Mitochondrial dysfunction and oxidative stress are involved in the mechanism of methotrexate-induced renal injury and electrolytes imbalance

Heidari, Reza; Ahmadi, Asrin; Mohammadi, Hamidreza; Ommati, Mohammad Mehdi; Azarpira, Negar; Niknahad, Hossein

doi:10.1016/j.biopha.2018.08.050

Cited by 85 publications

(72 citation statements)

References 44 publications

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“…The increase in GSH level and GSH‐dependent enzyme activities in animals administered PCA and MTX signifies an improvement in the antioxidant defence mechanism that is related to the intrinsic antioxidant activity of PCA. The marked increase in the testicular and epididymal levels of RONS and MDA following MTX administration observed in this study corroborates earlier reports attributed to oxidative stress in MTX‐mediated toxic injury (Najafi, Atashfaraz, & Farokhi, ) (Heidari et al, ). RONS and MDA levels in rats administered MTX and PCA were markedly reduced by the presence of PCA, which can be associated with PCA antioxidant properties as earlier reported (Han et al, ; Safaeian, Emami, Hajhashemi, & Haghighatian, ).…”

Section: Discussionsupporting

confidence: 92%

Protocatechuic acid inhibits testicular and epididymal toxicity associated with methotrexate in rats

et al. 2019

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We examined the effect of protocatechuic acid (PCA) on methotrexate (MTX)-induced testicular and epididymal toxicity in Wistar rats, treated with MTX (20 mg/kg) alone or in combination with PCA (25 and 50 mg/kg) body weight for a week. PCA significantly abated MTX-mediated increase in reactive oxygen and nitrogen species generation and lipid peroxidation as well as enhances glutathione balance and antioxidant enzymes in the testes and epididymis of treated animals. PCA suppressed MTX-mediated increases in interleukin-1β, tumour necrosis factor alpha and caspase-3 activity in treated animals. Additionally, PCA treatment mediated increases in luteinising and follicle-stimulating hormones, prolactin and testosterone levels with marker enzymes of testicular function, accompanied with increase in sperm functionality in treated animals. Conclusively, PCA may serve as potential supplementation, enhancing reproductive health in males undergoing MTX therapy. K E Y W O R D Sapoptosis, methotrexate, oxido-inflammation, protocatechuic acid, reproductive toxicity

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Section: Discussionsupporting

confidence: 92%

Protocatechuic acid inhibits testicular and epididymal toxicity associated with methotrexate in rats

et al. 2019

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“…Mitochondrial injury plays a key role in experimental AKI models triggered by sepsis [94,97,98], IRI [99][100][101][102][103], and nephrotoxicity [104][105][106]. Mitochondrial damage in AKI is associated with mitochondrial fragmentation [107], reduced mitochondrial mass [108], mitochondrial swelling and cristae disruption [109,110], apoptosis [111], and, in general, with impaired mitochondrial function [104][105][106]. Mutations or large deletions on mtDNA or nuclear genes encoding for mitochondrial proteins may result in kidney cysts or glomerular or tubular disease [112][113][114][115][116].…”

Section: Morphological and Functional Changes Of Mitochondriamentioning

confidence: 99%

The Role of PGC-1α and Mitochondrial Biogenesis in Kidney Diseases

et al. 2020

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Chronic kidney disease (CKD) is one of the fastest growing causes of death worldwide, emphasizing the need to develop novel therapeutic approaches. CKD predisposes to acute kidney injury (AKI) and AKI favors CKD progression. Mitochondrial derangements are common features of both AKI and CKD and mitochondria-targeting therapies are under study as nephroprotective agents. PGC-1α is a master regulator of mitochondrial biogenesis and an attractive therapeutic target. Low PGC-1α levels and decreased transcription of its gene targets have been observed in both preclinical AKI (nephrotoxic, endotoxemia, and ischemia-reperfusion) and in experimental and human CKD, most notably diabetic nephropathy. In mice, PGC-1α deficiency was associated with subclinical CKD and predisposition to AKI while PGC-1α overexpression in tubular cells protected from AKI of diverse causes. Several therapeutic strategies may increase kidney PGC-1α activity and have been successfully tested in animal models. These include AMP-activated protein kinase (AMPK) activators, phosphodiesterase (PDE) inhibitors, and anti-TWEAK antibodies. In conclusion, low PGC-1α activity appears to be a common feature of AKI and CKD and recent characterization of nephroprotective approaches that increase PGC-1α activity may pave the way for nephroprotective strategies potentially effective in both AKI and CKD.

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“…Decreased cellular GSH by methotrexate leads to reduced systemic antioxidant defense [ 122 ]. In addition, methotrexate generates mitochondrial dysfunction causing decreased activity of mitochondrial dehydrogenases, mitochondrial membrane potential, GSH, ATP concentrations, and increased LPO [ 123 ]. Methotrexate modifies the inflammatory response of different cells and cytokines with proinflammatory properties [ 124 ].…”

Section: Introductionmentioning

confidence: 99%

The Role of Oxidative Stress in Physiopathology and Pharmacological Treatment with Pro- and Antioxidant Properties in Chronic Diseases

García-Sánchez

Miranda-Díaz

Cardona-Muñoz

2020

Oxidative Medicine and Cellular Longevity

186

106

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Oxidative stress (OS) has the ability to damage different molecules and cellular structures, altering the correct function of organs and systems. OS accumulates in the body by endogenous and exogenous mechanisms. Increasing evidence points to the involvement of OS in the physiopathology of various chronic diseases that require prolonged periods of pharmacological treatment. Long-term treatments may contribute to changes in systemic OS. In this review, we discuss the involvement of OS in the pathological mechanisms of some chronic diseases, the pro- or antioxidant effects of their pharmacological treatments, and possible adjuvant antioxidant alternatives. Diseases such as high blood pressure, arteriosclerosis, and diabetes mellitus contribute to the increased risk of cardiovascular disease. Antihypertensive, lipid-lowering, and hypoglycemic treatments help reduce the risk with an additional antioxidant benefit. Treatment with methotrexate in autoimmune systemic inflammatory diseases, such as rheumatoid arthritis, has a dual role in stimulating the production of OS and producing mitochondrial dysfunction. However, it can also help indirectly decrease the systemic OS induced by inflammation. Medicaments used to treat neurodegenerative diseases tend to decrease the mechanisms related to the production of reactive oxygen species (ROS) and balance OS. On the other hand, immunosuppressive treatments used in cancer or human immunodeficiency virus infection increase the production of ROS, causing significant oxidative damage in different organs and systems without widely documented exogenous antioxidant administration alternatives.

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Mitochondrial dysfunction and oxidative stress are involved in the mechanism of methotrexate-induced renal injury and electrolytes imbalance

Cited by 85 publications

References 44 publications

Protocatechuic acid inhibits testicular and epididymal toxicity associated with methotrexate in rats

Protocatechuic acid inhibits testicular and epididymal toxicity associated with methotrexate in rats

The Role of PGC-1α and Mitochondrial Biogenesis in Kidney Diseases

The Role of Oxidative Stress in Physiopathology and Pharmacological Treatment with Pro- and Antioxidant Properties in Chronic Diseases

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