BackgroundWnt5a is a member of the wingless-type patterning regulators important in pre-natal development. The expression and distribution of Wnt5a and its receptors frizzled (fzd) 3 and fzd 5 in adult human skin have not been comprehensively studied to date.Methodology/Principal FindingsWe here show that Wnt5a, fzd3, fzd5, as well as fzd6 are restricted to specific layers in normal epidermis, analogous to their zonal distribution in hair follicles, suggesting a role in adult skin differentiation. In line, Wnt5a and fzd5 are both overexpressed and re-distributed in the epidermis of psoriasis which involves disturbed keratinocyte differentiation. Functionally, Wnt5a lowers the concentration of IFN required to induce target genes, and increases the magnitude of IFN target gene induction, suggesting a molecular mechanism underlying IFN hypersensitivity in psoriasis. Finally, we identify nedd8 and the amyloid precursor APP, previously shown to be upregulated in psoriasis, as targets of synergistic IFNα/Wnt5a induction.Conclusions/SignificanceThe present data (i) suggest that Wnt5a regulates epidermal differentiation even in adult skin and (ii) identify synergistic induction of type 1 IFN target genes as a novel mode of Wnt5a action. Targeting Wnt5a in the skin may reduce IFN hypersensitivity and be of therapeutical value.
Wnt5a is one of the so-called non-canonical Wnt ligands which do not act through β-catenin. In normal development, Wnt5a is secreted and directs the migration of target cells along concentration gradients. The effect of Wnt5a on target cells is regulated by many factors, including the expression level of inhibitors and receptors. Dysregulated Wnt5a signalling facilitates invasion of multiple tumor types into adjacent tissue. However, the expression and distribution of Wnt5a in cutaneous squamous cell carcinoma (SCC) and basal cell carcinoma (BCC), as well as the effect of Wnt5a on keratinocyte migration has not been studied in detail to date. We here report that Wnt5a is upregulated in SCC and BCC and localised to the leading edge of tumors, as well as tumor-associated fibroblasts. The Wnt5a-triggered bundling of its receptor Fzd3 provides evidence of Wnt5a concentration gradients projecting into the tumor. In vitro migration assays show that Wnt5a concentration gradients determine its effect on keratinoctye migration: While chemotactic migration is inhibited by Wnt5a present in homogenous concentrations, it is enhanced in the presence of a Wnt5a gradient. Expression profiling of the Wnt pathway shows that the upregulation of Wnt5a in SCC is coupled to repression of canonical Wnt signalling. This is confirmed by immunohistochemistry showing lack of nuclear β-catenin, as well as absent accumulation of Axin2. Since both types of Wnt signalling act mutually antogonistically at multiple levels, the concurrent repression of canonical Wnt signalling suggests hyper-active Wnt5a signal transduction. Significantly, this combination of gene dysregulation is not observed in the benign hyperproliferative inflammatory skin disease psoriasis. Collectively, our data strongly suggest that Wnt5a signalling contributes to tissue invasion by non-melanoma skin cancer.
We have examined simultaneous changes in thirst, plasma osmolality and arginine vasopressin, after oral water loading or hypertonic saline infusion. The studies were carried out in the same subjects, comprising young controls aged 26.8 years (SD 4.8, n = 10) and health status-defined elderly people aged 72.1 years (SD 3.1, n = 10). Water loading caused significant falls in plasma osmolality (p < 0.001) and thirst (p < 0.001), but there was no variation with age. Infusion with 462 mmol/l of sodium chloride increased plasma osmolality significantly (p < 0.001), but there was no variation with age (p = 0.12). The perception of thirst during the osmotic loading experiment was recorded differently by the two age groups (p < 0.0001). However, linear regression analysis showed no age difference in the relationship between thirst and plasma osmolality during osmotic loading. During osmotic loading the relationship between the plasma concentration of arginine vasopressin in response to increasing plasma osmolality varied significantly (slope: p = 0.02; intercept: p = 0.02). Plasma arginine vasopressin rose more rapidly with increasing plasma osmolality in old subjects.
1 Doxazosin is a quinazoline derivative, related to prazosin, recently developed for the treatment of hypertension. 2 The intravenous administration of doxazosin (12 micrograms/kg) to six healthy normotensive subjects resulted in significant fall in erect blood pressure, with a corresponding increase in heart rate, but there were no significant changes in supine blood pressure or heart rate. 3 The changes in blood pressure and heart rate were maximal at 6 h after intravenous dosing. With prazosin the maximum effects occurred within the first hours. 4 Pressor response studies with phenylephrine confirmed that doxazosin is a relatively selective postsynaptic alpha‐ adrenoceptor antagonist. 5 The mean elimination half‐life of doxazosin was 11 h. This compared with a T1/2 of 2.5 h for prazosin.
Initiation of prazosin therapy may be complicated by the first-dose response of acute postural hypotension and tachycardia. The effects of beta-blocker on the responses to oral prazosin were studied in eight normotensive men. After 1 mg oral prazosin there was a marked postural fall in blood pressure to a lowest mean standing systolic pressure of 88 +/- 7 mm Hg (mean +/- SD), associated with a tachycardia of 117 +/- 13 bpm, and an increase in mean plasma norepinephrine concentration to 9.6 +/- 7.9 nmole/l. There was a linear relationship (r = 0.93) between plasma prazosin concentration and hypotensive effect. Concurrent propranolol 80 mg or primidolol 100 mg (a cardioselective beta-blocker) increased the severity and duration of the postural hypotensive response, with lowest mean systolic blood pressure (BP) of 79 +/- 7 and 75 +/- 9 mm Hg. There was no effect on the orthostatic release of norepinephrine but there was attenuation of the postural tachycardia. Concurrent beta-adrenergic blocking therapy, selective or nonselective, intensifies the immediate postural hypotensive response to the initial dose of prazosin.
Plasma noradrenaline concentration increases with age. This study was designed to investigate whether an increased rate of noradrenaline release into the circulation or a decrease in clearance is primarily responsible for this age related change in concentration. Sixteen healthy male subjects were studied, eight young (21-36 years) and eight old (65-78 years). Clearance was calculated from steady state noradrenaline concentrations during constant rate infusions of unlabelled noradrenaline. Clearance did not differ between the two groups: young 4.8 l/min (range 2.7-6.1), old 4.1 (range 2.6-8.2). The old subjects had significantly greater rates of release. Supine: young 10.3 nmol/min (range 5.3-17.6), old 19.7 (range 10.1-30), P less than 0.05. Standing: young 17.2 (range 11-36.4), old 29.2 (range 21.8-47.9), P less than 0.01. No significant relationship was found in either supine or standing position between rate of noradrenaline release and either systolic or diastolic blood pressure. These results indicate that plasma noradrenaline concentration rises with age because of an increased rate of release, but that this increased release is not responsible for the higher blood pressure seen in the elderly.
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