Editorial

3 pages, 183 KiB

Open AccessEditorial

Cellular Senescence in Physiological and Pathological Processes

by Mauro Finicelli, Gianfranco Peluso and Tiziana Squillaro

Int. J. Mol. Sci. 2022, 23(21), 13342; https://doi.org/10.3390/ijms232113342 - 01 Nov 2022

Viewed by 1254

This Special Issue aims to address the impact of cellular senescence on human biology, looking at both physiological and pathological processes [...] Full article

(This article belongs to the Special Issue Cellular Senescence in Physiological and Pathological Processes 2.0)

Research

Jump to: Editorial, Review, Other

17 pages, 3560 KiB

Open AccessArticle

Impact of Senolytic Treatment on Gene Expression in Aged Lung

by Soo Jung Cho, Alexander Pronko, Jianjun Yang and Heather Stout-Delgado

Int. J. Mol. Sci. 2023, 24(8), 7628; https://doi.org/10.3390/ijms24087628 - 21 Apr 2023

Viewed by 1484

Abstract

Cellular senescence plays a key role in mediating tissue remodeling and modulation of host responses to pathogenic stimuli. Our current study was designed to gain a better understanding of the impact of short-term senolytic treatment or inflammatory stimulation on lung senescence. The results [...] Read more.

Cellular senescence plays a key role in mediating tissue remodeling and modulation of host responses to pathogenic stimuli. Our current study was designed to gain a better understanding of the impact of short-term senolytic treatment or inflammatory stimulation on lung senescence. The results of our study demonstrate that short term treatment of aged adult mice (20 months of age) with senolytics, quercetin, and dasatinib decreases p16 and p21 expression in lung tissue. Short-term treatment with senolytics also significantly improved the expression of genes associated with genomic instability, telomere attrition, mitochondrial dysfunction, DNA binding, and the inflammatory response. In contrast, in response to low-dose LPS administration, there was increased expression of genes associated with genomic instability, mitochondrial dysfunction, and heightened inflammatory responses in young adult murine lung (3 months of age). Taken together, the results of our current study illustrate the efficacy of senolytic treatment on modulating responses in aged lung and the potential role of chronic low dose inflammation on senescence induction in the lung. Full article

(This article belongs to the Special Issue Cellular Senescence in Physiological and Pathological Processes 2.0)

► Show Figures

Figure 1

24 pages, 7305 KiB

Open AccessArticle

Modulation of Cellular Senescence in HEK293 and HepG2 Cells by Ultrafiltrates UPla and ULu Is Partly Mediated by Modulation of Mitochondrial Homeostasis under Oxidative Stress

by Junxian Zhou, Kang Liu, Chris Bauer, Gerald Bendner, Heike Dietrich, Jakub Peter Slivka, Michael Wink, Michelle B. F. Wong, Mike K. S. Chan and Thomas Skutella

Int. J. Mol. Sci. 2023, 24(7), 6748; https://doi.org/10.3390/ijms24076748 - 04 Apr 2023

Cited by 1 | Viewed by 2197

Abstract

Protein probes, including ultrafiltrates from the placenta (UPla) and lung (ULu) of postnatal rabbits, were investigated in premature senescent HEK293 and HepG2 cells to explore whether they could modulate cellular senescence. Tris-Tricine–PAGE, gene ontology (GO), and LC–MS/MS analysis were applied to describe the [...] Read more.

