BACKGROUND AND PURPOSEToll-like receptors (TLRs) play a crucial role in recognizing invading pathogens and endogenous danger signal to induce immune and inflammatory responses. Since dysregulation of TLRs enhances the risk of immune disorders and chronic inflammatory diseases, modulation of TLR activity by phytochemicals could be useful therapeutically. We investigated the effect of caffeic acid phenethyl ester (CAPE) on TLR-mediated inflammation and the underlying regulatory mechanism. EXPERIMENTAL APPROACHInhibitory effects of CAPE on TLR4 activation were assessed with in vivo murine skin inflammation model and in vitro production of inflammatory mediators in macrophages. In vitro binding assay, cell-based immunoprecipitation study and liquid chromatography-tandem mass spectrometry analysis were performed to determine lipopolysaccharide (LPS) binding to MD2 and to identify the direct binding site of CAPE in MD2. KEY RESULTSTopical application of CAPE attenuated dermal inflammation and oedema induced by intradermal injection of LPS (a TLR4 agonist). CAPE suppressed production of inflammatory mediators and activation of NFkB and interferon-regulatory factor 3 (IRF3) in macrophages stimulated with LPS. CAPE interrupted LPS binding to MD2 through formation of adduct specifically with Cys133 located in hydrophobic pocket of MD2. The inhibitory effect on LPS-induced IRF3 activation by CAPE was not observed when 293T cells were reconstituted with MD2 (C133S) mutant. CONCLUSIONS AND IMPLICATIONSOur results show a novel mechanism for anti-inflammatory activity of CAPE to prevent TLR4 activation by interfering with interaction between ligand (LPS) and receptor complex (TLR4/MD2). These further provide beneficial information for the development of therapeutic strategies to prevent chronic inflammatory diseases.

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With the recent quantum leap in chemoprevention by dietary products, their use as cancer therapeutics is garnering worldwide attention. The concept of effortlessly fighting this deadly disease by gulping cups of green tea or swallowing green tea extract capsules is appreciated universally. Epigallocatechin-3-gallate (EGCG), a major polyphenol in green tea, has generated significant interest in controlling carcinogenesis due to its growth-inhibitory efficacy against a variety of cancers by targeting multiple signaling pathways. However, the success of EGCG in preclinical studies is difficult to translate into clinical trials due to issues of low solubility, bioavailability and an uncertain therapeutic window. The laborious and expensive journey of drugs from the laboratory to commercialization can be improved by utilizing nanoparticles as anti-cancer drug carriers. Exploitation of biopolymeric nanoparticles in recent years has improved EGCG's biodistribution, stability and tumor selectivity, revealing its superior chemopreventive effects. This review briefly summarizes recent developments regarding the targets and side effects of EGCG, complications associated with its low bioavailability and critically analyses the application of biopolymeric nanoparticles encapsulating EGCG as a next generation delivery systems.

Diets with naturally occuring chemopreventive agents are showing good potentials in serving dual purposes: firstly, for maintaining health, and secondly, for emerging as most puissant cost-effective strategy against chronic diseases like cancer. Genistein, one of the active soy isoflavone, is gaining attention due to its ability to impede carcinogenic processes by regulating wide range of associated molecules and signalling mechanisms. Epidemiologic and preclinical evidences suggest that sufficient consumption of soy-based food having genistein can be correlated to the reduction of cancer risk. However, certain adverse effects like poor oral bioavailability, low aqueous solubility and inefficient pharmacokinetics have pushed it down in the list of phytoconstituents currently undergoing successful clinical trials. In order to maximise the utilisation of therapeutic benefits of this phytoestrogen, suitable drug carrier designs are required. Recently, nanocarriers, mainly composed of polymeric materials, are progressively and innovatively exploited with the aim to improve pharmacokinetics and pharmacodynamics of genistein. Here, we have briefly reviewed (a) the targeted molecular mechanisms of geinstein, (b) nanopolymeric approaches opted so far in designing carriers and (c) the reasons behind their restricted clinical applications. Finally, some mechanism-based approaches are proposed presenting genistein as the future paradigm in cancer therapy.

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