PMID: 

Proc Natl Acad Sci U S A. 2003 Jun 10 ;100(12):7360-5. Epub 2003 May 27. PMID: 12771381

Abstract Title: 

Glycerol replacement corrects defective skin hydration, elasticity, and barrier function in aquaporin-3-deficient mice.

Abstract: 

Mice deficient in the epidermal water/glycerol transporter aquaporin-3 (AQP3) have reduced stratum corneum (SC) hydration and skin elasticity, and impaired barrier recovery after SC removal. SC glycerol content is reduced 3-fold in AQP3 null mice, whereas SC structure, protein/lipid composition, and ion/osmolyte content are not changed. We show here that glycerol replacement corrects each of the defects in AQP3 null mice. SC water content, measured by skin conductance and 3H2O accumulation, was 3-fold lower in AQP3 null vs. wild-type mice, but became similar after topical or systemic administration of glycerol in quantities that normalized SC glycerol content. SC water content was not corrected by glycerol-like osmolytes such as xylitol, erythritol, and propanediol. Orally administered glycerol fully corrected the reduced skin elasticity in AQP3 null mice as measured by the kinetics of skin displacement after suction, and the delayed barrier recovery as measured by transepidermal water loss after tape-stripping. Analysis of [14C]glycerol kinetics indicated reduced blood-to-SC transport of glycerol in AQP3 null mice, resulting in slowed lipid biosynthesis. These data provide functional evidence for a physiological role of glycerol transport by an aquaglyceroporin, and indicate that glycerol is a major determinant of SC water retention, and mechanical and biosynthetic functions. Our findings establish a scientific basis for the>200-yr-old empirical practice of including glycerol in cosmetic and medicinal skin formulations.

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PMID: 

Eur J Immunol. 2014 Mar ;44(3):728-41. Epub 2013 Dec 27. PMID: 24272050

Abstract Title: 

Riboflavin (vitamin B2 ) deficiency impairs NADPH oxidase 2 (Nox2) priming and defense against Listeria monocytogenes.

Abstract: 

Riboflavin, also known as vitamin B2 , is converted by riboflavin kinase (RFK) into flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), which are essential cofactors of dehydrogenases, reductases, and oxidases including the phagocytic NADPH oxidase 2 (Nox2). Riboflavin deficiency is common in young adults and elderly individuals, who are at the coincidental risk for listeriosis. To address the impact of acute riboflavin deficiency on host defense against Listeria monocytogenes (L.m.), we generated conditional RFK knockout (KO) strains of mice. Phagocyte-specific RFK KO impaired the capability of phagocytes to control intracellular L.m., which corresponded to a greater susceptibility of mice to in vivo challenge with L.m. The oxidative burst of RFK-deficient phagocytes in response to L.m. infection was significantly reduced. Mechanistically, TNF-induced priming of Nox2, which is needed for oxidative burst, was defective in RFK-deficient phagocytes. Lack of riboflavin in wild-type macrophages for only 6 h shut down TNF-induced, RFK-mediated de novo FMN/FAD generation, which was accompanied by diminished ROS production and impaired anti-listerial activity. Vice versa, ROS production by riboflavin-deprived macrophages was rapidly restored by riboflavin supplementation. Our results suggest that acute riboflavin deficiency immediately impairs priming of Nox2, which is of crucial relevance for an effective phagocytic immune response in vivo.

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PMID: 

J Invest Dermatol. 2003 May ;120(5):835-41. PMID: 12713590

Abstract Title: 

Topical N-acetyl cysteine and genistein prevent ultraviolet-light-induced signaling that leads to photoaging in human skin in vivo.

