Language：English   Publishing type：Research paper (scientific journal)   Publisher：Translational Research  

Chronic kidney disease (CKD) induces cardiac inflammation and fibrosis and reduces survival. We previously demonstrated that G protein-coupled receptor 68 (GPR68) promotes cardiac inflammation and fibrosis in mice with 5/6 nephrectomy (5/6Nx) and patients with CKD. However, no method of GPR68 inhibition has been found that has potential for therapeutic application. Here, we report that Cephalotaxus harringtonia var. nana extract and homoharringtonine ameliorate cardiac inflammation and fibrosis under CKD by suppressing GPR68 function. Reagents that inhibit the function of GPR68 were explored by high-throughput screening using a medicinal plant extract library (8,008 species), and we identified an extract from Cephalotaxus harringtonia var. nana as a GPR68 inhibitor that suppresses inflammatory cytokine production in a GPR68 expression-dependent manner. Consumption of the extract inhibited inflammatory cytokine expression and cardiac fibrosis and improved the decreased survival attributable to 5/6Nx. Additionally, homoharringtonine, a cephalotaxane compound characteristic of C. harringtonia, inhibited inflammatory cytokine production. Homoharringtonine administration in drinking water alleviated cardiac fibrosis and improved heart failure and survival in 5/6Nx mice. A previously unknown effect of C. harringtonia extract and homoharringtonine was revealed in which GPR68-dependent inflammation and cardiac dysfunction were suppressed. Utilizing these compounds could represent a new strategy for treating GPR68-associated diseases, including CKD.

DOI： 10.1016/j.trsl.2024.02.004

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：American Society for Pharmacology & Experimental Therapeutics (ASPET)  

Although vancomycin (VCM)—frequently used to treat drug-resistant bacterial infections—often induces acute kidney injury (AKI), discontinuation of the drug is the only effective treatment; therefore, analysis of effective avoidance methods is urgently needed. Here, we report the differences in the induction of AKI by VCM in 1/2-nephrectomized mice depending on the time of administration. Despite the lack of difference in the accumulation of VCM in the kidney between the light (ZT2) and dark (ZT14) phases, the expression of AKI markers due to VCM was observed only in the ZT2 treatment. Genomic analysis of the kidney suggested that the time of administration was involved in VCM-induced changes in monocyte and macrophage activity, and VCM had time-dependent effects on renal macrophage abundance, ATP activity, and interleukin (IL)-1b expression. Furthermore, the depletion of macrophages with clodronate abolished the induction of IL-1b and AKI marker expression by VCM administration at ZT2. This study provides evidence of the need for time-dependent pharmacodynamic considerations in the prevention of VCM-induced AKI as well as the potential for macrophage-targeted AKI therapy.

DOI： 10.1124/jpet.123.001864

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

Chronic kidney disease (CKD) induces an imbalance in the intestinal microbiota, affecting various physiological functions and leading to cardiovascular inflammation and fibrosis. However, the cardiotoxic impact of intestinal microbiota-derived uremic substances in advanced renal dysfunction remains unexplored. Therefore, we developed a 5/6 nephrectomy (5/6Nx) mouse model to investigate the intestinal microbiota and the effects of administering vancomycin (VCM) on the microbiota and the cardiac pathology associated with CKD. Despite VCM administration after the development of irreversible glomerulosclerosis and tubulointerstitial fibrosis, blood indoxyl sulfate and phenyl sulfate levels, which are intestinal bacteria-derived uremic substances, brain natriuretic peptide levels, and the fibrotic area in the heart were decreased. Moreover, VCM administration prevented 5/6Nx-induced weight loss and prolonged survival time. Our findings suggest that VCM-induced changes in the intestinal microbiota composition ameliorate heart failure and improve survival rates by reducing intestinal microbiota-derived cardiotoxic substances despite advanced renal dysfunction. This highlights the potential of using the intestinal microbiota as a target to prevent and treat cardiovascular conditions associated with CKD.

