EFNA4 as a potential prognostic biomarker and therapeutic target for GBMLGG DOI Creative Commons
Qingyu Tang,

Zhuomiao Zhang,

Shixuan Liu

et al.

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 30, 2024

Abstract Background Ephrin-A4 (EFNA4) is present in numerous tissues and connected to the growth development of multiple types cancer. The differences EFNA4 expression various cancer its impact on glioblastoma low-grade glioma (GBMLGG) are not well understood. This research seeks determine prognostic value predicting outcomes GBMLGG examine role tumorigenesis GBMLGG. Methods Cancer Genome Atlas (TCGA) Genotype-Tissue Expression (GTEx) databases were used differential genetic alterations EFNA4, their relationship with patient survival 33 types. Multiple algorithms correlation between infiltration cancer-associated fibroblasts, immune landscape, immunomodulatory genes, tumor mutational burden (TMB), microsatellite instability (MSI) score Univariate multivariate Cox regression models a nomogram developed forecast patients We also established protein-protein interaction networks, identified related functional signaling pathways, conducted drug sensitivity analyses progression Results In most cancer, there was an increase mRNA expression, which found be associated prognosis. had positive fibroblast levels types, markedly elevated comparison normal Overexpression significantly correlated progression, poor prognosis, high scores status demonstrated ability accurately predict Moreover, it discovered that considerable genes biological processes such as cell infiltration, tyrosine kinase pathway, neurotransmitter transmission synapses, epithelial-mesenchymal transition Conclusions findings this indicate has great potential both biomarker target for therapy

Language: Английский

Subcellular structure, heterogeneity, and plasticity of senescent cells DOI Creative Commons
Thais Cardoso Bitencourt, José Eduardo Vargas,

Andrew Oliveira Silva

et al.

Aging Cell, Journal Year: 2024, Volume and Issue: 23(4)

Published: March 30, 2024

Abstract Cellular senescence is a state of permanent growth arrest. It can be triggered by telomere shortening (replicative senescence) or prematurely induced stresses such as DNA damage, oncogene overactivation, loss tumor suppressor genes, oxidative stress, tissue factors, and others. Advances in techniques experimental designs have provided new evidence about the biology senescent cells (SnCs) their importance human health disease. This review aims to describe main aspects SnCs phenotype focusing on alterations subcellular compartments like plasma membrane, cytoskeleton, organelles, nuclei. We also discuss heterogeneity, dynamics, plasticity SnCs' phenotype, including SASP, pro‐survival mechanisms. advance multiple layers phenotypic heterogeneity SnCs, between inducers, tissues within population discussing relevance these raise challenges well alternatives overcome them. Ultimately, we present open questions perspectives understanding from perspective basic applied questions.

Language: Английский

Citations

16
Effect of peripheral cellular senescence on brain aging and cognitive decline DOI Creative Commons

Vivekananda Budamagunta,

Ashok Kumar, Asha Rani

et al.

Aging Cell, Journal Year: 2023, Volume and Issue: 22(5)

Published: March 23, 2023

Abstract We examine similar and differential effects of two senolytic treatments, ABT‐263 dasatinib + quercetin (D Q), in preserving cognition, markers peripheral senescence, brain aging thought to underlie cognitive decline. Male F344 rats were treated from 12 18 months age with D Q, ABT‐263, or vehicle, compared young (6 months). Both treatments rescued memory, preserved the blood–brain barrier (BBB) integrity, prevented age‐related decline hippocampal N‐methyl‐D‐aspartate receptor (NMDAR) function associated impaired cognition. Senolytic decreased senescence‐associated secretory phenotype (SASP) inflammatory cytokines/chemokines plasma (IL‐1β, IP‐10, RANTES), some more responsive Q (TNFα) (IFNγ, leptin, EGF). was effective decreasing senescence genes spleen. expression immune response oxidative stress increased synaptic dentate gyrus (DG). However, influenced twice as many ABT‐263. Relative group exhibited DG linked cell death negative regulation apoptosis microglial activation. Furthermore, at morphological The results indicate that cognition removal senescent cells, systemic inflammation normally drives neuroinflammation, BBB breakdown, function. Dissimilarities transcription divergence central mechanisms, possibly due access.

