Senescent cells persist and continuously secrete proinflammatory and tissue-remodeling molecules that poison surrounding cells, leading to various age-related diseases, including diabetes, atherosclerosis, and Alzheimer's disease. The underlying mechanism of cellular senescence has not yet been fully explored. Emerging evidence indicates that hypoxia is involved in the regulation of cellular senescence. Hypoxia-inducible factor (HIF)- 1α accumulates under hypoxic conditions and regulates cellular senescence by modulating the levels of the senescence markers p16, p53, lamin B1, and cyclin D1. Hypoxia is a critical condition for maintaining tumor immune evasion, which is promoted by driving the expression of genetic factors (such as p53 and CD47) while triggering immunosenescence. Under hypoxic conditions, autophagy is activated by targeting BCL-2/adenovirus E1B 19-kDa interacting protein 3, which subsequently induces p21WAF1/CIP1 as well as p16Ink4a and increases β-galactosidase (β-gal) activity, thereby inducing cellular senescence. Deletion of the p21 gene increases the activity of the hypoxia response regulator poly (ADP-ribose) polymerase-1 (PARP-1) and the level of nonhomologous end joining (NHEJ) proteins, repairs DNA double-strand breaks, and alleviates cellular senescence. Moreover, cellular senescence is associated with intestinal dysbiosis and an accumulation of D-galactose derived from the gut microbiota. Chronic hypoxia leads to a striking reduction in the amount of Lactobacillus and D-galactose-degrading enzymes in the gut, producing excess reactive oxygen species (ROS) and inducing senescence in bone marrow mesenchymal stem cells. Exosomal microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) play important roles in cellular senescence. miR-424-5p levels are decreased under hypoxia, whereas lncRNA-MALAT1 levels are increased, both of which induce cellular senescence. The present review focuses on recent advances in understanding the role of hypoxia in cellular senescence. The effects of HIFs, immune evasion, PARP-1, gut microbiota, and exosomal mRNA in hypoxia-mediated cell senescence are specifically discussed. This review increases our understanding of the mechanism of hypoxia-mediated cellular senescence and provides new clues for anti-aging processes and the treatment of aging-related diseases.

• Klíčová slova
• Anti-aging, Cellular senescence, Gut microbiota, Hypoxia, PARP-1,
• MeSH
• galaktosa * farmakologie   MeSH
• hypoxie MeSH
• inhibitor p21 cyklin-dependentní kinasy metabolismus   MeSH
• lidé MeSH
• nádorový supresorový protein p53 * metabolismus   MeSH
• PARP inhibitory farmakologie   MeSH
• stárnutí buněk MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• galaktosa * MeSH
• inhibitor p21 cyklin-dependentní kinasy MeSH
• nádorový supresorový protein p53 * MeSH
• PARP inhibitory MeSH

Cell cycle checkpoints, oncogene-induced senescence and programmed cell death represent intrinsic barriers to tumorigenesis. Protein phosphatase magnesium-dependent 1 (PPM1D) is a negative regulator of the tumour suppressor p53 and has been implicated in termination of the DNA damage response. Here, we addressed the consequences of increased PPM1D activity resulting from the gain-of-function truncating mutations in exon 6 of the PPM1D. We show that while control cells permanently exit the cell cycle and reside in senescence in the presence of DNA damage caused by ionising radiation or replication stress induced by the active RAS oncogene, RPE1-hTERT and BJ-hTERT cells carrying the truncated PPM1D continue proliferation in the presence of DNA damage, form micronuclei and accumulate genomic rearrangements revealed by karyotyping. Further, we show that increased PPM1D activity promotes cell growth in the soft agar and formation of tumours in xenograft models. Finally, expression profiling of the transformed clones revealed dysregulation of several oncogenic and tumour suppressor pathways. Our data support the oncogenic potential of PPM1D in the context of exposure to ionising radiation and oncogene-induced replication stress.

