicative senescence dictates the emergence of disease-associated microglia and contributes to Aβ pathology. Cell Rep 2021; 35:109228. [PMID: 34107254 PMCID: PMC8206957 DOI: 10.1016/j.celrep.2021.109228] [Citation(s) in RCA: 150] [Impact Index Per Article: 37.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Revised: 01/29/2021] [Accepted: 05/17/2021] [Indexed: 12/22/2022] Open
Abstract
The sustained proliferation of microglia is a key hallmark of Alzheimer's disease (AD), accelerating its progression. Here, we aim to understand the long-term impact of the early and prolonged microglial proliferation observed in AD, hypothesizing that extensive and repeated cycling would engender a distinct transcriptional and phenotypic trajectory. We show that the early and sustained microglial proliferation seen in an AD-like model promotes replicative senescence, characterized by increased βgal activity, a senescence-associated transcriptional signature, and telomere shortening, correlating with the appearance of disease-associated microglia (DAM) and senescent microglial profiles in human post-mortem AD cases. The prevention of early microglial proliferation hinders the development of senescence and DAM, impairing the accumulation of Aβ, as well as associated neuritic and synaptic damage. Overall, our results indicate that excessive microglial proliferation leads to the generation of senescent DAM, which contributes to early Aβ pathology in AD.
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Affiliation(s)
- Yanling Hu
- School of Biological Sciences, University of Southampton, Southampton General Hospital, Southampton, UK
| | - Gemma L Fryatt
- School of Biological Sciences, University of Southampton, Southampton General Hospital, Southampton, UK
| | - Mohammadmersad Ghorbani
- Antibody and Vaccine Group, Centre for Cancer Immunology, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK
| | - Juliane Obst
- School of Biological Sciences, University of Southampton, Southampton General Hospital, Southampton, UK
| | - David A Menassa
- School of Biological Sciences, University of Southampton, Southampton General Hospital, Southampton, UK
| | - Maria Martin-Estebane
- School of Biological Sciences, University of Southampton, Southampton General Hospital, Southampton, UK
| | - Tim A O Muntslag
- School of Biological Sciences, University of Southampton, Southampton General Hospital, Southampton, UK
| | - Adrian Olmos-Alonso
- School of Biological Sciences, University of Southampton, Southampton General Hospital, Southampton, UK
| | - Monica Guerrero-Carrasco
- School of Biological Sciences, University of Southampton, Southampton General Hospital, Southampton, UK
| | - Daniel Thomas
- School of Biological Sciences, University of Southampton, Southampton General Hospital, Southampton, UK
| | - Mark S Cragg
- Antibody and Vaccine Group, Centre for Cancer Immunology, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK
| | - Diego Gomez-Nicola
- School of Biological Sciences, University of Southampton, Southampton General Hospital, Southampton, UK.
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11
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Ma J, Zhong M, Xiong Y, Gao Z, Wu Z, Liu Y, Hong X. Emerging roles of nucleotide metabolism in cancer development: progress and prospect. Aging (Albany NY) 2021; 13:13349-13358. [PMID: 33952722 PMCID: PMC8148454 DOI: 10.18632/aging.202962] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Accepted: 03/29/2021] [Indexed: 02/07/2023]
Abstract
Abnormal cancer metabolism occurs throughout the development of tumors. Recent studies have shown that abnormal nucleotide metabolism not only accelerates the development of tumors but also inhibits the normal immune response in the tumor microenvironment. Although few relevant experiments and reports are available, study of the interaction between nucleotide metabolism and cancer development is rapidly developing. The intervention, alteration or regulation of molecular mechanisms related to abnormal nucleotide metabolism in tumor cells has become a new idea and strategy for the treatment of tumors and prevention of recurrence and metastasis. Determining how nucleotide metabolism regulates the occurrence and progression of tumors still needs long-term and extensive research and exploration.
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Affiliation(s)
- Jingsong Ma
- Institute of Gastrointestinal Oncology, School of Medicine, Xiamen University, Fujian, Xiamen 361000, China
- Department of Gastrointestinal Surgery, Zhongshan Hospital, Xiamen University, Fujian, Xiamen 361000, China
| | - Mengya Zhong
- Institute of Gastrointestinal Oncology, School of Medicine, Xiamen University, Fujian, Xiamen 361000, China
- Department of Gastrointestinal Surgery, Zhongshan Hospital, Xiamen University, Fujian, Xiamen 361000, China
| | - Yubo Xiong
- Institute of Gastrointestinal Oncology, School of Medicine, Xiamen University, Fujian, Xiamen 361000, China
- Department of Gastrointestinal Surgery, Zhongshan Hospital, Xiamen University, Fujian, Xiamen 361000, China
| | - Zhi Gao
- National Center for International Research of Biological Targeting Diagnosis and Therapy, Guangxi Key Laboratory of Biological Targeting Diagnosis and Therapy Research, Guangxi Medical University, Guangxi, Nanning 53000, China
| | - Zhengxin Wu
- Medical College of Guangxi University, Guangxi, Nanning 530000, China
| | - Yu Liu
- General Surgery Center, Bazhong Central Hospital, Sichuan, Bazhong 636000, China
| | - Xuehui Hong
- Institute of Gastrointestinal Oncology, School of Medicine, Xiamen University, Fujian, Xiamen 361000, China
- Department of Gastrointestinal Surgery, Zhongshan Hospital, Xiamen University, Fujian, Xiamen 361000, China
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12
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Kumari R, Jat P. Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype. Front Cell Dev Biol 2021; 9:645593. [PMID: 33855023 PMCID: PMC8039141 DOI: 10.3389/fcell.2021.645593] [Citation(s) in RCA: 840] [Impact Index Per Article: 210.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Accepted: 02/16/2021] [Indexed: 01/10/2023] Open
Abstract
Cellular senescence is a stable cell cycle arrest that can be triggered in normal cells in response to various intrinsic and extrinsic stimuli, as well as developmental signals. Senescence is considered to be a highly dynamic, multi-step process, during which the properties of senescent cells continuously evolve and diversify in a context dependent manner. It is associated with multiple cellular and molecular changes and distinct phenotypic alterations, including a stable proliferation arrest unresponsive to mitogenic stimuli. Senescent cells remain viable, have alterations in metabolic activity and undergo dramatic changes in gene expression and develop a complex senescence-associated secretory phenotype. Cellular senescence can compromise tissue repair and regeneration, thereby contributing toward aging. Removal of senescent cells can attenuate age-related tissue dysfunction and extend health span. Senescence can also act as a potent anti-tumor mechanism, by preventing proliferation of potentially cancerous cells. It is a cellular program which acts as a double-edged sword, with both beneficial and detrimental effects on the health of the organism, and considered to be an example of evolutionary antagonistic pleiotropy. Activation of the p53/p21WAF1/CIP1 and p16INK4A/pRB tumor suppressor pathways play a central role in regulating senescence. Several other pathways have recently been implicated in mediating senescence and the senescent phenotype. Herein we review the molecular mechanisms that underlie cellular senescence and the senescence associated growth arrest with a particular focus on why cells stop dividing, the stability of the growth arrest, the hypersecretory phenotype and how the different pathways are all integrated.
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Affiliation(s)
- Ruchi Kumari
- MRC Prion Unit at UCL, UCL Institute of Prion Diseases, London, United Kingdom
| | - Parmjit Jat
- MRC Prion Unit at UCL, UCL Institute of Prion Diseases, London, United Kingdom
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13
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Singh BK, Tripathi M, Sandireddy R, Tikno K, Zhou J, Yen PM. Decreased autophagy and fuel switching occur in a senescent hepatic cell model system. Aging (Albany NY) 2020; 12:13958-13978. [PMID: 32712601 PMCID: PMC7425478 DOI: 10.18632/aging.103740] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Accepted: 06/18/2020] [Indexed: 02/05/2023]
Abstract
Although aging in the liver contributes to the development of chronic liver diseases such as NAFLD and insulin resistance, little is known about the molecular and metabolic details of aging in hepatic cells. To examine these issues, we used sequential oxidative stress with hydrogen peroxide to induce premature senescence in AML12 hepatic cells. The senescent cells exhibited molecular and metabolic signatures, increased SA-βGal and γH2A.X staining, and elevated senescence and pro-inflammatory gene expression that resembled livers from aged mice. Metabolic phenotyping showed fuel switching towards glycolysis and mitochondrial glutamine oxidation as well as impaired energy production. The senescent AML12 cells also had increased mTOR signaling and decreased autophagy which likely contributed to the fuel switching from β-oxidation that occurred in normal AML12 cells. Additionally, senescence-associated secretory phenotype (SASP) proteins from conditioned media of senescent cells sensitized normal AML12 cells to palmitate-induced toxicity, a known pathological effect of hepatic aging. In summary, we have generated senescent AML12 cells which displayed the molecular hallmarks of aging and also exhibited the aberrant metabolic phenotype, mitochondrial function, and cell signaling that occur in the aged liver.
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Affiliation(s)
- Brijesh Kumar Singh
- Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, Singapore 169857, Singapore
| | - Madhulika Tripathi
- Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, Singapore 169857, Singapore
| | - Reddemma Sandireddy
- Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, Singapore 169857, Singapore
| | - Keziah Tikno
- Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, Singapore 169857, Singapore
| | - Jin Zhou
- Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, Singapore 169857, Singapore
| | - Paul Michael Yen
- Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, Singapore 169857, Singapore.,Duke University School of Medicine, Durham, NC 27710, USA
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14
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Targeting perivascular and epicardial adipose tissue inflammation: therapeutic opportunities for cardiovascular disease. Clin Sci (Lond) 2020; 134:827-851. [PMID: 32271386 DOI: 10.1042/cs20190227] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2020] [Revised: 03/20/2020] [Accepted: 03/30/2020] [Indexed: 02/07/2023]
Abstract
Major shifts in human lifestyle and dietary habits toward sedentary behavior and refined food intake triggered steep increase in the incidence of metabolic disorders including obesity and Type 2 diabetes. Patients with metabolic disease are at a high risk of cardiovascular complications ranging from microvascular dysfunction to cardiometabolic syndromes including heart failure. Despite significant advances in the standards of care for obese and diabetic patients, current therapeutic approaches are not always successful in averting the accompanying cardiovascular deterioration. There is a strong relationship between adipose inflammation seen in metabolic disorders and detrimental changes in cardiovascular structure and function. The particular importance of epicardial and perivascular adipose pools emerged as main modulators of the physiology or pathology of heart and blood vessels. Here, we review the peculiarities of these two fat depots in terms of their origin, function, and pathological changes during metabolic deterioration. We highlight the rationale for pharmacological targeting of the perivascular and epicardial adipose tissue or associated signaling pathways as potential disease modifying approaches in cardiometabolic syndromes.
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15
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Mohamad Kamal NS, Safuan S, Shamsuddin S, Foroozandeh P. Aging of the cells: Insight into cellular senescence and detection Methods. Eur J Cell Biol 2020; 99:151108. [PMID: 32800277 DOI: 10.1016/j.ejcb.2020.151108] [Citation(s) in RCA: 139] [Impact Index Per Article: 27.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Accepted: 07/10/2020] [Indexed: 01/10/2023] Open
Abstract
Cellular theory of aging states that human aging is the result of cellular aging, in which an increasing proportion of cells reach senescence. Senescence, from the Latin word senex, means "growing old," is an irreversible growth arrest which occurs in response to damaging stimuli, such as DNA damage, telomere shortening, telomere dysfunction and oncogenic stress leading to suppression of potentially dysfunctional, transformed, or aged cells. Cellular senescence is characterized by irreversible cell cycle arrest, flattened and enlarged morphology, resistance to apoptosis, alteration in gene expression and chromatin structure, expression of senescence associated- β-galactosidase (SA-β-gal) and acquisition of senescence associated secretory phenotype (SASP). In this review paper, different types of cellular senescence including replicative senescence (RS) which occurs due to telomere shortening and stress induced premature senescence (SIPS) which occurs in response to different types of stress in cells, are discussed. Biomarkers of cellular senescence and senescent assays including BrdU incorporation assay, senescence associated- β-galactosidase (SA-β-gal) and senescence-associated heterochromatin foci assays to detect senescent cells are also addressed.
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Affiliation(s)
- Nor Shaheera Mohamad Kamal
- School of Health Sciences, Universiti Sains Malaysia Health Campus, 16150 Kubang Kerian, Kelantan, Malaysia
| | - Sabreena Safuan
- School of Health Sciences, Universiti Sains Malaysia Health Campus, 16150 Kubang Kerian, Kelantan, Malaysia
| | - Shaharum Shamsuddin
- School of Health Sciences, Universiti Sains Malaysia Health Campus, 16150 Kubang Kerian, Kelantan, Malaysia; USM-RIKEN International Centre for Ageing Science (URICAS), Universiti Sains Malaysia, 11800 Georgetown, Penang, Malaysia
| | - Parisa Foroozandeh
- USM-RIKEN International Centre for Ageing Science (URICAS), Universiti Sains Malaysia, 11800 Georgetown, Penang, Malaysia.
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16
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Kumar A, Bano D, Ehninger D. Cellular senescence in vivo: From cells to tissues to pathologies. Mech Ageing Dev 2020; 190:111308. [PMID: 32622996 DOI: 10.1016/j.mad.2020.111308] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Revised: 06/24/2020] [Accepted: 06/26/2020] [Indexed: 01/22/2023]
Abstract
Senescent cells accumulate during aging in a variety of tissues. Although scarce, they could influence tissue function non-cell-autonomously via secretion of a range of factors in their neighborhood. Recent studies support a role of senescent cells in age-related morbidity, including neurodegenerative diseases, cardiovascular pathologies, cancers, aging-associated nephrological alterations, chronic pulmonary disease and osteoarthritis, indicating that senescent cells could represent an interesting target for therapeutic exploitation across a range of pathophysiological contexts. In this article, we review data available to indicate which cell types can undergo senescence within various mammalian tissue environments and how these processes may contribute to tissue-specific pathologies associated with old age. We also consider markers used to identify senescent cells in vitro and in vivo. The data discussed may serve as an important starting point for an extended definition of molecular and functional characteristics of senescent cells in different organs and may hence promote the development and refinement of targeting strategies aimed at removing senescent cells from aging tissues.
