Cofilin, an actin‐depolymerizing protein, is essential for the functional dynamics of the actin cytoskeleton and for cell viability. In unstimulated human peripheral blood T lymphocytes cofilin is phosphorylated and localized in the cytoplasm. Following co‐stimulation through accessory receptors (e.g. CD2 or CD28) – however, not following TCR/CD3 stimulation alone – cofilin undergoes dephosphorylation. The subcellular localization as well as the actin‐binding activity of cofilin are regulated by the phosphorylation state of serine‐3. Thus, only the dephosphorylated form of cofilin associates with the actin cytoskeleton and possesses the capability to translocate into the nucleus. Recently, LIM‐kinase 1 was shown to inactivate cofilin through phosphorylation. Here, we have identified the functional counterparts of LIM‐kinase 1: the serine/threonine phosphatases of type 1 and type 2A not only associate with cofilin but also dephosphorylate this 19‐kDa protein and thereby mediate cofilin activation. In malignant T lymphoma cells, activation of these phosphatases occurs spontaneously, independent of external stimuli. In untransformed human peripheral blood T lymphocytes, these phosphatases function through a cyclosporin A/FK506‐resistant co‐stimulatory signaling pathway which is common for the accessory receptors CD2 and CD28. This co‐stimulatory signaling pathway is also not affected by a series of other clinically established immunosuppressive drugs (i.e. rapamycin, dexamethasone, leflunomide or mycophenolic acid).
Endogenous antioxidants are decreased in skin and blood during UV exposure. Combined supplementation of β-carotene, α-tocopherol and ascorbic acid in addition to topical sunscreens may help to lower the risk of sunburning. Acute UV erythema with sunburn reaction are the most important factors in conjunction with the cumulative life-long UV dose for inducing skin damage resulting in photoageing and precancerous and cancerous lesions. Therefore, a clinical, randomized, double-blind, parallel group, placebo-controlled study was conducted in healthy young female volunteers (skin type II) investigating the preventive, photoprotective effect of supplementation with Seresis®, an antioxidative combination containing both lipid and water-soluble compounds: carotenoids (β-carotene and lycopene), vitamins C and E, selenium and proanthocyanidins. In this study, the oral administration of Seresis appeared to be well tolerated. The preparation contains antioxidant compounds in quantities occurring at physiological levels and can therefore be used safely over a long period of time. Despite the fact that the assessment of the light sensitivity (minimal erythemal dose, chromametry) of the skin did not show any statistically significant differences between the Seresis and the placebo group, a clear statistical trend, however, could be demonstrated, i.e. Seresis was able to slow down the time of the development and grade of UVB-induced erythema. The primary efficacy parameter matrix metalloproteinases 1 (MMP-1) between treatment and placebo group following UV irradiation showed a significant difference (p < 0.05), which occurred due to the fact that after a 2-week UV irradiation, MMP-1 slightly increased (p < 0.03) in the placebo group and decreased (p < 0.044) in the treated group. The MMP-9 changes showed a clear tendency of decrease in the Seresis group (p < 1.393) and increase (p < 0.048) in the placebo group. These data emphasise that supplementation with Seresis decreases the UV-induced expression of MMP-1 and 9, which might be important in photoprotective processes. From our data, we thus finally draw the conclusion that by the combination of antioxidants, such as in the formulation of Seresis, a selective protection of the skin against irradiation can be achieved. This might be important for future recommendations for immediate suppression of the early phase of UV-induced erythema, that means pharmacological prevention of sunburn reaction as well as subsequent chronic skin damage.
Combined treatment with PAIA and rituximab showed rapid and long-lasting response, thereby allowing substantial reduction of dosage of concomitant immunosuppressive medication. We hereby confirm data from other investigators that PAIA/rituximab treatment is a promising therapeutical modality for pemphigus, pemphigoids and EBA, characterized by a favourable ratio of beneficial efficacy and minimized long-term adverse effects.
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