The role of vitamin D and β-defensin 103 on skin: from defence to pigmentation regulation

294 p.El objetivo principal de esta tesis era investigar la posible relación entre la pigmentación de la piel y el sistema inmunitario en humanos. Para ello, hemos analizado por un lado la diversidad del gen DEFB103 que codifica un péptido antimicrobiano, la expresión de este gen por los queratinocitos, y la influencia del péptido sobre los melanocitos. Por otro lado, hemos analizado el efecto de la vitamina D sobre el los melanocitos, mediante RNA-Seq. Con este trabajo demostramos que la pigmentación de la piel puede ser modulada por moléculas que están implicadas en el sistema inmunitario. En particular la beta-defensinas 103 y la vitamina D activa, las cuales hemos visto que tienen la capacidad de influir en la expresión de genes melanogénicos. Además, el efecto de ambos factores parece estar relacionado con los niveles de pigmentación. El efecto de la vitamina D en los melanocitos es diferente con respecto al fenotipo pigmentario y su efecto en la pigmentación parece ser solo en melanocitos ligeramente pigmentadosThis work was supported by a predoctoral fellowship from the Basque Government to Arrate Sevilla (PRE_2014_1_419), an EMBO Short-Term Fellowship (7014), a MINECO proyect grant (CGL2014-58526-P), by FEDER (Fondo Europeo de Desarrollo Regional), and by projects from the Basque Goverment (IT1138-16 and SAIOTEK2012: S-PE12UN051)

The role of vitamin D and β-defensin 103 on skin: from defence to pigmentation regulation

294 p.El objetivo principal de esta tesis era investigar la posible relación entre la pigmentación de la piel y el sistema inmunitario en humanos. Para ello, hemos analizado por un lado la diversidad del gen DEFB103 que codifica un péptido antimicrobiano, la expresión de este gen por los queratinocitos, y la influencia del péptido sobre los melanocitos. Por otro lado, hemos analizado el efecto de la vitamina D sobre el los melanocitos, mediante RNA-Seq. Con este trabajo demostramos que la pigmentación de la piel puede ser modulada por moléculas que están implicadas en el sistema inmunitario. En particular la beta-defensinas 103 y la vitamina D activa, las cuales hemos visto que tienen la capacidad de influir en la expresión de genes melanogénicos. Además, el efecto de ambos factores parece estar relacionado con los niveles de pigmentación. El efecto de la vitamina D en los melanocitos es diferente con respecto al fenotipo pigmentario y su efecto en la pigmentación parece ser solo en melanocitos ligeramente pigmentadosThis work was supported by a predoctoral fellowship from the Basque Government to Arrate Sevilla (PRE_2014_1_419), an EMBO Short-Term Fellowship (7014), a MINECO proyect grant (CGL2014-58526-P), by FEDER (Fondo Europeo de Desarrollo Regional), and by projects from the Basque Goverment (IT1138-16 and SAIOTEK2012: S-PE12UN051)

Coordinating Stem Cell Behavior in the Hair Follicle

Tissue stem cells perform important functions throughout an organism’s life. They generate new cells to replenish cells that are lost during normal wear and tear or in response to acute injury. Remarkably, hair follicles naturally undergo repetitive cycles of regeneration and degeneration, a process that is accomplished with the support of stem cells within the hair follicles. It is this feature that makes this miniorgan an attractive model system to study stem cell biology. Interestingly, hair follicle is home to two distinct stem cell populations: epithelial hair follicle stem cells (HFSCs), which contribute to the formation of hair shafts, and melanocyte stem cells (McSCs), which contribute to hair pigmentation. During the hair cycle, HFSCs and McSCs work in harmony to generate a pigmented hair. However, little is known about the inter-stem-cell crosstalk governing this intricate coordination. To identify candidate transcription factors that specify HFSCs in mouse, the gene expression profiles of the HFSCs residing in the bulge of hair follicles versus the epithelial basal cells outside the bulge were compared. One of the “molecular signature” genes being upregulated in the HFSCs is nuclear factor I/B (Nfib). Embryonic ablation of Nfib revealed that Nfib is required for the hair follicle morphogenesis and hair folliclemediated re-epithelization during wound repair. Meanwhile, to address the function of Nfib in established HFSCs, I conditionally induced Nfib ablation in the adult HFSCs. Interestingly, I found that the ablation of Nfib in the adult HFSCs did not perturb the HFSC maintenance, as the growth of hair follicles and the hair cycle proceeded relatively normally. Instead, and even more unexpected, NFIB loss in the HFSCs promoted the proliferation and precocious differentiation of their nearby McSCs. These findings provide new insights into how McSC and HFSC behaviors maintain reliance upon cooperative factors within the hair follicle and how this might be uncoupled in injury, stress and disease states

