Resveratrol Alleviates Diabetic Periodontitis-Induced Alveolar Osteocyte Ferroptosis Possibly via Regulation of SLC7A11/GPX4

Abstract

The mode and mechanism of diabetic periodontitis-induced alveolar-osteocyte death are still unclear. This study aimed to investigate the occurrence of ferroptosis in alveolar osteocytes during diabetic periodontitis and the therapeutic potential of resveratrol to alleviate osteocyte ferroptosis. Diabetic periodontitis was induced in C57/BL6-male mice and treated with or without resveratrol. Periodontitis pathogenicity was analyzed by micro-CT and histology, and alveolar-osteocyte ferroptosis was analyzed by immunohistochemistry. MLOY4 osteocytes were treated with P. gingivalis-derived lipopolysaccharide (LPS)+advanced glycosylated end products (AGEs) mimicking diabetic periodontitis condition in vitro, with or without resveratrol or ferrostatin-1 (ferroptosis inhibitor). Osteocyte ferroptosis and expression of inflammatory mediators were analyzed. Diabetic periodontitis aggravated periodontitis pathogenicity and inhibited the expression of GPX4 and SLC7A11 in alveolar osteocytes and resveratrol alleviated these effects. LPS+AGEs triggered osteocyte ferroptosis in vitro as indicated by the downregulated GPX4 and SLC7A11, upregulated malondialdehyde, disrupted mitochondrial morphology, and overexpressed pro-inflammatory mediators IL-1β, TNF-α, SOST, RANKL, and IL-6, and ferrostatin-1 or resveratrol treatment reversed these effects. LPS+AGEs upregulated pIKBα and pNF-κB p65 expression in osteocytes, and resveratrol or ferrostatin-1 reversed this effect. In conclusion, diabetic periodontitis triggers alveolar osteocyte ferroptosis possibly via disruption of the SLC7A11/GPX4 axis, and resveratrol has therapeutic potential to correct this biological event.

Beyond Mortality: Exploring the Influence of Plant Phenolics on Modulating Ferroptosis—A Systematic Review

“…It is defined by the body’s incapacity to regulate normal blood sugar levels, stemming from either insulin resistance or insufficient insulin production. Additionally, diabetes can contribute to the development of other conditions, such as diabetic nephropathy, cardiomyopathy, and neuropathies [ 77 , 78 , 79 ]. Interestingly, polyphenols quercetin, rhein, and glabridin have been shown to attenuate diabetic nephropathy through inhibition of ferroptosis.…”

Ferroptosis inhibitors: past, present and future

“…The non-flavonoid polyphenolic compound Resveratrol (RES) was found to promote ferroptosis-mediated recovery of motor function in SCI mice by modulating the Nrf2/GPX4 pathway in an SCI model ( Ni et al, 2023 ). Meanwhile, RES protects human bronchial epithelial cells (BEAS-2B) from ferroptosis by acting on the ferroptosis pathway and inhibits diabetic periodontitis-induced ferroptosis in alveolar osteoblasts ( Li et al, 2023c ), which offers the possibility of disease treatment. Furthermore, Kosuke Kato et al showed that quercetin and RES inhibit ferroptosis by inhibiting iron-catalyzed hydroxyl radicals and are independent of the Nrf2-ARE pathway ( Kato et al, 2023 ).…”

Mitochondria: An Emerging Unavoidable Link in the Pathogenesis of Periodontitis Caused by Porphyromonas gingivalis

“…Similarly, mitochondrial oxidative deregulation was proved to be a mutual systemic cytopathological feature of periodontitis and type 2 diabetes [17,18]. Moreover, there is evidence to suggest that the application of prominent polyphenolic compounds that optimize mitochondrial function, such as resveratrol, ameliorated the destruction of renal structures in mice with periodontitis [19] and alleviated the ferroptosis of alveolar osteocytes in mice with diabetic periodontitis [20]. In light of the mitochondrial pathway being so extensively involved in the pathological process of periodontitis, it has received mounting interest in exploring how the crucial periodontal pathogen, P. gingivalis, disrupts mitochondria.…”