Language: Английский

Citations

34
An Overview of the Epigenetic Modifications in the Brain under Normal and Pathological Conditions DOI Open Access
Laura Lossi, Claudia Castagna, Adalberto Merighi

et al.

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(7), P. 3881 - 3881

Published: March 30, 2024

Epigenetic changes are in gene expression that do not involve alterations to the DNA sequence. These lead establishing a so-called epigenetic code dictates which and when genes activated, thus orchestrating regulation playing central role development, health, disease. The brain, being mostly formed by cells undergo renewal process throughout life, is highly prone risk of leading neuronal death neurodegenerative disorders, mainly at late age. Here, we review main modifications have been described with particular attention on those related onset developmental anomalies or conditions and/or occurring old methylation several types histone (acetylation, methylation, phosphorylation, ubiquitination, sumoylation, lactylation, crotonylation) major players these processes. They directly indirectly involved neurodegeneration Alzheimer's Parkinson's Therefore, this briefly describes roles mechanisms brain maturation, aging some most important factors dynamically regulating contributing changes, such as oxidative stress, inflammation, mitochondrial dysfunction.

Language: Английский

Citations

14
Blood-brain barrier disruption: a culprit of cognitive decline? DOI Creative Commons
Ji Che,

Yinying Sun,

Yixu Deng

et al.

Fluids and Barriers of the CNS, Journal Year: 2024, Volume and Issue: 21(1)

Published: Aug. 7, 2024

Cognitive decline covers a broad spectrum of disorders, not only resulting from brain diseases but also systemic diseases, which seriously influence the quality life and expectancy patients. As highly selective anatomical functional interface between circulation, blood-brain barrier (BBB) plays pivotal role in maintaining homeostasis normal function. The pathogenesis underlying cognitive may vary, nevertheless, accumulating evidences support BBB disruption as most prevalent contributing factor. This mainly be attributed to inflammation, metabolic dysfunction, cell senescence, oxidative/nitrosative stress excitotoxicity. However, direct evidence showing that causes is scarce, interestingly, manipulation opening alone exert beneficial or detrimental neurological effects. A overview present literature shows close relationship decline, risk factors disruption, well cellular molecular mechanisms disruption. Additionally, we discussed possible leading by potential therapeutic strategies prevent enhance repair. review aims foster more investigations on early diagnosis, effective therapeutics, rapid restoration against would yield better outcomes patients with dysregulated function, although their causative has yet been completely established.

Language: Английский

Citations

14
Senolytic treatment alleviates doxorubicin‐induced chemobrain DOI Creative Commons

Vivekananda Budamagunta,

Ashok Kumar, Asha Rani

et al.

Aging Cell, Journal Year: 2024, Volume and Issue: 23(2)

Published: Jan. 15, 2024

Abstract Doxorubicin (Dox), a widely used treatment for cancer, can result in chemotherapy‐induced cognitive impairments (chemobrain). Chemobrain is associated with inflammation and oxidative stress similar to aging. As such, Dox has also been as model of However, it unclear if induces brain changes that observed during aging since does not readily enter the brain. Rather, mechanism chemobrain likely involves induction peripheral cellular senescence release senescence‐associated secretory phenotype (SASP) factors these SASP disrupt cognition. We examined effect on markers In addition, we employed senolytic, ABT‐263, which limited access The results indicate plasma brain, activating microglia, increasing stress, altering gene transcription. turn, synaptic function required memory was reduced response altered redox signaling. ABT‐263 prevented or most Dox‐induced effects. emphasize link between decline from senescent cells some differences well similarities advanced age treatment.

Language: Английский

Citations

9
The senolytic ABT-263 improves cognitive functions in middle-aged male, but not female, atherosclerotic LDLr−/−;hApoB100+/+ mice DOI Creative Commons
Mélanie Lambert,

Géraldine Miquel,

Louis Villeneuve

et al.

GeroScience, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 21, 2025

Language: Английский

Citations

1
Senolytic therapy is neuroprotective and improves functional outcome long-term after traumatic brain injury in mice DOI Creative Commons
Jing Wang,

Yujiao Lu,

Christopher E. Carr

et al.

