P16INK4A—More Than a Senescence Marker

Life, Год журнала: 2022, Номер 12(9), С. 1332 - 1332

Опубликована: Авг. 28, 2022

Aging is a biological feature that characterized by gradual degeneration of function in cells, tissues, organs, or an intact organism due to the accumulation environmental factors and stresses with time. Several have been attributed aging such as oxidative stress augmented production exposure reactive oxygen species, inflammatory cytokines production, telomere shortening, DNA damage, and, importantly, deposit senescent cells. These are irreversibly mitotically inactive, yet metabolically active The reason underlying their senescence lies within extrinsic intrinsic arms. arm mainly expression secretory profile known senescence-associated phenotype (SASP). results from impact several genes meant regulate cell cycle, tumor suppressor genes. P16

Язык: Английский

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Atherosclerosis Is a Smooth Muscle Cell–Driven Tumor-Like Disease

Circulation, Год журнала: 2024, Номер 149(24), С. 1885 - 1898

Опубликована: Апрель 30, 2024

BACKGROUND: Atherosclerosis, a leading cause of cardiovascular disease, involves the pathological activation various cell types, including immunocytes (eg, macrophages and T cells), smooth muscle cells (SMCs), endothelial cells. Accumulating evidence suggests that transition SMCs to other known as phenotypic switching, plays central role in atherosclerosis development complications. However, characteristics SMC-derived underlying mechanisms SMC disease pathogenesis remain poorly understood. Our objective is characterize tumor cell–like behaviors atherosclerosis, with ultimate goal developing interventions targeting for prevention treatment atherosclerosis. METHODS: We used lineage tracing mice human tissues applied range methods, molecular, cellular, histological, computational, genetics, pharmacological approaches, investigate features RESULTS: mouse exhibit multiple characteristics, genomic instability, evasion senescence, hyperproliferation, resistance death, invasiveness, comprehensive cancer-associated gene regulatory networks. Specific expression oncogenic mutant Kras G12D accelerates switching exacerbates Furthermore, we provide proof concept niraparib, an anticancer drug DNA damage repair, attenuates progression induces regression lesions advanced models. CONCLUSIONS: findings demonstrate SMC-driven tumor-like advancing our understanding its opening prospects innovative precision molecular strategies aimed at preventing treating atherosclerotic disease.

Язык: Английский

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CNS Ageing in Health and Neurodegenerative Disorders

Journal of Clinical Medicine, Год журнала: 2023, Номер 12(6), С. 2255 - 2255

Опубликована: Март 14, 2023

The process of ageing is characteristic multicellular organisms associated with late stages the lifecycle and manifested through a plethora phenotypes. Its underlying mechanisms are correlated age-dependent diseases, especially neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s (PD) multiple sclerosis (MS) that accompanied by social financial difficulties for patients. Over time, people not only become more prone to neurodegeneration but they also lose ability trigger pivotal restorative mechanisms. In this review, we attempt present already known molecular cellular hallmarks characterize in association their impact on central nervous system (CNS)’s structure function intensifying possible preexisting pathogenetic conditions. A thorough elucidative study will be able contribute further development new therapeutic interventions effectively treat manifestations diseases.

Язык: Английский

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Endothelial-Ercc1 DNA repair deficiency provokes blood-brain barrier dysfunction

Cell Death and Disease, Год журнала: 2025, Номер 16(1)

Опубликована: Янв. 3, 2025

Abstract Aging of the brain vasculature plays a key role in development neurovascular and neurodegenerative diseases, thereby contributing to cognitive impairment. Among other factors, DNA damage strongly promotes cellular aging, however, genomic instability endothelial cells (EC) its potential effect on homeostasis is still largely unclear. We here investigated how aging impacts blood-brain barrier (BBB) function by using excision repair cross complementation group 1 (ERCC1)-deficient human ECs an EC-specific Ercc1 knock out (EC-KO) mouse model. In vitro, ERCC1-deficient displayed increased senescence-associated secretory phenotype expression, reduced BBB integrity, higher sprouting capacities due underlying dysregulation Dll4-Notch pathway. line, EC-KO mice showed more P21 + cells, augmented expression angiogenic markers, concomitant increase number pericytes. Moreover, leakage enhanced cell adhesion molecule accompanied peripheral immune infiltration into brain. These findings were confined white matter, suggesting regional susceptibility. Collectively, our results underline as driver impaired function, sprouting, migration brain, observed during process.