DOI： 10.1016/j.bbrc.2023.07.015

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

Proteins localize to their respective organelles in cells. This localization is changed by activation or repression in response to signal transduction. Therefore, the appropriate intracellular localization of proteins is important for their functions to be exerted. However, difficulties are associated with controlling the localization of endogenous proteins. In the present study, we developed a conceptually new method of controlling the intracellular localization of endogenous proteins using bispecific nanobodies (BiNbs). BiNbs recognize proteins expressed in the inner membrane, cytoskeleton, nucleus, and peroxisomes, but not in mitochondria or endoplasmic reticulum. BiNbs designed to recognize β-CATENIN and the intrinsic cytosolic protein VIMENTIN (3 × Flag β-CAT-VIM BiNbs) decreased the β-CATENIN-mediated transactivation of target genes by preventing its nuclear localization. Furthermore, 3 × Flag β-CAT-VIM BiNbs suppressed the proliferation and invasion of the VIMENTIN-expressing breast cancer cell line MDA-MB-231, but not MDA-MB-468, in which the expression of VIMENTIN was defective. The present results revealed that changes in the intracellular localization of specific proteins by BiNbs modulated the physiology and functions of cells. The development of BiNbs to recognize proteins specifically expressed in target cells may be a useful approach for eliciting cell-selective effects.

DOI： 10.1016/j.bcp.2023.115708

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of Medicinal Chemistry  

The choice of an appropriate electrophile is crucial in the design of targeted covalent inhibitors (TCIs). In this report, we systematically investigated the glutathione (GSH) reactivity of various haloacetamides and the aqueous stability of their thiol adducts. Our findings revealed that dihaloacetamides cover a broad range of GSH reactivity depending on the combination of the halogen atoms and the structure of the amine scaffold. Among the dihaloacetamides, dichloroacetamide (DCA) exhibited slightly lower GSH reactivity than chlorofluoroacetamide (CFA). The DCA-thiol adduct is readily hydrolyzed under aqueous conditions, but it can stably exist in the solvent-sequestered binding pocket of the protein. These reactivity profiles of DCA were successfully exploited in the design of TCIs targeting noncatalytic cysteines of KRASG12C and EGFRL858R/T790M. These inhibitors exhibited strong antiproliferative activities against cancer cells. Our findings provide valuable insights for designing dihaloacetamide-based reversible covalent inhibitors.

DOI： 10.1021/acs.jmedchem.3c00737

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：American Chemical Society (ACS)  

Detection of metabolic activity enables us to reveal the inherent metabolic state of cells and elucidate mechanisms underlying cellular homeostasis and growth. However, a fluorescence approach for the study of metabolic pathways is still largely unexplored. Herein, we have developed a new chemical probe for the fluorescence-based detection of fatty acid β-oxidation (FAO), a key process in lipid catabolism, in cells and tissues. This probe serves as a substrate of FAO and forms a reactive quinone methide (QM) as a result of metabolic reactions. The liberated QM is covalently captured by intracellular proteins, and subsequent bio-orthogonal ligation with a fluorophore enables fluorescence analysis. This reaction-based sensing allowed us to detect FAO activity in cells at a desired emission wavelength using diverse analytical techniques including fluorescence imaging, in-gel fluorescence activity-based protein profiling (ABPP), and fluorescence-activated cell sorting (FACS). The probe was able to detect changes in FAO activity induced by chemical modulators in cultured cells. The probe was further employed for fluorescence imaging of FAO in mouse liver tissues and revealed the metabolic heterogeneity of FAO activity in hepatocytes by the combination of FACS and gene expression analysis, highlighting the utility of our probe as a chemical tool for fatty acid metabolism research.

DOI： 10.1021/jacs.3c02043

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of Medicinal Chemistry  

The coronavirus disease 2019 (COVID-19) pandemic has necessitated the development of antiviral agents against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). 3C-like protease (3CLpro) is a promising target for COVID-19 treatment. Here, we report a new class of covalent inhibitors of 3CLpro that possess chlorofluoroacetamide (CFA) as a cysteine-reactive warhead. Based on an aza-peptide scaffold, we synthesized a series of CFA derivatives in enantiopure form and evaluated their biochemical efficiency. The data revealed that 8a (YH-6) with the R configuration at the CFA unit strongly blocks SARS-CoV-2 replication in infected cells, and its potency is comparable to that of nirmatrelvir. X-ray structural analysis showed that YH-6 formed a covalent bond with Cys145 at the catalytic center of 3CLpro. The strong antiviral activity and favorable pharmacokinetic properties of YH-6 suggest its potential as a lead compound for the treatment of COVID-19. © 2022 American Chemical Society.

