Heike Beschmann

Psoriasis patients show signs of insulin resistance

Background  Recent observations suggest that psoriasis is a risk factor for the development of coronary artery calcification which in turn represents an indicator for atherosclerosis.

Specific TRPC6 Channel Activation, a Novel Approach to Stimulate Keratinocyte Differentiation

The protective epithelial barrier in our skin undergoes constant regulation, whereby the balance between differentiation and proliferation of keratinocytes plays a major role. Impaired keratinocyte differentiation and proliferation are key elements in the pathophysiology of several important dermatological diseases, including atopic dermatitis and psoriasis. Ca2+ influx plays an essential role in this process presumably mediated by different transient receptor potential (TRP) channels. However, investigating their individual role was hampered by the lack of specific stimulators or inhibitors. Because we have recently identified hyperforin as a specific TRPC6 activator, we investigated the contribution of TRPC6 to keratinocyte differentiation and proliferation. Like the endogenous differentiation stimulus high extracellular Ca2+ concentration ([Ca2+]o), hyperforin triggers differentiation in HaCaT cells and in primary cultures of human keratinocytes by inducing Ca2+ influx via TRPC6 channels and additional inhibition of proliferation. Knocking down TRPC6 channels prevents the induction of Ca2+- and hyperforin-induced differentiation. Importantly, TRPC6 activation is sufficient to induce keratinocyte differentiation similar to the physiological stimulus [Ca2+]o. Therefore, TRPC6 activation by hyperforin may represent a new innovative therapeutic strategy in skin disorders characterized by altered keratinocyte differentiation.

Effective continuous systemic therapy of severe plaque-type psoriasis is accompanied by amelioration of biomarkers of cardiovascular risk: results of a prospective longitudinal observational study

Background  Severe psoriasis is associated with significant cardiovascular mortality.

Reduced TRPC channel expression in psoriatic keratinocytes is associated with impaired differentiation and enhanced proliferation.

Psoriasis is a characteristic inflammatory and scaly skin condition with typical histopathological features including increased proliferation and hampered differentiation of keratinocytes. The activation of innate and adaptive inflammatory cellular immune responses is considered to be the main trigger factor of the epidermal changes in psoriatic skin. However, the molecular players that are involved in enhanced proliferation and impaired differentiation of psoriatic keratinocytes are only partly understood. One important factor that regulates differentiation on the cellular level is Ca2+. In normal epidermis, a Ca2+ gradient exists that is disturbed in psoriatic plaques, favoring impaired keratinocyte proliferation. Several TRPC channels such as TRPC1, TRPC4, or TRPC6 are key proteins in the regulation of high [Ca2+]ex induced differentiation. Here, we investigated if TRPC channel function is impaired in psoriasis using calcium imaging, RT-PCR, western blot analysis and immunohistochemical staining of skin biopsies. We demonstrated substantial defects in Ca2+ influx in psoriatic keratinocytes in response to high extracellular Ca2+ levels, associated with a downregulation of all TRPC channels investigated, including TRPC6 channels. As TRPC6 channel activation can partially overcome this Ca2+ entry defect, specific TRPC channel activators may be potential new drug candidates for the topical treatment of psoriasis.

Lipophilic prodrugs of amino acids and vitamin E as osmolytes for the compensation of hyperosmotic stress in human keratinocytes

Abstract:  Skin keratinocytes are subjected to changing osmotic conditions and evolved counteracting mechanisms. Particularly, the expression of osmolyte transporters serves for the maintenance of cell volume in a hypertonic environment. In this study, we show that hyperosmotic stress significantly decreases the proliferation in HaCaT keratinocytes. Supplementation of the culture medium with the amino acids glycine, sarcosine, betaine, taurine and proline restored the proliferation indicating osmoprotective properties of these substances. Amino acids are highly polar molecules and therefore unable to penetrate into deeper epidermal layers after topical application. Thus, we utilized a prodrug concept in which the tested amino acids are coupled to a lipophilic moiety. Ethyl glycinate as a first model compound also showed an osmoprotective effect. In addition, improved penetration of the glycine derivative into deeper epidermal layers could be demonstrated. The prodrug concept was further developed by using the lipid soluble antioxidant α‐tocopherol as a lipophilic moiety. The derivatives d,l‐α‐tocopheryl‐(mono‐) glycinate (TMG) and d,l‐α‐tocopheryl‐(mono‐) prolinate caused an increase in proliferation of HaCaT keratinocytes under salt stress and a decrease in apoptosis induced by hypertonic conditions. Furthermore, the osmoprotective effect of d,l‐TMG could be corroborated in normal human keratinocytes. Therefore, it seems feasible that amino acids and their lipophilic derivatives may help to improve the osmotic balance and the hydration of skin. Clinical and cosmetic indications such as atopic eczema, UV exposed skin or aged skin may benefit from this new concept.