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Affiliation(s)
- Avadh Kumar
- Translational Biogerontology Lab, German Center for Neurodegenerative Diseases (DZNE), Venusberg-Campus 1, 53127 Bonn, Germany
| | - Daniele Bano
- Aging and Neurodegeneration Lab, German Center for Neurodegenerative Diseases (DZNE), Venusberg-Campus 1, 53127 Bonn, Germany
| | - Dan Ehninger
- Translational Biogerontology Lab, German Center for Neurodegenerative Diseases (DZNE), Venusberg-Campus 1, 53127 Bonn, Germany.
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17
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A Novel Protocol for Detection of Senescence and Calcification Markers by Fluorescence Microscopy. Int J Mol Sci 2020; 21:ijms21103475. [PMID: 32423114 PMCID: PMC7278918 DOI: 10.3390/ijms21103475] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Revised: 05/09/2020] [Accepted: 05/11/2020] [Indexed: 02/01/2023] Open
Abstract
Vascular calcification and stiffening of the arterial wall is a systemic phenomenon that is associated with aging and it can be increased by several risk factors. The underlying mechanisms, especially the pathways of cellular senescence, are under current investigation. Easily manageable in vitro settings help to study the signaling pathways. The experimental setting presented here is based on an in vitro model using rat vascular smooth muscle cells and the detection of senescence and osteoblastic markers via immunofluorescence and RNAscope™. Co-staining of the senescence marker p21, the osteoblastic marker osteopontin, detection of senescence-associated heterochromatin foci, and senescence-associated β-galactosidase is possible within one test approach requiring fewer cells. The protocol is a fast and reliable evaluation method for multiplexing of calcifying and senescence markers with fluorescence microscopy detection. The experimental setting enables analysis on single cell basis and allows detection of intra-individual variances of cultured cells.
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18
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Kiss T, Nyúl-Tóth Á, Balasubramanian P, Tarantini S, Ahire C, DelFavero J, Yabluchanskiy A, Csipo T, Farkas E, Wiley G, Garman L, Csiszar A, Ungvari Z. Single-cell RNA sequencing identifies senescent cerebromicrovascular endothelial cells in the aged mouse brain. GeroScience 2020; 42:429-444. [PMID: 32236824 PMCID: PMC7205992 DOI: 10.1007/s11357-020-00177-1] [Citation(s) in RCA: 131] [Impact Index Per Article: 26.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Accepted: 03/01/2020] [Indexed: 01/21/2023] Open
Abstract
Age-related phenotypic changes of cerebromicrovascular endothelial cells lead to dysregulation of cerebral blood flow and blood-brain barrier disruption, promoting the pathogenesis of vascular cognitive impairment (VCI). In recent years, endothelial cell senescence has emerged as a potential mechanism contributing to microvascular pathologies opening the avenue to the therapeutic exploitation of senolytic drugs in preclinical studies. However, difficulties with the detection of senescent endothelial cells in wild type mouse models of aging hinder the assessment of the efficiency of senolytic treatments. To detect senescent endothelial cells in the aging mouse brain, we analyzed 4233 cells in fractions enriched for cerebromicrovascular endothelial cells and other cells associated with the neurovascular unit obtained from young (3-month-old) and aged (28-month-old) C57BL/6 mice. We define 13 transcriptomic cell types by deep, single-cell RNA sequencing. We match transcriptomic signatures of cellular senescence to endothelial cells identified on the basis of their gene expression profile. Our study demonstrates that with advanced aging, there is an increased ratio of senescent endothelial cells (~ 10%) in the mouse cerebral microcirculation. We propose that our single-cell RNA sequencing-based method can be adapted to study the effect of aging on senescence in various brain cell types as well as to evaluate the efficiency of various senolytic regimens in multiple tissues.
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Affiliation(s)
- Tamas Kiss
- Department of Biochemistry and Molecular Biology, Reynolds Oklahoma Center on Aging/Center for Geroscience and Healthy Brain Aging, Vascular Cognitive Impairment and Neurodegeneration Program, University of Oklahoma Health Sciences Center, 975 NE 10th Street, Oklahoma City, OK, 73104, USA
- Department of Medical Physics and Informatics, International Training Program in Geroscience, Theoretical Medicine Doctoral School, University of Szeged, Szeged, Hungary
| | - Ádám Nyúl-Tóth
- Department of Biochemistry and Molecular Biology, Reynolds Oklahoma Center on Aging/Center for Geroscience and Healthy Brain Aging, Vascular Cognitive Impairment and Neurodegeneration Program, University of Oklahoma Health Sciences Center, 975 NE 10th Street, Oklahoma City, OK, 73104, USA
- Biological Research Centre, Institute of Biophysics, Szeged, Hungary
| | - Priya Balasubramanian
- Department of Biochemistry and Molecular Biology, Reynolds Oklahoma Center on Aging/Center for Geroscience and Healthy Brain Aging, Vascular Cognitive Impairment and Neurodegeneration Program, University of Oklahoma Health Sciences Center, 975 NE 10th Street, Oklahoma City, OK, 73104, USA
| | - Stefano Tarantini
- Department of Biochemistry and Molecular Biology, Reynolds Oklahoma Center on Aging/Center for Geroscience and Healthy Brain Aging, Vascular Cognitive Impairment and Neurodegeneration Program, University of Oklahoma Health Sciences Center, 975 NE 10th Street, Oklahoma City, OK, 73104, USA
- Department of Health Promotion Sciences, College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Department of Public Health, International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine, Semmelweis University, Budapest, Hungary
| | - Chetan Ahire
- Department of Biochemistry and Molecular Biology, Reynolds Oklahoma Center on Aging/Center for Geroscience and Healthy Brain Aging, Vascular Cognitive Impairment and Neurodegeneration Program, University of Oklahoma Health Sciences Center, 975 NE 10th Street, Oklahoma City, OK, 73104, USA
| | - Jordan DelFavero
- Department of Biochemistry and Molecular Biology, Reynolds Oklahoma Center on Aging/Center for Geroscience and Healthy Brain Aging, Vascular Cognitive Impairment and Neurodegeneration Program, University of Oklahoma Health Sciences Center, 975 NE 10th Street, Oklahoma City, OK, 73104, USA
| | - Andriy Yabluchanskiy
- Department of Biochemistry and Molecular Biology, Reynolds Oklahoma Center on Aging/Center for Geroscience and Healthy Brain Aging, Vascular Cognitive Impairment and Neurodegeneration Program, University of Oklahoma Health Sciences Center, 975 NE 10th Street, Oklahoma City, OK, 73104, USA
- Department of Public Health, International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine, Semmelweis University, Budapest, Hungary
| | - Tamas Csipo
- Department of Biochemistry and Molecular Biology, Reynolds Oklahoma Center on Aging/Center for Geroscience and Healthy Brain Aging, Vascular Cognitive Impairment and Neurodegeneration Program, University of Oklahoma Health Sciences Center, 975 NE 10th Street, Oklahoma City, OK, 73104, USA
- Department of Health Promotion Sciences, College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Department of Cardiology, International Training Program in Geroscience, Division of Clinical Physiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Eszter Farkas
- Department of Medical Physics and Informatics, International Training Program in Geroscience, Theoretical Medicine Doctoral School, University of Szeged, Szeged, Hungary
| | - Graham Wiley
- Genes & Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA
| | - Lori Garman
- Genes & Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA
| | - Anna Csiszar
- Department of Biochemistry and Molecular Biology, Reynolds Oklahoma Center on Aging/Center for Geroscience and Healthy Brain Aging, Vascular Cognitive Impairment and Neurodegeneration Program, University of Oklahoma Health Sciences Center, 975 NE 10th Street, Oklahoma City, OK, 73104, USA.
- Department of Medical Physics and Informatics, International Training Program in Geroscience, Theoretical Medicine Doctoral School, University of Szeged, Szeged, Hungary.
- The Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA.
| | - Zoltan Ungvari
- Department of Biochemistry and Molecular Biology, Reynolds Oklahoma Center on Aging/Center for Geroscience and Healthy Brain Aging, Vascular Cognitive Impairment and Neurodegeneration Program, University of Oklahoma Health Sciences Center, 975 NE 10th Street, Oklahoma City, OK, 73104, USA
- Department of Medical Physics and Informatics, International Training Program in Geroscience, Theoretical Medicine Doctoral School, University of Szeged, Szeged, Hungary
- Department of Health Promotion Sciences, College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Department of Public Health, International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine, Semmelweis University, Budapest, Hungary
- The Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA
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19
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Antitumorigenic Effects of Inhibiting Ephrin Receptor Kinase Signaling by GLPG1790 against Colorectal Cancer Cell Lines In Vitro and In Vivo. JOURNAL OF ONCOLOGY 2020; 2020:9342732. [PMID: 32184826 PMCID: PMC7063197 DOI: 10.1155/2020/9342732] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Revised: 01/17/2020] [Accepted: 01/29/2020] [Indexed: 12/15/2022]
Abstract
Erythropoietin-producing hepatocellular receptors (Eph) promote the onset and sustain the progression of cancers such as colorectal cancer (CRC), in which the A2 subtype of Eph receptor expression has been shown to correlate with a poor prognosis and has been identified as a promising therapeutic target. Herein, we investigated, in vitro and in vivo, the effects of treatment with GLPG1790, a potent pan-Eph inhibitor. The small molecule has selective activity against the EphA2 isoform in human HCT116 and HCT15 CRC cell lines expressing a constitutively active form of RAS concurrently with a wild-type or mutant form of p53, respectively. GLPG1790 reduced EPHA2 phosphorylation/activation and induced G1/S cell-cycle growth arrest by downregulating the expression of cyclin E and PCNA, while upregulating p21Waf1/Cip1 and p27Cip/Kip. The inhibition of ephrin signaling induced quiescence in HCT15 and senescence in HCT116 cells. While investigating the role of CRC-related, pro-oncogenic p53 and RAS pathways, we found that GLPG1790 upregulated p53 expression and that silencing p53 or inhibiting RAS (human rat sarcoma)/ERKs (extracellular signal-regulated kinase) signaling restrained the ability of GLPG1790 to induce senescence in HCT116 cells. On the other hand, HCT15 silencing of p53 predisposed cells to GLPG1790-induced senescence, whilst no effects of ERK inhibition were observed. Finally, GLPG1790 hindered the epithelial-mesenchymal transition, reduced the migratory capacities of CRC, and affected tumor formation in xenograft models in vivo more efficiently using HCT116 than HCT15 for xenografts. Taken together, our data suggest the therapeutic potential of GLPG1790 as a signal transduction-based therapeutic strategy in to treat CRC.
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20
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Zhang R, Saredy J, Shao Y, Yao T, Liu L, Saaoud F, Yang WY, Sun Y, Johnson C, Drummer C, Fu H, Lu Y, Xu K, Liu M, Wang J, Cutler E, Yu D, Jiang X, Li Y, Li R, Wang L, Choi ET, Wang H, Yang X. End-stage renal disease is different from chronic kidney disease in upregulating ROS-modulated proinflammatory secretome in PBMCs - A novel multiple-hit model for disease progression. Redox Biol 2020; 34:101460. [PMID: 32179051 PMCID: PMC7327976 DOI: 10.1016/j.redox.2020.101460] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Revised: 01/28/2020] [Accepted: 02/07/2020] [Indexed: 12/17/2022] Open
Abstract
Background The molecular mechanisms underlying chronic kidney disease (CKD) transition to end-stage renal disease (ESRD) and CKD acceleration of cardiovascular and other tissue inflammations remain poorly determined. Methods We conducted a comprehensive data analyses on 7 microarray datasets in peripheral blood mononuclear cells (PBMCs) from patients with CKD and ESRD from NCBI-GEO databases, where we examined the expressions of 2641 secretome genes (SG). Results 1) 86.7% middle class (molecular weight >500 Daltons) uremic toxins (UTs) were encoded by SGs; 2) Upregulation of SGs in PBMCs in patients with ESRD (121 SGs) were significantly higher than that of CKD (44 SGs); 3) Transcriptomic analyses of PBMC secretome had advantages to identify more comprehensive secretome than conventional secretomic analyses; 4) ESRD-induced SGs had strong proinflammatory pathways; 5) Proinflammatory cytokines-based UTs such as IL-1β and IL-18 promoted ESRD modulation of SGs; 6) ESRD-upregulated co-stimulation receptors CD48 and CD58 increased secretomic upregulation in the PBMCs, which were magnified enormously in tissues; 7) M1-, and M2-macrophage polarization signals contributed to ESRD- and CKD-upregulated SGs; 8) ESRD- and CKD-upregulated SGs contained senescence-promoting regulators by upregulating proinflammatory IGFBP7 and downregulating anti-inflammatory TGF-β1 and telomere stabilizer SERPINE1/PAI-1; 9) ROS pathways played bigger roles in mediating ESRD-upregulated SGs (11.6%) than that in CKD-upregulated SGs (6.8%), and half of ESRD-upregulated SGs were ROS-independent. Conclusions Our analysis suggests novel secretomic upregulation in PBMCs of patients with CKD and ESRD, act synergistically with uremic toxins, to promote inflammation and potential disease progression. Our findings have provided novel insights on PBMC secretome upregulation to promote disease progression and may lead to the identification of new therapeutic targets for novel regimens for CKD, ESRD and their accelerated cardiovascular disease, other inflammations and cancers. (Total words: 279).
