Failure of senolytic treatment to prevent cognitive decline in a female rodent model of aging

Frontiers in Aging Neuroscience, Год журнала: 2024, Номер 16

Опубликована: Май 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.

Язык: Английский

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An Enteric Bacterial Infection Triggers Neuroinflammation and Neurobehavioral Impairment in 3xTg-AD Transgenic Mice

The Journal of Infectious Diseases, Год журнала: 2024, Номер 230(Supplement_2), С. S95 - S108

Опубликована: Март 29, 2024

Abstract Background Klebsiella pneumoniae is infamous for hospital-acquired infections and sepsis, which have also been linked to Alzheimer disease (AD)-related neuroinflammatory neurodegenerative impairment. However, its causative mechanistic role in AD pathology remains unstudied. Methods A preclinical model of K. enteric infection colonization developed an (3xTg-AD mice) investigate whether how pathogenesis exacerbates neuropathogenesis via the gut-blood-brain axis. Results pneumoniae, particularly under antibiotic-induced dysbiosis, was able translocate from gut bloodstream by penetrating epithelial barrier. Subsequently, infiltrated brain breaching blood-brain Significant phenotype observed mice with infection. pneumoniae-infected exhibited impaired neurobehavioral function elevated total tau levels brain. Metagenomic analyses revealed inverse correlation biome diversity commensal bacteria, highlighting dysbiosis triggers enteroseptic “pathobiome” signature implicated gut-brain perturbations. Conclusions The findings demonstrate infectious agents following consequent antibiotic regimen may induce pathobiome increase risk thereby increasing predisposition impairments

Язык: Английский

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Functional connectivity within sensorimotor cortical and striatal regions is regulated by sepsis in a sex-dependent manner

NeuroImage, Год журнала: 2025, Номер unknown, С. 120995 - 120995

Опубликована: Янв. 1, 2025

Sepsis is a state of systemic immune dysregulation and organ failure that frequently associated with severe brain disability. Epidemiological studies have indicated younger females better prognosis clinical outcomes relative to males, though the sex-dependent response sepsis during post-sepsis recovery remains largely uncharacterized. Using modified polymicrobial intra-abdominal murine model surgical sepsis, we characterized acute effects on peripheral inflammation, inflammation functional connectivity in young adult mice both sexes. Following male female survived procedure, regained body weight within 7 days showed reduced diversity their gut microbiome. Interestingly, compared sepsis-induced changes observed mice, post-septic exhibited comparatively robust profile splenic cell expansion intracerebral glial proliferation healthy counterparts. Analysis resting-state Magnetic Resonance Imaging (fMRI) data collected from revealed while somatosensory cortex were affected equally sexes, intra-network strength striatum preferentially increased males but remained near baseline mice. Additionally, network alterations projections periaqueductal gray superior colliculus as also between anterior cingulate striatum. Coupled sustained gliosis response, intra-striatal fMRI patterns could signify delayed sepsis. Together, our study provides evidence influences immunity, immunity manner, strongly indicating cognitive benefits recovering

Язык: Английский

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Sex, senescence, senolytics, and cognition

Frontiers in Aging Neuroscience, Год журнала: 2025, Номер 17

Опубликована: Март 4, 2025

This review focuses on sexual dimorphism in cellular senescence and senolytic treatment relation to brain health age-related cognitive decline. The stressors of aging, DNA damage, inflammation, oxidative stress induce cell senescence, a hallmark aging. Senescent cells change their function molecular profile are primed release pro-inflammatory cytokines. functional changes include the activation signals prevent death. cytokines from peripheral senescent during middle age induces neighbor heightens level systemic contributing neuroinflammation. In response neuroinflammation stress, some neurons alter physiology, decreasing neuronal excitability synaptic transmission. neurophysiology is protective against death due excitotoxicity, at expense loss normal function, inflammation may underlie prevalence, symptoms, pathogenesis diseases, including neurodegenerative diseases. Sex differences have been observed for astrocytes, microglia, cells, those involved innate adaptive immune responses. Interventions that remove such as drugs, can reduce or ameliorate aging-related function. Similarities responses males females depend system examined, regimen, burden, when initiated. Estrogen impacts several these factors influences transcription genes promoting growth, proliferation, survival programs manner opposite drugs. addition, estrogen has anti-aging effects independent rapidly modifying neurophysiology. Thus, it important recognize that, addition sex there other sexually dimorphic mechanisms contribute aging process. results indicate senolytics interact with fundamental biology, hormones.