Ethnopharmacological study on plants used for skincare and beauty by some Xhosa communities.

Doctoral Degree. University of KwaZulu-Natal, Pietermaritzburg.The paraphrase “beauty lies in the eyes of the beholder” by Plato, a Greek philosopher, has echoed through the fabrics of time and still echoes in our generation. The statement simply ought to refer to that the observer gets to decide what is “beautiful” in their eyes. The decision on what and who is beautiful is heavily influenced by one’s surroundings. In a digital-market environment the concept of beauty enhancement is paraded by bigger forces to drive their own agenda. The desire to enhance one’s facial appearance has significantly contributed to the observed growth of the beauty industry. The notable growth of the industry has in some cases resulted in unpleasant consequences due to the side effects of some of the products in the market. In this global-blooming industry products are traded and exchanged at a rapid rate. Introduction of safer natural beauty enhancement products are required for the South African market if we were to alleviate those with undesirable side effects and could combat some socio-economic challenges through job creation. The use of plants as the source of natural compounds has proven to be a reliable strategy in ethnopharmacological applications. The Eastern Cape Province has a rich plant biodiversity and the communities have immense indigenous knowledge (IK) on the use of these plants. There is a need to explore the pharmacological application of these plants by introducing beauty enhancement product formulations made from local resources. The project was aimed at documenting and conductingethnopharmacological evaluation of plants used for skincare and beauty for their potential in formulation of beauty enhancement products. An ethnobotanical survey was conducted to document plants that are used by communities in the Raymond Mhlaba municipality for skincare and beauty. Knowledge holders were identified by purpose sampling method and the interviews were conducted in isiXhosa using a structured questionnaire. Information on demographics, names of the plant, type of plant, plant part used, method of preparation and administration and frequency of use was collected and captured in the questionnaires. The Asphodelaceae and Asteraceae were the most represented families of the plants used for skincare and beauty. The communities used sustainable harvesting practices as the leaves were the most utilized plant parts. The most reported beauty enhancement uses were for achieving desired skin complexion and for skin smoothness, with both accounting up to 50% of the reported plant usages. Sixteen plants with the highest frequency index (FI) were selected from the ethnobotanical survey for ethnopharmacological studies related to beauty enhancement. This included Acokanthera oblongifolia (Hochst.) Codd, Aloe ferox Mill, Arctotis arctotoides (L.f) O.Hoffm, Bulbine frutescens (L.) Willd, Cassipourea flanaganii (Schinz) Alston, Chenopodium album L, Clausena anisata (Willd.) Hook.f ex Benth, Haemanthus albiflos Jacq, Marrubium vulgare L, Ilex mitis (L.) Radlk, Plantago lanceolata L, Rorippa nasturtium-aquaticum (L.) Hayek, Sonchus asper L, Symphytum officinale L, Ruta graveolens L and Urtica urens L. The antimicrobial activity of plant extracts was assessed using the microdilution bioassay to determine the minimum inhibitory concentrations (MIC). The antimicrobial activity of petroleum ether (PE), dichloromethane (DCM), 70% aqueous ethanol (v/v) and water extracts of the selected plants were assessed against infectious skin microorganisms including Bacillus subtilis ATCC 6051, Brevibacillus agric ATCC 51663, Staphylococcus aureus ATCC 12600, Staphylococcus epidermidis ATCC 12228, Escherichia coli ATCC 11775, Klebsiella pneumoniae ATCC 13883, Candida albicans ATCC 10231 and the dermatophytes Microsporum canis ATCC 36299, Trichophyton mentagrophytes ATCC 9533 and Trichophyton tonsurans ATCC 28942. The majority of the tested plant extracts were effective and inhibited the skin commensal bacteria E. coli with MIC values less than 100 μg/mL. Prolonged infections by commensal bacteria can condition the skin environment and provide favourable conditions for more opportunistic bacteria such as the Staphylococci genus. Ethanol extracts of C. flanaganii and U. urens expressed high antibacterial activity against S. aureus with MIC values less than 100 μg/mL. Ethanol extracts of R. graveolens and dichloromethane extracts of A. arctotoides were effective at inhibiting S. epidermidis and S. aureus, respectively. Inhibition of two opportunistic bacteria has a positive effect on skin tone, due to the scarring and darkening