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961.
Ryoji Yanai Lama Mulki Eiichi Hasegawa Kimio Takeuchi Harry Sweigard Jun Suzuki Philipp Gaissert Demetrios G. Vavvas Koh-Hei Sonoda Michael Rothe Wolf-Hagen Schunck Joan W. Miller Kip M. Connor 《Proceedings of the National Academy of Sciences of the United States of America》2014,111(26):9603-9608
Ocular neovascularization, including age-related macular degeneration (AMD), is a primary cause of blindness in individuals of industrialized countries. With a projected increase in the prevalence of these blinding neovascular diseases, there is an urgent need for new pharmacological interventions for their treatment or prevention. Increasing evidence has implicated eicosanoid-like metabolites of long-chain polyunsaturated fatty acids (LCPUFAs) in the regulation of neovascular disease. In particular, metabolites generated by the cytochrome P450 (CYP)–epoxygenase pathway have been shown to be potent modulators of angiogenesis, making this pathway a reasonable previously unidentified target for intervention in neovascular ocular disease. Here we show that dietary supplementation with ω-3 LCPUFAs promotes regression of choroidal neovessels in a well-characterized mouse model of neovascular AMD. Leukocyte recruitment and adhesion molecule expression in choroidal neovascular lesions were down-regulated in mice fed ω-3 LCPUFAs. The serum of these mice showed increased levels of anti-inflammatory eicosanoids derived from eicosapentaenoic acid and docosahexaenoic acid. 17,18-epoxyeicosatetraenoic acid and 19,20-epoxydocosapentaenoic acid, the major CYP-generated metabolites of these primary ω-3 LCPUFAs, were identified as key lipid mediators of disease resolution. We conclude that CYP-derived bioactive lipid metabolites from ω-3 LCPUFAs are potent inhibitors of intraocular neovascular disease and show promising therapeutic potential for resolution of neovascular AMD.Angiogenesis plays a central role in many diseases, including age-related macular degeneration (AMD), a leading cause of blindness. Advanced AMD exists in two forms, “atrophic” and “neovascular,” which are defined by the absence or presence of choroidal neovascularization (CNV), respectively (1). Neovascular AMD is characterized by the formation of abnormal blood vessels that grow from the choroidal vasculature, through breaks in Bruch’s membrane, toward the outer retina (1). These vessels generally are immature in nature and leak fluid below or within the retina (2). Although growth factors are thought to play an important role in the late stage of neovascular AMD progression, they likely do not contribute to the underlying cause of the disease. The current standard of care for individuals with neovascular AMD is based on the targeting of VEGF, which promotes both angiogenesis and vascular permeability (3). However, although VEGF-targeted therapy attenuates angiogenesis and vascular permeability, it does not lead to complete vascular regression or disease resolution (3).The ω-3 and ω-6 long-chain polyunsaturated fatty acids (LCPUFAs) are two classes of dietary lipids that are essential fatty acids and have opposing physiological effects. The ω-6 LCPUFA, arachidonic acid (AA), and its cytochrome P450 (CYP)-generated metabolites (epoxyeicosatrienoic acids, EETs) recently have attracted much attention as a result of increasing evidence that they play a role in cancer as well as in cardiovascular disease (4–9). EETs are part of the VEGF-activated signaling cascade leading to angiogenesis (10) and promote tumor growth and metastasis (11). The major dietary ω-3 LCPUFAs are docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), which are highly enriched in the central nervous system including the retina (12). The ω-3 LCPUFAs have antithrombotic, antiangiogenic, and anti-inflammatory properties, and they compete with ω-6 LCPUFAs as substrates for synthesis of downstream metabolites by CYP enzymes, cyclooxygenases (COX), and lipoxygenases (LOX) (6, 13–15). Moreover, dietary enrichment with ω-3 LCPUFAs has been shown to protect against pathological angiogenesis-associated cancer and retinopathy (2, 16–19). Of the three main pathways (COX, LOX, and CYP) involved in eicosanoid biosynthesis, the lipid mediators derived from the CYP branch are the most susceptible to changes in dietary fatty acid composition (20–23). The ω-3 double bond that