Abstract: 

Human skin is exposed to solar ultraviolet radiation. Ultraviolet radiation damages human skin and results in an old and wrinkled appearance, called photoaging. We have previously reported that molecular mechanisms by which ultraviolet light causes photoaging involve activation of growth factor and cytokine receptors in keratinocytes and dermal cells. They lead to downstream signal transduction through activation of mitogen-activated protein kinase (extracellular signal-regulated kinase, c-jun N-terminal protein kinase, and p38) pathways. These signaling pathways converge in the nucleus of cells to form an activated complex of transcription factor activator protein 1 (cFos/cJun), which induces matrix metalloproteinases that degrade skin connective tissue. In addition to cell surface receptor activation, generation of reactive oxygen species by ultraviolet radiation is believed to be critical in triggering mitogen-activated protein kinase pathways. We investigated the ability of (i) ultraviolet irradiation to generate reactive oxygen species in human skin in vivo; and (ii) genistein, which possesses both tyrosine kinase inhibitory and antioxidant activities, and n-acetyl cysteine, which can be converted into the endogenous antioxidant glutathione, to impair responses to ultraviolet light that eventuate in photoaging in human skin in vivo. Ultraviolet irradiation caused a rapid and significant increase in hydrogen peroxide levels in human skin in vivo. Pretreatment of human skin with genistein inhibited ultraviolet-induced epidermal growth factor receptor tyrosine kinase activity, whereas n-acetyl cysteine did not. Genistein inhibited ultraviolet induction of both extracellular signal-regulated kinase and cJun N-terminal protein kinase activities. n-Acetyl cysteine inhibited extracellular signal-regulated kinase but not cJun N-terminal protein kinase activation. Both genistein and n-acetyl cysteine prevented ultraviolet induction of cJun protein. Consistent with this, genistein and n-acetyl cysteine blocked ultraviolet induction of cJun-driven enzyme, collagenase. Neither genistein nor n-acetyl cysteine acted as sunscreens as they had no effect on ultraviolet-induced erythema. These data indicate that compounds similar to genistein and n-acetyl cysteine, which possess tyrosine kinase inhibitory and/or antioxidant activities, may prevent photoaging.

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PMID: 

Br J Nutr. 2014 Oct 14 ;112(7):1065-72. Epub 2014 Aug 8. PMID: 25105221

Abstract Title: 

Vitamins B2 and B6 as determinants of kynurenines and related markers of interferon-γ-mediated immune activation in the community-based Hordaland Health Study.

Abstract: 

Vitamins B2 and B6 are cofactors in the kynurenine pathway. Many of the kynurenines are neuroactive compounds with immunomodulatory effects. In the present study, we aimed to investigate plasma concentrations of vitamins B2 and B6 as determinants of kynurenines and two markers of interferon-γ-mediated immune activation (kynurenine:tryptophan ratio (KTR) and neopterin). We measured the concentrations of vitamins B2 and B6 vitamers, neopterin, tryptophan and six kynurenines (i.e. kynurenine, anthranilic acid, kynurenic acid, 3-hydroxykynurenine, 3-hydroxyanthranilic acid and xanthurenicacid) in plasma from 7051 individuals. Dietary intake of vitamins B2 and B6 was assessed using a validated FFQ. Associations were investigated using partial Spearman's correlations, generalised additive models, and segmented or multiple linear regression. The B2 vitamer, riboflavin, was positivelyassociated with 3-hydroxyanthranilic acid and xanthurenic acid, with correlation coefficients, as obtained by segmented regression, of 0·20 (95 % CI 0·16, 0·23) and 0·24 (95 % CI 0·19, 0·28), at riboflavin concentrations below the median value (13·0 nmol/l). The vitamin B6 vitamer, pyridoxal 5'-phosphate (PLP), was positively associated with most kynurenines at PLP concentrations

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PMID: 

Int J Mol Sci. 2014 May 2 ;15(5):7563-78. Epub 2014 May 2. PMID: 24798751

Abstract Title: 

Topical N-acetylcysteine accelerates wound healing in vitro and in vivo via the PKC/Stat3 pathway.

