bims-mideyd 2022-08-28 papers

Genes Genomics. 2022 Aug 26.

Activation of Nrf2/HO-1 antioxidant signaling correlates with the preventive effect of loganin on oxidative injury in ARPE-19 human retinal pigment epithelial cells.

Yung Hyun Choi.

BACKGROUND: Loganin, a type of iridoid glycoside derived from Corni Fructus, is known to have beneficial effects various chronic diseases. However, studies on mechanisms related to antioxidant efficacy in human retinal pigment epithelial (RPE) cells have not yet been conducted.
OBJECTIVES: This study was to investigate whether loganin could inhibit oxidative stress-mediated cellular damage caused by hydrogen peroxide (H2O2) in human RPE ARPE-19 cells.
METHODS: The preventive effect of loganin on H2O2-induced cytotoxicity, reactive oxygen species (ROS) generation, DNA damage and apoptosis was investigated. In addition, immunofluorescence staining and immunoblotting analysis were applied to evaluate the related mechanisms.
RESULTS: The loss of cell viability and increased ROS accumulation in H2O2-treated ARPE-19 cells were significantly abrogated by loganin pretreatment, which was associated with activation of nuclear factor erythroid 2-related factor 2 (Nrf2) and increased expression of heme oxygenase-1 (HO-1). Loganin also markedly attenuated H2O2-induced DNA damage, ultimately ameliorating apoptosis. In addition, H2O2-induced mitochondrial dysfunction was reversed in the presence of loganin as indicated by preservation of mitochondrial integrity, decrease of Bax/Bcl-2 expression ratio, reduction of caspase-3 activity and suppression of cytochrome c release into the cytoplasm. However, zinc protoporphyrin, a selective inhibitor of HO-1, remarkably alleviated the preventive effect offered by loganin against H2O2-mediated ARPE-19 cell injury, suggesting a critical role of Nrf2-mediated activation of HO-1 in the antioxidant activity of loganin.
CONCLUSION: The results of this study suggest that loganin-induced activation of the Nrf2/HO-1 axis is at least involved in protecting at least ARPE-19 cells from oxidative injury.

Keywords: Loganin; Nrf2/HO-1; ROS; Retinal pigment epithelial cells

DOI: https://doi.org/10.1007/s13258-022-01302-4

Oxid Med Cell Longev. 2022 ;2022 1497813

Downregulation of Inflammatory Response via Nrf2/Trx1/TXNIP Axis in Oxidative Stress-Induced ARPE-19 Cells and Mouse Model of AMD.

Qian Yang, Wenting Cai, Huizi Jin, Tianyi Shen, Jing Yu.

Aim: Chronic inflammation is crucial for age-related macular degeneration (AMD) pathogenesis. However, the mechanism involved in activating inflammation remains unclear. This study is aimed at investigating whether nuclear factor erythrocyte-associated factor 2 (Nrf2) negatively regulated the Nod-like receptor protein 3 (NLRP3) inflammasomes through the thioredoxin 1 (Trx1)/thioredoxin interaction protein (TXNIP) complex.
Methods: We determined the optimal hydrogen peroxide (H2O2) concentration, time, and changes in reactive oxygen species (ROS) levels. We also constructed animal models using blue LED irradiation. Then, the expression of Nrf2, TXNIP, Trx1, NLRP3, and inflammation-related factors and proteins, along with the changes in retinal thickness and functional status, was analyzed.
Results: The oxidative stress model was established after 1 h intervention with 100 μM H2O2. Nrf2 reduced ROS production, protected the ultrastructure of mitochondria, increased the thickness of the ONL layer, and increased the amplitude of a- and b-wave amplitudes in ERG. Trx1 knockdown increased the production of ROS, damaged the ultrastructure of mitochondria, reduced the thickness of the other ONL layer, and reduced the amplitudes of a- and b-waves in the electroretinogram (ERG). Thus, TXNIP in the cytoplasm activated the inflammasomes.
Conclusions: Nrf2 showed antioxidant and anti-inflammatory activity in the H2O2-induced cell stress model and blue LED-induced retinal light damage model. TXNIP transferred from the nucleus to the cytoplasm, activated NLRP3, and aggravated the retinal injury in both the cell stress model and the animal blue LED model. In contrast, Trx1 knockout promoted this process. This study revealed the possible role of the thioredoxin system in developing AMD while also providing newer insights for the future treatment of AMD.

DOI: https://doi.org/10.1155/2022/1497813

Cells. 2022 Aug 18. pii: 2567. [Epub ahead of print]11(16):

Chronic Hyperglycemia Compromises Mitochondrial Function in Corneal Epithelial Cells: Implications for the Diabetic Cornea.

Natalia Mussi, Whitney L Stuard, Jose Marcos Sanches, Danielle M Robertson.

Mitochondrial dysfunction is a major pathophysiological event leading to the onset of diabetic complications. This study investigated the temporal effects of hyperglycemia on mitochondrial metabolism in corneal epithelial cells. To accomplish this, human telomerase-immortalized corneal epithelial cells were cultured in a defined growth medium containing 6 mM glucose. To simulate hyperglycemia, cells were cultured in a medium containing 25 mM D-glucose, and control cells were cultured in mannitol. Using metabolic flux analysis, there was a hyperosmolar-mediated increase in mitochondrial respiration after 24 h. By day 5, there was a decrease in spare respiratory capacity in cells subject to high glucose that remained suppressed throughout the 14-day period. Although respiration remained high through day 9, glycolysis was decreased. Mitochondrial respiration was decreased by day 14. This was accompanied by the restoration of glycolysis to normoglycemic levels. These changes paralleled a decrease in mitochondrial polarization and cell cycle arrest. Together, these data show that chronic but not acute hyperglycemic stress leads to mitochondrial dysfunction. Moreover, the hyperglycemia-induced loss of spare respiratory capacity reduces the ability of corneal epithelial cells to respond to subsequent stress. Compromised mitochondrial function represents a previously unexplored mechanism that likely contributes to corneal complications in diabetes.

Keywords: cornea; diabetes; hyperglycemia; metabolism; mitochondria

DOI: https://doi.org/10.3390/cells11162567