Geraniol Averts Methotrexate-Induced Acute Kidney Injury via Keap1/Nrf2/HO-1 and MAPK/NF-κB Pathways

Younis, Nancy S.; Elsewedy, Heba S.; Shehata, Tamer M.; Mohamed, Maged E.

doi:10.3390/cimb43030123

Cited by 35 publications

(21 citation statements)

References 44 publications

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“…In the present study, MTX-induced nephrotoxicity was associated with disturbed renal function tests, elevated serum creatinine, and urea, and with induction of apoptosis as noticed through upregulation of the apoptosis marker BAX and downregulation of the anti-apoptosis marker BCL-2. We also determined that MTX could induce an inflammatory response, as seen through activation NF-kappaB, similar to the findings of Younis et al [ 32 ] who reported the cytotoxic effect of MTX, causing cell death. In addition, MTX caused renal oxidative stress as marked by increased renal MDA, NO, and decreased renal GSH, consistent with the previous reports [ 29 ].…”

Section: Discussionsupporting

confidence: 88%

Methotrexate-Induced Alteration of Renal Aquaporins 1 and 2, Oxidative Stress and Tubular Apoptosis Can Be Attenuated by Omega-3 Fatty Acids Supplementation

El-Agawy

Badawy

Rabei

et al. 2022

IJMS

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Methotrexate (MTX) is a potent anti-cancer drug, commonly associated with nephrotoxicity via the induction of oxidative stress and apoptosis with alteration of renal water channel proteins, namely aquaporins (AQPs). Omega-3 long-chain polyunsaturated fatty acids (LC-PUFA) have shown cytoprotective effects through their anti-oxidant and antiapoptotic activities. The present study aims for the first time to explore the role of LC-PUFA against MTX-induced nephrotoxicity. Rats were divided into the following groups: saline control, LC-PUFA control, MTX, MTX + LC-PUFA (150 mg/kg), or MTX + LC-PUFA (300 mg/kg). Then, H&E staining and immunohistochemical staining for the anti-apoptosis marker B-cell lymphoma 2 (BCL-2), the apoptosis marker BCL2-Associated X Protein (BAX), the proinflammatory marker Nuclear factor kappa B (NF-kB), AQPs 1 and 2 were performed in kidney sections with an assessment of renal oxidative stress. The MTX caused a renal histopathological alteration, upregulated renal BAX and NF-kB, downregulated Bcl-2 and AQP1, altered the distribution of AQP2, and caused oxidative stress. The LC-PUFA attenuated the pathological changes and decreased renal BAX and NF-kB, increased BCL-2 and AQP1, restored the normal distribution of AQP2, and decreased the oxidative stress. Therefore, LC-PUFA is a good adjuvant to MTX to prevent its adverse effects on kidneys through its antiapoptotic, antioxidant, and anti-inflammatory effect and its role in the restoration of the expression of AQPs 1 and 2.

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Section: Discussionsupporting

confidence: 88%

Methotrexate-Induced Alteration of Renal Aquaporins 1 and 2, Oxidative Stress and Tubular Apoptosis Can Be Attenuated by Omega-3 Fatty Acids Supplementation

El-Agawy

Badawy

Rabei

et al. 2022

IJMS

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“…The BCL-2 family of intracellular proteins are considered key regulators of apoptosis [36] . In the current study, increased ROS and inflammation were associated with oxidative DNA damage and upregulated Bax and Caspases [37] . NRF2 confers resistance to apoptosis by inducing expression of ROS-scavenging enzymes and BCL-2 family members, such as Bcl-2 and Bcl-xl [38] .…”

Section: Discussionsupporting

confidence: 52%

Fermented Lentinus edodes extract containing α-glucan ameliorates concanavalin A-induced autoimmune hepatitis in mice

