Peripheral Evolution of Tanshinone IIA and Cryptotanshinone for Discovery of a Potent and Specific NLRP3 Inflammasome Inhibitor

Journal of Medicinal Chemistry, Год журнала: 2025, Номер unknown

Опубликована: Янв. 23, 2025

Natural products (NPs) continue to serve as an invaluable source in drug discovery, and peripheral evolution of NPs is a highly efficient strategy. Herein, we describe unified "methyl amide" Tanshinone IIA Cryptotanshinone for discovery NLRP3 inflammasome inhibitors. There were 54 compounds designed prepared, while the chemoinformatic analysis revealed that these evolved NP analogues occupy unique chemical space. Biological evaluation identified 5m inhibitor, could directly bind NACHT domain protein block interaction ASC, thus suppressing ASC oligomerization assembly. Molecular dynamic stimulations amide moiety played vital role binding mode. Moreover, exhibited therapeutical efficacy sepsis NASH mouse model. In conclusion, this protocol provides new vision NPs' novel inhibitor.

Язык: Английский

---

Natural Compounds Regulate Macrophage Polarization and Alleviate Inflammation Against ALI/ARDS

Biomolecules, Год журнала: 2025, Номер 15(2), С. 192 - 192

Опубликована: Янв. 29, 2025

Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a pulmonary disease with high mortality associated inflammation. During the development of ALI/ARDS, macrophages usually polarize toward M1 pro-inflammatory macrophages, promoting inflammatory response in ALI/ARDS and aggravating tissue damage. Natural compounds anti-inflammatory activity have achieved excellent results treatment through different regulatory modes, including macrophage polarization. Of note, flavonoid, brevilin A, tetrahydropalmatine play an important role by modulating phenotypic polarization their cytokine expression innate immune cells lung. Flavonoids are kind naturally occurring polyphenol compound, which has antioxidant activities. Studies found that some flavonoids can alleviate inhibiting cytokines macrophages. Among them, 5-methoxyflavone, acacetin, grape seed proanthocyanidins, luteolin also regulate Therefore, in-depth exploration mechanism lay foundation for application alleviating inflammation-related injury. This review focuses on effects natural potential mechanisms ALI/ARDS.

Язык: Английский

---

Tamibarotene directly targets the NACHT domain of NLRP3 to alleviate acute myocardial infarction

Biochemical Pharmacology, Год журнала: 2025, Номер unknown, С. 116801 - 116801

Опубликована: Фев. 1, 2025

Язык: Английский

---

Cerium-doped Prussian blue biomimetic nanozyme as an amplified pyroptosis inhibitor mitigate Aβ oligomer-induced neurotoxicity in Alzheimer’s disease

Journal of Nanobiotechnology, Год журнала: 2025, Номер 23(1)

Опубликована: Март 6, 2025

Antioxidant enzyme therapy shows promise for treating Alzheimer's disease (AD), but significant challenges remain in achieving effective blood-brain barrier (BBB) penetration and sustained therapeutic effects. We developed a novel neutrophil membrane (NM)-coated cerium-doped Prussian blue biomimetic nanozyme (NM@PB-Ce) that demonstrates outstanding enzymatic properties targeted efficacy. Extensive physicochemical characterization using transmission electron microscopy, X-ray photoelectron spectroscopy, dynamic light scattering confirmed the successful synthesis of uniform nanoparticles (~ 142 nm) with preserved protein functionality. In vitro studies utilizing SH-SY5Y neuroblastoma cells revealed NM@PB-Ce effectively scavenged reactive oxygen species through multiple enzyme-mimetic activities (catalase, superoxide dismutase, peroxidase). The significantly suppressed NLRP3 inflammasome activation subsequent pyroptosis, reducing inflammatory markers (IL-1β, IL-18) while attenuating Aβ aggregation. Using sophisticated co-culture BBB model real-time vivo fluorescence imaging, we demonstrated NM@PB-Ce's ability to traverse accumulate specifically AD-affected regions. an Aβ1-42 oligomer-induced AD mouse model, systematic administration (320 μg/mL, 0.01 mL/g/day 14 days) improved cognitive performance across behavioral paradigms, including Morris water maze, Y-maze, open field tests. Molecular histological analyses decreased neuroinflammation (GFAP, Iba-1) hippocampus, reduced levels NLRP3, caspase-1, phosphorylated tau (demonstrated by Western blot ELISA), enhanced dendritic spine density (visualized Golgi staining). This comprehensive study establishes as promising platform treatment, providing both mechanistic insights into its mode action robust evidence efficacy targeting decline.

Язык: Английский

---

Costunolide Ameliorates the Methylmalonic Acidemia Via the PINK1/Parkin Pathway

Neurochemical Research, Год журнала: 2025, Номер 50(2)

Опубликована: Март 7, 2025

Язык: Английский

---