Язык: Английский

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Improved prediction of sepsis-associated encephalopathy in intensive care unit sepsis patients with an innovative nomogram tool

Frontiers in Neurology, Год журнала: 2024, Номер 15

Опубликована: Фев. 20, 2024

Background Sepsis-associated encephalopathy (SAE) occurs as a result of systemic inflammation caused by sepsis. It has been observed that the majority sepsis patients experience SAE while being treated in intensive care unit (ICU), and significant number survivors continue suffering from cognitive impairment even after recovering illness. The objective this study was to create predictive nomogram could be used identify risk factors with ICU Methods We conducted retrospective cohort using Medical Information Mart for Intensive Care IV (MIMIC-IV) database. defined Glasgow Coma Scale (GCS) score 15 or less, delirium. were randomly divided into training validation cohorts. least absolute shrinkage selection operator (LASSO) regression modeling optimize feature selection. Independent determined through multivariable logistic analysis, prediction model built. performance evaluated various metrics including area under receiver operating characteristic curve (AUC), calibration plots, Hosmer-Lemeshow test, decision analysis (DCA), net reclassification improvement (NRI), integrated discrimination (IDI). Results Among 4,476 screened, 2,781 (62.1%) developed SAE. In-hospital mortality higher group compared non-SAE (9.5% vs. 3.7%, p < 0.001). Several variables analyzed, patient’s age, gender, BMI on admission, mean arterial pressure, body temperature, platelet count, sodium level, use midazolam. These validate nomogram. nomogram’s performance, assessed AUC, NRI, IDI, DCA, found superior conventional SOFA combined Calibration plots test confirmed accuracy enhanced NRI IDI values demonstrated our scoring system outperformed traditional diagnostic approaches. Additionally, DCA indicated practicality clinical settings. Conclusion This successfully identified autonomous associated emergence utilized them formulate model. outcomes investigation have potential serve valuable resource timely detection patients.

Язык: Английский

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Sepsis compromises post-ischemic stroke neurological recovery and is associated with sex differences

Life Sciences, Год журнала: 2024, Номер 349, С. 122721 - 122721

Опубликована: Май 15, 2024

Язык: Английский

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Retinal response to systemic inflammation differs between sexes and neurons

Frontiers in Immunology, Год журнала: 2024, Номер 15

Опубликована: Фев. 7, 2024

Background Neurological dysfunction and glial activation are common in severe infections such as sepsis. There is a sexual dimorphism the response to systemic inflammation both patients animal models, but there few comparative studies. Here, we investigate effect of induced by intraperitoneal administration lipopolysaccharide (LPS) on retina male female mice determine whether antagonism NLRP3 inflammasome extrinsic pathway apoptosis have protective effects retina. Methods A single injection LPS (5 mg/kg) was administered two months old C57BL/6J mice. Retinas were examined longitudinally vivo using electroretinography spectral domain optical coherence tomography. Retinal ganglion cell (RGC) survival microglial analysed flat-mounts. extracts used for flow cytometric analysis CD45 CD11b positive cells. Matched plasma retinal levels proinflammatory cytokines measured ELISA. function RGC assessed animals treated with P2X7R TNFR1 antagonists alone or combination. Results In LPS-treated sexes, transient dysfunction, loss vision-forming not non-vision forming RGCs, swelling, activation, infiltration, increases TNF IL-1β. Compared females, males showed higher death, slower functional recovery, overexpression lymphotoxin alpha their retinas. antagonism, combination, rescued RGCs. also function. Response treatment better females than males. Conclusions Systemic has neuronal sex-specific adverse mouse retina, which counteracted targeting apoptosis. Our results highlight need analyse preclinical studies inflammatory diseases affecting central nervous system

Язык: Английский

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Potential of piperine for neuroprotection in sepsis-associated encephalopathy

