Erryn Tappy, Haolin Shi, Jessica Pruszynski, Maria Florian-Rodriguez
{"title":"在小鼠动物模型中使用衰老剂达沙替尼和槲皮素预防盆腔器官脱垂。","authors":"Erryn Tappy, Haolin Shi, Jessica Pruszynski, Maria Florian-Rodriguez","doi":"10.18632/aging.206120","DOIUrl":null,"url":null,"abstract":"<p><strong>Objective: </strong>Senolytic agents have the potential to target age-related pathology associated with cellular senescence and reduce senescent cell activity in several disease processes. We utilized a mouse model of pelvic organ prolapse, Fibulin-5 knockout (<i>Fbln-5<sup>-/-</sup>)</i> mice, to assess the ability of dasatinib and quercetin (D+Q) to prevent development of prolapse.</p><p><strong>Methods: </strong>Four-week-old female <i>Fbln-5<sup>-/-</sup></i> (n=63) and wild-type (WT) mice (n=54) were assigned to control (vehicle injection) or treatment (D = 5 mg/kg, Q = 50 mg/kg) groups. Weekly oral gavage injections were administered from weeks 4-8 of life. Pelvic organ prolapse quantification system measurements were obtained weekly. Vaginal tissue was harvested at 10, 12 and 20 weeks. Tissue analysis included immunostaining for cell cycle inhibitors, multiplex cytokine analysis, senescence-associated-β-galactosidase (SA-β-Gal) and histologic analysis of extracellular matrix proteins.</p><p><strong>Results: </strong>Perineal body length was significantly longer in <i>Fbln-5<sup>-/-</sup></i> treatment mice at 20 weeks. Expression of p16 and p53 was decreased in <i>Fbln-5<sup>-/-</sup></i> treatment mice compared to controls (4.0% vs. 26.7%, p=0.0124 and 2.9% vs. 16.8%, p=0.272) at 20 weeks. Expression of SA-β-Gal and senescence-associated cytokines did not vary significantly between groups. At 20 weeks, vaginal tissue elastin content in <i>Fbln-5<sup>-/-</sup></i> treatment mice increased compared to controls (1.04% vs. 0.84%, p=0.999).</p><p><strong>Conclusions: </strong>D+Q injections did not result in clinically significant differences in prolapse development but did demonstrate decreased expression of cellular senescence markers in <i>Fbln-5<sup>-/-</sup></i> mice. This suggests senolytic agents may mitigate contributions of cellular senescence to tissue dysfunction associated with prolapse. Further studies are needed to confirm ideal timing, dosage, and route of senolytics in prevention of prolapse.</p>","PeriodicalId":55547,"journal":{"name":"Aging-Us","volume":null,"pages":null},"PeriodicalIF":3.9000,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Use of the senolytics dasatinib and quercetin for prevention of pelvic organ prolapse in a mouse animal model.\",\"authors\":\"Erryn Tappy, Haolin Shi, Jessica Pruszynski, Maria Florian-Rodriguez\",\"doi\":\"10.18632/aging.206120\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Objective: </strong>Senolytic agents have the potential to target age-related pathology associated with cellular senescence and reduce senescent cell activity in several disease processes. We utilized a mouse model of pelvic organ prolapse, Fibulin-5 knockout (<i>Fbln-5<sup>-/-</sup>)</i> mice, to assess the ability of dasatinib and quercetin (D+Q) to prevent development of prolapse.</p><p><strong>Methods: </strong>Four-week-old female <i>Fbln-5<sup>-/-</sup></i> (n=63) and wild-type (WT) mice (n=54) were assigned to control (vehicle injection) or treatment (D = 5 mg/kg, Q = 50 mg/kg) groups. Weekly oral gavage injections were administered from weeks 4-8 of life. Pelvic organ prolapse quantification system measurements were obtained weekly. Vaginal tissue was harvested at 10, 12 and 20 weeks. Tissue analysis included immunostaining for cell cycle inhibitors, multiplex cytokine analysis, senescence-associated-β-galactosidase (SA-β-Gal) and histologic analysis of extracellular matrix proteins.