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Affiliation(s)
- Ruijing Zhang
- Center for Inflammation, Translational & Clinical Lung Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA; Department of Nephrology, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, 030013, China; Department of Nephrology, The Affiliated People's Hospital of Shanxi Medical University, Taiyuan, Shanxi, 030012, China
| | - Jason Saredy
- Centers for Metabolic Disease Research, Cardiovascular Research, & Thrombosis Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA
| | - Ying Shao
- Center for Inflammation, Translational & Clinical Lung Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA
| | - Tian Yao
- Shanxi Medical University, Taiyuan, Shanxi Province, 030001, China
| | - Lu Liu
- Centers for Metabolic Disease Research, Cardiovascular Research, & Thrombosis Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA
| | - Fatma Saaoud
- Center for Inflammation, Translational & Clinical Lung Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA
| | | | - Yu Sun
- Center for Inflammation, Translational & Clinical Lung Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA
| | - Candice Johnson
- Center for Inflammation, Translational & Clinical Lung Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA
| | - Charles Drummer
- Center for Inflammation, Translational & Clinical Lung Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA
| | - Hangfei Fu
- Center for Inflammation, Translational & Clinical Lung Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA
| | - Yifan Lu
- Center for Inflammation, Translational & Clinical Lung Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA
| | - Keman Xu
- Center for Inflammation, Translational & Clinical Lung Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA
| | - Ming Liu
- Center for Inflammation, Translational & Clinical Lung Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA; Shanxi Medical University, Taiyuan, Shanxi Province, 030001, China
| | - Jirong Wang
- Center for Inflammation, Translational & Clinical Lung Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA
| | - Elizabeth Cutler
- Center for Inflammation, Translational & Clinical Lung Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA; School of Science and Engineering, Tulane University, New Orleans, LA, 70118, USA
| | - Daohai Yu
- Department of Clinical Sciences, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA
| | - Xiaohua Jiang
- Center for Inflammation, Translational & Clinical Lung Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA
| | - Yafeng Li
- Department of Nephrology, The Affiliated People's Hospital of Shanxi Medical University, Taiyuan, Shanxi, 030012, China
| | - Rongshan Li
- Department of Nephrology, The Affiliated People's Hospital of Shanxi Medical University, Taiyuan, Shanxi, 030012, China
| | - Lihua Wang
- Department of Nephrology, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, 030013, China
| | - Eric T Choi
- Division of Vascular and Endovascular Surgery, Department of Surgery, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA; Centers for Metabolic Disease Research, Cardiovascular Research, & Thrombosis Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA; Departments of Pharmacology, Microbiology and Immunology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA
| | - Hong Wang
- Centers for Metabolic Disease Research, Cardiovascular Research, & Thrombosis Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA; Departments of Pharmacology, Microbiology and Immunology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA
| | - Xiaofeng Yang
- Center for Inflammation, Translational & Clinical Lung Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA; Centers for Metabolic Disease Research, Cardiovascular Research, & Thrombosis Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA; Departments of Pharmacology, Microbiology and Immunology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA.
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21
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Khorraminejad-Shirazi M, Sani M, Talaei-Khozani T, Dorvash M, Mirzaei M, Faghihi MA, Monabati A, Attar A. AICAR and nicotinamide treatment synergistically augment the proliferation and attenuate senescence-associated changes in mesenchymal stromal cells. Stem Cell Res Ther 2020; 11:45. [PMID: 32014016 PMCID: PMC6998366 DOI: 10.1186/s13287-020-1565-6] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2019] [Revised: 01/05/2020] [Accepted: 01/19/2020] [Indexed: 12/11/2022] Open
Abstract
Background Mesenchymal stromal cell (MSC) stemness capacity diminishes over prolonged in vitro culture, which negatively affects their application in regenerative medicine. To slow down the senescence of MSCs, here, we have evaluated the in vitro effects of 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), an AMPK activator, and nicotinamide (NAM), an activator of sirtuin1 (SIRT1). Methods Human adipose-derived MSCs were cultured to passage (P) 5. Subsequently, the cells were grown in either normal medium alone (control group), the medium supplemented with AICAR (1 mM) and NAM (5 mM), or in the presence of both for 5 weeks to P10. Cell proliferation, differentiation capacity, level of apoptosis and autophagy, morphological changes, total cellular reactive oxygen species (ROS), and activity of mTORC1 and AMPK were compared among different treatment groups. Results MSCs treated with AICAR, NAM, or both displayed an increase in proliferation and osteogenic differentiation, which was augmented in the group receiving both. Treatment with AICAR or NAM led to decreased expression of β-galactosidase, reduced accumulation of dysfunctional lysosomes, and characteristic morphologic features of young MSCs. Furthermore, while NAM administration could significantly reduce the total cellular ROS in aged MSCs, AICAR treatment did not. Moreover, AICAR-treated cells possess a high proliferation capacity; however, they also show the highest level of cellular apoptosis. The observed effects of AICAR and NAM were in light of the attenuated mTORC1 activity and increased AMPK activity and autophagy. Conclusions Selective inhibition of mTORC1 by AICAR and NAM boosts autophagy, retains MSCs’ self-renewal and multi-lineage differentiation capacity, and postpones senescence-associated changes after prolonged in vitro culture. Additionally, co-administration of AICAR and NAM shows an additive or probably a synergistic effect on cellular senescence.
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Affiliation(s)
- Mohammadhossein Khorraminejad-Shirazi
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran.,Cell and Molecular Medicine Student Research Group, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mahsa Sani
- Tissue Engineering Department, School of Advanced Medical Science and Technology, Shiraz University of Medical Science, Shiraz, Iran.,Tissue Engineering Lab, Department of Anatomical Sciences, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Tahereh Talaei-Khozani
- Tissue Engineering Lab, Department of Anatomical Sciences, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohammadreza Dorvash
- Cell and Molecular Medicine Student Research Group, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.,Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Malihe Mirzaei
- Persian BayanGene Research and Training Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohammad Ali Faghihi
- Persian BayanGene Research and Training Center, Shiraz University of Medical Sciences, Shiraz, Iran.,Center for Therapeutic Innovation, Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Ahmad Monabati
- Department of Pathology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.,Hematology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Armin Attar
- Department of Cardiovascular Medicine, Shiraz University of Medical Sciences, PO Box 71344-1864, Shiraz, Iran.
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22
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Banerjee J, Roy S, Dhas Y, Mishra N. Senescence-associated miR-34a and miR-126 in middle-aged Indians with type 2 diabetes. Clin Exp Med 2020; 20:149-158. [PMID: 31732824 DOI: 10.1007/s10238-019-00593-4] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2019] [Accepted: 11/01/2019] [Indexed: 12/16/2022]
Abstract
Rapid urbanization and unhealthy dietary patterns critically increase the risk of type 2 diabetes (T2D) in middle-aged Indians. However, despite recent evidence of senescence-associated microRNAs (SA-miRNAs) in regulating complex pathways of ageing, their expressions in middle-aged Indians with T2D remain unexplored. Hence we aimed to investigate the changes in expressions of SA-miRNAs miR-34a and miR-126 in middle-aged T2D patients. A total of 30 T2D patients and 30 controls were recruited of age 31-50 years. The expressions of plasma miR-34a and miR-126 were determined by quantitative PCR. Oxidized LDL (OxLDL) and malondialdehyde (MDA) levels were quantified using enzyme-linked immunosorbent assay (ELISA). The effect of different glucose concentrations on miR-34a, miR-126, senescence-associated, and oxidative stress-responsive genes were also studied in an in vitro model of mice pancreatic β-cells. MiR-34a was significantly upregulated, whereas miR-126 was nonsignificantly reduced in T2D patients as compared to controls. T2D patients showed elevated levels of oxidative stress markers than controls. Analysis of cultured mice pancreatic β-cells exposed to high glucose showed significant upregulation of miR-34a, miR-126, p53, and superoxide dismutase 2 (SOD2). We found that circulating miR-34a levels and oxidative stress markers levels were elevated in the middle-aged Indians with T2D as compared to controls. The presence of diabetes may aggravate the normal ageing process in the middle-aged Indians. These SA-miRNAs can also be used to check the cellular dysfunctions and ageing of pancreatic β-cells.
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Affiliation(s)
- Joyita Banerjee
- Symbiosis School of Biological Sciences (Formerly Symbiosis School of Biomedical Sciences), Symbiosis International (Deemed University), Lavale, Pune, 412115, India
| | - Swagata Roy
- Symbiosis School of Biological Sciences (Formerly Symbiosis School of Biomedical Sciences), Symbiosis International (Deemed University), Lavale, Pune, 412115, India
| | - Yogita Dhas
- Symbiosis School of Biological Sciences (Formerly Symbiosis School of Biomedical Sciences), Symbiosis International (Deemed University), Lavale, Pune, 412115, India
| | - Neetu Mishra
- Symbiosis School of Biological Sciences (Formerly Symbiosis School of Biomedical Sciences), Symbiosis International (Deemed University), Lavale, Pune, 412115, India.
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23
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Sur-Erdem I, Hussain MS, Asif M, Pınarbası N, Aksu AC, Noegel AA. Nesprin-1 impact on tumorigenic cell phenotypes. Mol Biol Rep 2019; 47:921-934. [PMID: 31741263 DOI: 10.1007/s11033-019-05184-w] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2019] [Accepted: 11/07/2019] [Indexed: 12/24/2022]
Abstract
The largest protein of the nuclear envelope (NE) is Nesprin-1 which forms a network along the NE interacting with actin, Emerin, Lamin, and SUN proteins. Mutations in the SYNE1 gene and reduction in Nesprin-1 protein levels have been reported to correlate with several age related diseases and cancer. In the present study, we tested whether Nesprin-1 overexpression can reverse the malignant phenotype of Huh7 cells, a human liver cancer cell line, which carries a mutation in the SYNE1 gene resulting in reduced Nesprin-1 protein levels, has altered nuclear shape, altered amounts and localization of NE components, centrosome localization and genome stability. Ectopic expression of a mini-Nesprin-1 led to an improvement of the nuclear shape, corrected the mislocalization of NE proteins, the centrosome positioning, and the alterations in the DNA damage response network. Additionally, Nesprin-1 had a profound effect on cellular senescence. These findings suggest that Nesprin-1 may be effective in tumorigenic cell phenotype correction of human liver cancer.
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Affiliation(s)
- Ilknur Sur-Erdem
- Institute of Biochemistry I, Medical Faculty, University Hospital Cologne, Cologne, Germany. .,Center for Molecular Medicine Cologne (CMMC) and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany. .,Koç University School of Medicine, 34450, Istanbul, Turkey. .,Koç University Research Center for Translational Medicine (KUTTAM), Istanbul, Turkey.
| | - Muhammed Sajid Hussain
- Institute of Biochemistry I, Medical Faculty, University Hospital Cologne, Cologne, Germany.,Center for Molecular Medicine Cologne (CMMC) and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.,Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany
| | - Maria Asif
- Institute of Biochemistry I, Medical Faculty, University Hospital Cologne, Cologne, Germany.,Center for Molecular Medicine Cologne (CMMC) and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.,Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany
| | - Nareg Pınarbası
- Koç University School of Medicine, 34450, Istanbul, Turkey.,Koç University Research Center for Translational Medicine (KUTTAM), Istanbul, Turkey
| | - Ali Cenk Aksu
- Koç University School of Medicine, 34450, Istanbul, Turkey.,Koç University Research Center for Translational Medicine (KUTTAM), Istanbul, Turkey
| | - Angelika A Noegel
- Institute of Biochemistry I, Medical Faculty, University Hospital Cologne, Cologne, Germany.,Center for Molecular Medicine Cologne (CMMC) and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
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24
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Huda N, Liu G, Hong H, Yan S, Khambu B, Yin XM. Hepatic senescence, the good and the bad. World J Gastroenterol 2019; 25:5069-5081. [PMID: 31558857 PMCID: PMC6747293 DOI: 10.3748/wjg.v25.i34.5069] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Revised: 07/25/2019] [Accepted: 08/07/2019] [Indexed: 02/06/2023] Open
Abstract
Gradual alterations of cell’s physiology and functions due to age or exposure to various stresses lead to the conversion of normal cells to senescent cells. Once becoming senescent, the cell stops dividing permanently but remains metabolically active. Cellular senescence does not have a single marker but is characterized mainly by a combination of multiple markers, such as, morphological changes, expression of cell cycle inhibitors, senescence associated β-galactosidase activity, and changes in nuclear membrane. When cells in an organ become senescent, the entire organism can be affected. This may occur through the senescence-associated secretory phenotype (SASP). SASP may exert beneficial or harmful effects on the microenvironment of tissues. Research on senescence has become a very exciting field in cell biology since the link between age-related diseases, including cancer, and senescence has been established. The loss of regenerative and homeostatic capacity of the liver over the age is somehow connected to cellular senescence. The major contributors of senescence properties in the liver are hepatocytes and cholangiocytes. Senescent cells in the liver have been implicated in the etiology of chronic liver diseases including cirrhosis and hepatocellular carcinoma and in the interference of liver regeneration. This review summarizes recently reported findings in the understanding of the molecular mechanisms of senescence and its relationship with liver diseases.
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Affiliation(s)
- Nazmul Huda
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Gang Liu
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Honghai Hong
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Shengmin Yan
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Bilon Khambu
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Xiao-Ming Yin
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, United States
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25
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Tacutu R, Thornton D, Johnson E, Budovsky A, Barardo D, Craig T, Diana E, Lehmann G, Toren D, Wang J, Fraifeld VE, de Magalhães JP. Human Ageing Genomic Resources: new and updated databases. Nucleic Acids Res 2019; 46:D1083-D1090. [PMID: 29121237 PMCID: PMC5753192 DOI: 10.1093/nar/gkx1042] [Citation(s) in RCA: 466] [Impact Index Per Article: 77.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2017] [Accepted: 10/18/2017] [Indexed: 12/17/2022] Open
Abstract
In spite of a growing body of research and data, human ageing remains a poorly understood process. Over 10 years ago we developed the Human Ageing Genomic Resources (HAGR), a collection of databases and tools for studying the biology and genetics of ageing. Here, we present HAGR’s main functionalities, highlighting new additions and improvements. HAGR consists of six core databases: (i) the GenAge database of ageing-related genes, in turn composed of a dataset of >300 human ageing-related genes and a dataset with >2000 genes associated with ageing or longevity in model organisms; (ii) the AnAge database of animal ageing and longevity, featuring >4000 species; (iii) the GenDR database with >200 genes associated with the life-extending effects of dietary restriction; (iv) the LongevityMap database of human genetic association studies of longevity with >500 entries; (v) the DrugAge database with >400 ageing or longevity-associated drugs or compounds; (vi) the CellAge database with >200 genes associated with cell senescence. All our databases are manually curated by experts and regularly updated to ensure a high quality data. Cross-links across our databases and to external resources help researchers locate and integrate relevant information. HAGR is freely available online (http://genomics.senescence.info/).
