Biology subjects

Morikawa, K.

Publications and source records attributed to Morikawa, K..

8 recordsLinked to original sources

bioRxiv2026

IL-17A Mediates Cardiac Hypertrophy in Chronic Kidney Disease through the IL-23/Th17 Axis.

Background: Chronic kidney disease (CKD) is a major risk factor for cardiovascular morbidity, promoting left ventricular hypertrophy (LVH) prior to overt heart failure. The mechanisms underlying early cardiac remodeling in CKD remain incompletely understood. The IL-23/Th17/IL-17A inflammatory axis has emerged as a key mediator of cardiovascular pathology; however, its role in CKD-associated cardiac remodeling remains unclear. This study aimed to elucidate the contribution of this pathway to the early cardiac changes in CKD. Methods: Using a 5/6 nephrectomy (5/6Nx) mouse model of CKD, we evaluated cardiac structure, mitochondrial function, and inflammatory signaling. Cardiomyocyte transcriptomes were analyzed by RamDA-seq to identify molecular alterations. Circulating cytokines were profiled longitudinally, and IL-17A neutralization experiments were performed to assess causality. In addition, serum IL-12p40 concentrations were measured in patients with CKD and correlated with their renal function and cardiac remodeling indices. Results: At 16 weeks post-5/6Nx, mice developed LVH with preserved systolic function, accompanied by increased oxidative stress and mitochondrial structural abnormalities, but without significant myocardial fibrosis. Transcriptomic analysis identified oxidative phosphorylation as the most significantly downregulated pathway in cardiomyocytes. Despite increased mitochondrial DNA copy number and elevated PGC-1 expression, ATP production and mitochondrial respiratory chain proteins were reduced, indicating mitochondrial dysfunction. Circulating IL-12p40 and IL-23 levels increased progressively, concurrent with expansion of splenic Th17 cells and elevated cardiac IL-17A expression. Recombinant IL-17A directly impaired mitochondrial respiration in cultured cardiomyocytes. In vivo, IL-17A neutralization attenuated LVH, reduced oxidative stress, and partially restored mitochondrial protein expression without improving renal function. In patients with CKD, serum IL-12p40 levels correlated inversely with estimated glomerular filtration rate and positively with left ventricular mass index, supporting clinical relevance. Conclusions: Activation of the systemic IL-23/Th17/IL-17A axis contributes to early CKD-associated cardiac remodeling by promoting oxidative stress and mitochondrial dysfunction. Circulating IL-12p40 may serve as a biomarker of cardiorenal remodeling, and the IL-23/IL-17A pathway represents a potential therapeutic target.

physiology↗

bioRxiv2026

Native receptor-targeted chemogenetics enables cell-type-specific inhibition of endogenous receptors in freely moving mice

Understanding brain function requires tools that allow precise manipulation of receptor signaling in defined cell types within intact neural circuits. Optogenetics and conventional chemogenetic approaches primarily enable cell-type-specific control of neuronal excitability using engineered receptors or ion channels. However, direct and reversible inhibition of endogenous neurotransmitter receptors in defined cell types has remained technically inaccessible. Here, we introduce native receptor-targeted chemogenetics (NARCH), a chemogenetic strategy that integrates structure-guided receptor engineering with allosteric ligand design to achieve reversible and temporally precise inhibition of endogenous receptor signaling with cell-type specificity in vivo. By applying NARCH to metabotropic glutamate receptor 1 (mGlu1), we demonstrate that mGlu1 signaling in cerebellar Purkinje cells is required for stabilization of motor learning across training sessions in freely moving mice. NARCH thus establishes a receptor-level chemogenetic framework for causal analysis of neural circuits and behavior.

