Gabriella Béke

Lycopene-derived bioactive retinoic acid receptors/retinoid-X receptors-activating metabolites may be relevant for lycopene's anti-cancer potential

Dietary consumption of tomato products and especially the red tomato pigment lycopene has been associated with lower risk of cancer. New evidence is emerging toward metabolic pathways mediating the anti-cancer activities of lycopene. In this review, we explore associations between tomatoes and lycopene intake and cancer and relate this to the metabolic activation pathways of lycopene via carotene oxygenases and further carotenoid/retinoid-metabolizing enzymes to apo-lycopenoids. Several of these apo-lycopenoids have already been identified but up to date no direct connection between lycopene metabolism and apo-lycopenoids mediated receptor activation pathways has been established. Retinoic acid receptors/retinoid-X receptors activation pathways in particular, may be mediated via lycopene metabolites that are related to retinoic acids. Various studies have shown an association between lower concentration of insulin-like growth factor-1 upon lycopene treatment, cancer incidences, and retinoid-mediated signaling. In this review, we interrelate tomato/lycopene ingestion and cancer incidence, with metabolic activation of lycopene and retinoid-mediated signaling. The aim is to discuss a potential mechanism to explain lycopene related anti-cancer activities by modulation of insulin-like growth factor-1 concentrations via lycopene metabolite activation of retinoid-mediated signaling.

Sebaceous Gland-Rich Skin Is Characterized by TSLP Expression and Distinct Immune Surveillance Which Is Disturbed in Rosacea

The microbial community exhibits remarkable diversity on topographically distinct skin regions, which may be accompanied by differences in skin immune characteristics. Our aim was to compare the immune milieu of healthy sebaceous gland-rich (SGR) and sebaceous gland-poor skin areas, and to analyze its changes in an inflammatory disease of SGR skin. For this purpose, immunohistochemical, immunocytochemical, and quantitative real-time PCR analyses of thymic stromal lymphopoietin (TSLP) and other cytokines, phenotypic immune cell markers and transcription factors were carried out in samples from sebaceous gland-poor, SGR skin and from papulopustular rosacea. TSLP mRNA and protein production was also studied in cultured keratinocytes. In SGR skin, higher TSLP expression, dendritic cell appearance without prominent activation, and T cell presence with IL-17/IL-10 cytokine milieu were detected compared with sebaceous gland-poor skin. Linoleic acid, a major sebum component, was found to induce TSLP expression dose-dependently in keratinocytes. In papulopustular rosacea, significantly decreased TSLP level and influx of inflammatory dendritic cells and T cells with IL-17/interferon-γ cytokine milieu were observed. According to our results, SGR skin is characterized by a distinct, noninflammatory immune surveillance, which may explain the preferred localization of inflammatory skin diseases, and can influence future barrier repair therapeutic concepts.

Immune-mediated skin inflammation is similar in severe atopic dermatitis patients with or without filaggrin mutation

Inflammatory cytokines can impair the skin barrier, but the question as to whether barrier alterations affect keratinocyte immune responses remains unanswered. The aim of this study was to investigate whether immune-mediated skin inflammation differs between severe atopic dermatitis patients with or without filaggrin mutation. The levels of filaggrin, inflammatory T helper 2 polarizing cytokines (thymic stromal lymphopoietin (TSLP) and interleukin 33 (IL-33)) and chemokine (C-C motif) ligand 27 (CCL27), histological severity markers, T and dendritic cell counts in biopsies from lesional skin of severe atopic dermatitis patients with and without filaggrin mutation and healthy skin were quantified by immunohistochemistry. The results were confirmed by quantitative PCR analyses. No significant differences were found between the 2 patient groups. Expression of atopic dermatitis-specific cytokines showed significant correlation with histological severity. These findings suggest that the immune-mediated skin inflammation (represented by keratinocyte-derived factors, T cell and dendritic cell counts) is similar in the 2 patient groups with severe atopic dermatitis, and that immune activation is connected to the severity of the disease rather than to the origin of barrier alterations.

