Ginkgo biloba Extract Protects against Methotrexate-Induced Hepatotoxicity: A Computational and Pharmacological Approach

Kury, Lina T. Al; Dayyan, Fazli; Shah, Fawad Ali; Malik, Zulkifal; Alattar, Abdullah; Alshaman, Reem; Ali, Amjad; Khan, Zahid

doi:10.3390/molecules25112540

Cited by 36 publications

(26 citation statements)

References 40 publications

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“…The slides were then kept under running water in a glass jar for 10 min and treated with 1% HCl and 1% ammonia water as reported previously. 43 Eosin solution was used afterward for 5-10 min for cytoplasmic staining. After the specified time, slides were rinsed with water and airdried for a short interval.…”

Section: Hematoxylin and Eosin (Hande) Stainingmentioning

confidence: 99%

Natural Dietary Supplement, Carvacrol, Alleviates LPS-Induced Oxidative Stress, Neurodegeneration, and Depressive-Like Behaviors via the Nrf2/HO-1 Pathway

Naeem¹,

Kury²,

Nasar³

et al. 2021

JIR

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Major depressive disorder (MDD) is a debilitating human health condition characterized by mood swings and is associated with a high probability of suicide attempts. Several studies have reported a role of neuroinflammation in MMD, yet the efficacy of natural drug substances on neuroinflammation-associated depression has not been wellinvestigated. The present study examined the neuroprotective effects of carvacrol on lipopolysaccharide (LPS)-induced neuroinflammation, depression, and anxiety-like behavior. Methods: Male Sprague Dawley rats were divided into two experimental cohorts to determine the effects and the effective dose of carvacrol (whether 20 mg/kg or 50 mg/kg), and further demonstrate the mechanism of action of nuclear factor E2-related factor (Nrf2) in depression. Results: We found marked neuronal alterations in the cortex and hippocampus of LPSintoxicated animals that were associated with higher inflammatory cytokine expression such as cyclooxygenase (COX2), tumor necrosis factor-alpha (TNF-α), and c-Jun N-terminal kinase (p-JNK). These detrimental effects exacerbated oxidative stress, as documented by a compromised antioxidant system due to high lipid peroxidase (LPO). Carvacrol (20 mg/kg) significantly reverted these changes by positively modulating the antioxidant gene Nrf2, a master regulator of the downstream antioxidant pathway. To further investigate the role of Nrf2, an inhibitor of Nrf2 called all-trans retinoic acid (ATRA) was used, which further exacerbated LPS toxicity with a higher oxidative and inflammatory cytokine level. To further support our notion, we performed virtual docking of carvacrol with the Nrf2-Keap1 target and the resultant drug-protein interactions validated the in vivo findings. Conclusion: Collectively, our findings suggest that carvacrol (20 mg/kg) could activate the endogenous master antioxidant Nrf2, which further regulates the expression of downstream antioxidants, eventually ameliorating LPS-induced neuroinflammation and neurodegeneration.

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Section: Hematoxylin and Eosin (Hande) Stainingmentioning

confidence: 99%

Natural Dietary Supplement, Carvacrol, Alleviates LPS-Induced Oxidative Stress, Neurodegeneration, and Depressive-Like Behaviors via the Nrf2/HO-1 Pathway

Naeem¹,

Kury²,

Nasar³

et al. 2021

JIR

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“…Several studies have documented the cross-talk between oxidative stress and the inflammation process ( Al Kury et al, 2019 ; Al Kury et al, 2020 ). Therefore, drug therapeutics should be designed to subside the inflammatory process and oxidative distress, by triggering the endogenous antioxidant defense system.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, the expression of COX-2 and iNOS can be prevented by antagonizing p-NFκB expression ( Ali A et al, 2020 ). Natural drug substances have significant anti-inflammatory potential, and we previously showed the inhibitory effect of carveol, polydatin, and Ginkgo biloba on NFkB, COX-2, and iNOS expression in different experimental models ( Al Kury et al, 2019 ; Al Kury et al, 2020 ; Malik et al, 2020 ). We postulated here that carveol reduces hepatocellular necrosis by negatively modulating the expression of mitogen kinase and other inflammatory cytokines.…”

