4-OI Protects MIN6 Cells from Oxidative Stress Injury by Reducing LDHA-Mediated ROS Generation

Abstract

Pancreatic beta cells are highly susceptible to oxidative stress, which plays a crucial role in diabetes outcomes. Progress has been slow to identify molecules that could be utilized to enhance cell survival and function under oxidative stress. Itaconate, a byproduct of the tricarboxylic acid cycle, has both anti-inflammatory and antioxidant properties. The effects of itaconate on beta cells under oxidative stress are relatively unknown. We explored the effects of 4-octyl itaconate—a cell-permeable derivative of itaconate—on MIN6 (a beta cell model) under oxidative stress conditions caused by hypoxia, along with its mechanism of action. Treatment with 4-OI reversed hypoxia-induced cell death, reduced ROS production, and inhibited cell death pathway activation and inflammatory cytokine secretion in MIN6 cells. The 4-OI treatment also suppressed lactate dehydrogenase A (LDHA)activity, which increases under hypoxia. Treatment of cells with the ROS scavenger NAC and LDHA-specific inhibitor FX-11 reproduced the beneficial effects of 4-OI on MIN6 cell viability under oxidative stress conditions, confirming its role in regulating ROS production. Conversely, overexpression of LDHA reduced the beneficial effects exerted by 4-OI on cells. Our findings provide a strong rationale for using 4-OI to prevent the death of MIN6 cells under oxidative stress.

Hu-Zhang Qing-Mai Formulation anti-oxidative stress alleviates diabetic retinopathy: Network pharmacology analysis and in vitro experiment

“…Reactive oxygen species are critical regulators of cellular redox state. [16] To evaluate the degree of oxidative stress, we determined ROS production levels. As shown in Figure 6A and B, the generation of intracellular ROS in ARPE-19 cells robustly increased under H 2 O 2 stimulation, whereas Que treatment significantly reduced ROS formation, especially at a dose of 25 µM.…”

The signaling pathways and therapeutic potential of itaconate to alleviate inflammation and oxidative stress in inflammatory diseases

“…Therefore, the determination of whether itaconate promotes the anti-inflammatory and antioxidant phenotype acquisition of macrophages by inhibiting glycolysis has become a popular research direction. Recent studies have shown that the anti-inflammatory and antioxidant effects of itaconate and its derivatives can be achieved by regulating aerobic glycolysis [ [104] , [105] , [106] ]. Qin et al developed a specific thiol-reactive probe to detect the quantitative chemoproteomic profiling of cysteine modifications mediated by itaconate and found that 260 proteins, including some key glycolytic enzymes, such as ALDOA and LDHA, were modified by itaconate.…”

The Pancreatic Beta Cell: Editorial

“…This issue focuses on the molecular mechanisms that control beta cell mass expansion and survival, particularly emphasising significant pathways for mature beta cell function. The contributions cover a broad range of topics, including the impact of oxidative stress on beta cells [ 1 , 2 , 3 ], inter-tissular communication [ 4 , 5 , 6 , 7 ], and master regulators of beta cell mass and function [ 8 , 9 , 10 ], among others.…”

“…The authors suggested that nuclear factor erythroid 2-related factor 2 (Nrf2) is a master regulator of the beta cell antioxidant response. Wu and colleagues [ 3 ] explored the effects of 4-octyl itaconate (4-OI) on pancreatic beta cells under oxidative stress conditions. The researchers found that 4-OI treatment reduced the production of reactive oxygen species, inhibited cell death pathway activation and inflammatory cytokine secretion, and reversed hypoxia-induced cell death, indicating that 4-OI might enhance beta cell survival under oxidative stress conditions.…”