SIRT6 overexpression in the nucleus protects mouse retinal pigment epithelium from oxidative stress.

Retinal pigment epithelium (RPE) is essential for the survival of retinal photoreceptors. To study retinal degeneration, sodium iodate (NaIO3) has been used to cause oxidative stress-induced RPE death followed by photoreceptor degeneration. However, analyses of RPE damage itself are still limited. Here, we characterized NaIO3-induced RPE damage, which was divided into three regions: periphery with normal-shaped RPE, transitional zone with elongated cells, and center with severely damaged or lost RPE. Elongated cells in the transitional zone exhibited molecular characteristics of epithelial-mesenchymal transition. Central RPE was more susceptible to stresses than peripheral RPE. Under stresses, SIRT6, an NAD+-dependent protein deacylase, rapidly translocated from the nucleus to the cytoplasm and colocalized with stress granule factor G3BP1, leading to nuclear SIRT6 depletion. To overcome this SIRT6 depletion, SIRT6 overexpression was induced in the nucleus in transgenic mice, which protected RPE from NaIO3 and partially preserved catalase expression. These results demonstrate topological differences of mouse RPE and warrant further exploring SIRT6 as a potential target for protecting RPE from oxidative stress-induced damage.

SIRT7 affects autophagy and activation of hepatic stellate cells by regulating the acetylation level of high mobility group protein 1.

OBJECTIVE: Preventing the progression of hepatic fibrosis is an important strategy to improve the prognosis of liver disease. The purpose of this study was to investigate the role of sirtuin7 (SIRT7) and high mobility group box 1 (HMGB1) acetylation in the occurrence and development of hepatic fibrosis. MATERIALS AND METHODS: Hepatic fibrosis mice model was induced by CCl4. TGF-ß1 was used to activated quiescent hepatic stellate cell (qHSC) into activated HSC (aHSC). Hematoxylin-eosin evaluated hepatic fibrosis in vivo, and the distribution of α-smooth muscle actin (α-SMA) or HMGB1 was detected by immunohistochemistry or immunofluorescence. The expressions of SIRT7, autophagy related proteins, and HSC activation-related proteins were detected by Western blot. Immunoprecipitation detected the acetylation level of HMGB1. Lysine mutants of HMGB1 were constructed in vitro to explore the acetylation sites of HMGB1. RESULTS: Hepatocyte autophagy and activation levels were enhanced in CCl4 group or aHSC group, and the acetylation level of HMGB1 was increased. Nuclear transfer of HMGB1 occurred in aHSC, and HMGB1was mainly distributed in cytoplasm. The expression of SIRT7 in CCl4 group or aHSC group was most significantly decreased, and knockdown of SIRT7 leads to increased levels of HSCs autophagy and activation. Overexpression of SIRT7 or interference of HMGB1 alone in aHSC can reduce the level of autophagy and activation of aHSC. However, continued overexpression of SIRT7 in shHMGB1-aHSC could not reduce the autophagy and activation levels of aHSC. Among the 11 Flag-HMGB1 mutants, the acetylation level of K86R-Flag-HMGB1 was the lowest. The acetylation level of K86R-Flag-HMGB1 did not change due to SIRT7 downregulation. CONCLUSION: This study proved that SIRT7 can directly target the K86R site of HMGB1 and participate in regulating the expression and distribution of HMGB1, thus affecting the autophagy and activation level of HSCs.

The modulation of sirtuins by natural compounds in the management of cisplatin-induced nephrotoxicity.

Cisplatin is a highly effective antitumor agent. However, its use is limited due to severe adverse effects, particularly nephrotoxicity, which occurs in approximately 30% of patients. There is a need for novel renoprotective compounds. Sirtuins play a vital role in various physiological and pathological processes such as oxidative stress, apoptosis, inflammation, and mitochondrial bioenergetics. It has been shown that sirtuins can exert a protective effect on cisplatin-induced acute kidney injury by targeting multiple signaling pathways. Besides, sirtuins not only did not reduce the anticancer effect of cisplatin but also increased it. Several natural compounds have been reported to inhibit cisplatin-mediated nephrotoxicity through sirtuin stimulation. These compounds exert their therapeutic effects on cisplatin-induced renal injury by targeting various signaling pathways including Sirt1/p53, Sirt1/NF-κb/p56, AMPK/Sirt1, Sirt1/PGC-1α, and/or by enhancing mitochondrial function.

Advances in the Development of Therapeutics for Cytomegalovirus Infections.

The development of therapeutics for cytomegalovirus (CMV) infections, while progressing, has not matched the pace of new treatments of human immunodeficiency virus (HIV) infections; nevertheless, recent developments in the treatment of CMV infections have resulted in improved human health and perhaps will encourage the development of new therapeutic approaches. First, the deployment of ganciclovir and valganciclovir for both the prevention and treatment of CMV infections and disease in transplant recipients has been further improved with the licensure of the efficacious and less toxic letermovir. Regardless, late-onset CMV disease, specifically pneumonia, remains problematic. Second, the treatment of congenital CMV infections with valganciclovir has beneficially improved both hearing and neurologic outcomes, both fundamental advances for these children. In these pediatric studies, viral load was decreased but not eliminated. Thus, an important lesson learned from studies in both populations is the need for new antiviral agents and the necessity for combination therapies as has been shown to be beneficial in the treatment of HIV infections, among others. The development of monoclonal antibodies, sirtuins, and cyclopropovir may provide new treatment options.

Liver-specific Sirtuin6 ablation impairs liver regeneration after 2/3 partial hepatectomy.

Sirtuin 6 (Sirt6) is an NAD+-dependent deacetylase that regulates central metabolic functions such as glucose homeostasis, fat metabolism, and cell apoptosis. However, the tissue-specific function of Sirt6 in liver regeneration remains unknown. Here, we show that liver-specific Sirt6 knockout (Sirt6LKO) impaired liver reconstitution after 2/3 partial hepatectomy, which was attributed to an alteration of cell cycle progression. Sirt6 LKO delayed hepatocyte transition into S phase during liver regeneration, as shown by the analysis of cell cycle-related proteins and the immuno staining of Ki-67 and 5-bromo-2-deoxyuridine (BrdU). The delayed cell cycle in Sirt6 LKO mice was attributed to the disruption of m-TOR and Akt activity, which is an important pro-proliferation pathway in liver regeneration. Sirt6 LKO also reduced carbon tetrachloride (CCl4 )-induced liver damage. Our results suggest that Sirt6 LKO impaired liver regeneration via delayed cell cycle and impaired m-TOR and Akt activity.