DOI： 10.1021/acs.jmedchem.2c01081

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Other Link： https://pubs.acs.org/doi/10.1021/acs.jmedchem.2c01081

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Molecular Cancer Research  

Cancer cells have acquired several pathways to escape from host immunity in the tumor microenvironment. Programmed death 1 (PD-1) receptor and its ligand PD-L1 are involved in the key pathway of tumor immune escape, and immune checkpoint therapy targeting PD-1 and PD-L1 has been approved for the treatment of patients with certain types of malignancies. Although PD-1 is a well-characterized receptor on T cells, the immune checkpoint receptor is also expressed on tumor-associated macrophages (TAM), a major immune component of the tumor microenvironment. In this study, we found significant diurnal oscillation in the number of PD-1-expressing TAMs collected from B16/BL6 melanoma-bearing mice. The levels of Pdcd1 mRNA, encoding PD-1, in TAMs also fluctuated in a diurnal manner. Luciferase reporter and bioluminescence imaging analyses revealed that a NF-κB response element in the upstream region of the Pdcd1 gene is responsible for its diurnal expression. A circadian regulatory component, DEC2, whose expression in TAMs exhibited diurnal oscillation, periodically suppressed NF-κB-induced transactivation of the Pdcd1 gene, resulting in diurnal expression of PD-1 in TAMs. Furthermore, the antitumor efficacy of BMS-1, a small molecule inhibitor of PD-1/PD-L1, was enhanced by administering it at the time of day when PD-1 expression increased on TAMs. These findings suggest that identification of the diurnal expression of PD-1 on TAMs is useful for selecting the most appropriate time of day to administer PD-1/PD-L1 inhibitors. IMPLICATIONS: Selecting the most appropriate dosing time of PD-1/PD-L1 inhibitors may aid in developing cancer immunotherapy with higher efficacy.

DOI： 10.1158/1541-7786.MCR-21-0786

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DOI： 10.1038/s41467-021-23050-x

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DOI： 10.1111/gtc.12758

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DOI： 10.1016/j.bbrc.2019.02.022

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DOI： 10.1016/j.ebiom.2016.10.008

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DOI： 10.1074/jbc.M115.696930

Language：English   Publisher：Journal of Controlled Release  

Achieving antigen-specific immune tolerance without systemic immunosuppression remains a major challenge in biomaterial-based immunotherapy. Here, we report a simple nanoparticle (NP)-based platform that enables a transient, B cell–targeted tolerance switch. NPs encapsulating metabolizable aryl hydrocarbon receptor (AhR) agonists—FICZ or ITE—preferentially accumulate in splenic marginal zone B cells and convert them into IL-10–producing regulatory B cells (Bregs). This study provides the first in vivo evidence that Bregs can directly present antigen and induce regulatory T cells (Tregs), establishing a NP-controlled Breg–Treg pathway. These Bregs promote antigen-specific Tregs expansion only when co-exposed to antigen, establishing time-gated, antigen-restricted immune regulation. By exploiting the rapid metabolism of AhR agonists, this system provides precise temporal control of tolerance induction while preserving vaccine responses. In mouse models, co-administration of FICZ-containing NP with antigen suppressed anti-drug antibody formation and ameliorated allergic inflammation. This NP platform demonstrates a strategy for safe, antigen-specific immunomodulation and offers a clinically adaptable framework for allergy and biotherapeutic tolerance.

DOI： 10.1016/j.jconrel.2026.115059

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Authorship：Lead author,　Corresponding author   Language：English   Publisher：Clinical and Translational Science  

Drug development for Alzheimer's disease (AD) remains challenging, with only a 0.4% success rate from Phase I trials to regulatory approval. Drug repositioning leverages existing approved drugs to identify promising drug alternatives, particularly when combined with real-world data (RWD) and target trial emulation. In this study, we comprehensively screened 1,241 approved drugs using a large-scale Japanese claims database (n = 2,090,465; 2005–2023). We identified patients newly prescribed a study drug and applied an active-comparator, new-user design. We used propensity score-based inverse probability of treatment weighting (IPTW) to balance the covariates. The primary outcome was incident AD, defined using ICD-10 codes (F00 and G30). We estimated cumulative incidence using IPTW-adjusted Kaplan–Meier analysis and Cox proportional hazards models and conducted sensitivity analyses using Fine–Gray competing risk models, empirical calibration with negative control outcomes, and E-value estimation. We performed in vitro validation using Aβ-Tet-ON SH-SY5Y cells and quantified Aβ expression using western blotting. Benzbromarone, a uricosuric agent, was associated with a decreased risk of AD onset (adjusted HR: 0.54, 95% CI: 0.41–0.71, p < 0.05 post-FDR correction); this association remained robust across sensitivity analyses. In vitro, benzbromarone reduced Aβ protein expression in SH-SY5Y cells in a dose-dependent manner, even following transcriptional blockade, suggesting a posttranscriptional regulatory mechanism. In conclusion, using a combined approach of RWD-based pharmacoepidemiology and in vitro validation, we identified benzbromarone as a novel candidate potentially associated with reduced AD risk. Our findings highlight the potential of drug repositioning strategies to accelerate AD drug discovery, promoting further mechanistic and clinical investigations.