Hu,

Cheng,

Zhang

et al. 2024

Food Science and Human Wellness

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Autoimmune hepatitis (AIH) is a chronic infl ammatory liver disease that threatens human health worldwide. The aim of this study was to detect the protective effect of a fermented Lentinus edodes extract containing α-glucan (FLA), in a concanavalin A (ConA)-induced AIH mouse model and to determine the underlying liver-protective mechanism. The results showed that compared with the model group, the level of proinfl ammatory cytokines in serum of FLA pretreated mice was signifi cantly decreased, and the degree of infl ammatory cell infi ltration in liver, thymus and spleen was signifi cantly reduced. Quantitative polymerase chain reaction, immunohistochemistry, and Western blotting showed that FLA pre-treatment inhibited the ConA-induced apoptosis of hepatocytes by down-regulating the expression of BAX and up-regulating the expression of BCL-2. Further research found that FLA may improve liver injury in mice by activating NRF2 signaling pathway and inhibiting TRAF6/NF-κB signaling pathway. Thus, FLA may improve liver injury in mice by shifting gut microbial composition to reduce the release of infl ammatory cytokines in the serum and prevent the necrosis of hepatocytes. Up-regulation of NRF2 signaling pathway, down-regulation of TRAF6/NF-κB signaling pathway, and an increase in the relative abundance of Lactobacillus_johnsonii and Ligilactobacillus_murinus play a protective role in liver.

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“…Although exposure to moderate OS can lead to Nrf2 activation, the excessive and sustained ROS generation can diminish Nrf2 signaling in the kidney and liver of rats challenged with MTX; thus, the diminished Nrf2/HO-1 pathway is a direct consequence of the sustained ROS generation induced by MTX (31) .…”

Section: Discussionmentioning

confidence: 99%

Possible protective effects of two different doses of cyanocobalamin against methotrexate nephrotoxicity in rats

Alduboni

Al-Shawi²

2022

IJPS

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Nephrotoxicity is defined as rapid deterioration in kidney functions. It arises from direct exposure to drugs or their metabolites. Methotrexate is a famous chemotherapeutic drug with anti-inflammatory and immunosuppressive properties. A high-dose methotrexate-induced renal dysfunction can be life threatening. Cyanocobalamin, one of the forms of vitamin B12, acts as a coenzyme in the conversion of homocysteine to methionine in the cytosol, and the conversion of methylmalonyl-CoA to succinyl-CoA in the mitochondrion. This study is designed to examine the effect of cyanocobalamin in two different doses each co-administered with methotrexate at 20 mg/kg induced nephrotoxicity in rats through the involvement of Nrf2/keap1 molecular mechanism in this respect. Rats utilized in this study were randomized into 4 groups (ten rats per each group); Group 1- (Control) rats intraperitoneally injected with 0.5ml normal saline once daily for 7 consecutive days. Group 2- Rats intraperitoneally injected with 0.5ml normal saline once daily for 7 consecutive days; and at day 2, a single intraperitoneal dose of methotrexate (20mg/kg) is to be injected. Group 3- Rats intraperitoneally injected with a 0.5mg/kg cyanocobalamin once daily for 7 consecutive days, and at day 2, a single intraperitoneal dose of methotrexate (20mg/kg). Group 4- Rats intraperitoneally injected with a 2mg/kg cyanocobalamin once daily for 7 consecutive days, and at day 2, a single intraperitoneal dose of methotrexate (20mg/kg). Co-administration of cyanocobalamin at doses cyanocobalamin 0.5mg/kg and 2mg/kg with methotrexate showed significant reduction (P<0.05) in malondialdehyde, significant elevation (P<0.05) in reduced glutathione level, significant upregulation in renal Nrf2 expression and significant down regulation in renal keap1 expression each compared to corresponding levels in methotrexate-only treated group. In conclusion this study demonstrated that co-administration of cyanocobalamin at two different doses with MTX resulted in attenuation of its nephrotoxicity by the utilization of selected parameters. Keywords: Nephrotoxicity, methotrexate, cyanocobalamin, malondialdehyde, glutathione, Nrf2, Keap1.

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Geraniol Averts Methotrexate-Induced Acute Kidney Injury via Keap1/Nrf2/HO-1 and MAPK/NF-κB Pathways

Cited by 35 publications

References 44 publications

Methotrexate-Induced Alteration of Renal Aquaporins 1 and 2, Oxidative Stress and Tubular Apoptosis Can Be Attenuated by Omega-3 Fatty Acids Supplementation

Methotrexate-Induced Alteration of Renal Aquaporins 1 and 2, Oxidative Stress and Tubular Apoptosis Can Be Attenuated by Omega-3 Fatty Acids Supplementation

Fermented Lentinus edodes extract containing α-glucan ameliorates concanavalin A-induced autoimmune hepatitis in mice

Possible protective effects of two different doses of cyanocobalamin against methotrexate nephrotoxicity in rats

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