ReferenceID 4543
Regulation of Keap-1/Nrf2/AKT and iNOS/NF-κB/TLR4 signals by apocynin abrogated methotrexate-induced testicular toxicity: Mechanistic insights and computational pharmacological analysis
Life Sci
AIM: Male reproductive toxicity is becoming of growing significance due to clinical chemotherapy usage. Methotrexate (MTX) is an anti-folate used on a large scale for different tumors and autoimmune conditions. Despite i
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Record Fields
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- Reference Id
- 4543
- Evidence Id
- 21133
- Core Evidence Id
- 21133
- Source Reference Id
- 2359
- Herb2 Reference Id
- HBREF003156
- Subject Paper Key
- HBIN016505_34450167
- Pubmed Id
- 34450167
- Doi
- 10.1016/j.lfs.2021.119911
- Paper Title
- Regulation of Keap-1/Nrf2/AKT and iNOS/NF-κB/TLR4 signals by apocynin abrogated methotrexate-induced testicular toxicity: Mechanistic insights and computational pharmacological analysis
- Paper Abstract
- AIM: Male reproductive toxicity is becoming of growing significance due to clinical chemotherapy usage. Methotrexate (MTX) is an anti-folate used on a large scale for different tumors and autoimmune conditions. Despite its wide clinical use, MTX is associated with severe testicular intoxication. The exact underlying mechanism is unclear. METHODS: Our study was conducted to explore the pathogenesis mechanism of MTX-induced testicular damage and the potential testicular protective effects of apocynin (APO) on testicular injury induced by single i.p. MTX (20 mg/kg). APO was administered orally (100 mg/kg) for ten days. RESULTS: As compared to rats given MTX alone, co-administration of MTX with APO demonstrated multiple beneficial effects evidenced by a marked increase in testosterone, FSH, and LH and significantly restored testes histopathological alterations. Mechanistically, APO restored antioxidant status through up-regulation of Nrf2, cytoglobin, PPAR-gamma, SIRT1, AKT, and p-AKT, while effectively lowering Keap-1. Moreover, APO significantly attenuated inflammation by down-regulating NF-kappaB-p65, iNOS, and TLR4 expressions confirmed by in-silico evidence. Additionally, network pharmacology analysis, a bioinformatics approach, was used to decipher various cellular processes' molecular mechanisms. SIGNIFICANCE: The current investigation proves the beneficial effects of APO in MTX-associated testicular damage through activation of cytoglobin, Keap-1/Nrf2/AKT, PPAR-gamma, SIRT1, and suppressing of TLR4/NF-kappaB-p65 signal. Our data collectively encourage extending the investigation to the clinical setting to explore APO effects in MTX-treated patients.
- Journal
- Life Sci
- Publish Year
- 2021
- Experiment Subject
- rat; patient
- Experiment Type
- Animal Experiment
- Phenotype Related
- Autoimmune Conditions; Testicular Injury; Testicular Intoxication; Tumors
- Paper Title Cn
- Paper Title En
- Regulation of Keap-1/Nrf2/AKT and iNOS/NF-κB/TLR4 signals by apocynin abrogated methotrexate-induced testicular toxicity: Mechanistic insights and computational pharmacological analysis
- Bilingual Status
- semi_complete