Pharmacological Research - Natural Products, Год журнала: 2023, Номер 1, С. 100006 - 100006
Опубликована: Ноя. 28, 2023
Язык: Английский
Journal of the American Chemical Society, Год журнала: 2024, Номер 146(26), С. 17801 - 17816
Опубликована: Июнь 18, 2024
Gangliosides, sialic acid bearing glycosphingolipids, are components of the outer leaflet plasma membranes all vertebrate cells. They contribute to cell regulation by interacting with proteins in their own (cis) or extracellular milieu (trans). As amphipathic membrane constituents, gangliosides present challenges for identifying ganglioside protein interactome. To meet these challenges, we synthesized bifunctional clickable photoaffinity gangliosides, delivered them cultured cells, then captured and identified interactomes using proteomic mass spectrometry. Installing probes on lipid glycan moieties, cis trans ganglioside–protein interactions. Ganglioside varied structure, type, site probe (lipid glycan). Gene ontology revealed that engage transmembrane transporters adhesion including integrins, cadherins, laminins. The approach developed is applicable other types, promising provide insights into molecular cellular gangliosides.
Язык: Английский
Процитировано
8
Translational Neurodegeneration, Год журнала: 2023, Номер 12(1)
Опубликована: Май 12, 2023
NCT03522129 https:// clini caltr ials.gov/ ct2/ show/ NCT03 522129.Investigational therapies for Alzheimer's disease (AD) target a wide range of mechanisms, yet promising disease-modifying remain huge unmet need.Much evidence indicates that the oligomeric form amyloid-beta (Aβ) is toxic species contributing to AD through synaptic damage and neuronal toxicity [1].In support this, Aβ oligomer reduction in an mouse model leads memory preservation [2, 3], clinical benefit was observed trials lecanemab, which targets oligomers protofibrils [4], patients, encouraging continued development oligomertargeting therapies.CT1812 novel, small-molecule, brain-penetrant sigma-2 receptor (S2R) modulator selectively prevents displaces from binding synapses, thereby mitigating downstream toxicity.This thought occur allosteric modulation
Язык: Английский
Процитировано
16
Experimental Eye Research, Год журнала: 2024, Номер 242, С. 109889 - 109889
Опубликована: Апрель 7, 2024
Язык: Английский
Процитировано
6
International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(15), С. 12025 - 12025
Опубликована: Июль 27, 2023
Sigma (σ) receptors are a class of unique proteins with two subtypes: the sigma-1 (σ1) receptor which is situated at mitochondria-associated endoplasmic reticulum (ER) membrane (MAM), and sigma-2 (σ2) receptor, located in ER-resident membrane. Increasing evidence indicates involvement both σ1 σ2 pathogenesis Alzheimer’s disease (AD), thus these represent potentially effective biomarkers for emerging AD therapies. The availability optimal radioligands positron emission tomography (PET) neuroimaging humans will provide tools to monitor progression treatment outcomes. In this review, we first summarize significance pathophysiology highlight therapeutic strategies related receptors. We then survey potential PET radioligands, an emphasis on requirements imaging or humans. Finally, discuss current challenges development receptors, opportunities elucidate as novel early diagnosis, monitoring drug efficacy.
Язык: Английский
Процитировано
15
Neurobiology of Disease, Год журнала: 2024, Номер 199, С. 106575 - 106575
Опубликована: Июнь 22, 2024
CT1812 is a novel, brain penetrant small molecule modulator of the sigma-2 receptor (S2R) that currently in clinical development for treatment Alzheimer's disease (AD). Preclinical and early data show that, through S2R, selectively prevents displaces binding amyloid beta (Aβ) oligomers from neuronal synapses improves cognitive function animal models AD. SHINE an ongoing Phase 2 randomized, double-blind, placebo-controlled trial (COG0201) participants with mild to moderate AD, designed assess safety efficacy 6 months treatment. To elucidate mechanism action AD patients pharmacodynamic biomarkers CT1812, present study reports exploratory cerebrospinal fluid (CSF) biomarker 18 interim analysis first set (part A). Untargeted mass spectrometry-based discovery proteomics detects >2000 proteins patient CSF has documented utility accelerating identification novel reflective diverse pathophysiologies beyond tau, enabling longitudinal interventional trials. We leveraged this technique analyze samples taken at baseline after Proteome-wide protein levels were detected using tandem tag-mass spectrometry (TMT-MS), change was calculated each participant, differential abundance by group performed. This revealed significantly impacted including pathway engagement (i.e., tied S2R biology) modification altered vs. healthy control but normalized correlated favorable trends ADAS-Cog11 scores). Brain network mapping, Gene Ontology, analyses impact on synapses, lipoprotein biology, neuroinflammation. Collectively, findings highlight method providing mechanistic insights which may facilitate enable appropriate pre-specification upcoming trials CT1812.
