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Cited by 48Dermatology and Skin DiseasesSkin Protection and AgingContact Dermatitis and Allergies

Antioxidant Artemisia princeps Extract Enhances the Expression of Filaggrin and Loricrin via the AHR/OVOL1 Pathway

Open access
Hirano, Akiko, Goto, Masashi, Mitsui, Tsukasa, Hashimoto-Hachiya, Akiko, Tsuji, Gaku, Furue, Masutaka·2017·International Journal of Molecular Sciences
DOI 10.3390/ijms18091948PMC PMC5618597
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Abstract

The Japanese mugwort, Artemisia princeps (yomogi in Japanese), has anti-inflammatory and antioxidant effects. Skin care products containing Artemisia princeps extract (APE) are known to improve dry skin symptoms in atopic dermatitis. Atopic dry skin is associated with a marked reduction of skin barrier proteins, such as filaggrin (FLG) and loricrin (LOR). Recently, aryl hydrocarbon receptor (AHR), and its downstream transcription factor OVO-like 1 (OVOL1), have been shown to regulate the gene expression of FLG and LOR. The focus of this paper is to evaluate the effects of APE on the AHR/OVOL1/FLG or LOR pathway since they have remained unknown to this point. We first demonstrated that non-cytotoxic concentrations of APE significantly upregulated antioxidant enzymes, NAD(P)H dehydrogenase quinone 1 and heme oxygenase 1, in human keratinocytes. Even at these low concentrations, APE induced nuclear translocation of AHR and significantly upregulated CYP1A1 (a specific target gene for AHR activation), FLG, and LOR expression. AHR knockdown downregulated OVOL1 expression. The APE-induced upregulation of FLG and LOR was canceled in keratinocytes with AHR or OVOL1 knockdown. In conclusion, antioxidant APE is a potent phytoextract that upregulates FLG and LOR expression in an AHR/OVOL1-dependent manner and this may underpin the barrier-repairing effects of APE in treating atopic dry skin.

AI snapshot

Written from the paper’s full text.

TL;DR

Antioxidant Artemisia princeps extract (APE) activates NRF2/NQO1·HO1 and AHR signaling in normal human epidermal keratinocytes. APE upregulates filaggrin (FLG) and loricrin (LOR) via an AHR/OVOL1-dependent pathway.

Key findings

  • Non-cytotoxic APE concentrations (≤0.03%) induced nuclear translocation of NRF2 and significantly upregulated antioxidant enzymes NQO1 and HO1 in NHEKs; APE >0.3% decreased cell viability.
  • APE induced AHR nuclear translocation and dose-dependent CYP1A1 upregulation; AHR siRNA transfection (91.9 ± 2.1% inhibition of AHR mRNA) canceled APE-induced CYP1A1 upregulation.
  • APE upregulated FLG and LOR gene expression in dose- and time-dependent manners; this upregulation was canceled by AHR knockdown or OVOL1 knockdown (OVOL1 siRNA inhibition efficiency 71.5 ± 2.4%).
  • APE-induced NQO1 expression was only minimally downregulated and HO1 expression was rather enhanced in AHR-knockdown NHEKs, suggesting an AHR-independent pathway mainly operates for APE-mediated NRF2/NQO1·HO1 signaling.

Methods

  • Normal human epidermal keratinocytes (NHEKs) were cultured and treated with APE (0.01% or 0.03% for gene expression; up to 1% for cytotoxicity). Cytotoxicity was assessed by WST-1 assay after 24 h.
  • Real-time PCR measured CYP1A1, FLG, LOR, OVOL1, NQO1, and HO1 with β-actin (ACTB) as housekeeping gene; immunofluorescence assessed AHR and NRF2 nuclear translocation.
  • siRNA transfection against AHR, OVOL1, or control was used, followed by 0.03% APE for 24 h; statistical analysis used unpaired Student’s t test with p < 0.05.

Limitations

  • The paper does not explicitly state limitations.
  • Evident from the text: all experiments were performed in cultured NHEKs in vitro, with no animal model or clinical validation.
  • Evident from the text: APE is a complex water extract with unidentified active constituents, and the AHR-independent NRF2/NQO1·HO1 pathway is inferred from knockdown results but not fully dissected.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.3390/ijms18091948

Cites

37 of 37 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

27 of 55 cited sources checked · 16 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    Upregulation of Flg is correlated with efficient barrier recovery of tape-stripped barrier-disrupted murine skin.

