Mutations in the Leucine-Rich Repeat Kinase 2 (LRRK2) gene are the most frequent known cause of Parkinson's disease (PD), but their prevalence varies markedly between populations. Here we studied the frequency and associated phenotype of four recurrent LRRK2 mutations (R1441C, R1441G, R1441H, and G2019S) in familial and sporadic PD from a single referral center in Lisbon, Portugal. Among 138 unrelated PD probands, we identified 9 heterozygous G2019S carriers (6.52%) and 1 heterozygous R1441H carrier (0.72%). The G2019S mutation was present in 4 of the 107 sporadic (3.74%) and in 5 of the 31 familial probands (16.1%). Mutations were not found among 101 Portuguese controls. The G2019S mutation was present on a single haplotype and displayed reduced penetrance. Heterozygous parkin gene mutations were also found in 2 G2019S-positive probands, but their pathogenic role is unclear. The clinical phenotype in patients with LRRK2 mutations was indistinguishable from that of typical PD, including impaired sense of smell. The G2019S mutation is a very common genetic determinant among the Portuguese patients with PD, and the R1441H mutation is also present in this population. These data have important implications for the diagnostic work-up and genetic counseling of patients with this disease in Portugal.
Human 15-lipoxygenase (LOX)-2 and mouse 8-LOX represent orthologous members of the LOX family but display different positional specificities and tissue distribution. To study the functional role of 15-LOX-2 and 8-LOX in keratinocytes, an inducible Tet-On gene expression system was established in the premalignant mouse keratinocyte cell line 308. Doxycycline (dox)-induced expression of enzymatically active 15-LOX-2 and 8-LOX led to an inhibition of cell growth that was associated with an inhibition of DNA synthesis, as shown by a 15-46% reduction of 5-bromo-2-deoxy-uridine (BrdU) incorporation. The inhibitory effects were increased in the presence of exogenous arachidonic acid. In contrast, addition of linoleic acid or the LOX inhibitor baicalein reversed the growth-inhibitory effects. Treatment of the cells with 15-hydroxyeicosatetraenoic acid (HETE) or 8-HETE resulted in a similar inhibition of BrdU incorporation, whereas 13-hydroxyoctadecadienoic acid (HODE) and 9-HODE, in contrast, had no effects. Doxinduced keratinocytes showed increased levels of reactive oxygen species (ROS). The antioxidant N-acetyl-L-cysteine and a specific inhibitor of p38 mitogen-activated protein kinase, but not of extracellular signal-regulated kinase 1/2 or c-Jun N-terminal kinase/stress-activated kinases, completely abolished the LOX-induced growth inhibition, indicating a critical role of ROS and p38. Our data suggest that 15-LOX-2 and 8-LOX, although displaying different positional specificity, may use common signaling pathways to induce growth inhibition in premalignant epithelial cells.-Schweiger, D., G. Fü rstenberger, and P. Krieg. Inducible expression of 15-lipoxygenase-2 and 8-lipoxygenase inhibits cell growth via common signaling pathways. J. Lipid Res.
Background/Aims: Dry, itchy and inflamed scalp conditions are common and often associated with diseases such as atopic dermatitis or psoriasis. To improve these symptoms, we investigated the efficacy of a new tonic containing the active ingredients urea, lactate, polidocanol, and Glycyrrhiza inflata root extract, containing licochalcone A. Study Design/Methods: 30 subjects with dry and itchy scalp conditions underwent a randomized half-head study for 4 weeks, applying the leave-on tonic three times a week on one side of the scalp. Tonic effects on skin hydration, itching, lipids, microinflammation, and substantivity of tonic compounds were determined using corneometry, middle-infrared spectroscopy, direct analysis in real-time mass spectrometry, and enzyme-linked immunosorbent assay. Volunteers performed a self-assessment; changes in scalp condition were documented by in vivo microscopy. Results: After tonic treatment, scalp moisture was significantly increased, whereas scalp itching and tautness were significantly reduced. Results also demonstrated a high substantivity of urea and lactate on the scalp, an increase in triglyceride, and a decrease in free fatty acid levels. The amount of total lipids was unchanged. Analyses of scalp wash-ups verified a significant reduction in important pro-inflammatory markers. Conclusion: Due to the actives urea, lactate, polidocanol, and the anti-inflammatory licochalcone A, the new scalp tonic exhibited excellent performance in alleviating scalp dryness, itching, microinflammation, and in normalizing disturbances of scalp lipids.
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