Kenjiro Takei

Cynaropicrin attenuates UVB-induced oxidative stress via the AhR-Nrf2-Nqo1 pathway

UNLABELLED Due to its antioxidant and anti-inflammatory activities, artichoke (Cynara scolymus) has been used as folk medicine to treat various diseases. Cynaropicrin (Cyn), a sesquiterpene lactone, is the major bioactive phytochemical in the artichoke; however, its pharmacological mechanism remains unknown. Because some phytochemicals exert their antioxidant activity by activating aryl hydrocarbon receptor (AhR), leading to subsequent induction of the antioxidant pathway including nuclear factor E2-related factor 2 (Nrf2) and NAD(P)H quinone oxidoreductase 1 (Nqo1), we investigated whether Cyn also activates the AhR-Nrf2-Nqo1 pathway. Cyn indeed induced the activation (nuclear translocation) of AhR, leading to nuclear translocation of Nrf2 and dose-dependent upregulation of Nrf2 and Nqo1 mRNAs in human keratinocytes. The Cyn-induced AhR-Nrf2-Nqo1 activation was AhR- and Nrf2-dependent, as demonstrated by the observation that it was absent in keratinocytes transfected by siRNA against either AhR or Nrf2. In accordance with these findings, Cyn actively inhibited generation of reactive oxygen species from keratinocytes irradiated with ultraviolet B (UVB) in a Nrf2-dependent manner. Cyn also inhibited the production of proinflammatory cytokines such as interleukin 6 and tumor necrosis factor-α from UVB-treated keratinocytes. Our findings demonstrate that Cyn is a potent activator of the AhR-Nrf2-Nqo1 pathway, and could therefore be applied to prevention of UVB-induced photo aging.

Antioxidant soybean tar Glyteer rescues T‐helper‐mediated downregulation of filaggrin expression via aryl hydrocarbon receptor

Soybean tar Glyteer (Gly) has been widely used for the treatment of various inflammatory skin diseases in Japan since 1924 as an alternative to coal tar remedy. Recently, coal tar has been shown to induce barrier repair in atopic dermatitis via aryl hydrocarbon receptor (AhR). In this study, we demonstrated that Gly activated AhR by inducing its cytoplasmic to nuclear translocation in keratinocytes. The AhR ligation by Gly was biologically active, with significant and dose‐dependent upregulation of CYP1A1 expression, which is a specific marker for AhR activation. Gly upregulated the expression of filaggrin in an AhR‐dependent manner because its enhancing effect was completely abrogated in AhR‐knockdown keratinocytes. T‐helper (Th)2 cytokines inhibited the expression of filaggrin; however, Gly completely restored the Th2‐mediated inhibition of filaggrin expression. Furthermore, Gly coordinately upregulated a series of epidermal differentiation complex genes, including involucrin, loricrin and hornerin. In addition, Gly exhibited potent antioxidant activity through the activation of nuclear factor‐erythroid 2‐related factor‐2 (Nrf2) and downstream antioxidant enzymes such as NAD(P)H:quinone oxidoreductase 1 (Nqo1), which actually inhibited the generation of reactive oxygen species in keratinocytes treated with tumor necrosis factor‐α or benzo[α]pyrene. In conclusion, antioxidant Gly rescues the downregulated expression of filaggrin (and plausibly other barrier proteins) in a Th2‐skewed milieu via AhR activation, which may partly explain its empirical anti‐inflammatory therapeutic effects.

Galactomyces fermentation filtrate prevents T helper 2-mediated reduction of filaggrin in an aryl hydrocarbon receptor-dependent manner

The aryl hydrocarbon receptor (AhR) recognizes diverse small molecules such as dioxins, tryptophan photoproducts and phytochemicals. It also plays crucial roles in epidermal homeostasis by upregulating epidermal barrier proteins. In preliminary screening, we found that Galactomyces fermentation filtrate (GFF), a cosmetic compound, was capable of activating AhR.

Cutaneous Sarcoidosis Clinically Mimicking Necrobiosis Lipoidica in a Patient with Systemic Sarcoidosis

A 70-year-old woman with an 8-year history of systemic sarcoidosis developed round, red-brown eruptions, with central atrophic lesions on her lower legs. The features of the biopsy specimen resembled those of necrobiosis lipoidica (NL), but although necrobiosis was present there were well-formed non-necrotizing granulomas in the dermis. The histological diagnosis was cutaneous sarcoidosis. Systemic sarcoidosis presenting with NL has rarely been reported. The histological features of cutaneous sarcoidosis sometimes mimic those of other granulomatous diseases, including NL and granuloma annulare, which are difficult to distinguish. We discuss the novel association between sarcoidosis and other granulomatous diseases.