    “upregulation of Flg is correlated with efficient barrier recovery of tape-stripped barrier-disrupted murine skin [32,33]”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [32] Hou, 2012, Topical hesperidin improves epidermal permeability barrier function and epidermal differentiation in normal murine skin, Exp. Dermatol. source
    • cites [33] Hou, 2013, Topical apigenin improves epidermal permeability barrier homoeostasis in normal murine skin by divergent mechanisms, Exp. Dermatol. source
  • Study design and conductcitation

    β-actin (ACTB) was used as a control housekeeping gene because its gene expression is not affected by AHR ligation.

    “We used β-actin (ACTB) as a control housekeeping gene, because its gene expression is not affected by AHR ligation [18,35].”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [18] Tsuji, 2017, Aryl hydrocarbon receptor activation restores filaggrin expression via OVOL1 in atopic dermatitis, Cell Death Dis. source

      The Materials and Methods section (Quantitative reverse transcription-PCR analysis; page not provided) says mRNA levels were normalized to β-actin, supporting its use as a control gene. The paper does not state or demonstrate that ACTB gene expression is unaffected by AHR ligation; that reason for choosing it is not supported. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [35] Frauenstein, 2013, Evidence for a novel anti-apoptotic pathway in human keratinocytes involving the aryl hydrocarbon receptor, E2F1, and checkpoint kinase 1, Cell Death Differ. source

      The Quantitative real-time PCR subsection of Materials and Methods (page unavailable) says gene expression was normalized to β-actin, supporting its use as a control. Our copy does not state or demonstrate that β-actin expression is unaffected by AHR ligation; the reported lack of response to an AHR agonist concerns E2F1 promoter activity, not β-actin. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
  • Premisecitation

    Perturbed barrier function is critical for the development of atopic dermatitis and other allergic disorders, namely atopic march.

    “Perturbed barrier function is critical for the development of not only atopic dermatitis but also other allergic disorders, namely, atopic march [8,9,10,11].”
    Quote in the paperSubstantial claim2 of 4 sources checked
    • cites [8] Elias, 2014, Mechanisms of abnormal lamellar body secretion and the dysfunctional skin barrier in atopic dermatitis, J. Allergy Clin. Immunol. source
    • cites [9] Kubo, 2012, Epidermal barrier dysfunction and cutaneous sensitization in atopic diseases, J. Clin. Investig. source
    • cites [10] Palmer, 2006, Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis, Nat. Genet. source
    • cites [11] Park, 2015, Novel FLG null mutations in Korean patients with atopic dermatitis and comparison of the mutational spectra in Asian populations, J. Dermatol. source
  • Premisecitation

    FLG and LOR expression levels are reduced in lesional and non-lesional skin in atopic dermatitis.

    “Atopic dry skin is associated with a marked reduction of skin barrier proteins, such as filaggrin (FLG) and loricrin (LOR).”
    • Also stated in: § 1. Introduction · plain
      “FLG and LOR expression levels have been reported to be reduced in lesional and non-lesional skin in atopic dermatitis [12,13].”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [12] Jensen, 2004, Impaired sphingomyelinase activity and epidermal differentiation in atopic dermatitis, J. Investig. Dermatol. source

      The Results (Figure 3; page unavailable) report significantly reduced filaggrin staining in both non-lesional and lesional atopic skin. But the Results (Figure 4; page unavailable) report increased, not reduced, loricrin levels in both. Thus the claim is supported for FLG but contradicted for LOR. (LLM, conf=0.90)

      Experimental — accuracy not yet measured
    • cites [13] Bergboer, 2013, Coal tar induces AHR-dependent skin barrier repair in atopic dermatitis, J. Clin. Investig.

      Not checked in the free run.

  • Premisecitation

    AHR is an essential transcription factor for human epidermal barrier proteins including FLG and LOR.

