Diosmetin Targeted at Peroxisome Proliferator-Activated Receptor Gamma Alleviates Advanced Glycation End Products Induced Neuronal Injury

Abstract

The present study aimed to evaluate the role of diosmetin in alleviating advanced glycation end products (AGEs)-induced Alzheimer’s disease (AD)-like pathology and to clarify the action mechanisms. Before stimulation with AGEs (200 μg/mL), SH-SY5Y cells were treated with diosmetin (10 μmol/L), increasing cell viability. The induction of AGEs on the reactive oxygen species overproduction and downregulation of antioxidant enzyme activities, including superoxide dismutase, glutathione peroxidase, and catalase, were ameliorated by diosmetin. Amyloid precursor protein upregulation, accompanied by increased production of amyloid-β, caused by AGEs, was reversed by diosmetin. In the presence of diosmetin, not only β-site amyloid precursor protein cleaving enzyme1 expression was lowered, but the protein levels of insulin-degrading enzyme and neprilysin were elevated. Diosmetin protects SH-SY5Y cells from endoplasmic reticulum (ER) stress response to AGEs by suppressing ER stress-induced glucose regulated protein 78, thereby downregulating protein kinase R-like endoplasmic reticulum kinase, eukaryotic initiation factor 2 α, activating transcription factor 4, and C/EBP homologous protein. Diosmetin-pretreated cells had a lower degree of apoptotic DNA fragmentation; this effect may be associated with B-cell lymphoma (Bcl) 2 protein upregulation, Bcl-2-associated X protein downregulation, and decreased activities of caspase-12/-9/-3. The reversion of diosmetin on the AGEs-induced harmful effects was similar to that produced by pioglitazone. The peroxisome proliferator-activated receptor (PPAR)γ antagonist T0070907 (5 μmol/L) abolished the beneficial effects of diosmetin on AGEs-treated SH-SY5Y cells, indicating the involvement of PPARγ. We conclude that diosmetin protects neuroblastoma cells against AGEs-induced ER injury via multiple mechanisms and may be a potential option for AD.

Diosmetin alleviates benzo[a]pyrene-exacerbated H1N1 influenza virus-induced acute lung injury and dysregulation of inflammation through modulation of the PPAR-γ-NF-κB/P38 MAPK signaling axis

“…25 A previous study reported that diosmetin possessed PPAR-γ-activating property, and thus provided a remedy for the treatment of neuronal injury. 42 However, there has not yet been any information on the role of PPAR-γ in the protective effects of diosmetin against influenza virus-induced or B[ a ]P exposure-exacerbated influenza virus-mediated lung damage. Therefore, a further goal of our study was to clarity whether the therapeutic effect of diosmetin was dependent on PPAR-γ in B[ a ]P exposure following influenza virus infection models.…”

“…[38][39][40][41] Interestingly, diosmetin has a potent PPAR-γ-activating property. 42 However, it is unclear whether diosmetin could provide protective effects on B[a]P-exacerbated influenza-associated illness. In the present study, we investigated the influence of diosmetin on inflammation and lung injury triggered by B[a]P stimulation or influenza virus infection, as well as B[a]P-exacerbated influenzarelated illness.…”

Anti-Inflammatory Properties of the Citrus Flavonoid Diosmetin: An Updated Review of Experimental Models

“…Simultaneously, it is worth noting that peroxisome proliferator-activated receptor-γ (PPAR-γ) is best known for its critical function in controlling exacerbated lung inflammation and injury [79]. And Dios possesses a potent PPAR-γ-activating property [80]. Based on this, Zhou et al investigated the influence of Dios on inflammation and lung injury triggered by benzo[a]pyrene (B[a]P) stimulation and influenza virus infection.…”

Flavonoids and fibrate modulate apoE4-induced processing of amyloid precursor protein in neuroblastoma cells

“…Another flavonoid, diosmetin which is the aglycone portion of the flavonoid glycoside diosmin ( Barreca et al, 2020 ) has multiple health benefits including anti-lipolytic activity ( Lee et al, 2020 ; Garg et al, 2022 ). A recent study showed that diosmetin decreased APP upregulation and β-secretase (BACE1) expression, thus reducing Aβ production in advanced glycation end products (AGEs)-induced Alzheimer’s disease (AD)-like pathology in neuronal cells probably through the activation of the peroxisome proliferator-activated receptor-gamma (PPARγ) (PPARγ) pathway ( Lai et al, 2022 ). While PPARs are expressed in brain cells, PPARγ is both expressed in neurons and astrocytes ( Warden et al, 2016 ).…”