DOI： 10.1111/cts.70650

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

The circadian clock regulates diverse immune functions, yet the role of clock components in macrophage inflammation remains controversial, with both pro- and anti-inflammatory effects reported. Here, we identify a previously unrecognized mechanism by which the core circadian clock component BMAL1 enhances the inflammatory response of macrophages through the nuclear translocation of the peroxisomal β-oxidation enzyme multi-functional protein 2 (MFP2). BMAL1 drives MFP2 accumulation in the nucleus, where MFP2 contributes to acetyl-CoA production and acetylation of the NF-κB subunit p65, thereby facilitating M1 polarization and inflammatory chemokine expression. Nuclear MFP2 levels oscillate in a diurnal manner in the liver, but this rhythmicity is abolished in Bmal1-deficient mice. Macrophage-specific deletion of BMAL1 alleviates diethylnitrosamine-induced hepatic inflammation and tumorigenesis, concomitant with reduced inflammatory gene expression. These findings uncover a BMAL1-dependent nuclear metabolic pathway that links circadian regulation of macrophage inflammation and suggest that targeting nuclear MFP2 may offer a therapeutic approach for inflammatory diseases and tumorigenesis.

DOI： 10.1016/j.celrep.2026.117480

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

The present review discusses vitamin A/retinoid metabolism as a cross-organ axis in which hepatic clock-dependent retinoid handling may affect immune clock gene expression through the stimulation of retinoic acid 6–Janus kinase 2–signal transducer and activator of transcription 5 signaling, potentially promoting pro-inflammatory monocyte states. We further highlight mechanosensory signaling as a second convergent layer that integrates hemodynamic forces with tissue microenvironmental cues. Among these pathways, G protein-coupled receptor 68, a proton- and flow-sensitive G protein-coupled receptor, is discussed as a representative druggable node linking mechanical and inflammatory signaling in chronic kidney disease-associated cardiac injury. Finally, we outline potential therapeutic directions, including (i) circadian alignment/chronopharmacology, (ii) modulation of retinoid metabolism and signaling, and (iii) targeted inhibition of primary immune and mechanosensory effectors.

DOI： 10.3390/ijms27083436

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Frontiers Media SA  

Introduction

Hericenone C exhibits antinociceptive effects in inflammatory pain; however, its molecular target and underlying mechanism remain unclear.

Methods and Results

We assessed the effect of hericenone C on formalin-induced nociceptive behavior in mice and explored its molecular target using in vitro experiments. Based on competitive affinity proteomics, we identified direct interactions between RORα and hericenone C; functional assays confirmed the role of hericenone C as a RORα antagonist that suppresses RORE-mediated transcriptional activity. Integrated bioinformatics and experimental validation indicated hericenone C-mediated suppression of TLR4 expression via inhibited RORα binding to the TLR4 promoter, which attenuates NF-κB signaling. This mechanism was further validated through pharmacological and genetic approaches, revealing that hericenone C and RORα antagonist SR3335 synergistically modulate TLR4 expression in RORα-modified macrophages. In the formalin-induced nociceptive pain model mice, formalin activated NF-κB through TLR4-dependent P65 phosphorylation, while macrophage depletion selectively suppressed phase 2 nociception. Critically, adoptive transfer of RORα-overexpressing or SR1078-pretreated monocyte-enriched PBMCs exacerbated pain, which was effectively reversed by hericenone C. Notably, hericenone C pretreatment reduced CD11c ⁺ cell infiltration and decreased TLR4 expression in inflamed paw tissues.

Conclusion

Overall, these findings establish hericenone C as a novel RORα antagonist that alleviates inflammatory pain through inhibition of the RORα-TLR4-NF-κB axis in CD11c ⁺ cells, offering a promising therapeutic strategy for pain management.

