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Summary of main observation and conclusion: An enantioselective desymmetric nucleophilic α‐addition of cyclohexanone to propiolamide has been developed through a 6‐exo‐dig cyclization reaction. By employing simple and readily available L‐proline sodium salt as a bifunctional catalyst, a series of chiral 6,6‐bicyclic bridged products bearing morphan scaffold have been isolated in good yields and excellent enantioselectivities. Density functional theory (DFT) calculations elucidated the origins of the enantioselectivity and regioselectivity of this transformation. A salt bridge that links the amide carbonyl group with proline carboxylate in the transition state was proven to be the driving force for the induction of excellent enantioselectivity. A new enantioselective approach to morphan core is developed based on the desymmetric intramolecular α‐addition of cyclohexanone to propiolamide, which represents a new method for asymmetric ketone α‐vinylation reaction. α‐Carbonyl tertiary stereocenter is formed without racemization due to its unique bridged bicyclic structure. A very simple and readily available catalyst L‐Pro‐Na is used for this reaction. [ABSTRACT FROM AUTHOR]

The proliferation of human skin dermal fibroblasts (HDFs) is a critical step in skin fibrosis, and transforming growth factor-beta1 (TGF-β1) exerts pro-oxidant and fibrogenic effects on HDFs. In addition, the oxidative stress system has been implicated in the pathogenesis of skin disease. However, the role of NADPH oxidase as a mediator of TGF-β1-induced effects in HDFs remains unknown. Thus, our aim was to investigate the role of NADPH in human skin dermal fibroblasts. Primary fibroblasts were cultured and pretreated with various stimulants. Real-time Q-PCR and Western blotting analyses were used for mRNA and protein detection. In addition, siRNA technology was applied for gene knock-down analysis. Hydrogen peroxide production and 20,70- dichlorofluorescein diacetate (DCFDA) measurement assay were performed. Here, our findings demonstrated that HDFs express key components of non-phagocytic NADPH oxidase mRNA. TGFβ1 induced NOX2 and reactive oxygen species formation via NADPH oxidase activity. In contrast, NOX3 was barely detectable, and other NOXs did not display significant changes. In addition, TGF-β1 phosphorylated MAPKs and increased activator protein-1 (AP-1) in a redox-sensitive manner, and NOX2 suppression inhibited baseline and TGF-β1-mediated stimulation of Smad2 phosphorylation. Moreover, TGF-β1 stimulated cell proliferation, migration, collagen I and fibronectin expression, and bFGF and PAI-1 secretion: these effects were attenuated by diphenylene iodonium (DPI), an NADPH oxidase inhibitor, and NOX2 siRNA. Importantly, NOX2 siRNA suppresses collagen production in primary keloid dermal fibroblasts. These findings provide the proof of concept for NADPH oxidase as a potential target for the treatment of skin fibrosis. [ABSTRACT FROM AUTHOR]