Palladium(II)-catalyzed aerobic oxidative O-H/C-H isocyanide insertion: facile access to pyrrolo[2,1-c][1,4]benzoxazine derivatives.

Palladium-catalyzed aerobic oxidative cyclizations of substituted 2-(1H-pyrrol-1-yl)phenols with isocyanides via an O-H/C-H insertion cascade have been developed. This strategy provides facile access to pyrrolo[2,1-c][1,4]benzoxazine derivatives in good to excellent yields under an O2 atmosphere. The notable features of this protocol include its mild reaction conditions, atom-economy, and broad functional group tolerance.

A dual removable activating group enabled the Povarov reaction of N-arylalanine esters: synthesis of quinoline-4-carboxylate esters.

A dual removable activating group enabled Povarov reaction of N-arylalanine esters was reported. N-Arylalanine ester was utilized as the sole carbon source to generate N-arylimine and its tautomer, enamine, in situ by aerobic oxidation of sp3 C-H bonds, and then the consecutive reaction delivered the desired quinoline-4-carboxylate esters in high yields.

Integrated microbiome and metabolomics revealed the protective effect of baicalin on alveolar bone inflammatory resorption in aging.

BACKGROUND: With the growing aging population and longer life expectancy, periodontitis and tooth loss have become major health concerns. The gut microbiota, as a key regulator in bone homeostasis, has gathered immense interest. Baicalin, a flavonoid compound extracted from Scutellaria baicalensis Georgi, has shown antioxidant and anti-inflammatory activities. PURPOSE: This study investigated, for the first time, the protective mechanism of baicalin against alveolar bone inflammatory resorption in aging mice by regulating intestinal flora and metabolites, as well as intestinal barrier function. METHODS: A ligature-induced periodontitis model was established in d-galactose (D-gal)-induced aging mice, and baicalin was administered at different dosages for 13 weeks. Body weight was measured weekly. The antioxidant and anti-inflammatory activity of baicalin were evaluated using serum superoxide dismutase (SOD), malonaldehyde (MDA), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) levels. The immune capability was assessed by thymus and spleen indices. Histopathological changes were observed in the heart, liver, ileum, and periodontal tissues. Alveolar bone absorption of maxillary second molars was examined, and osteoclasts were counted by tartrate-resistant acid phosphatase (TRAP) staining. Furthermore, fecal samples were analyzed using 16S rRNA sequencing and non-targeted metabolomics to identify differences in intestinal bacterial composition and metabolites. RESULTS: Baicalin exhibited anti-aging properties, as evidenced by increased SOD activity and decreased levels of MDA, IL-6, and TNF-α in serum compared to the control group. Baicalin also ameliorated alveolar bone loss in the d-gal-induced aging-periodontitis group (p < 0.05). Furthermore, baicalin restored ileal permeability by up-regulating the expression of ZO-1 and occludin in aging-periodontitis groups (p < 0.05). Alpha diversity analysis indicated that baicalin-treated mice harbored a higher diversity of gut microbe. PCoA and ANOSIM results revealed significant dissimilarity between groups. The Firmicutes/Bacteroidetes (F/B) ratio, which decreased in periodontitis mice, was restored by baicalin treatment. Additionally, medium-dosage baicalin promoted the production of beneficial flavonoids, and enriched short-chain fatty acids (SCFAs)-producing bacteria. CONCLUSION: Intestinal homeostasis is a potential avenue for treating age-related alveolar bone loss. Baicalin exerts anti-inflammatory, antioxidant, and osteo-protective properties by regulating the gut microbiota and metabolites.

Histone methyltransferase SETDB1 promotes osteogenic differentiation in osteoporosis by activating OTX2-mediated BMP-Smad and Wnt/ß-catenin pathways.