distinguishes DHA and EPA from their ω-6 counterparts provides a preferred epoxidation site for specific CYP family members (20, 22). In fact, most CYP isoforms can metabolize EPA and DHA with significantly higher catalytic efficiency than AA, making them uniquely susceptible to variations in the availability of these lipids (19–22). CYP epoxygenases target the ω-3 double bond, resulting in an accumulation of 17,18-epoxyeicosatetraenoic acid (17,18-EEQ) derived from EPA and 19,20-epoxydocosapentaenoic acid (19,20-EDP) from DHA (20, 22). Very recently, it was recognized that19,20-EDP inhibits angiogenesis, tumor growth, and metastasis (24). Thus, it appears that the CYP–epoxygenase pathway has the capacity to produce proangiogenic metabolites from ω-6 LCPUFAs (10, 11) and antiangiogenic metabolites from ω-3 LCPUFAs (24). This unique feature of the CYP enzymes may provide a previously unidentified mechanistic link between the ω-6/ω-3 ratio of dietary LCPUFAs and pathological angiogenesis; however, their roles in ocular angiogenesis have been largely unexplored to date.We now show that dietary enrichment with ω-3 LCPUFAs suppresses CNV, vascular leakage, and immune cell recruitment to the lesion site in a mouse model of laser-induced CNV. We characterized the CYP-dependent pathway by which dietary ω-3 LCPUFAs promote resolution of choroidal neovessels in this model and identified CYP-generated metabolites 17,18-EEQ and 19,20-EDP as mediators of disease resolution. Furthermore, we show that expression of adhesion molecules at the CNV site was down-regulated in association with inhibition of leukocyte recruitment in mice receiving ω-3 LCPUFAs. 相似文献
962.
A novel series of N′‐(2‐(3,5‐disubstituted‐4H‐1,2,4‐triazol‐4‐yl)acetyl)‐6/7/8‐substituted‐2‐oxo‐2H‐chromen‐3‐carbohydrazides were synthesized and studied for their α‐glucosidase inhibition activity. Most of the synthesized compounds exhibited potential α‐glucosidase inhibition activity with IC50 values ranging from 0.96 ± 0.02 to 32.86 ± 0.73 µg/ml. Among them, compounds 3e and 4e , having a methoxy group on the coumarin ring, proved to be the most potent ones, showing an enzyme inhibition activity with IC50 = 0.96 ± 0.02 and 1.44 ± 0.06 µg/ml, respectively. The kinetic study through Lineweaver–Burk plots revealed that the inhibition mechanism of the most active compounds 3d, 3e, 4d , and 4e , on the α‐glucosidase activity, was found to be in the competitive mode. 相似文献
963.
Mizuki Sone Takeshi Toyoda Young‐Man Cho Jun‐ichi Akagi Kohei Matsushita Yasuko Mizuta Tomomi Morikawa Akiyoshi Nishikawa Kumiko Ogawa 《Journal of applied toxicology : JAT》2019,39(6):868-876
Phosphorylated histone H2AX (γ‐H2AX) has been demonstrated as a DNA damage marker both in vitro and in vivo. We previously reported the effects of genotoxic carcinogens in the urinary bladder of rats by immunohistochemical analysis of γ‐H2AX using samples from 28‐day repeated‐dose tests. To evaluate the application of γ‐H2AX as a biomarker of carcinogenicity in the bladder, we examined species differences in γ‐H2AX formation in the urinary bladder of mice. Six‐week‐old male B6C3F1 mice were treated orally with 12 chemicals for 4 weeks. Immunohistochemical analysis demonstrated that N‐butyl‐N‐(4‐hydroxybutyl)nitrosamine, p‐cresidine and 2‐acetylaminofluorene (2‐AAF), classified as genotoxic bladder carcinogens, induced significant increases in γ‐H2AX levels in the bladder urothelium. In contrast, genotoxic (2‐nitroanisole, glycidol, N‐nitrosodiethylamine and acrylamide) and non‐genotoxic (dimethylarsinic acid and melamine) non‐bladder carcinogens did not upregulate γ‐H2AX. Importantly, 2‐nitroanisole, a potent genotoxic bladder carcinogen in rats, significantly increased the proportion of γ‐H2AX‐positive cells in rats only, reflecting differences in carcinogenicity in the urinary bladder between rats and mice. Significant upregulation of γ‐H2AX was also induced by uracil, a non‐genotoxic bladder carcinogen that may be associated with cell proliferation, as demonstrated by increased Ki67 expression. 2‐AAF caused γ‐H2AX formation mainly in the superficial layer, together with reduced and disorganized expression of uroplakin III, unlike in rats, suggesting the mouse‐specific cytotoxicity of 2‐AAF in umbrella cells. These results suggest γ‐H2AX is a useful biomarker reflecting species differences in carcinogenicity in the urinary bladder. 相似文献
964.
