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This study investigated the atheroprotective properties of olive oil polyphenol, hydroxytyrosol (HT), in combination with carbon monoxide-releasing molecule-2 (CORM-2) that acts as a carbon monoxide donor using vascular endothelial cells (VECs). Our results showed that CORM-2 could strengthen the cytoprotective and anti-apoptotic effects of HT against TNFα-induced cellular damage by enhancing cell survival and the suppression of caspase-3 activation. While HT alone attenuated NFκBp65 phosphorylation and IκBα degradation triggered by TNFα in a dose-dependent manner, combined treatment of HT with CORM-2 but not iCORM-2 nearly completely blocked these TNFα effects. Furthermore, combined action of both compounds results in the inhibition of NFκB nuclear translocation. Results also indicate that both compounds time-dependently increased eNOS phosphorylation levels and the combination of HT with CORM-2 was more effective in enhancing eNOS activation and NO production in VECs. The NOS inhibitor, L-NMMA, significantly suppressed the combined effects of HT and CORM-2 on TNFα-triggered NFκBp65 and IκBα phosphorylation as well as decreased cell viability. Together, these data suggest that carbon monoxide-dependent regulation of NO production by the combination of HT with CORM-2 may provide a therapeutic benefit in the treatment of endothelial dysfunction and atherosclerosis.

Red wine compounds have been reported to reduce the rate of atherosclerosis by inducing nitric oxide (NO) production and antioxidant enzyme expression in vascular endothelial cells (VECs). The present study compared the effects of the three red wine compounds resveratrol and its dimers, ε-viniferin and δ-viniferin, on VECs function for the first time. Both 5 μM ε-viniferin and δ-viniferin, but not 5 μM resveratrol, significantly stimulated wound repair of VECs. Increased levels of wound repair induced by 10 and 20 μM ε-viniferin were significantly higher than those stimulated by 10 and 20 μM resveratrol, respectively. These stimulatory effects of the three compounds were suppressed by the NO synthase inhibitor L-NAME. When VECs were exposed to each compound, endothelial NO synthase was activated and the expression of sirtuin 1 (SIRT1) and HO-1 was induced. Addition of the SIRT1 and HO-1 inhibitors EX527 and ZnPPiX, respectively, suppressed wound repair stimulated by the three compounds, demonstrating that SIRT1 and HO-1 are involved in these wound repair processes. Furthermore, each compound induced the suppression of H 2 O 2-dependent reduction of cell viability as well as the expression of the antioxidant enzyme catalase. These data suggest that not only resveratrol, but also its dimers, ε-viniferin and δ-viniferin, may be effective in preventing atherosclerosis by a similar molecular mechanism with different potency and efficacy.

Developing a biomaterial suitable for adipose-derived stem cell (ADSCs)-laden scaffolds that can directly bond to cartilage tissue surfaces in tissue engineering has still been a significant challenge. The bioinspired hybrid hydrogel approaches based on hyaluronic acid methacryloyl (HAMA) and gelatin methacryloyl (GelMA) appear to have more promise. Herein, we report the cartilage tissue engineering application of a novel photocured hybrid hydrogel system comprising HAMA, GelMA, and 0~1.0% (w/v) acrylate-functionalized nano-silica (AFnSi) crosslinker, in addition to describing the preparation of related HAMA, GelMA, and AFnSi materials and confirming their related chemical evidence. The study also examines the physicochemical characteristics of these hybrid hydrogels, including swelling behavior, morphological conformation, mechanical properties, and biodegradation. To further investigate cell viability and chondrogenic differentiation, the hADSCs were loaded with a two-to-one ratio of the HAMA-GelMA (HG) hybrid hydrogel with 0~1.0% (w/v) AFnSi crosslinker to examine the process of optimal chondrogenic development. Results showed that the morphological microstructure, mechanical properties, and longer degradation time of the HG+0.5% (w/v) AFnSi hydrogel demonstrated the acellular novel matrix was optimal to support hADSCs differentiation. In other words, the in vitro experimental results showed that hADSCs laden in the photocured hybrid hydrogel of HG+0.5% (w/v) AFnSi not only significantly increased chondrogenic marker gene expressions such as SOX-9, aggrecan, and type II collagen expression compared to the HA and HG groups, but also enhanced the expression of sulfated glycosaminoglycan (sGAG) and type II collagen formation. We have concluded that the photocured hybrid hydrogel of HG+0.5% (w/v) AFnSi will provide a suitable environment for articular cartilage tissue engineering applications.