Functional Diversity of SIRT7 Across Cellular Compartments: Insights and Perspectives

Abstract: ETHNOPHARMACOLOGICAL RELEVANCE Diabetic retinopathy (DR) is a major microvascular complication of diabetes characterized by oxidative stress, mitochondrial dysfunction, and inflammation. Sappanone A (SA), a natural flavonoid derived from Caesalpinia sappan, is known for its antioxidant activity, but its ocular pharmacological potential and underlying mechanisms remain unclear. AIM OF THE STUDY This study aimed to investigate the protective effects of SA against high glucose (HG)-induced retinal oxidative injury and mitochondrial dysfunction, and to clarify whether the SIRT7/NRF2 signaling pathway mediates these effects. MATERIALS AND METHODS We established an in vitro diabetic retinopathy (DR) model by incubating human retinal microvascular endothelial cells (HRMECs) with HG. DR rat model was induced by intraperitoneal injection of streptozotocin (STZ). We also constructed siRNA and adeno-associated virus (AAV) vectors to knock down SIRT7 in vitro and in vivo, respectively. The specific NRF2 inhibitor ML385 was also used. Cellular and tissue oxidative stress levels were evaluated by reactive oxygen species (ROS) detection, MitoSOX staining, and antioxidant enzyme expression. RESULTS SA significantly reduced HG-induced ROS accumulation, restored mitochondrial function, and alleviated inflammation and apoptotic levels both in vitro and in vivo models. Furthermore, SA exhibited good biocompatibility and safety. Mechanistically, we observed that SA suppressed oxidative stress by upregulating SIRT7 and NRF2. Knockdown of SIRT7 with siRNA or AAV-SIRT7 abolished therapeutic effects of SA, and similar results were obtained with ML385 treatment, which confirmed that the SIRT7/NRF2 axis mediates the retinal protective effects of SA. CONCLUSION This study demonstrated that SA alleviates retinal oxidative stress, restores mitochondrial function, and inhibits inflammation and apoptosis in DR by activating the SIRT7/NRF2 signaling pathway. Our findings suggested that SA is a potential therapeutic candidate for diabetic retinopathy and propose SIRT7 as a novel molecular target for DR intervention.

TL;DR: Researchers reveal the structural basis of SIRT7's specificity for deacetylating H3K36 or H3K18 within nucleosomes, identifying a unique nucleosome-binding domain and enzyme binding poses that determine target lysine specificity.

TL;DR: The notion that multiple human SIRT proteins have evolutionarily conserved and nonconserved functions at different cellular locations is supported and the lifespan of normal human cells, in contrast to that of lower eukaryotes, cannot be manipulated by increased expression of a single SIRT protein.

TL;DR: It is found that Sirt5 is an efficient protein lysine desuccinylase and demalonylase in vitro and may represent a posttranslational modification that can be reversed by Sirt 5 in vivo.

TL;DR: Findings show that the modulation of p62 by autophagy is a key factor in tumorigenesis, and place p62 at critical decision points that control cell death and survival.

TL;DR: Rodents fasted for 48 hr show increased levels of the NAD(+) biosynthetic enzyme Nampt and a concomitant increase in mitochondrial NAD(+) and the relevance of these findings to understanding how nutrition modulates physiology and to the evolution of apoptosis is discussed.