Comparative Study of a Potent CNS-Permeable RARβ-Modulator, Ellorarxine, in Neuronal Cells In Vitro

Published: March 8, 2024

.Vitamin A (retinol) and its derivatives (retinoids) assume critical roles in neural development, cellular differentiation, axon elongation, programmed cell apoptosis various fundamental processes. Retinoids function by binding to specific nuclear receptors, such as retinoic acid receptors (RARs) retinoid X (RXRs), activating signaling pathways the cells. Disruption of pathway can result neuroinflammation, ox-idative stress, mitochondrial dysfunction neurodegenerative processes, has been asso-ciated with a range diseases. The present study explores potential therapeutic application our innovative synthetic retinoid, Ellorarxine, also known DC645 NVG0645, for treatment disorders vitro. MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) tetrazolium assay, lactate dehy-drogenase (LDH) enzyme-linked immunosorbent assay (ELISA), senescence-associated (SA) β-galactosidase (β-gal) staining immunofluorescence were performed. re-sults showed that no cytotoxicity was detected at experimental concentrations Ellorarxine. Ellorarxine significantly reduced death, increased viability, num-ber senescent cells, modulated cytokine release regulated autophagy. Furthermore, Cyp26 selectively RARβ expression. These results make promising drug candidate should be further investigated .

Language: Английский

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Exercise to Mitigate Cerebrovascular Aging: A Geroscience Perspective

The Journals of Gerontology Series A, Journal Year: 2024, Volume and Issue: 79(7)

Published: March 22, 2024

Abstract Aging is characterized by a progressive loss of cellular functions that increase the risk developing chronic diseases, vascular dysfunction, and neurodegenerative conditions. The field geroscience has identified molecular hallmarks aging may serve as targets for future interventions to reduce age-related disease disability. These include genomic instability, telomere attrition, epigenetic alterations, proteostasis, deregulated nutrient sensing, mitochondrial senescence, stem cell exhaustion, altered intercellular communication. Several studies show exercise favorably affect these processes thereby have antiaging properties. primary mechanisms through which confers protective benefits in brain are still incompletely understood. To better understand effects leverage them help promote health, we present current findings supporting notion adaptive responses play pivotal role mitigating their on cerebrovasculature, ultimately contribute maintenance function across healthspan.

Language: Английский

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Cross-species analysis uncovers the mitochondrial stress response in the hippocampus as a shared mechanism in mouse early life stress and human depression

Neurobiology of Stress, Journal Year: 2024, Volume and Issue: 31, P. 100643 - 100643

Published: May 14, 2024

Depression, or major depressive disorder, poses a significant burden for both individuals and society, affecting approximately 10.8% of the general population. This psychiatric disorder leads to 800,000 deaths per year. A combination genetic environmental factors such as early life stress (ELS) increase risk development depression in humans, clear role hippocampus pathophysiology has been shown. Nevertheless, underlying mechanisms remain poorly understood, resulting lack effective treatments. To better understand core depression, we used cross-species design investigate shared hippocampal pathophysiological mouse ELS human depression. Mice were subjected by maternal separation paradigm, followed RNA sequencing analysis adult tissue. identified persistent transcriptional changes linked mitochondrial response pathways, with oxidative phosphorylation protein folding emerging main affected separation. Remarkably, there was overlap between pathways involved observed publicly available RNAseq data from tissue patients. conservation gene expression mitochondria-related genes suggests that may play pivotal Our findings highlight potential significance mechanism Further experimental investigations are required expand our understanding these mechanisms.

Language: Английский

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Exploring the thermodynamics of protein aggregation: an insight to Huntington's disease therapeutics

Neuroscience and Behavioral Physiology, Journal Year: 2024, Volume and Issue: 54(7), P. 1042 - 1060

Published: Aug. 27, 2024

Language: Английский

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Decoding the Molecular Script of 2’-O-Ribomethylation: Implications Across CNS Disorders

Heliyon, Journal Year: 2024, Volume and Issue: 10(21), P. e39036 - e39036

Published: Oct. 5, 2024

Emerging evidence underscores the critical role of impaired mRNA translation in various neurobiological conditions. Ribosomal RNA (rRNA), essential for protein synthesis, undergoes crucial post-transcriptional modifications such as 2'-O-ribose methylation, pseudouridylation, and base modifications. These modifications, particularly methylation is vital stabilizing rRNA structures optimizing efficiency by regulating integrity its interactions with proteins. Concentrated key regions like decoding sites peptidyl transferase center, dysregulation these can disrupt ribosomal function, contributing to pathogenesis diverse neurological conditions, including mental health disorders, developmental abnormalities, neurodegenerative diseases. Mechanistically, involves between small nucleolar RNAs (snoRNAs), snoRNPs, fibrillarin, forming a complex regulatory network maintaining function. Recent research highlights association defective ribosome biogenesis spectrum CNS emphasizing importance understanding mechanisms disease pathology. This review focuses on pivotal shaping function potential implications unraveling pathophysiology disorders. Insights gained from studying could pave way new therapeutic strategies targeting dysfunction associated neuropathological advancing precision medicine interventions.

Language: Английский

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