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Background: Rubinstein-Taybi Syndrome (RSTS, MIM 180849) is a rare congenital disorder characterized by mental and growth retardation, broad and duplicated distal phalanges of thumbs and halluces, facial dysmorphisms and increased risk of tumors. RSTS is caused by chromosomal rearrangements and point mutations in one copy of the CREB-binding protein gene (CREBBP or CBP) in 16p13.3. To date mutations in CREBBP have been reported in 56.6% of RSTS patients and an average figure of 10% has ascribed to deletions.

Binding of ligands to DNA gives rise to several relevant biological and biomedical effects. Here, through the use of atomic force microscopy (AFM), we studied the consequences of drug binding on the morphology of single DNA molecules. In particular, we quantitatively analyzed the effects of three different DNA-binding molecules (doxorubicin, ethidium bromide, and netropsin) that exert various pharmacologic and therapeutic effects. The results of this study show the consequences of intercalation and groove molecular binding on DNA conformation. These single-molecule measurements demonstrate morphological features that reflect the specific modes of drug-DNA interaction. This experimental approach may have implications in the design of therapeutically effective agents.

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Observational studies indicate that topical application of ricinoleic acid (RA), the main component of castor oil, exerts remarkable analgesic and anti-inflammatory effects. Pharmacological characterization has shown similarities between the effects of RA and those of capsaicin, suggesting a potential interaction of this drug on sensory neuropeptide-mediated neurogenic inflammation. The aim of this study was to assess RA anti-inflammatory activities in comparison with capsaicin in several models of acute and subchronic inflammation. The acute inflammation was induced by intradermal injection of carrageenan in the mouse or by histamine in the guinea-pig eyelid. In either experiment, the extent of the oedema thickness was measured. Subchronic oedema was induced by complete Freund's adjuvant injection in the ventral right paw of mice. Tissue substance P (SP) was measured in the carrageenan experiments by radioimmunoassay (RIA). It was found that the acute topical application of RA (0.9 mg/mouse) or capsaicin (0.09 mg/mouse) significantly increased the mouse paw oedema induced by carrageenan, while an 8-day repeated topical treatment with the same doses of both compounds resulted in a marked inhibition of carrageenan-induced paw oedema matched by a reduction in SP tissue levels. Similar effects were found against histamine-induced eyelid oedema in guinea-pigs after acute or repeated application of RA or capsaicin. RA and capsaicin given for 1-3 weeks reduced the established oedema induced by Freund's adjuvant, a subchronic model of inflammation, particularly if given by the intradermal route. Either in mouse paw or in guinea-pig eyelid, capsaicin but not RA by itself produced a slight hyperemia and activation of a behavioural response (e.g. scratching of the eyelids). On the basis of the present results, RA may be seen as a new capsaicin-like, non-pungent anti-inflammatory agent suitable for peripheral application.

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The effect of sensory neuropeptides and capsaicin on basal and stimulated tone of mouse bronchial smooth muscle has been evaluated. In basal conditions neither sensory neuropeptides (subtance P, neurokinin A or calcitonin gene‐related peptide (CGRP)) nor capsaicin exerted any contractile effects. However, when a tonic contraction was induced with carbachol (1 μm) a prompt relaxation was induced by substance P (1– 100 nm) and by neurokinin A (1– 100 nm), with substance P being more potent. A second application of substance P was without effect. CGRP (10 nm) produced only a very small and erratic relaxation. Relaxation was also induced by capsaicin (1 μm), and this response could be evoked only once in each preparation. In 4 out of 6 preparations a cross‐desensitization between substance P and capsaicin was observed. The selective NK1 tachykinin agonist, [Pro9]‐SP sulphone (1 μm), exerted potent bronchodilator actions on carbachol‐contracted mouse bronchial preparations. In contrast, neither [β Ala8]‐NKA (4–10) nor [MePhe7]‐NKB (both at a concentration of 1 μm), selective synthetic agonists for NK2 and NK3 receptors, exerted significant relaxant effects. Furthermore, the selective NK1 tachykinin antagonist, (±)‐CP 96,345 (1 μm), abolished substance P (1 nm)‐ but not isoprenaline (0.1 μm)‐induced relaxations. Application of electrical field stimulation (EFS) (20 Hz, supramaximal voltage, 0.5 ms for 10 s) to carbachol‐contracted preparations evoked a transient contraction followed by a relaxation. The tetrodotoxin‐sensitive slow component of this relaxation was reduced following capsaicin desensitization. In the presence of indomethacin (5 μm) the relaxation induced by substance P, capsaicin or EFS was suppressed. In conclusion, the mouse main bronchus appears to be a monoreceptorial tissue containing only NK1 receptors which subserve bronchodilator functions. Such receptors could be activated by exogenous or endogenously (capsaicin or EFS) released tachykinins and the consequent relaxation is probably mediated by the generation of prostanoids.

Genetic modification of cells and animals is an invaluable tool