記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Kidney360  

Key PointsSystemically administered anti-microRNA (miR)-21-serinol nucleic acid (SNA) accumulates in the kidneys and suppresses renal cyst growth.Anti-miR-21-SNA treatment alters mitochondrial metabolism, apoptotic signaling, and inhibits kidney tissue fibrosis.In human autosomal dominant polycystic kidney disease kidney cells, anti-miR-21-SNA treatment reduces cyst size and intracellular cAMP content and increases Ca2⁺ concentration.BackgroundHereditary 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 microRNA (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-microRNA activity and investigate its effects on cyst growth in vivo and in vitro.MethodsWe evaluated the effectiveness of anti-miR-21 treatment using an serinol nucleic acid-based antisense oligonucleotide in a mouse model of cystic kidney disease and human ADPKD cells.ResultsOur 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.ConclusionsOur 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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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Neuroscience Research  

Spinal cord injury (SCI) results in damage to neural circuits that cause long-term locomotor and sensory disability. The objective of the present study is to evaluate whether a clinical drug, protamine, can be employed as a therapeutic agent for SCI. First, we examined the rescue effect of protamine on dystrophic endballs (DEs) cultured on a chondroitin sulfate (CS) gradient coating. Consequently, axons with DE, which are unable to grow through the CS barrier, resumed growth after protamine treatment and were able to pass through the barrier. In addition, we tested whether protamine resolves the DE phenotype, accumulation of autophagosomes. The results demonstrated that protamine has significantly reduced the density of LC3 in DEs. Subsequently, mice were administered 1 mg/kg protamine via the tail vein one week following a contusion injury to the thoracic spinal cord. The hindlimb movements of the mice were evaluated in order to assess the therapeutic effect of protamine. Eleven venous administrations of protamine improved the symptoms. The current study has demonstrated that protamine cancels the CS inhibitory effect on axonal regrowth. Administrations of protamine were observed to alleviate hindlimb motor dysfunction in SCI mice. Our results suggest an effective therapeutic agent for SCI and a possibility for drug repositioning. It would be of interest to see if protamine also exerts a therapeutic effect in brain injury.

DOI： 10.1016/j.neures.2024.12.001

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Biochemistry  

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. Amongst 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 signalling in neuroblastoma.

DOI： 10.1093/jb/mvae055

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記述言語：英語  

記述言語：英語  

DOI： 10.1016/j.expneurol.2023.114444

記述言語：日本語