Biology subjects

Umeyama, T.

Publications and source records attributed to Umeyama, T..

6 recordsLinked to original sources

bioRxiv2026

STING restrains calcium-dependent microglial phagocytosis and protects against neuronal loss and cognitive impairment during epileptogenesis

Epileptogenesis is accompanied by robust neuroinflammation, yet the molecular pathways linking innate immune activation to neuronal dysfunction remain incompletely defined. Given the established pro-inflammatory role of the stimulator of interferon genes (STING), we initially hypothesized that its loss would attenuate neuroinflammatory responses during epileptogenesis. Contrary to our expectation, we found that STING deficiency instead amplified microglial activation. Using a kainic acid mouse model of temporal lobe epilepsy (TLE), we show that STING-deficient microglia exhibit pronounced lysosomal expansion and enhanced phagocytic engulfment of neurons, leading to increased hippocampal neuronal loss and cognitive impairment. Mechanistically, STING deficiency increased the expression and altered the subcellular distribution of stromal interaction molecule 1 (STIM1), an endoplasmic reticulum Ca{superscript 2} sensor that mediates store-operated calcium entry (SOCE), resulting in dysregulated intracellular calcium dynamics and elevated SOCE activity. Pharmacological inhibition of SOCE reduced microglia-neuron interactions and microglial phagocytic engulfment, improved neuronal survival in the CA3 region of the hippocampus, and rescued cognitive deficits following status epilepticus. Collectively, these findings redefine STING as a negative regulator of microglial activation and identify a previously unrecognized STING-STIM1-SOCE axis that constrains calcium-dependent microglial phagocytosis during epileptogenesis, highlighting microglial calcium signaling as a potential therapeutic target in TLE.

neuroscience↗

bioRxiv2025

Dormant viral pathways underlie space-induced neural senescence: a neuroprotective strategy for spaceflight and neurological diseases

Long-duration spaceflight is associated with neurological symptoms in astronauts, yet the underlying molecular mechanisms remain unclear. Using human brain organoids cultured aboard the International Space Station, we analyzed three independent spaceflights to demonstrate that exposure to the space environment triggers Space-Induced Neural Senescence (SINS), characterized by chromatin remodeling, mitochondrial dysfunction, and activation of viral-like transcriptional programs in the absence of infection. Multi-omics analyses identified upregulation of endogenous LINE-1 (L1) retroelements, whose activity was markedly enhanced in organoids lacking MECP2, a known L1 repressor implicated in Rett syndrome. The resulting accumulation of cytoplasmic L1 DNA elicited an IL-6-mediated inflammatory and neurotoxic response, which was reversed by reverse transcriptase inhibitors (RTi) such as lamivudine or stavudine. Parallel preclinical experiments in Mecp2-deficient mice confirmed that RTi treatment restored neuronal morphology, synaptogenesis, function, cognition, and survival. These findings reveal that the space environment reactivates dormant genomic retroelements, providing an unexpected mechanistic insight into astronaut neurobiology and identifying a potential therapeutic strategy for both space-induced and terrestrial neurological conditions. Our pioneering study demonstrates the value of space-enabling research in accelerating drug discovery and disease treatment on Earth.

neuroscience↗

bioRxiv2025

Discovery of a Selective Inhibitor of ZIP14 with Therapeutic Potential for Cancer-associated Cachexia

ZIP14/SLC39A14, a membrane-bound metal transporter, is essential for systemic metal homeostasis and has been implicated in inflammatory and metabolic disorders, including cancer-associated cachexia. Despite its biological and therapeutic significance, no selective inhibitors have been identified. Here, we identify 1-phenyl-8-(2-phenylethyl)-1,3,8-triazaspiro[4.5]decan-4-one (PPTD) as the first selective small-molecule inhibitor of ZIP14. PPTD efficiently blocks ZIP14-mediated uptake of zinc, iron, manganese, and cadmium, while sparing the closely related transporter ZIP8/SLC39A8. Mechanistically, PPTD binds specifically to a pocket formed at the dimer interface of ZIP14, as revealed by AlphaFold3 structural prediction, ligand-interaction profiling, structure-activity analyses, and site-directed mutagenesis, providing direct evidence for a targeted inhibition mechanism. ZIP14-driven metal influx promotes reactive oxygen species and lipid peroxidation, leading to cytotoxicity, which PPTD effectively reverses. In vivo, PPTD ameliorates major features of cancer cachexia in mice, including weight loss, reduced survival, muscle wasting, impaired locomotor activity, and disease progression. PPTD thus provides both a chemical probe to dissect ZIP14 function and a potential therapeutic candidate for cancer cachexia, establishing a foundation for the development of therapies targeting ZIP14-mediated metal dysregulation.