Язык: Английский

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Oxidative Stress-Induced Cellular Senescence in Aging Retina and Age-Related Macular Degeneration

Antioxidants, Год журнала: 2022, Номер 11(11), С. 2189 - 2189

Опубликована: Ноя. 5, 2022

Aging leads to a gradual decline of function in multiple organs. Cataract, glaucoma, diabetic retinopathy, and age-related macular degeneration (AMD) are ocular diseases. Because their pathogenesis is unclear, it challenging combat Cellular senescence cellular response characterized by cell cycle arrest. an important contributor aging diseases through the alteration secretion senescence-associated secretory phenotypes. As driver stress-induced premature senescence, oxidative stress triggers inducing markers via reactive oxygen species mitochondrial dysfunction. In this review, we focused on mechanism retinal cells its role AMD.

Язык: Английский

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A navitoclax-loaded nanodevice targeting matrix metalloproteinase-3 for the selective elimination of senescent cells

Acta Biomaterialia, Год журнала: 2024, Номер 176, С. 405 - 416

Опубликована: Янв. 5, 2024

Cellular senescence is implicated in the occurrence and progression of multiple age-related disorders. In this context, selective elimination senescent cells, senolysis, has emerged as an effective therapeutic strategy. However, heterogeneous phenotype hinders discovery a universal robust biomarker that limits senolytic with off-target toxic effects. Therefore, development more strategies represents promising approach to increase specificity therapy. study, we have developed innovative nanodevice for cells (SCs) based on specific enzymatic activity secretome. The results revealed when induced proliferating WI-38 by ionizing radiation (IR), secrete high levels matrix metalloproteinase-3 (MMP-3). Based result, mesoporous silica nanoparticles (MSNs) were loaded navitoclax (Nav) coated peptide which substrate MMP-3 (NPs(Nav)@MMP-3). Studies confirmed preferential release cargo IR-induced compared depending levels. Moreover, treatment NPs(Nav)@MMP-3 decrease viability SCs well protective effect non-proliferating cells. These demonstrate potential use NPs develop enhanced therapies microenvironment, clinical relevance. common β-galactosidase been exploited identification new biomarkers key factor improved strategies. scenario, report first time targeting We navitoclax-loaded responsive (MMP-3) associated phenotype. Our nanosystem achieves MMP-3-dependent manner while limiting effects non-senescent This opens possibility using able detect altered environment selectively its content, thus enhancing efficacy therapies.

Язык: Английский

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T-Cell Senescence in Human Metabolic Diseases

Diabetes & Metabolism Journal, Год журнала: 2024, Номер 48(5), С. 864 - 881

Опубликована: Авг. 28, 2024

Immunosenescence denotes a state of dysregulated immune cell function characterized by confluence factors, including arrested cycle, telomere shortening, markers cellular stress, mitochondrial dysfunction, loss proteostasis, epigenetic reprogramming, and secretion proinflammatory mediators. This primarily manifests during the aging process but can also be induced in various pathological conditions, encompassing chronic viral infections, autoimmune diseases, metabolic disorders. Age-associated system alterations extend to innate adaptive cells, with T-cells exhibiting heightened susceptibility immunosenescence. In particular, senescent have been identified context disorders such as obesity, diabetes, cardiovascular diseases. Recent investigations suggest direct link between T-cell senescence, inflammation, insulin resistance. The perturbation biological homeostasis appears intricately linked initiation progression particularly through inflammation-mediated Consequently, are emerging noteworthy therapeutic target. review aims elucidate intricate relationship diseases providing insights into potential roles pathogenesis Through comprehensive examination current research findings, this seeks contribute deeper understanding complex interplay immunosenescence health.