neuroscience↗

bioRxiv2026

Hepatic Ketogenesis Attenuates Cardiac Hypertrophy via Metabolic Reprogramming

BackgroundHeart failure with preserved ejection fraction (HfpEF) is increasingly recognized as a multisystem disorder linked to the cardiovascular-kidney-metabolic (CKM) syndrome. While the falling heart undergoes metabolic reprogramming, the interorgan crosstalk regulating myocardial substrate preference in HFpEF remains elusive. We aimed to clarify the role of systemic and local ketogenesis in the pathogenesis of cardiac hypertrophy and HFpEF. MethodsA mouse model of HFpEF was employed using a high-fat diet combined with NG-Nitro-L-arginine methyl ester hydrochloride (L-NAME). Cardiac hypertrophy and systemic metabolic profiling including ketogenesis were evaluated. To dissect the role of site-specific ketogenesis, we generated inducible cardiomyocyte-specific (Hmgcs2{Delta}iCM) and hepatocyte-specific (Hmgcs2{Delta}Hep) knockout mice of HMG-CoA synthase 2 (Hmgcs2), deficient in the rate-limiting enzyme for ketogenesis. Cardiomyocyte -specific nuclei were isolated for transcriptomic (RNA-seq) and in vitro assays in H9C2 cells were used to elucidate molecular mechanisms. ResultsThe HFpEF model successfully exhibited diastolic dysfunction, impaired exercise capacity and cardiac hypertrophy with elevated circulating ketone body concentration. Myocardial metabolomics and snRNA-seq identified a profound metabolic shift characterized by the accumulation of long-chain fatty acids and Krebs cycle intermediates, coupled with the transcriptional downregulation of insulin signaling and fatty acid degradation pathways. Although circulating ketone body level was upregulated, Hmgcs2{Delta}iCM mice showed no exacerbation of the HFpEF phenotype. In contrast, Hmgcs2{Delta}Hep mice exhibited significantly aggravated cardiac hypertrophy (HW/TL; Hmgcs2flox: 7.41 {+/-} 0.87: Hmgcs2{Delta}Hep: 8.29 {+/-} 0.73; p = 0.0154). Mechanistically, hepatic ketogenesis was required to maintain circulating beta-hydroxybutyrate (BHB) levels, which directly modulated cardiomyocyte metabolism. BHB acted as a metabolic signal to dampen fatty acid overload and facilitate glucose utilization. ConclusionsOur study identifies a critical "liver-heart axis" where hepatic ketogenesis serves as an essential regulator of myocardial metabolic resilience. Impaired hepatic ketogenesis creates a metabolic mismatch that drives pathological cardiac remodeling. These findings highlight the liver as a therapeutic target within the CKM syndrome framework, suggesting that restoring the hepato-cardiac metabolic bridge may ameliorate HFpEF progression. What is New?O_LIThis study identifies a novel liver-adipose-heart axis that governs myocardial metabolic resilience during the development of heart failure with preserved ejection fraction (HFpEF). C_LIO_LIWe demonstrate that while both the liver and heart upregulate ketogenesis under metabolic stress, only hepatic ketogenesis--and not cardiac-intrinsic ketogenesis--is essential for mitigating pathological cardiac remodeling. C_LIO_LIMechanistically, liver-derived {beta} -hydroxybutyrate acts as a critical C_LIO_LIendocrine signal that dampens fatty acid oxidation and facilitates myocardial glucose utilization. C_LI What Are the Clinical Implications?O_LIOur findings highlight the liver as a central therapeutic target within the cardiovascular-kidney-metabolic (CKM) syndrome framework, where hepatic metabolic failure directly drives cardiac dysfunction. C_LIO_LIRestoring the hepato-cardiac metabolic bridge, through either hepatic-targeted therapies or ketone body supplementation, represents a promising strategy to enhance myocardial metabolic flexibility and ameliorate HfpEF in patients with multi-organ metabolic disorders. C_LI

biochemistry↗

bioRxiv2025

Morphogenesis of the Carapace from Phyllosoma to Puerulus in Spiny Lobsters

Molting in exoskeleton-bearing organisms can result in dramatic body shape transformations. While this phenomenon has been well-studied in insects, limited knowledge exists for other taxa, including crustaceans. Among crustaceans, achelatan lobsters, such as Palinuridae and Scyllaridae, exhibit a unique metamorphic transition from a flattened phyllosoma larva to a three-dimensional puerulus or nisto larva in a single molt. This study investigates the mechanisms underlying this transformation, focusing on carapace deformation through histological analysis, live imaging, and computational modeling. Three-dimensional micro-computed tomography revealed a significant reduction in body length during metamorphosis. Live imaging captured dynamic morphological changes, including epithelial contraction and subsequent reshaping. Scanning electron microscopy identified a distinctive furrow structure on the carapace surface, absent in post-molt puerulus larvae, suggesting a role in the transformation process. To explore the formation of this furrow pattern, a computational model was developed based on differential shrinkage rates in vertical and horizontal directions. The model successfully reproduced similar patterns observed in natural specimens, implying that controlled anisotropic contraction could contribute to morphogenesis. Furthermore, three-dimensional shrinkage simulations demonstrated that local contraction with constrained out-of-plane deformation can generate folds, which later expand to form curved structures. This study provides novel insights into the biomechanics of arthropod molting, highlighting a previously unrecognized mechanism of two-dimensional-to-three-dimensional transformation. The findings enhance our understanding of achelatan lobster development and offer broader implications for exoskeletal morphogenesis across arthropods.