biochemistry↗

bioRxiv2024

Stratification of viral shedding patterns in saliva of COVID-19 patients

Living with COVID-19 requires continued vigilance against the spread and emergence of variants of concern (VOCs). Rapid and accurate saliva diagnostic testing, alongside basic public health responses, is a viable option contributing to effective transmission control. Nevertheless, our knowledge regarding the dynamics of SARS-CoV-2 infection in saliva is not as advanced as our understanding of the respiratory tract. Here we analyzed longitudinal viral load data of SARS-CoV-2 in saliva samples from 144 patients with mild COVID-19 (a combination of our collected data and published data). Using a mathematical model, we quantified individual-level viral dynamics and stratified them into three groups using a clustering approach. Notably, the three groups exhibited distinct differences viral RNA detection durations: 11.5 days (95% CI: 10.6 to 12.4), 17.4 days (16.6 to 18.2), and 30.0 days (28.1 to 31.8), respectively. Surprisingly, this stratified grouping remained unexplained despite our analysis of 47 types of clinical data, including basic demographic information, clinical symptoms, results of blood tests, and vital signs. Additionally, we quantified the expression levels of 92 micro-RNAs in a subset of saliva samples, but these also failed to explain the observed stratification, although the mir-1846 level may have been weakly correlated with peak viral load. Our study provides insights into SARS-CoV-2 infection dynamics in saliva, highlighting the challenges in predicting the duration of viral RNA detection without indicators that directly reflect an individuals immune response, such as antibody induction. Given the significant individual heterogeneity in the kinetics of saliva viral shedding, identifying biomarker(s) for viral shedding patterns will be crucial for improving public health interventions in the era of living with COVID-19.

microbiology↗

bioRxiv2022

Lifelong temporal dynamics of the gut microbiome associated with longevity in mice

The temporal changes of the gut microbiome are thought to be critical for understanding its interactions with host aging, but lifelong dynamics within the same individual remain largely unknown. Here we firstly report the high temporal resolution dynamics of gut microbiomes in mice sharing the same genetic background and environment from their birth to natural death, spanning >1,000 days. The 16S rRNA sequencing analysis revealed 9 patterns of OTU temporal dynamics and 38 common "life-core" bacterial species/operational taxonomic units (OTUs) in [≥]80% of all samples across the lifespan of individual mice. The life-core OTUs are largely represented by the phylum Bacteroidota, whereas the transient bacterial group predominantly includes the phylum Firmicutes (Bacillota). Despite the shared genetic background and dietary habits, the gut microbiome structure significantly diversified with age and among individuals. A positive correlation existed between longevity and the microbiome -diversity in middle age (200-500 days) followed by a negative correlation in old age (>700 days), likely influenced by the increase in diversity during the last days of life. The abundance of several "life-core" species also exhibited non-static correlation trends with lifespan. Overall, this research characterized the gut microbiomes based on its persistence over hosts lifetime and suggested a non-static host-microbiome relationship within individual mice.

microbiology↗

bioRxiv2018

Cas9/CRISPR genome editing to demonstrate the contribution of Cyp51A Gly138Ser to azole resistance in Aspergillus fumigatus

Azole resistance in Aspergillus fumigatus is predominantly associated with increased expression of Cyp51A (lanosterol 14-demethylase), the target enzyme of azole antifungal agents, or with single-nucleotide polymorphisms (SNPs) in cyp51A. Although several SNPs that may be linked to low susceptibility in azole-resistant isolates have previously been reported, few studies have been conducted to conclusively demonstrate the contribution of SNPs to decreased azole susceptibility. An A. fumigatus strain was isolated from the sputum of a 74-year-old male receiving long-term voriconazole treatment for chronic progressive pulmonary aspergillosis. Etest antifungal susceptibility testing showed low susceptibility to voriconazole, itraconazole, and posaconazole. Nucleotide sequencing of cyp51A from this isolate revealed the mutations Gly138Ser (GGC[->]AGC) and Asn248Lys (AAT[->]AAA) compared with the cyp51A of azole-susceptible isolates. PCR-amplified DNA fragments containing cyp51A with or without the mutations of interest and a hygromycin marker were simultaneously introduced along with the Cas9 protein and in vitro-synthesized single-guide RNA into protoplasts of the azole-resistant/susceptible strains. Etest azole susceptibility testing of recombinant strains showed an increased susceptibility via the replacement of Ser138 by glycine. In contrast, azole susceptibility was slightly decreased when a Ser138 mutation was introduced into the azole-susceptible strain AfS35, indicating that the serine at position 138 of Cyp51A contributes to low susceptibility in the azole-resistant isolate. Genetic recombination, which has been hampered thus far in clinical isolates, can now be achieved using Cas9/CRISPR genome editing. This technique could be useful to investigate the contribution of other SNPs of cyp51A to azole resistance.

microbiology↗