    “In addition to CYP1A1 induction, AHR is an essential transcription factor for human epidermal barrier proteins including FLG and LOR [17,28,29].”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [17] Furue, 2015, Gene regulation of filaggrin and other skin barrier proteins via aryl hydrocarbon receptor, J. Dermatol. Sci. source
    • cites [28] Sutter, 2011, 2,3,7,8-Tetrachlorodibenzo-p-dioxin increases the expression of genes in the human epidermal differentiation complex and accelerates epidermal barrier formation, Toxicol. Sci. source

      The Results (page unavailable) show that AHR activation increases transcription of human FLG. But the Discussion (page unavailable) explicitly says AHR is not essential for epidermal barrier formation, and the passages found do not establish that it is essential for FLG or LOR expression. A search for LOR/loricrin found no supporting passage. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [29] Kennedy, 2013, 2,3,7,8-Tetrachlorodibenzo-p-dioxin-mediated production of reactive oxygen species is an essential step in the mechanism of action to accelerate human keratinocyte differentiation, Toxicol. Sci. source

      The introductory passage under Abstract reports that TCDD-activated AHR binds the FLG promoter and directly regulates FLG transcription. The Results section, “TCDD Increases the Expression of Genes Required for Cornified Envelope Formation,” reports increased FLG expression, but the paper identifies LOR (loricrin) as a barrier protein without establishing that AHR regulates it or is essential for expression of either protein under normal conditions. Page numbers are unavailable in our copy. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
  • Classified as probably not a substantial claim. 15
  • May combine two claims. 12

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Topical agent with AHR agonistic activity is beneficial for atopic dermatitis in clinical trial.

    “Recently, topical agent with AHR agonistic activity has been reported to be beneficial for atopic dermatitis in clinical trial [36,37].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [36] Bissonnette, 2012, Efficacy and safety of topical WBI-1001 in patients with mild to severe atopic dermatitis: Results from a 12-week, multicentre, randomized, placebo-controlled double-blind trial, Br. J. Dermatol. source
    • cites [37] Smith, S.H., Jayawickreme, C., Rickard, D.J., Nicodeme, E., Bui, T., Simmons, C., Coquery, C.M., Neil, J., Pryor, W.M., and Mayhew, D. (2017). Tapinarof Is a Natural AhR Agonist that Resolves Skin Inflammation in Mice and Humans. J. Investig. Dermatol. source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Artemisia princeps extract (APE) has anti-inflammatory and antioxidant effects.

    “The Japanese mugwort, Artemisia princeps (yomogi in Japanese), has anti-inflammatory and antioxidant effects.”
    • Also stated in: § 1. Introduction · boosted
      “Many studies have demonstrated the anti-atherosclerotic, anti-oxidant, and anti-inflammatory effects of Artemisia princeps extract [1,2,3].”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [1] Chung, 2015, Chemopreventive effects of standardized ethanol extract from the aerial parts of Artemisia princeps Pampanini cv. Sajabal via NF-κB inactivation on colitis-associated colon tumorigenesis in mice, Food Chem. Toxicol. source
    • cites [2] Yamamoto, 2011, Anti-obesity and anti-diabetic effects of ethanol extract of Artemisia princeps in C57BL/6 mice fed a high-fat diet, Food Func. source
    • cites [3] Choi, 2013, Antioxidant and anticancer activity of Artemisia princeps var. orientalis extract in HepG2 and Hep3B hepatocellular carcinoma cells, Chin. J. Cancer Res. source

      The Discussion reports significant antioxidant activity of Artemisia princeps var. orientalis methanol extract in hepatocarcinoma cell lines. It does not report an anti-inflammatory effect, so the source supports only the antioxidant part of the claim. (LLM, conf=0.90)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The NRF2/NQO1 and HO1 axis is essentially involved in antioxidant activity in keratinocytes.

    “The NRF2/NQO1 and HO1 axis is essentially involved in antioxidant activity in keratinocytes [19].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [19] Furue, M., Uchi, H., Mitoma, C., Hashimoto-Hachiya, A., Chiba, T., Ito, T., Nakahara, T., and Tsuji, G. (2017). Antioxidants for healthy skin: The emerging role of aryl hydrocarbon receptors and nuclear factor-erythroid 2-related factor-2. Nutrients, 9. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Some ligands for AHR, such as coal tar and soybean tar, actively upregulate FLG and LOR expression.

    “Some ligands for AHR, such as coal tar and soybean tar, actively upregulate FLG and LOR expression [13,14].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [13] Bergboer, 2013, Coal tar induces AHR-dependent skin barrier repair in atopic dermatitis, J. Clin. Investig.

      Not checked in the free run.

