Grape Seed Proanthocyanidin Extract Moderated Retinal Pigment Epithelium Cellular Senescence Through NAMPT/SIRT1/NLRP3 Pathway

Abstract

Background: Retinal pigment epithelium (RPE) cellular senescence is an important process in degenerative retinal disorders. Grape seed proanthocyanidin extract (GSPE) alleviates senescence-related degenerative disorders; however, the potential effects of GSPE intake on RPE cellular senescence through regulating NAMPT/SIRT1/NLRP3 pathway remain unclear. Methods: The effects of GSPE on NAMPT expression and NAD+ contents were detected with Western blot and assay kit in both in-vivo and in-vitro AMD models. Senescencerelated biomarkers, including p16, p21 expressions and β-gal staining, were conducted in different groups. The protective effects of GSPE treatment on the mitochondrial homeostasis and barrier function of RPE cells were detected using mtDNA lesions analyses, JC-1 staining, ZO1 staining and trans-epithelial cell resistance (TEER) detection. The expression of senescence-associated secretory phenotype (SASP) in different groups would be conducted with qPCR. To demonstrate the potential effects of NAMPT/SIRT1/NLRP3 pathway after GSPE treatment, the protein levels of relevant key regulators after applications of NAMPT inhibitor, Fk866, and SIRT1 inhibitor, EX-527. Results: GSPE significantly improves the NAMPT expression and NAD+ content in aging mice, and thus alleviates the RPE cellular senescence. In advanced in-vitro studies, GSPE significantly up-regulated NAMPT content and thus relieved H 2 O 2 induced NAD+ depression through analyzing the NAD+ contents in different groups. In advanced analyses, it was reported that GSPE could alleviate mitochondrial permeability, mtDNA damage, ZO1 expression and SASP levels in aging RPE cells. Thus, GSPE treatment significantly decreased senescencerelated protein p16 and p21, as well as SASP levels in in-vitro aging model, and it was demonstrated that GSPE could illustrate a significant anti-aging effect. The Western blot data in GSPE treatment of aging RPE cells demonstrated that GSPE could significantly improve NAMPT and SIRT1 levels, and thus depressed NLRP3 expression. Conclusion:This study indicated that GSPE alleviated RPE cellular senescence through NAMPT/SIRT1/NLRP3 pathway. This study highlighted the potential effects of GSPE on degenerative retinopathy through the crosstalk of NAD+ metabolism, SIRT1 function and NLRP3 activation.

Manjari Medika Grape Seed Extract Protects Methotrexate-Induced Hepatic Inflammation: Involvement of NF-κB/NLRP3 and Nrf2/HO-1 Signaling System

“…The observation was also in line with the previous reports where grape seed proanthocyanidin (GSPE) alleviated NLRP3 activation in several model systems. 125 , 126 …”

“…The observation was also in line with the previous reports where grape seed proanthocyanidin (GSPE) alleviated NLRP3 activation in several model systems. 125,126 Many experiments have indicated that TLR is a central mediator of the inflammatory response and establishes a crucial link between inflammation and fibrosis in chronic hepatic disorders. 127 TLR has also been regarded as the direct activator of NF-κB in drug-induced anomalies.…”

Oligomeric Proanthocyanidins: An Updated Review of Their Natural Sources, Synthesis, and Potentials

“…Polyphenols are widely used today, and anti-aging is one of the important ways to use them; the main way involves the enhancement of the body's anti-aging ability by polyphenols through the increase in the body's antioxidant capacity, and the intake of polyphenols is also related to telomere size [115]. The GSPE can significantly increase the expression of related pathways such as nicotinamide phosphoribosyl transferase (NAMPT), relieve nicotinamide adenine dinucleotide (NAD+) inhibition caused by H 2 O 2 and slow the aging of cells [116]. The dimer proanthocyanidins B2 can increase the anti-aging ability by inhibiting the matrix metalloproteinase-1 (MMP-1) [117].…”

Nutritional components as mitigators of cellular senescence in organismal aging: a comprehensive review

“…Further, anti-SASP effects of dietary flavonoids apigenin and kaempferol in bleomycin-induced senescence in fibroblasts were also reported that involved inhibition of the NF-κB pathway via IRAK1/IκBα signaling (Lim et al, 2015 ). In addition, cellular senescence suppressive attributes of polyphenol-rich fractions isolated from fruits such as lemons (Shimizu et al, 2019 ), grape seed extract (Wan et al, 2021 ; Xu et al, 2021 ), as well as red wine (Botden et al, 2012 ) have also been documented. In addition, a growing interest amongst polyphenols is the identification of novel senolytics that may selectively induce apoptosis in SC and thus alleviate SC burden in tissues with age (Li et al, 2019 ; Wang et al, 2021 ).…”