Pathological BBB Crossing Melanin-Like Nanoparticles as Metal-Ion Chelators and Neuroinflammation Regulators against Alzheimer’s Disease

Research, Journal Year: 2023, Volume and Issue: 6

Published: Jan. 1, 2023

Inflammatory responses, manifested in excessive oxidative stress and microglia overactivation, together with metal ion-triggered amyloid-beta (Aβ) deposition, are critical hallmarks of Alzheimer’s disease (AD). The intricate pathogenesis causes severe impairment neurons, which, turn, exacerbates Aβ aggregation facilitates AD progression. Herein, multifunctional melanin-like ion chelators neuroinflammation regulators (named PDA@K) were constructed for targeted treatment AD. In this platform, intrinsically bioactive material polydopamine nanoparticles (PDA) potent chelating ROS scavenging effects decorated the KLVFF peptide, endowing system capacity enhanced pathological blood–brain barrier (BBB) crossing lesion site accumulation via hitchhiking. vitro vivo experiment revealed that PDA@K had high affinity toward able to hitch a ride on achieve increased BBB crossing. engineered effectively mitigated aggregate alleviated neuroinflammation. modulated inflammatory microenvironment by promoted microglial polarization M2-like phenotype, which restored their functions neuron care plaque removal. After 3-week PDA@K, spatial learning memory deficit as well neurologic changes FAD 4T transgenic mice largely rescued. Transcriptomics analysis further therapeutic mechanism PDA@K. Our study provided an appealing paradigm directly utilizing intrinsic properties nanomaterials therapeutics instead just using them nanocarriers, widen application therapy.

Language: Английский

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Microglial REV-ERBα regulates inflammation and lipid droplet formation to drive tauopathy in male mice

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Aug. 25, 2023

Alzheimer's disease, the most common age-related neurodegenerative is characterized by tau aggregation and associated with disrupted circadian rhythms dampened clock gene expression. REV-ERBα a core protein which also serves as nuclear receptor transcriptional repressor involved in lipid metabolism macrophage function. Global deletion has been shown to promote microglial activation mitigate amyloid plaque formation. However, cell-autonomous effects of healthy brain tauopathy are unexplored. Here, we show that enhances inflammatory signaling, disrupts metabolism, causes droplet (LD) accumulation specifically male microglia. These events impair phagocytosis, can be partially rescued blockage LD In vivo, exacerbates neuroinflammation two mouse models, mice. data demonstrate importance droplets reveal therapeutically accessible, sex-dependent regulator tauopathy.

Language: Английский

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Dysfunction of circadian and sleep rhythms in the early stages of Alzheimer's disease

Acta Physiologica, Journal Year: 2023, Volume and Issue: 238(2)

Published: March 31, 2023

Abstract Dysfunction of circadian and sleep rhythms is an early feature many neurodegenerative diseases. Alzheimer's disease (AD) a progressive disorder resulting in cognitive psychiatric disturbances. Although it largely unclear whether dysfunctions contribute to the etiology AD or are consequence disease, there evidence that these conditions involved complex self‐reinforcing bidirectional relationship. According recent studies, dysregulation clock already occurs during asymptomatic stage could promote neurodegeneration. Thus, restoration preclinical may represent opportunity for intervention slow course.

Language: Английский

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Immunotherapeutic approach to reduce senescent cells and alleviate senescence‐associated secretory phenotype in mice

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

Published: March 26, 2023

Abstract Accumulation of senescent cells (SNCs) with a senescence‐associated secretory phenotype (SASP) has been implicated as major source chronic sterile inflammation leading to many age‐related pathologies. Herein, we provide evidence that bifunctional immunotherapeutic, HCW9218, capabilities neutralizing TGF‐β and stimulating immune cells, can be safely administered systemically reduce SNCs alleviate SASP in mice. In the diabetic db/db mouse model, subcutaneous administration HCW9218 reduced islet β resulting improved glucose tolerance, insulin resistance, aging index. naturally aged mice, durably level SASP, lower expression pro‐inflammatory genes peripheral organs. treatment also reverted pattern key regulatory circadian gene mice levels observed young impacted associated metabolism fibrosis liver. Single‐nucleus RNA Sequencing analysis further revealed differentially changed transcriptomic landscape hepatocyte subtypes involving metabolic, signaling, cell‐cycle, pathways Long‐term survival studies showed physical performance without compromising health span Thus, represents novel immunotherapeutic approach clinically promising new class senotherapeutic agents targeting cellular diseases.

Language: Английский

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Glial control of sphingolipid levels sculpts diurnal remodeling in a circadian circuit

Neuron, Journal Year: 2022, Volume and Issue: 110(19), P. 3186 - 3205.e7

Published: Aug. 11, 2022

Language: Английский

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Is obstructive sleep apnea a circadian rhythm disorder?

