Biology subjects

Kawabe, T.

Publications and source records attributed to Kawabe, T..

7 recordsLinked to original sources

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

Perceiving direction of deformation-based motion

Transparent liquid flow deforms its background through light refraction, creating complex spatiotemporal patterns that challenge the visual system in discerning flow direction. This study investigates how the visual system perceptually resolves the direction of transparent liquid flow. Using two-dimensional 1/f noise as background, we sequentially deformed the noise with pre-defined displacement maps displaced across frames, systematically manipulating spatial frequency and displacement magnitude. Participants reported the perceived direction of deformation-based motion. The results emphasize the critical role of the relationship between the minimum wavelength and displacement magnitude. Performance declined when the displacement magnitude exceeded a certain proportion relative to the wavelength. Conversely, performance also dropped significantly under conditions of small displacements combined with low cut-off frequencies. Further analysis revealed the local deformation possibly hinders the detection of deformation-based motion. These findings enhance understanding of how global and local motion cues interact, providing insight into the visual systems processing of deformation-induced motion and transparency.

neuroscience↗

bioRxiv2024

Phosphodiesterase 3 inhibitors boost bone outgrowth

C-type natriuretic peptide (CNP) stimulates skeletal growth by acting on the growth plates of long bones, and a CNP variant is clinically used for achondroplasia treatment. We previously reported that CNP stimulates the autonomic Ca2+ influx mediated by TRPM7 channels in growth plate chondrocytes to facilitate extracellular matrix synthesis for bone growth. Here, we report that phosphodiesterase 3 (PDE3) inhibitors facilitate the Ca2+ influx and promote bone outgrowth. The representative PDE3 inhibitor cilostazol elevated cGMP levels and activated cell-surface K+ channels probably due to protein kinase G-mediated phosphorylation in growth-plate chondrocytes. The resulting hyperpolarization likely facilitated TRPM7-mediated Ca2+ influx by increasing the Ca2+-driving force. Moreover, cilostazol simulated the elongation of cultured bones and enlarged the body size of juvenile mice. Several PDE3 inhibitors have been used for clinical treatment of thrombosis, heart failure and asthma, while our observations suggest that the repositioning of PDE3 inhibitors would provide novel medications for syndromes involving short stature.

pharmacology and toxicology↗

bioRxiv2024

Glutathione supersulphide regulates T-cell receptor signalling

Immunometabolism regulates functions and fates of immune cells including T cells. Supersulphides, which are universal metabolites containing catenated sulphur atoms, have various physiological functions based on their unique redox properties. Here we found that activation of T-cell receptor (TCR) signalling was accompanied by supersulphide decrease, which suggests a regulatory contribution of sulphur metabolism to immune function. Consistently, inhibiting supersulphide synthesis facilitated TCR activation and exacerbated allergen-induced type 2 inflammation in mice. Supplementation with glutathione trisulphide (GSSSG), a major endogenous supersulphide, suppressed TCR signalling in naive CD4+ T cells and their differentiation and effectively alleviated the inflammation. Docking simulation revealed interaction of GSSSG with CD3{varepsilon} chain in the TCR/CD3 complex, which was supported by mass spectrometry detection of persulphidated glutathionylation at a functionally important CXXC motif of CD3{varepsilon} chain. This study identified a new post-translational modification with supersulfides and demonstrated a critical contribution of sulphur metabolism to TCR signalling regulation.

biochemistry↗

bioRxiv2023

Atypical cell death in the growth plate chondrocytes of Tric-b-knockout mice

TRIC-A and TRIC-B proteins form homotrimeric cation-permeable channels in the sarco/endoplasmic reticulum (SR/ER) and nuclear membranes and are thought to contribute to counterionic flux coupled with store Ca2+ release in various cell types. Serious mutations in the TRIC-B locus cause autosomal recessive osteogenesis imperfecta (OI), which is characterized by insufficient bone mineralization. We have reported that Tric-b-knockout mice can be used as an OI model. Here we report irregular cell death in proliferating growth plate chondrocytes in developing Tric-b-knockout bones. In the knockout chondrocytes, excess pro-collagen fibers were occasionally accumulated in severely dilated ER elements. Of the major ER stress pathways, the PERK pathway was preferentially hyperactivated in the knockout chondrocytes, and most likely altered gene expression to induce apoptosis-related proteins including CHOP and caspase 12. In Ca2+ imaging experiments, the knockout chondrocytes exhibited aberrant Ca2+ handling; ER Ca2+ release was impaired, and intracellular Ca2+ concentration was elevated. Our data suggest that Tric-b deficiency directs growth plate chondrocytes to pro-apoptotic stages by compromising cellular Ca2+-handling and exacerbating ER stress, leading to atypical apoptotic cell death.

developmental biology↗

bioRxiv2019

Perceived direction of deformation flow

In everyday circumstances, human observers can easily discriminate the direction of transparent liquid flow. However, the mechanism of direction discrimination is not so straightforward. The present study focused on the flow of image deformation, which is closely related to the flow of transparent liquid in the natural world. To determine what image information is important in discriminating the direction of deformation flow, a natural image in a stimulus clip was deformed by using a deformation vector map that translated leftward or rightward. The task of the observers was to judge whether the transparent liquid in the clip flowed leftward or rightward. Manipulating the amplitude of deformation, we found that the discrimination performance improved with the amplitude. Interestingly, the observers performance was high overall only when shearing deformation was applied to the stimuli, while the observers reported an opposite-motion direction when only compressive deformation was applied. We computationally analyzed motion statistics of stimuli and found that the combination of mean and skewness of horizontal motion vectors reliably predicted the performance. The results indicate that human observers use global motion directions in order to determine the direction of deformation flow.

neuroscience↗

bioRxiv2019

A computational mechanism for seeing dynamic deformation

Human observers perceptually discriminate the dynamic deformation of materials in the real world. However, the psychophysical and neural mechanisms responsible for the perception of dynamic deformation have not been fully elucidated. By using a deforming bar as the stimulus, we showed that the spatial frequency of deformation was a critical determinant of deformation perception. Simulating the response of direction-selective units (i.e., MT pattern motion cells) to stimuli, we found that the perception of dynamic deformation was well explained by assuming a higher-order mechanism monitoring the spatial pattern of direction responses. Our model with the higher-order mechanism also successfully explained the appearance of a visual illusion wherein a static bar apparently deforms against a tilted drifting grating. In particular, it was the lower spatial frequencies in this pattern that strongly contributed to the deformation perception. Finally, by manipulating the luminance of the static bar, we observed that the mechanism for the illusory deformation was more sensitive to luminance than contrast cues. Significance StatementFrom the psychophysical and computational points of view, the present study tried to answer the question, "how do human observers see deformation?". In the psychophysical experiment, we used a clip wherein a bar dynamically deformed. We also tested the illusory deformation of a bar, which was caused by tilted drifting grating, because it was unclear whether the illusory deformation could be described by our model. In the computational analysis, in order to explain psychophysical data for deformation perception, it was necessary to assume an additional unit monitoring the spatial pattern of direction responses of MT cells that were sensitive to local image motion.

neuroscience↗