Patch Testing With Tocopherol and Tocopherol Acetate: The North American Contact Dermatitis Group Experience, 2001 to 2016

Erin M Warshaw, Jenna L Ruggiero, Joel G DeKoven, Jonathan I Silverberg, Howard I Maibach, James S Taylor, Amber R Atwater, Kathryn A Zug, Denis Sasseville, Joseph F Fowler Jr, Anthony F Fransway, Melanie D Pratt, Donald V Belsito, Vincent A DeLeo, Margo J Reeder

Dermatitis . 2021 Sep-Oct 01;32(5):308-318. doi: 10.1097/DER.0000000000000706.


Background: Vitamin E (tocopherol) a naturally occurring mixture of antioxidants commonly used in topical skin care products, may cause allergic contact dermatitis.

Objective: The aim of this study was to characterize positive patch test reactions to tocopherol and tocopherol acetate.

Methods: This is a retrospective analysis of North American Contact Dermatitis Group patch test data to tocopherols (dl-α-tocopherol 100% and/or dl-α-tocopherol acetate 100%) from 2001 to 2016.

Results: Of the 38,699 patients patch tested to tocopherol and/or tocopherol acetate, 349 (0.9%) had positive reactions; of these, 87.6% were currently relevant. Most (51.4%) were weak (+) and/or not related to occupation (99.1%). Compared with tocopherol-negative patients, tocopherol-positive individuals were more likely to be female (72.5% vs 67.2%, P = 0.0355), have a final primary diagnosis of allergic contact dermatitis (74.2% vs 52.6%, P < 0.0001), and have dermatitis in a scattered generalized distribution (23.8% vs 18.2%, P = 0.0072); they were also less likely to have hand involvement (16.6% vs 22.3%, P = 0.0064). The most common source of tocopherol was personal care products, especially moisturizers.

Conclusions: Positive patch test reactions to tocopherols were relatively rare given their widespread use. When positive, current clinical relevance was high. Tocopherol-positive patients were more likely to be female and presented with dermatitis on the face or in a scattered generalized pattern.

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Vitamin E supplementation in inflammatory skin diseases

Enzo Berardesca, Norma Cameli

Dermatol Ther . 2021 Oct 16;e15160. doi: 10.1111/dth.15160. Online ahead of print.


Vitamin E is a powerful lipophilic antioxidant that protects membranes from lipid peroxidation, and consequently, oxidative damage. Oxidative stress plays a role in the development of neurodegenerative diseases. Vitamin E supplementation is recommended in patients with vitamin E deficiency due to fat malabsorption. The addition of vitamin E to the diet slows Alzheimer’s disease progression and protects older patients against respiratory infections. Recent studies also point to the involvement of oxidative stress in the pathology of immune-mediated skin diseases, such as atopic dermatitis and psoriasis. We reviewed the available clinical trials that investigated the role of vitamin E supplementation in preventing and treating atopic dermatitis and psoriasis. Data from these studies point to a positive role of vitamin E supplementation in these diseases. Still, due to limitations in study design, further evidence is needed to reach a definite conclusion.

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Oat ( Avena sativa) Extract against Oxidative Stress-Induced Apoptosis in Human Keratinocytes

Sooji Song, Yoon-Mi Lee, Yu Young Lee, Kyung-Jin Yeum

Molecules . 2021 Sep 13;26(18):5564. doi: 10.3390/molecules26185564.


Oat (Avena sativa) is well known for its various health benefits. The protective effect of oat extract against oxidative stress-induced apoptosis in human keratinocytes HaCaT was determined. First, extracts of two varieties of oat, Daeyang and Choyang, were analyzed for fat-soluble antioxidants such as α-tocotrienol, γ-oryzanols, lutein and zeaxanthin using an UPLC system and for antioxidant activity using a DPPH assay. Specifically, an 80% ethanol extract of Daeyang oat (Avena sativa cv. Daeyang), which had high amounts of antioxidants and potent radical scavenging activity, was further evaluated for protective effect against oxidative stress-induced cell death, intracellular reactive oxygen species levels, the phosphorylation of DNA damage mediating genes such as H2AX, checkpoint kinase 1 and 2, and p53 and the activation of apoptotic genes such as cleaved caspase-3 and 7 and poly (ADP-ribose) polymerase in HaCaT cells. The Daeyang and Choyang oat 80% ethanol extracts had 26.9 and 24.1 mg/100 g γ-oryzanols, 7.69 and 8.38 mg/100 g α-tocotrienol, 1.25 and 0.34 mg/100 g of lutein and 1.20 and 0.17 mg/100 g of zeaxanthin, respectively. The oat 80% ethanol extract treatment (Avena sativa cv. Daeyang) had a protective effect on oxidative stress-induced cell death in HaCaT cells. In addition, the oat 80% ethanol extracts led to a significant decrease in the intracellular ROS level at a concentration of 50-200 μg/mL, the attenuation of DNA damage mediating genes and the inhibition of apoptotic caspase activities in a dose dependent manner (50-200 μg/mL). Thus, the current study indicates that an oat (Avena sativa cv. Daeyang) extract rich in antioxidants, such as polyphenols, avenanthramides, γ-oryzanols, tocotrienols and carotenoids, has a protective role against oxidative stress-induced keratinocyte injuries and that oat may a useful source for oxidative stress-associated skin damage.