DOI： 10.3389/fphar.2026.1703176

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

Abstract

Immune checkpoint inhibitors (ICIs) are widely used to treat various types of cancer; however, their effectiveness varies, with some patients exhibiting resistance. Recent studies have shown that the efficacy of ICIs depends on the localization of immune cells, particularly T cells, within the tumor microenvironment (TME). Although the circadian clock is known to regulate immune cell migration into tumors, its role in orchestrating spatially precise intratumoral localization remains unclear. Here, we found that the distribution of CD8 ⁺ T cells within the TME varied according to the time of day, accompanied by diurnal expression of C‐X‐C chemokine receptor type 4 (CXCR4). The amplitude of the Cxcr4 expression rhythm was more pronounced in tumor‐infiltrated T cells than in those from the spleen and was associated with time‐dependent changes in their migration toward CXCL12‐expressing cancer‐associated fibroblasts (CAFs). Reanalysis of single‐cell RNA‐seq data from T cells of lung cancer patients also revealed that upregulation of CXCR4 expression in tumor‐infiltrated CD8 ⁺ T cells was linked to TGF‐β‐SMAD signaling. The TGF‐β‐SMAD signaling‐mediated transactivation of Cxcr4 was time‐dependently repressed by SMAD7, resulting in diurnal CXCR4 expression. Consequently, administration of a CXCR4 inhibitor during the circadian phase of elevated CXCR4 expression in tumor‐infiltrated CD8 ⁺ T cells promotes their dispersion throughout tumor tissues, thereby enhancing the efficacy of ICIs. Our findings highlight an unrecognized mechanism underlying diurnal changes in the aggregation and dispersion of CD8 ⁺ T cells within tumors, offering a novel approach to enhance the anti‐tumor immune effects of ICIs.

DOI： 10.1002/ijc.70252

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

The advent of direct electron detectors (DEDs) has driven a major breakthrough in cryo-electron microscopy (cryo-EM), particularly in single-particle analysis (SPA), establishing DEDs as essential tools for achieving near-atomic resolution. In this study, we re-evaluated the performance of the TVIPS TemCam-XF416, an indirect scintillator-coupled CMOS camera (scintillator camera). Using a JEOL CRYOARM 300II, we performed SPA on two well-established benchmark specimens, β-galactosidase and apoferritin, at a 300 kV acceleration voltage. The resulting reconstructions reached resolutions of 2.6 Å and 2.1 Å, respectively. Notably, the apoferritin map clearly resolves the central holes of aromatic side chains—a level of detail previously considered exclusive to DEDs. These results were achieved by implementing the latest standard reconstruction workflows, including motion correction and contrast transfer function refinement, underscoring the critical role of computational methods in attaining high-resolution structures. While scintillator cameras inherently exhibit a lower signal-to-noise ratio than DEDs, our findings with XF416 demonstrate that, with appropriate data collection and processing, such cameras can deliver near-atomic resolution structures. This work establishes a crucial technical benchmark for the scintillator camera evaluated in this study on a high-end 300 kV cryo-EM platform, demonstrating its capability to achieve resolutions suitable for many structural biology applications and providing an updated perspective on its performance capabilities.

DOI： 10.1016/j.jsb.2026.108286

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Language：English   Publisher：Journal of Structural Biology  

The authors regret the error in the declaration of competing interest section. It should read as “S.A. is an employee of TVIPS GmbH, the manufacturer of the TemCam-XF416 detector evaluated in this study. All other authors declare no competing interests”. The authors would like to apologise for any inconvenience caused.

DOI： 10.1016/j.jsb.2026.108292

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Language：English   Publisher：Journal of Biological Chemistry  

5-Fluorouracil (5-FU) is a commonly used chemotherapeutic agent for breast cancer. Its efficacy relies on the function of p53, and mutations in p53 contribute to the development of resistance during 5-FU chemotherapy. Here, we report that microcurrent stimulation (MCS) of a p53-mutant breast cancer cell line induces p53-mediated cell death. Although MDA-MB-231 and MDA-MB-468 cells, both human breast cancer cell lines, are less sensitive to 5-FU due to p53 mutations, MCS (300 μA for 30 min) induced apoptosis in these cells and improved the antitumor effect of 5-FU in tumor-bearing mice. MCS-induced apoptosis was mediated by an increase in intracellular Cu²⁺ ions and reactive oxygen species, along with the concurrent transcriptional enhancement of pro-apoptotic genes by p53. Furthermore, MCS induced apoptosis in MDA-MB-231 cells that had developed resistance to 5-FU and inhibited tumor growth in tumor-bearing mice with reduced 5-FU sensitivity. These findings suggest that an approach involving MCS could serve as a foundation for developing breast cancer treatment strategies to overcome p53 mutations.

