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Reduced renal clearance of methotrexate has been associated to increase its half-life and making leucovorin ineffective which may induce the further toxicities such as myelosuppression, mucositis and more pronounced nephrotoxicity.94 Higher plasma concentration of methotrexate significantly decreases the NADPH production and subsequent depletion of GSH that ultimately results into impaired antioxidant defense system and cellular oxidative stress.95 Jahovic et al

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RAW 264.7 macrophages treated with Luteolin (50 g/mL) showed no protective effect on the reduced-to-oxidized glutathione ratio but did interfere with heme oxygenase (HO)-1 oxidative stress protein expression [161]

Our article also has the following limitations: First, how FGF21 mechanistically influences AFG3L2 activity remains unclear