• MeSH
• buněčná smrt genetika   MeSH
• lidé MeSH
• myši MeSH
• nádorová transformace buněk * genetika   MeSH
• nádorový supresorový protein p53 genetika   metabolismus   MeSH
• poškození DNA * genetika   MeSH
• proliferace buněk genetika   MeSH
• proteinfosfatasa 2C * genetika   metabolismus   MeSH
• proteinfosfatasy genetika   metabolismus   MeSH
• stárnutí buněk * genetika   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• nádorový supresorový protein p53 MeSH
• PPM1D protein, human MeSH Prohlížeč
• proteinfosfatasa 2C * MeSH
• proteinfosfatasy MeSH

Cellular senescence is a physiological state generally defined as a stable arrest of proliferation by preventing the cells from cycling. Unlike terminally differentiated cells, that also do not show proliferative activity, cellular senescence is stress induced and blocks the proliferation of cells with theoretical ability to divide (such as progenitor, stem or cancer cells) due to the activity of specific signaling pathways. The number of senescent cells increases during the ontogenesis of an organism. Senescent cells are not only associated with aging, but also significantly influence this process - a fact that is becoming increasingly well documented.

• Klíčová slova
• Cockayne syndrome, Werner syndrome, aging, ataxia telangiectasia, cellular senescence, progeria,
• MeSH
• stárnutí buněk * MeSH
• stárnutí * MeSH
• Publikační typ
• časopisecké články MeSH

The circadian rhythm is a key biological mechanism that aligns organisms' physiological processes with Earth's 24-h light-dark cycle, crucial for cellular and tissue homeostasis. Disruption of this system is linked to accelerated aging and age-related diseases. Central to circadian regulation is the CLOCK protein, which controls gene transcription related to tissue homeostasis, cellular senescence, and DNA repair. Research reveals CLOCK's dual role: in normal cells, it supports rejuvenation by activating DNA repair factors like XPA and modulating metabolism; in tumor cells, CLOCK signaling is often hijacked by oncogenic drivers like c-MYC and Pdia3, which inhibit telomere shortening / cellular senescence, thereby fostering uncontrolled proliferation and tumorigenesis. Additionally, gut microbiota-derived aryl hydrocarbon receptor (AhR) signals can disrupt the CLOCK-BMAL1 complex, affecting circadian rhythms. CLOCK also interacts with mTOR and NF-κB pathways to regulate autophagy and mitigate harmful secretions impacting tissue function. This review examines the molecular links between CLOCK and cellular senescence, drawing from animal and human studies, to highlight CLOCK's role in aging and its potential as a target for anti-aging therapies.

• Klíčová slova
• Aging, Aging-related diseases, CLOCK, Cellular senescence, Circadian rhythm,
• MeSH
• cirkadiánní hodiny * fyziologie   MeSH
• cirkadiánní rytmus fyziologie   MeSH
• lidé MeSH
• proteiny CLOCK metabolismus   MeSH
• signální transdukce * fyziologie   MeSH
• stárnutí buněk * fyziologie   MeSH
• stárnutí * fyziologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• proteiny CLOCK MeSH

Cellular senescence is defined as irreversible cell cycle arrest caused by various processes that render viable cells non-functional, hampering normal tissue homeostasis. It has many endogenous and exogenous inducers, and is closely connected with age, age-related pathologies, DNA damage, degenerative disorders, tumor suppression and activation, wound healing, and tissue repair. However, the literature is replete with contradictory findings concerning its triggering mechanisms, specific biomarkers, and detection protocols. This may be partly due to the wide range of cellular and in vivo animal or human models of accelerated aging that have been used to study senescence and test senolytic drugs. This review summarizes recent findings concerning senescence, presents some widely used cellular and animal senescence models, and briefly describes the best-known senolytic agents.

• Klíčová slova
• aging, cellular model, mouse model, senescence, senolytics,
• MeSH
• biologické markery MeSH
• kontrolní body buněčného cyklu MeSH
• poškození DNA MeSH
• stárnutí buněk * genetika   MeSH
• stárnutí * genetika   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• biologické markery MeSH

