14 research outputs found
Polymeric stilbene derivatives in winemaking byproducts affect NF-kB mediated inflammatory response in Caco-2 cells
No full textResiduals from winemaking represents one of the most important byproducts in the Italian agri-food
scenario. Grape skins and stems reportedly contain high levels of various phenolics-based bioactives that - in
the family of stilbenoids - include resveratrol and the products ensuing from its radical-based polymerization.
Among these is the family of viniferins, that reportedly are able to interfere with the glucose metabolism in the
gut, by inhibiting extracellular or membrane enzymes involved in the final steps of starch breakdown and –
eventually - in glucose uptake[1, 2]. These same reports also highlighted the possibility that molecules in the
stilbenoids family could display some physiologically relevant synergism in their inhibitory activities[2].
Whereas resveratrol is known to interfere with a number of cellular processes, including suppression of
NF-B mediated responses, little is known about the ability of polymeric or modified stilbenoids in this regard.
Therefore, we took advantage of the introduction of a RT-qPCR-based assay for intracellular expression of
NF-B[3] to assess whether a number of naturally occurring and semi-synthetic resveratrol polymers (at
concentrations in the 5-25 M range) may affect intracellular expression of NF-B in response to the addition
of IL-1β, and to verify whether any effect of these species was synergistic with those observed for resveratrol
alone (at a fixed 5 M concentration).
In short, we observed concentration-dependent suppression of NF-B expression for all the tested
compounds but pterostilbene and pallidol (see structures here below). The inhibitory effect was in the order -
viniferin > L34 -viniferin > L23> resveratrol, where L34 (trimethoxy-resveratrol) and L23 (pterostilbene-transdihydrodimer)
represent a fully methylated analogue of resveratrol and a vastly methylated analogue of -
viniferin, respectively. However, L23 and L34 elicited only modest effects when added at 5-20 M to 5 M
resveratrol in synergistic studies. On the contrary, similar concentrations of the naturally occurring viniferins
significantly increased the effects of 5 M resveratrol, with -viniferin providing the largest suppressive effects,
evident already at viniferin concentrations as low as 5 M.
These data suggest that the bioactivities associated with resveratrol derivatives in wine and
winemaking byproducts are dictated by specific molecular features, and are not limited to the inhibition of
extracellular enzymes. Evidence is also provided as for possible co-operativity occurring – rather than
competition – among chemically related species. Further studies will verify whether these observations can be
of practical relevance, but these data circumstantially appear to support the “food better than pills” working
hypothesis as for outlining possible intervention strategies.
[1] Lavelli V., Harsha P. S. C. S., Ferranti P., Scarafoni A. & Iametti S. (2016) Grape skin phenolics as inhibitors
of mammalian alpha-glucosidase and alpha-amylase - effect of food matrix and processing on efficacy. Food
& Function 7, 1655-1663.
[2] Mattio L. M., Marengo M., Parravicini C., Eberini I., Dallavalle S., Bonomi F., Iametti S. & Pinto A. (2019)
Inhibition of pancreatic alpha-amylase by resveratrol derivatives: Biological activity and molecular modelling
evidence for cooperativity between viniferin enantiomers. Molecules 24, Art. Nr: 3225, DOI:
10.3390/molecules24183225
[3] Barbiroli, A., Capraro, J., Marulo, S., Gamba, M. & Scarafoni, A. (2019). Effects on the Caco-2 cells of a
hypoglycemic protein from lupin seeds in a solution and adsorbed on polystyrene nanoparticles to mimic a
complex food matrix. Biomolecules, 9(10), 606; https://doi.org/10.3390/biom910060
Inhibitory activity of stilbenes against filamentous fungi
No full textStilbenoids (resveratrol and its derivatives) are secondary metabolites produced by plants as defence mechanism to microbial infection. These compounds are known for their anti-inflammatory action and health benefits in preventing a wide range of disorders (e.g. cancer and cardiovascular diseases). However, their antimicrobial properties are less investigated. A series of 8 stilbenoid compounds were synthesized and their antifungal activity against 19 wild strains of filamentous fungi and yeasts (isolated from the environment and food) was tested in vitro. Using an agar diffusion assay, compounds were tested at the concentration of 100 μg/ml on filamentous fungi and yeasts at 104 CFU/ml. The results showed that tested derivatives possess moderate antifungal activity: in particular, monomeric stilbenoids 3’-hydroxy-pterostilbene and piceatannol, and dimeric stilbenoids (±)-trans-δ-viniferin and pallidol were active against mycotoxigenic fungi
Structure-dependent biological activities of food-related stilbene derivatives isomers
No full textResveratrol, piceatannol and pterostilbene are stilbene derivatives in which two aromatic rings linked by an olefin bridge. Many stilbene derivatives have proven beneficial to human health, acting on risk factors for cancer, on cardiovascular and neurodegenerative diseases, on diabetes, and on osteoporosis.