Язык: Английский

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Senescent renal tubular epithelial cells activate fibroblasts by secreting Shh to promote the progression of diabetic kidney disease

Frontiers in Medicine, Год журнала: 2023, Номер 9

Опубликована: Янв. 25, 2023

Diabetic kidney disease (DKD) is one of the complications diabetes; however, pathogenesis not yet clear. A recent study has shown that senescence associated with course DKD. In present study, we explored whether senescent renal tubular cells promote tubulointerstitial fibrosis by secreting Sonic hedgehog (Shh) which mediates fibroblast activation and proliferation in DKD.A 36-week-old db/db mice model epithelial were cultured high glucose (HG, 60 mmol/L) medium for vivo vitro experiments.Compared to db/m mice, blood glucose, microalbuminuria, serum creatinine, urea nitrogen, UACR (microalbuminuria/urine creatinine) markedly increased mice. Collagen III, monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-α) also kidneys, suggesting inflammation organ. Moreover, detection SA-β-galactosidase (SA-β-Gal) showed activity SA-β-Gal cytoplasm increased, cell cycle inhibition expression senescence-related gene inhibitor p16 INK4A protein p21 indicating was accompanied senescence. Furthermore, Shh highly expressed injured tubules tissue as detected enzyme-linked immunosorbent assay (ELISA). The results immunofluorescence staining positive decreased Lamin B1, but γH2A.X expression; similar obtained vitro. addition, HG stimulated secrete supernatant medium. D-gal treatment levels p21. We found enhanced fibroblasts proliferative effect significantly diminished when co-cultured cyclopamine (CPN), an pathway.In conclusion, induces senescence, secretion senescence-associated proteins inflammatory responses proliferation, ultimately leading fibrosis.

Язык: Английский

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Melatonin Exerts Prominent, Differential Epidermal and Dermal Anti-Aging Properties in Aged Human Eyelid Skin Ex Vivo

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(21), С. 15963 - 15963

Опубликована: Ноя. 4, 2023

Human skin aging is associated with functional deterioration on multiple levels of physiology, necessitating the development effective senotherapeutics. The well-tolerated neurohormone melatonin unfolds anti-aging properties in vitro and vivo, but it remains unclear whether these effects translate to aged human ex vivo. We tested this organ-cultured, full-thickness eyelid (5-6 donors; 49-77 years) by adding culture medium, followed assessment core biomarkers via quantitative immunohistochemistry. Over 6 days, 200 µM significantly downregulated intraepidermal activity aging-promoting mTORC1 pathway (as visualized reduced S6 phosphorylation) MMP-1 protein expression epidermis compared vehicle-treated control skin. Conversely, transmembrane collagen 17A1, a key stem cell niche matrix molecule that declines aging, mitochondrial markers (e.g., TFAM, MTCO-1, VDAC/porin) were upregulated. Interestingly, 100 also increased epidermal VEGF-A protein, which required sufficient for inducing rejuvenation. In dermis, fibrillin-1 improved fibrillin structural organization, indicating an elastic fiber network. contrast, other (SIRT-1, lamin-B1, p16INK4, I) remained unchanged. This vivo study provides proof principle indeed exerts long-suspected never conclusively demonstrated surprisingly differential dermis.

Язык: Английский

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Cellular senescence triggers intracellular acidification and lysosomal pH alkalinized via ATP6AP2 attenuation in breast cancer cells

Communications Biology, Год журнала: 2023, Номер 6(1)

Опубликована: Ноя. 22, 2023

Abstract Several chemotherapeutic drugs induce senescence in cancer cells; however, the mechanisms underlying intracellular pH dysregulation senescent cells remain unclear. Adenosine triphosphatase H + transporting accessory protein 2 (ATP6AP2) plays a critical role maintaining homeostasis cellular compartments. Herein, we report regulatory of ATP6AP2 breast treated with doxorubicin (Doxo) and abemaciclib (Abe). A decline triggers aberrant levels that impair lysosomal function cause immune profile changes cells. Doxo Abe elicited stable phenotype altered expression senescence-related genes. Additionally, show inflammatory transcriptional profiles due to reprogramming senescence-associated secretory phenotype. These findings elucidate ATP6AP2-mediated regulation suggest potential link alteration during therapy-induced cells, providing insights into involved response anticancer therapy.

Язык: Английский

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