Abstract
Citrus flavonoids have well-documented protective effects on cardiovascular system, but the poor water solubility and reduced bioavailability restrict their therapeutic use. We aimed to overcome these limitations and encapsulated naringenin and hesperetin into lipid nanoemulsions (LNs), targeted to vascular cell adhesion molecule-1 (VCAM-1), which is expressed on activated endothelial cells (ECs). LNs were characterized by a hydrodynamic size of ~200 nm, negative zeta potential, an encapsulation efficiency of flavonoids higher than 80%, good in vitro stability and steady release of the cargo. The LNs were neither cytotoxic to human ECs line EA.hy926, nor provoked in vitro lysis of murine erithrocytes. Then, we tested whether these nanoformulations reduce tumor necrosis factor-alpha (TNF-α) induced EC-activation. We found that flavonoid-loaded LNs, either non-targeted or targeted to the endothelium, were taken up by the EA.hy926 cells in a dose-dependent manner, but dependent on TNF-α only in the case of endothelium-targeted LNs. Moreover, these nanoparticles inhibited both the adhesion and transmigration of THP-1 monocytes on/through activated ECs, by mechanisms involving a reduced expression of the pro-inflammatory chemokine monocyte chemotactic protein 1 (MCP-1) and diminished nuclear translocation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB).
Highlights
Naringenin and hesperetin, the main citrus flavonoids, either in their free form or as the corresponding naturally occurring glycosides (Table 1), are intensely investigated recently for their therapeutic potential in atherosclerosis and type II diabetes, two of the dreadful pandemics of the developed society
A series of in vitro and in vivo studies indicated that adhesion of monocytes to endothelial cells, an early pro-inflammatory step in atherogenesis, is reduced by the treatment with citrus flavanones via the decreased expression of cell adhesion molecules (i.e., vascular cell adhesion molecule-1 (VCAM-1), intercellular Adhesion Molecule 1 (ICAM-1) and E-selectin) and pro-inflammatory cytokines (such as fractalkine known as chemokine (C-X3-C motif) ligand 1 (CX3CL1), monocyte chemotactic protein 1 (MCP-1) and regulated on activation, normal T cell expressed and secreted (RANTES) [3,4,5], mediated at least partially through the diminished nuclear translocation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) transcription factor [6]
To increase the water solubility of the two flavonoids, we incorporated naringenin and hesperetin in a suitable hydrophobic environment provided by lipid nanoemulsions
Summary
Naringenin and hesperetin, the main citrus flavonoids, either in their free form or as the corresponding naturally occurring glycosides (Table 1), are intensely investigated recently for their therapeutic potential in atherosclerosis and type II diabetes, two of the dreadful pandemics of the developed society. A series of in vitro and in vivo studies indicated that adhesion of monocytes to endothelial cells, an early pro-inflammatory step in atherogenesis, is reduced by the treatment with citrus flavanones via the decreased expression of cell adhesion molecules (i.e., vascular cell adhesion molecule-1 (VCAM-1), intercellular Adhesion Molecule 1 (ICAM-1) and E-selectin) and pro-inflammatory cytokines (such as fractalkine known as chemokine (C-X3-C motif) ligand 1 (CX3CL1), monocyte chemotactic protein 1 (MCP-1) and regulated on activation, normal T cell expressed and secreted (RANTES) [3,4,5], mediated at least partially through the diminished nuclear translocation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) transcription factor [6]. International Union of Pure and Applied Chemistry (IUPAC) name, Chemical Abstracts Service (RANTES) [3,4,5], mediated at least(pRaArtNiaTllEySt)h[r3o–u5g],hmthedeidaitmedinaitslheeadstnpuacrlteiaarllytrathnrsoloucgahtiothneodfinmuicnliesahred nuclear translocation of nuclear (CAS). Biochemical details of flavoTnaobidles 1in. cBoiropcohreamteidcailndtoetnaialns ooefmfulalvsioonnosid(cshienmcoicraplorsatrtuedctuinreto, nanoemulsions (chemical structure, International Union of Pure and AppInliteedrnCathioenmailstUryni(oInUPoAf CP)urneamaned, CAhpepmliiecdal CAhbesmtriasctrtsy S(IeUrvPiAceC) name, Chemical Abstracts Service
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