IL6/STAT Signaling Pathway and PPARα are Involved in Mediating the dose Dependent Cardioprotective Effect of Fenofibrate in 5-fluorouracil induced Cardiotoxicity

Q: What are the key findings of this study?

Fenofibrate significantly protected against 5-fluorouracil-induced cardiotoxicity in a dose-dependent manner, reducing cardiac enzymes such as CK-MB and oxidative stress markers.

Q: What is the clinical evidence from this study?

Population: 5-fluorouracil induced cardiotoxicity (n=40). Intervention: Fenofibrate vs. 5-fluorouracil alone. Primary outcome: Serum CK-MB levels (U/L) (p=<0.05).

Q: What does this research mean for the field?

Fenofibrate exerts dose-dependent cardioprotective effects against 5-fluorouracil-induced cardiotoxicity via PPARα upregulation, IL6/STAT pathway inhibition, and attenuation of oxidative stress and apoptosis. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

Q: What question did this study set out to answer?

To evaluate the cardioprotective efficacy of fenofibrate against 5-fluorouracil-induced cardiotoxicity and investigate the underlying molecular mechanisms.

Marwa Monier Mahmoud Refaie; Sayed Shehata; Asmaa M. A. Bayoumi; Nashwa Fathy Gamal El‐Tahawy; Walaa Yehia Abdelzaher

doi:10.21203/rs.3.rs-415786/v1

April 16, 2021Open Access

IL6/STAT Signaling Pathway and PPARα are Involved in Mediating the dose Dependent Cardioprotective Effect of Fenofibrate in 5-fluorouracil induced Cardiotoxicity

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Key result

Fenofibrate protects against 5-fluorouracil-induced cardiotoxicity, cutting CK-MB by ~64% alongside lowered oxidative stress.

P<0.05
n=40

Why the study?

Cardiotoxicity from 5-fluorouracil limits its clinical usefulness, creating a critical need for protective therapies, but no studies have evaluated the potential cardioprotective effects of fenofibrate in this setting.

Does fenofibrate prevent 5-fluorouracil-induced cardiotoxicity in a rat model?

Key Points

To evaluate the cardioprotective efficacy of fenofibrate against 5-fluorouracil-induced cardiotoxicity and investigate the underlying molecular mechanisms.
Administered oral fenofibrate at doses of 25, 50, and 100 mg/kg/day for 7 days in an experimental model.
Induced acute cardiotoxicity via a single intraperitoneal injection of 5-fluorouracil (150 mg/kg) on day 5 of the protocol.
5-fluorouracil administration caused severe cardiac damage, significantly increasing cardiac enzymes, malondialdehyde, interleukin 6, STAT4, and caspase 3, while reducing glutathione, total antioxidant capacity, and PPARα expression.
Fenofibrate treatment dose-dependently reversed 5-fluorouracil-induced cardiotoxicity by upregulating PPARα, inhibiting the IL6/STAT signaling cascade, and exerting antioxidant, anti-inflammatory, and anti-apoptotic effects.

Structured PICO

Does fenofibrate prevent 5-fluorouracil-induced cardiotoxicity in a rat model?

P

Population

40 male Wistar albino rats were used to evaluate the cardioprotective effect of fenofibrate against 5-fluorouracil-induced cardiotoxicity over 7 days.

I

Intervention

Fenofibrate (25, 50, or 100 mg/kg/day) orally for 7 days, with 5-fluorouracil (150 mg/kg i.p.) injected on the 5th day

C

Comparator

5-fluorouracil alone (150 mg/kg i.p. on the 5th day) and vehicle control (1% carboxymethyl cellulose orally for 7 days)

O

Outcome

Cardiac biomarkers (CK-MB, LDH, ALT, AST), oxidative stress parameters (MDA, GSH, TAC), histopathological changes, and expression of IL6, STAT4, caspase 3, and PPARαsurrogate

Main Result

Absolute Event Rate: 23.45% vs 64.92%

p-value: p=<0.05

Fenofibrate demonstrates a dose-dependent cardioprotective effect against 5-fluorouracil-induced cardiotoxicity in rats by modulating the IL6/STAT pathway and upregulating PPARα.

Limitations

Animal model study, requiring further studies to evaluate the protective effect in humans receiving 5-fluorouracil chemotherapy.

Implication

Hypothesis-generating for fenofibrate cardioprotection in 5-FU therapy; human trials required before any clinical consideration.

Abstract

Purpose: Cardiotoxicity of anticancer drugs such as 5-fluorouracil (5FU) and anthracyclines is a major complication that challenges their clinical usefulness. There is a critical need for finding new protecting drugs to defense against these harmful side effects. Up till now, there are no studies evaluate the possible cardioprotective effects of fenofibrate (FEN) in 5FU-induced cardiotoxicity. So that, we aimed in current model to evaluate such effect of FEN and explore different mechanisms mediating it.Methods: we used FEN (25, 50,100 mg/kg/day) orally for 7days with induction of cardiotoxicity by intraperitoneal (i.p.) injection of 5FU (150 mg/kg) on 5th day. Results: current study showed that 5FU succeeded in induction of cardiotoxicity and manifested by significant elevation of cardiac enzymes, tissue malondialdehyde (MDA), interleukin 6 (IL6), signal transducer and activator of transcription 4(STAT4) and caspase 3 levels. Furthermore, 5FU group showed toxic histopathological changes of marked cardiac damage and significant decrease in reduced glutathione (GSH), total antioxidant capacity (TAC) and peroxisome proliferator activated receptor alpha (PPARα) expression. FEN could reverse 5FU-induced cardiotoxicity by different mechanisms including upregulation of PPARα, inhibition of IL6/STAT signaling pathway, anti-inflammatory, anti-apoptotic and anti-oxidant properties.Conclusion: FEN had a significant cardioprotective effect against 5FU induced cardiac damage.

Discussion

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Cite This Study

Refaie et al. (2021) studied 5-fluorouracil induced cardiotoxicity (n=40). Fenofibrate vs. 5-fluorouracil alone was evaluated on Serum CK-MB levels (U/L) (p=<0.05). Fenofibrate significantly protected against 5-fluorouracil-induced cardiotoxicity in a dose-dependent manner, reducing cardiac enzymes such as CK-MB and oxidative stress markers.

synapsesocial.com/papers/6aa646006b1ae6e96478fcda https://doi.org/10.21203/rs.3.rs-415786/v1

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IL6/STAT Signaling Pathway and PPARα are Involved in Mediating the dose Dependent Cardioprotective Effect of Fenofibrate in 5-fluorouracil induced Cardiotoxicity

Key Points

Structured PICO

Main Result

Limitations

Implication

Abstract

Discussion

Cite This Study

IL6/STAT Signaling Pathway and PPARα are Involved in Mediating the dose Dependent Cardioprotective Effect of Fenofibrate in 5-fluorouracil induced Cardiotoxicity

Key Points

Structured PICO

Main Result

Limitations

Implication

Abstract

Discussion

Cite This Study

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