All these monomeric polyphenols are particularly prone to oligomerization processes through oxidative coupling, originating complex structures such as dimers or oligomers that may be responsible for their beneficial effects. These natural oligomers present stereogenic centers, that could play a pivotal role in the interaction of this class of molecules with biological targets.
In this study, isomers of these compounds were synthesized, purified, and tested as for their ability to inhibit enzymes relevant to glucose metabolism (such as brush-border glucosidase and pancreatic alpha amylase), and to control inflammatory response in a suitable Caco-2 cell model. Results highlight the requirement for peculiar structural features as for eliciting individual effects, both in terms of the polymerization state of these phenolics and in terms of their three-dimensional structure
Grapevine stilbenoids as natural food preservatives : calorimetric and spectroscopic insights into the interaction with model cell membranes
No full textFood contamination with pathogenic microorganisms, such as Listeria monocytogenes, Salmonella enterica, Staphylococcus aureus and Bacillus cereus, is a common health concern. Natural products, which have been the main source of antimicrobials for centuries, may represent a turning point in alleviating the antibiotic crisis, and plant polyphenolic compounds are considered a promising source for new antibacterial agents. Resveratrol and resveratrol-derived monomers and oligomers (stilbenoids) have been shown to exert a variegated pattern of efficacy as antimicrobials depending on both the polyphenols' structure and the nature of the microorganisms, and the bacterial cell membrane seems to be one of their primary targets. In this scenario and based on the thermodynamic information reported in the literature about cell membranes, this study aimed at the investigation of the direct interaction of selected stilbenoids with a simple but informative model cell membrane. Three complete stilbenoid "monomer/dimer/dehydro-dimer" sets were chosen according to different geometries and substitution patterns. Micro-DSC was performed on 2 : 3 DPPC : DSPC small unilamellar vesicles with incorporated polyphenols at physiological pH and the results were integrated using complementary NMR data. The study highlighted the molecular determinants and mechanisms involved in the stilbenoid-membrane interaction, and the results were well correlated with the microbiological evidence previously assessed
Inhibition of Pancreatic α-amylase by Resveratrol Derivatives : Biological Activity and Molecular Modelling Evidence for Cooperativity between Viniferin Enantiomers
No full textTo improve the current understanding of the role of stilbenoids in the management of diabetes, the inhibition of the pancreatic α-amylase by resveratrol derivatives was investigated. To approach in a systematic way, the mechanistic and structural aspects of the interaction, potential bioactive agents were prepared as single molecules, that were used for the biological evaluation of the determinants of inhibitory binding. Some dimeric stilbenoids—in particular, viniferin isomers— were found to be better than the reference drug acarbose in inhibiting the pancreatic α-amylase. Racemic mixtures of viniferins were more effective inhibitors than the respective isolated pure enantiomers at an equivalent total concentration, and displayed cooperative effects not observed with the individual enantiomers. The molecular docking analysis provided a thermodynamics-based rationale for the measured inhibitory ability and for the observed synergistic effects. Indeed, the binding of additional ligands on the surface of the alpha-amylase was found to decrease the dissociation constant of inhibitors bound to the active site of the enzyme, thus providing a mechanistic rationale for the observed inhibitory synergies
Inhibition of pancreatic α-amylase by resveratrol-derived viniferins relates to their geometrical features and implies co-operative binding
No full textTo improve current understanding of the role of stilbenoids in the management of diabetes, the hypoglycaemic potential of resveratrol derivatives was investigated in terms of alpha-amylase inhibition. To tackle the mechanistic and structural issues of the interaction with the target protein, bioactive agents were prepared as single molecules, to be used for biological evaluation of the binding determinants. Some dimeric stilbenoids – trans-delta-viniferins, in particular – were found to be much better inhibitors of pancreatic α-amylase.than the reference drug, acarbose. Racemic mixtures of viniferins were more effective than the respective isolated pure enantiomers at equivalent total concentration. A markedly sigmoidal inhibition curve was observed for the (S, S) enantiomer of trans-delta-viniferin, with a Hill cooperativity coefficient (n ) close to 4 and a relatively high Kiapp (0.058 mM). In contrast, values of n were close to unity for the (R, R) enantiomer (n = 1.5; Kiapp = 0.043 mM) and for the high-affinity binding of an equimolar mixture of the (R, R) and (S, S) enantiomers (n = 1.2; Kiapp = 0.012 mM). Molecular docking analysis provided a thermodynamics-based rationale for the inhibitory ability of individual stilbenoids, for the cooperative behavior of viniferin enantiomers, and for the synergistic inhibition discussed above. Indeed, binding of additional ligands on the surface of alpha-amylase was found to decrease the dissociation constant of inhibitors bound to the active site of the enzyme. Finally, viniferins do not appear to compete with acarbose in the inhibition of pancreatic α-amylase. Rather, the evidence gathered so far points to a possible synergy among these classes of inhibitors, in spite of their remarkable structural differences. Studies are in progress to assess whether these synergistic effects could be relevant to developing therapeutic or preventive strategies for diabetes management
