Molecular Mechanisms Underlying Protective Role of Quercetin on Copper Sulfate-Induced Nephrotoxicity in Mice

Peng, Xinyan; Dai, Chongshan; Zhang, Min; Gupta, S.

doi:10.3389/fvets.2020.586033

Cited by 25 publications

(17 citation statements)

References 60 publications

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“…The cross-talk between these pathways has indeed been previously reported, where upregulation of renal Nrf2/ HO-1 was concomitantly encountered together with a decrease in renal TNF-α by ergothioneine in cisplatininduced nephrotoxicity, 34 by phenethyl isothiocyanate in streptozotocin-induced diabetic nephropathy, 35 and by quercetin on copper sulfate-induced nephrotoxicity. 36 Similar findings have been reported linking the upregulation of renal Nrf2/HO-1 to caspase 3 downregulation by ergothioneine in cisplatin-induced nephrotoxicity, 34 by camel milk in cyclosporine-induced nephrotoxicity, 37 and by thymoquinone in diclofenacinduced acute kidney injury. 38 However, despite all previous reports, it is extremely difficult to hypothesize a cause-effect relationship between these complex pathways.…”

Section: Discussionsupporting

confidence: 71%

Protection of Hesperidin against Methotrexate- Induced Nephrotoxicity may be Mediated by Nrf2/HO-1 Pathway

Morsy¹,

El-Sheikh²,

Ibrahim³

et al. 2021

IJPER

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Background: Methotrexate (MTX), a successfully used chemotherapeutic in the treatment of various malignancies and autoimmune diseases, might cause severe nephrotoxicity. Here, we aimed at investigating possible nephroprotective effects of hesperidin (HES), a flavanone present in citrus fruits, against MTX-induced toxicity. Methods: Rats were divided into control, HES, MTX, and MTX/HES groups, where HES was administered in a dose of 100 mg/kg/day orally for 8 days and MTX in a single i.p. dose of 20 mg/kg on day 5 of the experiment. Results: Pretreatment with HES significantly improved MTXinduced deteriorated kidney function and structure, as well as reversed MTX effects on renal tumor necrosis factor (TNF)-α level and caspase 3 expression. MTX upregulated renal breast cancer resistance protein (BCRP); an efflux transporter that extrudes MTX from the kidney. Unfortunately, MTX/HES did not show a further increase in BCRP expression but rather showed downregulation. MTX also caused downregulation of renal nuclear factor erythroid 2-related factor 2 (Nrf2) and hemeoxygenase-1 (HO-1) expressions, whereas HES reversed the MTX effect and upregulated renal Nrf2/HO-1. Conclusion: HES conferred protection against MTX-mediated nephrotoxicity, at least in part via anti-inflammatory and anti-apoptotic mechanisms. Nrf2/HO-1 pathway, but not BCRP, may have a role in HES-induced nephroprotection against MTX toxicity.

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Section: Discussionsupporting

confidence: 71%

Protection of Hesperidin against Methotrexate- Induced Nephrotoxicity may be Mediated by Nrf2/HO-1 Pathway

Morsy¹,

El-Sheikh²,

Ibrahim³

et al. 2021

IJPER

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“…Shen et al (12) indicated that quercetin was able to decrease the secretion of IL-6, TNF-α and IL-1β in the serum and ankle joint tissues. In addition, another previous study suggested that quercetin attenuated copper sulfate-induced upregulation of TNF-α, IL-6 and IL-1β (13). The aforementioned results are consistent with those observed in the present study, indicating that quercetin has an anti-inflammatory effect.…”

Section: Discussionsupporting

confidence: 93%

Assessing the anti‑inflammatory effects of quercetin using network pharmacology and in vitro experiments

Zhang

Wang

et al. 2022

Exp Ther Med

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The present study aimed to investigate the anti-inflammatory effects of quercetin and the associated mechanisms involved. ELISA, reverse transcription-quantitative PCR and western blot analysis were performed to determine the anti-inflammatory effects of quercetin in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. The molecular mechanisms of quercetin were investigated using network pharmacology, molecular docking technology and in vitro experiments. The results revealed that quercetin reduced the LPS-induced production of TNF-α, IL-6 and IL-1β in RAW264.7 macrophages. Protein-protein interaction network topology analysis indicated that Akt was the target of quercetin. Kyoto Encyclopedia of Genes and Genomes analysis indicated that quercetin may regulate the PI3K/Akt signaling pathway to exert its anti-inflammatory effects. Furthermore, the molecular docking results indicated that quercetin had a good affinity for the active sites of Akt. Western blot analysis confirmed that quercetin inhibited the phosphorylation of Akt, with an efficacy stronger than that of an Akt inhibitor. Taken together, Akt served as a target as part of the mechanism of the anti-inflammatory effect of quercetin. This result lays a foundation for the clinical application of quercetin in the treatment of inflammatory diseases.

