Dihydromyricetin Modulates Nrf2 and NF-κB Crosstalk to Alleviate Methotrexate-Induced Lung Toxicity
Background: Methotrexate (MTX) is an effective anticancer, anti-inflammatory, and immunomodulatory agent. However, it induces a serious pneumonitis that leads to irreversible fibrotic lung damage. This study addresses the protective role of the natural flavonoid dihydromyricetin (DHM) against MTX-in...
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MDPI AG
2023-03-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/16/4/481 |
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| author | Asmaa I. Matouk Eman M. Awad Nashwa F. G. El-Tahawy Azza A. K. El-Sheikh Aliaa Anter |
| author_facet | Asmaa I. Matouk Eman M. Awad Nashwa F. G. El-Tahawy Azza A. K. El-Sheikh Aliaa Anter |
| author_sort | Asmaa I. Matouk |
| collection | DOAJ |
| description | Background: Methotrexate (MTX) is an effective anticancer, anti-inflammatory, and immunomodulatory agent. However, it induces a serious pneumonitis that leads to irreversible fibrotic lung damage. This study addresses the protective role of the natural flavonoid dihydromyricetin (DHM) against MTX-induced pneumonitis via modulation of Nrf2/NF-κB signaling crosstalk. Methods: Male Wistar rats were divided into 4 groups: control, which received the vehicle; MTX, which received a single MTX (40 mg/kg, i.p) at day 9 of the experiment; (MTX + DHM), which received oral DHM (300 mg/kg) for 14 days and methotrexate (40 mg/kg, i.p) on the 9th day; and DHM, which received DHM (300 mg/kg, p.o) for 14 days. Results: Lung histopathological examination and scoring showed a decline in MTX-induced alveolar epithelial damage and decreased inflammatory cell infiltration by DHM treatment. Further, DHM significantly alleviated the oxidative stress by decreasing MDA while increasing GSH and SOD antioxidant levels. Additionally, DHM suppressed the pulmonary inflammation and fibrosis through decreasing levels of NF-κB, IL-1β, and TGF-β1 while promoting the expression of Nrf2, a positive regulator of antioxidant genes, and its downstream modulator, HO-1. Conclusion: This study identified DHM as a promising therapeutic target against MTX-induced pneumonitis via activation of Nrf2 antioxidant signaling while suppressing the NF-κB mediated inflammatory pathways. |
| first_indexed | 2024-03-11T04:39:30Z |
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| language | English |
| last_indexed | 2024-03-11T04:39:30Z |
| publishDate | 2023-03-01 |
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| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-9a6299e7fabd4e7dbdd12c73c3eb97c92023-11-17T20:49:32ZengMDPI AGPharmaceuticals1424-82472023-03-0116448110.3390/ph16040481Dihydromyricetin Modulates Nrf2 and NF-κB Crosstalk to Alleviate Methotrexate-Induced Lung ToxicityAsmaa I. Matouk0Eman M. Awad1Nashwa F. G. El-Tahawy2Azza A. K. El-Sheikh3Aliaa Anter4Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, El-Minia 61511, EgyptDepartment of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, El-Minia 61511, EgyptDepartment of Histology and Cell Biology, Faculty of Medicine, Minia University, El-Minia 61511, EgyptBasic Health Sciences Department, College of Medicine, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi ArabiaDepartment of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, El-Minia 61511, EgyptBackground: Methotrexate (MTX) is an effective anticancer, anti-inflammatory, and immunomodulatory agent. However, it induces a serious pneumonitis that leads to irreversible fibrotic lung damage. This study addresses the protective role of the natural flavonoid dihydromyricetin (DHM) against MTX-induced pneumonitis via modulation of Nrf2/NF-κB signaling crosstalk. Methods: Male Wistar rats were divided into 4 groups: control, which received the vehicle; MTX, which received a single MTX (40 mg/kg, i.p) at day 9 of the experiment; (MTX + DHM), which received oral DHM (300 mg/kg) for 14 days and methotrexate (40 mg/kg, i.p) on the 9th day; and DHM, which received DHM (300 mg/kg, p.o) for 14 days. Results: Lung histopathological examination and scoring showed a decline in MTX-induced alveolar epithelial damage and decreased inflammatory cell infiltration by DHM treatment. Further, DHM significantly alleviated the oxidative stress by decreasing MDA while increasing GSH and SOD antioxidant levels. Additionally, DHM suppressed the pulmonary inflammation and fibrosis through decreasing levels of NF-κB, IL-1β, and TGF-β1 while promoting the expression of Nrf2, a positive regulator of antioxidant genes, and its downstream modulator, HO-1. Conclusion: This study identified DHM as a promising therapeutic target against MTX-induced pneumonitis via activation of Nrf2 antioxidant signaling while suppressing the NF-κB mediated inflammatory pathways.https://www.mdpi.com/1424-8247/16/4/481methotrexatedihydromyricetinNF-κBNrf2HO-1IL-1β |
| spellingShingle | Asmaa I. Matouk Eman M. Awad Nashwa F. G. El-Tahawy Azza A. K. El-Sheikh Aliaa Anter Dihydromyricetin Modulates Nrf2 and NF-κB Crosstalk to Alleviate Methotrexate-Induced Lung Toxicity Pharmaceuticals methotrexate dihydromyricetin NF-κB Nrf2 HO-1 IL-1β |
| title | Dihydromyricetin Modulates Nrf2 and NF-κB Crosstalk to Alleviate Methotrexate-Induced Lung Toxicity |
| title_full | Dihydromyricetin Modulates Nrf2 and NF-κB Crosstalk to Alleviate Methotrexate-Induced Lung Toxicity |
| title_fullStr | Dihydromyricetin Modulates Nrf2 and NF-κB Crosstalk to Alleviate Methotrexate-Induced Lung Toxicity |
| title_full_unstemmed | Dihydromyricetin Modulates Nrf2 and NF-κB Crosstalk to Alleviate Methotrexate-Induced Lung Toxicity |
| title_short | Dihydromyricetin Modulates Nrf2 and NF-κB Crosstalk to Alleviate Methotrexate-Induced Lung Toxicity |
| title_sort | dihydromyricetin modulates nrf2 and nf κb crosstalk to alleviate methotrexate induced lung toxicity |
| topic | methotrexate dihydromyricetin NF-κB Nrf2 HO-1 IL-1β |
| url | https://www.mdpi.com/1424-8247/16/4/481 |
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