The impact of Keap1/Nrf2, P38MAPK/NF-κB and Bax/Bcl2/caspase-3 signaling pathways in the protective effects of berberine against methotrexate-induced nephrotoxicity

Hassanein, Emad H.M.; Shalkami, Abdel-Gawad S; Khalaf, Marwa M.; Mohamed, Wafaa R.; Hemeida, Ramadan A.M.

doi:10.1016/j.biopha.2018.10.088

Cited by 92 publications

(47 citation statements)

References 52 publications

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“…Animals were randomly allocated into four groups ( n = 8) as follows: Normal control group : Individuals were treated with vehicle only (1% carboxymethyl cellulose, 1 ml/animal, PO) for 12 days. REB group: REB (suspended in 1% carboxymethyl cellulose) was administered to individuals at a dose of 100 mg kg −1 day −1 via oral gavage for 12 days (Kurata et al, 2015; Zakaria & El‐Sisi, 2016). MTX group: A single dose (20 mg/kg, ip) of MTX was injected to each individual (Hassanein, Shalkami, Khalaf, Mohamed, & Hemeida, 2019) along with vehicle (1% carboxymethyl cellulose, 1 mL/animal, PO, for 12 days). REB + MTX group: REB (100 mg kg −1 day −1 , via oral gavage) was administered daily for 7 days before and 5 days after MTX administration (20 mg/kg, ip). …”

Section: Methodsmentioning

confidence: 99%

Rebamipide potentially mitigates methotrexate‐induced nephrotoxicity via inhibition of oxidative stress and inflammation: A molecular and histochemical study

Elmansy

Seleem

Mahmoud

et al. 2020

The Anatomical Record

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Methotrexate (MTX) is a widely used chemotherapeutic agent; nevertheless, the nephrotoxicity associated with its use has limited its clinical use. Rebamipide (REB) is a gastro‐protective agent with diverse promising biological activities. Here, we investigated the renoprotective effects of REB against MTX‐induced nephrotoxicity in rats. Male Wistar rats were allocated into four groups: the normal control group, the REB group (100 mg kg−1 day−1, PO, for 12 days), the MTX group (which received a single injection of 20 mg/kg, ip), and the REB + MTX group (which received 100 mg kg−1 day−1 REB for 7 days before and 5 days after being injected with 20 mg/kg MTX). Interestingly, MTX triggered kidney injury, characterized by renal dysfunction along with histopathological alterations. Moreover, increased reactive oxygen species level and inflammatory response were detected in the kidney of MTX‐treated rats. However, REB prevented MTX‐induced oxidative kidney injury and boosted an antioxidant balance. Mechanistically, REB markedly activated the NRF‐2 protein and upregulated the expression of both SIRT‐1 and FOXO‐3 genes. Additionally, REB administration strongly inhibited the inflammatory response by downregulating both NF‐κB‐p65 and TLR‐4. Finally, the coadministration of REB and MTX activated the mTOR/PI3K/AKT signaling pathway. Simultaneously, REB treatment attenuated the reduction in glomerular size, the widening of the capsular spaces, and the tubular cell damage due to MTX administration. Taken together, these results indicate the potential of REB as adjuvant therapy to prevent nephrotoxicity in patients receiving MTX treatment.

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Section: Methodsmentioning

confidence: 99%

Rebamipide potentially mitigates methotrexate‐induced nephrotoxicity via inhibition of oxidative stress and inflammation: A molecular and histochemical study

Elmansy

Seleem

Mahmoud

et al. 2020

The Anatomical Record

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“…In the current study, the decreased caspase-3 gene expression with an increase in Bcl-2 gene expression proved the previously documented role of VPA as an inducer of the intrinsic apoptotic pathway [ 50 ]. Both are linked to the mechanism involved in decreased expression of the Nrf2 gene [ 51 ].…”

Section: Discussionmentioning

confidence: 99%

The Protective Role of Prenatal Alpha Lipoic Acid Supplementation against Pancreatic Oxidative Damage in Offspring of Valproic Acid-Treated Rats: Histological and Molecular Study

