A screen of small molecule and genetic modulators of life span in female Drosophila identifies etomoxir, RH5849 and unanticipated temperature effects.

IF 2.4 4区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY
Fly Pub Date : 2022-12-01 DOI:10.1080/19336934.2022.2149209
Gary N Landis, Sebastian Ko, Oscar Peng, Brett Bognar, Michael Khmelkov, Hans S Bell, John Tower
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引用次数: 0

Abstract

Mifepristone increases life span in female Drosophila melanogaster, and its molecular target(s) remain unclear. Here small molecule and genetic interventions were tested for ability to mimic mifepristone, or to decrease life span in a way that can be rescued by mifepristone. Etomoxir inhibits lipid metabolism, and significantly increased life span in virgin and mated females, but not males, at 50 µM concentration. Pioglitazone is reported to activate both mammalian PPARγ and its Drosophila homolog Eip75B. Pioglitazone produced minor and inconsistent benefits for female Drosophila life span, and only at the lowest concentrations tested. Ecdysone is a Drosophila steroid hormone reported to regulate responses to mating, and RH5849 is a potent mimic of ecdysone. RH5849 reduced virgin female life span, and this was partly rescued by mifepristone. Mifepristone did not compete with RH5849 for activation of an ecdysone receptor (EcR)-responsive transgenic reporter, indicating that the relevant target for mifepristone is not EcR. The conditional GAL4/GAL80ts system was used in attempt to test the effect of an Eip75B RNAi construct on female life span. However, the 29°C temperature used for induction reduced or eliminated mating-induced midgut hypertrophy, the negative life span effects of mating, and the positive life span effects of mifepristone. Even when applied after mating was complete, a shift to 29°C temperature reduced mating-induced midgut hypertrophy by half, and the life span effects of mating by 4.8-fold. Taken together, these results identify promising small molecules for further analysis, and inform the design of experiments involving the GAL4/GAL80ts system.

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对雌果蝇寿命的小分子和基因调节剂进行筛选,发现了依托莫西尔、RH5849 和意想不到的温度效应。
米非司酮能延长雌性黑腹果蝇的寿命,但其分子靶点仍不清楚。在这里,我们测试了小分子和基因干预措施模拟米非司酮的能力,或以米非司酮可以挽救的方式减少寿命的能力。Etomoxir 可抑制脂质代谢,在 50 µM 浓度下可显著延长处女和交配雌性的寿命,但不能延长雄性的寿命。据报道,吡格列酮可激活哺乳动物 PPARγ 及其果蝇同源物 Eip75B。吡格列酮对雌果蝇的寿命产生的益处很小,而且不一致,只有在测试的最低浓度下才产生益处。据报道,蜕皮激素是一种果蝇类固醇激素,可调节交配反应,而 RH5849 是蜕皮激素的有效模拟物。RH5849 会缩短雌性处女的寿命,而米非司酮可以部分缓解这种情况。米非司酮不能与 RH5849 竞争激活蜕皮激素受体(EcR)反应性转基因报告物,这表明米非司酮的相关靶标不是 EcR。为了测试 Eip75B RNAi 构建物对雌性寿命的影响,我们使用了条件性 GAL4/GAL80ts 系统。然而,用于诱导的 29°C 温度降低或消除了交配诱导的中肠肥大、交配对寿命的负面影响以及米非司酮对寿命的正面影响。即使在交配完成后使用,转到 29°C 的温度也能将交配诱导的中肠肥大减少一半,将交配对寿命的影响减少 4.8 倍。总之,这些结果为进一步分析确定了有希望的小分子,并为设计涉及 GAL4/GAL80ts 系统的实验提供了信息。
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来源期刊
Fly
Fly 生物-生化与分子生物学
CiteScore
2.90
自引率
0.00%
发文量
17
审稿时长
>12 weeks
期刊介绍: Fly is the first international peer-reviewed journal to focus on Drosophila research. Fly covers a broad range of biological sub-disciplines, ranging from developmental biology and organogenesis to sensory neurobiology, circadian rhythm and learning and memory, to sex determination, evolutionary biology and speciation. We strive to become the “to go” resource for every researcher working with Drosophila by providing a forum where the specific interests of the Drosophila community can be discussed. With the advance of molecular technologies that enable researchers to manipulate genes and their functions in many other organisms, Fly is now also publishing papers that use other insect model systems used to investigate important biological questions. Fly offers a variety of papers, including Original Research Articles, Methods and Technical Advances, Brief Communications, Reviews and Meeting Reports. In addition, Fly also features two unconventional types of contributions, Counterpoints and Extra View articles. Counterpoints are opinion pieces that critically discuss controversial papers questioning current paradigms, whether justified or not. Extra View articles, which generally are solicited by Fly editors, provide authors of important forthcoming papers published elsewhere an opportunity to expand on their original findings and discuss the broader impact of their discovery. Extra View authors are strongly encouraged to complement their published observations with additional data not included in the original paper or acquired subsequently.
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