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  • ICT is a product of


    ICT is a product of icariin via the metabolism of intestinal bacteria with estrogen-like activities [33]. ICT as a bone-protecting agent can enhance osteoblast differentiation while suppressing osteoclastic differentiation in vitro [19], and stimulate osteogenic differentiation and inhibit adipogenesis in mesenchymal stem Boc-D-FMK mg [29]. In previous studies, we found that ICT induced differentiation and promoted mineralization through estrogen receptor-mediated ERK1/2 and p38 signaling activation in MC3T3 E1 subclone 14 cells [36]. In this study, we demonstrated that ICT treatment restored the inhibition of differentiation induced by Pb and the regulation of key components of the canonical Wnt signaling. However, how ICT activates Wnt signaling and whether it is related to the estrogen receptor need to be further explored.
    Conflicts of interest
    Acknowledgements This work was supported by the National Natural Science Foundation of China (81673837) and Science and Technology Planning Project of Guangdong Province (2016A020226039). We also thank American Journal Experts for English expression polished.
    Introduction In response to external and internal cues, plants develop finely tuned growth programs adapted to environmental conditions and developmental stage (Naseem et al., 2015). Protein post-translational regulation by small ubiquitin-like modifier (SUMO) conjugation has emerged as a major molecular mechanism regulating plant growth and stress responses. As ubiquitin, SUMO is attached to protein targets through sequential reactions catalyzed by the E1, E2, and E3 enzymes (Gareau and Lima, 2010). SUMO proteases are responsible for SUMO maturation and deconjugation (Gareau and Lima, 2010). SUMO activation is a two-step ATP-dependent reaction catalyzed by the heterodimeric E1-activating enzyme, SAE2/SAE1, which is the first control point to enter the conjugation cascade (Supplemental Figure 1) (Walden et al., 2003, Castaño-Miquel et al., 2011). SAE2 is structured in four functional domains: adenylation, catalytic cysteine (SAE2Cys), ubiquitin-fold (domain structurally resembling ubiquitin, SAE2UFD), and C-terminal (SAE2Ct) domains (Lois and Lima, 2005). The E1 activating enzyme small subunit, SAE1, contributes the essential Arg21 to the adenylation domain (Lee and Schindelin, 2008). The adenylation domain is responsible for SUMO recognition and SUMO C-terminal adenylation. After adenylation, the SUMO C-terminal adenylate establishes a thioester bond with the E1 catalytic cysteine. Following thioester bond formation, SUMO can be transferred to the E2-conjugating enzyme in a reaction that involves E2 recruitment through the two interacting surfaces (Lois and Lima, 2005, Wang et al., 2007, Wang et al., 2010, Reiter et al., 2015) (Figure 1A). On one hand, the SAE2UFD domain establishes contacts with residues located at the α1-helix and the β1β2-loop of the E2 conjugating enzyme (Wang et al., 2009, Wang et al., 2010, Reiter et al., 2015). On the other, the SAE2Cys domain interacts with residues located at the E2 α4 N-terminus (Wang et al., 2007). Although both interactions surfaces involved SAE2 residues present in loops, SAE2UFD-E2 interactions display higher affinity (KD = 1.2 μM) (Reiter et al., 2013) than SAE2Cys-E2 interactions (KD = 80 μM) (Wang et al., 2007), supporting a major role of the SAE2UFD domain in E2 recruitment. Even though the SAE2UFD domain is essential in yeast (Lois and Lima, 2005), it remains unclear whether SAE2UFD is sufficient for efficient E2 recruitment in vivo. In plants, SUMOylation has been shown to modulate plant hormone signaling (Lois et al., 2003, Miura et al., 2009, Conti et al., 2014), root stem cell maintenance (Xu et al., 2013), and responses to abiotic and biotic stress (Lois, 2010). Many of the plant biological processes regulated by SUMOylation have been uncovered by the analysis of proteases and SUMO E3 ligase mutant plants, which display pleiotropic growth defects and reduced viability (Murtas et al., 2003, Miura et al., 2005, Huang et al., 2009, Ishida et al., 2009). Nonetheless, some of these mutations have also been proposed to confer adaptive responses to some stresses, such as salt, drought, resistance to plant viruses, and salicylic acid-mediated plant immunity (Yoo et al., 2006, Lee et al., 2007, Miura et al., 2011, Miura et al., 2013, Saleh et al., 2015).