Transcriptional induction of junctional adhesion molecule-C gene expression in activated T cells

Junctional adhesion molecule (JAM)‐C is an Ig superfamily protein, which is involved in the regulation of various inflammatory and vascular events such as transendothelial leukocyte migration. JAM‐C is expressed highly on the surface of endothelial cells and platelets, whereas expression in T lymphocytes is not well studied. To investigate the specific gene regulation of JAM‐C in T lymphocytes, we determined JAM‐C expression in quiescent and activated human T cells. Treatment with the polyclonal T cell activator PHA increased surface and total JAM‐C expression in T cells time‐ and dose‐dependently, as determined by flow cytometry and immunoblot analysis. In contrast, no up‐regulation of JAM‐A in activated T cells was detectable. The highest level of JAM‐C up‐regulation by PHA was observed in CD3+forkhead box P3+ and CD4+CD25high T cells. Moreover, TCR activation with combined anti‐CD3 and anti‐CD28 stimulation induced JAM‐C expression in T cells. JAM‐C induction occurred at the mRNA level, suggesting a transcriptional regulatory mechanism of JAM‐C expression. Accordingly, we studied the regulation of the human JAM‐C gene promoter in transiently transfected T cells. Luciferase activity of a JAM‐C promoter gene construct with three potential consensus sites for the transcription factor NFAT was induced markedly in activated T cells. Finally, pretreatment with two pharmacological inhibitors of calcineurin, cyclosporin A, and FK‐506, but not with MAPK inhibitors, blocked JAM‐C induction in activated T cells. In summary, JAM‐C is up‐regulated in activated human T lymphocytes via a transcriptional mechanism, suggesting a potential role of JAM‐C in T cell functions.

CELLULAR RESPONSES TO EGG-OIL (CHARISMON © )

Egg-oil (Charismon©) is known for its beneficial action in wound healing and other skin irritancies and its antibacterial activity. The physiological basis for these actions has been investigated using cells in culture: HaCaT-cells (immortalized human keratinocytes), human endothelial cells in culture (HUVEC), peripheral blood mononuclear lymphocytes (PBML) and a full thickness human skin model (FTSM). Emphasis was on the influence of egg-oil on cell migration and IL-8 production in HaCaT cells, respiration, mitochondrial membrane potential, reactive oxygen (ROS) production and proliferation in HUVEC and HaCaT cells, cytokine and interleukin production in PBML and UV-light induced damage of FTSM. IL-8 production by HaCaT cells is stimulated by egg-oil whilst in phythemagglutin in-activated PBMLs production of the interleukins IL-2, IL-6, IL-10 and IFN-γ and TFN-α is reduced. ROS-production after H(2)O(2) stimulation first is enhanced but later on reduced. Respiration becomes activated due to partial uncoupling of the mitochondrial respiratory chain and proliferation of HaCaT and HUVEC is reduced. Recovery of human epidermis cells in FTSM after UV-irradiation is strongly supported by egg-oil. These results support the view that egg-oil acts through reduction of inflammatory processes and ROS production. Both these processes are equally important in cellular aging as in healing of chronic wounds.

Krankheitslehre und Therapieansätze

Fertilitatsstorungen beim Mann konnen zahlreiche Ursachen haben, wie Erkrankungen des mannlichen Genitales selbst oder Funktionsstorungen regulierender Organsysteme, z. B. der Hirnanhangdrusen. Aber auch exogene Faktoren, wie Temperatureinflusse oder Pharmaka, haben mehr oder minder starken Einflus auf die Zeugungsfahigkeit des Mannes. Daruber hinaus kann ein Funktionsverlust der mannlichen Gonaden die Folge anderer, primar nicht die Reproduktionsorgane des Mannes betreffender Erkrankungen sein. Im Einzelfall ist der Beitrag jedes einzelnen Faktors oft schwierig zu erkennen und einzuordnen, da das „Symptom“, die eingeschrankte Samenqualitat, stets das gleiche ist. Nur selten lassen sich klare Zusammenhange zwischen verursachenden Faktoren und resultierenden Erkrankungen erkennen. Ausnahme hiervon sind meist klar zu beurteilende hormonelle Storungen. Infolgedessen gibt es in der Andrologie bisher keine generell akzeptierte „Krankheitslehre“, was sich in der Vielzahl der rein empirischen Behandlungsansatze mannlicher Fertilitatsstorungen widerspiegelt.

Kontrazeption beim Mann

Familienplanung umfast die Verwirklichung des Kinderwunsches sowie die Verhinderung ungewollter Schwangerschaften. Wahrend in den Entwicklungslandern die Bevolkerung nach wie vor stark expandiert, entspricht die Geburtenrate in den industrialisierten Landern in etwa der Sterberate. Dies liegt u. a. an der Verfugbarkeit moderner kontrazeptiver Verfahren, die in der Regel von der Frau anzuwenden sind. Mannliche Kontrazeption ist bisher nur uber Koitus interruptus (unsicher), periodische Enthaltsamkeit (ggf. unsicher), Kondome (unsicher) sowie Vasektomie (irreversibel) moglich (Schiff 1989). Um auch die Manner an der Verantwortung der Kontrazeption zu beteiligen, gab es in den letzten Jahren zahlreiche Studien mit dem Ziel, einer effektiven und reversiblen Verhinderung einer Konzeption naher zu kommen.

Biologie der Fortpflanzung

Als Individuen haben die Organismen eine begrenzte Lebensdauer. Die Fortpflanzung sichert jedoch die kontinuierliche Existenz ihrer.Art. Bei der Befruchtung im Rahmen der sexuellen Fortpflanzung vereinigen sich geschlechtlich unterschiedlich differenzierte, haploide Keimzellen (Gameten) zu einer diploiden Zygote, der Urzelle des neuen Individuums. Dabei wird die Erbsubstanz der zwei Elternindividuen zum Genotypus einer neuen Generation kombiniert.