Resveratrol-Linoleate protects from exacerbated endothelial permeability via a drastic inhibition of the MMP-9 activity

Abstract

Gelatinolytic matrix metalloproteinases (MMP-2, -9) play a critical role not only in mammals physiology but also during inflammation and healing processes. The natural stilbenoid, resveratrol (RES), exhibits potent antioxidant effects, in a hormetic mode of action, and is known to inhibit MMP-9. However, RES administration exhibits major issues, including poor bioavailability and water solubility, hampering its potential therapeutic effect in vivo. In the present study, we synthesized and evaluated five novel RES–lipid conjugates to increase their cell membrane penetration and improve their bioavailability. The best in vitro MMP-9 inhibitory activity of RES–lipids conjugates was observed with RES-linoleic acid (LA) (5 µM), when dissolved in a natural deep eutectic solvent (NADES), composed of an equimolar content of 1,2-propanediol:choline chloride (ChCl):water. The inhibition of MMP-9 expression by RES-LA in activated THP-1 monocytes, was, at least due to the deactivation of ERK1/2 and JNK1/2 MAP kinase signaling pathways. Moreover, RES-LA exhibited a strong effect protecting the TNF-α-induced exacerbated permeability in an HUVEC in vitro monolayer (by 81%) via the integrity protection of intercellular junction proteins from the MMP-9 activity. This effect was confirmed by using several complementary approaches including, the real-time monitoring of trans-endothelial electric resistance (TEER), the Transwell HUVEC permeability level, the microscopic examination of the platelet endothelial cell adhesion molecule-1 (CD31/PECAM-1) integrity as well as the fluorescence in intercellular spaces. Consequently, following this strong in vitro proof-of-concept, there is a need to test this promising RES–lipid derivative compound to control the pathological endothelial permeability in vivo.

New Lipophenol Antioxidants Reduce Oxidative Damage in Retina Pigment Epithelial Cells

“…Another argument for choosing this coupling position was to keep the resorcinol moiety accessible, which appears to be involved in trapping steps of toxic aldehyde in phloroglucinol or flavonoid structures [15,31]. The synthesis of resveratrol-4′-LA was performed as previously described [27] (Figure 2) using an enzymatic chemical strategy allowing to isolate only the 4′-acylated analogue. Using a freshly (and not recycled one) supported lipase Candida antartica (CALB, Novozyme 435), a first acetyl group was regio-selectively introduced at the 4’ position in good yield (85%) without any acetyl derivatives in 3 or 5 positions.…”

“…Using a previous chemical strategy [26] and by TIPS protection of the phenolic functions, the synthesis of phloroglucinol derivative was performed in four steps to access desired compound phloro-LA ( 3 ) with 34% overall yield. When considering resveratrol series, the synthesis performed as described by Shamseddin et al [27] allowed to isolate the desired resv-4′-LA ( 8 ). The global yield of the strategy was improved due to the amelioration of the 4′-enzymatic acetylation using a non-recycled supported lipase Candida antartica (CALB, Novozyme 435).…”

“…PUFAs are preferred to saturated ones, due to their observed benefits in AMD clinical trial [25]. This strategy has already shown promising results with acyl-phloroglucinol [26] and resveratrol [27] derivatives when coupled with docosahexaenoic (C22:6 ω-3, DHA) or linoleic (C18:2 ω-6, LA) acids, for their respective anti-carbonyl and anti-MMP9 activities in cell culture assays. However, only a few examples in the literature reported an improved antioxidant effect of polyphenol lipophilization with PUFA [23] compared to the native polyphenol [28].…”

Resveratrol-Coated Balloon Catheters in Porcine Coronary and Peripheral Arteries

“…Enhancement of the duration of action and bioavailability of resveratrol is currently under development. Recently, a resveratrol-eluting nanoparticle system for a sustained release of locally-administered resveratrol and a resveratrol–lipid conjugate to enhance the bioavailability of resveratrol were tested in vitro [13,14]. However, the benefits on vascular healing using a local single-dose administration of resveratrol as a balloon coating has not yet been tested.…”

Resveratrol and Resveratrol-Aspirin Hybrid Compounds as Potent Intestinal Anti-Inflammatory and Anti-Tumor Drugs

“…In an attempt to obtain in vivo rapid metabolization and reduction while maintaining or enhanced biological specificity, several groups have attempted to derivatize resveratrol. This includes several monoalkoxy, dialkoxy, and hydroxy analogs of resveratrol that have been observed to be more effective in activation of PKCα; [ 47 , 48 ] mono, di, and tri-acetoxy resveratrol(s) were more effective at in vitro inhibition of CYP3A4 [ 48 ]; other resveratrol-conjugates for inhibition of MMP-9, DNA damage, and activation of p53-p21 CIP1/WAF1 [ 49 , 50 , 51 ] and recently by our group the effects of aspirin-resveratrol fusions [ 23 , 24 ].…”