associated with infection by the Staphylococci genus. There was notable activity recorded against C. albicans and dermatophytes M. canis, T. mentagrophytes and T. tonsurans by extracts of A. oblongifolia, A. arctotoides, C. flanaganii, I. mitis and R. graveolens at different polarities with MIC’s less than 1000 μg/mL. The phenolic content and antioxidant activity of the plants were determined by assessing 50% aqueous methanol extracts (v/v) for their total phenolic and flavonoid content, 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity, ferric reducing antioxidant power (FRAP) and the coupled oxidation of linoleic acid and bleaching of β-carotene. The antioxidant mechanism of phenolic compounds associated with beauty enhancement has been proposed to be due to their free radical chain breaking capabilities, metal chelation, oxidant quenching and inhibition of enzymatic activity. The total phenolic content of A. ferox, I. mitis and C. flanaganii were significantly high with recorded values ranging from 37.87 to 50.34 mgGAE/g. The flavonoid content of C. flanaganii, A. oblongifolia and P. lanceolata were significantly high. Methanol extracts of R. graveolens and C. flanaganii expressed the highest antioxidant activity, with IC50 values comparable to the standard antioxidant when assessed for their DPPH radical scavenging activity. The presence of antioxidants in the skin structural layers has a positive effect on the health and function of the skin. Extracts of U. urens, A. ferox, C. flanaganii, B. frutescens, P. lanceolata, H. albiflos, M. vulgare, C. anisata, S. officinale and R. nasturtium-aquaticum expressed good metal chelating potential. The highest oxidative protection in the β-carotene linoleic acid model with comparative oxidation rate ratio (ORR) to the positive control was observed for C. flanaganii, S. officinale and U. urens. The results indicate the ability of the plant extracts to provide protection against increased levels of lipid peroxidation in the skin, an important factor in beauty enhancement, due to delaying the age process. The photo-protective effect of the plant extracts was measured by calculating the sun protection factor (SPF). The SPF is the ratio of ultraviolet (UV) radiation required to produce minimal erythema dose (MED) in protected skin to unprotected skin with higher values indicative of increased protection from photo damage. Ethanol extracts of P. lanceolata, C. flanaganii, A. oblongifolia, I. mitis and A. arctotoides exhibited SPF values of more than 15, which translated to photo protection of the skin against UVB radiation by more than 93.3%. The plant extracts demonstrated the highest absorbance of UVB radiation at a wavelength region between 300 – 305 nm. These will protect the skin against UV-induced oxidative damage and enhance the skin’s health and function. The inhibition of enzymes with beauty enhancement potential by the plant extracts was assessed against tyrosinase, secretory phospholipase A2 (sPLA2), lipoxygenase (15-LOX) and cyclooxygenase (COX-1 and COX-2). Ethanol extracts of R. nasturtium-aquaticum, C. anisata, S. officinale and C. flanaganii expressed good anti-tyrosinase activity. The coupled protection against UV-induced damage and modulation of the tyrosinase enzyme activity can be exploited to achieve the desired skin complexion. The anti-inflammatory studies revealed the potential of extracts of C. flanaganii, P. lanceolata and R. nasturtium-aquaticum to serve as dual inhibitors of 15-LOX and COX-2 enzymes. The inhibition of 15-LOX and COX-2 is effective at resolving psoriasis, a skin-inflammatory associated disease which has a negative effect on the health and beauty of the skin. The effectiveness of ethanol extracts of C. flanaganii, C. album, C. anisata and R. nasturtium-aquaticum in maintaining the cells health and function was examined on human epidermal melanocytes (HEM) cell lines. Ethanol extracts of C. flanaganii, C. album, C. anisata and R. nasturtium-aquaticum were able to inhibit cellular tyrosinase activity and therefore reduce melanin production. The effective concentrations of the extracts were further reported as non-toxic to melanocytes. The observed anti-tyrosinase activity of the extracts against HEM cell lines contribute positively in achieving the desired skin complexion while providing photo protection against UV-induced damage. Therefore, plant extracts that are efficient and safe to use can be incorporated into formulations intended for beauty enhancement and further analysed under clinical trials. The study further suggests that the model undertaken be promoted to individuals and corporations interested in formulation of cosmeceuticals to ensure the safety and efficiency of their products

