BackgroundAortic aneurysm is a common but life-threatening disease among the elderly, for which no effective medical therapy is currently available. Activation of prostaglandin E2 (PGE2) is known to increase the expression of matrix metalloproteinase (MMP) and the release of inflammatory cytokines, and may thus exacerbate abdominal aortic aneurism (AAA) formation. We hypothesized that selective blocking of PGE2, in particular, EP4 prostanoid receptor signaling, would attenuate the development of AAA.Methods and FindingsImmunohistochemical analysis of human AAA tissues demonstrated that EP4 expression was greater in AAA areas than that in non-diseased areas. Interestingly, EP4 expression was proportional to the degree of elastic fiber degradation. In cultured human aortic smooth muscle cells (ASMCs), PGE2 stimulation increased EP4 protein expression (1.4±0.08-fold), and EP4 stimulation with ONO-AE1-329 increased MMP-2 activity and interleukin-6 (IL-6) production (1.4±0.03- and 1.7±0.14-fold, respectively, P<0.05). Accordingly, we examined the effect of EP4 inhibition in an ApoE−/− mouse model of AAA infused with angiotensin II. Oral administration of ONO-AE3-208 (0.01–0.5 mg/kg/day), an EP4 antagonist, for 4 weeks significantly decreased the formation of AAA (45–87% reduction, P<0.05). Similarly, EP4+/−/ApoE−/− mice exhibited significantly less AAA formation than EP4+/+/ApoE−/− mice (76% reduction, P<0.01). AAA formation induced by periaortic CaCl2 application was also reduced in EP4+/− mice compared with wild-type mice (73% reduction, P<0.001). Furthermore, in human AAA tissue organ cultures containing SMCs and macrophages, doses of the EP4 antagonist at 10–100 nM decreased MMP-2 activation and IL-6 production (0.6±0.06- and 0.7±0.06-fold, respectively, P<0.05) without increasing MMP-9 activity or MCP-1 secretion. Thus, either pharmacological or genetic EP4 inhibition attenuated AAA formation in multiple mouse and human models by lowering MMP activity and cytokine release.ConclusionAn EP4 antagonist that prevents the activation of MMP and thereby inhibits the degradation of aortic elastic fiber may serve as a new strategy for medical treatment of AAA.
SynopsisThis paper describes a method to obtain contact angle by observing the shapf of a liquid drop attached to a monofilament. The relations between contact angle and the dimensions of drops are theoretically obtained. Thus, it is possible to calculate the contact angle if drop shape is measured. Through use of this method, the contact angles of epoxy resin on various kinds of monofilamente were measured. It was found that this method has practical utility for measurement of the contact angle between liquid and monofilament.
We have been successful in obtaining temperature-stable crystallized thin film of (Zr,Sn)TiO4. Preferential (111)-oriented (Zr,Sn)TiO4 thin film was prepared by pulsed laser deposition. Effects of crystallization were elucidated based on a comparison of electric properties of crystallized and amorphous (Zr,Sn)TiO4 film. For crystallized film, the temperature coefficient of capacitance (TCC) was 20 ppm/°C at 3 MHz and the dielectric constant εr=38 in the microwave range of 1–10 GHz. These values are superior to those for amorphous film (TCC=220 ppm/°C, εr=27). The crystallization of this material was found quite effective for improving dielectrical properties. Atomic force microscope images showed the surface morphologies of crystallized and amorphous film of (Zr,Sn)TiO4 to differ.
The FixJ/LuxR family transcription factor CsgD is a master regulator of biofilm formation in Escherichia coli. Previously, we identified more than 10 transcription factors that participate in regulation of the csgD promoter. After genomic SELEX screening of regulation targets, an uncharacterized TetR-type transcription factor YbjK was found to be involved in regulation of the csgD promoter. In addition, a number of stress-response genes were found to be under the direct control of YbjK. Taken together, we propose to rename it to RcdA (regulator of csgD). One unique feature of RcdA is its mode of DNA binding. Gel shift, DNase-I footprinting, and atomic force microscopic (AFM) analyses indicated that RcdA is a DNA-binding protein with a high level of cooperativity, with which it covers the entire surface of probe DNA through protein–protein interaction and moreover it induces the formation of aggregates of DNA–RcdA complexes.
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