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Genistein and curcumin block TGF-β₁-induced u-PA expression and migratory and invasive phenotype in mouse epidermal keratinocytes

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NUTRITION AND CANCER-AN INTERNATIONAL JOURNAL 2000年第1期37卷 49-54页

作者： Santibáñez, JF Quintanilla, M Martínez, J Univ Chile Inst Nutr & Tecnol Alimentos Lab Biol Celular Santiago 11 Chile Univ Autonoma Madrid CSIC Inst Invest Biomed Madrid 28029 Spain

Transforming growth factor-beta(1) (TGF-beta(1)) stimulates migration/invasion of mouse transformed keratinocytes and increases urokinase (u-PA) expression/secretion. In this report, we analyzed the biological behavior of two naturally occurring inhibitors of protein tyrosine kinases, genistein and curcumin, that could abrogate the enhancement of u-PA levels induced by TGF-beta(1) in transformed keratinocytes. Our results showed that genistein and curcumin blocked this response in a dose-dependent manner and also inhibited the TGF-beta(1)-induced synthesis of fibronectin, an early responsive gene to the growth factor. Both compounds also reduced TCF-beta(1)-stimulated cell migration and invasiveness. These results suggest that a tyrosine kinase-signaling pathway should be involved in TGF-beta(1)-mediated increased malignancy of transformed keratinocytes and that genistein and curcumin could play an important role in inhibiting tumor progression.

关键词：印迹法蛋白质细胞运动/药物作用细胞培养的姜黄素/药理学表皮/细胞学表皮/药物作用荧光抗体技术染料木黄酮/拮抗剂和抑制剂染料木黄酮/药理学角蛋白细胞/细胞学角蛋白细胞/药物作用角蛋白细胞/分泌蛋白酪氨酸激酶类/代谢转化生长因子β/药理学尿纤溶酶原激活物/药物作用尿纤溶酶原激活物/分泌动物小鼠

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R115866 inhibits all-trans-retinoic acid metabolism and exerts retinoidal effects in rodents

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 2000年第1期293卷 304-312页

作者： Stoppie, P Borgers, M Borghgraef, P Dillen, L Goossens, J Sanz, G Szel, H Van Hove, C Van Nyen, G Nobels, G Vanden Bossche, H Venet, M Willemsens, G Van Wauwe, J Janssen Res Fdn B-2340 Beerse Belgium

All-trans-retinoic acid (RA) regulates epithelial differentiation and growth through activation of specific nuclear RA receptors (RARs). Because high-rate metabolism largely impairs the biological efficacy of RA, we have sought for compounds capable of inhibiting the metabolic breakdown of the retinoid. This study identifies R115866 as a novel inhibitor of the cytochrome P450 (CYP)-mediated metabolism of RA. In vitro, nanomolar concentrations of R115866 inhibited the conversion of RA by CYP26, a RA-inducible RA metabolizing enzyme. in vivo, oral administration of R115866 (2.5 mg/kg) to rats induced marked and transient increases of endogenous RA levels in plasma, skin, fat, kidney, and testis. Consistent with its ability to enhance endogenous RA content in tissues, R115866 was found to exert retinoidal activities. Like RA, the title compound: 1) inhibited vaginal keratinization in estrogen-stimulated rats;2) induced epidermal hyperplasia in mouse ear skin;3) transformed mouse tail epidermis from a para- to an orthokeratotic skin type;and 4) up-regulated the CYP26 mRNA expression in rat liver. Furthermore, we found that the keratinization-suppressive and CYP26-inducing activities of R115866 could be reversed by concomitant administration of the RAR antagonist, AGN193109. Our data characterize R115866 as a potent, orally active inhibitor of RA metabolism, capable of enhancing RA levels and displaying retinoidal actions. These activities are reversed by RAR antagonism, supporting the idea that the actions of R115866 result from increased availability of endogenous RA and improved RAR triggering.