Cardiovascular disease is anticipated to remain the leading cause of death globally. Due to the current problems connected with using autologous arteries for bypass surgery, researchers are developing tissue-engineered vascular grafts (TEVGs). The major goal of vascular tissue engineering is to construct prostheses that closely resemble native blood vessels in terms of morphological, mechanical, and biological features so that these scaffolds can satisfy the functional requirements of the native tissue. In this setting, morphology and cellular investigation are usually prioritized, while mechanical qualities are generally addressed superficially. However, producing grafts with good mechanical properties similar to native vessels is crucial for enhancing the clinical performance of vascular grafts, exposing physiological forces, and preventing graft failure caused by intimal hyperplasia, thrombosis, aneurysm, blood leakage, and occlusion. The scaffold's design and composition play a significant role in determining its mechanical characteristics, including suturability, compliance, tensile strength, burst pressure, and blood permeability. Electrospun prostheses offer various models that can be customized to resemble the extracellular matrix. This review aims to provide a comprehensive and comparative review of recent studies on the mechanical properties of fibrous vascular grafts, emphasizing the influence of structural parameters on mechanical behavior. Additionally, this review provides an overview of permeability and cell growth in electrospun membranes for vascular grafts. This work intends to shed light on the design parameters required to maintain the mechanical stability of vascular grafts placed in the body to produce a temporary backbone and to be biodegraded when necessary, allowing an autologous vessel to take its place.

• Klíčová slova
• biopolymers, burst pressure, cellular activity, compliance, fiber orientation, permeability, physiological forces, porosity, vascular grafts, wall thickness,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

The glycoprotein clusterin (CLU) is involved in cell proliferation and DNA damage repair and is highly expressed in tumor cells. Here, we aimed to investigate the effects of CLU dysregulation on two human astrocytic cell lines: CCF-STTG1 astrocytoma cells and SV-40 immortalized normal human astrocytes. We observed that suppression of CLU expression by RNA interference inhibited cell proliferation, triggered the DNA damage response, and resulted in cellular senescence in both cell types tested. To further investigate the underlying mechanism behind these changes, we measured reactive oxygen species, assessed mitochondrial function, and determined selected markers of the senescence-associated secretory phenotype. Our results suggest that CLU deficiency triggers oxidative stress-mediated cellular senescence associated with pronounced alterations in mitochondrial membrane potential, mitochondrial mass, and expression levels of OXPHOS complex I, II, III and IV, indicating mitochondrial dysfunction. This report shows the important role of CLU in cell cycle maintenance in astrocytes. Based on these data, targeting CLU may serve as a potential therapeutic approach valuable for treating gliomas.

• Klíčová slova
• Astrocytes, Cellular senescence, Clusterin, Mitochondria, Oxidative stress,
• MeSH
• astrocyty * metabolismus   patologie   MeSH
• klusterin * nedostatek   metabolismus   MeSH
• lidé MeSH
• membránový potenciál mitochondrií MeSH
• mitochondrie metabolismus   MeSH
• nádorové buněčné linie MeSH
• oxidační stres MeSH
• oxidativní fosforylace MeSH
• poškození DNA MeSH
• proliferace buněk MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• stárnutí buněk * fyziologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• CLU protein, human MeSH Prohlížeč
• klusterin * MeSH
• reaktivní formy kyslíku MeSH

Mycotoxins induce oxidative stress, hypoxia, and cause immunosuppressive effects. Moreover, emerging evidence show that mycotoxins have a potential of inducing cellular senescence, which are involved in their immunomodulatory effects. Mycotoxins upregulate the expression of senescence markers γ-H2AX, senescence-associated β-galactosidase, p53, p16, and senescence-associated secretory phenotype (SASP) inflammatory factors. Moreover, mycotoxins cause senescence-associated cell cycle arrest by diminishing cyclin D1 and Cdk4 pathways, as well as increasing the expression of p53, p21, and CDK6. Mycotoxins may induce cellular senescence by activating reactive oxygen species (ROS)-induced oxidative stress. In addition, hypoxia acts as a double-edged sword on cell senescence; it could both act as the stress-induced senescence and also hinder the onset of cellular senescence. The SASP inflammatory factors have the ability to induce an immunosuppressive environment, while mycotoxins directly cause immunosuppression. Therefore, there is a potential relationship between mycotoxins and cellular senescence that synergistically cause immunosuppression. However, most of the current studies have involved the effect of mycotoxins on cell cycle arrest, but only limited in-depth research has been carried out to link the occurrence of this condition (cell cycle arrest) with cellular senescence.