DOI： 10.1016/j.jbc.2025.110414

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Language：English   Publisher：Journal of Biological Chemistry  

Glioblastoma (GBM) is the most common and aggressive form of malignant brain cancer, with a poor prognosis and a 5-year survival rate of approximately 15%. The malignancy of GBM, including its treatment resistance and high recurrence rate, is largely attributed to the presence of cancer stem cells. Recent studies have identified the N-acetyltransferase 10 (NAT10), an enzyme responsible for catalyzing N<inf>4</inf>-acetylcytidine (ac4C) modification in RNA, as a key factor in cancer biology, with diverse roles across multiple cancer types. However, the specific contribution of this RNA modification to the malignancy of GBM remains unexplored. Here, we demonstrate that NAT10 expression is associated with poor prognosis in GBM patients and that NAT10 promotes GBM malignancy by enhancing stemness properties in human GBM cell line U251 and A172. A search for the underlying mechanism of NAT10-mediated enhancement of GBM stemness led to identification of polycomb repressive complex 2 (PRC2)-related genes as an epigenetic regulator. NAT10 mediates the acetylation of the coding region of Jumonji and AT-rich Interaction Domain containing 2 (JARID2) mRNA, which results in increased mRNA stability and elevated protein levels. Notably, the knockdown of JARID2 significantly reduced GBM stemness, suppressed tumor growth, and extended the survival of xenograft mice. Our findings suggest that NAT10-mediated acetylation of JARID2 mRNA up-regulates its protein levels, thereby promoting stemness and contributing to the malignancy of GBM. Targeting this NAT10-JARID2 axis may represent a novel therapeutic approach for treatment of GBM.

DOI： 10.1016/j.jbc.2025.108544

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Language：English   Publisher：Investigative Ophthalmology and Visual Science  

PURPOSE. Proliferative vitreoretinal diseases, such as proliferative vitreoretinopathy (PVR) and neovascular age-related macular degeneration (nAMD), pose substantial challenges in their advanced stages owing to the development of retinal fibrous membranes. Current therapeutic modalities, including surgical interventions for PVR and antivascular endothelial growth factor therapy for nAMD, cannot effectively manage intraocular fibrosis associated with epithelial-to-mesenchymal transition (EMT) in retinal pigment epithelium (RPE) cells. Through drug screening, we identified ripasudil, a Rho-kinase inhibitor, as a remarkable suppressor of RPE-EMT. However, the short vitreal half-lives of small-molecule drugs, coupled with the limited stability of ripasudil in the ocular environment, impede its application in vitreoretinal diseases. Considering the advances in nanotechnology-assisted improvement in drug stability and cellular uptake as well as controlled release, we aimed to enhance the efficacy of ripasudil through liposome encapsulation. METHODS. After ripasudil encapsulation, we performed comprehensive in vivo and in vitro analyses and pharmacokinetic studies. RESULTS. Liposome-encapsulated ripasudil (Lipo-Ripa) demonstrated a substantial reduction in subretinal fibrosis in an advanced AMD model and more effective inhibition of PVR progression in rabbits than that induced by ripasudil alone. Pharmacokinetic studies revealed that Lipo-Ripa exhibited improved retention capacity in the vitreous and retina, alongside reduced permeability through the RPE barrier and increased cellular uptake. These characteristics resulted in a sustained elevation of drug concentration within the ocular tissues over time. CONCLUSIONS. Our findings suggest that liposomal encapsulation of ripasudil supports enhanced bioavailability and effectiveness of the drug, presenting a promising innovative therapeutic approach for the treatment of proliferative vitreoretinopathy.

DOI： 10.1167/iovs.66.6.56

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Language：English   Publisher：Biochemical and Biophysical Research Communications  

Circadian rhythm alterations are related to the onset and severity of various diseases. The expression of the dopamine receptor D3 (DRD3) is regulated by clock genes, and DRD3 functional abnormalities are linked to various neurological diseases. However, the relationship between DRD3 function and circadian machinery is unclear. Here, we demonstrate the influence of DRD3 on the circadian machinery. Although the expression of DRD3 in mouse suprachiasmatic nucleus (SCN) did not show a circadian rhythm, the expression of Per1 mRNA was altered in the SCN of Drd3 knockout (Drd3^−/−) mice compared to that in wild-type (WT) mice. These differences were caused by the upregulation of the DRD3–extracellular signal–regulated kinase–cAMP response element binding protein (DRD3–ERK–CREB) signaling pathway in cultured cells and SCN. In addition, Drd3^−/− mice demonstrated increased period length of locomotor activity than WT mice only under constant dark conditions. Expression of clock genes in the liver, which does not express DRD3, was affected by the loss of DRD3 only under constant dark conditions, similar to that in the SCN. These results suggest that DRD3 expressed in the SCN regulates the central clock via endogenous ligands and affects peripheral organs. This may provide new evidence to unravel the relationship between dopamine neurotransmission and the circadian clock, which has not yet been fully elucidated.