    • cites [14] Takei, 2015, Antioxidant soybean tar Glyteer rescues T-helper-mediated downregulation of filaggrin expression via aryl hydrocarbon receptor, J. Dermatol. source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The ligand/AHR complex binds to specific DNA recognition sites and upregulates transcription of responsive genes, such as CYP1A1, leading to robust generation of reactive oxygen species.

    “The ligand/AHR complex then binds to specific DNA recognition sites, namely, xenobiotic-responsive elements or dioxin-responsive elements, and upregulates the transcription of a series of responsive genes, such as CYP1A1 leading to a robust generation of reactive oxygen species [16,24].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [16] Furue, 2014, Role of AhR/ARNT system in skin homeostasis, Arch. Dermatol. Res. source

      The AhR/ARNT signaling section says the ligand–AhR–ARNT complex binds xenobiotic- or dioxin-responsive elements and induces CYP1A1; its Fig. 1 caption says CYP1A1 metabolism of ligands such as dioxins produces many reactive oxygen species. But the oxidative-stress section says ROS production is ligand-dependent and that some AhR ligands activate the pathway without producing ROS. The claim overgeneralizes that outcome. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [24] Ikuta, 2009, AhR protein trafficking and function in the skin, Biochem. Pharmacol. source

  • May combine two claims.

    Premisecitation

    Ligation of AHR activates OVOL1, which induces FLG and LOR expression.

    “A recent study has also clarified that the ligation of AHR activates the downstream transcription factor OVO-like 1 (OVOL1), which then induces FLG and LOR expression [18].”
    • Also stated in: § 3. Discussion · boosted
      “Our recent study demonstrated that OVOL1 is engaged in the AHR-mediated upregulation of FLG and LOR [18].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [18] Tsuji, 2017, Aryl hydrocarbon receptor activation restores filaggrin expression via OVOL1 in atopic dermatitis, Cell Death Dis. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Various external and internal ligands, such as dioxins, polycyclic aromatic pollutants, benzo[a]pyrene, and phytochemicals, can bind to and activate AHR.

    “Various external and internal ligands, such as dioxins, polycyclic aromatic pollutants, benzo[a]pyrene, and phytochemicals, can bind to and activate AHR [15,16].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [15] Esser, 2013, Functions of the aryl hydrocarbon receptor in the skin, Semin. Immunopathol. source
    • cites [16] Furue, 2014, Role of AhR/ARNT system in skin homeostasis, Arch. Dermatol. Res. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Other antioxidant phytochemicals such as cinnamaldehyde activate NRF2 without activating AHR.

    “Other antioxidant phytochemicals such as cinnamaldehyde activate NRF2 without activating AHR [19,22].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [19] Furue, M., Uchi, H., Mitoma, C., Hashimoto-Hachiya, A., Chiba, T., Ito, T., Nakahara, T., and Tsuji, G. (2017). Antioxidants for healthy skin: The emerging role of aryl hydrocarbon receptors and nuclear factor-erythroid 2-related factor-2. Nutrients, 9. source
    • cites [22] Uchi, 2017, Inhibition of aryl hydrocarbon receptor signaling and induction of NRF2-mediated antioxidant activity by cinnamaldehyde in human keratinocytes, J. Dermatol. Sci. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Some antioxidant phytochemicals such as soybean tar and Opuntia ficus-indica extract activate NRF2 via the AHR pathway.

    “Some antioxidant phytochemicals such as soybean tar and Opuntia ficus-indica extract activate NRF2 via AHR pathway [14,19,21].”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [14] Takei, 2015, Antioxidant soybean tar Glyteer rescues T-helper-mediated downregulation of filaggrin expression via aryl hydrocarbon receptor, J. Dermatol. source
    • cites [19] Furue, M., Uchi, H., Mitoma, C., Hashimoto-Hachiya, A., Chiba, T., Ito, T., Nakahara, T., and Tsuji, G. (2017). Antioxidants for healthy skin: The emerging role of aryl hydrocarbon receptors and nuclear factor-erythroid 2-related factor-2. Nutrients, 9. source
    • cites [21] Nakahara, 2015, Antioxidant Opuntia ficus-indica extract activates AHR-NRF2 signaling and upregulates filaggrin and loricrin expression in human keratinocytes, J. Med. Food source

  • May combine two claims.

    Premisecitation

    Both coal tar and soybean tar actively enhance the expression of FLG and LOR via AHR.