developmental biology↗

bioRxiv2025

Multifaceted suppression of staphylococcal virulence: in vitro study of a cellular status with reduced Agr activity and impaired biofilm

Anti-quorum sensing (QS) therapy has been focused on to reduce the virulence of pathogenic bacteria. However, a series of studies have shown that suppression of the staphylococcal QS Agr system promotes biofilm formation. In this study, we found that both Agr activity and the biofilm of Staphylococcus aureus can be reduced by a sappanwood extract (SWe). The impaired biofilm in the presence of SWe exhibited reduced extracellular DNA (eDNA) and increased extracellular polysaccharides. SWe also reduced pigmentation. The RNA-seq analysis showed that SWe suppressed multiple key virulence regulators, including the Agr and SaeRS systems. SWe downregulated cell-wall-associated proteins and several Agr-regulated virulence factors such as hemolysins and phenol-soluble modulins (PSMs). The present study did not intend the clinical application of the SWe but exemplified that it is possible to achieve anti-Agr and anti-biofilm activities simultaneously, suggesting a new therapeutic concept to combat S. aureus infection.

microbiology↗

bioRxiv2024

One-step N-terminomics based on isolation of protein N-terminal peptides from LysargiNase digests by tip-based strong cation exchange chromatography

We have developed a one-step isolation method for protein N-terminal peptides from LysargiNase digests by pipette tip-based strong cation exchange (SCX) chromatography. This CHAMP-N (CHromatographic AMplification of Protein N-terminal peptides) method using disposable and parallel-processable SCX tips instead of conventional HPLC SCX columns facilitates simple, sensitive and high-throughput N-terminomic profiling without sacrificing the high identification numbers and selectivity achieved by the HPLC-based method. By applying the CHAMP-N method to HEK293T cells, we identified novel cleavage sites for signal and transit peptides, and non-canonical translation initiation sites. Finally, for proteome-wide terminomics, we present a simple and comprehensive N-and C-terminomics platform employing three different tip-based approaches, including CHAMP-N, in which protease digestion and one-step isolation by tip LC are commonly used to achieve complementary terminome coverages.

biochemistry↗

bioRxiv2020

Novel multicellular prokaryote discovered next to an underground stream

The emergence of multicellularity is a key event in the evolution of life and is an attractive challenge among researchers, including those investigating the artificial design of cellular behavior1. Multicellular organisms are widely distributed on Earth, and retracing the specific conditions conducive for the initial transition from unicellularity to multicellularity is difficult. However, by examining organisms that inhabit unique (e.g., isolated) environmental niches, we may be able to get a glimpse into primitive multicellularity in the context of a given environment. Here we report the discovery of a new bacterium that displayed multicellular-like characteristics and behavior. The bacterium, which was isolated adjacent to an underground stream in a limestone cave, is to be named Jeongeupia sacculi sp. nov. HS-3. On a solid surface, HS-3 self-organizes its filamentous cells to form an appearance similar to the nematic phase of a liquid crystal2. Mature colonies produce and accommodate clusters of coccobacillus progeny, and release them upon contact with water. HS-3 demonstrated novel, spatiotemporally regulated multicellularity that can resolve the so-called competition-dispersal trade-off problem3. This study illustrates a hypothetical missing link on the emergence of multicellularity.

evolutionary biology↗

bioRxiv2020

MRSA emerges through natural transformation

Methicillin-resistant Staphylococcus aureus (MRSA) carries the resistance gene mecA in the staphylococcal cassette chromosome (SCC) that disseminates among staphylococci but the cell-to-cell transmission mechanism of SCC has not been clarified for half a century1. Here, we present evidence for efficient natural transformation in Staphylococcus aureus and its relevance in SCCmec transmission. We found that growth in biofilm conditions increased the transformation efficiency in a dependent manner on two component signal transduction systems, TCS13 (AgrCA) and TCS17 (BraSR). Strikingly, we demonstrate that natural transformation mediates the transfer of SCCmec from MRSA or methicillin-resistant coagulase negative staphylococci to methicillin-sensitive S. aureus. The site-specific insertion/excision system mediated by cassette chromosome recombinases was essential for SCCmec transformation while the stability of SCCmec varied depending on SCC types and recipients. We propose that natural transformation is the key process in the emergence of MRSA.

microbiology↗