醉茄素 A 通过调节炎症细胞因子的表达改善卵巢癌诱导的肾损伤。

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

机构信息

Deparment of Biology, University of Louisville, Louisville, KY, USA.

Department of Biology and Chemistry, Liberty University, Lynchburg, VA, USA.

出版信息

J Ovarian Res. 2024 Oct 11;17(1):199. doi: 10.1186/s13048-024-01519-9.

DOI:10.1186/s13048-024-01519-9

PMID:39394174

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11468018/

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 -80C. 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.

摘要

背景

恶病质是一种多因素综合征，是癌症患者的常见后遗症。根据肿瘤分期的不同，恶病质的发生率在 42%至 80%之间，直接导致这些患者 30%的死亡。我们实验室的先前研究表明，在 NSG 小鼠中产生的腹膜卵巢癌导致骨骼肌和心肌萎缩-导致骨骼肌质量和力量丧失以及心脏功能障碍（恶病质）。用醉茄素 A（WFA）治疗患有腹腔肿瘤的小鼠可逆转骨骼肌和心肌恶病质。本研究旨在确定腹膜卵巢肿瘤对肾脏损伤的影响以及 WFA 治疗对改善肾脏损伤的影响。

方法

我们通过向雌性 NSG 小鼠注射卵巢癌细胞系（A2780）来产生腹腔卵巢癌。在注射癌细胞一周后，每隔三天用 WFA（4mg/kg）治疗小鼠，共三周。在注射癌细胞四周后，处死小鼠并收集各种组织，包括肾脏和血液，在液氮中迅速冷冻，并储存在-80°C。通过 ELISA 测量血浆中肾脏生物标志物肌酐的存在。从小鼠肾脏中分离出 mRNA，并用于检查信号蛋白，炎性细胞因子和诱导恶病质的基因（IL-1β，IL-6，TNF-α，TGF-β，GDF-15 和 MYD88）的表达水平。

结果

我们的结果表明，与对照组相比，肿瘤荷瘤小鼠中炎性细胞因子 IL-1β（p <0.01），IL-6（p <0.001），TNF-α（p <0.001）和其他相关基因（TRAF6（p <0.01），MYD88（p <0.01）和 GDF-15（p = 0.005）的表达水平显着增加。用 WFA 治疗荷瘤小鼠可减弱每种基因的表达增加。此外，我们的结果表明，与对照组相比，肿瘤荷瘤小鼠的循环中肌酐水平显着升高。用 WFA 治疗荷瘤小鼠可使肿瘤荷瘤小鼠的血浆肌酐水平显着降低。