    “As both remedies actively enhance the expression of FLG and LOR via aryl hydrocarbon receptor (AHR) [13,14], the AHR-mediated upregulation of barrier proteins has attracted increasing attention in skin barrier and inflammation research [15,16,17].”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [13] Bergboer, 2013, Coal tar induces AHR-dependent skin barrier repair in atopic dermatitis, J. Clin. Investig.

      Not checked in the free run.

    • cites [14] Takei, 2015, Antioxidant soybean tar Glyteer rescues T-helper-mediated downregulation of filaggrin expression via aryl hydrocarbon receptor, J. Dermatol. source

      The Introduction reports that coal tar activates AhR and upregulates filaggrin and loricrin. The Results show that soybean tar Glyteer activates AhR, upregulates both genes, and requires AhR for its effect on filaggrin; they do not establish that its loricrin upregulation requires AhR. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    AHR-targeting antioxidant phytochemicals or antioxidant medicinal chemicals do not generate appreciable amounts of reactive oxygen species, probably due to efficient induction of antioxidant enzymes mediated by NRF2 activation.

    “Notably, the AHR-targeting antioxidant phytochemicals or antioxidant medicinal chemicals do not generate appreciable amounts of reactive oxygen species probably due to efficient induction of antioxidant enzymes mediated by NRF2 activation [19,20,21,27].”
    Quote in the paperNot a substantial claim1 of 4 sources checked
    • cites [19] Furue, M., Uchi, H., Mitoma, C., Hashimoto-Hachiya, A., Chiba, T., Ito, T., Nakahara, T., and Tsuji, G. (2017). Antioxidants for healthy skin: The emerging role of aryl hydrocarbon receptors and nuclear factor-erythroid 2-related factor-2. Nutrients, 9. source

      Section 2 (page not available) says that ketoconazole activates AHR without producing ROS and that antioxidant phytochemicals can activate AHR–NRF2 signaling without appreciable ROS production. The Introduction and Conclusions say NRF2 induces antioxidant enzymes, but the paper does not establish that this induction explains the lack of ROS production; it says the mechanisms remain largely unknown. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [20] Tsuji, 2012, Identification of ketoconazole as an AhR-Nrf2 activator in cultured human keratinocytes: The basis of its anti-inflammatory effect, J. Investig. Dermatol. source
    • cites [21] Nakahara, 2015, Antioxidant Opuntia ficus-indica extract activates AHR-NRF2 signaling and upregulates filaggrin and loricrin expression in human keratinocytes, J. Med. Food source
    • cites [27] Takei, 2015, Galactomyces fermentation filtrate prevents T helper 2-mediated reduction of filaggrin in an aryl hydrocarbon receptor-dependent manner, Clin. Exp. Dermatol. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Antioxidant phytochemicals activate and induce cytoplasmic-to-nuclear translocation of NRF2, a master transcription factor for gene expression of antioxidant enzymes such as NQO1 and HO1 in keratinocytes.

    “In general, antioxidant phytochemicals activate and induce the cytoplasmic-to-nuclear translocation of nuclear factor-erythroid 2-related factor-2 (NRF2), which is a master transcription factor for gene expression of antioxidant enzymes such as NAD(P)H dehydrogenase quinone 1 (NQO1) and heme oxygenase 1 (HO1) in keratinocytes [19,20].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [19] Furue, M., Uchi, H., Mitoma, C., Hashimoto-Hachiya, A., Chiba, T., Ito, T., Nakahara, T., and Tsuji, G. (2017). Antioxidants for healthy skin: The emerging role of aryl hydrocarbon receptors and nuclear factor-erythroid 2-related factor-2. Nutrients, 9. source
    • cites [20] Tsuji, 2012, Identification of ketoconazole as an AhR-Nrf2 activator in cultured human keratinocytes: The basis of its anti-inflammatory effect, J. Investig. Dermatol. source

  • May combine two claims.

    Premisecitation

    Skin inflammation decreases FLG and LOR expression and disrupts epidermal barrier function; barrier dysfunction augments skin inflammation.

