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Anti-Aging Drug Discovery in Experimental Gerontological Studies
Published in Shamim I. Ahmad, Aging: Exploring a Complex Phenomenon, 2017
Alexander N. Khokhlov, Alexander A. Klebanov, Galina V. Morgunova
Our numerous experiments provide evidence that changes in the cells occurring in our cytogerontological model system of stationary phase aging are indeed similar to those in the cells of aging multicellular organisms. They include accumulation of DNA single-strand breaks and DNA-protein crosslinks, DNA demethylation, changes in the level of spontaneous sister chromatid exchanges, structural defects in the cell nucleus, alterations in the plasma membrane, retardation of mitogen-stimulated proliferation, impairment of colony-forming capacity, changes in dealkylase activity of cytochrome P450, accumulation of 8-oxo-2′-deoxyguanosine (a known biomarker of aging and oxidative stress) in the DNA, increase in the number of cells with senescence-associated beta-galactosidase (SA-β-Gal) activity, inhibition of poly(ADP-ribosyl)ation of chromatin proteins, etc. (Khokhlov et al. 1984a, 1985a, 1986, 1987a, 1988; Khokhlov 1988, 2013a; Prokhorov et al. 1994; Shram et al. 2006; Esipov et al. 2008; Vladimirova et al. 2012).
Management of male androgenetic alopecia
Published in Pierre Bouhanna, Eric Bouhanna, The Alopecias, 2015
Naito et al.8 analyzed the effect of the lipid peroxides on hair follicles and observed that the topical application of linolein hydroperoxides, one of the lipid peroxides, leads to the early onset of the catagen phase in murine hair cycles. Furthermore, they found that lipid peroxides induced apoptosis of hair follicle cells. They also induced apoptosis in human epidermal keratinocytes by upregulating apoptosis-related genes. These results indicate that lipid peroxides, which can cause free radicals, induce the apoptosis of hair follicle cells, and this is followed by early onset of the catagen phase. Ultimately, Bahta et al.9 cultured dermal hair papilla cells (DPCs) from balding and nonbalding scalp and demonstrated that balding DPCs grow slower in vitro than nonbalding DPCs. Loss of proliferative capacity of balding DPCs was associated with changes in cell morphology, expression of senescence-associated beta-galactosidase, decreased expression of proliferating cell nuclear antigen and Bmi-1, upregulation of p16(INK4a)/pRb, and nuclear expression of markers of oxidative stress and DNA damage, including heat shock protein-27, super oxide dismutase catalase, ataxia-telangiectasia-mutated (ATM) kinase, and ATM- and Rad3-related protein. The finding of premature senescence of balding DPC in vitro, in association with expression of markers of oxidative stress and DNA damage, suggests that balding DPCs are particularly sensitive to environmental stress, such as cigarette smoking or ultraviolet radiation (UVR).
The hepatic microenvironment essentially determines tumor cell dormancy and metastatic outgrowth of pancreatic ductal adenocarcinoma
Published in OncoImmunology, 2018
Lennart Lenk, Maren Pein, Olga Will, Beatriz Gomez, Fabrice Viol, Charlotte Hauser, Jan-Hendrik Egberts, Jan-Paul Gundlach, Ole Helm, Sanjay Tiwari, Ralf Weiskirchen, Stefan Rose-John, Christoph Röcken, Wolfgang Mikulits, Patrick Wenzel, Günter Schneider, Dieter Saur, Heiner Schäfer, Susanne Sebens
While a profound influence of inflammatory processes on primary PDAC development is well appreciated, the impact of the hepatic microenvironment on regulation of survival and growth behavior of disseminated PDECs is insufficiently understood. Several studies on other tumor entities support the view that disseminated tumor cells (DTCs) can persist in secondary sites in a viable but non-dividing state thereby remaining clinically unobtrusive and undetectable for extended time periods.19,20 This reversible state of quiescence is termed dormancy in which tumor mass dormancy can be distinguished from cellular dormancy, the latter implying a reversible growth arrest of solitary cells. Hallmarks of cellular dormancy are a flattened cell morphology, Ki67-negativity, reduced ratio of phosphorylated ERK (p-ERK) to phosphorylated p38 (p-p38) and increased p21 expression.19,20,21 All these features are also characteristics of senescent cells, which additionally exhibit an elevated senescence-associated β-galactosidase (SABG) activity.20,22 The acquisition of further mutations (e.g., in P53) as well as microenvironmental alterations may induce reawakening of dormant cells leading to local relapse and/or outgrowth of metastases even after curative therapy.23 A recent study strongly supports the role of inflammation in escape from tumor latency.24 However, underlying mechanisms leading to such microenvironmental alterations and favoring dormancy reversal in PDAC are poorly understood.
Pro- and anti-tumorigenic functions of the senescence-associated secretory phenotype
Published in Expert Opinion on Therapeutic Targets, 2019
Replicative senescence was hypothesized by some to correspond to an in vitro artifact of cell culture. This view was challenged when senescent cells were identified in specific physiological contexts in vivo. Enlarged and flattened endothelial cells were found in atherosclerotic plaques, a similar morphology to senescent fibroblasts in culture [7,8]. Since then, the usage of the biomarker senescence-associated beta-galactosidase (SA-βgal) allowed for the identification of senescent cells in other tissues, such as human skin, prostate, and breast [9–11]. Importantly, SA-βgal-positive cells harboring dysfunctional telomeres were discovered in the skin of aging baboons, establishing a clear link between senescence and aging [12].
Ambient PM2.5 exposure causes cellular senescence via DNA damage, micronuclei formation, and cGAS activation
Published in Nanotoxicology, 2022
Tao Wu, Shengmin Xu, Biao Chen, Lingzhi Bao, Jie Ma, Wei Han, An Xu, Kwan Ngok Yu, Lijun Wu, Shaopeng Chen
Cellular senescence is known as a stress-induced irreversible cell cycle arrest which is characterized by complex characteristics, such as cytokine secretion disorder, expression of senescence associated-beta-galactosidase (SA-β-Gal), and dysregulated protein expression (Kamal et al. 2020; Wang, Chen, and Cai 2021). Senescence occurs when mitotic progression is progressively interrupted following genomic instability, especially double-strand breaks (DSBs) (Van Deursen 2014; Ogrodnik et al. 2019). Meanwhile, senescent cells are more abundant in aged and diseased tissues, driving a large number of age-related pathologies including atherosclerosis and pulmonary fibrosis (Baker et al. 2016; Childs et al. 2016; Demaria et al. 2017).