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Background <p>Diabetic retinopathy (DRP) is a leading cause of vision loss associated with chronic hyperglycemia-induced oxidative stress (OS), inflammation, and mitochondrial dysfunction in retinal pigment epithelium (RPE) cells. Zingerone (ZGN), a phenolic compound derived from <i>Zingiber officinale</i>, exhibits potent antioxidant and anti-inflammatory properties; however, its molecular targets in diabetic retinal damage remain unclear.</p> Methods <p>This study investigated the protective effects of ZGN against high glucose (HG)-induced cytotoxicity in human ARPE-19 cells, focusing on the ROS/PARP-1/TRPM2 signaling pathway. The cells were exposed to HG (30 mM) and treated with ZGN (0–80 µM) for 24&#xa0;h.</p> Results <p>HG incubation significantly increased MDA, PARP-1, ROS, intracellular calcium ion ([Ca²⁺]<sub>i</sub>), and pro-inflammatory cytokines (IL-1β and TNF-α) in ARPE-19 cells, while decreasing GSH levels and cell viability. ZGN significantly restored OS, reduced cytokine release, [Ca²⁺]<sub>i</sub>, and preserved mitochondrial membrane potential. Western blot and fluorescence analyses showed that ZGN reduced TRPM2 protein expression and suppressed [Ca²⁺]<sub>i</sub> overload. Moreover, pharmacological inhibition of TRPM2 with 2-APB and of PARP-1 with DPQ enhanced the cytoprotective effects of ZGN, confirming that the ROS/PARP-1/TRPM2 axis mediates HG-induced oxidative damage.</p> Conclusions <p>These findings suggest that ZGN protects ARPE-19 cells by integrating OS with [Ca²⁺]<sub>i</sub> homeostasis, providing a mechanistic rationale for its potential therapeutic use in preventing OS–related retinal damage in DRP.</p> Graphical Abstract <p>High glucose (HG) exposure triggers excessive production of reactive oxygen species (ROS) in retinal pigment epithelial (ARPE-19) cells, leading to oxidative stress (OS), inflammation, mitochondrial depolarisation, and subsequent cell death. The overproduction of ROS activates poly (ADP-ribose) polymerase-1 (PARP-1), generating ADP-ribose (ADPR) and thereby stimulating the TRPM2 channel to promote Ca²⁺ influx. Elevated intracellular Ca²⁺ further disrupts mitochondrial homeostasis, amplifies ROS accumulation, and initiates apoptotic signaling cascades. Consequently, OS depletes cellular antioxidant defences (GSH) while increasing lipid peroxidation (MDA) and pro-inflammatory cytokines (IL-1β and TNF-α). ZGN interrupts this vicious cycle through its potent antioxidant and anti-inflammatory actions, enhancing GSH levels, scavenging ROS, suppressing MDA, IL-1β, and TNF-α production, and preventing TRPM2-mediated Ca²⁺ overload. By restoring OS, reducing inflammatory mediators, and preserving mitochondrial integrity, ZGN effectively prevents HG-induced apoptosis and cell death, underscoring its therapeutic potential against OS-associated retinal injury.</p> <p></p>

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Protective role of zingerone against high glucose-Induced retinal pigment epithelial cell damage through modulation of the TRPM2 channel pathway

  • 期刊论文

  • 发表日期：

    2026年1月20日

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  • Esmanur Çiğ,
  • Mahmut Yardımcı,
  • Ramazan Çınar,
  • Kenan Yıldızhan

摘要

Background

Diabetic retinopathy (DRP) is a leading cause of vision loss associated with chronic hyperglycemia-induced oxidative stress (OS), inflammation, and mitochondrial dysfunction in retinal pigment epithelium (RPE) cells. Zingerone (ZGN), a phenolic compound derived from Zingiber officinale, exhibits potent antioxidant and anti-inflammatory properties; however, its molecular targets in diabetic retinal damage remain unclear.

Methods

This study investigated the protective effects of ZGN against high glucose (HG)-induced cytotoxicity in human ARPE-19 cells, focusing on the ROS/PARP-1/TRPM2 signaling pathway. The cells were exposed to HG (30 mM) and treated with ZGN (0–80 µM) for 24 h.

Results

HG incubation significantly increased MDA, PARP-1, ROS, intracellular calcium ion ([Ca²⁺]i), and pro-inflammatory cytokines (IL-1β and TNF-α) in ARPE-19 cells, while decreasing GSH levels and cell viability. ZGN significantly restored OS, reduced cytokine release, [Ca²⁺]i, and preserved mitochondrial membrane potential. Western blot and fluorescence analyses showed that ZGN reduced TRPM2 protein expression and suppressed [Ca²⁺]i overload. Moreover, pharmacological inhibition of TRPM2 with 2-APB and of PARP-1 with DPQ enhanced the cytoprotective effects of ZGN, confirming that the ROS/PARP-1/TRPM2 axis mediates HG-induced oxidative damage.

Conclusions

These findings suggest that ZGN protects ARPE-19 cells by integrating OS with [Ca²⁺]i homeostasis, providing a mechanistic rationale for its potential therapeutic use in preventing OS–related retinal damage in DRP.

Graphical Abstract

High glucose (HG) exposure triggers excessive production of reactive oxygen species (ROS) in retinal pigment epithelial (ARPE-19) cells, leading to oxidative stress (OS), inflammation, mitochondrial depolarisation, and subsequent cell death. The overproduction of ROS activates poly (ADP-ribose) polymerase-1 (PARP-1), generating ADP-ribose (ADPR) and thereby stimulating the TRPM2 channel to promote Ca²⁺ influx. Elevated intracellular Ca²⁺ further disrupts mitochondrial homeostasis, amplifies ROS accumulation, and initiates apoptotic signaling cascades. Consequently, OS depletes cellular antioxidant defences (GSH) while increasing lipid peroxidation (MDA) and pro-inflammatory cytokines (IL-1β and TNF-α). ZGN interrupts this vicious cycle through its potent antioxidant and anti-inflammatory actions, enhancing GSH levels, scavenging ROS, suppressing MDA, IL-1β, and TNF-α production, and preventing TRPM2-mediated Ca²⁺ overload. By restoring OS, reducing inflammatory mediators, and preserving mitochondrial integrity, ZGN effectively prevents HG-induced apoptosis and cell death, underscoring its therapeutic potential against OS-associated retinal injury.