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Affiliation(s)
- Robi Tacutu
- Integrative Genomics of Ageing Group, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool L7 8TX, UK.,Computational Biology of Aging Group, Institute of Biochemistry, Romanian Academy, Bucharest 060031, Romania
| | - Daniel Thornton
- Integrative Genomics of Ageing Group, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool L7 8TX, UK
| | - Emily Johnson
- Integrative Genomics of Ageing Group, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool L7 8TX, UK
| | - Arie Budovsky
- The Shraga Segal Department of Microbiology, Immunology and Genetics, Center for Multidisciplinary Research on Aging, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel.,Judea Regional Research & Development Center, Carmel 90404, Israel
| | - Diogo Barardo
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore City 117597, Singapore.,Science Division, Yale-NUS College, Singapore City 138527, Singapore
| | - Thomas Craig
- Integrative Genomics of Ageing Group, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool L7 8TX, UK
| | - Eugene Diana
- Integrative Genomics of Ageing Group, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool L7 8TX, UK
| | - Gilad Lehmann
- The Shraga Segal Department of Microbiology, Immunology and Genetics, Center for Multidisciplinary Research on Aging, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel
| | - Dmitri Toren
- The Shraga Segal Department of Microbiology, Immunology and Genetics, Center for Multidisciplinary Research on Aging, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel
| | - Jingwei Wang
- Integrative Genomics of Ageing Group, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool L7 8TX, UK
| | - Vadim E Fraifeld
- The Shraga Segal Department of Microbiology, Immunology and Genetics, Center for Multidisciplinary Research on Aging, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel
| | - João P de Magalhães
- Integrative Genomics of Ageing Group, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool L7 8TX, UK
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26
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Chen FJ, Liu B, Wu Q, Liu J, Xu YY, Zhou SY, Shi JS. Icariin Delays Brain Aging in Senescence-Accelerated Mouse Prone 8 (SAMP8) Model via Inhibiting Autophagy. J Pharmacol Exp Ther 2019; 369:121-128. [PMID: 30837279 DOI: 10.1124/jpet.118.253310] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2018] [Accepted: 02/06/2019] [Indexed: 11/22/2022] Open
Abstract
Icariin (ICA), a major flavonoid extracted from the Chinese tonic herb Epimedium, exerts beneficial effects in a variety of age-dependent diseases, such as Alzheimer's disease (AD). However, the antiaging mechanisms remain unclear. The senescence-accelerated mouse-prone 8 (SAMP8) model has been used to study age-related neurodegenerative changes associated with aging and the pathogenesis of AD. Hence, the current study was designed to examine the effect of ICA on age-related cognitive decline in SAMP8 mice and explore the role of autophagy in the ICA-mediated neuroprotection. SAMP8 mice were administered with ICA starting at 5 months of age, and the treatment lasted for 3 consecutive months. Morris water maze was used to evaluate cognitive function. The senescence-associated β-galactosidase staining was used to determine the number of senescence cells. The neuronal morphologic changes were examined via Nissl staining. The hippocampal neuronal ultrastructure was examined by transmission electron microscopy. The expression of autophagy protein was examined by Western blot. ICA-treated SAMP8 mice exhibited a robust improvement in spatial learning and memory function. Meanwhile, ICA reduced the number of senescence cells in the brains of SAMP8 mice, inhibited neuronal loss, and reversed neuronal structural changes in the hippocampi of SAMP8 mice. Moreover, ICA treatment also decreased the formation of autophagosomes in the hippocampus of SAMP8 mice, and reduced the expression of autophagy-related proteins LC3-II and p62. These results demonstrate that ICA possesses the ability to delay brain aging in SAMP8 mice, and the mechanisms are possibly mediated through the regulation of autophagy.
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Affiliation(s)
- Fa-Ju Chen
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, People's Republic of China
| | - Bo Liu
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, People's Republic of China
| | - Qin Wu
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, People's Republic of China
| | - Jie Liu
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, People's Republic of China
| | - Yun-Yan Xu
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, People's Republic of China
| | - Shao-Yu Zhou
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, People's Republic of China
| | - Jing-Shan Shi
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, People's Republic of China
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27
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Basu A, Pal D, Blaydes R. Differential effects of protein kinase C-eta on apoptosis versus senescence. Cell Signal 2019; 55:1-7. [DOI: 10.1016/j.cellsig.2018.12.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Revised: 12/07/2018] [Accepted: 12/07/2018] [Indexed: 12/17/2022]
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28
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Trias E, Beilby PR, Kovacs M, Ibarburu S, Varela V, Barreto-Núñez R, Bradford SC, Beckman JS, Barbeito L. Emergence of Microglia Bearing Senescence Markers During Paralysis Progression in a Rat Model of Inherited ALS. Front Aging Neurosci 2019; 11:42. [PMID: 30873018 PMCID: PMC6403180 DOI: 10.3389/fnagi.2019.00042] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Accepted: 02/13/2019] [Indexed: 12/12/2022] Open
Abstract
Age is a recognized risk factor for amyotrophic lateral sclerosis (ALS), a paralytic disease characterized by progressive loss of motor neurons and neuroinflammation. A hallmark of aging is the accumulation of senescent cells. Yet, the pathogenic role of cellular senescence in ALS remains poorly understood. In rats bearing the ALS-linked SOD1G93A mutation, microgliosis contribute to motor neuron death, and its pharmacologic downregulation results in increased survival. Here, we have explored whether gliosis and motor neuron loss were associated with cellular senescence in the spinal cord during paralysis progression. In the lumbar spinal cord of symptomatic SOD1G93A rats, numerous cells displayed nuclear p16INK4a as well as loss of nuclear Lamin B1 expression, two recognized senescence-associated markers. The number of p16INK4a-positive nuclei increased by four-fold while Lamin B1-negative nuclei increased by 1,2-fold, respect to non-transgenic or asymptomatic transgenic rats. p16INK4a-positive nuclei and Lamin B1-negative nuclei were typically localized in a subset of hypertrophic Iba1-positive microglia, occasionally exhibiting nuclear giant multinucleated cell aggregates and abnormal nuclear morphology. Next, we analyzed senescence markers in cell cultures of microglia obtained from the spinal cord of symptomatic SOD1G93A rats. Although microglia actively proliferated in cultures, a subset of them developed senescence markers after few days in vitro and subsequent passages. Senescent SOD1G93A microglia in culture conditions were characterized by large and flat morphology, senescence-associated beta-Galactosidase (SA-β-Gal) activity as well as positive labeling for p16INK4a, p53, matrix metalloproteinase-1 (MMP-1) and nitrotyrosine, suggesting a senescent-associated secretory phenotype (SASP). Remarkably, in the degenerating lumbar spinal cord other cell types, including ChAT-positive motor neurons and GFAP-expressing astrocytes, also displayed nuclear p16INK4a staining. These results suggest that cellular senescence is closely associated with inflammation and motor neuron loss occurring after paralysis onset in SOD1G93A rats. The emergence of senescent cells could mediate key pathogenic mechanisms in ALS.
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Affiliation(s)
| | - Pamela R Beilby
- Department of Biochemistry and Biophysics, Oregon State University, Corvallis, OR, United States.,Linus Pauling Institute, Oregon State University, Corvallis, OR, United States
| | | | | | | | | | - Samuel C Bradford
- Linus Pauling Institute, Oregon State University, Corvallis, OR, United States
| | - Joseph S Beckman
- Department of Biochemistry and Biophysics, Oregon State University, Corvallis, OR, United States.,Linus Pauling Institute, Oregon State University, Corvallis, OR, United States
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29
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The Enigmatic Protein Kinase C-eta. Cancers (Basel) 2019; 11:cancers11020214. [PMID: 30781807 PMCID: PMC6406448 DOI: 10.3390/cancers11020214] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2019] [Revised: 02/04/2019] [Accepted: 02/10/2019] [Indexed: 01/02/2023] Open
Abstract
Protein kinase C (PKC), a multi-gene family, plays critical roles in signal transduction and cell regulation. Protein kinase C-eta (PKCη) is a unique member of the PKC family since its regulation is distinct from other PKC isozymes. PKCη was shown to regulate cell proliferation, differentiation and cell death. It was also shown to contribute to chemoresistance in several cancers. PKCη has been associated with several cancers, including renal cell carcinoma, glioblastoma, breast cancer, non-small cell lung cancer, and acute myeloid leukemia. However, mice lacking PKCη were more susceptible to tumor formation in a two-stage carcinogenesis model, and it is downregulated in hepatocellular carcinoma. Thus, the role of PKCη in cancer remains controversial. The purpose of this review article is to discuss how PKCη regulates various cellular processes that may contribute to its contrasting roles in cancer.
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30
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Oost W, Talma N, Meilof JF, Laman JD. Targeting senescence to delay progression of multiple sclerosis. J Mol Med (Berl) 2018; 96:1153-1166. [PMID: 30229272 PMCID: PMC6208951 DOI: 10.1007/s00109-018-1686-x] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2018] [Revised: 07/18/2018] [Accepted: 08/09/2018] [Indexed: 12/11/2022]
Abstract
Multiple sclerosis (MS) is a chronic and often progressive, demyelinating disease of the central nervous system (CNS) white and gray matter and the single most common cause of disability in young adults. Age is one of the factors most strongly influencing the course of progression in MS. One of the hallmarks of aging is cellular senescence. The elimination of senescent cells with senolytics has very recently been shown to delay age-related dysfunction in animal models for other neurological diseases. In this review, the possible link between cellular senescence and the progression of MS is discussed, and the potential use of senolytics as a treatment for progressive MS is explored. Currently, there is no cure for MS and there are limited treatment options to slow the progression of MS. Current treatment is based on immunomodulatory approaches. Various cell types present in the CNS can become senescent and thus potentially contribute to MS disease progression. We propose that, after cellular senescence has indeed been shown to be directly implicated in disease progression, administration of senolytics should be tested as a potential therapeutic approach for the treatment of progressive MS.
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Affiliation(s)
- Wendy Oost
- University of Groningen, Groningen, The Netherlands
| | - Nynke Talma
- European Institute for the Biology of Ageing (ERIBA), University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.,Department of Neuroscience, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Jan F Meilof
- Department of Neurology, Martini Hospital, Groningen, The Netherlands.,MS Center Noord Nederland (MSCNN), University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Jon D Laman
- Department of Neuroscience, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. .,MS Center Noord Nederland (MSCNN), University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
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31
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Phosphorylation of gH2AX as a novel prognostic biomarker for laryngoesophageal dysfunction-free survival. Oncotarget 2017; 7:31723-37. [PMID: 27166270 PMCID: PMC5077972 DOI: 10.18632/oncotarget.9172] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2015] [Accepted: 04/22/2016] [Indexed: 01/13/2023] Open
Abstract
Current larynx preservation treatments have achieved an improvement of laryngoesophageal dysfunction-free survival (LDS) but lead to significant toxicities and recurrences. At present, there is no evidence to select the group of patients that may benefit from preservation approaches instead of surgery. Therefore, laryngeal biomarkers could facilitate pretreatment identification of patients who could respond to chemoradiation-based therapy. In this study, we evaluated retrospectively 53 patients with larynx cancer to determine whether gH2AX phosphorylation (pH2AX) alone or in combination with the membrane protein MAP17 (PDZK1IP1) could be used as prognostic biomarkers. We also evaluated whether the completion of cisplatin treatment and radiotherapy could predict survival in combination with pH2AX. We found that the dose of cisplatin received but not the length of the radiotherapy influenced LDS. High-pH2AX expression was associated with prolonged LDS (HR 0.26, p = 0.02) while MAP17 correlated with overall survival (OS) (HR 0.98, p = 0.05). High-MAP17 and high-pH2AX combined analysis showed improved LDS (with 61.35 months vs 32.2 months, p = 0.05) and OS (with 66.6 months vs 39.8 months, p = 0.01). Furthermore, the subgroup of high-pH2AX and optimal dose of cisplatin was also associated with OS (72 months vs 38.6 months, p = 0.03) and LDS (66.9 months vs 27 months, p = 0.017). These findings suggest that pH2AX alone or better in combination with MAP17 may become a novel and valuable prognostic biomarker for patients with laryngeal carcinoma treated with preservation approaches.
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32
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Of Energy and Entropy: The Ineluctable Impact of Aging in Old Age Dementia. Int J Mol Sci 2017; 18:ijms18122672. [PMID: 29232829 PMCID: PMC5751274 DOI: 10.3390/ijms18122672] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2017] [Revised: 12/04/2017] [Accepted: 12/07/2017] [Indexed: 01/20/2023] Open
Abstract
Alzheimer’s disease (AD) represents the most common form of dementia among older age subjects, and despite decades of studies, the underlying mechanisms remain unresolved. The definition of AD has changed over the past 100 years, and while early-onset AD is commonly related to genetic mutations, late-onset AD is more likely due to a gradual accumulation of age-related modifications. “Normal brain aging” and AD may represent different pathways of successful or failed capability to adapt brain structures and cerebral functions. Cellular senescence and age-related changes (ARCs) affecting the brain may be considered as biologic manifestations of increasing entropy, a measure of disorder. Late-onset AD may be regarded as the final effect of a reduced energy production, due to exhausted mitochondria, and an increased entropy in the brain. This unique trajectory enables a bioenergetics-centered strategy targeting disease-stage specific profile of brain metabolism for disease prevention and treatment.
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33
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MicroRNA Regulation of Oxidative Stress-Induced Cellular Senescence. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2017; 2017:2398696. [PMID: 28593022 PMCID: PMC5448073 DOI: 10.1155/2017/2398696] [Citation(s) in RCA: 76] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/01/2017] [Revised: 03/31/2017] [Accepted: 04/11/2017] [Indexed: 12/18/2022]
Abstract
Aging is a time-related process of functional deterioration at cellular, tissue, organelle, and organismal level that ultimately brings life to end. Cellular senescence, a state of permanent cell growth arrest in response to cellular stress, is believed to be the driver of the aging process and age-related disorders. The free radical theory of aging, referred to as oxidative stress (OS) theory below, is one of the most studied aging promoting mechanisms. In addition, genetics and epigenetics also play large roles in accelerating and/or delaying the onset of aging and aging-related diseases. Among various epigenetic events, microRNAs (miRNAs) turned out to be important players in controlling OS, aging, and cellular senescence. miRNAs can generate rapid and reversible responses and, therefore, are ideal players for mediating an adaptive response against stress through their capacity to fine-tune gene expression. However, the importance of miRNAs in regulating OS in the context of aging and cellular senescence is largely unknown. The purpose of our article is to highlight recent advancements in the regulatory role of miRNAs in OS-induced cellular senescence.
