4-Aminopyrazolopyrimidine scaffold and its deformation in the design of tyrosine and serine/threonine kinase inhibitors in medicinal chemistry.

The 4-Aminopyrazolopyrimidine scaffold has been an interesting pharmacophore since the disclosure of the intimate connection between small-molecule inhibitors and the treatment of diseases. Modification of the 4-aminopyrazolopyrimidine scaffold according to different targets, especially tyrosine kinase and serine/threonine kinase, has resulted in a variety of small-molecule inhibitors. Kinase inhibitors with 4-aminopyrazolopyrimidine derivatives as scaffolds have been widely applied in the treatment of diseases. In this article, we summarized the reports on 4-aminopyrazolopyrimidine as well as its deformation and the application of its derivatives in designing small-molecule inhibitors and the treatment of diseases.

Metformin-loaded ß-TCP/CTS/SBA-15 composite scaffolds promote alveolar bone regeneration in a rat model of periodontitis.

Periodontitis is a progressive infectious inflammatory disease, which leads to alveolar bone resorption and loss of periodontal attachment. It is imperative for us to develop a therapeutic scaffold to repair the alveolar bone defect of periodontitis. In this study, we designed a new composite scaffold loading metformin (MET) by using the freeze-drying method, which was composed of ß-tricalcium phosphate (ß-TCP), chitosan (CTS) and the mesoporous silica (SBA-15). The scaffolds were expected to combine the excellent biocompatibility of CTS, the good bioactivity of ß-TCP, and the anti-inflammatory properties of MET. The MET-loaded ß-TCP/CTS/SBA-15 scaffolds showed improved cell adhesion, appropriate porosity and good biocompatibility in vitro. This MET composite scaffold was implanted in the alveolar bone defects area of rats with periodontitis. After 12 weeks, Micro-CT and histological analysis were performed to evaluate different degrees of healing and mineralization. Results showed that the MET-loaded ß-TCP/CTS/SBA-15 scaffolds promoted alveolar bone regeneration in a rat model of periodontitis. To our knowledge, this is the first report that MET-loaded ß-TCP/CTS/SBA-15 scaffolds have a positive effect on alveolar bone regeneration in periodontitis. Our findings might provide a new and promising strategy for repairing alveolar bone defects under the condition of periodontitis.

Nicotinamide mononucleotide attenuates isoproterenol-induced cardiac fibrosis by regulating oxidative stress and Smad3 acetylation.

AIMS: Cardiac fibrosis is a pathological hallmark of progressive heart diseases currently lacking effective treatment. Nicotinamide mononucleotide (NMN), a member of the vitamin B3 family, is a defined biosynthetic precursor of nicotinamide adenine dinucleotide (NAD+). Its beneficial effects on cardiac diseases are known, but its effects on cardiac fibrosis and the underlying mechanism remain unclear. We aimed to elucidate the protective effect of NMN against cardiac fibrosis and its underlying mechanisms of action. MATERIALS AND METHODS: Cardiac fibrosis was induced by isoproterenol (ISO) in mice. NMN was administered by intraperitoneal injection. In vitro, cardiac fibroblasts (CFs) were stimulated by transforming growth factor-beta (TGF-ß) with or without NMN and sirtinol, a SIRT1 inhibitor. Levels of cardiac fibrosis, NAD+/SIRT1 alteration, oxidative stress, and Smad3 acetylation were evaluated by real-time polymerase chain reaction, western blots, immunohistochemistry staining, immunoprecipitation, and assay kits. KEY FINDINGS: ISO treatment induced cardiac dysfunction, fibrosis, and hypertrophy in vivo, whereas NMN alleviated these changes. Additionally, NMN suppressed CFs activation stimulated by TGF-ß in vitro. Mechanistically, NMN restored the NAD+/SIRT1 axis and inhibited the oxidative stress and Smad3 acetylation induced by ISO or TGF-ß. However, the protective effects of NMN were partly antagonized by sirtinol in vitro. SIGNIFICANCE: NMN could attenuate cardiac fibrosis in vivo and fibroblast activation in vitro by suppressing oxidative stress and Smad3 acetylation in a NAD+/SIRT1-dependent manner.

Comparison of the transfer accuracy of two digital indirect bonding trays for labial bracket bonding.

OBJECTIVES: To compare the transfer accuracy of two digital transfer trays, the three-dimensional printed (3D printed) tray and the vacuum-formed tray, in the indirect bonding of labial brackets. MATERIALS AND METHODS: Ten digital dental models were constructed by oral scans using an optical scanning system. 3D printed trays and vacuum-formed trays were obtained through the 3Shape indirect bonding system and rapid prototyping technology (10 in each group). Then labial brackets were transferred to 3D printed models, and the models with final bracket positioning were scanned. Linear (mesiodistal, vertical, buccolingual) and angular (angulation, torque, rotation) transfer errors were measured using GOM Inspect software. The mean transfer errors and prevalence of clinically acceptable errors (linear errors of ≤0.5 mm and angular errors of ≤2°) of two digital trays were compared using the Mann-Whitney U-test and the Chi-square test, respectively. RESULTS: The 3D printed tray had a lower mean mesiodistal transfer error (P < .01) and a higher prevalence of rotation error within the limit of 2° (P = .03) than did the vacuum-formed tray. Linear errors within 0.5 mm were higher than 90% for both groups, while torque errors within 2° were lowest at 50.9% and 52.9% for the 3D printed tray and vacuum-formed tray, respectively. Both groups had a directional bias toward the occlusal, mesial, and buccal. CONCLUSIONS: The 3D printed tray generally scored better in terms of transfer accuracy than did the vacuum-formed tray. Both types of trays had better linear control than angular control of brackets.