Disseminated protothecosis manifesting with multiple, rapidly-progressing skin ulcers: Successful treatment with amphotericin B

Protothecosis is a rare infection caused by Prototheca species, which are achlorophyllous algae found ubiquitously in nature [1]. Herein, we report a case of disseminated P. wickerhamii infection in a patient with systemic lupus erythematosus (SLE). The disease presented as multiple, rapidly-progressing skin ulcers and was successfully treated with systemic antifungal agents.A 65-year-old Japanese woman was referred to our hospital with a two-week history of extensive ulcerative lesions on the right [...]

Cutaneous Pseudallescheria boydii/Scedosporium apiospermum complex infection in immunocompromised patients: A report of two cases

Dear Editor, We describe two cases of cutaneous Pseudallescheria boydii/ Scedosporium apiospermum complex infection. In case 1, a 62-year-old man with rheumatoid arthritis treated with prednisone (27.5 mg daily) and methotrexate (8 mg weekly) developed a swelling of the right forearm, which had been injured 1 month previously. He also complained of headaches and left leg listlessness on admission. Physical examination revealed a subcutaneous abscess on the right forearm (Fig. 1a). Laboratory examination showed an increased number of leukocytes (9030/mm) and elevated C-reactive protein (CRP; 3.01 mg/dL) and lactate dehydrogenase (283 U/L) levels. b-D-glucan levels were not measured. Cranial computed tomography revealed a solitary, rounded, hypodense lesion with ring contrast enhancement in the right thalamus (Fig. 1b). The patient died of intracranial hypertension 1 week after dermatological consultation. An autopsy was performed and the brain tissue was examined. Fungal cultures from the right forearm abscess and brain tissue yielded cottony, grayish white colonies with radial sulci (Fig. 1c). Microscopic examination revealed septate hyphae with ovoid conida borne terminally on branched conidiophores, indicative of P. boydii/S. apiospermum complex (Fig. 1d). A molecular identification was not performed. In case 2, a 60-year-old man suffering from chronic kidney failure presented with a swelling of the left lower leg that was not improved after initial antibiotic therapy (Fig. 1e). Physical examination revealed a subcutaneous abscess on

Simultaneous onset of sporotrichosis in mother and daughter

increased white blood cell count (14840/mm), and elevated CRP (3.91 mg/dL), blood urea nitrogen (43 mg/dL) and creatinine (2.68 mg/dL) levels. b-D-glucan levels were not measured. Because microscopic analysis during dermatological consultation revealed filamentous fungus in the abscess, voriconazole (400 mg daily) was administrated. However, his general condition worsened and increased creatinine kinase levels were detected, suggesting deep soft-tissue infection or necrotizing fasciitis. The patient died of multiple organ failure 1 week later. Histological examination of the leg lesion revealed fibrous granulation tissue with mixed cellular infiltration of neutrophils, lymphocytes, histiocytes and multinucleated foreign body-type giant cells (Fig. 1f). No fungal elements were stained by Grocott’s stain, probably due to prior voriconazole therapy. P. boydii/S. apiospermum complex was isolated from a leg biopsy specimen by fungal culture (Figs 1g,h). A molecular identification was not performed. Pseudallescheria boydii/S. apiospermum complex is a ubiquitous fungus found in soil and stagnant or wastewater. It is a rare but important cause of cutaneous and subcutaneous infections in immunocompromised patients. The standard treatment of this fungus is not well established. Voriconazole exerts antifungal effects against P. boydii/ S. apiospermum complex, although the protocol has not been optimized. Pseudallescheria boydii/S. apiospermum complex can cause severe cerebral infections, as noted in case 1. The prognoses of patients with central nervous system (CNS) infections are poor, and the success rate of voriconazole therapy against the CNS infections is only 43%. The high mortality rate associated with CNS infections may be due to delayed diagnosis. Therefore, P. boydii/S. apiospermum complex is an important opportunistic pathogen causing invasive mycosis with high mortality rates. Early diagnosis is essential for successful treatment.