We have conducted studies using primary mouse epidermal keratinocyte and whole hair follicle cultures to investigate the mechanism of the hypertrichotic activity of potassium channel openers. In a time course study, the extent of stimulation of epidermal keratinocyte DNA synthesis by minoxidil increased as the rate of DNA synthesis in control cultures declined. Minoxidil stimulation of DNA synthesis in 7-day cultures required prolonged (> 1 day) exposure to the agent. Pinacidil and diazoxide also stimulated DNA synthesis in mouse epidermal keratinocyte cultures. In addition, minoxidil, pinacidil, diazoxide, and cromakalim stimulated DNA synthesis in whole-organ cultures of mouse hair follicles. These results suggest that potassium channel openers retard the loss of proliferative activity of differentiating keratinocytes and support the hypothesis that these agents stimulate hair growth through a direct effect on hair follicles.
No abstract
We have used a series of bisindolylmaleimide selective pro-tein-kinase C (PKC) inhibitors to investigate the role of this enzyme in the regulation of cell proliferation in mouse hair follicle organ cultures. Mouse whisker follicles were isolated by microdissection, and rates of DNA synthesis during culture were determined from 3H-thymidine incorporation. The bis-indolylmaleimides Ro 31-7549, Ro 31-8161, Ro 31-8425 and Ro 31-8830 inhibit isolated brain PKC with IC50 values of 8-80 nM, are > 60-fold less potent against protein kinase A, and inhibit PKC-mediated protein phosphorylation in platelets with IC50 values in the range 0.25-4.4 μM. These PKC inhibitors were found to increase levels of mouse hair follicle DNA synthesis, with EC50 values in the range 1-4 μM and maximal levels in the range 151-197% of control. Ro 31-7549 had an IC50 value 50-fold lower than that of minoxidil, while the maximal level of DNA synthesis for the PKC inhibitor was 86% higher. Incubation of mouse hair follicles with Ro 31-7549 resulted in a delay of approximately 24 h in the onset of decline in follicular DNA synthesis rates. Ro 31-6045 and Ro 31-7208, bisindolylmaleimides without activity in the platelet PKC assay, did not affect mouse hair follicle DNA synthesis rates. Taken together, these findings show that PKC mediates, at least in part, the rapid loss of proliferative activity that occurs in mouse whisker follicles in culture, and provide further evidence that PKC plays a role as a negative proliferative signal in hair follicles.
The polyamines spermidine and spermine and the diamines putrescine and cadaverine have been determined in their free and unbound state in the sera of patients with colorectal carcinoma. The obtained values were compared with normal control levels. Elevated levels of putrescine and spermidine were found in untreated patients and declined to the control range after surgical and chemotherapeutic treatment. Spermine levels remained unchanged throughout the observation at normal control levels.
Diphenhydramine has been in medical use for 35 years äs an antihistamine and hypnotic. We evaluated the pharmacokinetic parameters, which are not only important for disposition studies, in the serum of 10 volunteers who received a single dose of 31 mg diphenhydramine.For this purpose a suitable capillary GC-method was developed, which has a detection limit of 2 §/1 (serum); the calibration curve is linear between 2.5 and 120 g/l, the reproducibility is always better than 3.6% and the average recovery is about 100.1%.The combination of a relatively nofi-polar extraction solvent, a selective detector (N-FID) and a fused silica, bonded-phase capillary column led to a more rapid sample clean-up procedure (no back-extraction needed) and is sensitive and specific enough for the quantitative determination of diphenhydramine, orphenadrine or other ethanolamines in human serum. Quantitative Bestimmung von Diphenhydramin und Orphenadrin im Serum des Menschen durch Kapillar-GaschromatographieZusammenfassung: Diphenhydramin findet seit über 35 Jahren als Antihistaminicum und Hypnoticum medizinische Verwendung. Wir bestimmten die nicht nur für pharmakologische Studien wichtigen pharmakokinetischen Kenngrößen im Serum von 10 Probanden nach Gabe einer Einzeldosis von 31 mg Diphenhydramin.Hierzu entwickelten wir eine geeignete kapillar-gaschroinatographische Methode mit einer Nachweisgrenze von 2 ^g/l Serum; die Kalibrierungskurve ist linear zwischen 2,5 und 120 g/l, die Wiederholbarkeit immer besser als 3,6% und die Wiederfindungsrate lag bei 100,1%.Die Kombination eines relativ unpolaren Lösungsmittels zur Extraktion mit einem selektiven Detektor (N-FID) und einer fused-silica, bonded phase-Kapillare führt, da keine Rückextraktion benötigt wird, zu kürze-ren Proberiaufbefeitungszeiten und ist empfindlich und spezifisch genug für die quantitative Bestimmung von Diphenhydramin, Orphenadrin und anderen Ethanolaminen im menschlichen Serum.
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