Agouti modulation of both adipocyte and pancreatic islet function via a Ca²⁺-dependent mechanism

Dominant mutations at the promoter of the mouse agouti gene results in a yellow coat color as well as obesity, hyperinsulinemia, insulin resistance and gender-dependent hyperglycemia. Both central and peripheral actions of agouti contribute to agouti-induced obesity syndromeThe human analogue of agouti is expressed in adipose tissue and exerts potent peripheral effects. Recombinant agouti protein has been shown to stimulate adipocyte intracellular calcium ([Ca2+]i) and up-regulate fatty acid synthase (FAS), a key enzyme in de novo lipogenesis in human adipocytes via a Ca2+-dependent mechanism, thereby promoting lipid storage in adipose tissue. However, transgenic mice overexpressing agouti only in adipose tissue under the control of aP2 promoter do not become obese unless hyperinsulinemia is concomitantly present, suggesting an interaction between hyperinsulinemia and adipose tissue agouti expression. In addition, adipocyte lipolysis is also impaired in agouti mutants compared to wild type animals. We therefore further investigated the effect of recombinant agouti protein on both human adipocyte and pancreatic islet function. We demonstrated that the human homologue of agouti is expressed in the pancreas. Agouti protein also induced a significant Ca2+ influx into human pancreatic islets, and serves as a potent secretagogue for both insulin and amylin release in human pancreatic islets, which may contribute to hyperinsulinemia and hyperamylinemia. In human adipocyte, recombinant agouti protein potently inhibited both ACTH- and forskolin-induced lipolysis via a Ca2+-dependent mechanism, indicating a post receptor event. Further investigation of the mechanism whereby increasing in [Ca2+]i results in inhibition of lipolysis demonstrated that the anti-lipolytic effect of increasing [Ca2+]i is exerted by the activation of adipocyte phosphodiesterase (PDE 3B), leading to a decrease in cAMP, a net decrease in hormone sensitive lipase phosphorylation and inhibition of lipolysis. In addition, we demonstrated that human adipocyte agouti is up-regulated during adipocyte differentiation. Using human adipose tissue obtained from plastic surgery with body mass index (BMI) ranging from 21 to 31, we found a positive correlation between adipose tissue agouti content and FAS activity, as well as between adipose tissue agouti mRNA level and FAS mRNA levelThese data suggest that agouti may modulate both adipocyte and pancreatic islet function via a Ca2+- dependent mechanismIn the pancreas, agouti-induced hyperinsulinemia and hyperamylinemia may serve as a compensatory system in regulating blood glucose by coordinately regulating glucose input and clearance, respectively. However, agouti- induced hyperinsulinemia may contribute to insulin resistance and obesity. In addition, agouti stimulation of amylin release may result in islet amyloid deposits, impaired B-cell function and diabetes. In the adipose tissue, agouti potently inhibits agonists-stimulated lipolysis by activating adipocyte PDE 3B, thereby resulting in a coordinated regulation of adipocyte lipid metabolism, which may contribute to adipose tissue lipid storageIn addition, we have shown a correlation between human adipose tissue agouti expression and FAS activity and expression. As humans normally express agouti in adipose tissue and pancreas, it is possible that agouti and FAS may be regulated in a similar manner. Alternatively, agouti may be one of adipocyte synthesized factors that may in part contribute to the modulation of adipose tissue lipid metabolism in vivo. Finally, agouti-induced hyperinsulinemia may synergistically act with adipocyte agouti in modulating adipocyte lipid metabolism, thereby contributing to obesity