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“…The strong antioxidant effect of QUR was attributed to its hydroxyl group on the side phenyl ring, which gives it the ability to scavenge free radical, and improve enzymatic antioxidants and glutathione. The molecular mechanisms may include regulation of signaling pathways such as Nrf2/HO-1, MAPK, and TLR4/PI3K [ 49 , 50 ].…”

Section: Discussionmentioning

confidence: 99%

“…QUR was reported to have an immunoregulatory activity in human dendritic cells, where it shifted the immune balance from inflammation to resolution [ 66 ]. The protective anti-inflammatory activity of QUR was previously described in a mouse nephrotoxicity model [ 50 ] and in rats and mice with chronic prostatitis and rheumatoid arthritis [ 67 , 68 ]. This activity of QUR was supposed to be mediated via suppression of the activation of NLRP3 inflammasome and regulating SIRT1 pathway [ 69 ], and downregulation of NF-κB [ 50 ], inq21f, and MAPK signaling pathways [ 67 ].…”

Section: Discussionmentioning

confidence: 99%

“…Also, QUR suppressed the microcystin-induced DNA fragmentation in lymphocytes in vitro [ 74 ]. Furthermore, QUR supplementation attenuated the increased activity of caspases-9 and −3, Bax, and p53 transcripts in the kidney of copper-treated mice [ 50 ]. The anti-apoptotic activity of QUR is suggested to be mediated by down-regulation of the pro-apoptotic proteins such as Bax, and up-regulation of the anti-apoptotic proteins such as Bcl-2 [ 50 ].…”

Section: Discussionmentioning

confidence: 99%

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Quercetin Alleviates the Immunotoxic Impact Mediated by Oxidative Stress and Inflammation Induced by Doxorubicin Exposure in Rats

et al. 2021

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Doxorubicin (DOX) is a chemotherapeutic agent against hematogenous and solid tumors with undesirable side effects including immunosuppression. Quercetin (QUR), a natural flavonoid abundant in fruits and vegetables, has a potent antioxidant activity. The aim of the current study was to assess the impact of QUR on DOX-induced hematological and immunological dysfunctions in a rodent model. Randomly grouped rats were treated as follows: control, QUR alone (50 mg/kg for 15 days per os), DOX alone (2.5 mg/kg I/P, three times a week, for two weeks), and co-treated rats with QUR for 15 days prior to and concomitantly with DOX (for two weeks), at the doses intended for groups two and three. DOX alone significantly disrupted the erythrogram and leukogram variables. Serum immunoglobulin (IgG, IgM, and IgE) levels and the activities of catalase (CAT) and superoxide dismutase (SOD) in spleen were declined. The DNA damage traits in spleen were elevated with an upregulation of the expression of the apoptotic markers (p53 and Caspase-3 genes) and the proinflammatory cytokines (IL-6 and TNF-α genes), while the expression of CAT gene was downregulated. These biochemical changes were accompanied by morphological changes in the spleen of DOX-treated rats. Co-treatment with QUR abated most of the DOX-mediated alterations in hematological variables, serum immunoglobulins, and spleen antioxidant status, pro-inflammatory and apoptotic responses, and histopathological alterations. In essence, these data suggest that QUR alleviated DOX-induced toxicities on the bone marrow, spleen, and antibody-producing cells. Supplementation of chemotherapy patients with QUR could circumvent the DOX-induced inflammation and immunotoxicity, and thus prevent chemotherapy failure.

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Molecular Mechanisms Underlying Protective Role of Quercetin on Copper Sulfate-Induced Nephrotoxicity in Mice

Cited by 25 publications

References 60 publications

Protection of Hesperidin against Methotrexate- Induced Nephrotoxicity may be Mediated by Nrf2/HO-1 Pathway

Protection of Hesperidin against Methotrexate- Induced Nephrotoxicity may be Mediated by Nrf2/HO-1 Pathway

Assessing the anti‑inflammatory effects of quercetin using network pharmacology and in vitro experiments

Quercetin Alleviates the Immunotoxic Impact Mediated by Oxidative Stress and Inflammation Induced by Doxorubicin Exposure in Rats

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