Biology subjects

Kuroda, R.

Publications and source records attributed to Kuroda, R..

4 recordsLinked to original sources

bioRxiv2025

Dual inhibition of glutaminolysis and autophagy suppresses proliferation of Rheumatoid arthritis fibroblast-like synoviocytes and mitigates arthritis in SKG mice

Recent evidence highlights the critical role of immune metabolism in the pathogenesis of rheumatoid arthritis (RA). We previously demonstrated that glutaminase 1 (GLS1), a key enzyme in glutamine metabolism, is upregulated in fibroblast-like synoviocytes from RA patients (RA-FLS) and that GLS1 inhibition exerts an antiproliferative effect on RA-FLS. Glutaminolysis has also been shown to suppress autophagy, raising the possibilitiy that inhibiting glutaminolysis may enhance autophagy. Given this interplay, we hypothesized that dual inhibition of glutaminolysis and autophagy could synergistically suppress RA-FLS proliferation. This study aimed to investigate the effects of combining autophagy and glutaminolysis inhibition on RA-FLS and arthritis in SKG mice. We utilized chloroquine (CQ) as an autophagy inhibitor and compound 968 (C968), a GLS1 inhibitor, to suppress glutaminolysis. Treatment with C968 upregulated LC3B and ATG5 expression and increased LC3-II protein levels in RA-FLS, indicative of enhanced autophagy. Furthermore, C968 promoted autophagosome formation in RA-FLS. These findings confirm that glutaminolysis inhibition enhances autophagy in RA-FLS. The combination of C968 and CQ significantly inhibited RA-FLS proliferation and increased apoptotic cell death. Moreover, C968-CQ co-treatment markedly alleviated arthritis severity in SKG mice. Our findings suggest that concurrent suppression of glutaminolysis and autophagy represents a promising therapeutic strategy for RA.

immunology↗

bioRxiv2025

Vertical rooting caused by enhanced functional allele of qSOR1 improves rice yield under drought stress

Drought considerably affects crop productivity, and its severity is being intensified by climate change. Therefore, enhancing drought resistance is a crucial priority in crop breeding for ensuring sustainable agriculture. The root system architecture (RSA) influences the efficiency of water acquisition from land; therefore, a deep RSA is advantageous for avoiding drought stress. Here, we demonstrated that deeper RSA promoted by the qSOR1-v mutant allele (an enhanced functional allele of the quantitative trait locus for SOIL SURFACE ROOTING 1) significantly improves rice yield under drought when compared to the deep RSA achieved through the functional qSOR1 allele that originated from natural variation. The qSOR1-v mutant exhibited stronger root gravitropism than the wild type. This was characterized by a more pronounced polarization of auxin on the lower side during root curvature, leading to a robust vertical rooting phenotype that was consistently expressed across different soil-water environments. Additionally, the qSOR1-v mutation site was well conserved among angiosperm orthologs, and the corresponding mutation in LZY3 of Arabidopsis (qSOR1 ortholog) resulted in a steeper root growth angle. The rice introgression line, which was substituted from the functional qSOR1 allele to qSOR1-v through marker-assisted selection, showed vertical rooting, resulting in increased grain yield in an upland field under drought stress. No yield penalty was observed for this line under well-watered upland conditions than the original variety. These findings highlight the potential of qSOR1-v and corresponding mutations in angiosperm orthologs to promote vertical rooting across plant species, which can help sustain crop yields in drought-prone areas. Significance StatementGenetic modification of the root system architecture in crops represents a viable strategy for the development of climate-resilient crops. This study identified the qSOR1-v allele that consistently demonstrates a vertical rooting phenotype in rice across diverse growth conditions, from dry to wet. The preservation of the qSOR1 and LZY3 orthologs in angiosperms provides opportunities for the development of genotypes characterized by vertical rooting. The introgression of the qSOR1-v allele enhanced drought resistance under upland conditions. These findings underscore the potential of these genetic modifications to improve crop resilience in an era characterized by water scarcity.

plant biology↗

bioRxiv2025

A skeletal muscle-sympathetic nerve-intestine network underlies muscle inflammation and atrophy induced by immobilization

Immobility is a common cause of muscle atrophy, but the underlying mechanisms have remained unclear. Here we show that limb immobilization in mice elicits inflammation and atrophy of skeletal muscle that are preventable by neutralizing antibodies to the chemokine CXCL10. Limb immobilization also induced changes to the gut microbiota and intestinal inflammation, and either sterilization of the intestine with antibiotics or administration of 10-hydroxy-cis-12-octadecenoic acid--a linoleic acid-derived gut microbial metabolite--prevented intestinal and muscle inflammation as well as muscle atrophy induced by immobilization, implicating intestinal inflammation in muscle inflammation and atrophy. Limb immobilization activated sympathetic nerves and increased {beta}2-adrenergic receptor gene (Adrb2) expression in the intestine. Single-cell RNA-sequencing analysis revealed that, among cells expressing Adrb2 in the intestine, immobilization increased only the population of macrophages. Pharmacological inhibition or macrophage-specific ablation of Adrb2 prevented immobilization-induced intestinal and muscle inflammation. Our results thus implicate a previously unrecognized muscle-nerve-intestine network in immobilization-induced muscle atrophy.

molecular biology↗

bioRxiv2024

A nucleic acid prodrug activates mitochondrial respiration and extends lifespan

Mitochondrial dysfunction caused by aging leads to decreased energy metabolism, resulting in functional decline and increased frailty in multiple tissues. Strategies for protecting and activating mitochondria under stressful conditions are required to suppress aging and age-related diseases. However, it is challenging to develop drugs capable of boosting mitochondrial respiration and compensating for the reduced intracellular adenosine triphosphate (ATP) levels. In this study, we developed a prodrug that stimulates the metabolism of intracellular adenine nucleotides (AXP: adenosine monophosphate (AMP), adenosine diphosphate (ADP), and ATP). It enhances AMP-activated protein kinase activity, fatty acid oxidation, oxidative stress resistance, and mitochondrial respiration, thereby increasing the intracellular ATP levels. Furthermore, this prodrug markedly extended the lifespan of Caenorhabditis elegans. AXP-driven stimulation of cellular energy metabolism proposed herein represents a novel geroprotective strategy and paves the way for the development of bioenergetic-molecule therapeutics.

bioengineering↗