Biology subjects

Itoh, S.

Publications and source records attributed to Itoh, S..

3 recordsLinked to original sources

bioRxiv2025

Selective PPAR-α activation with pemafibrate attenuates macrophage-mediated progression of calcific aortic valve disease

BACKGROUNDCalcific aortic valve disease (CAVD) compromises valve compliance and cardiac hemodynamics leading to aortic stenosis (AS) and cardiovascular dysfunction. With treatment for severe AS limited to valve replacement and no effective pharmacotherapies, new interventions are urgently needed for patients. This study evaluated pemafibrate, a selective peroxisome proliferator-activated receptor alpha (PPAR) activator as a novel therapeutic for CAVD and AS. METHODS AND RESULTSIn an aortic valve wire injury (AVWI) model of AS in Ldlr-/- mice, pemafibrate administration (0.2 mg/kg/day) for 15 weeks improved aortic valve function and reduced valvular calcification by 39% (p<0.001), accompanied by reduced leaflet inflammation and CD68 macrophage infiltration. These effects were independent of changes in plasma triglyceride levels. In vitro, pemafibrate suppressed inflammation-mediated calcification of primary human valvular interstitial cells (VICs) by modulating macrophage-derived secreted factors, identifying macrophage-VIC crosstalk as a key disease mechanism. Direct treatment of macrophages with pemafibrate, or exposure to serum from pemafibrate-treated participants in the PROMINENT randomized controlled trial, shifted macrophages toward a less inflammatory and less chemotactic phenotype. Proteomic analyses of patient serum substantiated these findings by reflecting a systemic reduction in inflammatory parameters and monocyte activation. Network integration of the in vitro derived pemafibrate-responsive proteome with human calcified AV tissue proteomes identified aberrant protein translation (GNB2L1, GSPT1) and disrupted bioenergetics (MYDGF, PDIA4) as potential clinically relevant pemafibrate-responsive pathways and effector proteins relevant to AS progression. CONCLUSIONSPemafibrate slows experimental AS progression and valve calcification through modulation of macrophage-VIC crosstalk, independent of lipid lowering. These findings support further evaluation of pemafibrate as a potential pharmacological approach for CAVD and support further testing in randomized clinical trials.

pharmacology and toxicology↗

bioRxiv2023

Astrocyte-specific inhibition of primary cilium functions improves cognitive impairment during neuroinflammation by suppressing A1 astrocyte differentiation.

A1 astrocytes play a neurotoxic role in various neurodegenerative diseases. While inhibiting the differentiation of A1 astrocytes can slow disease progression, the mechanisms controlling A1 astrocyte differentiation are largely unknown. The primary cilium is a cellular organelle that receives extracellular signals and regulates cell proliferation, differentiation, and maturation. To elucidate the physiological function of the primary cilium in A1 astrocytes, we utilized primary astrocytes and an inflammation mouse model. We found that the length of the primary cilium was increased in astrocytes, and the inhibition of primary cilium formation inhibited their differentiation into A1 astrocytes. Since mice with systemic ciliogenesis defects exhibit embryonic lethality, the function of the primary cilium in adults has remained largely unclear. Therefore, we established conditional knockout (cKO) mice that specifically inhibit primary cilium function in astrocytes upon drug stimulation. In a neuroinflammation mouse model in which lipopolysaccharide (LPS) was intraperitoneally injected into wild-type mice, increases in A1 astrocyte number and primary cilium length were observed in the brain. In contrast, cKO mice exhibited a reduction in the proportions of A1 astrocytes and apoptotic cells in the brain. Additionally, the novel object recognition (NOR) score observed in the cKO mice was higher than that observed in the neuroinflammation model mice. These results suggest that the primary cilium in astrocytes is essential for A1 astrocyte differentiation, which leads to a decline brain function. We propose that regulating astrocyte-specific primary cilium signalling may be a novel strategy for the suppression of neuroinflammation.

neuroscience↗

bioRxiv2021

Direct Energy Transfer from Allophycocyanin-Free Rod-Type CpcL-Phycobilisome to Photosystem I

Phycobilisomes (PBSs) are photosynthetic antenna megacomplexes comprised of pigment-binding proteins (cores and rods) joined with linker proteins. A rod-type PBS that does not have a core is connected to photosystem I (PSI) by a pigment-free CpcL linker protein, which induces a red-shift of the absorption band of phycocyanobilin (PCB) in the rod (red-PCB). Herein, the isolated supercomplex of the rod-type PBS and the PSI tetramer from Anabaena sp. PCC 7120 were probed by picosecond laser spectroscopy at 77 K and by decay-associated spectral analysis to show that red-PCB mediates the fast (time constant = 90 ps) and efficient (efficiency = 95%) transfer of excitation energy from PCB in rod to chlorophyll a (Chl a) in PSI. According to the Forster energy transfer mechanism, this high efficiency corresponds to a 4-nm distance between red-PCB and Chl a, suggesting that {beta}-84 PCB in rod acts as red-PCB. TOC GRAPHIC O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

biophysics↗