English (United Kingdom)

https://curated-unify.zendy.io/wp-json/zendy-region/v1/featured_content/oa?rat=en

https://curated-unify.zendy.io/wp-json/zendy-region/v1/highlighted_journal/

Zendy Pro

Presents the zaia usage as premium feature

ZAIA

Presents AI Discovery search usage as a premium feature

AI Discovery

Presents AI Discovery explain and summary usage as a premium feature

Content Analysis

Presents the keyphrase highlighting as premium feature

Keyphrase Highlighting

Presents the summarisation as premium feature

Summarisation

Presents the pdf analysis as premium feature

PDF Analysis

1500 Top-up

3000 Top-up

Zendy Basic

2500 Top-up

Zendy Unlimited

Presents the access of premium content as premium feature

Premium Content

Alzheimer’s disease (AD) is the most common neurodegenerative disorder. Neuroinflammation is a prevalent pathogenic stress leading to neuronal death in AD. Targeting neuroinflammation to keep neurons alive is an attractive strategy for AD therapy. 1-Trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU) is a potent inhibitor of soluble epoxide hydrolase (sEH) and can enter into the brain. It has good efficacy on a wide range of chronic inflammatory diseases in preclinical animal models. However, the anti-neuroinflammatory effects and molecular mechanisms of TPPU for potential AD interventions remain elusive. With an aim to develop multitarget therapeutics for neurodegenerative diseases, we screened TPPU against sEH from different mammalian species and a broad panel of human kinases in vitro for potential new targets relevant to neuroinflammation in AD. TPPU inhibits both human sEH and p38β kinase, two key regulators of inflammation, with nanomolar potencies and distinct selectivity. To further elucidate the molecular mechanisms, differentiated SH-SY5Y human neuroblastoma cells were used as an AD cell model, and we investigated the neuroprotection of TPPU against amyloid oligomers. We found that TPPU effectively prevents neuronal death by mitigating amyloid neurotoxicity, tau hyperphosphorylation, and mitochondrial dysfunction, promoting neurite outgrowth and suppressing activation and nuclear translocation of NF-κB for inflammatory responses in human nerve cells. The results indicate that TPPU is a potent and selective dual inhibitor of sEH and p38β kinase, showing a synergistic action in multiple AD signaling pathways. Our study sheds light upon TPPU and other sEH/p38β dual inhibitors for potential pharmacological interventions in AD.

figshare

1‑Trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl)\nUrea, a Selective and Potent Dual Inhibitor of Soluble Epoxide Hydrolase\nand p38 Kinase Intervenes in Alzheimer’s Signaling in Human\nNerve Cells