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In vitro antiaging evaluation of sunscreen formulated from nanostructured lipid carrier and tocotrienol-rich fraction

Chee Chin Chu, Zafarizal Aldrin Bin Azizul Hasan, Chin Ping Tan, Kar Lin Nyam

J Pharm Sci . 2021 Aug 20;S0022-3549(21)00423-8. doi: 10.1016/j.xphs.2021.08.020.


Chronic exposure to ultraviolet (UV) radiation leads to photoaging. There is a tremendous rise in products having a dual activity of photoprotection and antiaging. In vitro analysis in dermal fibroblasts and their biological mechanisms involved are critical to determine antiaging potential. The study aimed to investigate the antiaging potential of sunscreen formulated from nanostructured lipid carrier and tocotrienol-rich fraction (NLC-TRF sunscreen). The antioxidant activity of the NLC-TRF sunscreen was evaluated by radical scavenging and hydrogen peroxide inhibition properties. Also, collagenase, elastase and matrix metalloproteinase-1 (MMP-1) inhibition activities, and type I collagen and elastin protein expression were studied. Quantitative real-time polymerase chain reaction (qPCR) was used to evaluate the mRNA expression of fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), transforming growth factor-β1 (TGF-β1), type I collagen (COL1A1), elastin (ELN), MMP-1, MMP-2, and tissue inhibitor matrix metalloproteinase-1 (TIMP-1). The results suggested that NLC-TRF sunscreen is effective in radical, anti-hydrogen peroxide, and collagenase, elastase and MMP-1 inhibition activities. Besides, a significant increase for type I collagen (3.47-fold) and elastin (2.16-fold) protein and fibroblast regeneration genes (FGF (2.12-fold), VEGF (1.91-fold), TGF-β1 (2.84-fold), TIMP-1 (1.42-fold), ELN (2.13-fold)) were observed after sample treatment. These findings support the therapeutic potential of NLC-TRF sunscreen in antiaging.

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Biochemical and Clinical Effects of Vitamin E Supplementation in Hungarian Smith-Lemli-Opitz Syndrome Patients

Katalin Koczok, László Horváth, Zeljka Korade, Zoltán András Mezei, Gabriella P Szabó, Ned A Porter, Eszter Kovács, Károly Mirnics, István Balogh

Biomolecules . 2021 Aug 17;11(8):1228. doi: 10.3390/biom11081228.


Smith-Lemli-Opitz syndrome (SLOS) is a severe monogenic disorder resulting in low cholesterol and high 7-dehydrocholesterol (7-DHC) levels. 7-DHC-derived oxysterols likely contribute to disease pathophysiology, and thus antioxidant treatment might be beneficial because of high oxidative stress. In a three-year prospective study, we investigated the effects of vitamin E supplementation in six SLOS patients already receiving dietary cholesterol treatment. Plasma vitamin A and E concentrations were determined by the high-performance liquid chromatography (HPLC) method. At baseline, plasma 7-DHC, 8-dehydrocholesterol (8-DHC) and cholesterol levels were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. The clinical effect of the supplementation was assessed by performing structured parental interviews. At baseline, patients were characterized by low or low-normal plasma vitamin E concentrations (7.19-15.68 μmol/L), while vitamin A concentrations were found to be normal or high (1.26-2.68 μmol/L). Vitamin E supplementation resulted in correction or significant elevation of plasma vitamin E concentration in all patients. We observed reduced aggression, self-injury, irritability, hyperactivity, attention deficit, repetitive behavior, sleep disturbance, skin photosensitivity and/or eczema in 3/6 patients, with notable individual variability. Clinical response to therapy was associated with a low baseline 7-DHC + 8-DHC/cholesterol ratio (0.2-0.4). We suggest that determination of vitamin E status is important in SLOS patients. Supplementation of vitamin E should be considered and might be beneficial.