关键词：芳香酶抑制剂苯并噻唑类细胞色素P450酶系统/遗传学酶抑制剂/药理学表皮/药物作用表皮/代谢增生/化学诱导角化病/化学诱导卵巢切除术 RNA 信使/生物合成 RNA 信使/遗传学大鼠 Wistar 维生素A酸类/代谢逆转录聚合酶链反应噻唑类/药理学组织分布维甲酸/代谢三唑类/药理学阴道/代谢动物女(雌)性人类男(雄)性小鼠大鼠

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Structural analysis of a defective transfer-like region in a staphylococcal aminoglycoside resistance plasmid

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DIAGNOSTIC MICROBIOLOGY AND INFECTIOUS DISEASE 2000年第2期38卷 69-77页

作者： von David, W Rogolsky, M Univ Missouri Sch Med Dept Basic Med Sci Kansas City MO 64108 USA

Staphylococcus epidermidis clinical isolate MH6502 contained the 51.9-kb nonconjugal plasmid pMH6502, which has homology to a major part of the transfer gene region of a known conjugal plasmid. Plasmid pMH6502 mediates aminoglycoside and ethidium bromide resistance. During restriction digest analysis of pMH6502, a double logarithmic regression of marker data gave a better linear relationship than a semi-logarithmic one. The analysis indicated several differences in the transfer-like region of pMH6502 compared to the analogous region of the S. aureus conjugal plasmid pG01. The transfer-like region was in the opposite orientation compared to pG01. An EcoRI site that is within the transfer-like region of pMH6502, has no analogue in pG01. A HindIII site, located outside a 6.3-kb EcoRI fragment in the transfer gene region of pG01, is inside the analogous fragment of pMH6502. A model is proposed to describe how a conjugal ancestral plasmid of pMH6502 could alter to its present form. (C) 2000 Elsevier Science Inc. All rights reserved.

关键词：氨基糖苷类抗菌药/药理学 DNA 细菌/化学抗药性微生物/遗传学核酸构象质粒/化学限制性内切酶图谱法/方法葡萄球菌金黄色/药物作用葡萄球菌金黄色/遗传学葡萄球菌表皮/药物作用葡萄球菌表皮/遗传学人类

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Absence of caveolin-1 sensitizes mouse skin to carcinogen-induced epidermal hyperplasia and tumor formation

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AMERICAN JOURNAL OF PATHOLOGY 2003年第6期162卷 2029-2039页

作者： Capozza, F Williams, TM Schubert, W McClain, S Bouzahzah, B Sotgia, F Lisanti, MP Albert Einstein Coll Med Dept Mol Pharmacol Bronx NY 10461 USA Albert Einstein Coll Med Albert Einstein Canc Ctr Bronx NY 10461 USA Albert Einstein Coll Med Dept Pathol Bronx NY 10461 USA Montefiore Med Ctr Bronx NY 10467 USA Albert Einstein Coll Med Div Cardiol Dept Med Bronx NY 10461 USA Albert Einstein Coll Med Div Infect Dis Dept Med Bronx NY 10461 USA

Caveolin-1 is the principal Protein component of caveolae membrane domains, which are located at the cell surface in most cell types. Evidence has accumulated suggesting that caveolin-1 may function as a suppressor of cell transformation in cultured cells. The human CAV-1 gene is located at a putative tumor suppressor locus (7q31.1/D7S522) and a known fragile site (FRA7G) that is deleted in a variety of epithelial-derived tumors. Mechanistically, caveolin-1 is known to function as a negative regulator of the Ras-p42/44 MAP kinase cascade and as a transcriptional repressor of cyclin D1, possibly explaining its transformation suppressor activity in cultured cells. However, it remains unknown whether caveolin-1 functions as a tumor suppressor gene in vivo. Here, we examine the tumor suppressor function of caveolin-1 using Cav-1 (-/-) null mice as a model system. Cav-1 null mice and their wild-type counterparts were subjected to carcinogen-induced skin tumorigenesis, using 7,12-dimethylbenzanthracene (DMBA). Mice were monitored weekly for the development of tumors. We demonstrate that Cav-1 null mice are dramatically more susceptible to carcinogen-induced tumorigenesis, as they develop skin tumors at an increased rate. After 16 weeks of DMBA-treatment, Cav-1 null mice showed a 10-fold increase in tumor incidence, a 15-fold increase in tumor number per mouse (multiplicity), and a 35-fold increase in tumor area per mouse, as compared with wild-type litter-mate mice. Moreover, before the development of tumors, DMBA-treatment induced severe epidermal hyperplasia in Cav-1 null mice. Both the basal cell layer and the suprabasal cell layers were expanded in treated Cav-1 null mice, as evidenced by immunostaining with cell-type specific differentiation markers (keratin-10 and keratin-14). In addition, cyclin D1 and phospho-ERK1/2 levels were up-regulated during epidermal hyperplasia, suggesting a possible mechanism for the increased susceptibility of Cav-1 null mice to tumorige

