Biology subjects

Owada, Y.

Publications and source records attributed to Owada, Y..

3 recordsLinked to original sources

bioRxiv2025

A lipid-driven, microbe-independent mechanism of acne via Lrig1+ follicular progenitor cells

Long-chain saturated fatty acids (lcSFAs) are abundant in the skin, but their pathogenic roles in acne remain unclear. In human sebum profiling, C16:0, the most abundant lcSFA, was the only fatty acid significantly elevated in acne and correlated with inflammatory comedone counts. We then established a mouse model that faithfully recapitulates human acne phenotypes, in which topical C16:0 penetrated the epidermis and induced sebocyte hyperplasia, comedogenesis, and follicular inflammation. Mechanistically, C16:0 activated keratinization and inflammatory pathways and drove sebocyte-lineage differentiation from Lrig1+progenitor cells, which function as cutaneous lipid sensors. These effects persisted in germ-free mice and were unaffected by fatty acid transporter modulation, while MyD88 signaling was partially required for inflammatory cell recruitment. Together, our findings identified C16:0 as a human acne-associated lipid that recapitulates disease hallmarks through a microbe-independent, lipid-driven pathway, highlighting Lrig1+cells as central hubs in remodeling of the pilosebaceous unit.

cell biology↗

bioRxiv2025

Non-DNA-damaging DNA-PK activation improving hearing and prolonging life due to NAD+ and SIRT upregulation

Emerging evidence strongly supports a close relationship between age-related hearing loss and frailty, highlighting the importance of early detection and intervention. Recently, we invented a mitochondria-homing drug named mitochonic acid 5 (MA-5), that increases the adenosine triphosphate (ATP) levels, rescue mitochondrial function, and protect tissue damages. Currently, the phase I clinical trial has been finished in Japan (jRCT2031210495) and the phase 2 clinical trial has already been approved by PMDA. Here we show that MA-5 improved various types of hearing loss in mouse models. Structural chemical bioanalysis revealed that MA-5 is a mixture of equal amount of S- and R- enantiomer and both S- and R- enantiomer increase ATP by binding mitochondrial protein, mitofilin. However, S-enantiomer significantly increased the NAD+ levels by binding to the NAD+-producing key enzyme nicotinamide phosphoribosyltransferase (NAMPT). Moreover, the S-enantiomer increased the sirtuin 1 protein by suppressing polyubiquitination induced by tripartite motif containing 28 (TRIM28) phosphorylation which was triggered by DNA-dependent protein kinase (DNA-PK) activation in the absence of DNA damage. Transcriptomic signatures showed that the signature of MA-5 shows an inverse correlation with aging and mortality and is oriented in the same direction as the OSKM-related iPSCs, suggesting the modification of aging pathways. Oral administration of MA-5 to mitochondrial disease model mouse showed increased survival. Our findings suggest that, in addition to enhancing ATP levels, the coordinated regulation of NAD+ metabolism, SIRT protein expression, and DNA-PK activity-constituting a novel therapeutic triad may contribute to the amelioration of hearing impairment and mitochondrial dysfunction, thereby improving life prognosis.

cell biology↗

bioRxiv2025

The astrocyte Fabp7 gene regulates diurnal seizure threshold and activity-dependent gene expression in mice

Epileptic seizures are often influenced by time-of-day and changes in vigilance state, yet the molecular and cellular mechanisms underpinning these associations remain poorly understood. Astrocytes, a pivotal type of glial cell, play a critical role in modulating neuronal excitability and circadian rhythms, and they express Fatty Acid Binding Protein 7 (Fabp7), a molecule vital for sleep regulation, lipid signaling, and gene transcription. This study investigates the role of Fabp7 in determining time-of-day dependent seizure susceptibility. We assessed electroshock seizure thresholds in male C57/BL6N wild-type (WT) and Fabp7 knockout (KO) mice. Results demonstrated that, compared to WT mice, Fabp7 KO mice displayed significantly elevated general and maximal electroshock seizure thresholds (GEST and MEST) during the dark phase, but not during the light phase. To explore the impact of Fabp7 on activity-dependent gene expression during seizures, we conducted RNA sequencing (RNA-seq) on cortical and hippocampal tissues from WT and Fabp7 KO mice following MEST and SHAM procedures during the dark period. While immediate early genes (IEGs) showed considerable differential expression between WT-MEST and WT-SHAM, this expression was absent in Fabp7 KO-MEST compared to Fabp7 KO-SHAM. Gene ontology analyses revealed significant overlaps between the WT-MEST:WT-SHAM and Fabp7 KO-SHAM:WT-SHAM comparisons, indicating that the basal mRNA expression profiles in Fabp7 KO brains resemble those of WT brains in a post-ictal state. Collectively, these findings suggest that Fabp7 is a key regulator of time-of-day dependent neural excitability and that astrocyte-mediated signaling pathways involving Fabp7 interact with neuronal activity to influence gene expression in response to seizures. Significance StatementChanges in sleep/wake state and/or circadian time-of-day are thought to influence neural excitability, which may confer seizure susceptibility. Here we describe a role for astrocytic Fabp7 in regulating nocturnal seizure threshold and gene expression associated with differences in seizure susceptibility, introducing an astrocyte factor that may represent a novel antiepileptic target for drug development.

neuroscience↗