Effect of Statin Therapy on Diabetes Retinopathy in People With Type 2 Diabetes Mellitus: A Meta-Analysis.

Objective: We tried to find the relationship between statin and diabetes retinopathy (DR) in patients with type 2 diabetes mellitus (T2DM). Methods: We searched the databases of PubMed, EMBASE, and the Cochrane Library for eligible studies reporting on the relationships between statin use and DR, from inception to September 25, 2020. The terms searched including Diabetes Mellitus, Type 2, Hydroxymethylglutaryl-CoA Reductase Inhibitors, and Diabetic Retinopathy. We expressed the results as the odds ratios (ORs) with 95% confidence intervals (CIs) which were calculated using a random-effects model. Results: A total of 6 eligible studies, including 43 826 patients, were included in the meta-analysis. The meta-analysis showed that statin was not associated with elevated risk of DR [OR = 0.96 (95% CI: 0.80-1.16), P = .68]. Similarly, no differences were found between statin and placebo in participants ≥500 [OR = 0.98 (95% CI: 0.80-1.21)] or participants <500 [OR = 0.90 (95% CI: 0.49-1.66)]. Further, we conducted a meta-analysis to study the effect of statin therapy on DR in people with type 2 diabetes according to age and found that statin use was associated with a decreased risk of DR in patients with type 2 diabetes 40 years of age or older [OR = 0.87 (95% CI: 0.82-0.92)]. Conclusion: Our meta-analysis revealed that statin was not associated with elevated risk of DR in patients with T2DM. Moreover, statin use was associated with a lower incidence of DR in patients with type 2 diabetes 40 years of age or older.

E2F1 regulates p53R2 gene expression in p53-deficient cells.

The p53R2 gene encoding a small subunit of the ribonucleotide reductase has been identified as a p53-inducible gene. Although this gene is discovered as a target for p53 family proteins, the mechanism underlying p53R2 induction by DNA damage in p53-defiencient cells remains to be elucidated. In this study, we demonstrate that transcription factor E2F1 regulates the p53R2 gene expression in p53-deficient cells. We found that p53R2 was a target for E2F1 in DNA damage response (DDR), because ectopic expression of E2F1 in HCT116-p53(-/-) cells resulted in the increase of p53R2 mRNA and protein expression, and silencing E2F1 diminished its basic expression. Combination of luciferase reporter assay with overexpression or knockdown of E2F1 revealed that E2F1 directly activates the p53R2 gene. Chromatin immunoprecipitation (ChIP) assay showed E2F1 directly bound to the site (TTTGGCGG) at position -684 to -677 of the promoter under E2F1 overexpression or adriamycin (ADR) exposure. Moreover, silencing p53R2 could enhance apoptotic cell death in both HCT116-p53(-/-) and HCT116-p53(+/+) compared to ADR exposure, indicating that p53R2 may protect cancer cell from ADR-induced apoptosis. Together, we have identified a new role of E2F1 in the regulation of p53R2 expression in DDR, and silencing p53R2 may sensitize cancer cells to ADR-induced apoptosis. Our data support the notion that p53R2 is a potential target for cancer therapy. The involvement of E2F1-dependent p53R2 activation in DDR will provide further insight into the induction of p53R2 in p53-deficient cells. These data also give us a deeper understanding of E2F1 role in DDR.

Effects of myogenin on expression of late muscle genes through MyoD-dependent chromatin remodeling ability of myogenin.

MyoD and myogenin (Myog) recognize sets of distinct but overlapping target genes and play different roles in skeletal muscle differentiation. MyoD is sufficient for near-full expression of early targets, while Myog can only partially enhance expression of MyoD-initiated late muscle genes. However, the way in which Myog enhances the expression of MyoD-initiated late muscle genes remains unclear. Here, we examine the effects of Myog on chromatin remodeling at late muscle gene promoters and their activation within chromatin environment. Chromatin immunoprecipitation (ChIP) assay showed that Myog selectively bound to the regulatory sequences of late muscle genes. Overexpression of Myog was found to overcome sodium butyrateinhibited chromatin at late muscle genes in differentiating C2C12 myoblasts, shifting the transcriptional activation of these genes to an earlier time period. Furthermore, overexpression of Myog led to increased hyperacetylation of core histone H4 in differentiating C2C12 myoblasts but not NIH3T3 fibroblasts, and hyperacetylated H4 was associated directly with the late muscle genes in differentiating C2C12, indicating that Myog can induce chromatin remodeling in the presence of MyoD. In addition, co-immunoprecipitation (CoIP) revealed that Myog was associated with the nuclear protein Brd4 in differentiating C2C12 myoblasts. Together, these results suggest that Myog enhances the expression of MyoD-initiated late muscle genes through MyoD-dependent ability of Myog to induce chromatin remodeling, in which Myog-Brd4 interaction may be involved.

E2F1 enhances 8-chloro-adenosine-induced G2/M arrest and apoptosis in A549 and H1299 lung cancer cells.

The E2F1 transcription factor is a well known regulator of cell proliferation and apoptosis, but its role in response to DNA damage is less clear. 8-Chloro-adenosine (8-Cl-Ado), a nucleoside analog, can inhibit proliferation in a variety of human tumor cells. However, it is still elusive how the agent acts on tumors. Here we show that A549 and H1299 cells formed DNA double-strand breaks after 8-Cl-Ado exposure, accompanied by E2F1 upregulation at protein level. Overexpressed wild-type (E2F1-wt) colocalized with double-strand break marker γ-H2AX and promoted G2/M arrest in 8-Cl-Ado-exposed A549 and H1299, while expressed S31A mutant of E2F1 (E2F1-mu) significantly reduced ability to accumulate at sites of DNA damage and G2/M arrest, suggesting that E2F1 is required for activating G2/M checkpoint pathway upon DNA damage. Transfection of either E2F1-wt or E2F1-mu plasmid promoted apoptosis in 8-Cl-Ado-exposed cells, indicating that 8-Cl-Ado may induce apoptosis in E2F1-dependent and E2F1-independent ways. These findings demonstrate that E2F1 plays a crucial role in 8-Cl-Ado-induced G2/M arrest but is dispensable for 8-Cl-Ado-induced apoptosis. These data also suggest that the mechanism of 8-Cl-Ado action is complicated.