Ghoneim

Alrefai

Elsamanoudy

et al. 2020

Biology

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Background: Sodium valproate (VPA) is an antiepileptic drug (AED) licensed for epilepsy and used during pregnancy in various indications. Alpha-lipoic acid (ALA) is a natural compound inducing endogenous antioxidant production. Our study aimed to investigate the effect of prenatal administration of VPA on the pancreas of rat offspring and assess the potential protective role of ALA co-administration during pregnancy. Methods: Twenty-eight pregnant female albino rats were divided into four groups: group I (negative control), group II (positive control, ALA treated), group III (VPA-treated), and group IV (VPA-ALA-treated). The pancreases of the rat offspring were removed at the fourth week postpartum and prepared for histological, immune-histochemical, morphometric, molecular, and oxidative stress marker studies. Results: In group III, there were pyknotic nuclei, vacuolated cytoplasm with ballooning of acinar, α, and β cells of the pancreas. Ultrastructural degeneration of cytoplasmic organelles was detected. Additionally, there was a significant increase in oxidative stress, a decrease in insulin-positive cell percentage, and an increase in glucagon positive cells in comparison to control groups. Moreover, VPA increased the gene expression of an apoptotic marker, caspase-3, with a decrease in anti-apoptotic Bcl2 and nuclear factor erythroid 2-related factor 2 (Nrf2) transcriptional factor. Conversely, ALA improved oxidative stress and apoptosis in group VI, and a consequent improvement of the histological and ultrastructure picture was detected. Conclusion: ALA co-administration with VPA significantly improved the oxidative stress condition, histological and morphometric picture of the pancreas, and restored normal expression of related genes, including Nrf2, caspase-3, and Bcl-2. Administration of α-lipoic acid has a protective effect against VPA-induced pancreatic oxidative damage via its cytoprotective antioxidant effect.

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“…Activation of p38 MAPK under stress is a key event in apoptosis induction [42]. Antiapoptotic Bcl-2 levels decrease with rising p38 MAPK activity, indicating that p38 MAPK is the primary upstream signal controlling the balance between Bcl-2 and Bax expression in mitochondria [43,44,45]. Phosphorylation of p38 MAPK induces the release of Cyt C from mitochondria by inhibiting Bcl-2 and shifting the Bcl-2: Bax ratio, resulting in sequential activation of apoptotic proteases apof-1, caspase-9, and caspase-3 in germ cells [46].…”

Section: Discussionmentioning

confidence: 99%

β-Endorphin Induction by Psychological Stress Promotes Leydig Cell Apoptosis through p38 MAPK Pathway in Male Rats

Xiong

Zhang

Fan

et al. 2019

Cells

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Psychological stress (PS) disturbs the reproductive endocrine system and promotes male infertility, but the underlying pathogenic mechanisms have not been extensively studied. This study aimed to uncover the mechanisms of PS-induced male reproductive related abnormalities subjected to a ‘terrified sound’ exposure. Male rats subjected to PS displayed slow growth, decreased sperm quality, abnormal levels of the reproductive endocrine hormones, decreased expression of the reproductive-related proteins androgen-binding protein (ABP) and bromodomain-containing protein (BRDT), increased apoptosis in the testis, and accompanied by elevated levels of β-endorphin (β-EP). These effects were reversed by naloxone. Furthermore, PS-induced β-EP could promote mu opioid receptor (MOR) activation and ensure intracellular p38 MAPK phosphorylation and then lead to Leydig cells (LCs) apoptosis. The current result showed that β-EP was a key factor to PS-induced male infertility.

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The impact of Keap1/Nrf2, P38MAPK/NF-κB and Bax/Bcl2/caspase-3 signaling pathways in the protective effects of berberine against methotrexate-induced nephrotoxicity

Cited by 92 publications

References 52 publications

Rebamipide potentially mitigates methotrexate‐induced nephrotoxicity via inhibition of oxidative stress and inflammation: A molecular and histochemical study

Rebamipide potentially mitigates methotrexate‐induced nephrotoxicity via inhibition of oxidative stress and inflammation: A molecular and histochemical study

The Protective Role of Prenatal Alpha Lipoic Acid Supplementation against Pancreatic Oxidative Damage in Offspring of Valproic Acid-Treated Rats: Histological and Molecular Study

β-Endorphin Induction by Psychological Stress Promotes Leydig Cell Apoptosis through p38 MAPK Pathway in Male Rats

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