关键词： 9 10-二甲基-1 2-苯并蒽/毒性致癌物/毒性窖蛋白1 细胞质膜微囊蛋白/遗传学细胞质膜微囊蛋白/代谢细胞分裂/药物作用细胞周期蛋白D1/代谢表皮/药物作用表皮/病理学增生免疫组织化学角蛋白细胞/药物作用角蛋白细胞/代谢角蛋白细胞/超微结构小鼠近交C57BL 小鼠基因敲除显微镜检查电子丝裂原活化蛋白激酶1/代谢丝裂原活化蛋白激酶3 丝裂原激活蛋白激酶类/代谢肿瘤实验性/化学诱导肿瘤实验性/病理学磷酰化皮肤/药物作用皮肤/病理学皮肤/超微结构时间因素增量调节动物小鼠

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Chemical composition and antimicrobial action of the essential oils of Salvia desoleana and S-sclarea

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PLANTA MEDICA 1999年第8期65卷 752-754页

作者： Peana, AT Moretti, MDL Juliano, C Univ Sassari Dipartimento Sci Farm I-07100 Sassari Italy

The chemical composition of the essential oils of Salvia desoleana Atzei & Picci and Salvia sclarea L. from Sardinia (Italy) was analysed by GC and GC/MS. S. desoleana oil had a high content of monoterpenic esters (linalyl acetate and alpha-terpinyl acetate) and a lower amount of the corresponding alcohols while S. sclarea oil was characterised by a higher content of alcohols and lower quantity of esters. We studied the antimicrobial activity of these oils concerning their use in pharmaceutical preparations for local application. Only weak microbiostatic inhibitory activity was seen against S. aureus, E. coli, S. epidermidis and C. albicans, but since inhibition increased progressively with contact time, better results could be obtained by using these oils in bioadhesive formulations that would also have anti-inflammatory and peripheral analgesic action at a local level, as demonstrated in experimental animals following systemic application.

关键词：抗菌药/化学抗菌药/药理学大肠杆菌/药物作用气相色谱-质谱法唇形科/化学微生物敏感性试验油类挥发/化学油类挥发/药理学葡萄球菌金黄色/药物作用葡萄球菌表皮/药物作用

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Foreign body infection: a new rat model for prophylaxis and treatment

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JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY 1999年第5期44卷 669-674页

作者： Van Wijngaerden, E Peetermans, WE Vandersmissen, J Van Lierde, S Bobbaers, H Van Eldere, J Catholic Univ Louvain Infect Dis Res Grp Dept Pathophysiol B-3000 Louvain Belgium Catholic Univ Louvain Infect Dis Res Grp Dept Microbiol & Immunol B-3000 Louvain Belgium

A subcutaneous catheter model in the rat was developed that allowed the study of prevention and treatment strategies for foreign body infection. In contrast to earlier models, the foreign body was inoculated with a low inoculum of Staphylococcus epidermidis just before implantation, thus mimicking intraoperative contamination with skin flora. Reproducible infection of all catheters followed if no prophylaxis was given. However, foreign body infection could be prevented or treated with antibiotics such as teicoplanin, which was marginally effective, and rifampicin, which proved very effective.