Pitkäaaltoisen UV-säteilyn vaikutus hiiren melanoomaan in vitro ja in vivo

The skin cancer incidence has increased substantially over the past decades and the role of ultraviolet (UV) radiation in the etiology of skin cancer is well established. Ultraviolet B radiation (280-320 nm) is commonly considered as the more harmful part of the UV-spectrum due to its DNA-damaging potential and well-known carcinogenic effects. Ultraviolet A radiation (320-400 nm) is still regarded as a relatively low health hazard. However, UVA radiation is the predominant component in sunlight, constituting more than 90% of the environmentally relevant solar ultraviolet radiation. In the light of the recent scientific evidence, UVA has been shown to have genotoxic and immunologic effects, and it has been proposed that UVA plays a significant role in the development of skin cancer. Due to the popularity of skin tanning lamps, which emit high intensity UVA radiation and because of the prolonged sun tanning periods with the help of effective UVB blockers, the potential deleterious effects of UVA has emerged as a source of concern for public health. The possibility that UV radiation may affect melanoma metastasis has not been addressed before. UVA radiation can modulate various cellular processes, some of which might affect the metastatic potential of melanoma cells. The aim of the present study was to investigate the possible role of UVA irradiation on the metastatic capacity of mouse melanoma both in vitro and in vivo. The in vitro part of the study dealt with the enhancement of the intercellular interactions occurring either between tumor cells or between tumor cells and endothelial cells after UVA irradiation. The use of the mouse melanoma/endothelium in vitro model showed that a single-dose of UVA to melanoma cells causes an increase in melanoma cell adhesiveness to non-irradiated endothelium after 24-h irradiation. Multiple-dose irradiation of melanoma cells already increased adhesion at a 1-h time-point, which suggests the possible cumulative effect of multiple doses of UVA irradiation. This enhancement of adhesiveness might lead to an increase in binding tumor cells to the endothelial lining of vasculature in various internal organs if occurring also in vivo. A further novel observation is that UVA induced both decline in the expression of E-cadherin adhesion molecule and increase in the expression of the N-cadherin adhesion molecule. In addition, a significant decline in homotypic melanoma-melanoma adhesion (clustering) was observed, which might result in the reduction of E-cadherin expression. The aim of the in vivo animal study was to confirm the physiological significance of previously obtained in vitro results and to determine whether UVA radiation might increase melanoma metastasis in vivo. The use of C57BL/6 mice and syngeneic melanoma cell lines B16-F1 and B16-F10 showed that mice, which were i.v. injected with B16-F1 melanoma cells and thereafter exposed to UVA developed significantly more lung metastases when compared with the non-UVA-exposed group. To study the mechanism behind this phenomenon, the direct effect of UVA-induced lung colonization capacity was examined by the in vitro exposure of B16-F1 cells. Alternatively, the UVA-induced immunosuppression, which might be involved in increased melanoma metastasis, was measured by standard contact hypersensitivity assay (CHS). It appears that the UVA-induced increase of metastasis in vivo might be caused by a combination of UVA-induced systemic immunosuppression, and to the lesser extent, it might be caused by the increased adhesiveness of UVA irradiated melanoma cells. Finally, the UVA effect on gene expression in mouse melanoma was determined by a cDNA array, which revealed UVA-induced changes in the 9 differentially expressed genes that are involved in angiogenesis, cell cycle, stress-response, and cell motility. These results suggest that observed genes might be involved in cellular response to UVA and a physiologically relevant UVA dose have previously unknown cellular implications. The novel results presented in this thesis offer evidence that UVA exposure might increase the metastatic potential of the melanoma cells present in blood circulation. Considering the wellknown UVA-induced deleterious effects on cellular