Frontiers in Neuroscience, Journal Year: 2023, Volume and Issue: 17

Published: July 27, 2023

Introduction Chronic neuroinflammation can exist for months to years following traumatic brain injury (TBI), although the underlying mechanisms remain poorly understood. Methods In current study, we used a controlled cortical impact mouse model of TBI examine whether proinflammatory senescent cells are present in long-term (months) after and ablation these via administration senolytic drugs improve functional outcome TBI. The results revealed that astrocytes microglia cerebral cortex, hippocampus, corpus callosum lateral posterior thalamus colocalized cell markers, p16 Ink4a or p21 Cip1/Waf1 at 5 weeks post (5wpi) 4 (4mpi) (CCI) model. Intermittent drugs, dasatinib quercetin ( D + Q ) beginning 1-month 13 significantly ablated -positive- -positive-cells animals, reduced expression major senescence-associated secretory phenotype (SASP) pro-inflammatory factors, interleukin-1β interleukin-6. Senolytic treatment also attenuated neurodegeneration enhanced neuron number 18 ipsilateral thalamus. Behavioral testing further therapy rescued defects spatial reference memory recognition memory, as well depression-like behavior mice. Discussion Taken whole, findings indicate there is robust widespread induction TBI, drug begun efficiently ablate cells, reduce SASP neurodegeneration, rescue depressive behavior.

Language: Английский

Citations

22
Proteostasis disruption and senescence in Alzheimer’s disease pathways to neurodegeneration DOI
Riya Thapa, Asif Ahmad Bhat, Moyad Shahwan

et al.

Brain Research, Journal Year: 2024, Volume and Issue: 1845, P. 149202 - 149202

Published: Aug. 30, 2024

Language: Английский

Citations

8
Failure of senolytic treatment to prevent cognitive decline in a female rodent model of aging DOI Creative Commons
Asha Rani, Linda A. Bean,

Vivekananda Budamagunta

et al.

Frontiers in Aging Neuroscience, Journal Year: 2024, Volume and Issue: 16

Published: May 15, 2024

There are sex differences in vulnerability and resilience to the stressors of aging subsequent age-related cognitive decline. Cellular senescence occurs as a response damaging or stress-inducing stimuli. The includes state irreversible growth arrest, development senescence-associated secretory phenotype, release pro-inflammatory cytokines associated with diseases. Senolytics compounds designed eliminate senescent cells. Our recent work indicates that senolytic treatment preserves function male F344 rats. current study examined effect on female Female rats (12 months) were treated dasatinib (1.2 mg/kg) + quercetin ABT-263 vehicle for 7 months. Examination estrus cycle indicated females had undergone estropause during treatment. Senolytic may have increased behavioral stress responsivity, particularly initial training cued version watermaze. However, pre-training cue task reduced responsivity spatial all groups learned discrimination. In contrast preserved memory observed senolytic-treated males, older exhibited impaired episodic relative young (6-month) females. We suggest not been able compensate loss estradiol, which can act mechanisms anxiety independent cellular senescence.

Language: Английский

Citations

6
Senolytic intervention improves cognition, metabolism, and adiposity in female APPNL−F/NL−F mice DOI Creative Commons
Yimin Fang, Mackenzie R. Peck,

Kathleen Quinn

et al.

GeroScience, Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 9, 2024

Abstract Senescent cells accumulate throughout the body and brain contributing to unhealthy aging Alzheimer’s disease (AD). The APP NL−F/NL−F amyloidogenic AD mouse model exhibits increased markers of senescent senescence-associated secretory phenotype (SASP) in visceral white adipose tissue hippocampus before plaque accumulation cognitive decline. We hypothesized that senolytic intervention would alleviate cellular senescence thereby improving spatial memory mice. Thus, 4-month-old male female mice were treated monthly with vehicle, 5 mg/kg dasatinib + 50 quercetin, or 100 fisetin. Blood glucose levels, energy metabolism, memory, amyloid burden, cell assayed. Dasatinib quercetin treatment oxygen consumption expenditure resulting decreased mass. White mass was along markers, SASP, blood glucose, plasma insulin triglycerides. Hippocampal SASP reduced soluble insoluble amyloid-β (Aβ) 42 senescence-associated-β-gal activity leading improved memory. Fisetin had negligible effects on these measures while neither altered parameters Considering women have a greater risk dementia, identifying senotherapeutics appropriate for sex stage is necessary personalized medicine. Graphical

Language: Английский

Citations

5