Renoprotective effects of umbelliferone on methotrexate-induced renal injury through regulation of Nrf-2/Keap-1, P38MAPK/NF-κB, and apoptosis signaling pathways

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

doi:10.1016/j.fct.2018.03.041

Cited by 58 publications

(31 citation statements)

References 45 publications

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“…In this study, Pb significantly downregulated the gene expression of testicular Nrf2, NQO-1, and HO-1 which was clearly reversed by UMB treatment. Our findings are consistent with earlier studies reporting remarkable enhancement of Nrf2 or its target protective enzymes by UMB in different organ systems, 24,28 suggesting that the protective effect of UMB against Pb toxicity was partly mediated by the activation of Nrf2 and its target protective genes. Additionally, UMB increased HO-1 activity in the testes of Pb-intoxicated rats.…”

Section: Dovepresssupporting

confidence: 93%

“…Previous reports confirmed the significant harmful effects of Pb poisoning on male reproductive functions, 14,15,45 and several studies have been escalating to find better and effective natural compounds to mitigate Pb-induced testicular damage. 11,23,46 Studies from our lab as well as other investigators have reported the protective effect of UMB against multiple toxicants in different organs, including liver, brain and heart [24][25][26][27][28][29] and testicular ischemia/reperfusion (I/R) injury in rodents. 47 However, the protective effect of UMB on Pb-induced testicular injury has not been reported yet.…”

Section: Discussionmentioning

confidence: 96%

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<p>Umbelliferone Inhibits Spermatogenic Defects and Testicular Injury in Lead-Intoxicated Rats by Suppressing Oxidative Stress and Inflammation, and Improving Nrf2/HO-1 Signaling</p>

Alotaibi¹,

Al-Joufi²,

Seif³

et al. 2020

DDDT

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Introduction: Lead (Pb) is an environmental toxic metal that threatens human health. Umbelliferone (UMB) is a coumarin with known medicinal and protective properties against cytotoxicity. This study explored the ameliorative effect of UMB against Pb-induced testicular toxicity in rats, focusing on steroidogenesis, oxidative stress and inflammation. Materials and Methods: Rats received lead acetate (50 mg/kg) and UMB (25, 50 or 100 mg/kg) via oral gavage for 4 weeks. Results: Pb-intoxicated rats exhibited testicular tissue injury and decreased serum levels of LH, FSH and testosterone. The count, viability, motility and normal morphology of the sperms were decreased accompanied with downregulated steroidogenesis markers in Pbinduced group. UMB prevented testicular injury, increased serum levels of LH, FSH and testosterone, upregulated steroidogenesis markers and improved the semen quality. In addition, UMB attenuated oxidative stress and oxidative DNA damage, downregulated the expression of pro-inflammatory mediators and Bax, boosted antioxidant defenses and Bcl-2, and upregulated Nrf2/HO-1 signaling in Pb-intoxicated rats. Conclusion: UMB prevents Pb-induced testicular injury by suppressing oxidative damage, inflammation and cell death, and boosting antioxidant defenses, Nrf2/HO-1 signaling and pituitary-gonadal axis. Thus, UMB may represent a protective and cost-effective agent against Pb testicular toxicity, pending further investigations to elucidate other underlying mechanisms.

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Section: Dovepresssupporting

confidence: 93%

Section: Discussionmentioning

confidence: 96%

<p>Umbelliferone Inhibits Spermatogenic Defects and Testicular Injury in Lead-Intoxicated Rats by Suppressing Oxidative Stress and Inflammation, and Improving Nrf2/HO-1 Signaling</p>

Alotaibi¹,

Al-Joufi²,

Seif³

et al. 2020

DDDT

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“…Furthermore, UMB protected against renal injury induced by methotrexate (MTX) and attenuated oxidative injury via downregulation of Keap1 and upregulation of Nrf2. The results have also shown that UMB inhibited inflammatory responses via downregulation of both NF-κB and p38 MAPK in the kidney of MTX-intoxicated rats [174].…”

Section: Urolithin Amentioning

confidence: 74%

“…The Umbelliferae family is inclusive of economically important herbs, such as celery, cumin, fennel, parsley alexanders, angelica, asafoetida, and giant hogweed [9,170]. UMB possesses a variety of bioactivities, and several investigators have previously reported its in vivo antioxidant and anti-inflammatory effects and studied the underlying mechanisms of action in several animal models [30,[171][172][173][174][175]. The anticancer activity of UMB in hepatocellular [176], colon [177], and oral [178] carcinomas has been well-acknowledged.…”