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34
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Chen J, Chen KH, Fu BQ, Zhang W, Dai H, Lin LR, Wang LM, He YN. Isolation and identification of senescent renal tubular epithelial cells using immunomagnetic beads based on DcR2. Exp Gerontol 2017; 95:116-127. [PMID: 28461078 DOI: 10.1016/j.exger.2017.04.008] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2016] [Revised: 04/21/2017] [Accepted: 04/21/2017] [Indexed: 12/21/2022]
Abstract
Cell senescence plays a major role in the progression of tumors and chronic conditions such as diabetes and chronic kidney disease. Senescent cells are an important model for the study of aging-related diseases, and there is currently no efficient method for sorting out senescent cells. Decoy receptor 2 (DcR2) is a transmembrane receptor of the tumor necrosis factor superfamily, which is specifically expressed in senescent cells. In this study, we used magnetic activated cell sorting (MACS) isolation of a highly-pure populations DcR2-positive renal tubular epithelial cells (RTECs) based on three senescent cell models including the fifth passage cells, advanced glycation end-products (AGEs)- and H2O2-induced cells. The percentages of DcR2 positive RTECs in G1 and S phases increased by 20% and 4%, respectively, as compared to that in the pre-sorted cells. The positivity rates of SA-β-gal, p16, and senescence-associated heterochromatin foci (SAHF) in DcR2-positive RTECs were about 40%, 30%, and 44% higher than that prior to cell sorting. The levels of IL-6 and TGF-β1 in the supernatant were increased by 1.7 and 1.5 folds, respectively, as compared to that observed prior to sorting. No significant cell death was observed after 5days of continuous culture. Ki-67 positive expression rate in DcR2 negative RTECs was significantly higher than that in DcR2 positive RTECs after MACS. We demonstrated the use of DcR2 to classify live, senescent RTECs with a high specificity and stability. Our findings lay the foundation for further study of senescent RTECs in the progression of chronic kidney disease.
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Affiliation(s)
- Jia Chen
- Department of Nephrology, Daping Hospital, Third Military Medical University, Chongqing, China
| | - Ke-Hong Chen
- Department of Nephrology, Daping Hospital, Third Military Medical University, Chongqing, China
| | - Bi-Qiong Fu
- Department of Nephrology, Daping Hospital, Third Military Medical University, Chongqing, China
| | - Weiwei Zhang
- Department of Nephrology, Daping Hospital, Third Military Medical University, Chongqing, China
| | - Huanzi Dai
- Department of Nephrology, Daping Hospital, Third Military Medical University, Chongqing, China
| | - Li-Rong Lin
- Department of Nephrology, Daping Hospital, Third Military Medical University, Chongqing, China
| | - Li-Ming Wang
- Department of Nephrology, Daping Hospital, Third Military Medical University, Chongqing, China
| | - Ya-Ni He
- Department of Nephrology, Daping Hospital, Third Military Medical University, Chongqing, China.
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35
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Zhao J, Fuhrmann‐Stroissnigg H, Gurkar AU, Flores RR, Dorronsoro A, Stolz DB, St. Croix CM, Niedernhofer LJ, Robbins PD. Quantitative Analysis of Cellular Senescence in Culture and In Vivo. ACTA ACUST UNITED AC 2017; 79:9.51.1-9.51.25. [DOI: 10.1002/cpcy.16] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Affiliation(s)
- Jing Zhao
- Department of Metabolism and Aging, The Scripps Research Institute Jupiter Florida
| | | | - Aditi U. Gurkar
- Department of Metabolism and Aging, The Scripps Research Institute Jupiter Florida
| | - Rafael R. Flores
- Department of Metabolism and Aging, The Scripps Research Institute Jupiter Florida
| | - Akaitz Dorronsoro
- Department of Metabolism and Aging, The Scripps Research Institute Jupiter Florida
| | - Donna B. Stolz
- Department of Cell Biology, University of Pittsburgh School of Medicine Pittsburgh Pennsylvania
| | - Claudette M. St. Croix
- Department of Cell Biology, University of Pittsburgh School of Medicine Pittsburgh Pennsylvania
| | | | - Paul D. Robbins
- Department of Metabolism and Aging, The Scripps Research Institute Jupiter Florida
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36
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Guijarro MV, Carnero A. Genome-Wide miRNA Screening for Genes Bypassing Oncogene-Induced Senescence. Methods Mol Biol 2017; 1534:53-68. [PMID: 27812867 DOI: 10.1007/978-1-4939-6670-7_5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/06/2023]
Abstract
MicroRNAs are small noncoding RNAs that regulate gene expression by binding to sequences within the 3'-UTR of mRNAs. Genome-wide screens have proven powerful in associating genes with certain phenotypes or signal transduction pathways and thus are valuable tools to define gene function. Here we describe a genome-wide miRNA screening strategy to identify miRNAs that are required to bypass oncogene-induced senescence.
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Affiliation(s)
- Maria V Guijarro
- Musculoskeletal and Oncology Lab, Department of Orthopaedics and Rehabilitation, University of Florida, 1600 Archer Road, MSB M2-212, Gainesville, FL, 32610, USA.
| | - Amancio Carnero
- Molecular Biology of Cancer Group, Oncohematology and Genetic Department, Instituto de Biomedicina de Sevilla (IBIS/HUVR/CSIC/Universidad de Sevilla), Campus HUVR, Edificio IBIS, Avda. Manuel Siurot s/n. 41013, Sevilla, Spain.
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37
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Bourseguin J, Bonet C, Renaud E, Pandiani C, Boncompagni M, Giuliano S, Pawlikowska P, Karmous-Benailly H, Ballotti R, Rosselli F, Bertolotto C. FANCD2 functions as a critical factor downstream of MiTF to maintain the proliferation and survival of melanoma cells. Sci Rep 2016; 6:36539. [PMID: 27827420 PMCID: PMC5101529 DOI: 10.1038/srep36539] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2016] [Accepted: 10/18/2016] [Indexed: 11/09/2022] Open
Abstract
Proteins involved in genetic stability maintenance and safeguarding DNA replication act not only against cancer initiation but could also play a major role in sustaining cancer progression. Here, we report that the FANC pathway is highly expressed in metastatic melanoma harboring the oncogenic microphthalmia-associated transcription factor (MiTF). We show that MiTF downregulation in melanoma cells lowers the expression of several FANC genes and proteins. Moreover, we observe that, similarly to the consequence of MiTF downregulation, FANC pathway silencing alters proliferation, migration and senescence of human melanoma cells. We demonstrate that the FANC pathway acts downstream MiTF and establish the existence of an epistatic relationship between MiTF and the FANC pathway. Our findings point to a central role of the FANC pathway in cellular and chromosomal resistance to both DNA damage and targeted therapies in melanoma cells. Thus, the FANC pathway is a promising new therapeutic target in melanoma treatment.
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Affiliation(s)
- Julie Bourseguin
- CNRS UMR 8200, Gustave Roussy, Villejuif, F-94805 France.,Gustave Roussy, Université Paris-Saclay, Villejuif, F-94805, France.,Equipe Labellisée "ARC", C3M, Nice, F-06204, France
| | - Caroline Bonet
- Equipe Labellisée "ARC", C3M, Nice, F-06204, France.,Inserm, U1065, Equipe 1, Biologie et pathologies des mélanocytes: de la pigmentation cutanée au mélanome, C3M, Nice, F-06204, France.,Université Nice Sophia-Antipolis, UFR Médecine, Nice, F-06107, France
| | - Emilie Renaud
- CNRS UMR 8200, Gustave Roussy, Villejuif, F-94805 France.,Gustave Roussy, Université Paris-Saclay, Villejuif, F-94805, France.,Equipe Labellisée "ARC", C3M, Nice, F-06204, France
| | - Charlotte Pandiani
- Equipe Labellisée "ARC", C3M, Nice, F-06204, France.,Inserm, U1065, Equipe 1, Biologie et pathologies des mélanocytes: de la pigmentation cutanée au mélanome, C3M, Nice, F-06204, France.,Université Nice Sophia-Antipolis, UFR Médecine, Nice, F-06107, France
| | - Marina Boncompagni
- Equipe Labellisée "ARC", C3M, Nice, F-06204, France.,Inserm, U1065, Equipe 1, Biologie et pathologies des mélanocytes: de la pigmentation cutanée au mélanome, C3M, Nice, F-06204, France.,Université Nice Sophia-Antipolis, UFR Médecine, Nice, F-06107, France
| | - Sandy Giuliano
- Equipe Labellisée "ARC", C3M, Nice, F-06204, France.,Inserm, U1065, Equipe 1, Biologie et pathologies des mélanocytes: de la pigmentation cutanée au mélanome, C3M, Nice, F-06204, France.,Université Nice Sophia-Antipolis, UFR Médecine, Nice, F-06107, France
| | - Patrycja Pawlikowska
- CNRS UMR 8200, Gustave Roussy, Villejuif, F-94805 France.,Gustave Roussy, Université Paris-Saclay, Villejuif, F-94805, France.,Equipe Labellisée "ARC", C3M, Nice, F-06204, France
| | | | - Robert Ballotti
- Equipe Labellisée "ARC", C3M, Nice, F-06204, France.,Inserm, U1065, Equipe 1, Biologie et pathologies des mélanocytes: de la pigmentation cutanée au mélanome, C3M, Nice, F-06204, France.,Université Nice Sophia-Antipolis, UFR Médecine, Nice, F-06107, France
| | - Filippo Rosselli
- CNRS UMR 8200, Gustave Roussy, Villejuif, F-94805 France.,Gustave Roussy, Université Paris-Saclay, Villejuif, F-94805, France.,Equipe Labellisée "ARC", C3M, Nice, F-06204, France
| | - Corine Bertolotto
- Equipe Labellisée "ARC", C3M, Nice, F-06204, France.,Inserm, U1065, Equipe 1, Biologie et pathologies des mélanocytes: de la pigmentation cutanée au mélanome, C3M, Nice, F-06204, France.,Université Nice Sophia-Antipolis, UFR Médecine, Nice, F-06107, France
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Pacheco-Rivera R, Fattel-Fazenda S, Arellanes-Robledo J, Silva-Olivares A, Alemán-Lazarini L, Rodríguez-Segura M, Pérez-Carreón J, Villa-Treviño S, Shibayama M, Serrano-Luna J. Double staining of β-galactosidase with fibrosis and cancer markers reveals the chronological appearance of senescence in liver carcinogenesis induced by diethylnitrosamine. Toxicol Lett 2016; 241:19-31. [DOI: 10.1016/j.toxlet.2015.11.011] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2015] [Revised: 11/06/2015] [Accepted: 11/07/2015] [Indexed: 01/04/2023]
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39
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Goodson WH, Lowe L, Carpenter DO, Gilbertson M, Manaf Ali A, Lopez de Cerain Salsamendi A, Lasfar A, Carnero A, Azqueta A, Amedei A, Charles AK, Collins AR, Ward A, Salzberg AC, Colacci AM, Olsen AK, Berg A, Barclay BJ, Zhou BP, Blanco-Aparicio C, Baglole CJ, Dong C, Mondello C, Hsu CW, Naus CC, Yedjou C, Curran CS, Laird DW, Koch DC, Carlin DJ, Felsher DW, Roy D, Brown DG, Ratovitski E, Ryan EP, Corsini E, Rojas E, Moon EY, Laconi E, Marongiu F, Al-Mulla F, Chiaradonna F, Darroudi F, Martin FL, Van Schooten FJ, Goldberg GS, Wagemaker G, Nangami GN, Calaf GM, Williams GP, Wolf GT, Koppen G, Brunborg G, Lyerly HK, Krishnan H, Ab Hamid H, Yasaei H, Sone H, Kondoh H, Salem HK, Hsu HY, Park HH, Koturbash I, Miousse IR, Scovassi A, Klaunig JE, Vondráček J, Raju J, Roman J, Wise JP, Whitfield JR, Woodrick J, Christopher JA, Ochieng J, Martinez-Leal JF, Weisz J, Kravchenko J, Sun J, Prudhomme KR, Narayanan KB, Cohen-Solal KA, Moorwood K, Gonzalez L, Soucek L, Jian L, D’Abronzo LS, Lin LT, Li L, Gulliver L, McCawley LJ, Memeo L, Vermeulen L, Leyns L, Zhang L, Valverde M, Khatami M, Romano MF, Chapellier M, Williams MA, Wade M, et alGoodson WH, Lowe L, Carpenter DO, Gilbertson M, Manaf Ali A, Lopez de Cerain Salsamendi A, Lasfar A, Carnero A, Azqueta A, Amedei A, Charles AK, Collins AR, Ward A, Salzberg AC, Colacci AM, Olsen AK, Berg A, Barclay BJ, Zhou BP, Blanco-Aparicio C, Baglole CJ, Dong C, Mondello C, Hsu CW, Naus CC, Yedjou C, Curran CS, Laird DW, Koch DC, Carlin DJ, Felsher DW, Roy D, Brown DG, Ratovitski E, Ryan EP, Corsini E, Rojas E, Moon EY, Laconi E, Marongiu F, Al-Mulla F, Chiaradonna F, Darroudi F, Martin FL, Van Schooten FJ, Goldberg GS, Wagemaker G, Nangami GN, Calaf GM, Williams GP, Wolf GT, Koppen G, Brunborg G, Lyerly HK, Krishnan H, Ab Hamid H, Yasaei H, Sone H, Kondoh H, Salem HK, Hsu HY, Park HH, Koturbash I, Miousse IR, Scovassi A, Klaunig JE, Vondráček J, Raju J, Roman J, Wise JP, Whitfield JR, Woodrick J, Christopher JA, Ochieng J, Martinez-Leal JF, Weisz J, Kravchenko J, Sun J, Prudhomme KR, Narayanan KB, Cohen-Solal KA, Moorwood K, Gonzalez L, Soucek L, Jian L, D’Abronzo LS, Lin LT, Li L, Gulliver L, McCawley LJ, Memeo L, Vermeulen L, Leyns L, Zhang L, Valverde M, Khatami M, Romano MF, Chapellier M, Williams MA, Wade M, Manjili MH, Lleonart ME, Xia M, Gonzalez Guzman MJ, Karamouzis MV, Kirsch-Volders M, Vaccari M, Kuemmerle NB, Singh N, Cruickshanks N, Kleinstreuer N, van Larebeke N, Ahmed N, Ogunkua O, Krishnakumar P, Vadgama P, Marignani PA, Ghosh PM, Ostrosky-Wegman P, Thompson PA, Dent P, Heneberg P, Darbre P, Leung PS, Nangia-Makker P, Cheng Q(S, Robey R, Al-Temaimi R, Roy R, Andrade-Vieira R, Sinha RK, Mehta R, Vento R, Di Fiore R, Ponce-Cusi R, Dornetshuber-Fleiss R, Nahta R, Castellino RC, Palorini R, Hamid RA, Langie SA, Eltom SE, Brooks SA, Ryeom S, Wise SS, Bay SN, Harris SA, Papagerakis S, Romano S, Pavanello S, Eriksson S, Forte S, Casey SC, Luanpitpong S, Lee TJ, Otsuki T, Chen T, Massfelder T, Sanderson T, Guarnieri T, Hultman T, Dormoy V, Odero-Marah V, Sabbisetti V, Maguer-Satta V, Rathmell W, Engström W, Decker WK, Bisson WH, Rojanasakul Y, Luqmani Y, Chen Z, Hu Z. Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead. Carcinogenesis 2015; 36 Suppl 1:S254-S296. [PMID: 26106142 PMCID: PMC4480130 DOI: 10.1093/carcin/bgv039] [Show More Authors] [Citation(s) in RCA: 186] [Impact Index Per Article: 18.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2014] [Revised: 01/23/2015] [Accepted: 01/31/2015] [Indexed: 02/07/2023] Open
Abstract
Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology.