965.
966.
目的 探讨伊班膦酸钠注射液联合骨化三醇胶丸治疗老年骨质疏松症的临床疗效。方法 选取2016年11月-2017年12月在上海市第三康复医院和第二军医大学附属公利医院收治的123例老年骨质疏松症患者作为研究对象,将患者随机分为骨化三醇组、伊班膦酸钠组、联合组,每组各41例。骨化三醇组患者口服骨化三醇胶丸,2粒/次,1次/d;伊班膦酸钠组患者静脉滴注伊班膦酸钠注射液,2 mg溶于0.9%氯化钠溶液250 mL中,滴注时间大于2 h,1次/3个月;联合组给予伊班膦酸钠注射液联合骨化三醇胶丸,用法用量同上。3组患者均连续治疗12个月。观察3组患者的临床疗效,比较3组患者治疗前后的数字疼痛评分(NRS)、骨密度(BMD)、血磷、血钙、抗酒石酸酸性磷酸酶5b(TRAP-5b)、骨源性碱性磷酸酶(BALP)水平和不良反应。结果 治疗后,骨化三醇组、伊班膦酸钠组、联合组的总有效率分别为82.93%、85.37%和95.12%,联合组总有效率显著优于骨化三醇组和伊班膦酸钠组,差异具有统计学意义(P<0.05)。治疗6、12个月后,3组患者的NRS评分值均显著降低,平均腰椎BMD和平均股骨颈BMD均显著升高,同组治疗前后比较差异具有统计学意义(P<0.05);治疗6、12个月后,联合组患者的NRS评分值显著低于同期骨化三醇组和伊班膦酸钠组,而平均腰椎BMD和平均股骨颈BMD均明显高于同期骨化三醇组和伊班膦酸钠组,差异具有统计学意义(P<0.05)。治疗后,3组患者血钙、血磷相较于治疗前差异无统计学意义,且联合组患者的血钙、血磷较其他两组差异均无统计学意义。治疗6、12个月后,3组患者TRAP-5b、BALP水平均显著降低,同组治疗前后比较差异具有统计学意义(P<0.05);治疗6、12个月后,联合组患者TRAP-5b、BALP水平显著低于同期骨化三醇组和伊班膦酸钠组,差异具有统计学意义(P<0.05)。3组患者的不良反应发生情况差异无统计学意义。结论 伊班膦酸钠注射液联合骨化三醇胶丸治疗老年性骨质疏松症具有较好的临床疗效,能够改善骨密度,减少疼痛,维持骨生化指标,具有一定的临床推广应用价值。 相似文献
967.
目的研究miR-21抑制物在A549细胞球增殖的作用及其相关机制。方法在无血清培养基中培养A549细胞球,形成细胞球后进行CD133+CD44+表达检测。实验分为A549细胞球组:未经处理;IHN组:miR-21抑制物转染A549细胞球组;IHN-NC组:miR-21抑制物阴性对照物转染A549细胞球组。Western印迹检测A549细胞和A549细胞球中DKK2、β-catenin蛋白以及QPCR检测miR-21在两种细胞中的表达;合成miR-21抑制物和阴性对照,分别转染A549细胞球48 h后,应用QPCR检测转染前后miR-21的表达变化,以及使用Western印迹分析DKK2、β-catenin蛋白的表达变化,利用噻唑蓝(MTT)检测12、24、48 h细胞的增殖能力。结果流式细胞术检测A549细胞球中CD133+CD44+阳性率为65.800%;IHN组miR-21的表达以及β-catenin蛋白的表达较A549细胞球组和IHN-NC组显著下调(P<0.05),而DKK2蛋白表达显著升高(P<0.05);MTT结果示IHN组和IHN-NC组在12、24、48 h时抑制率显著高于A549 sphere组(P<0.05),IHN组在24、48 h时相点抑制率明显高于IHN-NC组(P<0.05)。结论miR-21抑制物可有效抑制A549 sphere的增殖,其可能成为治疗肺癌的潜在靶点。 相似文献
968.
969.