• Klíčová slova
• Cell cycle arrest, Cellular senescence, Mycotoxins, Oxidative stress, p53,
• MeSH
• hypoxie MeSH
• imunosupresivní léčba MeSH
• lidé MeSH
• nádorový supresorový protein p53 * metabolismus   MeSH
• oxidační stres MeSH
• stárnutí buněk * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• nádorový supresorový protein p53 * MeSH

The stilbenoids, a group of naturally occurring phenolic compounds, are found in a variety of plants, including some berries that are used as food or for medicinal purposes. They are known to be beneficial for human health as anti-inflammatory, chemopreventive, and antioxidative agents. We have investigated a group of 19 stilbenoid substances in vitro using a cellular model of THP-1 macrophage-like cells and pyocyanin-induced oxidative stress to evaluate their antioxidant or pro-oxidant properties. Then we have determined any effects that they might have on the expression of the enzymes catalase, glutathione peroxidase, and heme oxygenase-1, and their effects on the activation of Nrf2. The experimental results showed that these stilbenoids could affect the formation of reactive oxygen species in a cellular model, producing either an antioxidative or pro-oxidative effect, depending on the structure pinostilbene (2) worked as a pro-oxidant and also decreased expression of catalase in the cell culture. Piceatannol (4) had shown reactive oxygen species (ROS) scavenging activity, whereas isorhapontigenin (18) had a mild direct antioxidant effect and activated Nrf2-antioxidant response element (ARE) system and elevated expression of Nrf2 and catalase. Their effects shown on cells in vitro warrant their further study in vivo.

• Klíčová slova
• Nrf2, antioxidant, macrophages, pro-oxidant, pyocyanin, stilbenoid,
• MeSH
• antioxidační responzivní elementy účinky léků   MeSH
• antioxidancia chemie   farmakologie   MeSH
• buňky Hep G2 MeSH
• faktor 2 související s NF-E2 genetika   MeSH
• lidé MeSH
• peroxidace lipidů účinky léků   MeSH
• pyokyanin chemie   MeSH
• stilbeny chemie   farmakologie   MeSH
• thiobarbituráty chemie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antioxidancia MeSH
• faktor 2 související s NF-E2 MeSH
• NFE2L2 protein, human MeSH Prohlížeč
• pyokyanin MeSH
• stilbeny MeSH
• thiobarbituráty MeSH
• thiobarbituric acid MeSH Prohlížeč

Increasing evidence has revealed that cellular senescence drives NDs, including Alzheimer's disease (AD) and Parkinson's disease. Different senescent cell populations secrete senescence-associated secretory phenotypes (SASP), including matrix metalloproteinase-3, interleukin (IL)-1α, IL-6, and IL-8, which can harm adjacent microglia. Moreover, these cells possess high expression levels of senescence hallmarks (p16 and p21) and elevated senescence-associated β-galactosidase activity in in vitro and in vivo ND models. These senescence phenotypes contribute to the deposition of β-amyloid and tau-protein tangles. Selective clearance of senescent cells and SASP regulation by inhibiting p38/mitogen-activated protein kinase and nuclear factor kappa B signaling attenuate β-amyloid load and prevent tau-protein tangle deposition, thereby improving cognitive performance in AD mouse models. In addition, telomere shortening, a cellular senescence biomarker, is associated with increased ND risks. Telomere dysfunction causes cellular senescence, stimulating IL-6, tumor necrosis factor-α, and IL-1β secretions. The forced expression of telomerase activators prevents cellular senescence, yielding considerable neuroprotective effects. This review elucidates the mechanism of cellular senescence in ND pathogenesis, suggesting strategies to eliminate or restore senescent cells to a normal phenotype for treating such diseases.

• Klíčová slova
• Alzheimer’s disease, Amyloid β · tau protein, Cellular senescence, Neurodegenerative diseases, Telomere shortening,
• MeSH
• Alzheimerova nemoc MeSH
• amyloidní beta-protein metabolismus   MeSH
• lidé MeSH
• neurodegenerativní nemoci * MeSH
• Parkinsonova nemoc metabolismus   MeSH
• sekreční fenotyp asociovaný se senescencí MeSH
• signální transdukce MeSH
• stárnutí buněk * účinky léků   MeSH
• zkracování telomer účinky léků   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• amyloidní beta-protein MeSH