scholarly journals Immune Surveillance of Senescent Cells

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. 248-248
Author(s):  
Scott Lowe
Keyword(s):  
Cellular Senescence ◽  
Immune Surveillance ◽  
Therapeutic Benefit ◽  
Tumor Evolution ◽  
Laboratory Studies ◽  
Conventional Chemotherapy ◽  
Regenerative Capacity ◽  
Cycle Arrest ◽  
Anticancer Effects ◽  
Car T

Abstract Cellular senescence involves a stable cell cycle arrest and a secretory program that modulates the tissue environment. In cancer, senescence acts as a potent barrier to tumorigenesis and, though many cancers evade senescence during the course of tumor evolution, ionizing radiation and conventional chemotherapy can, to varying degrees, induce senescence in tumor cells leading to potent anticancer effects. Conversely, the aberrant accumulation of senescent cells can reduce regenerative capacity and lead to tissue decline, contributing to tissue pathologies associated with age or the debilitating side-effects of cancer therapy. Our laboratory studies mechanisms of cellular senescence with the ultimate goal of developing strategies to modulate senescence for therapeutic benefit. We have focused on how senescent cells trigger immune surveillance to facilitate their own elimination or, when that fails, how synthetic immune cells (i.e. CAR T cells) can be directed to eliminate senescent cells. Recent advances in understanding senescent cell surveillance by the immune system will be discussed.

scholarly journals Senescence under appraisal: hopes and challenges revisited

2021 ◽  
Author(s):  
Camilla S. A. Davan-Wetton ◽  
Emanuela Pessolano ◽  
Mauro Perretti ◽  
Trinidad Montero-Melendez
Keyword(s):  
Cellular Senescence ◽  
Clinical Success ◽  
Immune Surveillance ◽  
Favourable Outcome ◽  
Cellular Growth ◽  
Therapeutic Approaches ◽  
Cycle Arrest ◽  
Therapeutic Development ◽  
The Right ◽  
Inflammation Resolution

AbstractIn recent years, cellular senescence has become the focus of attention in multiple areas of biomedical research. Typically defined as an irreversible cell cycle arrest accompanied by increased cellular growth, metabolic activity and by a characteristic messaging secretome, cellular senescence can impact on multiple physiological and pathological processes such as wound healing, fibrosis, cancer and ageing. These unjustly called ‘zombie cells’ are indeed a rich source of opportunities for innovative therapeutic development. In this review, we collate the current understanding of the process of cellular senescence and its two-faced nature, i.e. beneficial/detrimental, and reason this duality is linked to contextual aspects. We propose the senescence programme as an endogenous pro-resolving mechanism that may lead to sustained inflammation and damage when dysregulated or when senescent cells are not cleared efficiently. This pro-resolving model reconciles the paradoxical two faces of senescence by emphasising that it is the unsuccessful completion of the programme, and not senescence itself, what leads to pathology. Thus, pro-senescence therapies under the right context, may favour inflammation resolution. We also review the evidence for the multiple therapeutic approaches under development based on senescence, including its induction, prevention, clearance and the use of senolytic and senomorphic drugs. In particular, we highlight the importance of the immune system in the favourable outcome of senescence and the implications of an inefficient immune surveillance in completion of the senescent cycle. Finally, we identify and discuss a number of challenges and existing gaps to encourage and stimulate further research in this exciting and unravelled field, with the hope of promoting and accelerating the clinical success of senescence-based therapies.

Cellular Senescence: Mechanisms, Morphology, and Mouse Models

2020 ◽  
Vol 57 (6) ◽  
pp. 747-757
Author(s):  
Jessica Beck ◽  
Izumi Horikawa ◽  
Curtis Harris
Keyword(s):  
Mouse Models ◽  
Cellular Senescence ◽  
Cardiac Fibrosis ◽  
Therapeutic Benefit ◽  
Associated Diseases ◽  
Cycle Arrest ◽  
A Cell ◽  
Secretory Phenotype ◽  
Global Population