</p><p><strong>Results: </strong>Perineal body length was significantly longer in <i>Fbln-5<sup>-/-</sup></i> treatment mice at 20 weeks. Expression of p16 and p53 was decreased in <i>Fbln-5<sup>-/-</sup></i> treatment mice compared to controls (4.0% vs. 26.7%, p=0.0124 and 2.9% vs. 16.8%, p=0.272) at 20 weeks. Expression of SA-β-Gal and senescence-associated cytokines did not vary significantly between groups. At 20 weeks, vaginal tissue elastin content in <i>Fbln-5<sup>-/-</sup></i> treatment mice increased compared to controls (1.04% vs. 0.84%, p=0.999).</p><p><strong>Conclusions: </strong>D+Q injections did not result in clinically significant differences in prolapse development but did demonstrate decreased expression of cellular senescence markers in <i>Fbln-5<sup>-/-</sup></i> mice. This suggests senolytic agents may mitigate contributions of cellular senescence to tissue dysfunction associated with prolapse. Further studies are needed to confirm ideal timing, dosage, and route of senolytics in prevention of prolapse.</p>\",\"PeriodicalId\":55547,\"journal\":{\"name\":\"Aging-Us\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":3.9000,\"publicationDate\":\"2024-09-26\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Aging-Us\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.18632/aging.206120\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"CELL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Aging-Us","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.18632/aging.206120","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
引用次数: 0
摘要
目的:衰老溶解剂有可能针对与细胞衰老有关的年龄相关病理,并在多种疾病过程中降低衰老细胞的活性。我们利用盆腔器官脱垂的小鼠模型--Fibulin-5基因敲除(Fbln-5-/-)小鼠来评估达沙替尼和槲皮素(D+Q)预防脱垂发生的能力:方法:将四周大的雌性Fbln-5-/-小鼠(n=63)和野生型(WT)小鼠(n=54)分为对照组(注射车辆)或治疗组(D=5 mg/kg,Q=50 mg/kg)。在小鼠出生后第4-8周,每周对其进行口服灌胃注射。盆腔器官脱垂定量系统每周测量一次。10、12和20周时采集阴道组织。组织分析包括细胞周期抑制剂免疫染色、多重细胞因子分析、衰老相关-β-半乳糖苷酶(SA-β-Gal)和细胞外基质蛋白组织学分析:结果:20 周时,Fbln-5-/- 治疗小鼠的会阴体长明显较长。与对照组相比,Fbln-5-/-治疗小鼠的p16和p53表达量在20周时有所下降(4.0% vs. 26.7%,p=0.0124;2.9% vs. 16.8%,p=0.272)。SA-β-Gal和衰老相关细胞因子的表达在组间无显著差异。20 周时,与对照组相比,Fbln-5-/- 治疗小鼠的阴道组织弹性蛋白含量有所增加(1.04% vs. 0.84%,p=0.999):结论:D+Q注射并没有导致脱垂发展的临床显著差异,但确实表明Fbln-5-/-小鼠细胞衰老标记物的表达减少。这表明,衰老剂可减轻细胞衰老对脱垂相关组织功能障碍的影响。还需要进一步的研究来确认使用衰老分解剂预防脱垂的理想时机、剂量和途径。
Use of the senolytics dasatinib and quercetin for prevention of pelvic organ prolapse in a mouse animal model.
Objective: Senolytic agents have the potential to target age-related pathology associated with cellular senescence and reduce senescent cell activity in several disease processes. We utilized a mouse model of pelvic organ prolapse, Fibulin-5 knockout (Fbln-5-/-) mice, to assess the ability of dasatinib and quercetin (D+Q) to prevent development of prolapse.
Methods: Four-week-old female Fbln-5-/- (n=63) and wild-type (WT) mice (n=54) were assigned to control (vehicle injection) or treatment (D = 5 mg/kg, Q = 50 mg/kg) groups. Weekly oral gavage injections were administered from weeks 4-8 of life. Pelvic organ prolapse quantification system measurements were obtained weekly. Vaginal tissue was harvested at 10, 12 and 20 weeks. Tissue analysis included immunostaining for cell cycle inhibitors, multiplex cytokine analysis, senescence-associated-β-galactosidase (SA-β-Gal) and histologic analysis of extracellular matrix proteins.
Results: Perineal body length was significantly longer in Fbln-5-/- treatment mice at 20 weeks. Expression of p16 and p53 was decreased in Fbln-5-/- treatment mice compared to controls (4.0% vs. 26.7%, p=0.0124 and 2.9% vs. 16.8%, p=0.272) at 20 weeks. Expression of SA-β-Gal and senescence-associated cytokines did not vary significantly between groups. At 20 weeks, vaginal tissue elastin content in Fbln-5-/- treatment mice increased compared to controls (1.04% vs. 0.84%, p=0.999).
Conclusions: D+Q injections did not result in clinically significant differences in prolapse development but did demonstrate decreased expression of cellular senescence markers in Fbln-5-/- mice. This suggests senolytic agents may mitigate contributions of cellular senescence to tissue dysfunction associated with prolapse. Further studies are needed to confirm ideal timing, dosage, and route of senolytics in prevention of prolapse.