Transactive response DNA binding protein of 43/histone deacetylase 6 axis alleviates H 2 O 2 -induced retinal ganglion cells injury through inhibiting apoptosis and autophagy.

Oxidative damage is believed to contribute to the pathogenesis of diabetic retinopathy (DR). The current study aimed to detect the effects of transactive response DNA binding protein of 43 (TDP-43) on cell damage induced by hydrogen peroxide (H2 O2 ) in retinal ganglion cells (RGCs) and to investigate the molecular mechanisms involved in this process. We observed that TDP-43 was highly expressed in RGC-5 cells induced by H2 O2 , and that repression of TDP-43 obviously ameliorated H2 O2 -induced RGC-5 cell injury. In addition, loss of TDP-43 profoundly mitigated H2 O2 -triggered oxidative stress by decreasing the production of intracellular reactive oxygen species and the activity of oxidative stress indicator malondialdehyde, as well as enhancing the content of antioxidant enzymes superoxide dismutase, glutathione peroxidase and catalase to restore the antioxidant defense system. Moreover, suppression of TDP-43 obviously obstructed H2 O2 -induced apoptosis. Meanwhile, knockdown of TDP-43 attenuated the expression of the proapoptotic proteins Bax and Cytochrome c, elevated the anti-apoptotic protein Bcl-2, and suppressed the activation of caspase 3 in H2 O2 -induced RGC-5 cells. Moreover, elimination of TDP-43 inhibited H2 O2 -triggered autophagy, which appeared as decreased expression of LC3II/I and Beclin-1, along with p62 degradation. Importantly, silencing of TDP-43 diminished the expression of histone deacetylase 6 (HDAC6), and HDAC6 also abolished the inhibitory effect of TDP-43 inhibition on H2 O2 -induced apoptosis and autophagy. Collectively, our findings demonstrated that depletion of TDP-43 may protect RGC-5 cells against oxidative stress-mediated apoptosis and autophagy by suppressing its target HDAC6. Thus, the TDP-43/HDAC6 axis might be a promising strategy for the treatment of DR.

(3R)-5,6,7-trihydroxy-3-isopropyl-3-methylisochroman-1-one alleviates lipoteichoic acid-induced photoreceptor cell damage.

OBJECTIVE: Exposure to oxidative stress will lead to the progression of retinal degenerative diseases, and unfortunately the exact mechanisms have not been fully understood. In this study, the protective effects of (3R)-5,6,7-trihydroxy-3-isopropyl-3-methylisochroman-1-one (TIM) against the lipoteichoic acid (LTA)-induced cell damage in mouse photoreceptor-derived 661W cells were investigated. METHODS: 661W cells were pre-treated with TIM at different concentrations (0.1-2.5 µM) before exposure to LTA. The oxidative stress and inflammatory response were detected in 661W cells. RESULTS: Pre-treatment of 661W cells with TIM (0.1-2.5 µM) for 4 h significantly decreased the LTA-induced toxicity. Meanwhile, pre-treatment with TIM could attenuate the imbalance state of redox in 661W cells by decreasing the levels of intracellular ROS and MDA, as well as enhancing the SOD activity and the level of GSH, through increasing the protein expression of Nrf2. Moreover, TIM pre-treatment decreased pro-inflammatory factors IL-1ß, IL-12 and TNFα, through inhibiting the nuclear factor kappa B. Pre-treatment with TIM also suppressed Egr1, Fosl1, and Lox12 gene expression. CONCLUSION: These results suggested that TIM may exert its protective effects against LTA-induced toxicity in 661W cells, through counteracting the oxidative stress and inhibiting inflammatory response. Our findings provided the scientific rational to develop TIM in the treatment of oxidative stress-induced photoreceptor cell damage.