level, this study further supports the notion that UVA radiation might have more potential impact on health than previously suggested. The possibility of the pro-metastatic effects of UVA exposure might not be of very high significance for daily exposures. However, UVA effects might gain physiological significance following extensive sunbathing or solaria tanning periods. Whether similar UVA-induced pro-metastatic effects occur in people sunbathing or using solaria remains to be determined. In the light of the results presented in this thesis, the avoidance of solaria use could be well justified.Ihosyöpien ilmaantuvuus on lisääntynyt voimakkaasti viimeisten vuosikymmenten aikana ja ultraviolettisäteilyn (UV-säteilyn) vaikutus ihosyöpien ilmaantuvuuteen on kiistaton. Ultravioletti B -säteily (280-320 nm) on tunnetusti haitallista DNA:ta vaurioittavien ja karsinogeenisten vaikutustensa vuoksi. Ultravioletti A -säteilyn (320-400 nm) terveysvaikutuksia on puolestaan pidetty pitkään harmittomampana kuin UVB-säteilyn vaikutuksia. Maanpinnalle saapuvasta auringonvalosta kuitenkin yli 90% on UVA-säteilyä. Viimeaikaisten tutkimustulosten perusteella UVA-säteilyllä on kuitenkin havaittu olevan perimää vaurioittavia ja immunologisia vaikutuksia ja lisäksi sillä saattaa olla myös merkittävä rooli ihosyöpien kehittymisessä. UVA-säteilyaltistuksen aiheuttamat epäsuotuisat terveysvaikutukset ovat nousseet huolenaiheeksi ihmisten ruskettaessa itseään solariumeissa, jotka säteilevät voimakasta UVA-säteilyä, tai ottaessa pitkiä aikoja aurinkoa tehokkaiden UVB-aurinkosuojien turvin, jotka suojelevat ihoa tehokkaasti UVB-säteilyn aiheuttamalta palamiselta suojaten kuitenkin ihoa vähemmän UVA-säteilyltä. UV-säteilyn vaikutuksia melanooman kykyyn lähettää etäpesäkkeitä ei ole tutkittu aikaisemmin. UVA-säteilyn on kuitenkin havaittu aiheuttavan soluissa monia sellaisia fysiologisia muutoksia, jotka saattavat lisätä syöpäsolujen taipumusta lähettää etäpesäkkeitä (syövän metastasointi). Tämän väitöstutkimuksen tarkoituksena oli tarkastella UVA-säteilyn vaikutusta hiiren melanoomasolujen metastaattisiin ominaisuuksiin. Soluviljelmin tehdyissä tutkimuksissa tarkasteltiin UVA-säteilyn vaikutusta melanoomasolujen ja endoteelisolujen väliseen sitoutumiseen. UVA-säteilyn havaittiin lisäävän melanoomasolujen sitoutumista säteilyttämättömiin endoteelisoluihin, mutta samanaikaisesti melanoomasolujen keskinäinen sitoutuminen kuitenkin toisiinsa väheni. Nämä seikat saattavat lisätä melanoomasolujen metastaasitaipumusta tapahtuessaan elävässä organismissa. Tästä syystä saatuja tuloksia tarkasteltiin hiirimallissa, jossa tutkittiin, ovatko solulinjoilla tehdyt havainnot muutoksista melanoomasolujen adhesiivisuudessa fysiologisesti merkittäviä ja sitä, lisääkö UVA-säteily melanooman etäpesäkkeiden muodostumista hiirissä. UVA-säteilyn havaittiin lisäävän keuhkometastaasien määrää UVA-käsitellyissä hiirissä verrattuna kontrolliryhmään, jotka eivät olleet saaneet säteilyä. Tutkimusten mukaan UVA-säteilyn kyky lisätä hiiren melanoomasolujen metastaattista aktiivisuutta saattaa johtua sekä UVA-säteilyn suorista vaikutuksista melanoomasoluihin ja myös sen aiheuttamasta immunosuppressiosta. Tutkimuksessa tarkasteltiin myös UVA-säteilyn vaikutusta hiiren melanoomasolujen geenien ilmentymiseen. UVA-säteilyn havaittiin muuttavan yhdeksän geenin ilmenemisprofiilia melanoomasoluissa säteilytyksen jälkeen. Näiden tulosten perusteella havaittujen geenien voidaan arvella olevan osa UVA-säteilyn aiheuttamaa soluvastetta ja sen lisäksi osa UVA-säteilyn aiemmin tuntemattomia vaikutuksia soluissa. Tässä väitöstutkimuksessa on osoitettu ensimmäistä kertaa, että UVA-säteily saattaa lisätä verenkierrossa olevien melanoomasolujen metastaattista kapasiteettia. Nämä tulokset tukevat aiempien tutkimustulosten näkemystä siitä, että UVA-säteilyllä saattaa olla enemmän terveysvaikutuksia kuin aiemmin on osattu epäillä. Jokapäiväisessä elämässä UVA-säteilyn vaikutukset ovat pieniä, mutta ne saattavat olla merkityksellisiä solariumia käytettäessä tai otettaessa pitkään aurinkoa, jolloin altistuminen UVA-säteilylle on voimakasta. UVA-säteilyn vaikutukset ihmisen melanooman kykyyn lähettää etäpesäkkeitä jää vielä selvitettäväksi. Tämän tutkimuksen perusteella solariumin käytön välttäminen saattaa kuitenkin olla aiheellista