    “Skin inflammation decreases FLG and LOR expression and disrupts epidermal barrier function; moreover, in the opposite direction, barrier dysfunction augments skin inflammation [12,13,26].”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [12] Jensen, 2004, Impaired sphingomyelinase activity and epidermal differentiation in atopic dermatitis, J. Investig. Dermatol. source

      The Discussion reports reduced filaggrin in atopic skin, and the passage labeled Abstract describes barrier disruption promoting eczematous dermatitis. But the Results and Discussion report increased—not decreased—loricrin in both lesional and non-lesional atopic skin. The paper also does not establish that inflammation caused the observed expression changes. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [13] Bergboer, 2013, Coal tar induces AHR-dependent skin barrier repair in atopic dermatitis, J. Clin. Investig.

      Not checked in the free run.

    • cites [26] Egawa, 2016, Multifactorial skin barrier deficiency and atopic dermatitis: Essential topics to prevent the atopic march, J. Allergy Clin. Immunol. source

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    AHR is a xenobiotic chemical sensor expressed abundantly in epidermal keratinocytes.

    “AHR is a xenobiotic chemical sensor that is expressed abundantly in epidermal keratinocytes [15,16].”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [15] Esser, 2013, Functions of the aryl hydrocarbon receptor in the skin, Semin. Immunopathol. source
    • cites [16] Furue, 2014, Role of AhR/ARNT system in skin homeostasis, Arch. Dermatol. Res. source

      The Introduction describes AhR as a receptor for exogenous chemicals and says keratinocytes possess it; the AhR/ARNT signaling section links it to responses to xenobiotics. Neither passage establishes that AhR is expressed abundantly in epidermal keratinocytes. Page numbers are unavailable in our copy. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Various herbal and antioxidant phytochemicals activate AHR.

    “Various herbal and antioxidant phytochemicals have been shown to activate AHR [16,17,19].”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [16] Furue, 2014, Role of AhR/ARNT system in skin homeostasis, Arch. Dermatol. Res. source
    • cites [17] Furue, 2015, Gene regulation of filaggrin and other skin barrier proteins via aryl hydrocarbon receptor, J. Dermatol. Sci. source
    • cites [19] Furue, M., Uchi, H., Mitoma, C., Hashimoto-Hachiya, A., Chiba, T., Ito, T., Nakahara, T., and Tsuji, G. (2017). Antioxidants for healthy skin: The emerging role of aryl hydrocarbon receptors and nuclear factor-erythroid 2-related factor-2. Nutrients, 9. source

  • May combine two claims.

    Study design and conductown data

    The siRNA transfection did not affect cell viability and the inhibitory efficiency of AHR siRNA transfection for AHR mRNA expression was 91.9 ± 2.1%.

    “The siRNA transfection did not affect cell viability and the inhibitory efficiency of AHR siRNA transfection for AHR mRNA expression was 91.9 ± 2.1%.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Skin barrier maturation is accomplished by sequential and coordinated expression of various skin barrier proteins, such as FLG and LOR.

    “Skin barrier maturation is accomplished by sequential and coordinated expression of various skin barrier proteins, such as filaggrin (FLG) and loricrin (LOR) [7].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [7] Proksch, 2008, The skin: An indispensable barrier, Exp. Dermatol. source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Flg-deficient mice exhibit reduced epidermal barrier function with enhanced susceptibility to environmental sensitization.

    “Flg-deficient mice exhibit reduced epidermal barrier function with enhanced susceptibility to environmental sensitization [31]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [31] Kawasaki, 2012, Altered stratum corneum barrier and enhanced percutaneous immune responses in filaggrin-null mice, J. Allergy Clin. Immunol. source

  • May combine two claims.

    Premisecitation

    LOR expression is markedly decreased in the lesional skin of atopic dermatitis and is normalized after topical treatment.

    “In parallel, the expression of LOR is markedly decreased in the lesional skin of atopic dermatitis and is normalized after topical treatment [13,34].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [13] Bergboer, 2013, Coal tar induces AHR-dependent skin barrier repair in atopic dermatitis, J. Clin. Investig.

      Not checked in the free run.

    • cites [34] Chiricozzi, 2009, Broad defects in epidermal cornification in atopic dermatitis identified through genomic analysis, J. Allergy Clin. Immunol. source

  • May combine two claims.

    Premisecitation

    APE-containing cosmetic products improve desquamation, dryness, itching, and erythema in patients with atopic dermatitis.

