Targeting macrophages and their recruitment in the oral cavity using swellable (+) alpha tocopheryl phosphate nanostructures

Harper, Robert A.; Petersen, Latrisha K.; Saleh, Mais; Proctor, Gordon; Carpenter, Guy; Gambogi, Robert J.; Hider, Robert C.; Jones, Stuart A.

doi:10.1016/j.nano.2019.04.013

Cited by 3 publications

(6 citation statements)

References 30 publications

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“…α-TP reduced HaCaT keratinocyte viability more than α-T (LD 50 was 1.1-1.8 mM vs > 4.70 mM, respectively) suggesting the phosphate group enhanced the molecule's ability to enter the cells and cause cytotoxicity. This has also been shown in oral mucosal cells in a study that hypothesised that toxicity was caused by disruption of intracellular enzymes 29 . Previous studies in other cells lines support selective cell toxicity by α-TP, but α-T is generally well tolerated 30 .…”

Section: Discussionmentioning

confidence: 66%

The photoprotective properties of α-tocopherol phosphate against long-wave UVA1 (385 nm) radiation in keratinocytes in vitro

Saleh

Lawrence

Jones

et al. 2021

Sci Rep

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UVA1 radiation (340–400 nm), especially longwave UVA1 (> 370 nm), is often ignored when assessing sun protection due to its low sunburning potential, but it generates reactive oxygen species (ROS) and is poorly attenuated by sunscreens. This study aimed to investigate if α-tocopherol phosphate, (α-TP) a promising new antioxidant, could protect against long-wave UVA1 induced cell death and scavenge UVA1 induced ROS in a skin cell model. HaCaT keratinocyte cell viability (24 h) was assessed with Alamar Blue and Neutral Red assays. The metabolism of α-TP into α-T, assessed using mass spectrometry, and the compound's radical scavenging efficacy, assessed by the dichlorodihydrofluorescein (H2DCFDA) ROS detection assay, was monitored in HaCaTs. The mechanism of α-TP ROS scavenging was determined using non-cell based DPPH and ORAC assays. In HaCaT keratinocytes, irradiated with 226 J/cm2 UVA1 in low-serum (2%, starved) cell culture medium, pretreatment with 80 µM α-TP significantly enhanced cell survival (88%, Alamar Blue) compared to control, whereas α-T pre-treatment had no effect survival (70%, Alamar Blue). Pre-treatment of cells with 100 μM α-TP or 100 μM α-T before 57 J/cm2 UVA1 also significantly reduced ROS generation over 2 h (24.1% and 23.9% respectively) compared to the control and resulted in α-TP bioconversion into α-T. As α-TP displayed weak antioxidant activity in the cell-free assays thus its photoprotection was assigned to its bioconversion to α-T by cellular phosphatases. Through this mechanism α-TP prevented long-wave UVA1 induced cell death and scavenged UVA1 induced ROS in skin cells when added to the starved cell culture medium before UVA1 exposure by bioconversion into α-T.

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Section: Discussionmentioning

confidence: 66%

The photoprotective properties of α-tocopherol phosphate against long-wave UVA1 (385 nm) radiation in keratinocytes in vitro

Saleh

Lawrence

Jones

et al. 2021

Sci Rep

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show abstract

“…α-TP reduced HaCaT keratinocyte viability more than α-T (LD 50 was 1.1-1.8 mM vs > 4.70 mM, respectively) suggesting the phosphate group enhanced the molecule's ability to enter the cells and cause cytotoxicity. This has also been shown in oral mucosal cells in a study that hypothesised that toxicity was caused by disruption of intracellular enzymes 30,31 . Previous studies in other cells lines support selective cell toxicity by α-TP, but α-T is generally well tolerated 30,32 .…”

Section: Discussionmentioning

confidence: 69%

The Photoprotective Properties of α-Tocopherol Phosphate Against Long-Wave UVA1 (385 nm) Radiation in Keratinocytes in Vitro

Saleh

Lawrence

Jones

et al. 2021

Preprint

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Long-wave UVA1 radiation (375 nm – 400 nm) is often ignored when assessing sun protection due to its low sunburning potential, but it generates reactive oxygen species (ROS) and is poorly attenuated by sunscreens. This study aimed to investigate if α-tocopherol phosphate, (α-TP) a promising new antioxidant, could protect against long-wave UVA1 induced cell death and scavenge UVA1 induced ROS in a skin cell model. HaCaT keratinocytes cell viability (24 h) was assessed with Alamar blue® and neutral red assays. Radical scavenging efficacy of α-T and α-TP in vitro was monitored by the dichlorodihydrofluorescein (H2DCFDA) ROS detection assay over 2 h. The mechanism of α-TP ROS scavenging was determined using chemical DPPH and ORAC assays.In HaCaT keratinocytes, irradiated with 226 J/cm2 UVA1 in low-serum (2%, starved) cell culture medium, pretreatment with 80 µM α-TP significantly enhanced cell survival (88%, Alamar blue) compared to control, whereas α-T pre-treatment had no effect survival (70%, Alamar blue). Pre-treatment of cells with 100 μM α-TP or 100 μM α-T before 57 J/cm2 UVA1 also significantly reduced ROS generation over 2 h (24.1% and 23.9% respectively) compared to the control. However, α-TP displayed weak antioxidant activity in cell free assays suggesting its photoprotection was due to bioconversion to α-T by cellular phosphatases.Treatment with α-TP prevented long-wave UVA1 induced cell death and scavenged UVA1 induced ROS in skin cells when added to the starved cell culture medium before UVA1 exposure by bioconversion into α-T.