Cellular senescence is a cell cycle arrest in damaged or aged cells. Although this represents a critical mechanism of tumor suppression, persistence of senescent cells during aging induces chronic inflammation and tissue dysfunction through the adoption of the senescence-associated secretory phenotype (SASP). This has been shown to promote the progression of age-associated diseases such as Alzheimer’s disease, pulmonary fibrosis, and atherosclerosis. As the global population ages, the role of cellular senescence in disease is becoming a more critical area of research. In this review, mechanisms, biomarkers, and pathology of cellular senescence and SASP are described with a brief discussion of literature supporting a role for cellular senescence in veterinary diseases. Cell culture and mouse models used in senescence studies are also reviewed including the senescence-accelerated mouse—prone (SAMP), senescence pathway knockout mice (p53, p21 [CDKN1A], and p16 [CDKN2A]), and the more recently developed senolysis mice, which allow for direct visualization and elimination (or lysis) of senescent cells in live mice (p16-3MR and INK-ATTAC). These and other mouse models have demonstrated the importance of cellular senescence in embryogenesis and wound healing but have also identified a therapeutic benefit for targeting persistent senescent cells in age-associated diseases including neurodegeneration, diabetes, and cardiac fibrosis.

scholarly journals Extract of Pogostemon cablin Possesses Potent Anticancer Activity against Colorectal Cancer Cells In Vitro and In Vivo

2020 ◽  
Vol 2020 ◽  
pp. 1-11 ◽  
Author(s):  
Ju-Huei Chien ◽  
Shan-Chih Lee ◽  
Kai-Fu Chang ◽  
Xiao-Fan Huang ◽  
Yi-Ting Chen ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Apoptosis ◽  
Cycle Arrest ◽  
Anticancer Effects ◽  
Pogostemon Cablin ◽  
Colorectal Cancer Cells ◽  
Potential Applicability ◽  
Cancer Suppression

Pogostemon cablin (PCa), an herb used in traditional Chinese medicine, is routinely used in the amelioration of different types of gastrointestinal discomfort. However, the mechanisms underlying the cancer suppression activity of PCa in colorectal cancer (CRC) cells have yet to be clarified. The aim of this study was to investigate the anticancer effects of PCa, specifically the induction of apoptosis in CRC cells. The growth inhibition curve of CRC cells following exposure to PCa was detected by an MTT assay. Moreover, PCa combined with 5-FU revealed a synergic effect of decreased cell viability. PCa inhibited cell proliferation and induced cell cycle arrest at the G0/G1 phase and cell apoptosis through regulation of associated protein expression. An in vivo study showed that PCa suppressed the growth of CRC via induction of cell apoptosis with no significant change in body weight or organ histology. Our results demonstrated that PCa inhibits the growth of CRC cells and induces apoptosis in vitro and in vivo, which suggests the potential applicability of PCa as an anticancer agent.

scholarly journals Cellular Senescence in Liver Disease and Regeneration

2021 ◽  
Author(s):  
Sofia Ferreira-Gonzalez ◽  
Daniel Rodrigo-Torres ◽  
Victoria L. Gadd ◽  
Stuart J. Forbes
Keyword(s):  
Cell Cycle ◽  
Liver Disease ◽  
Cell Cycle Arrest ◽  
Genomic Instability ◽  
Cellular Senescence ◽  
Cell Populations ◽  
Cycle Arrest ◽  
Relevant Role ◽  
Extent Of Damage

AbstractCellular senescence is an irreversible cell cycle arrest implemented by the cell as a result of stressful insults. Characterized by phenotypic alterations, including secretome changes and genomic instability, senescence is capable of exerting both detrimental and beneficial processes. Accumulating evidence has shown that cellular senescence plays a relevant role in the occurrence and development of liver disease, as a mechanism to contain damage and promote regeneration, but also characterizing the onset and correlating with the extent of damage. The evidence of senescent mechanisms acting on the cell populations of the liver will be described including the role of markers to detect cellular senescence. Overall, this review intends to summarize the role of senescence in liver homeostasis, injury, disease, and regeneration.

scholarly journals Quantitative Model of Cell Cycle Arrest and Cellular Senescence in Primary Human Fibroblasts

PLoS ONE ◽  
2012 ◽  
Vol 7 (8) ◽  
pp. e42150 ◽  
Author(s):  
Sascha Schäuble ◽  
Karolin Klement ◽  
Shiva Marthandan ◽  
Sandra Münch ◽  
Ines Heiland ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cellular Senescence ◽  
Human Fibroblasts ◽  
Quantitative Model ◽  
Cycle Arrest

scholarly journals The p53/miR-34a/SIRT1 Positive Feedback Loop in Quercetin-Induced Apoptosis