Osteogenic differentiation plays important roles in the pathogenesis of osteoporosis. In this study, we explored the regulatory mechanism of histone methyltransferase SET domain bifurcated 1 (SETDB1) underlying the osteogenic differentiation in osteoporosis. The common osteoporosis-related genes were retrieved from the GeneCards, CTD, and Phenolyzer databases. The enrichment analysis was conducted on the candidate osteoporosis-related genes using the PANTHER software, and the binding site between transcription factors and target genes predicted by hTFtarget. The bioinformatics analyses suggested 6 osteoporosis-related chromatin/chromatin binding protein or regulatory proteins (HDAC4, SIRT1, SETDB1, MECP2, CHD7, and DKC1). Normal and osteoporosis tissues were collected from osteoporosis patients to examine the expression of SETDB1. It was found that SETDB1 was poorly expressed in osteoporotic femoral tissues, indicating that SETDB1 might be involved in the development of osteoporosis. We induced SETDB1 overexpression/knockdown, orthodenticle homeobox 2 (OTX2) overexpression, activation of Wnt/ß-catenin or BMP-Smad pathways alone or in combination in osteoblasts or ovariectomized mice. The data indicated that SETDB1 methylation regulated H3K9me3 in the OTX2 promoter region and inhibited the expression of OTX2. Besides, the BMP-Smad and Wnt/ß-catenin pathways were inhibited by OTX2, thereby resulting in inhibited osteogenic differentiation. Animal experiments showed that overexpressed SETDB1 could promote the increase of calcium level and differentiation of femoral tissues. In conclusion, upregulation of SETDB1 promotes osteogenic differentiation by inhibiting OTX2 and activating the BMP-Smad and Wnt/ß-catenin pathways in osteoporosis.

Transcatheter vs surgical aortic valve replacement in low to intermediate surgical risk aortic stenosis patients: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Transcatheter aortic valve replacement (TAVR) is regarded as the most superior alternative treatment approach for patients with aortic stenosis (AS) who are associated with high surgical risk, whereas the effectiveness of TAVR vs surgical aortic valve replacement (SAVR) in low to intermediate surgical risk patients remained inconclusive. This study aimed to determine the best treatment strategies for AS with low to intermediate surgical risk based on published randomized controlled trials (RCTs). HYPOTHESIS AND METHODS: RCTs that compared TAVR vs SAVR in AS patients with low to intermediate surgical risk were identified by PubMed, EmBase, and the Cochrane library from inception till April 2019. The pooled relative risks (RRs) with 95% confidence intervals (CIs) were calculated for the data collected using random-effects models. RESULTS: Seven RCTs with a total of 6929 AS patients were enrolled. We noted that TAVR significantly increased the risk of transient ischemic attack (TIA) (RR: 1.43; 95%CI: 1.04-1.96; P = .029), and permanent pacemaker implantation (RR: 3.00; 95%CI: 1.70-5.30; P < .001). However, TAVR was associated with lower risk of post-procedural bleeding (RR: 0.57; 95%CI: 0.33-0.98; P = .042), new-onset or worsening of atrial fibrillation (RR: 0.32; 95%CI: 0.23-0.45; P < .001), acute kidney injury (RR: 0.40; 95%CI: 0.25-0.63; P < .001), and cardiogenic shock (RR: 0.34; 95%CI: 0.19-0.59; P < .001). The risk of aortic-valve reintervention at 1- (RR: 2.63; 95%CI: 1.34-5.15; P = .005), and 2 years (RR: 3.19; 95%CI: 1.63-6.24; P = .001) in low to intermediate surgical risk patients who received TAVR was significantly increased than those who received SAVR. CONCLUSIONS: These findings indicated that low to intermediate surgical risk patients who received TAVR had low risk of complications, whereas the risk of TIA, permanent pacemaker implantation, and aortic-valve reintervention was increased.

Transition-metal and oxidant-free approach for the synthesis of diverse N-heterocycles by TMSCl activation of isocyanides.

A highly efficient TMSCl-mediated addition of N-nucleophiles to isocyanides has been achieved. This transition-metal and oxidant-free strategy has been applied to the construction of various N-heterocyles such as quinazolinone, benzimidazole and benzothiazole derivatives by the use of distinct amino-based binucleophiles. The notable feature of this protocol includes its mild reaction condition, broad functional group tolerance and excellent yield.