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“…In previous experiments, αTP inhibited cell proliferation more efficiently than αT in a number of cell lines, and cytotoxic and apoptotic effects of αTP in THP‐1 monocytes were observed above 50 μM, 33 with a LD50 of 304 μM in THP‐1 macrophages 51 . Therefore, it was interesting to check whether the formation of an αTP/βCD complex enhances or impairs the ability of αTP to inhibit cell proliferation or increases apoptotic activity 33,51 .…”

Section: Resultsmentioning

confidence: 99%

“…In previous experiments, αTP inhibited cell proliferation more efficiently than αT in a number of cell lines, and cytotoxic and apoptotic effects of αTP in THP-1 monocytes were observed above 50 μM, 33 with a LD50 of 304 μM in THP-1 macrophages. 51 Therefore, it was interesting to check whether the formation of an αTP/βCD complex enhances or impairs the ability of αTP to inhibit cell proliferation or increases apoptotic activity. 33,51 Incubation of THP-1 monocytes with increasing concentrations of αTP in an αTP/βCD or αTP/γCD complex for 72 h inhibited cell proliferation with slightly higher efficiency when compared to αTP, whereas βCD had no significant effect (MTS assay) (Figure 2A).…”

Section: Characterization Of the αTp/βcd Complexmentioning

confidence: 99%

“…51 Therefore, it was interesting to check whether the formation of an αTP/βCD complex enhances or impairs the ability of αTP to inhibit cell proliferation or increases apoptotic activity. 33,51 Incubation of THP-1 monocytes with increasing concentrations of αTP in an αTP/βCD or αTP/γCD complex for 72 h inhibited cell proliferation with slightly higher efficiency when compared to αTP, whereas βCD had no significant effect (MTS assay) (Figure 2A). Since most assays were done after shorter incubation times (<24 h) we checked cell proliferation and cytotoxicity also at shorter timepoints.…”

Section: Characterization Of the αTp/βcd Complexmentioning

confidence: 99%

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Modulation of CD36‐mediated lipid accumulation and senescence by vitamin E analogs in monocytes and macrophages

et al. 2022

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The CD36/FAT scavenger receptor/fatty acids transporter regulates cellular lipid accumulation important for inflammation, atherosclerosis, lipotoxicity, and initiation of cellular senescence. Here we compared the regulatory effects of the vitamin E analogs alpha‐tocopherol (αT), alpha‐tocopheryl phosphate (αTP), and αTP/βCD (a nanocarrier complex between αTP and β‐cyclodextrin [βCD]) and investigated their regulatory effects on lipid accumulation, phagocytosis, and senescence in THP‐1 monocytes and macrophages. Both, αTP and αTP/βCD inhibited CD36 surface exposition stronger than αT leading to more pronounced CD36‐mediated events such as inhibition of DiI‐labeled oxLDL uptake, phagocytosis of fluorescent Staphylococcus aureus bioparticles, and cell proliferation. When compared to βCD, the complex of αTP/βCD extracted cholesterol from cellular membranes with higher efficiency and was associated with the delivery of αTP to the cells. Interestingly, both, αTP and more so αTP/βCD inhibited lysosomal senescence‐associated beta‐galactosidase (SA‐β‐gal) activity and increased lysosomal pH, suggesting CD36‐mediated uptake into the endo‐lysosomal phagocytic compartment. Accordingly, the observed pH increase was more pronounced with αTP/βCD in macrophages whereas no significant increase occurred with αT, alpha‐tocopheryl acetate (αTA) or βCD. In contrast to αT and αTA, the αTP molecule is di‐anionic at neutral pH, but upon moving into the acidic endo‐lysosomal compartment becomes protonated and thus is acting as a base. Moreover, it is expected to be retained in lysosomes since it still carries one negative charge, similar to lysosomotropic drugs. Thus, treatment with αTP or αTP/βCD and/or inhibition of conversion of αTP to αT as it occurs in aged cells may counteract CD36‐mediated overlapping inflammatory, senescent, and atherosclerotic events.

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Targeting macrophages and their recruitment in the oral cavity using swellable (+) alpha tocopheryl phosphate nanostructures

Cited by 3 publications

References 30 publications

The photoprotective properties of α-tocopherol phosphate against long-wave UVA1 (385 nm) radiation in keratinocytes in vitro

The photoprotective properties of α-tocopherol phosphate against long-wave UVA1 (385 nm) radiation in keratinocytes in vitro

The Photoprotective Properties of α-Tocopherol Phosphate Against Long-Wave UVA1 (385 nm) Radiation in Keratinocytes in Vitro

Modulation of CD36‐mediated lipid accumulation and senescence by vitamin E analogs in monocytes and macrophages

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