Section: Discussionmentioning

confidence: 99%

Carveol a Naturally-Derived Potent and Emerging Nrf2 Activator Protects Against Acetaminophen-Induced Hepatotoxicity

et al. 2021

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Acetaminophen (N-acetyl p-aminophenol or APAP) is used worldwide for its antipyretic and anti-inflammatory potential. However, APAP overdose sometimes causes severe liver damage. In this study, we elucidated the protective effects of carveol in liver injury, using molecular and in silico approaches. Male BALB/c mice were divided into two experimental cohorts, to identify the best dose and to further assess the role of carveol in the nuclear factor E2-related factor; nuclear factor erythroid 2; p45-related factor 2 (Nrf2) pathway. The results demonstrated that carveol significantly modulated the detrimental effects of APAP by boosting endogenous antioxidant mechanisms, such as nuclear translocation of Nrf2 gene, a master regulator of the downstream antioxidant machinery. Furthermore, an inhibitor of Nrf2, called all-trans retinoic acid (ATRA), was used, which exaggerated APAP toxicity, in addition to abrogating the protective effects of carveol; this effect was accompanied by overexpression of inflammatory mediators and liver = 2ltoxicity biomarkers. To further support our notion, we performed virtual docking of carveol with Nrf2-keap1 target, and the resultant drug-protein interactions validated the in vivo findings. Together, our findings suggest that carveol could activate the endogenous master antioxidant Nrf2, which further regulates the expression of downstream antioxidants, eventually ameliorating the APAP-induced inflammation and oxidative stress.

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“…The exact molecular mechanisms underlying Mtx hepatotoxicity are not clearly understood. Recent studies have indicated that Mtx induced hepatic injury may be due to increasing levels of reactive oxygen species (ROS), hydroxyl radicals and hydrogen peroxide as a result of oxidative injury of the DNA and triggers lipid peroxidation along with decreased levels of antioxidant defense molecules (8,(11)(12)(13)(14).…”

Section: Introductionmentioning

confidence: 99%

The role of resveratrol in hepatotoxicity caused by methotrexate

Özgöçmen

Yeşilot

2021

Veterinary Journal of Mehmet Akif Ersoy University

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Methotrexate is an immunosuppressive and antineoplastic drug that may induce hepatotoxicity. Resveratrol is a compound that has a protective effect thanks to its antioxidant role. In present study was aimed to investigate posibble protective effects of resveratrol in methotrexate induced hepatotoxicity. Eighteen Wistar Albino rats were equally divided into three groups: Control, Methotrexate, Methotrexate + Resveratrol. After a single dose of methotrexate (15 mg/kg, i.p.), resveratrol (10 mg/kg, orally) was applied for 7 days. Fallowing 7 days, rats were sacrificed. Histopathological (H-E staining), immunohistochemical (Tumor Necrosis Factor Alpha, inducible Nitric Oxide Synthases, Nuclear Factor Kappa) and biochemical (Total Oxidant Status, Total antioxidants Status and Oxidative Stress Index) analyses were assayed in liver tissue samples. Additionally, Aspartate Aminotransferase, Alanine Aminotransferase, Gamma Glutamyl Transferase and Total Biluribin activities were assayed in serum samples for biochemical analyses. Normal liver tissues were observed in control groups. Histopatholocigal changes, high staining of Tumor Necrosis Factor Alpha, inducible Nitric Oxide Synthases, Nuclear Factor Kappa, increasing levels of tissue Total Oxidant Status, Oxidative Stress Index and decreasing levels of tissue Total antioxidants Status were observed in methotrexate groups. Moreover, Aspartate Aminotransferase, Alanine Aminotransferase, Gamma Glutamyl Transferase and Total Biluribin levels increased in methotrexate groups too (p<0.05). However, these findings were lower in the Methotrexate + Resveratrol groups (p<0.05). In this study were observed that oxidant levels could increase after methotrexate applied in the liver, whereas resveratrol alleviated effects of hepatotoxicity by histopathological, immunohistochemical and biochemical analyses.

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Ginkgo biloba Extract Protects against Methotrexate-Induced Hepatotoxicity: A Computational and Pharmacological Approach

Cited by 36 publications

References 40 publications

Natural Dietary Supplement, Carvacrol, Alleviates LPS-Induced Oxidative Stress, Neurodegeneration, and Depressive-Like Behaviors via the Nrf2/HO-1 Pathway

Natural Dietary Supplement, Carvacrol, Alleviates LPS-Induced Oxidative Stress, Neurodegeneration, and Depressive-Like Behaviors via the Nrf2/HO-1 Pathway

Carveol a Naturally-Derived Potent and Emerging Nrf2 Activator Protects Against Acetaminophen-Induced Hepatotoxicity

The role of resveratrol in hepatotoxicity caused by methotrexate

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