Bioactive polyphenols and cardiovascular disease: chemical antagonists, pharmacological agents or xenobiotics that drive an adaptive response?

Abstract

Polyphenols are widely regarded to have a wide range of health-promoting qualities, including beneficial effects on cardiovascular disease. Historically, the benefits have been linked to their well-recognized powerful antioxidant activity. However, the concept that the beneficial effects are attributable to direct antioxidant activity in vivo does not pay sufficient heed to the fact that polyphenols degrade rapidly, are poorly absorbed and rapidly metabolized, resulting in very low bioavailability. This review explores alternative mechanisms by which polyphenols, or their metabolites, exert biological activity via mechanisms that can be activated by physiologically relevant concentrations. Evidence is presented to support the action of phenolic derivatives on receptors and signalling pathways to induce adaptive responses that drive changes in endogenous antioxidant, antiplatelet, vasodilatory and anti-inflammatory effects. The implications are that in vitro antioxidant measures as predictors of polyphenol protective activity in vivo hold little relevance and that closer attention needs to be paid to bioavailable metabolites to understand the mode of action of these diet-derived components. LINKED ARTICLESThis article is part of a themed section on Principles of Pharmacological Research of Nutraceuticals. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.11/issuetoc Abbreviations A549, adenocarcinomic human alveolar basal epithelial cells; CD62P, P-selectin; CSE, cigarette smoke extract; EGCG, epigallocatechin-3-gallate; eNOS, endothelial NOS; ER-α/β, oestrogen receptor-α/β; GR, glutathione reductase; GSL, glutamylcysteine ligase; GST, GSH-S-transferase; HO1, haem oxygenase 1; ICAM-1, intercellular adhesion molecule 1; IκB-α, inhibitor of κ-B α; Nrf2, nuclear factor E2-related factor 2;˙OH, hydroxyl radical; ONOO À , peroxynitrite; ox-LDL, oxidized LDL; VCAM-1, vascular cell adhesion molecule 1

The ellagitannin metabolite urolithin C is a glucose‐dependent regulator of insulin secretion through activation of L‐type calcium channels

“…In this context, plant polyphenols are likely good candidates since several of these well‐known antioxidant compounds are now widely regarded as pharmacological agents that regulate target proteins and associated signalling pathways including in pancreatic beta cells (Dall'Asta et al, ; Goszcz, Duthie, Stewart, Leslie, & Megson, ; Oak et al, ; Saponara, Carosati, Mugnai, Sgaragli, & Fusi, ). The possibility of developing polyphenol‐based therapeutics is further supported by studies reporting that a number of polyphenols elicit therapeutic‐like effects at pharmacological micromolar concentrations in cells, tissues, and various animal models (Bai et al, ; Gu et al, ; Wright, ; Zhao et al, ).…”

“…The possibility of developing polyphenol‐based therapeutics is further supported by studies reporting that a number of polyphenols elicit therapeutic‐like effects at pharmacological micromolar concentrations in cells, tissues, and various animal models (Bai et al, ; Gu et al, ; Wright, ; Zhao et al, ). However and in contrast to the naturally occurring plant polyphenols, the bioactivity of their metabolite derivatives has more recently emerged and hence is still poorly characterized (Del Rio et al, ; Espín, Larrosa, García‐Conesa, & Tomás‐Barberán, ; Goszcz et al, ). In particular, the extensive metabolism of polyphenols in both the gastrointestinal tract and liver offers a collection of potential valuable compounds whose pharmacology on beta cell function is largely unknown.…”

Functional mechanism of tracheal relaxation, antiasthmatic, and toxicological studies of 6‐hydroxyflavone

“…Natural products are an important source for discovery and development of new drugs with novel therapeutic targets for more specific treatments and less adverse effects. Within this context, flavonoids are privileged scaffolds that possess several activities and mechanisms of action (Goszcz, Duthie, Stewart, Leslie, & Megson, ; Harborne & Williams, ; Wang et al, ). In previous reports, the potential effect of flavonoids as antiasthmatic drugs, especially those possessing powerful antioxidant, anti‐allergic, anti‐inflammatory, immune‐modulating, and airway smooth muscle relaxant effects, have been described (Flores‐Flores et al, ; Goszcz et al, ; Tanaka & Takahashi, ; Wang et al, ).…”

“…Within this context, flavonoids are privileged scaffolds that possess several activities and mechanisms of action (Goszcz, Duthie, Stewart, Leslie, & Megson, ; Harborne & Williams, ; Wang et al, ). In previous reports, the potential effect of flavonoids as antiasthmatic drugs, especially those possessing powerful antioxidant, anti‐allergic, anti‐inflammatory, immune‐modulating, and airway smooth muscle relaxant effects, have been described (Flores‐Flores et al, ; Goszcz et al, ; Tanaka & Takahashi, ; Wang et al, ). The majority of these induce their antiasthmatic effect via the inhibition of the release of chemical mediators, the synthesis of Th2 type cytokines such as interleukin (IL)‐4 and IL‐13, and CD40 ligand expression by high‐affinity IgE receptor‐expressing cells such as mast cells and basophils (Tanaka & Takahashi, ).…”

Targeting endothelial metaflammation to counteract diabesity cardiovascular risk: Current and perspective therapeutic options

“…-Polyphenols -Polyphenols contained in fruits, vegetables, and beverages are well known for their anti-oxidant properties [264]. Scientific interest in polyphenols as therapeutic agents is constantly increasing, and results from several experimental studies suggest that these compounds may improve endothelial function by multiple mechanisms related, but not limited, to the ability to increase eNOS expression and prostacyclin production, or to inhibit ET-1 and endothelial NADPH oxidase activity, or via more complex intercellular activities that reduce matrix metalloproteinase (MMP) activation, inhibit vascular cells migration and proliferation, and modulate angiogenesis.…”