Modulation of eNOS/iNOS by nebivolol protects against cyclosporine A-mediated nephrotoxicity through targeting inflammatory and apoptotic pathways

El-Sheikh, Azza A. K.; Morsy, Mohamed A.; Abdel‐latif, Rania G.

doi:10.1016/j.etap.2019.03.018

Cited by 16 publications

(25 citation statements)

References 44 publications

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“…Several interventions have been introduced to halt the pathogenesis of cyclosporine-evoked renal failure; a serious complication during the therapy with cyclosporine in patients with autoimmune diseases and organ transplantation [ 1 , 2 , 3 , 4 ]. The present work suggests that camel milk is a promising natural agent for counteracting cyclosporine-triggered nephrotoxicity.…”

Section: Discussionmentioning

confidence: 99%

“…The dose of cyclosporine and the experimental regimen was based on former studies that demonstrated the marked cyclosporine nephrotoxicity and robust renal inflammation [ 1 , 2 , 19 , 20 ]. Camel milk dose is consistent with former studies that demonstrated the 10 mL/kg dose as an effective dose against several models of inflammation in rats [ 10 , 13 , 14 , 15 , 16 ].…”

Section: Methodsmentioning

confidence: 99%

“…The widespread use of the immunosuppressant cyclosporine A (CsA) in organ transplantation and autoimmune disorders, e.g., psoriasis and rheumatoid arthritis, has demonstrated marked clinical outcomes in patients with these ailments [ 1 , 2 , 3 ]. However, renal toxicity has emerged as a serious adverse effect, which progresses to chronic renal failure upon long-term administration [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

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Camel Milk Mitigates Cyclosporine-Induced Renal Damage in Rats: Targeting p38/ERK/JNK MAPKs, NF-κB, and Matrix Metalloproteinases

Arab

Ashour

Alqarni

et al. 2021

Biology

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Renal damage is a devastating adverse effect for cyclosporine; a widely used immunosuppressant drug. The present work examined the potential of camel milk, a natural agent with marked anti-inflammatory/antioxidant properties, to attenuate cyclosporine-induced renal injury. The kidney tissue was examined with the aid of Western blotting, immunohistochemistry, biochemical assays, including colorimetric and ELISA kits. The present findings revealed that camel milk (10 mL/kg/day; for 3 weeks by gavage) significantly lowered serum creatinine, BUN, and KIM-1 renal dysfunction markers. Mechanistically, camel milk inhibited renal inflammation, as seen by significant decrease of the pro-inflammatory cytokines (MCP-1, TNF-α, IL-1β, and IL-18) and extracellular degradation signals (MMP-2 and MMP-9) and enhanced the generation of the anti-inflammatory IL-10. Moreover, it inhibited the upstream pro-inflammatory p38/ERK/JNK MAPK pathway by lowering the phosphorylation of the 3 subfamilies of MAPKs (p38 MAPK, JNK1/2, and ERK1/2). Furthermore, camel milk curbed the NF-κB pathway activation by downregulating the protein expression of activated NF-κBp65, p-NF-κBp65, and p-IκBα proteins. Additionally, camel milk inhibited renal oxidative stress by lowering the MPO activity and augmenting the reduced/oxidized glutathione ratio and total antioxidant capacity. These findings propose that camel milk may be a promising agent that inhibits cyclosporine-triggered renal inflammation via curtailing the p38/ERK/JNK MAPK and NF-κB pathways, matrix metalloproteinases, and pro-inflammatory cytokines.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Camel Milk Mitigates Cyclosporine-Induced Renal Damage in Rats: Targeting p38/ERK/JNK MAPKs, NF-κB, and Matrix Metalloproteinases

Arab

Ashour

Alqarni

et al. 2021

Biology

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“…From this point of view, nebivolol (NEB) can be a promising therapeutic agent as it has been displayed to have antiinflammatory and anti-apoptotic effects besides its antioxidant properties. 13,14 Nebivolol is a third-generation selective beta-1 receptor antagonist. It is administered orally for the treatment of arterial hypertension owing to its nitric oxide-mediated effects.…”

Section: Introductionmentioning

confidence: 99%

“…In addition, the levels of tumor necrosis factor‐alpha (TNF‐α) and other proinflammatory cytokines increase in reperfusion injury; suggesting that anti‐inflammatory agents can be involved more effectively in the prevention of ischemic damage compared to antioxidants. From this point of view, nebivolol (NEB) can be a promising therapeutic agent as it has been displayed to have anti‐inflammatory and anti‐apoptotic effects besides its antioxidant properties 13,14 …”