Section: Urolithin Amentioning

confidence: 99%

Coumarins as Modulators of the Keap1/Nrf2/ARE Signaling Pathway

Hassanein

Sayed

Hussein

et al. 2020

Oxidative Medicine and Cellular Longevity

164

106

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The Keap1/Nrf2/ARE system is a central defensive mechanism against oxidative stress which plays a key role in the pathogenesis and progression of many diseases. Nrf2 is a redox-sensitive transcription factor controlling a variety of downstream antioxidant and cytodefensive genes. Nrf2 has a powerful anti-inflammatory activity mediated via modulating NF-κB. Therefore, pharmacological activation of Nrf2 is a promising therapeutic strategy for the treatment/prevention of several diseases that are underlined by both oxidative stress and inflammation. Coumarins are natural products with promising pharmacological activities, including antioxidant, anticancer, antimicrobial, and anti-inflammatory efficacies. Coumarins are found in many plants, fungi, and bacteria and have been widely used as complementary and alternative medicines. Some coumarins have shown an ability to activate Nrf2 signaling in different cells and animal models. The present review compiles the research findings of seventeen coumarin derivatives of plant origin (imperatorin, visnagin, urolithin B, urolithin A, scopoletin, esculin, esculetin, umbelliferone, fraxetin, fraxin, daphnetin, anomalin, wedelolactone, glycycoumarin, osthole, hydrangenol, and isoimperatorin) as antioxidant and anti-inflammatory agents, emphasizing the role of Nrf2 activation in their pharmacological activities. Additionally, molecular docking simulations were utilized to investigate the potential binding mode of these coumarins with Keap1 as a strategy to disrupt Keap1/Nrf2 protein-protein interaction and activate Nrf2 signaling.

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“…Umbelliferone reportedly exhibits neuroprotective properties in a chronic unpredictable mild stress-induced rat model of depression (Qin et al, 2017), a rat model of focal cerebral ischaemiareperfusion (Wang, Li, Wang, Fu, & Ma, 2015), and a mouse model of Parkinson's disease (Subramaniam & Ellis, 2013). Additionally, accumulating evidence suggests that umbelliferone activates nuclear factor erythroid-derived 2-like 2 (Nrf2) in various animal models, resulting in upregulation of haem oxygenase-1 (HO-1) and attenuation of excessive inflammatory responses (Hassanein, Mohamed, Shalkami, Khalaf, & Hemeida, 2018;Mahmoud, Germoush, Alotaibi, & Hussein, 2017;Mohamed, Emam, Hassan, & Mogadem, 2014).…”

Section: Introductionmentioning

confidence: 99%

Xanthotoxin and umbelliferone attenuate cognitive dysfunction in a streptozotocin‐induced rat model of sporadic Alzheimer's disease: The role of JAK2/STAT3 and Nrf2/HO‐1 signalling pathway modulation

Hindam

Sayed

Skalicka‐Woźniak

et al. 2020

Phytotherapy Research

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The aim of the present study was to assess the neuroprotective effects of xanthotoxin and umbelliferone in streptozotocin (STZ)‐induced cognitive dysfunction in rats. Animals were injected intracerebroventricularly (ICV) with STZ (3 mg/kg) once to induce a sporadic Alzheimer's disease (SAD)‐like condition. Xanthotoxin or umbelliferone (15 mg/kg, i.p.) were administered 5 hr after ICV‐STZ and daily for 20 consecutive days. Xanthotoxin or umbelliferone prevented cognitive deficits in the Morris water maze and object recognition tests. In parallel, xanthotoxin or umbelliferone reduced hippocampal acetylcholinestrase activity and malondialdehyde level. Moreover, xanthotoxin or umbelliferone increased glutathione content. These coumarins also modulated neuronal cell death by reducing the level of proinflammatory cytokines (tumour necrosis factor‐alpha and interleukin‐6), inhibiting the overexpression of inflammatory markers (nuclear factor κB [NF‐κB] and cyclooxygenase II), and upregulating the expression of NF‐κB inhibitor (IκB‐α). Interestingly, xanthotoxin diminished phosphorylated JAK2 and phosphorylated STAT3 protein expression, while umbelliferone markedly replenished nuclear factor erythroid‐derived 2‐like 2 (Nrf2) and haem oxygenase‐1 (HO‐1) levels. The current study provides evidence for the protective effect of xanthotoxin and umbelliferone in STZ‐induced cognitive dysfunction in rats. This effect may be attributed, at least in part, to inhibiting acetylcholinestrase and attenuating oxidative stress, neuroinflammation and neuronal loss.

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Renoprotective effects of umbelliferone on methotrexate-induced renal injury through regulation of Nrf-2/Keap-1, P38MAPK/NF-κB, and apoptosis signaling pathways

Cited by 58 publications

References 45 publications

<p>Umbelliferone Inhibits Spermatogenic Defects and Testicular Injury in Lead-Intoxicated Rats by Suppressing Oxidative Stress and Inflammation, and Improving Nrf2/HO-1 Signaling</p>

<p>Umbelliferone Inhibits Spermatogenic Defects and Testicular Injury in Lead-Intoxicated Rats by Suppressing Oxidative Stress and Inflammation, and Improving Nrf2/HO-1 Signaling</p>

Coumarins as Modulators of the Keap1/Nrf2/ARE Signaling Pathway

Xanthotoxin and umbelliferone attenuate cognitive dysfunction in a streptozotocin‐induced rat model of sporadic Alzheimer's disease: The role of JAK2/STAT3 and Nrf2/HO‐1 signalling pathway modulation

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