Diastereo- and Enantioselective Synthesis of Tetracyclic Cycloheptanols through (4+3) Annulation via C-C/C-H Activation Cascade.

Transition metal-catalyzed annulations of four-membered rings via C-C activation are powerful tools to construct complex fused and bridged ring systems. Despite significant progress in (4+1), (4+2) and (4+4) annulations, the (4+3) annulation remains unexplored. Herein, we develop an asymmetric Rh-catalyzed intramolecular (4+3) annulation of α-arylalkene-tethered benzocyclobutenols for the synthesis of dihydrofuran-annulated dibenzocycloheptanols with two discontinuous chiral carbon centers via a C-C and C-H activation cascade. The reaction features excellent diastereo- and enantioselectivities and 100 % atom economy, and is applicable to late-stage modification of complex molecules.

TFPI2 suppresses the interaction of TGF-ß2 pathway regulators to promote endothelial-mesenchymal transition in diabetic nephropathy.

Endothelial-mesenchymal transition (EndMT) is an important source of myofibroblasts, but also contributes to the progression of diabetic nephropathy (DN). By several differential gene expression analyses from the Gene Expression Omnibus (GEO) database, the tissue factor pathway inhibitor 2 (TFPI2) gene, known as a tumor suppressor, was shown to be dysregulated in DN; however, the potential role and regulatory mechanism of TFPI2 in DN are unclear. Here, we found abnormal upregulation of TFPI2 in the renal cortex of diabetic mice, accompanied by impaired renal function. We also injected a single dose of adeno-associated virus (AAV)2 carrying shRNA targeting TFPI2 intravenously into these mice and found that knockdown of TFPI2 improved renal function and reduced renal fibrosis and cell apoptosis in experimental DN. Furthermore, hyperglycemia-induced EndMT was inhibited in the absence of TFPI2, as evidenced by increased expression of endothelial markers (VE-cadherin and CD31) and decreased expression of mesenchymal markers (α-SMA, desmin, and FSP-1). To further explore the mechanism in vitro, human renal glomerular endothelial cells (hRGECs) were incubated in the presence of high glucose or transforming growth factor beta (TGF-ß)2. TFPI2 deficiency inhibited high glucose-induced cell apoptosis and TGF-ß2-induced EndMT in hRGECs, while overexpression of TFPI2 had the opposite effects. Importantly, TGF-ß2 is a crucial driver of EndMT, and we found that TFPI2 promoted TGF-ß2/Smad signaling activation by interferring the interaction of TGF-ß pathway regulators (SMURF2 with SMAD7). Our results show that TFPI2 regulates EndMT and the TGF-ß2 signaling pathway and is a potential promoter of DN pathogenesis.

miR-448-3p alleviates diabetic vascular dysfunction by inhibiting endothelial-mesenchymal transition through DPP-4 dysregulation.

Diabetes mellitus (DM) often causes vascular endothelial damage and alters vascular microRNA (miR) expression. miR-448-3p has been reported to be involved in the development of DM, but whether miR-448-3p regulates diabetic vascular endothelial dysfunction remains unclear. To investigate the molecular mechanism of diabetic vascular endothelial dysfunction and the role of miR-448-3p therein, Sprague-Dawley rats were injected with streptozotocin (STZ) to establish diabetic animal model and the rat aortic endothelial cells were treated with high glucose to establish diabetic cell model. For the treatment group, after the induction of diabetes, the miR-448-3p levels in vivo and in vitro were upregulated by adeno-associated virus serotype 2 (AAV2)-miR-448-3p injection and miR-448-3p mimic transfection, respectively. Our results showed that AAV2-miR-448-3p injection alleviated the body weight loss and blood glucose level elevation induced by STZ injection. The miR-448-3p level was significantly decreased and the dipeptidyl peptidase-4 (DPP-4) messenger RNA level was increased in diabetic animal and cell models, which was reversed by miR-448-3p treatment. Moreover, the diabetic rats exhibited endothelial damage and endothelial-mesenchymal transition (EndMT), while AAV2-miR-448-3p injection relieved those situations. In vitro experiments demonstrated that miR-448-3p overexpression in endothelial cells alleviated endothelial damage by inhibiting EndMT through blocking the transforming growth factor-ß/Smad pathway. We further proved that miR-448-3p negatively regulated DPP-4 by binding to its 3'-untranslated region, and DPP-4 overexpression reversed the effect of miR-448-3p overexpression on EndMT. Overall, we conclude that miR-448-3p overexpression inhibits EndMT via targeting DPP-4 and further ameliorates diabetic vascular endothelial dysfunction, indicating that miR-448-3p may serve as a promising therapeutic target for diabetic endothelial dysfunction.

Skeleton Reorganization of Substituted Benzocyclobutenols through Rh-Catalyzed C-C Bond Cleavage Manipulated by Hydrogen Transfer.

Although transition-metal-catalyzed C-C bond activation has been investigated extensively, C-C bond cleavage manipulated by hydrogen transfer has been unexplored. In this work, we disclose a skeleton reorganization of alkene-tethered benzocyclobutenols through Rh-catalyzed C-C bond cleavage coupled with intra- and intermolecular hydrogen transfer. The reaction pathway was well-tuned by the catalytic systems. As a result, divergent benzofurans bearing 4-ß-hydroxy or 4-ß-keto moieties were synthesized under pH- and redox-neutral conditions.