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Affiliation(s)
- William H. Goodson
- *To whom correspondence should be addressed. William H.Goodson III, California Pacific Medical Center Research Institute, 2100 Webster Street #401, San Francisco, CA 94115, USA. Tel: +41 59 233925; Fax: +41 57 761977;
| | - Leroy Lowe
- Getting to Know Cancer, Room 229A, 36 Arthur Street, Truro, Nova Scotia B2N 1X5, Canada
- Lancaster Environment Centre, Lancaster University, Bailrigg, Lancaster LA1 4AP, UK
| | - David O. Carpenter
- Institute for Health and the Environment, University at Albany, 5 University Pl., Rensselaer, NY 12144, USA
| | | | - Abdul Manaf Ali
- School of Biotechnology, Faculty of Agriculture Biotechnology and Food Sciences, Sultan Zainal Abidin University, Tembila Campus, 22200 Besut, Terengganu, Malaysia
| | | | - Ahmed Lasfar
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers, State University of New Jersey, Piscataway, NJ 08854, USA
| | - Amancio Carnero
- Instituto de Biomedicina de Sevilla, Consejo Superior de Investigaciones Cientificas. Hospital Universitario Virgen del Rocio, Univ. de Sevilla., Avda Manuel Siurot sn. 41013 Sevilla, Spain
| | - Amaya Azqueta
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, University of Navarra, Pamplona 31008, Spain
| | - Amedeo Amedei
- Department of Experimental and Clinical Medicine, University of Firenze, Florence 50134, Italy
| | - Amelia K. Charles
- School of Biological Sciences, University of Reading, Hopkins Building, Reading, Berkshire RG6 6UB, UK
| | | | - Andrew Ward
- Department of Biochemistry and Biology, University of Bath, Claverton Down, Bath BA2 7AY, UK
| | - Anna C. Salzberg
- Department of Public Health Sciences, College of Medicine, Pennsylvania State University, Hershey, PA 17033, USA
| | - Anna Maria Colacci
- Center for Environmental Carcinogenesis and Risk Assessment, Environmental Protection and Health Prevention Agency, 40126 Bologna, Italy
| | - Ann-Karin Olsen
- Department of Chemicals and Radiation, Division of Environmental Medicine, Norwegian Institute of Public Health, Oslo N-0403, Norway
| | - Arthur Berg
- Department of Public Health Sciences, College of Medicine, Pennsylvania State University, Hershey, PA 17033, USA
| | | | - Binhua P. Zhou
- Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40508, USA
| | - Carmen Blanco-Aparicio
- Spanish National Cancer Research Centre, CNIO, Melchor Fernandez Almagro, 3, 28029 Madrid, Spain
| | - Carolyn J. Baglole
- Department of Medicine, McGill University, Montreal, Quebec H4A 3J1, Canada
| | - Chenfang Dong
- Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40508, USA
| | - Chiara Mondello
- Istituto di Genetica Molecolare, CNR, Via Abbiategrasso 207, 27100 Pavia, Italy
| | - Chia-Wen Hsu
- Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Bethesda, MD 20892–3375, USA
| | - Christian C. Naus
- Department of Cellular and Physiological Sciences, Life Sciences Institute, Faculty of Medicine, The University of British Columbia, Vancouver, British Columbia V5Z 1M9, Canada
| | - Clement Yedjou
- Department of Biology, Jackson State University, Jackson, MS 39217, USA
| | - Colleen S. Curran
- Department of Molecular and Environmental Toxicology, University of Wisconsin-Madison, Madison, WI 53706, USA
| | - Dale W. Laird
- Department of Anatomy and Cell Biology, University of Western Ontario, London, Ontario N6A 3K7, Canada
| | - Daniel C. Koch
- Stanford University Department of Medicine, Division of Oncology, Stanford, CA 94305, USA
| | - Danielle J. Carlin
- Superfund Research Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27560, USA
| | - Dean W. Felsher
- Department of Medicine, Oncology and Pathology, Stanford University,Stanford, CA 94305, USA
| | - Debasish Roy
- Department of Natural Science, The City University of New York at Hostos Campus, Bronx, NY 10451, USA
| | - Dustin G. Brown
- Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO 80523–1680, USA
| | - Edward Ratovitski
- Department of Head and Neck Surgery/Head and Neck Cancer Research, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Elizabeth P. Ryan
- Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO 80523–1680, USA
| | - Emanuela Corsini
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, 20133 Milan, Italy
| | - Emilio Rojas
- Department of Genomic Medicine and Environmental Toxicology, Institute for Biomedical Research, National Autonomous University of Mexico, Mexico City 04510, México
| | - Eun-Yi Moon
- Department of Bioscience and Biotechnology, Sejong University, Seoul 143–747, Korea
| | - Ezio Laconi
- Department of Biomedical Sciences, University of Cagliari, 09124 Cagliari, Italy
| | - Fabio Marongiu
- Department of Biomedical Sciences, University of Cagliari, 09124 Cagliari, Italy
| | - Fahd Al-Mulla
- Department of Pathology, Kuwait University, Safat 13110, Kuwait
| | - Ferdinando Chiaradonna
- Department of Biotechnology and Biosciences, University of Milano-Bicocca, 20126 Milan, Italy
- SYSBIO Centre of Systems Biology, Department of Biotechnology and Biosciences, University of Milano-Bicocca, 20126 Milan, Italy
| | - Firouz Darroudi
- Human Safety and Environmental Research, Department of Health Sciences, College of North Atlantic, Doha 24449, State of Qatar
| | - Francis L. Martin
- Lancaster Environment Centre, Lancaster University, Bailrigg, Lancaster LA1 4AP, UK
| | - Frederik J. Van Schooten
- Department of Toxicology, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University, Maastricht 6200, The Netherlands
| | - Gary S. Goldberg
- Department of Molecular Biology, School of Osteopathic Medicine, Rowan University, Stratford, NJ 08084, USA
| | - Gerard Wagemaker
- Hacettepe University, Center for Stem Cell Research and Development, Ankara 06640, Turkey
| | - Gladys N. Nangami
- Department of Biochemistry and Cancer Biology, Meharry Medical College, Nashville, TN 37208, USA
| | - Gloria M. Calaf
- Center for Radiological Research, Columbia University Medical Center, New York, NY 10032, USA
- Instituto de Alta Investigacion, Universidad de Tarapaca, Arica, Chile
| | - Graeme P. Williams
- School of Biological Sciences, University of Reading, Reading, RG6 6UB, UK
| | - Gregory T. Wolf
- Department of Otolaryngology - Head and Neck Surgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Gudrun Koppen
- Environmental Risk and Health Unit, Flemish Institute for Technological Research, 2400 Mol, Belgium
| | - Gunnar Brunborg
- Department of Chemicals and Radiation, Division of Environmental Medicine, Norwegian Institute of Public Health, Oslo N-0403, Norway
| | - H. Kim Lyerly
- Department of Surgery, Pathology, Immunology, Duke University Medical Center, Durham, NC 27710, USA
| | - Harini Krishnan
- Department of Molecular Biology, School of Osteopathic Medicine, Rowan University, Stratford, NJ 08084, USA
| | - Hasiah Ab Hamid
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, 43400 Universiti Putra Malaysia, Serdang, Selangor, Malaysia
| | - Hemad Yasaei
- Department of Life Sciences, College of Health and Life Sciences and the Health and Environment Theme, Institute of Environment, Health and Societies, Brunel University Kingston Lane, Uxbridge, Middlesex UB8 3PH, UK
| | - Hideko Sone
- National Institute for Environmental Studies, 16-2 Onogawa, Tsukuba, Ibraki 3058506, Japan
| | - Hiroshi Kondoh
- Department of Geriatric Medicine, Kyoto University Hospital 54 Kawaharacho, Shogoin, Sakyo-ku Kyoto, 606–8507, Japan
| | - Hosni K. Salem
- Department of Urology, Kasr Al-Ainy School of Medicine, Cairo University, El Manial, Cairo 11559, Egypt
| | - Hsue-Yin Hsu
- Department of Life Sciences, Tzu-Chi University, Hualien 970, Taiwan
| | - Hyun Ho Park
- School of Biotechnology, Yeungnam University, Gyeongbuk 712-749, South Korea
| | - Igor Koturbash
- Department of Environmental and Occupational Health, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
| | - Isabelle R. Miousse
- Department of Environmental and Occupational Health, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
| | - A.Ivana Scovassi
- Istituto di Genetica Molecolare, CNR, Via Abbiategrasso 207, 27100 Pavia, Italy
| | - James E. Klaunig
- Department of Environmental Health, Indiana University, School of Public Health, Bloomington, IN 47405, USA
| | - Jan Vondráček
- Department of Cytokinetics, Institute of Biophysics Academy of Sciences of the Czech Republic, Brno, CZ-61265, Czech Republic
| | - Jayadev Raju
- Regulatory Toxicology Research Division, Bureau of Chemical Safety, Food Directorate, Health Canada, Ottawa, Ontario K1A 0K9, Canada
| | - Jesse Roman
- Department of Medicine, University of Louisville, Louisville, KY 40202, USA
- Robley Rex VA Medical Center, Louisville, KY 40202, USA
| | - John Pierce Wise
- Department of Applied Medical Sciences, University of Southern Maine, 96 Falmouth St., Portland, ME 04104, USA
| | - Jonathan R. Whitfield
- Mouse Models of Cancer Therapies Group, Vall d’Hebron Institute of Oncology (VHIO), 08035 Barcelona, Spain
| | - Jordan Woodrick
- Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington DC 20057, USA
| | - Joseph A. Christopher
- Cancer Research UK. Cambridge Institute, University of Cambridge, Robinson Way, Cambridge CB2 0RE, UK
| | - Josiah Ochieng
- Department of Biochemistry and Cancer Biology, Meharry Medical College, Nashville, TN 37208, USA
| | | | - Judith Weisz
- Departments of Obstetrics and Gynecology and Pathology, Pennsylvania State University College of Medicine, Hershey PA 17033, USA
| | - Julia Kravchenko
- Department of Surgery, Pathology, Immunology, Duke University Medical Center, Durham, NC 27710, USA
| | - Jun Sun
- Department of Biochemistry, Rush University, Chicago, IL 60612, USA
| | - Kalan R. Prudhomme
- Environmental and Molecular Toxicology, Environmental Health Science Center, Oregon State University, Corvallis, OR 97331, USA
| | | | - Karine A. Cohen-Solal
- Department of Medicine/Medical Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA
| | - Kim Moorwood
- Department of Biochemistry and Biology, University of Bath, Claverton Down, Bath BA2 7AY, UK
| | - Laetitia Gonzalez
- Laboratory for Cell Genetics, Vrije Universiteit Brussel, 1050 Brussels, Belgium
| | - Laura Soucek
- Mouse Models of Cancer Therapies Group, Vall d’Hebron Institute of Oncology (VHIO), 08035 Barcelona, Spain
- Catalan Institution for Research and Advanced Studies (ICREA), Barcelona 08010, Spain
| | - Le Jian
- School of Public Health, Curtin University, Bentley, WA 6102, Australia
- Department of Urology, University of California Davis, Sacramento, CA 95817, USA
| | - Leandro S. D’Abronzo
- Department of Urology, University of California Davis, Sacramento, CA 95817, USA
| | - Liang-Tzung Lin
- Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Lin Li
- School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, NT, Hong Kong SAR, The People’s Republic of China
| | - Linda Gulliver
- Faculty of Medicine, University of Otago, Dunedin 9054, New Zealand
| | - Lisa J. McCawley
- Department of Biomedical Engineering and Cancer Biology, Vanderbilt University, Nashville, TN 37235, USA
| | - Lorenzo Memeo
- Department of Experimental Oncology, Mediterranean Institute of Oncology, Via Penninazzo 7, Viagrande (CT) 95029, Italy
| | - Louis Vermeulen
- Center for Experimental Molecular Medicine, Academic Medical Center, Meibergdreef 9, Amsterdam 1105 AZ, The Netherlands
| | - Luc Leyns
- Laboratory for Cell Genetics, Vrije Universiteit Brussel, 1050 Brussels, Belgium
| | - Luoping Zhang
- Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, CA 94720-7360, USA
| | - Mahara Valverde
- Department of Genomic Medicine and Environmental Toxicology, Institute for Biomedical Research, National Autonomous University of Mexico, Mexico City 04510, México
| | - Mahin Khatami
- Inflammation and Cancer Research, National Cancer Institute (NCI) (Retired), National Institutes of Health, Bethesda, MD 20892, USA
| | - Maria Fiammetta Romano
- Department of Molecular Medicine and Medical Biotechnology, Federico II University of Naples, 80131 Naples, Italy
| | - Marion Chapellier
- Centre De Recherche En Cancerologie,De Lyon, Lyon, U1052-UMR5286, France
| | - Marc A. Williams
- United States Army Institute of Public Health, Toxicology Portfolio-Health Effects Research Program, Aberdeen Proving Ground, Edgewood, MD 21010-5403, USA
| | - Mark Wade
- Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia, Via Adamello 16, 20139 Milano, Italy
| | - Masoud H. Manjili
- Department of Microbiology and Immunology, Virginia Commonwealth University, Massey Cancer Center, Richmond, VA 23298, USA
| | - Matilde E. Lleonart
- Institut De Recerca Hospital Vall D’Hebron, Passeig Vall d’Hebron, 119–129, 08035 Barcelona, Spain
| | - Menghang Xia
- Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Bethesda, MD 20892–3375, USA
| | - Michael J. Gonzalez Guzman
- University of Puerto Rico, Medical Sciences Campus, School of Public Health, Nutrition Program, San Juan 00921, Puerto Rico
| | - Michalis V. Karamouzis
- Department of Biological Chemistry, Medical School, University of Athens, Institute of Molecular Medicine and Biomedical Research, 10676 Athens, Greece
| | | | - Monica Vaccari
- Center for Environmental Carcinogenesis and Risk Assessment, Environmental Protection and Health Prevention Agency, 40126 Bologna, Italy
| | | | - Neetu Singh
- Advanced Molecular Science Research Centre (Centre for Advanced Research), King George’s Medical University, Lucknow, Uttar Pradesh 226 003, India
| | - Nichola Cruickshanks
- Departments of Neurosurgery and Biochemistry and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA
| | - Nicole Kleinstreuer
- Integrated Laboratory Systems Inc., in support of the National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods, RTP, NC 27709, USA
| | - Nik van Larebeke
- Analytische, Milieu en Geochemie, Vrije Universiteit Brussel, Brussel B1050, Belgium
| | - Nuzhat Ahmed
- Department of Obstetrics and Gynecology, University of Melbourne, Victoria 3052, Australia
| | - Olugbemiga Ogunkua
- Department of Biochemistry and Cancer Biology, Meharry Medical College, Nashville, TN 37208, USA
| | - P.K. Krishnakumar
- Center for Environment and Water, Research Institute, King Fahd University of Petroleum and Minerals, Dhahran 3126, Saudi Arabia
| | - Pankaj Vadgama
- School of Engineering and Materials Science, Queen Mary University of London, Mile End Road, London, E1 4NS, UK
| | - Paola A. Marignani
- Department of Biochemistry and Molecular Biology, Dalhousie University, Halifax, Nova Scotia B3H 4R2, Canada
| | - Paramita M. Ghosh
- Department of Urology, University of California Davis, Sacramento, CA 95817, USA
| | - Patricia Ostrosky-Wegman
- Department of Genomic Medicine and Environmental Toxicology, Institute for Biomedical Research, National Autonomous University of Mexico, Mexico City 04510, México
| | - Patricia A. Thompson
- Department of Pathology, Stony Brook School of Medicine, Stony Brook University, The State University of New York, Stony Brook, NY 11794-8691, USA
| | - Paul Dent
- Departments of Neurosurgery and Biochemistry and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA
| | - Petr Heneberg
- Charles University in Prague, Third Faculty of Medicine, CZ-100 00 Prague 10, Czech Republic
| | - Philippa Darbre
- School of Biological Sciences, The University of Reading, Whiteknights, Reading RG6 6UB, England
| | - Po Sing Leung
- School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, NT, Hong Kong SAR, The People’s Republic of China
| | | | - Qiang (Shawn) Cheng
- Computer Science Department, Southern Illinois University, Carbondale, IL 62901, USA
| | - R.Brooks Robey
- White River Junction Veterans Affairs Medical Center, White River Junction, VT 05009, USA
- Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA
| | - Rabeah Al-Temaimi
- Human Genetics Unit, Department of Pathology, Faculty of Medicine, Kuwait University, Jabriya 13110, Kuwait
| | - Rabindra Roy
- Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington DC 20057, USA
| | - Rafaela Andrade-Vieira
- Department of Biochemistry and Molecular Biology, Dalhousie University, Halifax, Nova Scotia B3H 4R2, Canada
| | - Ranjeet K. Sinha
- Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - Rekha Mehta
- Regulatory Toxicology Research Division, Bureau of Chemical Safety, Food Directorate, Health Canada, Ottawa, Ontario K1A 0K9, Canada
| | - Renza Vento
- Department of Biological, Chemical, and Pharmaceutical Sciences and Technologies, Polyclinic Plexus, University of Palermo, Palermo 90127, Italy
- Sbarro Institute for Cancer Research and Molecular Medicine, Temple University, Philadelphia, PA 19122, USA
| | - Riccardo Di Fiore
- Department of Biological, Chemical, and Pharmaceutical Sciences and Technologies, Polyclinic Plexus, University of Palermo, Palermo 90127, Italy
| | | | - Rita Dornetshuber-Fleiss
- Department of Pharmacology and Toxicology, University of Vienna, Vienna A-1090, Austria
- Institute of Cancer Research, Department of Medicine, Medical University of Vienna, Wien 1090, Austria
| | - Rita Nahta
- Departments of Pharmacology and Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA 30322, USA
| | - Robert C. Castellino
- Division of Hematology and Oncology, Department of Pediatrics, Children’s Healthcare of Atlanta, GA 30322, USA
- Department of Pediatrics, Emory University School of Medicine, Emory University, Atlanta, GA 30322, USA
| | - Roberta Palorini
- Department of Biotechnology and Biosciences, University of Milano-Bicocca, 20126 Milan, Italy
- SYSBIO Centre of Systems Biology, Department of Biotechnology and Biosciences, University of Milano-Bicocca, 20126 Milan, Italy
| | - Roslida A. Hamid
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, 43400 Universiti Putra Malaysia, Serdang, Selangor, Malaysia
| | - Sabine A.S. Langie
- Environmental Risk and Health Unit, Flemish Institute for Technological Research, 2400 Mol, Belgium
| | - Sakina E. Eltom
- Department of Biochemistry and Cancer Biology, Meharry Medical College, Nashville, TN 37208, USA
| | - Samira A. Brooks
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, NC 27599, USA
| | - Sandra Ryeom
- Department of Cancer Biology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Sandra S. Wise
- Department of Applied Medical Sciences, University of Southern Maine, 96 Falmouth St., Portland, ME 04104, USA
| | - Sarah N. Bay
- Program in Genetics and Molecular Biology, Graduate Division of Biological and Biomedical Sciences, Emory University, Atlanta, GA 30322, USA
| | - Shelley A. Harris
- Population Health and Prevention, Research, Prevention and Cancer Control, Cancer Care Ontario, Toronto, Ontario, M5G 2L7, Canada
- Departments of Epidemiology and Occupational and Environmental Health, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, M5T 3M7, Canada
| | - Silvana Papagerakis
- Department of Otolaryngology - Head and Neck Surgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Simona Romano
- Department of Molecular Medicine and Medical Biotechnology, Federico II University of Naples, 80131 Naples, Italy
| | - Sofia Pavanello
- Department of Cardiac, Thoracic and Vascular Sciences, Unit of Occupational Medicine, University of Padova, Padova 35128, Italy
| | - Staffan Eriksson
- Department of Anatomy, Physiology and Biochemistry, The Swedish University of Agricultural Sciences, PO Box 7011, VHC, Almas Allé 4, SE-756 51, Uppsala, Sweden
| | - Stefano Forte
- Department of Experimental Oncology, Mediterranean Institute of Oncology, Via Penninazzo 7, Viagrande (CT) 95029, Italy
| | - Stephanie C. Casey
- Stanford University Department of Medicine, Division of Oncology, Stanford, CA 94305, USA
| | - Sudjit Luanpitpong
- Siriraj Center of Excellence for Stem Cell Research, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Tae-Jin Lee
- Department of Anatomy, College of Medicine, Yeungnam University, Daegu 705–717, South Korea,
| | - Takemi Otsuki
- Department of Hygiene, Kawasaki Medical School, Matsushima Kurashiki, Okayama 701-0192, Japan,
| | - Tao Chen
- Division of Genetic and Molecular Toxicology, National Center for Toxicological Research, United States Food and Drug Administration, Jefferson, AR 72079, USA
| | - Thierry Massfelder
- INSERM U1113, team 3 ‘Cell Signalling and Communication in Kidney and Prostate Cancer’, University of Strasbourg, Faculté de Médecine, 67085 Strasbourg, France
| | - Thomas Sanderson
- INRS-Institut Armand-Frappier, 531 Boulevard des Prairies, Laval, QC H7V 1B7, Canada,
| | - Tiziana Guarnieri
- Department of Biology, Geology and Environmental Sciences, Alma Mater Studiorum Università di Bologna, Via Francesco Selmi, 3, 40126 Bologna, Italy
- Center for Applied Biomedical Research, S. Orsola-Malpighi University Hospital, Via Massarenti, 9, 40126 Bologna, Italy
- National Institute of Biostructures and Biosystems, Viale Medaglie d’ Oro, 305, 00136 Roma, Italy
| | - Tove Hultman
- Department of Biosciences and Veterinary Public Health, Faculty of Veterinary Medicine, Swedish University of Agricultural Sciences, PO Box 7028, 75007 Uppsala, Sweden
| | - Valérian Dormoy
- INSERM U1113, team 3 ‘Cell Signalling and Communication in Kidney and Prostate Cancer’, University of Strasbourg, Faculté de Médecine, 67085 Strasbourg, France
- Department of Cell and Developmental Biology, University of California, Irvine, CA 92697, USA
| | - Valerie Odero-Marah
- Department of Biology/Center for Cancer Research and Therapeutic Development, Clark Atlanta University, Atlanta, GA 30314, USA
| | - Venkata Sabbisetti
- Harvard Medical School/Brigham and Women’s Hospital, Boston, MA 02115, USA
| | - Veronique Maguer-Satta
- United States Army Institute of Public Health, Toxicology Portfolio-Health Effects Research Program, Aberdeen Proving Ground, Edgewood, MD 21010-5403, USA
| | - W.Kimryn Rathmell
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, NC 27599, USA
| | - Wilhelm Engström
- Department of Biosciences and Veterinary Public Health, Faculty of Veterinary Medicine, Swedish University of Agricultural Sciences, PO Box 7028, 75007 Uppsala, Sweden
| | | | - William H. Bisson
- Environmental and Molecular Toxicology, Environmental Health Science Center, Oregon State University, Corvallis, OR 97331, USA
| | - Yon Rojanasakul
- Department of Pharmaceutical Sciences, West Virginia University, Morgantown,WV, 26506,USA
| | - Yunus Luqmani
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kuwait University, PO Box 24923, Safat 13110, Kuwait and
| | - Zhenbang Chen
- Department of Biochemistry and Cancer Biology, Meharry Medical College, Nashville, TN 37208, USA
| | - Zhiwei Hu
- Department of Surgery, The Ohio State University College of Medicine, The James Comprehensive Cancer Center, Columbus, OH 43210, USA
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Carnero A, Blanco-Aparicio C, Kondoh H, Lleonart ME, Martinez-Leal JF, Mondello C, Ivana Scovassi A, Bisson WH, Amedei A, Roy R, Woodrick J, Colacci A, Vaccari M, Raju J, Al-Mulla F, Al-Temaimi R, Salem HK, Memeo L, Forte S, Singh N, Hamid RA, Ryan EP, Brown DG, Wise JP, Wise SS, Yasaei H. Disruptive chemicals, senescence and immortality. Carcinogenesis 2015; 36 Suppl 1:S19-S37. [PMID: 26106138 PMCID: PMC4565607 DOI: 10.1093/carcin/bgv029] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2014] [Revised: 08/04/2014] [Accepted: 08/05/2014] [Indexed: 12/16/2022] Open
Abstract
Carcinogenesis is thought to be a multistep process, with clonal evolution playing a central role in the process. Clonal evolution involves the repeated 'selection and succession' of rare variant cells that acquire a growth advantage over the remaining cell population through the acquisition of 'driver mutations' enabling a selective advantage in a particular micro-environment. Clonal selection is the driving force behind tumorigenesis and possesses three basic requirements: (i) effective competitive proliferation of the variant clone when compared with its neighboring cells, (ii) acquisition of an indefinite capacity for self-renewal, and (iii) establishment of sufficiently high levels of genetic and epigenetic variability to permit the emergence of rare variants. However, several questions regarding the process of clonal evolution remain. Which cellular processes initiate carcinogenesis in the first place? To what extent are environmental carcinogens responsible for the initiation of clonal evolution? What are the roles of genotoxic and non-genotoxic carcinogens in carcinogenesis? What are the underlying mechanisms responsible for chemical carcinogen-induced cellular immortality? Here, we explore the possible mechanisms of cellular immortalization, the contribution of immortalization to tumorigenesis and the mechanisms by which chemical carcinogens may contribute to these processes.