Impact of food-derived stilbenoids on the defensive response of dendritic cells to bacterial infection
No full textStilbenoids are a vast class of food-derived anti-inflammatory and antioxidant compounds, that include resveratrol. At difference with resveratrol, the action of most other stilbenoids is much less characterized, in particular for what attains the relationships occurring among chemical structure, antioxidant capacity, and their activity as inhibitors of specific enzymes or as potential regulators of complex pathways of cellular responses. Here we compared a number of monomeric and dimeric stilbenoids – obtained in sterically pure forms by chemical synthesis, as for their ability to modulate bacterially-induced cytokine production and the ROS-based defense response in bone marrow-derived dendritic cells. Despite having the highest chemical antioxidant activity, the two dimeric stilbenoids were weak inhibitors of LPS-induced ROS production in the cell system used in our studies, a response strongly inhibited by resveratrol and piceatannol. In summary, the anti-inflammatory and the antioxidant activity showed no straight relationship, and appeared related to several factors, such as the type of the pro-inflammatory signal, and the chemical structure and bioavailability of the stilbenoids. As for eliciting interleukin-based responses, all monomeric species - but none of the dimeric ones - showed dose-dependent inhibition of E. coli Nissle 1917 induced IL-12 and TNF-alpha, whereas only resveratrol and piceatannol inhibited IL-10 production. All monomers except trimethoxy-resveratrol inhibited IL-12, IL-10, and TNF-alfa production upon stimulation with L. acidophilus NCFM, while dehydro-delta-viniferin increased the IL-12 production. This comparative study shows that stilbenoids may affect cytokine production in ways trelated to the specific structure of the stilbenoid and to the type of microbial stimulation. Knowledge of how individual structures modulate the defense response may be exploited in future strategies for development on new drugs and nutraceuticals
Investigation of the Effects of Monomeric and Dimeric Stilbenoids on Bacteria-Induced Cytokines and LPS-Induced ROS Formation in Bone Marrow-Derived Dendritic Cells
No full textStilbenoids are anti-inflammatory and antioxidant compounds, with resveratrol being the most investigated molecule in this class. However, the actions of most other stilbenoids are much less studied. This study compares five monomeric (resveratrol, piceatannol, pterostilbene, pinostilbene, and trimethoxy-resveratrol) and two dimeric (dehydro-δ-viniferin and trans-δ-viniferin) stilbenoids for their capability to modulate the production of bacteria-induced cytokines (IL-12, IL-10, and TNF-α), as well as lipopolysaccharide (LPS)-induced reactive oxygen species (ROS), in murine bone marrow-derived dendritic cells. All monomeric species showed dose-dependent inhibition of E. coli-induced IL-12 and TNF-α, whereas only resveratrol and piceatannol inhibited IL-10 production. All monomers, except trimethoxy-resveratrol, inhibited L. acidophilus-induced IL-12, IL-10, and TNF-α production. The dimer dehydro-δ-viniferin remarkably enhanced L. acidophilus-induced IL-12 production. The contrasting effect of resveratrol and dehydro-δ-viniferin on IL-12 production was due, at least in part, to a divergent inactivation of the mitogen-activated protein kinases by the two stilbenoids. Despite having moderate to high total antioxidant activity, dehydro-δ-viniferin was a weak inhibitor of LPS-induced ROS formation. Conversely, resveratrol and piceatannol potently inhibited LPS-induced ROS formation. Methylated monomers showed a decreased antioxidant capacity compared to resveratrol, also depending on the methylation site. In summary, the immune-modulating effect of the stilbenoids depends on both specific structural features of tested compounds and the stimulating bacteria
Structural Requirements of Benzofuran Derivatives Dehydro-δ- and Dehydro-ε-Viniferin for Antimicrobial Activity Against the Foodborne Pathogen Listeria monocytogenes
No full textIn a recent study, we investigated the antimicrobial activity of a collection of resveratrol-derived monomers and dimers against a series of foodborne pathogens. Out of the tested molecules, dehydro-δ-viniferin and dehydro-ε-viniferin emerged as the most promising derivatives. To define the structural elements essential to the antimicrobial activity against the foodborne pathogen L. monocytogenes Scott A as a model Gram-positive microorganism, the synthesis of a series of simplified benzofuran-containing derivatives was carried out. The systematic removal of the aromatic moieties of the parent molecules allowed a deeper insight into the most relevant structural features affecting the activity. While the overall structure of compound 1 could not be altered without a substantial loss of antimicrobial activity, the structural simplification of compound 2 (minimal inhibitory concentration (MIC) 16 µg/mL, minimal bactericidal concentration (MBC) >512 µg/mL) led to the analogue 7 with increased activity (MIC 8 µg/mL, MBC 64 µg/mL)