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Controlled Release of the α-Tocopherol-Derived Metabolite α-13′-Carboxychromanol from Bacterial Nanocellulose Wound Cover Improves Wound Healing

Jessica Hoff, Berit Karl, Jana Gerstmeier, Uwe Beekmann, Lisa Schmölz, Friedemann Börner, Dana Kralisch, Michael Bauer, Oliver Werz, Dagmar Fischer, Stefan Lorkowski, Adrian T Press

Nanomaterials (Basel) . 2021 Jul 28;11(8):1939. doi: 10.3390/nano11081939.


Inflammation is a hallmark of tissue remodeling during wound healing. The inflammatory response to wounds is tightly controlled and well-coordinated; dysregulation compromises wound healing and causes persistent inflammation. Topical application of natural anti-inflammatory products may improve wound healing, in particular under chronic pathological conditions. The long-chain metabolites of vitamin E (LCM) are bioactive molecules that mediate cellular effects via oxidative stress signaling as well as anti-inflammatory pathways. However, the effect of LCM on wound healing has not been investigated. We administered the α-tocopherol-derived LCMs α-13′-hydroxychromanol (α-13′-OH) and α-13′-carboxychromanol (α-13′-COOH) as well as the natural product garcinoic acid, a δ-tocotrienol derivative, in different pharmaceutical formulations directly to wounds using a splinted wound mouse model to investigate their effects on the wounds’ proinflammatory microenvironment and wound healing. Garcinoic acid and, in particular, α-13′-COOH accelerated wound healing and quality of the newly formed tissue. We next loaded bacterial nanocellulose (BNC), a valuable nanomaterial used as a wound dressing with high potential for drug delivery, with α-13′-COOH. The controlled release of α-13′-COOH using BNC promoted wound healing and wound closure, mainly when a diabetic condition was induced before the injury. This study highlights the potential of α-13′-COOH combined with BNC as a potential active wound dressing for the advanced therapy of skin injuries.

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Alpha-Tocopherol Protects Human Dermal Fibroblasts by Modulating Nitric Oxide Release, Mitochondrial Function, Redox Status, and Inflammation

Lara Camillo, Elena Grossini, Serena Farruggio, Patrizia Marotta, Laura Cristina Gironi, Elisa Zavattaro, Paola Savoia

Skin Pharmacol Physiol . 2021 Jul 8;1-12. doi: 10.1159/000517204. Online ahead of print.


Background: The altered balance between oxidants/antioxidants and inflammation, changes in nitric oxide (NO) release, and mitochondrial function have a role in skin aging through fibroblast modulation. Tocopherol is promising in counteracting the abovementioned events, but the effective mechanism of action needs to be clarified.

Objective: The aim of this study was to examine the effects of α-tocopherol on cell viability/proliferation, NO release, mitochondrial function, oxidants/antioxidants, and inflammation in human dermal fibroblasts (HDF) subjected to oxidative stress.

Methods: HDF were treated with H2O2 in the presence or absence of 1-10 μM α-tocopherol. Cell viability, reactive oxygen species (ROS), NO release, and mitochondrial membrane potential were measured; glutathione (GSH), superoxide dismutase (SOD)-1 and -2, glutathione peroxidase-1 (GPX-1), inducible NO synthase (iNOS), and Ki-67 were evaluated by RT-PCR and immunofluorescence; cell cycle was analyzed using FACS. Pro- and anti-inflammatory cytokine gene expression was analyzed through qRT-PCR.

Results: α-Tocopherol counteracts H2O2, although it remains unclear whether this effect is dose dependent. Improvement of cell viability, mitochondrial membrane potential, Ki-67 expression, and G0/G1 and G2/M phases of the cell cycle was observed. These effects were accompanied by the increase of GSH content and the reduction of SOD-1 and -2, GPX-1, and ROS release. Also, iNOS expression and NO release were inhibited, and pro-inflammatory cytokine gene expression was decreased, confirming the putative role of α-tocopherol against inflammation.

Conclusion: α-Tocopherol exerts protective effects in HDF which underwent oxidative stress by modulating the redox status, inflammation, iNOS-dependent NO release, and mitochondrial function. These observations have a potential role in the prevention and treatment of photoaging-related skin cancers.

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Topical cream containing nanoparticles with vitamin E to prevent radiodermatitis in women with breast cancer: a clinical trial protocol

Fernanda Mateus Queiróz Schmidt, Carol V Serna González, Rodrigo Calixto Mattar, Luciana Biagini Lopes, Marinilce Fagundes Dos Santos, Vera L C de Gouveia Santos

J Wound Care . 2021 Jun 1;30(Sup6):S44-S50. doi: 10.12968/jowc.2021.30.Sup6.S44.


