Withaferin A ameliorates ovarian cancer-induced renal damage through the regulation of expression of inflammatory cytokines.

IF 3.8 3区 医学 Q1 REPRODUCTIVE BIOLOGY Journal of Ovarian Research Pub Date : 2024-10-11 DOI:10.1186/s13048-024-01519-9
Kusum Kumar, Katherine Bosch, Vasa Vemuri, Nicholas Kratholm, Madhavi Rane, Sham S Kakar
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Abstract

Background: Cachexia a multifactorial syndrome is a common sequala in patients with cancer. It varies from 42 to 80% depending upon the oncological stage and is directly responsible for 30% of deaths in these patients. Previous research from our laboratory demonstrated that peritoneal ovarian cancer generated in NSG mice resulted in skeletal and cardiac muscle atrophy - leading to loss of skeletal muscle mass and strength, and cardiac dysfunction (cachexia). Treatment of mice bearing i.p. tumors with withaferin A (WFA) showed reversal of skeletal muscle and cardiac cachexia. The present study is focused on determining effects of peritoneal ovarian tumors on kidney damage and effects of WFA treatment on ameliorating kidney damage.

Methods: We generated intraperitoneal ovarian cancer by injecting female NSG mice with ovarian cancer cell line (A2780). After one week of injecting cancer cells, mice were treated with WFA (4 mg/kg) every third day, for three weeks. After 4 weeks of injection of cancer cells, the mice were sacrificed and various tissues including kidney and blood were collected, snap-frozen in liquid nitrogen, and stored at -800C. The presence of kidney biomarker creatinine, was measured in the plasma by an ELISA. The mRNA was isolated from mouse kidneys and was used to examine the expression levels of signaling proteins, inflammatory cytokines, and genes responsible for inducing cachexia (IL-1β, IL-6, TNF-α, TGF-β, GDF-15, and MYD88).

Results: Our results showed a significant increase in levels of expression of inflammatory cytokine IL-1 β (p < 0.01), IL-6 (p < 0.001), TNF-α (p < 0.001), and other related genes including TRAF6 (p < 0.01), MYD88 (p < 0.01), and GDF-15 (p = 0.005) in tumor-bearing mice compared to controls. Treatment of mice bearing tumors with WFA attenuated the increase in expression of each gene. In addition, our results showed a significant increase in creatinine levels in circulation in tumor-bearing mice compared to control mice. Treatment of tumor-bearing mice with WFA resulted in a significant decrease in plasma creatinine levels compared to tumor-bearing mice.

Conclusions: Our results conclude that ovarian tumors in NSG mice caused kidney damage and renal dysfunction, which was effectively ameliorated by WFA treatment, suggesting a protective effect of WFA on kidney injury induced by ovarian cancer.

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Withaferin A 可通过调节炎症细胞因子的表达来改善卵巢癌诱发的肾损伤。
背景:恶病质是癌症患者常见的一种多因素综合征。根据肿瘤阶段的不同,恶病质的比例从 42% 到 80% 不等,而且 30% 的死亡是由恶病质直接造成的。我们实验室以前的研究表明,NSG 小鼠腹膜卵巢癌会导致骨骼肌和心肌萎缩,从而导致骨骼肌质量和力量下降以及心功能障碍(恶病质)。用干扰素 A(WFA)治疗腹腔肿瘤小鼠可逆转骨骼肌和心肌恶病质。本研究的重点是确定腹膜卵巢肿瘤对肾损伤的影响以及WFA治疗对改善肾损伤的影响:方法:我们给雌性 NSG 小鼠注射卵巢癌细胞株(A2780),产生腹腔卵巢癌。注射癌细胞一周后,小鼠每隔三天接受一次 WFA(4 毫克/千克)治疗,连续三周。注射癌细胞 4 周后,小鼠被处死,收集包括肾脏和血液在内的各种组织,用液氮速冻并保存在 -800C 温度下。用酶联免疫吸附法测定血浆中肾脏生物标志物肌酐的含量。从小鼠肾脏中分离出 mRNA,用于检测信号蛋白、炎症细胞因子和诱导恶病质基因(IL-1β、IL-6、TNF-α、TGF-β、GDF-15 和 MYD88)的表达水平:结果表明,炎性细胞因子 IL-1 β 的表达水平明显升高(p 结论:我们的结果表明,卵巢肿瘤中的炎性细胞因子表达水平明显升高:我们的结果表明,NSG 小鼠的卵巢肿瘤会导致肾脏损伤和肾功能障碍,而 WFA 治疗可有效改善这些症状,这表明 WFA 对卵巢癌引起的肾脏损伤具有保护作用。
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来源期刊
Journal of Ovarian Research
Journal of Ovarian Research REPRODUCTIVE BIOLOGY-
CiteScore
6.20
自引率
2.50%
发文量
125
审稿时长
>12 weeks
期刊介绍: Journal of Ovarian Research is an open access, peer reviewed, online journal that aims to provide a forum for high-quality basic and clinical research on ovarian function, abnormalities, and cancer. The journal focuses on research that provides new insights into ovarian functions as well as prevention and treatment of diseases afflicting the organ. Topical areas include, but are not restricted to: Ovary development, hormone secretion and regulation Follicle growth and ovulation Infertility and Polycystic ovarian syndrome Regulation of pituitary and other biological functions by ovarian hormones Ovarian cancer, its prevention, diagnosis and treatment Drug development and screening Role of stem cells in ovary development and function.
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