关键词：抗菌药/治疗应用抗生素预防疾病模型动物异物假体相关感染/药物疗法假体相关感染/预防和控制大鼠近交F344 大鼠 Wistar 利福平/治疗应用葡萄球菌感染/药物疗法葡萄球菌感染/预防和控制葡萄球菌表皮/药物作用替考拉宁/治疗应用动物大鼠

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Metal analysis of scales taken from Arctic grayling

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ARCHIVES OF ENVIRONMENTAL CONTAMINATION AND TOXICOLOGY 2000年第4期39卷 515-522页

作者： Farrell, AP Hodaly, AH Wang, S Simon Fraser Univ Dept Biol Sci Burnaby BC V5A 1S6 Canada Elemental Res Inc N Vancouver BC V7M 1A5 Canada

This study examined concentrations of metals in fish scales taken from Arctic grayling using laser ablation-inductively coupled plasma mass spectrometry (LA-ICPMS). The purpose was to assess whether scale metal concentrations reflected whole muscle metal concentrations and whether the spatial distribution of metals within an individual scale varied among the growth annuli of the scales. Ten elements (Mg, Ca, Ni, Zn, As, Se, Cd, Sb, Hg, and Pb) were measured in 10 to 16 ablation sites (5 mum radius) on each scale sample from Arctic grayling (Thymallus arcticus) (n = 10 fish). Ca, Mg, and Zn were at physiological levels in all scale samples. Se, Hg, and As were also detected in all scale samples. Only Cd was below detection limits of the LA-ICPMS for all samples, but some of the samples were below detection limits for Sb, Pb, and Ni. The mean scale concentrations for Se, Hg, and Pb were not significantly different from the muscle concentrations and individual fish values were within fourfold of each other. Cd was not detected in either muscle or scale tissue, whereas Sb was detected at low levels in some scale samples but not in any of the muscle samples. Similarly, As was detected in all scale samples but not in muscle, and Ni was detected almost all scale samples but only in one of the muscle samples. Therefore, there were good qualitative and quantitative agreements between the metal concentrations in scale and muscle tissues, with LA-ICPMS analysis of scales appearing to be a more sensitive method of detecting the body burden of Ni and As when compared with muscle tissue. Correlation analyses, performed for Pb, Hg, and Se concentrations, revealed that the scale concentrations for these three metals generally exceeded those of the muscle at low muscle concentrations. The LA-ICPMS analysis of scales had the capability to resolve significant spatial differences in metal concentrations within a fish scale. We conclude that metal analysis of fish scales using LA-ICPMS

关键词：年表表皮/化学表皮/药物作用表皮/生长和发育表皮/病理学鱼类/生理学质谱分析法/方法金属重/分析金属重/毒性肌骨骼/化学肌骨骼/药物作用痕量元素/分析痕量元素/毒性动物女(雌)性男(雄)性

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Effects of UV light and tumor promoters on endogenous vitamin E status in mouse skin

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CARCINOGENESIS 2000年第2期21卷 221-225页

作者： Liebler, DC Burr, JA Univ Arizona Coll Pharm Dept Pharmacol & Toxicol Tucson AZ 85721 USA Univ Arizona Coll Pharm SW Environm Hlth Sci Ctr Tucson AZ 85721 USA

Recent reports indicate that both orally administered and topically applied alpha-tocopherol (vitamin E, Tn) prevent UVB-induced skin carcinogenesis in mice. Because UVB exposure causes the formation of oxidants associated with tumor promotion, epidermal Tn status may be an important determinant of susceptibility to photocarcinogenesis. To test this hypothesis, we studied the status of epidermal Tn in C3H mice following exposure to single and repeated UVB exposures at doses typical of chronic photocarcinogenesis protocols. Exposure of mice to a single 13 kJ/m(2) dose over 60 min resulted in no acute depletion of epidermal Tn and a modest increase in TH within 6-12 h. Daily exposure to 6.5 kJ/m(2) over 30 min resulted in a gradual increase in epidermal Tn, which reached 5-fold after five daily exposures. The increase in epidermal TH was accompanied by an increase in the Tn oxidation products alpha-tocopherolquinone (TQ) and alpha-tocopherolhydroquinone (THQ), We also studied the effect of the prooxidant chemical tumor promoter benzoyl peroxide and the prooxidant azo initiators azobis(amidinopropane HCl) and azobis(2,4-dimethylvaleronitrile). Topical application of these prooxidant chemicals acutely oxidized epidermal Tn to TQ and THQ. Topical treatments with the phorbol ester tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) increased epidermal Tn levels without producing a significant accumulation of Tn oxidation products, The results indicate that UVB and tumor promoting chemicals all exert qualitatively different effects on epidermal Tn status and that UVB and TPA trigger an adaptive response involving epidermal Tn accumulation.

