TFEB; Beyond Its Role as an Autophagy and Lysosomes Regulator

Cells, Год журнала: 2022, Номер 11(19), С. 3153 - 3153

Опубликована: Окт. 7, 2022

Transcription factor EB (TFEB) is considered the master transcriptional regulator of autophagy and lysosomal biogenesis, which regulates target gene expression through binding to CLEAR motifs. TFEB dysregulation has been linked development numerous pathological conditions; however, several other lines evidence show that might be a point convergence diverse signaling pathways therefore modulate important biological processes such as cellular senescence, DNA repair, ER stress, carbohydrates, lipid metabolism WNT signaling-related processes. The regulation occurs predominantly at post-translational level, including phosphorylation, acetylation, SUMOylating, PARsylation, glycosylation. It noteworthy activation context-dependent; therefore, its subjected coordinated mechanisms respond not only nutrient fluctuations but also stress cell programs ensure proper homeostasis organismal health. In this review, we provide updated insights into novel modifications regulate activity give an overview beyond widely known role in pathway, thus opening possibility considering potential therapeutic target.

Язык: Английский

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Aging Hallmarks and Progression and Age-Related Diseases: A Landscape View of Research Advancement

ACS Chemical Neuroscience, Год журнала: 2023, Номер 15(1), С. 1 - 30

Опубликована: Дек. 14, 2023

Aging is a dynamic, time-dependent process that characterized by gradual accumulation of cell damage. Continual functional decline in the intrinsic ability living organisms to accurately regulate homeostasis leads increased susceptibility and vulnerability diseases. Many efforts have been put forth understand prevent effects aging. Thus, major cellular molecular hallmarks aging identified, their relationships age-related diseases malfunctions explored. Here, we use data from CAS Content Collection analyze publication landscape recent aging-related research. We review advances knowledge delineate trends research advancements on factors attributes across time geography. also current concepts related molecular, cellular, organismic level, age-associated diseases, with attention brain health, as well biochemical processes associated Major outlined, correlations features are hope this will be helpful for apprehending field mechanisms progression, an effort further solve remaining challenges fulfill its potential.

Язык: Английский

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Therapy-induced senescent cancer cells contribute to cancer progression by promoting ribophorin 1-dependent PD-L1 upregulation

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Янв. 3, 2025

Язык: Английский

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Cellular senescence in the tumor with a bone niche microenvironment: friend or foe?

Clinical and Experimental Medicine, Год журнала: 2025, Номер 25(1)

Опубликована: Янв. 23, 2025

Cellular senescence is understood to be a biological process that defined as irreversible growth arrest and was originally recognized tumor-suppressive mechanism prevents further propagation of damaged cells. More recently, cellular has been shown have dual role in prevention tumor promotion. Senescent cells carry senescence-associated secretory phenotype (SASP), which altered by factors including pro-inflammatory cytokines, chemokines, other proteases, leading the alteration tissue microenvironment. Though would eventually halt cancerous potential cells, SASP contributes environment promoting inflammation, matrix remodeling, cell invasion. The paradox prevention/promotion particularly relevant bone niche microenvironment, where longer-lasting, chronic inflammation promotes formation. Insights into mechanistic understanding provide basis for targeted therapies, such senolytics, aim eliminate senescent or inhibitors, tumor-promoting effects senescence. These therapeutic interventions offer significant clinical implications treating cancer healthy aging.

Язык: Английский

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Neurons and glial cells acquire a senescent signature after repeated mild traumatic brain injury in a sex-dependent manner

Frontiers in Neuroscience, Год журнала: 2022, Номер 16

Опубликована: Ноя. 3, 2022

Mild traumatic brain injury (mTBI) is an important public health issue, as it can lead to long-term neurological symptoms and risk of neurodegenerative disease. The pathophysiological mechanisms driving this remain unclear, currently there are no effective therapies for mTBI. In study on repeated mTBI (rmTBI), we have induced three mild closed-skull injuries or sham procedures, separated by 24 h, in C57BL/6 mice. We show that rmTBI mice prolonged righting reflexes astrogliosis, with impairment the Morris water maze (MWM) light dark test. Cortical hippocampal tissue analysis revealed DNA damage form double-strand breaks, oxidative damage, R-loops, markers cellular senescence including p16 p21, signaling mediated cGAS-STING pathway. This identified novel sex differences after Although these were all increased both sexes, females had higher levels lower protein p16, proteins compared their male counterparts. Single-cell RNA sequencing mouse activation response, evidence senescence, pro-inflammatory reminiscent senescence-associated secretory phenotype (SASP) neurons glial cells. Cell-type specific changes also present immune activation, neurotransmission alterations excitatory inhibitory neurons, vascular dysfunction. Treatment injured senolytic drug ABT263 significantly reduced only males, but was not therapeutic females. reduction accompanied improved performance MWM. provides compelling contributes dysfunction rmTBI, may do so a sex-dependent manner.

