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Morin mitigates ifosfamide induced nephrotoxicity by regulation of NF-kappaB/p53 and Bcl-2 expression
Selim Çomaklı1, Fatih Mehmet Kandemir2, Sefa Küçükler2
1Department of Pathology, Faculty of Veterinary Medicine, Atatürk University, Erzurum, Turkey.
Abstract:
Ifosfamide (IFO) is used for treating childhood solid tumors, but its use is limited by its adverse effects on kidneys. Morin may be used to prevent nephrotoxic and other side effects. We investigated the underlying mechanisms of the protective effects of morin on IFO induced nephrotoxicity. We used 35 male rats divided into five groups of seven: control group, morin group, IFO group, 100 mg/kg morin + IFO group and 200 mg/kg morin + IFO group. We measured kidney tissue oxidant, antioxidant and inflammatory parameters using ELISA, and apoptosis was evaluated using immunohistochemistry and real time PCR. Serum urea, creatinine and kidney injury molecule-1 (KIM-1) levels were increased by IFO treatment; elevated levels were decreased significantly by treatment with both 100 and 200 mg/kg morin. Morin treatment also decreased oxidative stress and lipid oxidation in IFO treated rats. The ameliorative effect of morin on inflammatory response was due to reduced levels of NF-κB and TNF-α. Morin also reduced NF-κB/p53 levels by increasing Bcl-2 expression in IFO treated kidneys. Morin may prevent IFO induced nephrotoxicity via the NF-κB/p53 and Bcl-2 signaling pathways.
Insights
Morin protects against ifosfamide (IFO) induced kidney damage by reducing oxidative stress and inflammation. This study reveals morin’s potential to mitigate IFO nephrotoxicity through specific molecular pathways.
Area of Science:
- Pharmacology
- Toxicology
- Biochemistry
Background:
- Ifosfamide (IFO) is a crucial chemotherapy agent for childhood solid tumors.
- IFO treatment can cause significant kidney damage (nephrotoxicity), limiting its clinical use.
- Morin, a natural flavonoid, shows potential in preventing drug-induced side effects.
Purpose of the Study:
- To investigate the protective mechanisms of morin against ifosfamide-induced nephrotoxicity in a rat model.
- To elucidate the role of oxidative stress, inflammation, and apoptosis in IFO nephrotoxicity and morin's intervention.
Main Methods:
- A rat model was used, divided into control, morin, IFO, and morin + IFO groups (100 and 200 mg/kg).
- Kidney tissue analysis included oxidant/antioxidant markers (ELISA), apoptosis (immunohistochemistry, real-time PCR), and serum markers (urea, creatinine, KIM-1).
- Key signaling pathways (NF-κB, TNF-α, p53, Bcl-2) were assessed.
Main Results:
- IFO treatment significantly increased serum urea, creatinine, and KIM-1 levels, indicating kidney injury.
- Morin administration (100 and 200 mg/kg) dose-dependently reduced these elevated markers.
- Morin decreased oxidative stress, lipid peroxidation, and inflammatory markers (NF-κB, TNF-α).
- Morin modulated apoptosis by reducing NF-κB/p53 and increasing Bcl-2 expression.
Conclusions:
- Morin demonstrates significant protective effects against ifosfamide-induced nephrotoxicity in rats.
- The protective mechanisms involve the inhibition of oxidative stress, inflammation, and apoptosis.
- Morin's action on the NF-κB/p53 and Bcl-2 signaling pathways highlights its therapeutic potential in mitigating IFO-related kidney damage.
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