Abstract
4-Hexylresorcinol (4HR) is used as a food preservative and an ingredient of toothpaste and cosmetics. The present study was performed using 233 antisera to determine the changes in protein expression induced by 4HR in human umbilical cord vein endothelial cells (HUVECs), and evaluated the 4HR-induced effects in comparison with previous results (Kim et al., 2019). Similar to RAW 264.7 cells, 4HR-treated HUVECs showed decreases in the expression of the proliferation-related proteins, cMyc/MAX/MAD network proteins, p53/RB and Wnt/β-catenin signaling, and they showed inactivation of DNA transcription and protein translation compared to the untreated controls. 4HR upregulated growth factors (TGF-β1, β2, β3, SMAD2/3, SMAD4, HGF-α, Met, IGF-1) and RAS signaling proteins (RAF-B, p38, p-p38, p-ERK-1, and Rab-1), and induced stronger expression of the cellular protection-, survival-, and differentiation-related proteins in HUVECs than in RAW 264.7 cells. 4HR suppressed NFkB signaling in a manner that suggests potential anti-inflammatory and wound healing effects by reducing M1 macrophage polarization and increasing M2 macrophage polarization in both cells. 4HR-treated HUVECs tended to increase the ER stress mediators by upregulating eIF2AK3, ATF4, ATF6, lysozyme, and LC3 and downregulating eIF2α and GADD153 (CHOP), resulting in PARP-1/AIF-mediated apoptosis. These results indicate that 4HR has similar effects on the protein expression of HUVECs and RAW 264.7 cells, but their protein expression levels differ according to cell types. The 4HR-treated cells showed global protein expression characteristic of anticancer and wound healing effects, which could be alleviated simultaneously by other proteins exerting opposite functions. These results suggest that although 4HR has similar effects on the global protein expression of HUVECs and RAW 264.7 cells, the 4HR-induced molecular interferences in those cells are complex enough to produce variable protein expression, leading different cell functions. Moreover, HUVECs have stronger wound healing potential to overcome the impact induced by 4HR than RAW 264.7 cells.
Highlights
Resorcinolic lipids were suggested to induce dormancy in micro-organisms, and they have an anti-microbial effect [1]. 4-Hexylresorcinol (4HR) is a synthetic resorcinolic lipid that is synthesized from resorcinol and caproic acid [2]. 4HR has a long alkyl group, and can bind to the hydrophobic pocket of enzymes such as tyrosinase [3]. 4HR has been used as a food preservative because of its strong inhibitory effect [4]
As angiogenesis and osteogenesis are important phenomena for tissue organogenesis, it is suggested that human umbilical cord vein endothelial cells (HUVECs), which are the counterparts of RAW 264.7 cells in inflammation and wound healing, need to be explored for their global protein expression changes induced by 4HR
Regarding the protein expression relevant to endothelial cell differentiation, the immunostainings of E-cadherin and VE-cadherin, cell adhesion molecules forming cadherin-catenin complex, were conspicuously positive in the 4HR-treated HUVECs compared to the untreated control cells
Summary
Resorcinolic lipids were suggested to induce dormancy in micro-organisms, and they have an anti-microbial effect [1]. 4-Hexylresorcinol (4HR) is a synthetic resorcinolic lipid that is synthesized from resorcinol and caproic acid [2]. 4HR has a long alkyl group, and can bind to the hydrophobic pocket of enzymes such as tyrosinase [3]. 4HR has been used as a food preservative because of its strong inhibitory effect [4]. In the previous IP-HPLC-based study [19], the administration of 4HR to macrophages (RAW 264.7 cells) produced significant reductions in the expression of proliferation-, inflammation-, protection-, and oncogenesis-related proteins but uncertain effects on angiogenesis and osteogenesis. As angiogenesis and osteogenesis are important phenomena for tissue organogenesis, it is suggested that HUVECs (endothelial cells), which are the counterparts of RAW 264.7 cells (macrophages) in inflammation and wound healing, need to be explored for their global protein expression changes induced by 4HR. In the present study, HUVECs were used to investigate the 4HR-induced protein expression changes by IP-HPLC, and results were compared with a previous report [19]
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