11/3/2023 0 Comments Narcolepsy cataplexy breast cancer![]() Overall, these studies help to elucidate how cholangiocyte proliferation mitigates the consequences of bile duct damage they also provide the framework for a rational understanding of how to prevent endstage liver damage from chronic bile duct injury. The sonic hedgehog pathway is a leading candidate to activate Foxl1. Future studies are planned to perform a detailed molecular analysis of the factors that upregulate Foxl1 and lead to activation of the wnt/α-catenin pathway. ![]() Interestingly, cholangiocyte proliferation appears to be mediated by Foxl1 through the canonical wnt/α-catenin pathway. The researchers found that liver damage in this model is associated with a defect in cholangiocyte proliferation. Furthermore, Foxl1 −/− mice die uniformly within 14 days of bile duct ligation. They have now extended this observation to show that mice harboring a germline knockout of Foxl1 (Foxl1 −/−) have more extensive liver damage in a bile duct ligation model of obstructive cholestasis than do Foxl1 wild-type littermate controls. Recently, Sackett and colleagues discovered that Foxl1, a member of the forkhead box family of transcriptional regulators, is upregulated in cholangiocytes in response to bile duct damage. Therefore, molecular characterization of the response to damage could be instrumental in developing therapies that can enhance liver repair and minimize damage. If the injury is not resolved, chronic bile duct injury can result in ductopenia and fibrosis. ![]() The liver responds to bile duct injury with biliary hyperplasia. AZD1152-HQPA was found to synergize with vincristine to inhibit proliferation of BL cells, laying the groundwork for a rationale-based approach for the treatment of BL and possibly other high-grade NHLs.īile duct injury is the hallmark of a number of acquired and genetic diseases collectively known as cholangiopathies. Additional experiments with vincristine, a tubulin depolymerizing agent, found that vincristine treatment induced Aurora B kinase expression and that induction was dependent on c-Jun N-terminal kinase. Treatment of BL cells in culture with an Aurora B-selective inhibitor, AZD1152-HQPA, resulted in reduced proliferation and increased cell death. Furthermore, they showed that Aurora B expression correlated with high grade and advanced clinical stage. To determine whether Aurora B might be involved in the pathogenesis of non- Hodgkin lymphoma (NHL), Ikezoe and colleagues examined a large collection of NHL samples by immunohistochemistry with antibodies to Aurora B and found that more aggressive NHLs, such as Burkitt/s lymphoma (BL), tended to express Aurora B in a larger proportion of their cells than less aggressive NHLs, such as follicular lymphoma. Hopefully, their results will stimulate further developments in this field and eventually lead to treatments for this serious disease. Identification of the antigen is required for a detailed understanding of the pathogenesis of narcolepsy. In their future work, the authors plan to focus on the identification of the antigen recognized by their narcolepsy-related IgG, which will require the development of cellbased assays. Their work suggests that the narcolepsyrelated IgG antibody blocked both excitatory and inhibitory motor neurons, probably by binding to an autoantigen expressed on both populations of neurons. In the current work, the authors used their whole-colon bioassay system to perform a pharmacological dissection of the mechanism of action of their IgG antibody. Recently, Jackson and co-workers reported finding an immunoglobulin G (IgG) antibody in patients with narcolepsy that abolished neuronally mediated colon migrating motor complexes in a bioassay they developed to study narcolepsy. An autoimmune etiology has been suggested to explain the selective loss of hypocretin-secreting neurons due to a tight association between narcolepsy and the HLA-DQB1 0602 allele and an association with the T-cell-receptor α-locus. Given that hypocretins appear to promote wakefulness, loss of hypocretin explains the symptoms associated with narcolepsy. Narcolepsy with cataplexy is associated with selective loss of hypocretin- (also known as orexin) secreting neurons in the hypothalamus. Narcolepsy is a debilitating illness characterized by excessive daytime sleepiness, cataplexy (sudden and transient loss of muscle tone triggered by emotions), and abnormal rapideye-movement sleep.
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