Dihydromyricetin alleviates methotrexate-induced hepatotoxicity via suppressing the TLR4/NF-κB pathway and NLRP3 inflammasome/caspase 1 axis
The anticancer drug methotrexate (MTX) is known to cause hepatotoxicity as a possibly fatal adverse effect that hinders its clinical application. Although the natural flavonoid, dihydromyricetin (DHM), has antioxidant and anti-inflammatory effects; its role against MTX-induced hepatotoxicity has not...
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| Format: | Article |
| Language: | English |
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Elsevier
2022-11-01
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| Series: | Biomedicine & Pharmacotherapy |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0753332222011416 |
| _version_ | 1811339996340158464 |
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| author | Asmaa I. Matouk Eman M. Awad Nashwa F.G. El-Tahawy Azza A.K. El-Sheikh Shaimaa Waz |
| author_facet | Asmaa I. Matouk Eman M. Awad Nashwa F.G. El-Tahawy Azza A.K. El-Sheikh Shaimaa Waz |
| author_sort | Asmaa I. Matouk |
| collection | DOAJ |
| description | The anticancer drug methotrexate (MTX) is known to cause hepatotoxicity as a possibly fatal adverse effect that hinders its clinical application. Although the natural flavonoid, dihydromyricetin (DHM), has antioxidant and anti-inflammatory effects; its role against MTX-induced hepatotoxicity has not been explored yet. For this, rats were administrated DHM orally for two weeks at a dose of 300 mg/kg per day, with or without a single i.p. injection of 40 mg/kg MTX on the 9th day of the experiment. MTX caused deterioration in liver structure and function, depicted by an increase in liver enzymes; ALT and AST. Moreover, MTX induced oxidative stress, shown by increasing malondialdehyde and decreasing reduced glutathione and total antioxidant capacity, initiated the inflammatory response via upregulated expression of Toll-like receptor 4 (TLR4) and its downstream transcription factor, nuclear factor-kappa B (NF-κB p65). Consequent to TLR4 signaling cascade, Nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) inflammosome was activated and caused caspase 1 mediated transformation of proinflammatory cytokines interleukin 1β (IL-1β) and interleukin 18 (IL-18) into their active forms. Interestingly, administering DHM with MTX improved liver structure and function, as well as significantly decreased all oxidative stress and inflammatory signaling. Collectively, DHM possesses antioxidant and anti-inflammatory properties that can ameliorate MTX-induced hepatotoxicity, through down-regulation of liver TLR4/NF-κB and therefore prohibit activation of NLRP3/caspase 1 pathway. |
| first_indexed | 2024-04-13T18:34:47Z |
| format | Article |
| id | doaj.art-08ca29b37ec9424abe29e9affffbcaea |
| institution | Directory Open Access Journal |
| issn | 0753-3322 |
| language | English |
| last_indexed | 2024-04-13T18:34:47Z |
| publishDate | 2022-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Biomedicine & Pharmacotherapy |
| spelling | doaj.art-08ca29b37ec9424abe29e9affffbcaea2022-12-22T02:34:55ZengElsevierBiomedicine & Pharmacotherapy0753-33222022-11-01155113752Dihydromyricetin alleviates methotrexate-induced hepatotoxicity via suppressing the TLR4/NF-κB pathway and NLRP3 inflammasome/caspase 1 axisAsmaa I. Matouk0Eman M. Awad1Nashwa F.G. El-Tahawy2Azza A.K. El-Sheikh3Shaimaa Waz4Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, El-Minia, EgyptDepartment of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, El-Minia, EgyptDepartment of Histology and Cell Biology, Faculty of Medicine, Minia University, El-Minia, EgyptBasic Health Sciences Department, College of Medicine, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi ArabiaDepartment of Biochemistry, Faculty of Pharmacy, Minia University, El-Minia, Egypt; Corresponding author.The anticancer drug methotrexate (MTX) is known to cause hepatotoxicity as a possibly fatal adverse effect that hinders its clinical application. Although the natural flavonoid, dihydromyricetin (DHM), has antioxidant and anti-inflammatory effects; its role against MTX-induced hepatotoxicity has not been explored yet. For this, rats were administrated DHM orally for two weeks at a dose of 300 mg/kg per day, with or without a single i.p. injection of 40 mg/kg MTX on the 9th day of the experiment. MTX caused deterioration in liver structure and function, depicted by an increase in liver enzymes; ALT and AST. Moreover, MTX induced oxidative stress, shown by increasing malondialdehyde and decreasing reduced glutathione and total antioxidant capacity, initiated the inflammatory response via upregulated expression of Toll-like receptor 4 (TLR4) and its downstream transcription factor, nuclear factor-kappa B (NF-κB p65). Consequent to TLR4 signaling cascade, Nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) inflammosome was activated and caused caspase 1 mediated transformation of proinflammatory cytokines interleukin 1β (IL-1β) and interleukin 18 (IL-18) into their active forms. Interestingly, administering DHM with MTX improved liver structure and function, as well as significantly decreased all oxidative stress and inflammatory signaling. Collectively, DHM possesses antioxidant and anti-inflammatory properties that can ameliorate MTX-induced hepatotoxicity, through down-regulation of liver TLR4/NF-κB and therefore prohibit activation of NLRP3/caspase 1 pathway.http://www.sciencedirect.com/science/article/pii/S0753332222011416MethotrexateDihydromyricetinTLR4NF-κBNLRP3Caspase 1 |
| spellingShingle | Asmaa I. Matouk Eman M. Awad Nashwa F.G. El-Tahawy Azza A.K. El-Sheikh Shaimaa Waz Dihydromyricetin alleviates methotrexate-induced hepatotoxicity via suppressing the TLR4/NF-κB pathway and NLRP3 inflammasome/caspase 1 axis Biomedicine & Pharmacotherapy Methotrexate Dihydromyricetin TLR4 NF-κB NLRP3 Caspase 1 |
| title | Dihydromyricetin alleviates methotrexate-induced hepatotoxicity via suppressing the TLR4/NF-κB pathway and NLRP3 inflammasome/caspase 1 axis |
| title_full | Dihydromyricetin alleviates methotrexate-induced hepatotoxicity via suppressing the TLR4/NF-κB pathway and NLRP3 inflammasome/caspase 1 axis |
| title_fullStr | Dihydromyricetin alleviates methotrexate-induced hepatotoxicity via suppressing the TLR4/NF-κB pathway and NLRP3 inflammasome/caspase 1 axis |
| title_full_unstemmed | Dihydromyricetin alleviates methotrexate-induced hepatotoxicity via suppressing the TLR4/NF-κB pathway and NLRP3 inflammasome/caspase 1 axis |
| title_short | Dihydromyricetin alleviates methotrexate-induced hepatotoxicity via suppressing the TLR4/NF-κB pathway and NLRP3 inflammasome/caspase 1 axis |
| title_sort | dihydromyricetin alleviates methotrexate induced hepatotoxicity via suppressing the tlr4 nf κb pathway and nlrp3 inflammasome caspase 1 axis |
| topic | Methotrexate Dihydromyricetin TLR4 NF-κB NLRP3 Caspase 1 |
| url | http://www.sciencedirect.com/science/article/pii/S0753332222011416 |
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