关键词：脒类/药理学抗氧化剂/代谢偶氮化合物/药理学过氧苯甲酰/药理学致癌物/药理学辅致癌作用表皮/药物作用表皮/代谢表皮/辐射效应氢醌类/代谢小鼠近交C3H 腈类/药理学氧化性应激光化学十四酰佛波乙酯/药理学紫外线维生素E/类似物和衍生物维生素E/代谢 α生育酚/类似物和衍生物动物女(雌)性小鼠

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A sunscreen-tanning compromise: 3D visualization of the actions of titanium dioxide particles and dihydroxyacetone on human epiderm

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PHOTOCHEMISTRY AND PHOTOBIOLOGY 2000年第4期71卷 426-430页

作者： Puccetti, G Leblanc, RM Univ Miami Dept Chem Coral Gables FL 33124 USA Univ Miami Ctr Supramol Sci Coral Gables FL 33124 USA

The self-fanning agent dihydroxyacetone (DHA) was applied to human skin samples, and its effect on light absorption was followed in time to study the DHA influence inside the different layers of skin. Application of DHA shows increased light absorption in the visible light region, as evidenced by skin taming, The tanning effect is enhanced by UV irradiation and appears localized in the near-stratum corneum layer as revealed by depth analysis of the time signal. As a reference, application of an emulsion containing titanium dioxide particles shows clear surface stability and a screening of light penetration beyond the stratum corneum.

关键词：二羟丙酮/药理学表皮/药物作用日光疗法防晒剂/药理学钛/药理学人类

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Passive sustainable hydration of the stratum corneum following surfactant challenge

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CLINICAL AND EXPERIMENTAL DERMATOLOGY 1999年第4期24卷 308-311页

作者： Goffin, V Piérard-Franchimont, C Piérard, GE Univ Liege Belgian SSTC Res Ctr 5596 Liege Belgium

Surfactants exhibit a protein-denaturating potency which is responsible for water uptake and swelling of the stratum corneum. There is also an increased transepidermal water loss related to the alteration of the barrier function. Ln the present prospective study, we evaluated sodium lauryl sulphate (SLS)-dependent changes in electrometric properties of skin. Single and iterative SLS challenges were performed. Measurements were made using a NOVA DPM on continuous mode for 5 min in order to assess both the baseline surface hydration and the rate of changes during probe occlusion. The present noninvasive instrumental evaluation of surfactant irritancy shows high sensitivity in each subject, but suffers from large inter-individual variability in the skin response following single and iterative sodium lauryl sulphate (SLS) challenges. The baseline surface hydration, that is almost unaffected I h after removing SLS patches, significantly decreases after a lag time of 24 h. The rate of water accumulation in the stratum corneum during the probe occlusion is significantly increased by SLS and is proportional to the SLS concentration and the number of iterative patches. Single water- or SLS-patch-tests fail to predict the skin response to cumulative SLS challenges and interindividual variability is large for all electrometric variables.

关键词：身体水份/药物作用身体水份/代谢剂量效应关系药物表皮/药物作用表皮/代谢皮电反应/药物作用刺激剂/投药和剂量刺激剂/药理学斑片试验前瞻性研究蛋白质变性回归分析十二烷硫酸钠/投药和剂量十二烷硫酸钠/药理学表面活性剂/投药和剂量表面活性剂/药理学失水无感觉/药物作用成年人人类中年人

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