Protein probes, including ultrafiltrates from the placenta (UPla) and lung (ULu) of postnatal rabbits, were investigated in premature senescent HEK293 and HepG2 cells to explore whether they could modulate cellular senescence. Tris-Tricine–PAGE, gene ontology (GO), and LC–MS/MS analysis were applied to describe the characteristics of the ultrafiltrates. HEK293 and HepG2 cells (both under 25 passages) exposed to a sub-toxic concentration of hydrogen peroxide (H₂O₂, 300 μM) became senescent; UPla (10 μg/mL), ULu (10 μg/mL), as well as positive controls lipoic acid (10 μg/mL) and transferrin (10 μg/mL) were added along with H₂O₂ to the cells. Cell morphology; cellular proliferation; senescence-associated beta-galactosidase (SA-β-X-gal) activity; expression of senescence biomarkers including p16 INK4A (p16), p21 Waf1/Cip1 (p21), HMGB1, MMP-3, TNF-α, IL-6, lamin B1, and phospho-histone H2A.X (γ-H2AX); senescence-related gene expression; reactive oxygen species (ROS) levels; and mitochondrial fission were examined. Tris-Tricine–PAGE revealed prominent detectable bands between 10 and 100 kDa. LC–MS/MS identified 150–180 proteins and peptides in the protein probes, and GO analysis demonstrated a distinct enrichment of proteins associated with “extracellular space” and “proteasome core complex”. UPla and ULu modulated senescent cell morphology, improved cell proliferation, and decreased beta-galactosidase activity, intracellular and mitochondrial ROS production, and mitochondrial fission caused by H₂O₂. The results from this study demonstrated that UPla and Ulu, as well as lipoic acid and transferrin, could protect HEK293 and HepG2 cells from H₂O₂-induced oxidative damage via protecting mitochondrial homeostasis and thus have the potential to be explored in anti-aging therapies. Full article

(This article belongs to the Special Issue Cellular Senescence in Physiological and Pathological Processes 2.0)

► Show Figures

Figure 1

12 pages, 11346 KiB

Open AccessArticle

Generation of a p21 Reporter Mouse and Its Use to Identify and Eliminate p21^high Cells In Vivo

by Zimei Yi, Le Ren, Yu Wei, Siyi Chen, Jiechen Zhao, Jiayu Zhu and Junhua Wu

Int. J. Mol. Sci. 2023, 24(6), 5565; https://doi.org/10.3390/ijms24065565 - 14 Mar 2023

Cited by 1 | Viewed by 1805

Abstract

P21 and p16 have been identified as inducers of senescence. Many transgenic mouse models have been developed to target cells expressing high levels of p16^Ink4a (p16^high) and investigate their potential contribution to tissue dysfunction in aging, obesity, and other pathological [...] Read more.

P21 and p16 have been identified as inducers of senescence. Many transgenic mouse models have been developed to target cells expressing high levels of p16^Ink4a (p16^high) and investigate their potential contribution to tissue dysfunction in aging, obesity, and other pathological conditions. However, the specific roles of p21 in various senescence-driven processes remain unclear. To gain a deeper understanding of p21, we built a p21-3MR mouse model containing a p21 promoter-driven module that allowed us to target cells with high p21^Chip expression (p21^high). Using this transgenic mouse, we monitored, imaged, and eliminated p21^high cells in vivo. We also applied this system to chemically induced weakness and found that the clearance of p21^high cells improved doxorubicin (DOXO)-induced multi-organ toxicity in mice. By recognizing p21 transcriptional activation spatially and temporally, the p21-3MR mouse model can be a valuable and powerful tool for studying p21^high cells to further understand senescence biology. Full article

(This article belongs to the Special Issue Cellular Senescence in Physiological and Pathological Processes 2.0)

► Show Figures

Figure 1

Review

Jump to: Editorial, Research, Other

12 pages, 273 KiB

Open AccessReview

The Cytoprotective Role of Autophagy in Response to BRAF-Targeted Therapies

by Ahmed M. Elshazly and David A. Gewirtz

Int. J. Mol. Sci. 2023, 24(19), 14774; https://doi.org/10.3390/ijms241914774 - 30 Sep 2023

Cited by 2 | Viewed by 1188

Abstract

BRAF-targeted therapies are widely used for the treatment of melanoma patients with BRAF V600 mutations. Vemurafenib, dabrafenib as well as encorafenib have demonstrated substantial therapeutic activity; however, as is the case with other chemotherapeutic agents, the frequent development of resistance limits their efficacy. [...] Read more.