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Affiliation(s)
- Amancio Carnero
- *To whom correspondence should be addressed. Tel: +34955923111; Fax: +34955923101;
| | - Carmen Blanco-Aparicio
- Spanish National Cancer Research Center, Experimental Therapuetics Department, Melchor Fernandez Almagro, 3, 28029 Madrid, Spain
| | - Hiroshi Kondoh
- Department of Geriatric Medicine, Kyoto University Hospital, 54 Kawaharacho, Shogoin, Sakyo-ku Kyoto 606-8507, Japan
| | - Matilde E. Lleonart
- Institut De Recerca Hospital Vall D’Hebron, Passeig Vall d’Hebron, 119–129, 08035 Barcelona, Spain
| | | | - Chiara Mondello
- Istituto di Genetica Molecolare, CNR, Via Abbiategrasso 207, 27100 Pavia, Italy
| | - A. Ivana Scovassi
- Istituto di Genetica Molecolare, CNR, Via Abbiategrasso 207, 27100 Pavia, Italy
| | - William H. Bisson
- Environmental and Molecular Toxicology, Environmental Health Science Center, Oregon State University, Corvallis, OR 97331, USA
| | - Amedeo Amedei
- Department of Experimental and Clinical Medicine, University of Firenze, Italy, Florence 50134, Italy
| | - Rabindra Roy
- Molecular Oncology Program, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA
| | - Jordan Woodrick
- Molecular Oncology Program, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA
| | - Annamaria Colacci
- Center for Environmental Carcinogenesis and Risk Assessment, Environmental Protection and Health Prevention Agency, Bologna 40126, Italy
| | - Monica Vaccari
- Center for Environmental Carcinogenesis and Risk Assessment, Environmental Protection and Health Prevention Agency, Bologna 40126, Italy
| | - Jayadev Raju
- Toxicology Research Division, Bureau of Chemical Safety Food Directorate, Health Products and Food Branch Health Canada, Ottawa, Ontario K1A0K9, Canada
| | - Fahd Al-Mulla
- Department of Pathology, Kuwait University, Safat 13110, Kuwait
| | | | - Hosni K. Salem
- Urology Department, kasr Al-Ainy School of Medicine, Cairo University, El Manial, Cairo 12515, Egypt
| | - Lorenzo Memeo
- Mediterranean Institute of Oncology, Viagrande 95029, Italy
| | - Stefano Forte
- Mediterranean Institute of Oncology, Viagrande 95029, Italy
| | - Neetu Singh
- Centre for Advanced Research, King George’s Medical University, Chowk, Lucknow, Uttar Pradesh 226003, India
| | - Roslida A. Hamid
- Department of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 Serdang, Selangor 43400, Malaysia
| | - Elizabeth P. Ryan
- Department of Environmental and Radiological Health Sciences, Colorado State University/Colorado School of Public Health, Fort Collins, CO 80523-1680, USA
| | - Dustin G. Brown
- Department of Environmental and Radiological Health Sciences, Colorado State University/Colorado School of Public Health, Fort Collins, CO 80523-1680, USA
| | - John Pierce Wise
- The Wise Laboratory of Environmental and Genetic Toxicology, Maine Center for Toxicology and Environmental Health, Department of Applied Medical Sciences, University of Southern Maine, 96 Falmouth Street, Portland, ME 04104, USA and
| | - Sandra S. Wise
- The Wise Laboratory of Environmental and Genetic Toxicology, Maine Center for Toxicology and Environmental Health, Department of Applied Medical Sciences, University of Southern Maine, 96 Falmouth Street, Portland, ME 04104, USA and
| | - Hemad Yasaei
- Brunel Institute of Cancer Genetics and Pharmacogenomics, Health and Environment Theme, Institute of Environment, Health and Societies, Brunel University London, Kingston Lane, Uxbridge, UB8 3PH, UK
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Jie B, Weilong C, Ming C, Fei X, Xinghua L, Junhua C, Guobin W, Kaixiong T, Xiaoming S. Enhancer of zeste homolog 2 depletion induces cellular senescence via histone demethylation along the INK4/ARF locus. Int J Biochem Cell Biol 2015; 65:104-12. [PMID: 26004298 DOI: 10.1016/j.biocel.2015.05.011] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2015] [Revised: 04/06/2015] [Accepted: 05/13/2015] [Indexed: 10/23/2022]
Abstract
Polycomb group proteins are epigenetic transcriptional repressors that function through recognition and modification of histone methylation and chromatin structure. As a member of PcG proteins, enhancer of zeste homolog 2 (EZH2) targets cell cycle regulatory proteins which govern cell cycle progression and cellular senescence. In previous work, we reported that EZH2 depletion functionally induced cellular senescence in human gastric cancer cells with mutant p53. However, whether EZH2 expression contributes to the change of key cell cycle regulators and the mechanism involved are still unclear. To address this issue, we investigated the effects of EZH2 depletion on alteration of histone methylation pattern. In gastric cancer cells, INK4/ARF locus was activated to certain extent in consequence of a decrease of H3K27me3 along it caused by EZH2 silence, which contributed substantially to an increase in the expression of p15(INK4b), p14(ARF) and p16(INK4a) and resulted in cellular senescence ultimately. Furthermore, MKN28 cells, which did not express p16(INK4a) and p21(cip), could be induced to senescence via p15(INK4b) activation and suppression of p15(INK4b) reversed senescence progression induced by EZH2 downregulated. These data unravel a crucial role of EZH2 in the regulation of INK4/ARF expression and senescence procedure in gastric cancer cells, and show that the cellular senescence could just depend on the activation of p15(INK4b)/Rb pathway, suggesting the cell-type and species specificity involved in the mechanisms of senescence inducement.
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Affiliation(s)
- Bai Jie
- Department of Gastrointestinal Surgery II, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan, Hubei Province 430022, People's Republic of China.
| | - Chang Weilong
- Department of Gastrointestinal Surgery II, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan, Hubei Province 430022, People's Republic of China.
| | - Cai Ming
- Department of Gastrointestinal Surgery II, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan, Hubei Province 430022, People's Republic of China.
| | - Xu Fei
- Department of Gastrointestinal Surgery II, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan, Hubei Province 430022, People's Republic of China.
| | - Liu Xinghua
- Department of Gastrointestinal Surgery II, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan, Hubei Province 430022, People's Republic of China.
| | - Chen Junhua
- Department of Gastrointestinal Surgery II, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan, Hubei Province 430022, People's Republic of China.
| | - Wang Guobin
- Department of Gastrointestinal Surgery II, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan, Hubei Province 430022, People's Republic of China.
| | - Tao Kaixiong
- Department of Gastrointestinal Surgery II, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan, Hubei Province 430022, People's Republic of China.
| | - Shuai Xiaoming
- Department of Gastrointestinal Surgery II, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan, Hubei Province 430022, People's Republic of China.
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Kilic Eren M, Kilincli A, Eren Ö. Resveratrol Induced Premature Senescence Is Associated with DNA Damage Mediated SIRT1 and SIRT2 Down-Regulation. PLoS One 2015; 10:e0124837. [PMID: 25924011 PMCID: PMC4414559 DOI: 10.1371/journal.pone.0124837] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2014] [Accepted: 03/19/2015] [Indexed: 12/24/2022] Open
Abstract
The natural polyphenolic compound resveratrol (3,4,5-trihydroxy-trans-stilbene) has broad spectrum health beneficial activities including antioxidant, anti-inflammatory, anti-aging, anti-cancer, cardioprotective, and neuroprotective effects. Remarkably, resveratrol also induces apoptosis and cellular senescence in primary and cancer cells. Resveratrol's anti-aging effects both in vitro and in vivo attributed to activation of a (NAD)-dependent histone deacetylase family member sirtuin-1 (SIRT1) protein. In mammals seven members (SIRT1-7) of sirtuin family have been identified. Among those, SIRT1 is the most extensively studied with perceptive effects on mammalian physiology and suppression of the diseases of aging. Yet no data has specified the role of sirtuins, under conditions where resveratrol treatment induces senescence. Current study was undertaken to investigate the effects of resveratrol in human primary dermal fibroblasts (BJ) and to clarify the role of sirtuin family members in particular SIRT1 and SIRT2 that are known to be involved in cellular stress responses and cell cycle, respectively. Here, we show that resveratrol decreases proliferation of BJ cells in a time and dose dependent manner. In addition the increase in senescence associated β-galactosidase (SA-β-gal) activity and methylated H3K9-me indicate the induction of premature senescence. A significant increase in phosphorylation of γ-H2AX, a surrogate of DNA double strand breaks, as well as in levels of p53, p21CIP1 and p16INK4A is also detected. Interestingly, at concentrations where resveratrol induced premature senescence we show a significant decrease in SIRT1 and SIRT2 levels by Western Blot and quantitative RT-PCR analysis. Conversely inhibition of SIRT1 and SIRT2 via siRNA or sirtinol treatment also induced senescence in BJ fibroblasts associated with increased SA-β-gal activity, γ-H2AX phosphorylation and p53, p21CIP1 and p16INK4A levels. Interestingly DNA damaging agent doxorubicin also induced senescence in BJ fibroblasts associated with decreased SIRT1/2 levels. In conclusion our data reveal that resveratrol induced premature senescence is associated with SIRT1 and SIRT2 down regulation in human dermal fibroblasts. Here we suggest that the concomitant decline in SIRT1/2 expression in response to resveratrol treatment may be a cause for induction of senescence, which is most likely mediated by a regulatory mechanism activated by DNA damage response.
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Affiliation(s)
- Mehtap Kilic Eren
- Department of Medical Biology, Adnan Menderes University Medical School, Aydın, Turkey
- ADU-BILTEM (Adnan Menderes University, Science and Technology Research and Application Center), Aydin, Turkey
- * E-mail:
| | - Ayten Kilincli
- Department of Biology, Adnan Menderes University, Aydin, Turkey
| | - Özkan Eren
- Department of Biology, Adnan Menderes University, Aydin, Turkey
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Cellular senescence: a hitchhiker’s guide. Hum Cell 2015; 28:51-64. [DOI: 10.1007/s13577-015-0110-x] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2014] [Accepted: 02/03/2015] [Indexed: 12/21/2022]
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Perrigue PM, Silva ME, Warden CD, Feng NL, Reid MA, Mota DJ, Joseph LP, Tian YI, Glackin CA, Gutova M, Najbauer J, Aboody KS, Barish ME. The histone demethylase jumonji coordinates cellular senescence including secretion of neural stem cell-attracting cytokines. Mol Cancer Res 2015; 13:636-50. [PMID: 25652587 DOI: 10.1158/1541-7786.mcr-13-0268] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2013] [Accepted: 01/12/2015] [Indexed: 01/09/2023]
Abstract
UNLABELLED Jumonji domain-containing protein 3 (JMJD3/KDM6B) demethylates lysine 27 on histone H3 (H3K27me3), a repressive epigenetic mark controlling chromatin organization and cellular senescence. To better understand the functional consequences of JMJD3 its expression was investigated in brain tumor cells. Querying patient expression profile databases confirmed JMJD3 overexpression in high-grade glioma. Immunochemical staining of two glioma cell lines, U251 and U87, indicated intrinsic differences in JMJD3 expression levels that were reflected in changes in cell phenotype and variations associated with cellular senescence, including senescence-associated β-galactosidase (SA-β-gal) activity and the senescence-associated secretory phenotype (SASP). Overexpressing wild-type JMJD3 (JMJD3wt) activated SASP-associated genes, enhanced SA-β-gal activity, and induced nuclear blebbing. Conversely, overexpression of a catalytically inactive dominant negative mutant JMJD3 (JMJD3mut) increased proliferation. In addition, a large number of transcripts were identified by RNA-seq as altered in JMJD3 overexpressing cells, including cancer- and inflammation-related transcripts as defined by Ingenuity Pathway Analysis. These results suggest that expression of the SASP in the context of cancer undermines normal tissue homeostasis and contributes to tumorigenesis and tumor progression. These studies are therapeutically relevant because inflammatory cytokines have been linked to homing of neural stem cells and other stem cells to tumor loci. IMPLICATIONS This glioma study brings together actions of a normal epigenetic mechanism (JMJD3 activity) with dysfunctional activation of senescence-related processes, including secretion of SASP proinflammatory cytokines and stem cell tropism toward tumors.
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Affiliation(s)
- Patrick M Perrigue
- Department of Neurosciences, City of Hope Beckman Research Institute and Medical Center, Duarte, California. Irell and Manella Graduate School of Biological Sciences, City of Hope Beckman Research Institute and Medical Center, Duarte, California
| | - Michael E Silva
- Department of Neurosciences, City of Hope Beckman Research Institute and Medical Center, Duarte, California
| | - Charles D Warden
- Bioinformatics Core Facility, City of Hope Beckman Research Institute and Medical Center, Duarte, California
| | - Nathan L Feng
- Department of Neurosciences, City of Hope Beckman Research Institute and Medical Center, Duarte, California
| | - Michael A Reid
- Department of Neurosciences, City of Hope Beckman Research Institute and Medical Center, Duarte, California. Irell and Manella Graduate School of Biological Sciences, City of Hope Beckman Research Institute and Medical Center, Duarte, California
| | - Daniel J Mota
- Department of Neurosciences, City of Hope Beckman Research Institute and Medical Center, Duarte, California
| | - Lauren P Joseph
- Department of Neurosciences, City of Hope Beckman Research Institute and Medical Center, Duarte, California
| | - Yangzi Isabel Tian
- Department of Neurosciences, City of Hope Beckman Research Institute and Medical Center, Duarte, California
| | - Carlotta A Glackin
- Department of Neurosciences, City of Hope Beckman Research Institute and Medical Center, Duarte, California
| | - Margarita Gutova
- Department of Neurosciences, City of Hope Beckman Research Institute and Medical Center, Duarte, California
| | - Joseph Najbauer
- Department of Neurosciences, City of Hope Beckman Research Institute and Medical Center, Duarte, California
| | - Karen S Aboody
- Department of Neurosciences, City of Hope Beckman Research Institute and Medical Center, Duarte, California. Division of Neurosurgery, City of Hope Beckman Research Institute and Medical Center, Duarte, California
| | - Michael E Barish
- Department of Neurosciences, City of Hope Beckman Research Institute and Medical Center, Duarte, California.
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Are there roles for brain cell senescence in aging and neurodegenerative disorders? Biogerontology 2014; 15:643-60. [PMID: 25305051 DOI: 10.1007/s10522-014-9532-1] [Citation(s) in RCA: 83] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2014] [Accepted: 09/13/2014] [Indexed: 12/30/2022]
Abstract
The term cellular senescence was introduced more than five decades ago to describe the state of growth arrest observed in aging cells. Since this initial discovery, the phenotypes associated with cellular senescence have expanded beyond growth arrest to include alterations in cellular metabolism, secreted cytokines, epigenetic regulation and protein expression. Recently, senescence has been shown to play an important role in vivo not only in relation to aging, but also during embryonic development. Thus, cellular senescence serves different purposes and comprises a wide range of distinct phenotypes across multiple cell types. Whether all cell types, including post-mitotic neurons, are capable of entering into a senescent state remains unclear. In this review we examine recent data that suggest that cellular senescence plays a role in brain aging and, notably, may not be limited to glia but also neurons. We suggest that there is a high level of similarity between some of the pathological changes that occur in the brain in Alzheimer's and Parkinson's diseases and those phenotypes observed in cellular senescence, leading us to propose that neurons and glia can exhibit hallmarks of senescence previously documented in peripheral tissues.
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46
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MicroRNAs in human skin ageing. Ageing Res Rev 2014; 17:9-15. [PMID: 24784027 DOI: 10.1016/j.arr.2014.04.003] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2014] [Revised: 04/14/2014] [Accepted: 04/17/2014] [Indexed: 12/20/2022]
Abstract
The skin protects humans from the surrounding environment. Tissues undergo continuous renewal throughout an individual's lifetime; however, there is a decline in the regenerative potential of tissue with age. The accumulation of senescent cells over time probably reduces tissue regenerative capacity and contributes to the physiological ageing of the tissue itself. The mechanisms that govern ageing remain unclear and are under intense investigation, and insight could be gained by studying the mechanisms involved in cellular senescence. In vitro, keratinocytes and dermal fibroblasts undergo senescence in response to multiple cellular stresses, including the overproduction of reactive oxygen species and the shortening of telomeres, or simply by reaching the end of their replicative potential (i.e., reaching replicative senescence). Recent findings demonstrate that microRNAs play key roles in regulating the balance between a cell's proliferative capacity and replicative senescence. Here, we will focus on the molecular mechanisms regulated by senescence-associated microRNAs and their validated targets in both keratinocytes and dermal fibroblasts.
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