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  • Because macrophages clear the injured tissue of

    2020-04-06

    Because macrophages clear the injured tissue of dead dna-pk inhibitor and matrix debris, macrophage infiltration is essential for normal tissue repair. In cardiac remodeling by MI, however, macrophages infiltrate excessively into not only the infarct area and marginal area of MI. Infiltrated macrophages, which are activated by TGF-β1, synthesize cytokines and chemokines, such as MCP-1, and promote tissue inflammation and remodeling. Thus, TGF-β1 also plays a critical role in this process. In our study, linagliptin administration reduced MI-induced macrophage infiltration and expression level of MCP-1 in the marginal area (Fig. 4, Fig. 5D). These findings may result from linagliptin-mediated suppression of TGF-β1. As well as MCP-1, MMPs including MMP-2 and 9, play important roles in cardiac function. Cardiac MMP-2 expression independently induces marked cardiac remodeling. Cardiac-specific expression of MMP-2 leads to heart failure, and deletion of MMP-2 attenuates cardiac remodeling in experimental MI.32, 33 In the present study, the expression levels of MMP-2 and 9 are decreased by treatment with linagliptin in DPP-4 deficient dna-pk inhibitor rat hearts (Fig. 5E,F). Moreover, linagliptin downregulated MMP-2 level in CFs from DPP-4-deficient rat hearts in a dose-dependent manner (Fig. 6A). These data supported that linagliptin may attenuate cardiac remodeling by disrupting MMP expression in CFs independently of DPP-4.
    Conflicts of interest This work was partially supported by a grant from Boehringer Ingelheim.
    Acknowledgments
    Diabetes is a major global problem nowadays. It currently affects nearly 425 million people worldwide in 2017, and this number will rise to 700 million in 2045. Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are both incretin hormones increasing insulin biosynthesis and therefore contributing to glycemic control., However, both hormones are rapidly inactivated by the serine protease DPP-4, leading to limiting their therapeutic practicality. The idea of inhibiting DPP-4 was developed as a promising new therapy for type 2 diabetes mellitus (T2DM) 20 years ago. To date, twelve DPP-4 inhibitors (sitagliptin, vildagliptin, saxagliptin, alogliptin, linagliptin, anagliptin, gemigliptin, teneligliptin, evogliptin, omarigliptin, trelagliptin and gosogliptin) have been approved for the treatment of T2DM (). Yet, there is still strong enthusiasm in developing novel DPP-4 inhibitors since some undesirable side effects exist in current drugs. Bromophenols are a set of natural products widely distributed in seaweed, most of which exhibit many biological activities, including hypoglycemic effect, anticancer, antioxidant, antimicrobial and other potent bioactivities. In our previous study, a variety of bromophenols (), isolated from the red marine algae of the Rhodomelaceae family or synthesized derivatives, showed potent hypoglycemic effects and ., , , Herein, bromophenols are used as potent hypoglycemic agents and are considered as part of a new therapeutic strategy for treatment of type 2 diabetes. The fully understanding of the interaction between DPP-4 enzyme and the bioactive substances plays a significant role in designing novel DPP-4 inhibitors. From the binding models we found that pyrimidinedione forms π-π interactions with Tyr547, which undergoes a conformational change in the S1 subsite; in addition, the cyanobenzyl group or the butynyl group binds to the S1 subsite., Moreover, aminopiperidine is crucial for DPP-4 inhibitory activity, which forms salt bridge with Glu205, Glu206 and Tyr662 in S2 pocket., Synergistic activity is often attributed to molecular hybrids with different pharmacophores. Apart from pyrimidinedione core, we determined bromophenol, butynyl group, fluorocyanobenzyl or ()-3-aminopiperidine as substituents. The widespread application of fluorine in drug design benefits from distinctive properties, including lipophilicity, eletrophilicity, metabolic stability, chemical stability, et al. In view of these observations, a novel series of pyrimidinedione derivatives were designed and evaluated for DPP-4 inhibitory activity. Among these pyrimidinedione derivatives, compound showed the most potent inhibitory activity of DPP-4 and was potent hypoglycemic effect. Structure-activity relationships (SARs) of these pyrimidinedione derivatives are also discussed in this paper.