Language：English   Publishing type：Research paper (scientific journal)   Publisher：Ovid Technologies (Wolters Kluwer Health)  

Background:

Hereditary cystic kidney diseases are ciliopathies characterized by functional defects in the primary cilia of renal tubules. Abnormalities in the primary cilia enhance cell proliferation signals and cause cyst enlargement. The most common type is autosomal dominant polycystic kidney disease (ADPKD), but other diseases, such as nephronophthisis, have been discovered to be more common than previously considered. In ADPKD, several microRNAs are reportedly aberrantly expressed and involved in disease pathogenesis. Among these, we focused on miR-21, which is upregulated in response to cAMP signaling. In this study, we aimed to newly generate an anti-miR-21 oligonucleotide synthesized from serinol nucleic acid (Anti-miR-21-SNA) to improve anti-miRNA activity and investigate its effects on cyst growth in vivo and in vitro.

Methods:

We evaluated the effectiveness of anti-miR-21 treatment using an SNA-based antisense oligonucleotide in a mouse model of cystic kidney disease and human ADPKD cells.

Results:

Our study revealed that Anti-miR-21-SNA effectively prevented cyst growth in vivo and in vitro. In the mouse model of cystic kidney disease, we systemically administered Anti-miR-21-SNA and observed its accumulation primarily in the kidneys, suggesting effective drug delivery. Anti-miR-21-SNA treatment reduced kidney size and blood urea nitrogen levels without inducing hepatotoxicity. Mechanistically, molecules related to mitochondrial metabolism, apoptosis, and fibrosis pathways were involved. In vitro, Anti-miR-21-SNA treatment of primary cultured kidney cells from an ADPKD patient reduced cyst volume and intracellular cAMP content and increased Ca²⁺ concentration, supporting the efficacy of this treatment.

Conclusions:

Our results showed that Anti-miR-21-SNA treatment represents a potential therapeutic strategy for cystic kidney disease.

DOI： 10.34067/KID.0000000771

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.neures.2024.12.001

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

Anaplastic lymphoma kinase (ALK) is a well-known oncogene involved in various malignancies such as anaplastic large cell lymphoma, lung cancer and neuroblastoma. Several substrates for fused ALK have been identified and their biological functions have been described. However, the lack of a comprehensive identification of ALK substrates limits our understanding of the biological roles of receptor ALK. Thus, this study aimed to identify novel ALK substrates and characterize their biological functions. We screened the interactors of the kinase domain of receptor ALK using proximity-dependent biotin identification and identified 43 interactors. We narrowed down the candidates by evaluating whether these interactors were downstream of ALK in a neuroblastoma cell line, NB-1. Among these, we identified amyloid beta precursor protein binding family B member 1 (APBB1) as an ALK downstream molecule involved in NB-1 cell viability. Finally, we assessed the kinase-substrate relationship between ALK and APBB1 and found that ALK phosphorylated multiple tyrosine residues in APBB1 both in-cell and in-tube assays, with tyrosine 269 as a major target. In conclusion, we successfully identified a new substrate for receptor ALK. Our results may help further elucidate the molecular mechanism of ALK downstream signaling in neuroblastoma.

DOI： 10.1093/jb/mvae055

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Language：English  

Language：English  

DOI： 10.1016/j.expneurol.2023.114444

Language：Japanese