The digestable parent cyclodextrin

The enzymatic digestibility of parent γ-cyclodextrin by human saliva α-amylase was investigated aiming at the determination of lifespan of intact macro ring. It was found that the ring-opening reaction was the slowest step of the γ-cyclodextrin degradation process. The reaction products were mainly maltose and malto-triose, while no higher malto-oligomers were detected. The enzymatic degradation of γ-cyclodextrin reduces the possibility of influencing bioavailability of nutritional lipophiles or drug actives co-administered with γ-cyclodextrin as an excipient or additive. Though there are numerous papers on the ring opening of cyclodextrins by amylases and the same capability of the human α-amylase is expected now we prove this activity. The hydrolysis reaction was followed by direct measurement of the resulting maltose and malto-triose, for the first time.

Activation of TRPV3 Regulates Inflammatory Actions of Human Epidermal Keratinocytes

Transient receptor potential (TRP) ion channels were first characterized on neurons, where they are classically implicated in sensory functions; however, research in recent decades has shown that many of these channels are also expressed on nonneuronal cell types. Emerging findings have highlighted the role of TRP channels in the skin, where they have been shown to be important in numerous cutaneous functions. Of particular interest is TRPV3, which was first described on keratinocytes. Its functional importance was supported when its gain-of-function mutation was linked to Olmsted syndrome, which is characterized by palmoplantar keratoderma, periorifacial hyperkeratosis, diffuse hypotrichosis and alopecia, and itch. Despite these exciting results, we have no information about the role and functionality of TRPV3 on keratinocytes at the cellular level. In this study, we identified TRPV3 expression both on human skin and cultured epidermal keratinocytes. TRPV3 stimulation was found to function as a Ca2+-permeable ion channel that suppresses proliferation of epidermal keratinocytes and induces cell death. Stimulation of the channel also triggers a strong proinflammatory response via the NF-κB pathway. Collectively, our data show that TRPV3 is functionally expressed on human epidermal keratinocytes and that it plays a role in cutaneous inflammatory processes.

Immunotopographical Differences of Human Skin

The immunological barrier of the healthy skin is considered to be unified on the whole body surface—however, recent indirect findings have challenged this dogma since microbial and chemical milieu (e.g., sebum, sweat, and pH) exhibit remarkable differences on topographically distinct skin areas. Therefore, in the present study, we performed whole transcriptomic and subsequent pathway analyses to assess differences between sebaceous gland rich (SGR) and sebaceous gland poor (SGP) regions. Here, we provide the first evidence that different skin regions exhibit a characteristic innate and adaptive immune and barrier milieu as we could detect significantly increased chemokine (CCL2, 3, 19, 20, 23, 24) and antimicrobial peptide (S100A7, A8, A9, lipocalin, β-defensin-2) expression, altered barrier (keratin 17, 79) functions, and a non-inflammatory Th17/IL-17 dominance in SGR skin compared to SGP. Regarding pro-inflammatory molecules (IL-1α, IL-6, IL-8, IL-33, TNF-α), similarly low levels were detected in both regions. Our data may explain the characteristic topographical localization of some immune-mediated and autoimmune skin disorders and we also propose that the term “healthy skin control sample,” widely used in experimental Dermatology, should only be accepted if researchers carefully specify the exact region of the healthy skin (along with the site of the diseased sample).

Myeloid but not plasmacytoid blood DCs possess Th1 polarizing and Th1/Th17 recruiting capacity in psoriasis

Psoriasis is a common inflammatory skin disease and dendritic cells (DCs) play crucial role in the development of skin inflammation. Although the characteristics of skin DCs in psoriasis are well defined, less is known about their peripheral blood precursors. Our aim was to characterize the phenotypic features as well as the cytokine and chemokine production of CD1c+ myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) in the blood samples of psoriatic patients. Blood DCs were isolated by using a magnetic separation kit, and their intracytoplasmic cytokine production and CD83/CD86 maturation/activation marker expression were investigated by 8-colour flow cytometry. In CD1c+ mDCs the intracellular productions of Th1, Th2, Th17, Th22 and Treg polarizing cytokines were examined simultaneously, whereas in pDCs the amounts of IFNα as well as IL-12, IL-23 and IL-6 were investigated. The chemokine production of both DC populations was investigated by flow-cytometry and ELISA. According to our results psoriatic CD1c+ mDCs were in a premature state since their CD83/CD86 maturation/activation marker expression, IL-12 cytokine, CXCL9 and CCL20 chemokine production was significantly higher compared to control cells. On the other hand, blood pDCs neither produced any of the investigated cytokines and chemokines nor expressed CD83/CD86 maturation/activation markers. Our results indicate that in psoriasis not only skin but also blood mDCs perform Th1 polarizing and Th1/Th17 recruiting capacity, while pDCs function only in the skin milieu.

