These findings disclose a novel regulatory pathway that is composed of HRCR, miR-223, and ARC. Modulation of their levels provides an attractive therapeutic target for the treatment of cardiac hypertrophy and heart failure.

E3 ligases are a class of enzymes that can transfer ubiquitin to substrates for their degradation, which are of importance in cellular homeostasis. Since many oncogenic or tumor-suppressive proteins are reported to be regulated by the ubiquitin-proteasome system (UPS), E3 ligases, which function as substrate interacting modules, have been attracting more and more attention as promising anticancer drug targets due to their pivotal role in conferring substrate specificity. Generally, based on their molecular structure and functional mechanism, E3 ligases can be divided into three major types: homologous to E6-associated protein C-terminus (HECT), really interesting new gene (RING), and RING-in-between-RING (RBR) E3 ligases. Based on the significance of their functions, more bioactive compounds targeting E3 ligases should be developed in the future. In this review, we discuss the important roles of E3 ligases involved in cancer as well as available bioactive compounds targeting various E3 ligases for potential anticancer activity.

Novel reducible disulfide-containing cross-linked polyethylenimines (PEI-SS-CLs) were synthesized via click chemistry and evaluated as nonviral gene delivery vectors. First, about four azide pendant groups were introduced into a low-molecular-weight (LMW) PEI (1.8 kDa) to get an azide-terminated PEI. Then, click reaction between a disulfide-containing dialkyne cross-linker and the azide functionalized LMW PEI resulted in a high-molecular-weight disulfide-containing cross-linked PEI composed of LMW constitute via a reducible cross-linker. The synthesized polymers were characterized by (1)H NMR, FTIR, and size-exclusion chromatography (SEC). It was shown that the obtained disulfide-containing cross-linked PEIs were able to condense plasmid DNA into positively charged nanoparticles. The degradation of the disulfide cross-linked polymers PEI-SS-CLs induced by DTT was confirmed by a gel retardation assay and SEC analysis. In vitro experiments revealed that the reducible PEI-SS-CLs were less cytotoxic and more effective in gene transfection (in both the presence and absence of serum) than the control nondegradable 25-kDa PEI. This study demonstrates that a reducibly degradable cationic polymer composed of LMW PEI cross-linked via a disulfide-containing linker possesses both higher gene transfection efficiency and lower cytotoxicity than PEI (25 kDa). These polymers are therefore attractive candidates for further in vivo evaluations.