Abstract: 

N-Acetylcysteine (Nac) is an antioxidant administered in both oral and injectable forms. In this study, we used Nac topically to treat burn wounds in vitro and in vivo to investigate mechanisms of action. In vitro, we monitored glutathione levels, cell proliferation, migration, scratch-wound healing activities and the epithelialization-related proteins, matrixmetalloproteinase-1 (MMP-1) and proteins involved in regulating the expression of MMP-1 in CCD-966SK cells treated with Nac. Various Nac concentrations (0.1, 0.5, and 1.0 mM) increased glutathione levels, cell viability, scratch-wound healing activities and migration abilities of CCD-966SK cells in a dose-dependent manner. The MMP-1 expression of CCD-966SK cells treated with 1.0 mM Nac for 24 h was significantly increased. Levels of phosphatidylinositol 3-kinase (PI3K), protein kinase C (PKC), janus kinase 1 (Jak1), signal transducer and activator of transcription 3 (Stat3), c-Fos and Jun, but not extracellular signal-regulated protein kinases 1 and 2 (Erk1/2), were also significantly increased in a dose-dependent manner compared to the controls. In addition, Nac induced collagenous expression of MMP-1 via the PKC/Stat3 signaling pathway. In vivo, a burn wound healing rat model was applied to assess the stimulation activity and histopathological effects of Nac, with 3.0% Nac-treated wounds being found to show better characteristics on re-epithelialization. Our results demonstrated that Nac can potentially promote wound healing activity, and may be a promising drug to accelerate burn wound healing.

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PMID: 

Int Surg. 2015 Apr ;100(4):656-61. Epub 2015 Jan 13. PMID: 25583306

Abstract Title: 

Topical N-acetylcysteine improves wound healing comparable to dexpanthenol: an experimental study.

Abstract: 

In this study, we aimed to compare the effects of dexpanthenol and N-acetylcysteine on wound healing. The wound healing process is a multifaceted sequence of activities associated with tissue restoration process. A number of investigations and clinical studies have been performed to determine new approaches for the improvement of wound healing. A total of 30 rats were divided into 3 equal groups. A linear 2-cm incision was made in the rats' skin. No treatment was administered in the first (control) group. Dexpanthenol cream was administered to the rats in the second group and 3% N-acetylcysteine cream was administered to the rats in the third group. The wound areas of all of the rats were measured on certain days. On the 21st day, all wounds were excised and histologically evaluated. The epithelialization and granulation rates between the groups were revealed to be similar in microscopic evaluations. Although the fibrosis was remarkable in the control group as compared with the other groups, it was similar in N-acetylcysteine and dexpanthenol groups. Angiogenesis rate was remarkable in the N-acetylcysteine group compared with the others. In multiple-comparison analysis, Dexpanthenol and N-acetylcysteine groups had similar results in terms of wound healing rates (P0.05). The efficacy of N-acetylcysteine in wound healing is comparable to dexpanthenol, and both substances can be used to improve wound healing.

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PMID: 

Nutr Cancer. 2020 Apr 14:1-13. Epub 2020 Apr 14. PMID: 32286088

Abstract Title: 

Antiproliferative Effects of Thymoquinone in MCF-7 Breast and HepG2 Liver Cancer Cells: Possible Role of Ceramide and ER Stress.

Abstract: 

We aimed to investigate the impact of thymoquinone (TQ), on sphingolipid metabolites, ER stress and apoptotic pathways in MCF-7 and HepG2 cancer cells. Antiproliferative effect was exerted in cancer cells via TQ incubation at different doses and durations. Cell viability was measured by MTT assay. Levels of sphingosine-1-phosphate (S1P), C16-C24 sphingomyelins (SM) and C16-C24 ceramides (CER) were determined by LC-MS/MS. Neutral sphingomyelinase (N-SMase) enzyme activity was measured by colorimetric assay and ceramide-1-phosphate (C1P) levels were determined by immunoassay. Nuclear factor kappa-b subunit 1 (NFκB1) and glucose-regulated protein 78-kd (GRP78) gene expressions were evaluated by quantitative PCR analysis, while NF-κB p65, GRP 78 and cleaved caspase-3 protein levels were assesed by immunofluorescence and western blot analysis. Incubation with TQ significantly decreased cell viability, S1P,C1P, NF-κB1 mRNA and NF-κB p65 protein levels in cancer cells compared to controls. A significant increase was observed in N-SMase activity, cellular levels of C16-C24 CERs and cleaved caspase-3 levels in cancer cells treated with TQ. GRP78 mRNA and protein levels also increased in cancer cells treated with TQ. In conclusion, TQ-induced ceramide accumulation and ER stress in conjunction with decreased S1P, C1P and NF-κB mediated cell survival may promote cancer cell death by triggering apoptosis.