Life Sciences, Год журнала: 2023, Номер 337, С. 122353 - 122353

Опубликована: Дек. 15, 2023

Язык: Английский

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Analysis of the effects of early screening combined with blood lactate on the severity of patients with sepsis

Heliyon, Год журнала: 2024, Номер 10(11), С. e31907 - e31907

Опубликована: Май 24, 2024

This work aimed to investigate the adoption value of blood lactic acid (BLA) combined with National Early Warning Score (NEWS) in early screening sepsis patients and assessing their severity. The data materials utilized this were obtained from electronic medical record system 537 anonymized who received emergency rescue area Liuzhou People's Hospital, Guangxi, July 1, 2020, December 26, 2020. Based on 28-day outcomes patients, records rolled into Group S (407 survival cases) D (130 dead cases). Basic information such as mode hospital admission, initial management, use ventilator within 24 hours NEWS score, arterial oxygen pressure/alveolar pressure ratio (PaO2/PAO2), alveolar-arterial difference (A-aDO2), serum creatinine (SCr), urea nitrogen (BUN), oxygenation index (OI), Glasgow Coma Scale (GCS), D-dimer, vasoactive drugs C-reactive protein (CRP), procalcitonin (PCT), interleukin-6 (IL-6), N-terminal pro-B-type natriuretic peptide (NT-proBNP), quick Sequential Organ Failure Assessment (qSOFA) SOFA BLA level, lactate (NEWS-L) score including level (SOFA-L) Intensive Care Unit (ICU) length stay, total ICU stay/total septic shock condition compared between groups. Logistic regression analysis was performed assess impact various predictive factors prognosis plot receiver operating characteristic (ROC) curve. results suggested marked differences terms mean age (t=-5.620; OR=-9.96, 95% CI: -13.44∼-6.47; P<0.001). showed drastic admission (χ2=9.618, P<0.01), method management (χ2=51.766, P<0.001), (χ2=98.564, incidence (χ2=77.545, (χ2=102.453, heart rate (t=-4.063, respiratory (t=-4.758, status (χ2=20.547, (t=-6.120, PaO2/PAO2 (t=2.625, A-aDO2 (Z=-3.581, OI (Z=-3.106, PLT (Z=-2.305, P<0.05), SCr (Z=-3.510, BUN (Z=-3.170, D-dimer (Z=-4.621, CRP (Z=-4.057, PCT (Z=-2.783, IL-6 (Z=-2.904, stay (Z=-4.138, (Z=-8.488, CCU/total (Z=-9.118, (t=-6.961, SOFA-L (Z=-4.609, NEWS-L (Z=-5.845, (Z=-6.557, GCS (Z=6.909, P<0.001) when D. ventilators, shock, PCT, identified independent risk for predicting (P<0.001). areas under ROC curve (AUC) acid, NEWS, NEWS-L, GCS, SOFA, 0.695, 0.665, 0.692, 0.698, 0.477, 0.700, 0.653, respectively. These findings indicate that combination has certain advantages sepsis.

Язык: Английский

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Advancements in Immunity and Dementia Research: Highlights from the 2023 AAIC Advancements: Immunity Conference

Alzheimer s & Dementia, Год журнала: 2024, Номер unknown

Опубликована: Дек. 18, 2024

Abstract The immune system is a key player in the onset and progression of neurodegenerative disorders. While brain resident cell‐mediated neuroinflammation peripheral cell (eg, T cell) infiltration into have been shown to significantly contribute Alzheimer's disease (AD) pathology, nature extent responses context AD related dementias (ADRD) remain unclear. Furthermore, roles driving ADRD pathology incompletely elucidated. In March 2023, Association convened International Conference (AAIC), Advancements: Immunity, discuss ADRD. A wide range topics were discussed, such as animal models that replicate human immune‐related biomarkers clinical trials, lessons from other fields describing neurodegeneration. This manuscript presents highlights conference outlines avenues for future research on immunity Highlights plays central role pathogenesis disease. exerts numerous effects throughout amyloid‐beta, tau, pathways. 2023 AAIC, encouraged discussions collaborations understanding system.

Язык: Английский

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