BRAF-targeted therapies are widely used for the treatment of melanoma patients with BRAF V600 mutations. Vemurafenib, dabrafenib as well as encorafenib have demonstrated substantial therapeutic activity; however, as is the case with other chemotherapeutic agents, the frequent development of resistance limits their efficacy. Autophagy is one tumor survival mechanism that could contribute to BRAF inhibitor resistance, and multiple studies support an association between vemurafenib-induced and dabrafenib-induced autophagy and tumor cell survival. Clinical trials have also demonstrated a potential benefit from the inclusion of autophagy inhibition as an adjuvant therapy. This review of the scientific literature relating to the role of autophagy that is induced in response to BRAF-inhibitors supports the premise that autophagy targeting or modulation could be an effective adjuvant therapy. Full article

(This article belongs to the Special Issue Cellular Senescence in Physiological and Pathological Processes 2.0)

13 pages, 1098 KiB

Open AccessReview

Role of Senescent Astrocytes in Health and Disease

by Jacopo Meldolesi

Int. J. Mol. Sci. 2023, 24(10), 8498; https://doi.org/10.3390/ijms24108498 - 09 May 2023

Cited by 2 | Viewed by 2600

Abstract

For many decades after their discovery, astrocytes, the abundant glial cells of the brain, were believed to work as a glue, supporting the structure and metabolic functions of neurons. A revolution that started over 30 years ago revealed many additional functions of these [...] Read more.

For many decades after their discovery, astrocytes, the abundant glial cells of the brain, were believed to work as a glue, supporting the structure and metabolic functions of neurons. A revolution that started over 30 years ago revealed many additional functions of these cells, including neurogenesis, gliosecretion, glutamate homeostasis, assembly and function of synapses, neuronal metabolism with energy production, and others. These properties have been confirmed, limited however, to proliferating astrocytes. During their aging or following severe brain stress lesions, proliferating astrocytes are converted into their no-longer-proliferating, senescent forms, similar in their morphology but profoundly modified in their functions. The changed specificity of senescent astrocytes is largely due to their altered gene expression. The ensuing effects include downregulation of many properties typical of proliferating astrocytes, and upregulation of many others, concerned with neuroinflammation, release of pro-inflammatory cytokines, dysfunction of synapses, etc., specific to their senescence program. The ensuing decrease in neuronal support and protection by astrocytes induces the development, in vulnerable brain regions, of neuronal toxicity together with cognitive decline. Similar changes, ultimately reinforced by astrocyte aging, are also induced by traumatic events and molecules involved in dynamic processes. Senescent astrocytes play critical roles in the development of many severe brain diseases. The first demonstration, obtained for Alzheimer’s disease less than 10 years ago, contributed to the elimination of the previously predominant neuro-centric amyloid hypothesis. The initial astrocyte effects, operating a considerable time before the appearance of known Alzheimer’s symptoms evolve with the severity of the disease up to their proliferation during the final outcome. Involvement of astrocytes in other neurodegenerative diseases and cancer is now intensely investigated. Full article

(This article belongs to the Special Issue Cellular Senescence in Physiological and Pathological Processes 2.0)

► Show Figures

Figure 1

26 pages, 2014 KiB

Open AccessReview

Senescence of Tumor Cells in Anticancer Therapy—Beneficial and Detrimental Effects

by Wiktoria Monika Piskorz and Marzanna Cechowska-Pasko

Int. J. Mol. Sci. 2022, 23(19), 11082; https://doi.org/10.3390/ijms231911082 - 21 Sep 2022

Cited by 8 | Viewed by 3141

Abstract

Cellular senescence process results in stable cell cycle arrest, which prevents cell proliferation. It can be induced by a variety of stimuli including metabolic stress, DNA damage, telomeres shortening, and oncogenes activation. Senescence is generally considered as a process of tumor suppression, both [...] Read more.