Язык: Английский

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Epigenetic Mechanisms of Aging and Aging-Associated Diseases

Cells, Год журнала: 2023, Номер 12(8), С. 1163 - 1163

Опубликована: Апрель 14, 2023

Aging is an inevitable outcome of life, characterized by a progressive decline in tissue and organ function. At molecular level, it marked the gradual alterations biomolecules. Indeed, important changes are observed on DNA, as well at protein that influenced both genetic environmental parameters. These directly contribute to development or progression several human pathologies, including cancer, diabetes, osteoporosis, neurodegenerative disorders others aging-related diseases. Additionally, they increase risk mortality. Therefore, deciphering hallmarks aging represents possibility for identifying potential druggable targets attenuate process, then age-related comorbidities. Given link between aging, genetic, epigenetic alterations, given reversible nature mechanisms, precisely understanding these factors may provide therapeutic approach disease. In this review, we center regulatory mechanisms their aging-associated changes, highlighting inferences age-associated

Язык: Английский

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Strategies for senolytic drug discovery

Aging Cell, Год журнала: 2023, Номер 22(10)

Опубликована: Авг. 7, 2023

Abstract Senolytics are a category of drugs that reduce the impact cellular senescence, an effect associated with range chronic and age‐related diseases. Since discovery first senolytics in 2015, number known senolytic agents has grown dramatically. This review discusses broad categories senolytics—kinase inhibitors, Bcl‐2 family protein naturally occurring polyphenols, heat shock BET P53 stabilizers, repurposed anti‐cancer drugs, cardiac steroids, PPAR‐alpha agonists, antibiotics. The approaches used to screen for new articulated including methods induce different target cell types, various assays, markers. choice can greatly influence outcomes screen, high‐quality screens featuring robust systems, adequate controls, extensive validation alternate assays. Recent advances single‐cell analysis computational identification also discussed. There is significant potential further drug discovery, but this will require additional research into targets mechanisms actions their subsequent rigorous evaluation pre‐clinical models human trials.

Язык: Английский

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Clinical perspectives on the age-related increase of immunosuppressive activity

Journal of Molecular Medicine, Год журнала: 2022, Номер 100(5), С. 697 - 712

Опубликована: Апрель 6, 2022

The aging process is associated with a remodeling of the immune system involving chronic low-grade inflammation and gradual decline in function system. These processes are also called inflammaging immunosenescence. age-related many clinical changes, e.g., risk for cancers infections increases, whereas efficiency vaccination immunotherapy declines aging. On other hand, there convincing evidence that inflammatory states promote premature process. or conditions stimulates counteracting immunosuppression which protects tissues from excessive injuries but promotes Immunosuppression driving force tumors it induces tolerance to immunotherapies. Immunosuppressive cells, myeloid-derived suppressor cells (MDSC), regulatory T (Treg), type M2 macrophages, have crucial role tumorigenesis as well Interestingly, substantial an increased immunosuppressive activity, upregulation anti-inflammatory cytokines. Given both involve activation immunosenescence, this might explain why factor conversely, insults humans.

Язык: Английский

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Distinct mechanisms mediating therapy-induced cellular senescence in prostate cancer

Cell & Bioscience, Год журнала: 2022, Номер 12(1)

Опубликована: Дек. 15, 2022

Abstract Background Prostate cancer (PCa) is an age-related malignancy in men with a high incidence rate. PCa treatments face many obstacles due to cell resistance and bypassing mechanisms escape therapy. According the intricacy of PCa, standard therapies are being used depending on stages including radical prostatectomy, radiation therapy, androgen receptor (AR) targeted therapy (androgen deprivation supraphysiological androgen, AR antagonists) chemotherapy. Most aforementioned have been implicated induce cellular senescence. Cellular senescence defined as stable cycle arrest G1 phase one that prevent proliferation. Results In this review, we provide analyze different therapy-induced (TIS) their effects tumor. Interestingly, it seems molecular pathways by cells for TIS. Understanding complexity underlying very critical its role tumorigenesis. The most prevalent analyzed TIS p53/p21 WAF1/CIP1 , p15 INK4B /p16 INK4A /pRb/E2F/Cyclin D, ROS/ERK, p27 Kip1 /CDK/pRb, /Skp2/C/EBP β signaling. Despite growth inhibition, senescent highly metabolically active. addition, secretome, which termed senescence-associated secretory phenotype (SASP), affects within tumor microenvironment neighboring non-tumor thereby may regulate tumors. Induction therefore double-edged sword can lead reduced or enhanced growth. Conclusion Thus, dependent type inducer specific senescence-induced pathway, useful develop pathway-specific senolytic compounds specifically targeting order evict reduce SASP side effects.

Язык: Английский

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Connecting epigenetics and inflammation in vascular senescence: state of the art, biomarkers and senotherapeutics

Frontiers in Genetics, Год журнала: 2024, Номер 15

Опубликована: Фев. 26, 2024

Vascular diseases pose major health challenges, and understanding their underlying molecular mechanisms is essential to advance therapeutic interventions. Cellular senescence, a hallmark of aging, cellular state characterized by cell-cycle arrest, senescence-associated secretory phenotype macromolecular damage, metabolic dysregulation. senescence has been demonstrated play key role in different vascular diseases, such as atherosclerosis, peripheral arterial disease, hypertension, stroke, diabetes, chronic venous ulcers. Even though was first described 1961, significant gaps persist comprehending the epigenetic driving its subsequent inflammatory response. Through comprehensive analysis, we aim elucidate these knowledge exploring network alterations that contribute senescence. In addition, describe consequent cascades triggered modifications. Finally, explore translational applications involving biomarkers emerging field senotherapy targeting this biological process.

Язык: Английский

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