University of Louisville

Withaferin A as a Potential Therapeutic Target for the Treatment of Angiotensin II-Induced Lung Dysfunction (Cachexia)

Sophomore

Neuroscience

University of Louisville

Department of Physiology

Cachexia is a complex syndrome that impacts 50-80% of advanced cancer patients,

contributing to 20-25% of cancer-related deaths. Cardiac cachexia, a severe form of the

syndrome, involves extensive muscle wasting and cardiac myocyte damage, which

significantly impairs heart function. This study explores the therapeutic potential of

Withaferin A (WFA), a bioactive compound derived from Withania somnifera (ashwagandha),

known for its anti-inflammatory, anti-cancer, and cardioprotective effects, in an Angiotensin

II (Ang II)-induced cachexia model.

Methods: Eleven-week-old female C57BL/6J mice were stratified into groups and baseline

recordings for body weight, forelimb strength, and total grip strength were obtained. Mice

were implanted with osmotic minipumps delivering Ang II or saline for 4 weeks. After one

week, mice received i.p. injections of WFA or vehicle every three days for 3 weeks. Cardiac

functions were evaluated by performing echocardiography. Lund tissues were collected after

scarifying the animals. Lung tissues were sectioned and stained to assess fibrosis and

inflammation. Gene expression of Collagen-1, TGF-β, NLRP3, IL-6, and Casp-1 was

analyzed using real-time PCR.

Results: Ang II vehicle group showed increased fibrosis, mRNA expression of Collagen-1,

TGF-β, NLRP3, IL-6, and Casp-1 indicating activation of the inflammasome pathway and

Fibrosis pathway leading to lung dysfunction. WFA treatment significantly reduced fibrosis,

and the expression of these genes, suggesting its potential to reverse Ang II-induced effects.

However, high variation from sample-to-sample rendered the results somewhat inconclusive.

Conclusion: WFA significantly lowers the expression of inflammasome-related genes and

Fibrosis-related genes in Ang II-induced lung dysfunction, demonstrating its anti-

inflammatory and anti-fibrosis effects. Although preliminary, this study suggests that WFA

reverses cardiac dysfunction, which in turn mitigates lung dysfunction induced by high

circulation of Ang II.

Future Directions: To enhance the conclusiveness of our findings, future studies should

increase sample sizes and explore detailed molecular mechanisms. These steps will help to

validate WFA's therapeutic potential and facilitate its clinical translation. This study provides

a foundational understanding of WFA's effects on cachexia-induced cardiac and lung

dysfunction, highlighting its potential as a therapeutic agent in managing cachexia

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