    “Skin care products containing Artemisia princeps extract (APE) are known to improve dry skin symptoms in atopic dermatitis.”
    • Also stated in: § 1. Introduction · plain
      “Moreover, APE-containing cosmetic products, such as body cream, skin lotion, and shampoo, improve desquamation, dryness, itching, and erythema in patients with atopic dermatitis [6].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [6] Sasaki, 1995, Clinical evaluation of skin-care-products on atopic dermatitis, J. Pediatr. Dermatol.

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Loss-of-function mutation of the FLG gene is associated with the development of atopic dermatitis.

    “loss-of-function mutation of the FLG gene is associated with the development of atopic dermatitis [10,11]”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [10] Palmer, 2006, Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis, Nat. Genet. source
    • cites [11] Park, 2015, Novel FLG null mutations in Korean patients with atopic dermatitis and comparison of the mutational spectra in Asian populations, J. Dermatol. source

  • May combine two claims.

    Study design and conductown data

    NHEKs were constantly viable with APE ≤0.03%, and these concentrations were used throughout the experiments.

    “As NHEKs were constantly viable with APE ≤ 0.03%, these concentrations were used throughout the experiments.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Barrier function is significantly disturbed in Ahr-null mice, indicating AHR plays a pivotal role in skin barrier integrity.

    “In addition, barrier function is significantly disturbed in Ahr-null mice, indicating that AHR plays a pivotal role in skin barrier integrity [30].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [30] Haas, 2016, Aryl hydrocarbon receptor in keratinocytes is essential for murine skin barrier integrity, J. Investig. Dermatol. source
23 of 23

  • The paper relies on this without support.

    Upregulation of FLG and LOR gene expression by APE in cultured NHEKs is sufficient to produce barrier-repairing effects in atopic dry skin.

    “In conclusion, antioxidant APE is a potent phytoextract that upregulates FLG and LOR expression in an AHR/OVOL1-dependent manner and this may underpin the barrier-repairing effects of APE in treating atopic dry skin.”

  • The paper relies on this without support.

    The AHR/OVOL1 pathway operates similarly in cultured NHEKs and in atopic dry skin in vivo.

    “Targeting AHR/OVOL1/FLG or LOR signaling may be a promising strategy to overcome atopic dry skin.”
2 of 2

Cites

Flagged first, then by citations

1 of the 38 references couldn’t be matched to a known paper.

Research works printed but not linked: 1

  1. Sasaki, 1995, Clinical evaluation of skin-care-products on atopic dermatitis, J. Pediatr. Dermatol., 14, 89

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Related

Authors
Hirano, A., Goto, M., Mitsui, T., Hashimoto-Hachiya, A., Tsuji, G., & Furue, M.
Affiliations
  • Sunstar (Japan) (JP)
  • Department of Dermatology, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka 812-8582, Japan
  • Kyushu University (JP)
Corresponding author
Hirano, Akiko
ORCID
Venue
International Journal of Molecular Sciences
Publisher
MDPI AG
Published
2017-09-11
Volume
18
Issue
9
Pages
1948
ISSN
1422-0067 (ISSN-L)
DOI
10.3390/ijms18091948
PMC
PMC5618597
OpenAlex
W2756224750
Cited by
48
References
38
Citations by year
2026: 4 · 2025: 1 · 2024: 6 · 2023: 6 · 2022: 8 · 2021: 6 · 2020: 6 · 2019: 7 · 2018: 4
FWCI
5.29
Type
journal article
Language
en
Open access
Licence
Locations
  • International Journal of Molecular Sciences (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics
  • Health Sciences › Medicine › Dermatology › Dermatology and Skin Diseases
  • Health Sciences › Medicine › Dermatology › Skin Protection and Aging
  • Health Sciences › Medicine › Dermatology › Contact Dermatitis and Allergies
Keywords
Artemisia princeps, aryl hydrocarbon receptor, OVOL1, filaggrin, loricrin, skin barrier proteins, keratinocytes, heme oxygenase-1, NQO1, CYP1A1, gene expression regulation
MeSH terms
Filaggrin Proteins, Antioxidants, Cell Line, DNA-Binding Proteins, Humans, Intermediate Filament Proteins, Membrane Proteins, NADPH Dehydrogenase, Plant Extracts, Transcription Factors, Keratinocytes, Receptors, Aryl Hydrocarbon, Artemisia, Cytochrome P-450 CYP1A1, Basic Helix-Loop-Helix Proteins, Basic Helix-Loop-Helix Transcription Factors

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-31.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-31.

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