Original ArticleActivation of Transient Receptor Potential Vanilloid 3 Regulates Inflammatory Actions of Human Epidermal Keratinocytes

Transient receptor potential (TRP) ion channels were first characterized on neurons, where they are classically implicated in sensory functions; however, research in recent decades has shown that many of these channels are also expressed on nonneuronal cell types. Emerging findings have highlighted the role of TRP channels in the skin, where they have been shown to be important in numerous cutaneous functions. Of particular interest is TRPV3, which was first described on keratinocytes. Its functional importance was supported when its gain-of-function mutation was linked to Olmsted syndrome, which is characterized by palmoplantar keratoderma, periorifacial hyperkeratosis, diffuse hypotrichosis and alopecia, and itch. Despite these exciting results, we have no information about the role and functionality of TRPV3 on keratinocytes at the cellular level. In this study, we identified TRPV3 expression both on human skin and cultured epidermal keratinocytes. TRPV3 stimulation was found to function as a Ca2+-permeable ion channel that suppresses proliferation of epidermal keratinocytes and induces cell death. Stimulation of the channel also triggers a strong proinflammatory response via the NF-κB pathway. Collectively, our data show that TRPV3 is functionally expressed on human epidermal keratinocytes and that it plays a role in cutaneous inflammatory processes.

Activation of Transient Receptor Potential Vanilloid 3 Regulates Inflammatory Actions of Human Epidermal Keratinocytes.

Transient receptor potential (TRP) ion channels were first characterized on neurons, where they are classically implicated in sensory functions; however, research in recent decades has shown that many of these channels are also expressed on nonneuronal cell types. Emerging findings have highlighted the role of TRP channels in the skin, where they have been shown to be important in numerous cutaneous functions. Of particular interest is TRPV3, which was first described on keratinocytes. Its functional importance was supported when its gain-of-function mutation was linked to Olmsted syndrome, which is characterized by palmoplantar keratoderma, periorifacial hyperkeratosis, diffuse hypotrichosis and alopecia, and itch. Despite these exciting results, we have no information about the role and functionality of TRPV3 on keratinocytes at the cellular level. In this study, we identified TRPV3 expression both on human skin and cultured epidermal keratinocytes. TRPV3 stimulation was found to function as a Ca2+-permeable ion channel that suppresses proliferation of epidermal keratinocytes and induces cell death. Stimulation of the channel also triggers a strong proinflammatory response via the NF-κB pathway. Collectively, our data show that TRPV3 is functionally expressed on human epidermal keratinocytes and that it plays a role in cutaneous inflammatory processes.

CD1c+ Blood Dendritic Cells in Atopic Dermatitis are Premature and Can Produce Disease-specific Chemokines

Skin dendritic cells of patients with atopic dermatitis (AD) are well characterized, but less is known about their peripheral blood precursors. The aim of this study was to investigate the phenotypic features and chemokine production of myeloid pre-dendritic cells of patients with AD ex vivo and after stimulation with Staphylococcus enterotoxin B and thymic stromal lymphopoietin, representing an AD-like microenvironment. The expression of cell surface markers was measured by flow cytometry, while chemokine production was monitored with chemokine antibody array and confirmed by enzyme-linked immunoassays. AD pre-dendritic cells expressed higher levels of Fc?RI and the maturation and activation markers tended to be altered. They produced both AD (CCL17/18/22) and maturation-related (CCL3/4/5) chemokines at higher level than controls. The production of CCL3/4 and CCL18 were significantly higher even without AD-specific stimulation, while the production of CCL17 and CCL22 were significantly higher only after stimulation. These results indicate that circulating AD pre-dendritic cells are premature and bear atopic characteristics even without tissue-specific stimulation, suggesting that their development is not only influenced by the skin microenvironment, but even earlier by the local milieu in the blood.