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https://doi.org/10.3390/ijms24021445
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dc.title | Diclofenac Disrupts the Circadian Clock and through Complex Cross-Talks Aggravates Immune-Mediated Liver Injury—A Repeated Dose Study in Minipigs for 28 Days | |
dc.contributor.author | Selvaraj, Saravanakumar | |
dc.contributor.author | Oh, Jung-Hwa | |
dc.contributor.author | Yoon, Seokjoo | |
dc.contributor.author | Borlak, Jürgen | |
dc.date.accessioned | 2023-06-12T08:59:27Z | |
dc.date.available | 2023-06-12T08:59:27Z | |
dc.date.issued | 2023 | |
dc.identifier.citation | Selvaraj, Saravanakumar, Oh, Jung-Hwa, Yoon, Seokjoo, Borlak, Jürgen (2023). Diclofenac Disrupts the Circadian Clock and through Complex Cross-Talks Aggravates Immune-Mediated Liver Injury—A Repeated Dose Study in Minipigs for 28 Days. International Journal of Molecular Sciences 24 (2) : 1445-1445. ScholarBank@NUS Repository. https://doi.org/10.3390/ijms24021445 | |
dc.identifier.issn | 1422-0067 | |
dc.identifier.uri | https://scholarbank.nus.edu.sg/handle/10635/241882 | |
dc.description.abstract | <jats:p>Diclofenac effectively reduces pain and inflammation; however, its use is associated with hepato- and nephrotoxicity. To delineate mechanisms of injury, we investigated a clinically relevant (3 mg/kg) and high-dose (15 mg/kg) in minipigs for 4 weeks. Initially, serum biochemistries and blood-smears indicated an inflammatory response but returned to normal after 4 weeks of treatment. Notwithstanding, histopathology revealed drug-induced hepatitis, marked glycogen depletion, necrosis and steatosis. Strikingly, the genomic study revealed diclofenac to desynchronize the liver clock with manifest inductions of its components CLOCK, NPAS2 and BMAL1. The > 4-fold induced CRY1 expression underscored an activated core-loop, and the dose dependent > 60% reduction in PER2mRNA repressed the negative feedback loop; however, it exacerbated hepatotoxicity. Bioinformatics enabled the construction of gene-regulatory networks, and we linked the disruption of the liver-clock to impaired glycogenesis, lipid metabolism and the control of immune responses, as shown by the 3-, 6- and 8-fold induced expression of pro-inflammatory CXCL2, lysozyme and ß-defensin. Additionally, diclofenac treatment caused adrenocortical hypertrophy and thymic atrophy, and we evidenced induced glucocorticoid receptor (GR) activity by immunohistochemistry. Given that REV-ERB connects the circadian clock with hepatic GR, its > 80% repression alleviated immune responses as manifested by repressed expressions of CXCL9(90%), CCL8(60%) and RSAD2(70%). Together, we propose a circuitry, whereby diclofenac desynchronizes the liver clock in the control of the hepatic metabolism and immune response.</jats:p> | |
dc.publisher | MDPI AG | |
dc.source | Elements | |
dc.type | Article | |
dc.date.updated | 2023-06-06T02:15:04Z | |
dc.contributor.department | DUKE-NUS MEDICAL SCHOOL | |
dc.description.doi | 10.3390/ijms24021445 | |
dc.description.sourcetitle | International Journal of Molecular Sciences | |
dc.description.volume | 24 | |
dc.description.issue | 2 | |
dc.description.page | 1445-1445 | |
dc.published.state | Unpublished | |
Appears in Collections: | Elements Staff Publications |
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ijms-24-01445-v2.pdf | Published version | 31.66 MB | Adobe PDF | OPEN | None | View/Download |
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