Journal of Sleep Research, Journal Year: 2023, Volume and Issue: 32(4)

Published: March 15, 2023

Summary Obstructive sleep apnea is the most common sleep‐related breathing disorder worldwide and remains underdiagnosed. Its multiple associated comorbidities contribute to a decreased quality of life work performance as well an increased risk death. Standard treatment seems have limited effects on cardiovascular metabolic aspects disease, emphasising need for early diagnosis additional therapeutic approaches. Recent evidence suggests that dysregulation circadian rhythms, processes with endogenous rhythmicity are adjusted environment through various cues, involved in pathogenesis comorbidities. In patients obstructive apnea, altered gene expression patterns been demonstrated. respiratory events may promote disturbance intermittent hypoxia, subsequent inflammation disruption neural hormonal homeostasis. this review, current knowledge rhythm regulation, disorders summarised. Studies connect abnormalities critically evaluated. Furthermore, pathogenetic mechanisms underlie association, notably hypoxia signalling, presented. A bidirectional relationship between proposed. Approaching prove beneficial development new, personalised diagnostic, prognostic tools. However, further studies needed before clinical approach includes targeting system.

Language: Английский

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Prognostic utility of rhythmic components in 24-h ambulatory blood pressure monitoring for the risk stratification of chronic kidney disease patients with cardiovascular co-morbidity

Journal of Human Hypertension, Journal Year: 2024, Volume and Issue: 38(5), P. 420 - 429

Published: Jan. 11, 2024

Chronic kidney disease (CKD) represents a significant global burden. Hypertension is modifiable risk factor for rapid progression of CKD. We extend the stratification by introducing non-parametric determination rhythmic components in 24-h profiles ambulatory blood pressure monitoring (ABPM) Renal Insufficiency Cohort (CRIC) and African American Study Kidney Disease (AASK) cohort using Cox proportional hazards models. find that profiling BP through JTK_CYCLE analysis identifies subgroups CRIC participants were more likely to die due cardiovascular causes. While our fully adjusted model shows trend towards association between absent cyclic death full (HR: 1.71,95% CI: 0.99-2.97, p = 0.056), with history (CVD) their profile had at any time 3.4-times higher than CVD patients present 3.37, 95% 1.45-7.87, 0.005). This increased was not explained dipping or non-dipping pattern ABPM. Due large differences patient characteristics, results do replicate AASK cohort. study suggests as potential novel biomarker unmask excess among CKD prior disease.

Language: Английский

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Circadian rhythms as modulators of brain health during development and throughout aging

Frontiers in Neural Circuits, Journal Year: 2023, Volume and Issue: 16

Published: Jan. 19, 2023

The circadian clock plays a prominent role in neurons during development and throughout aging. This review covers topics pertinent to the of 24-h rhythms neuronal function, their tendency decline with Pharmacological or behavioral modification that augment function our internal may be central cognitive disease future chronotherapy for aging-related diseases nervous system.

Language: Английский

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Sleep-Related Changes Prior to Cognitive Dysfunction

Current Neurology and Neuroscience Reports, Journal Year: 2023, Volume and Issue: 23(4), P. 177 - 183

Published: March 7, 2023

Language: Английский

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MYC disrupts transcriptional and metabolic circadian oscillations in cancer and promotes enhanced biosynthesis

PLoS Genetics, Journal Year: 2023, Volume and Issue: 19(8), P. e1010904 - e1010904

Published: Aug. 28, 2023

The molecular circadian clock, which controls rhythmic 24-hour oscillation of genes, proteins, and metabolites in healthy tissues, is disrupted across many human cancers. Deregulated expression the MYC oncoprotein has been shown to alter clock leading a disruption cancer types. It remains unclear what benefit cells gain from suppressing oscillation, how this loss impacts global gene metabolism cancer. We hypothesized that or its paralog N-MYC (collectively termed herein) suppress upregulate pathways involved biosynthesis static, non-oscillatory fashion. To test this, distinct types with inducible were examined, using time-series RNA-sequencing metabolomics, determine extent activation disrupts pathways, metabolites. focused our analyses on changed common multiple cell line models. report here over 85% oscillating while instead promoting enhanced ribosomal mitochondrial biogenesis suppressed attachment pathways. Notably, when activated, biosynthetic programs formerly flipped being upregulated an oscillation-free manner. Further, ablates nutrient transporter proteins greatly upregulating expression, surface localization, intracellular amino acid pools. Finally, we metabolite oscillations temporal segregation nucleotide metabolism. Our results demonstrate releases metabolic processes control, may provide advantage cells.

Language: Английский

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