Notch‐Hes1 signaling activation in Caroli disease and polycystic liver disease

Takahashi, Kenta; Sato, Yasunori; Yamamura, Minako; Nakada, Satoko; Tamano, Yuko; Sasaki, Motoko; Harada, Kenichi

doi:10.1111/pin.13130

Cited by 6 publications

(3 citation statements)

References 24 publications

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“…[40] It was shown that Hes-1 is a contributing factor to several liver diseases such as biliary diseases and liver fibrosis and mostly due to Notch1 activation. [41][42][43] As a result, blocking of Notch1 signaling may present a therapeutic target to alleviate drug-induced organ toxicity. Accordingly, blocking Notch1 by γ-secretase inhibitor, diabenzazepine, downregulated Hes-1 expression with augmenting cisplatin chemotherapeutic effect while mitigating its nephrotoxic effect.…”

Section: Discussionmentioning

confidence: 99%

The beneficial effects of l‐carnitine and infliximab in methotrexate‐induced hepatotoxicity: Emphasis on Notch1/Hes‐1 signaling

Radwan,

Abdel‐Latif,

Abbas

et al. 2023

Archiv der Pharmazie

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Methotrexate (MTX)‐induced hepatotoxicity is a serious adverse effect that may limit its use. Therefore, eligible drugs to ameliorate MTX‐induced hepatotoxicity are required. l‐Carnitine (LC) is a natural molecule with beneficial metabolic effects and infliximab (INF) is an anti‐inflammatory monoclonal antibody against tumor necrosis factor‐alpha (TNF‐α). Recently, Notch1/Hes‐1 signaling was found to play a key role in the pathogenesis of liver injury. However, its role in MTX‐induced hepatotoxicity is unclear. This study aimed to evaluate the modulatory effects of LC or INF on MTX‐induced hepatotoxicity and to explore the underlying mechanism with emphasis on the Notch1/Hes‐1 signaling pathway. Sixty rats were randomized into six groups (n = 10): (1) control (saline); (2) MTX (20 mg/kg MTX, intraperitoneal [ip], once); (3) LC group (500 mg/kg ip, 5 days); (4) INF (7 mg/kg INF ip, once); (5) MTX+LC (20 mg/kg ip, once, 500 mg/kg ip, 5 days, respectively); (6) MTX+INF (20 mg/kg ip, once, 7 mg/kg INF ip, once, respectively). Oxidative stress, inflammatory markers, and Notch1/Hes‐1 were investigated. MTX induced the expression of Notch1 and Hes‐1 proteins and increased the levels of TNF‐α, interleukin (IL)‐6, and IL‐1β in the liver. Cotreatment with LC or INF showed apparent antioxidant and anti‐inflammatory effects. Interestingly, the downregulation of Notch1 and Hes‐1 expression was more prominent in LC cotreatment as compared with INF. In conclusion, LC or INF attenuates MTX‐induced hepatotoxicity through modulation of Notch1/Hes‐1 signaling. The LC ameliorative effect against MTX‐induced hepatotoxicity is significantly better than that of INF. Therefore, LC cotreatment may present a safe and therapeutically effective therapy in alleviating MTX‐induced hepatotoxicity.

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Section: Discussionmentioning

confidence: 99%

The beneficial effects of l‐carnitine and infliximab in methotrexate‐induced hepatotoxicity: Emphasis on Notch1/Hes‐1 signaling

Radwan,

Abdel‐Latif,

Abbas

et al. 2023

Archiv der Pharmazie

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“…Ductal plate malformation (DPM) may play a role in the pathogenesis of Caroli disease, which leads to persistent embryonic bile ducts after birth [ 81 , 82 ]. Beyond DPM, Takahashi et al identified that activation of Notch signaling involving Notch1 and Hes1 may also participate in the progression of biliary cystogenesis in Caroli disease [ 83 ].…”

Section: Introductionmentioning

confidence: 99%

Pathogenesis of Choledochal Cyst: Insights from Genomics and Transcriptomics

Lui

Tam

2022

Genes

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Choledochal cysts (CC) is characterized by extra- and/or intra-hepatic b\ile duct dilations. There are two main theories, “pancreaticobiliary maljunction” and “congenital stenosis of bile ducts” proposed for the pathogenesis of CC. Although family cases or CC associated with other anomalies have been reported, the molecular pathogenesis of CC is still poorly understood. Recent advances in transcriptomics and genomics analysis platforms have unveiled key expression signatures/genes/signaling pathways in the pathogenesis of human diseases including CC. This review summarizes insights from genomics and transcriptomics studies into the pathogenesis of CC, with the aim to improve (i) our understanding of its underlying complex pathomechanisms, and (ii) clinical management of different subtypes of CC, in particular their associated hepatic fibrotic change and their risk of malignancy transformation.

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“…One of the main signaling pathways implementing EMT is the Jagged1/Notch pathway [14]. This cascade is activated in many models of liver fibrosis and is abnormally increased in patients with fibrotic complications in several diseases, including non-alcoholic steatohepatitis NASH [17][18][19]. It was also shown that the Jagged1/Notch signaling pathway could selectively mediate the fibrogenic properties of TGFβ1, which is required to stimulate the production and deposition of ECM components [20].…”

Section: Introductionmentioning

confidence: 99%

Jagged-1/Notch Pathway and Key Transient Markers Involved in Biliary Fibrosis during Opisthorchis felineus Infection

et al. 2022

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Chronic opisthorchiasis associated with Opisthorchis felineus infection is accompanied by severe fibrotic complications. It is of high practical significance to elucidate the mechanisms of hepatic fibrosis in chronic infection dynamics. The goal of the study is to investigate the temporal profile of key markers and the Jagged1/Notch signaling pathway in the implementation of fibrosis in a chronic O. felineus infection. For the first time, using histological methods and real-time PCR analysis, we demonstrated the activation of the Jagged1/Notch pathway in liver fibrogenesis, including the activation of the Hes1 and Hey1 target genes during experimental opisthorchiasis in Mesocricetus auratus. Cluster analysis followed by regression analysis of key markers during the infection showed that Jagged1 and Mmp9have the greatest contribution to the development of cholangiofibrosis and periductal fibrosis. Moreover, we detected a significant increase in the number of Jagged1-positive cells in the liver of chronic opisthorchiasis patients compared to that of the control group without infection. The results of the study are extremely informative both in terms of investigation both diverse fibrosis mechanisms as well as potential targets in complex antihelmintic therapy.

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Notch‐Hes1 signaling activation in Caroli disease and polycystic liver disease

Cited by 6 publications

References 24 publications

The beneficial effects of l‐carnitine and infliximab in methotrexate‐induced hepatotoxicity: Emphasis on Notch1/Hes‐1 signaling

The beneficial effects of l‐carnitine and infliximab in methotrexate‐induced hepatotoxicity: Emphasis on Notch1/Hes‐1 signaling

Pathogenesis of Choledochal Cyst: Insights from Genomics and Transcriptomics

Jagged-1/Notch Pathway and Key Transient Markers Involved in Biliary Fibrosis during Opisthorchis felineus Infection

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