Investigating the role of inflammation on other cell lineages at the wound repair site:A study in zebrafish

Wound repair is vital for restoring skin integrity and function following damage.It is a complex process that requires the coordination of multiple cell types.One of the key stages of wound repair is inflammation, which is essential forthe clearance of debris and pathogens at the wound site and can evencoordinate downstream repair events. However, when inflammation becomesdysregulated, or fails to resolve it can lead to a multitude of pathologiesassociated with wound healing including hyperpigmentation and chronicwounds. The precise molecular mechanisms driving these pathologies remainunclear, resulting in a lack of truly effective treatment options for patients. Here,I have used the zebrafish (Danio rerio) as a model system to explore the rolesof two lesser studied cell types in the context of wound repair: melanocyteswhich drive wound hyperpigmentation, and adipocytes which are oftendysregulated in obese and diabetic patients who suffer from chronic wounds.Taking advantage of the optical transparency of zebrafish, I investigate thedynamic interaction between inflammatory cells and both melanocytes andadipocytes. I show here that macrophages drive the recruitment ofmelanocytes to a wound causing wound hyperpigmentation, in part, throughsignalling via ACVR2A, as revealed by a proteomic comparison study. I alsoshow through light and electron microscopy that macrophages crown woundedge adipocytes, and that these adipocytes subsequently lose their lipid andcellular identity. My data demonstrate the importance of the impact ofinflammation upon other cell lineages at the repair site, and how the modelspresented here could reveal potential targets for therapeutic interventions toimprove the outcome of pathologic cases of wound repair

Stevia Genus: Phytochemistry and Biological Activities Update

The Stevia genus (Asteraceae) comprises around 230 species, distributed from the southern United States to the South American Andean region. Stevia rebaudiana, a Paraguayan herb that produces an intensely sweet diterpene glycoside called stevioside, is the most relevant member of this genus. Apart from S. rebaudiana, many other species belonging to the Stevia genus are considered medicinal and have been popularly used to treat different ailments. The members from this genus produce sesquiterpene lactones, diterpenes, longipinanes, and flavonoids as the main types of phytochemicals. Many pharmacological activities have been described for Stevia extracts and isolated compounds, antioxidant, antiparasitic, antiviral, anti-inflammatory, and antiproliferative activities being the most frequently mentioned. This review aims to present an update of the Stevia genus covering ethnobotanical aspects and traditional uses, phytochemistry, and biological activities of the extracts and isolated compounds.Fil: Borgo, Jimena. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Metabolismo del Fármaco. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Metabolismo del Fármaco; ArgentinaFil: Laurella, Laura Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Metabolismo del Fármaco. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Metabolismo del Fármaco; ArgentinaFil: Martini, María Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Metabolismo del Fármaco. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Metabolismo del Fármaco; ArgentinaFil: Catalán, Cesar A. N.. Universidad Nacional de Tucumán. Facultad de Bioquímica, Química y Farmacia. Instituto de Química Orgánica; ArgentinaFil: Sülsen, Valeria Patricia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Metabolismo del Fármaco. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Metabolismo del Fármaco; Argentin