ACS Medicinal Chemistry Letters, Год журнала: 2024, Номер 15(8), С. 1203 - 1204
Опубликована: Июль 29, 2024
Provided herein are novel compounds as NLRP3 inhibitors, pharmaceutical compositions, use of such in treating Alzheimer's disease and Parkinson's disease, processes for preparing compounds.
Язык: Английский
Cellular and Molecular Immunology, Год журнала: 2025, Номер unknown
Опубликована: Март 13, 2025
Abstract Neuroinflammation plays an important role in the pathogenesis of various central nervous system (CNS) diseases. The NLRP3 inflammasome is intracellular multiprotein complex composed innate immune receptor NLRP3, adaptor protein ASC, and protease caspase-1. activation can induce pyroptosis release proinflammatory cytokines IL-1β IL-18, thus playing a inflammatory responses. Recent studies have revealed that activated brain to neuroinflammation, leading further neuronal damage functional impairment, contributes pathological process neurological diseases, such as multiple sclerosis, Parkinson’s disease, Alzheimer’s stroke. In this review, we summarize neuroinflammation course CNS diseases discuss potential approaches target for treatment
Язык: Английский
Процитировано
5
Immunological Reviews, Год журнала: 2024, Номер unknown
Опубликована: Окт. 17, 2024
Summary The NLRP3 inflammasome is a multiprotein complex that upon activation by the innate immune system drives broad inflammatory response. primary initial mediators of this response are pro‐IL‐1β and pro‐IL‐18, both which in an inactive form. Formation activates caspase‐1, cleaves pro‐IL‐18 triggers formation gasdermin D pores. Gasdermin pores allow for secretion active IL‐1β IL‐18 initiating organism‐wide can be beneficial to host; however, if inappropriately activated it lead significant pathology. While components known, precise details assembly less well defined conflicting. Here, we discuss several proposed pathways inflammasome. We examine role subcellular localization reciprocal regulation autophagy. focus on roles mitochondria mitophagy activating regulating Finally, detail impact pathologic responses development manifestations pulmonary disease.
Язык: Английский
Процитировано
10
Journal of Medicinal Chemistry, Год журнала: 2025, Номер unknown
Опубликована: Янв. 13, 2025
The P2X4 receptor is implicated in various pathological conditions, including neuropathic pain and cancer. This study reports the development of 1,4-naphthodiazepinedione-based antagonists aimed at both therapeutic applications potential use as PET tracers for imaging expression Structure–activity relationship studies aided by docking molecular dynamics simulations led to a series compounds with potent antagonism, promising vitro inhibition interleukin-1β release THP-1 cells suitability radiolabeling fluorine-18. most were further evaluated their physicochemical properties, metabolic stability, vivo biodistribution using mice. While these exhibited strong binding serum rapid metabolism limited tracers, highlighting need structural optimization. advances understanding antagonism underscores challenges developing effective this target.
Язык: Английский
Процитировано
2
International Journal of Molecular Sciences, Год журнала: 2025, Номер 26(7), С. 3272 - 3272
Опубликована: Апрель 1, 2025
Chronic alcohol consumption leads to excessive production of reactive oxygen species (ROS), driving oxidative stress that contributes both use disorder (AUD) and Alzheimer's disease (AD). This review explores how ROS-mediated mitochondrial dysfunction neuroinflammation serve as shared pathological mechanisms linking these conditions. We highlight the role alcohol-induced damage in exacerbating neurodegeneration compare ROS-related pathways AUD AD. Finally, we discuss emerging therapeutic strategies, including antioxidants inflammasome inhibitors, target mitigate neurodegeneration. Understanding overlapping may provide new insights for preventing treating ROS-driven neurodegenerative disorders.
Язык: Английский
Процитировано
1
Frontiers in Pharmacology, Год журнала: 2025, Номер 16
Опубликована: Апрель 3, 2025
Alzheimer’s disease (AD) is one of the most common diseases characterized by neurodegeneration and becoming a major public health problem worldwide. AD manifested mainly progressive impairments in cognition, emotion, language memory elderly population. Many treatment strategies have been explored for decades; however, there still no effective way to address root cause pathogenesis, only target symptoms improve patient cognitive outcomes. Intracerebral administration difficult because challenges posed blood‒brain barrier (BBB). NPs are materials with sizes between 1 100 nm that can biocompatibility, extend half-life, transport macromolecules, be delivered across BBB central nervous system, exhibit good targeting capabilities. provide new ideas terms their antiaging, antineuroinflammatory, antioxidative, nerve repair-promoting effects. In this manuscript, we first describe relationship BBB. Second, introduce application nanoparticles treatment. Finally, summarize faced AD.