Язык: Английский
Процитировано
5
Molecular Therapy — Nucleic Acids, Год журнала: 2025, Номер 36(1), С. 102460 - 102460
Опубликована: Янв. 21, 2025
Язык: Английский
Процитировано
0
Organic Process Research & Development, Год журнала: 2025, Номер unknown
Опубликована: Янв. 29, 2025
Язык: Английский
Процитировано
0
Scientific Reports, Год журнала: 2025, Номер 15(1)
Опубликована: Фев. 10, 2025
Trafficking defects in retinal pigmented epithelial (RPE) cells contribute to RPE atrophy, a hallmark of geographic atrophy (GA) dry age-related macular degeneration (AMD). Dry AMD pathogenesis is multifactorial, including amyloid-β (Aβ) accumulation and oxidative stress-common features Alzheimer's disease (AD). The Sigma-2 receptor (S2R) regulates lipid protein trafficking, S2R modulators reverse trafficking deficits neurodegeneration vitro models. Given overlapping mechanisms contributing AD AMD, modulator effects on function were investigated. CT1812 clinical trials for AD, dementia with Lewy bodies, GA. Leveraging testing CT1812, unbiased analyses patient biofluid proteomes revealed that proteins altered by associated GA ontologies overlapped AMD. Differential expression analysis transcripts from APP-Swedish/London mutant transgenic mice, model featuring Aβ accumulation, reversal autophagy/trafficking modulator-treated animals versus vehicle toward healthy control levels. Photoreceptor outer segment (POS) human showed response Aβ1-42 or hydrogen peroxide compared vehicle. normalized stressor-induced POS deficits, resembling control. Taken together, modulation may provide novel therapeutic strategy
Язык: Английский
Процитировано
0
Biomedicines, Год журнала: 2025, Номер 13(3), С. 540 - 540
Опубликована: Фев. 21, 2025
Background/Objectives: While positive symptoms of schizophrenia are often satisfactorily controlled, negative difficult to treat, persisting despite treatment. Different strategies have been devised deal with this problem. We aimed review drug treatment for in controlled trials marketed drugs. Methods: searched the PubMed database and resulting records’ reference lists identify eligible using schizophrenia[ti] AND “negative symptom*”[ti] as a search strategy. determined eligibility through Delphi rounds among all authors. Results: On 11 February 2025, we identified 1485 records on 3 more from lists. Eligible were 95 records. Most studies double-blind, randomized trials, carried-out add-on patients stabilized antipsychotics. Other antipsychotics most frequent comparators, followed by antidepressants, recently, antioxidants gaining importance trials. Many especially those conducted Western world, found no significant effects compared placebo, while Iranian positive, although not strong effect size. Conclusions: Current research has contributed little progress schizophrenia. The reason might reside absence knowledge mechanisms whereby these generated, which prevents us designing possibly effective strategies, and/or chronicity symptoms, they first be established even when do become fully apparent.
Язык: Английский
Процитировано
0
Drug Design Development and Therapy, Год журнала: 2024, Номер Volume 18, С. 4003 - 4016
Опубликована: Сен. 1, 2024
Acne vulgaris (AV), a chronic inflammatory pilosebaceous disorder, affects 80-90% of teenagers. This study aimed to discover lipid profiles and biomarkers the rabbit ear acne model, investigate mechanism isotretinoin in treating at level.
Язык: Английский
Процитировано
3