Section: Introductionmentioning

confidence: 99%

Protective effects of nebivolol on ovarian ischemia–reperfusion injury in rat

Çolak

Gürlek

Topçu

et al. 2020

J of Obstet and Gynaecol

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Aim: Ovarian torsion is a common gynecological emergency of reproductive ages, occurring at rates of 2.7-7.4%. This study aimed to evaluate the antioxidant effects of Nebivolol (NEB) and histopathological changes in experimental ischemic (I) and ischemic-reperfusion (I/R) injury in rat ovaries. Methods: Forty-eight adult female rats were randomly separated into six groups as group 1 (control) receiving an oral saline solution for 3 days; group 2 (I) that underwent ischemia for 3 h with the application of atraumatic vascular clips; group 3 (I/R); group 4 (I + NEB) receiving 10 mg/kg NEB by oral gavage 30 min prior to the ischemia induction; group 5 (I/R + NEB) receiving 10 mg/kg NEB, and group 6 (control + NEB) receiving oral 10 mg/kg NEB for 3 days before ischemia induction followed by consequent reperfusion. Ovarian tissue damage was scored by histopathological analysis. Ovarian tissue malondialdehyde (MDA) and glutathione (GSH) levels were measured biochemically. Results: The levels of MDA and tumor necrosis factor-alpha (TNF-α), and TUNEL assay positivity scores increased in the I and I/R groups. GSH levels decreased in all case groups (P < 0.05). The oral administration of NEB (10 mg/kg) to the I-and I/R-groups reduced the levels of MDA and TNF-α and TUNEL assay immunopositivity scores (P < 0.05). GSH levels increased in the treatment groups. Conclusion: The current experimental ovarian torsion study suggests a protective role for NEB against I and I/R injury in rat ovaries. NEB may be a novel agent for decreasing ovarian I/R injury.

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Inhibition of oxidative stress and apoptosis by camel milk mitigates cyclosporine‐induced nephrotoxicity: Targeting Nrf2/HO‐1 and AKT/eNOS/NO pathways

Arab

Eid

Gad

et al. 2021

Food Science & Nutrition

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Cyclosporine (CsA) is a widely used immunosuppressive agent that incurs marked nephrotoxicity in the clinical setting. Thus, there is a need for finding safe/effective agents that can attenuate CsA‐induced kidney injury. Meanwhile, the underlying mechanisms for CsA‐associated nephrotoxicity are inadequately investigated, in particular, the AKT/eNOS/NO pathway. Here, the present work aimed to explore the potential of camel milk, a natural product with distinguished antioxidant/anti‐inflammatory actions, to ameliorate CsA‐induced nephrotoxicity in rats. The molecular mechanisms related to renal oxidative aberrations and apoptosis were studied, including Nrf2/HO‐1 and AKT/eNOS/NO pathways. The kidney tissues were inspected using histopathology, ELISA, Western blotting, and immunohistochemistry. The present findings demonstrated that camel milk (10 ml/kg) significantly lowered creatine, BUN, and NGAL nephrotoxicity markers and the aberrant histopathology, with similar efficacy to the reference quercetin. Moreover, camel milk suppressed the renal oxidative stress, as evidenced by significantly lowering NOX‐1 and lipid peroxides and significantly augmenting the renal antioxidant moieties (GSH, GPx, and SOD), thereby, driving the restoration of Nrf2/HO‐1 pathway. Meanwhile, camel milk counteracted the pro‐apoptotic reactions by significantly lowering Bax protein expression, caspase‐3 activity/cleavage, and PARP cleavage, alongside significantly increasing the expression of the proliferation signal PCNA. Regarding the anti‐apoptotic AKT/eNOS/NO pathway, camel milk activated its signaling by significantly increasing the protein expression of PI3Kp110, p‐AKT(Ser473)/total AKT, and p‐eNOS (Ser1177)/total eNOS besides significantly boosting the renoprotective NO levels. In conclusion, these findings reveal that camel milk may be a promising candidate for the alleviation of CsA‐induced nephrotoxicity.

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Modulation of eNOS/iNOS by nebivolol protects against cyclosporine A-mediated nephrotoxicity through targeting inflammatory and apoptotic pathways

Cited by 16 publications

References 44 publications

Camel Milk Mitigates Cyclosporine-Induced Renal Damage in Rats: Targeting p38/ERK/JNK MAPKs, NF-κB, and Matrix Metalloproteinases

Camel Milk Mitigates Cyclosporine-Induced Renal Damage in Rats: Targeting p38/ERK/JNK MAPKs, NF-κB, and Matrix Metalloproteinases

Protective effects of nebivolol on ovarian ischemia–reperfusion injury in rat

Inhibition of oxidative stress and apoptosis by camel milk mitigates cyclosporine‐induced nephrotoxicity: Targeting Nrf2/HO‐1 and AKT/eNOS/NO pathways

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