DOI： 10.1016/j.bbrc.2025.151470

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Rationale: Macrophage phagocytosis plays a role in cancer immunotherapy. The phagocytic activity of macrophages, regulated by circadian clock genes, shows time-dependent variation. Intervening in the circadian clock machinery of macrophages is a potentially novel approach to cancer immunotherapy; however, data on this approach are scarce. Microcurrent stimulation (MCS) promotes inflammation, proliferation, and remodeling, suggesting its potential to modulate macrophage function; however, its application has been limited. In this study, we investigated the impact of MCS on macrophage phagocytosis of cancer cells using mouse/human macrophage cell lines and various mouse/human cancer cell lines. / Methods: Cells and mice received 300 µA, 400 Hz bidirectional pulsed MCS. Gene expression, protein expression, and phagocytosis activity were assessed in intraperitoneal macrophages collected from mice, as well as in RAW264.7, and THP-1 cells. Flow cytometry, population, phagocytosis activity, RNA-seq, and immunohistochemistry analyses were performed. / Results: Noninvasive MCS prevented time-dependent reduction in macrophage phagocytosis of cancer cells by modulating the circadian clock genes. MCS also enhanced phagocytosis in mouse RAW264.7 and human THP-1 cells across various cancer types by promoting actin polymerization; similar in vivo effects were observed in mice. This enhancement occurred in abdominal macrophages of both sexes and was mediated by changes in clock gene expression. Specifically, suppressing the clock gene Per1 nullified the effects of MCS. Moreover, although macrophage phagocytosis typically declined during the dark period, MCS during the light period prevented this reduction. MCS also increased phagocytosis of peritoneally implanted cancer cells (4T1, ID8, and Hepa1-6) in mice, significantly reducing tumor engraftment and growth, and ultimately improving prognosis. / Conclusions: The findings of this study suggest that targeting macrophage circadian mechanisms via MCS could enhance cancer immunity, offering new avenues for cancer immunotherapy.

CiNii Research

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Rationale: Macrophage phagocytosis plays a role in cancer immunotherapy. The phagocytic activity of macrophages, regulated by circadian clock genes, shows time-dependent variation. Intervening in the circadian clock machinery of macrophages is a potentially novel approach to cancer immunotherapy; however, data on this approach are scarce. Microcurrent stimulation (MCS) promotes inflammation, proliferation, and remodeling, suggesting its potential to modulate macrophage function; however, its application has been limited. In this study, we investigated the impact of MCS on macrophage phagocytosis of cancer cells using mouse/human macrophage cell lines and various mouse/human cancer cell lines. Methods: Cells and mice received 300 µA, 400 Hz bidirectional pulsed MCS. Gene expression, protein expression, and phagocytosis activity were assessed in intraperitoneal macrophages collected from mice, as well as in RAW264.7, and THP-1 cells. Flow cytometry, population, phagocytosis activity, RNA-seq, and immunohistochemistry analyses were performed. Results: Noninvasive MCS prevented time-dependent reduction in macrophage phagocytosis of cancer cells by modulating the circadian clock genes. MCS also enhanced phagocytosis in mouse RAW264.7 and human THP-1 cells across various cancer types by promoting actin polymerization; similar in vivo effects were observed in mice. This enhancement occurred in abdominal macrophages of both sexes and was mediated by changes in clock gene expression. Specifically, suppressing the clock gene Per1 nullified the effects of MCS. Moreover, although macrophage phagocytosis typically declined during the dark period, MCS during the light period prevented this reduction. MCS also increased phagocytosis of peritoneally implanted cancer cells (4T1, ID8, and Hepa1-6) in mice, significantly reducing tumor engraftment and growth, and ultimately improving prognosis. Conclusions: The findings of this study suggest that targeting macrophage circadian mechanisms via MCS could enhance cancer immunity, offering new avenues for cancer immunotherapy.