Cellular senescence process results in stable cell cycle arrest, which prevents cell proliferation. It can be induced by a variety of stimuli including metabolic stress, DNA damage, telomeres shortening, and oncogenes activation. Senescence is generally considered as a process of tumor suppression, both by preventing cancer cells proliferation and inhibiting cancer progression. It can also be a key effector mechanism for many types of anticancer therapies such as chemotherapy and radiotherapy, both directly and through bioactive molecules released by senescent cells that can stimulate an immune response. Senescence is characterized by a senescence-associated secretory phenotype (SASP) that can have both beneficial and detrimental impact on cancer progression. Despite the negatives, attempts are still being made to use senescence to fight cancer, especially when it comes to senolytics. There is a possibility that a combination of prosenescence therapy—which targets tumor cells and causes their senescence—with senotherapy—which targets senescent cells, can be promising in cancer treatment. This review provides information on cellular senescence, its connection with carcinogenesis and therapeutic possibilities linked to this process. Full article

(This article belongs to the Special Issue Cellular Senescence in Physiological and Pathological Processes 2.0)

► Show Figures

Figure 1

Other

Jump to: Editorial, Research, Review

13 pages, 2000 KiB

Open AccessBrief Report

Doxorubicin–Mediated miR–433 Expression on Exosomes Promotes Bystander Senescence in Multiple Myeloma Cells in a DDR–Independent Manner

by Elisabetta Vulpis, Lorenzo Cuollo, Cristiana Borrelli, Fabrizio Antonangeli, Laura Masuelli, Marco Cippitelli, Cinzia Fionda, Giulio Caracciolo, Maria Teresa Petrucci, Angela Santoni, Alessandra Zingoni and Alessandra Soriani

Int. J. Mol. Sci. 2023, 24(7), 6862; https://doi.org/10.3390/ijms24076862 - 06 Apr 2023

Cited by 3 | Viewed by 1758

Abstract

The success of senescence-based anticancer therapies relies on their anti-proliferative power and on their ability to trigger anti-tumor immune responses. Indeed, genotoxic drug-induced senescence increases the expression of NK cell-activating ligands on multiple myeloma (MM) cells, boosting NK cell recognition and effector functions. [...] Read more.

The success of senescence-based anticancer therapies relies on their anti-proliferative power and on their ability to trigger anti-tumor immune responses. Indeed, genotoxic drug-induced senescence increases the expression of NK cell-activating ligands on multiple myeloma (MM) cells, boosting NK cell recognition and effector functions. Senescent cells undergo morphological change and context-dependent functional diversification, acquiring the ability to secrete a vast pool of molecules termed the senescence-associated secretory phenotype (SASP), which affects neighboring cells. Recently, exosomes have been recognized as SASP factors, contributing to modulating a variety of cell functions. In particular, evidence suggests a key role for exosomal microRNAs in influencing many hallmarks of cancer. Herein, we demonstrate that doxorubicin treatment of MM cells leads to the enrichment of miR-433 into exosomes, which in turn induces bystander senescence. Our analysis reveals that the establishment of the senescent phenotype on neighboring MM cells is p53- and p21-independent and is related to CDK-6 down-regulation. Notably, miR-433-dependent senescence does not induce the up-regulation of activating ligands on MM cells. Altogether, our findings highlight the possibility of miR-433-enriched exosomes to reinforce doxorubicin-mediated cellular senescence. Full article

(This article belongs to the Special Issue Cellular Senescence in Physiological and Pathological Processes 2.0)

► Show Figures

Figure 1

Journal Menu

Journal Browser

Cellular Senescence in Physiological and Pathological Processes 2.0

Share This Special Issue

Special Issue Editors

Special Issue Information

Published Papers (8 papers)

Editorial

Research

Review

Other

Further Information

Guidelines

MDPI Initiatives

Follow MDPI