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PMID: 

J Clin Aesthet Dermatol. 2019 May ;12(5):20-26. Epub 2019 May 1. PMID: 31320973

Abstract Title: 

The Potential Uses of N-acetylcysteine in Dermatology: A Review.

Abstract: 

In recent studies, N-acetylcysteine has been shown to be efficacious in several dermatologic conditions.The aim was to review clinical trials that assess the efficacy of N-acetylcysteine in cutaneous disorders.The PubMed database was searched and a manual search of clinical trials in the references was performed. Studies included randomized, controlled studies, uncontrolled studies, meta-analyses, and systemic reviews published between years 1966 and 2017.Efficacy of N-acetylcysteine was shown in excoriation disorder, onychophagia disorder, trichotillomania, acne vulgaris, Type I lamellar ichthyosis, bullous morphea, systemic sclerosis, toxic epidermal necrolysis, atopic dermatitis, xeroderma pigmentosum, and pseudoporphyria. Studies also show benefits in wound healing and photoprotection.The review of available literature suggests that N-acetylcysteine could potentially serve as a safe, tolerable, and effective therapeutic option for a variety of dermatologic conditions.

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PMID: 

J Cosmet Sci. 2013 May-Jun;64(3):219-26. PMID: 23752036

Abstract Title: 

A novel topical ingredient derived from seaweed significantly reduces symptoms of acne vulgaris: a general literature review.

Abstract: 

Currently, benzoyl peroxide, antibiotics, and retinoids are the mainstay topical treatments for acne vulgaris. However, potential benefits may be offered by natural, marine-derived ingredients, such as those derived from brown seaweed (Laminaria digitata). This article will review the available literature on two ingredients;"seaweed oligosaccharides,"which are those derived from the polysaccharide membrane of Laminaria digitata, and a novel seaweed oligosaccharide-zinc complex (SOZC) (Phycosaccharide AC, The Mentholatum Company, East Kilbride, UK). Findings from a recent double-blind, placebo-controlled, randomized clinical trial (RCT) will also be reported and likely mechanisms discussed. The findings taken together suggest that SOZC can significantly ameliorate symptoms of acne vulgaris, particularly in terms of reducing sebum production and populations of Propionibacterium acnes.

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PMID: 

Avicenna J Phytomed. 2020 Mar-Apr;10(2):181-189. PMID: 32257890

Abstract Title: 

Effect ofoil extracts on inflammatory and oxidative stress markers in Behcet's disease: A randomized, double-blind, placebo-controlled clinical trial.

Abstract: 

Objective: Behcet's disease (BD) is a chronic inflammatory disorder characterized by recurrent oral and genital aphthous ulcers, uveitis and skin lesions. Oxidative stress and inflammation have important role in the pathogenesis of BD. The aim of this study was to assess the effect of(NS) oil administration on malondialdehyde (MDA), total anti-oxidant capacity (TAC), tumor necrosis factor-α (TNF-α), IL-10 and high sensitivity C-reactive protein (hs- CRP) levels in patients with BD.Materials and Methods: In this randomized, double-blind and placebo-controlled clinical trial, 96 BD patients were randomly assigned to NS or placebo groups. Study groups received 1000 mg/day NS oil and placebo soft gels for 8 weeks. Serum levels of TNF-α, IL-10, hs-CRP, MDA and TAC were measured before and after treatment.Results: Eighty-nine individuals completed the study. Significant decreases in the serum levels of MDA and increases in the serum levels of TAC were found in the NS group. However, differences in the changes of MDA and TAC in the NS and placebo groups were not significant. Pre- and post-intervention changes of TNF-α, IL-10 and hs-CRP levels in the NS group were non-significant.Conclusion: NS 1000 mg per day is probably not effective in reducing the inflammatory and oxidative markers in BD.

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