2015 ◽  
Vol 35 (6) ◽  
pp. 2192-2202 ◽  
Author(s):  
Guohua Lou ◽  
Yanning Liu ◽  
Shanshan Wu ◽  
Jihua Xue ◽  
Fan Yang ◽  
...  
Keyword(s):  
Cell Apoptosis ◽  
Feedback Loop ◽  
Molecular Mechanisms ◽  
Rt Pcr ◽  
Cycle Arrest ◽  
Anticancer Effects ◽  
Huh7 Cells ◽  
Mirnas Expression ◽  
Induced Apoptosis

Background: The anti-tumor effects of quercetin have been reported, but the underlying molecular mechanisms remain to be elucidated. The aim of present study was to explore the role of miRNA in the anticancer effects of quercetin. Methods: The differential miRNAs expression between the HepG2 and Huh7 cells treated by quercetin were detected by microarray. The xCELLigence, Flow cytometry, RT-PCR and Western blot were used to analyze the cell proliferation, cell apoptosis, cell cycle arrest, anti-tumor genes, and protein expression. Results: miR-34a was up-regulated in HepG2 cells treated by quercetin exhibiting wild-type p53. When inhibiting the miR-34a, the sensitivity of the cells to quercetin decreased and the expression of the SIRT1 was up-regulated, but the acetylation of p53 and the expression of some genes related to p53 down-regulated. Conclusion: miR-34a plays an important role in the anti-tumor effects of querctin in HCC, miR-34a may be a tiemolecule between the p53 and SIRT1 and is composed of a p53/miR-34a/SIRT1 signal feedback loop, which could enhance apoptosis signal and significantly promote cell apoptosis.

Abstract 20492: Mlf1 Regulates Myocyte Proliferation in Postnatal Hearts

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Shalini Muralidhar ◽  
Feng Xiao ◽  
Suwannee Thet ◽  
Hesham Sadek
Keyword(s):  
Cell Cycle ◽  
Transcription Factors ◽  
Cell Cycle Arrest ◽  
Molecular Mechanisms ◽  
Gene Array ◽  
Bhlh Transcription Factor ◽  
Cardiomyocyte Proliferation ◽  
Regenerative Capacity ◽  
Cycle Arrest ◽  
Endogenous Expression

Lower vertebrates, such as newt and zebrafish, retain a robust cardiac regenerative capacity following injury. Although adult mammals lack this cardiac regenerative potential, there is ample interest in understanding how heart regeneration occurs, and to reawaken this process in adult humans. Recently, we showed that mice are capable of regenerating their hearts shortly after birth following injury. This regenerative response is associated with robust proliferation of cardiomyocytes without significant hypertrophy or fibrosis. However, this regenerative capacity is lost by 7 days postnatally, coinciding with cell cycle arrest. In an effort to determine the mechanism of cardiomyocytes cell cycle arrest after the first week of life, we performed a gene array after cardiac injury at multiple post-natal time points. This enabled us to identify a number of transcription factors that are differentially expressed during this postnatal window. We recently reported that one of these transcription factors Meis1 regulates postnatal cell cycle arrest of cardiomyocytes. Furthermore, Myeloid leukemia factor 1 (Mlf1), a bhlh transcription factor that has not been previously studied in the heart has similar dysregulated pattern following injury. Our preliminary data with in-vitro knockdown of Mlf1 in cardiomyocyte resulted in 2-fold increase in cardiomyocyte proliferation. Furthermore, immunohistochemistry results indicated that the endogenous expression and nuclear localization of Mlf1 in the post-natal cardiomyocytes coincides with cell cycle arrest. To explore this pattern, we generated a cardiomyocyte-specific Mlf1 knockout mouse, and showed that loss of Mlf1 results in robust cardiomyocyte proliferation in postnatal hearts (P14). Additionally, we confirmed previous reports that Mlf1 regulates p53 and induces cell cycle arrest by induction of CDK inhibitors like p21 and p57 in these Mlf1 KO mice. This suggests a role of Mlf1 in promoting reactivation of injured myocardium through induction of cardiomyocyte proliferation. These findings will further provide evidences of molecular mechanisms involved in the dormant regenerative capacity in adult mammals that can be a potential target of therapeutic approaches.

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