Objective: Little is known about the efficacy of products aiming to prevent radiodermatitis, which affects between 90-95% of women with breast cancer. The use of antioxidants is promising, however, there is a lack of evidenceon their effectiveness. Here, the authors present a clinical trial protocol to evaluate the effects of applying a cream containing nanoparticles with vitamin E to prevent radiodermatitis in patients with breast cancer.

Method: The protocol recommends that 108 women with breast cancer, receiving radiotherapy, are included in this triple-blinded, randomized, controlled study at an oncology hospital. Patients will be divided in three groups of 36 individuals each: group A will receive a cream with lipid nanoparticles and vitamin E, group B will receive a cream without nanoparticles nor vitamin E, and group C will receive a cream with nanoparticles without vitamin E. The primary endpoints will evaluate the incidence, degree, and time of onset of radiodermatitis. The secondary endpoints will focus on the quality of life, symptoms, and local temperature. Patients will be assessed three times a week, from the start of their radiotherapy treatment to two weeks after the last session. This protocol was approved by the research ethics committee of the institutions involved and registered on an international trials database.

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An evaluation of tocotrienol ethosomes for transdermal delivery using Strat-M ® membrane and excised human skin

Rajesh Sreedharan Nair, Nashiru Billa, Chee-Onn Leong, Andrew P Morris

Pharm Dev Technol . 2021 Feb;26(2):243-251. doi: 10.1080/10837450.2020.1860087. Epub 2020 Dec 15.


Tocotrienol (TRF) ethosomes were developed and evaluated in vitro for potential transdermal delivery against melanoma. The optimised TRF ethosomal size ranged between 64.9 ± 2.2 nm to 79.6 ± 3.9 nm and zeta potential (ZP) between -53.3 mV to -62.0 ± 2.6 mV. Characterisation of the ethosomes by ATR-FTIR indicated the successful formation of TRF-ethosomes. Scanning electron microscopy (SEM) images demonstrated the spherical shape of ethosomes, and the entrapment efficiencies of all the formulations were above 66%. In vitro permeation studies using full-thickness human skin showed that the permeation of gamma-T3 from the TRF ethosomal formulations was significantly higher (p < 0.05) than from the control. The cumulative amount of gamma-T3 permeated from TRF ethosome after 48 hours was 1.03 ± 0.24 µg cm-2 with a flux of 0.03 ± 0.01 µg cm-2 h-1. Furthermore, the flux of gamma-T3 across the Strat-M ® and the epidermal membrane was significantly higher than that across full-thickness human skin (p < 0.05). In vitro cytotoxicity studies on HaCat cells showed significantly higher cell viability than the pure drug solution (p < 0.05). The enhanced skin permeation and high cell viability associated with this formulation suggest a promising carrier for transdermal delivery.

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Advancing skin delivery of α-tocopherol and γ-tocotrienol for dermatitis treatment via nanotechnology and microwave technology

Mohd Saufi Harun, Tin Wui Wong, Chee Wai Fong

Int J Pharm . 2021 Jan 25;593:120099. doi: 10.1016/j.ijpharm.2020.120099. Epub 2020 Nov 28.


This study investigated combination nanocarrier and microwave system for α-tocopherol and γ-tocotrienol delivery against dermatitis, without skin thinning effect of steroids. The vitamin E was formulated into water-rich/water-poor nanoemulsions, and had their droplet size, zeta potential, morphology, therapeutic content, encapsulation efficiency and release, in vitro skin therapeutics/nanoemulsion penetration, retention and permeation profiles, and in vivo pharmacodynamics characteristics examined, with skin pre-treated by precision microwave when applicable. The nanoemulsions had droplet sizes <150 nm and negative zeta potential values. The skin pre-treatment by microwave (1 mW/3985 MHz) promoted therapeutics accumulation in epidermis through enhancing nanoemulsion penetration into skin. The combination nano- and microwave technologies fluidized skin lipid and protein domains with epidermal microstructures being fluidized to a greater extent than dermis, allowing a relatively high epidermal-to-dermal nanoemulsion distribution. Microwave of lower or higher than 3985 MHz brought about lower skin therapeutics/nanoemulsion accumulation due to insufficient lipid/protein domain fluidization or microwave-skin interaction limiting at skin surfaces only. Using water-rich nanoemulsion with higher therapeutic release and skin pre-treatment with 3985 MHz microwave, dermatitis was alleviated in vivo without skin thinning of standard steroid. The use of combination microwave and nanotechnology promotes vitamin delivery and translates to positive dermatitis treatment outcome that warrants future investigation.

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