Язык: Английский
Процитировано
1
Neural Regeneration Research, Год журнала: 2024, Номер 20(6), С. 1644 - 1664
Опубликована: Июль 10, 2024
Traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer’s disease are three distinct neurological disorders that share common pathophysiological mechanisms involving neuroinflammation. One sequela of neuroinflammation includes the pathologic hyperphosphorylation tau protein, an endogenous microtubule-associated protein protects integrity neuronal cytoskeletons. Tau results in misfolding subsequent accumulation tangles forming neurotoxic aggregates. These misfolded proteins characteristic can lead to downstream neuroinflammatory processes, including assembly activation inflammasome complex. Inflammasomes refer a family multimeric units that, upon activation, release cascade signaling molecules resulting caspase-induced cell death inflammation mediated by interleukin-1β cytokine. specific inflammasome, NOD-like receptor 3, has been proposed be key regulator phosphorylation where it shown prolonged 3 acts as causal factor pathological spreading. This review begins describing epidemiology pathophysiology disease. Next, we highlight overriding theme discuss role formation deposits how such tauopathic entities spread throughout brain. We then propose novel framework linking inflammasome-dependent pathologies exist along temporal continuum. Finally, potential therapeutic targets may intercept this pathway ultimately minimize long-term decline.
Язык: Английский
Процитировано
3
Cells, Год журнала: 2024, Номер 13(17), С. 1426 - 1426
Опубликована: Авг. 26, 2024
There is an urgent need for effective disease-modifying therapeutic interventions Alzheimer's disease (AD)-the most prevalent cause of dementia with a profound socioeconomic burden. Most clinical trials targeting the classical hallmarks this disease-β-amyloid plaques and neurofibrillary tangles-failed, showed discrete effects, or were accompanied by concerning side effects. has been ongoing search novel targets. Neuroinflammation, now widely recognized as hallmark all neurodegenerative diseases, proven to be major contributor AD pathology. Here, we summarize role neuroinflammation in pathogenesis progression discuss potential targets such microglia, TREM2, complement system, inflammasomes, cytosolic DNA sensors. We also present overview studies specific innate immune system components, highlighting progress field drug research while bringing attention delicate nature modulations AD.
Язык: Английский
Процитировано
3
medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown
Опубликована: Янв. 10, 2025
Abstract Background Alzheimer’s disease (AD) is the most common neurodegenerative disorder, NLRP3 inflammasome has been shown to play a pivotal role in pathogenesis of AD, and with increasing attention its involvement AD. Therefore, we applied bibliometric methods describe current research status This study aims analyze trends hotspots this field from 2013 2024, providing valuable insights for AD research. Methods We have selected on Web Science Core Collection, time range January 1, 2013, November 30, exported all publications plain text format. Visualization analysis was performed using CiteSpace 6.4.R1, VOSviewer 1.6.20, Scimago Graphica 1.0.46. Results A total 759 related were included study. The number annual showed general upward trend. top three countries terms publication volume China, United States, Italy. University Manchester institution highest publications. author Michael Heneka, while cited Eicke Latz. International Journal Molecular Sciences published articles also frequently journal. keywords disease, inflammasome, neuroinflammation, Aβ, microglia. Conclusion primary focus pathology, potential as therapeutic target, strategies modulate neuroinflammation through targeting inflammasome. Future should further investigate interactions between other molecular pathways, assess clinical potential, provide new early diagnosis treatment
Язык: Английский
Процитировано
0
Journal of Alzheimer s Disease, Год журнала: 2025, Номер unknown
Опубликована: Март 2, 2025
As a recently identified cytokine, interleukin-34 (IL-34) is predominantly produced by neurons and functions as modulator for glial functions. Emerging evidence indicates that IL-34 exerted neuroprotective effects in Alzheimer's disease (AD), but the underlying mechanism remained elusive. To uncover mechanisms which provides neuroprotection AD. Using senescence-accelerated mouse prone substrain 8 (SAMP8) mice, well-established model sporadic AD, we investigated dynamic changes brain concentrations during AD progression. Afterwards, SAMP8 mice received 4-week continuous intracerebroventricular infusion of IL-34. Morris water maze test was employed to assess spatial cognitive Neuronal synaptic markers, oxidative stress makers, pro-inflammatory cytokines activation markers brains were measured. Finally, amyloid-β (Aβ)42-stimulated primary microglia, lentivirus-mediated gene knockdown strategy co-immunoprecipitation assay utilized possible In revealed gradually decreased A rescued impairments, ameliorated neuronal damage, suppressed microglia-mediated inflammation mice. Aβ42-stimulated demonstrated first time microglial NLRP3 inflammasome release interacting with triggering receptor expressed on myeloid cells 2 (TREM2), key regulator These findings indicating IL-34/TREM2 signaling may represent novel therapeutic this devastating disease.
Язык: Английский
Процитировано
0
NeuroMolecular Medicine, Год журнала: 2025, Номер 27(1)
Опубликована: Март 7, 2025
Язык: Английский
Процитировано
0