DOI： 10.7150/thno.100748

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

Defects in Aryl hydrocarbon receptor nuclear translocator-like 1 (ARNTL), a central component of the circadian clock mechanism, may promote or inhibit the induction of inflammation by monocytes/macrophages, with varying effects on different diseases. However, ARNTL’s role in monocytes/macrophages under chronic kidney disease (CKD), which presents with systemic inflammation, is unclear. Here, we report that the expression of Arntl in monocytes promoted CKD-induced cardiac damage. The expression of G-protein-coupled receptor 68 (GPR68), which exacerbates CKD-induced cardiac disease, was regulated by ARNTL. Under CKD conditions, GPR68 expression was elevated via ARNTL, particularly in the presence of PU.1, a transcription factor specific to monocytes and macrophages. In CKD mouse models lacking monocyte-specific ARNTL, GPR68 expression in monocytes was reduced, leading to decreased cardiac damage and fibrosis despite no improvement in renal excretory capacity or renal fibrosis and increased angiotensin II production. The loss of ARNTL did not affect the expression of marker molecules, indicating the origin or differentiation of cardiac macrophages, but affected GPR68 expression only in cardiac macrophages derived from mature monocytes, highlighting the significance of the interplay between GPR68 and ARNTL in monocytes/macrophages and its influence on cardiac pathology. Understanding this complex relationship between circadian clock mechanisms and disease could help uncover novel therapeutic strategies.

DOI： 10.3390/ijms252313009

Web of Science

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PubMed

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Heliyon  

The retina is the only organ projecting external light to the suprachiasmatic nucleus. Cholecystokinin receptor type A (Cckar/Cckar) is one of the essential factors for light reception in retinal cells. As there was a lack of literature on the matter, we aimed to elucidate the cause of the time-dependent phase change in clock gene expression. We found that Cckar mRNA expression in retinal cells exhibited diurnal variations. The rhythm of expression of the clock gene Per1/Per2 in retinal cells was altered in Cckar -/- mice. The light sensitivity of retinal cells was evaluated in wild-type mice, which showed c-Fos was activated in the ganglion cell layer more than in the inner granular layer. This increase in the number of c-Fos-positive cells was suppressed by lorglumide, a Cckar antagonist. Treatment of rat retina primary cells with lorglumide suppressed Per2 transcription, which was altered in a time-dependent manner relative to the Per2 expression. Light irradiation studies in Cckar -/- mice did not exhibit an increase in Period expression in the suprachiasmatic nucleus. These results indicate that Cckar is among the factors that regulate the cycle of clock genes on the retina. Cckar knockout attenuates the light responsiveness of suprachiasmatic nucleus and reduces the expression amplitude of Period genes in the retina. Thus, Cckar may contribute to entrainment of the light environment and maintenance of the expression cycle of Period gene, which is one of the core clock genes.

DOI： 10.1016/j.heliyon.2024.e32653

Web of Science

Scopus

PubMed

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Language：Japanese  

Web of Science

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Event date： 2024

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Event date： 2024

Language：Japanese  

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Event date： 2024

Language：English  

Venue：Hawaii   Country：United States  

Event date： 2024

Presentation type：Symposium, workshop panel (nominated)  

Event date： 2024

Presentation type：Symposium, workshop panel (nominated)  

Event date： 2024

Presentation type：Oral presentation (invited, special)  

Event date： 2023.10

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：横浜   Country：Japan  

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Venue：横浜   Country：Japan  

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Event date： 2022.12

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：横浜   Country：Japan  

Dysfunction of the circadian clock has been implicated in the pathogenesis of cardiovascular disease. Particularly, the CLOCK protein is a core molecular component of the circadian oscillator, so that mice with a mutated Clock gene (Clk/Clk) exhibit abnormal rhythms in numerous physiological processes. In this study, we analyzed the relationship between heart failure and Clock in 5/6 nephrectomy (5/6Nx) mice, which induce heart failure by chronic kidney disease (CKD). Surprisingly, cardiac inflammation and fibrosis were attenuated in Clock mutant (Clk/Clk) 5/6Nx mice even though they had high blood pressure and increased serum angiotensin II levels. A search for the underlying cause of the attenuation of heart disorder led to identification of the monocytic expression of G protein-coupled receptor 68 (GPR68) as a risk factor of CKD-induced inflammation and fibrosis of heart. 5/6Nx induced the expression of GPR68 in circulating monocytes via altered CLOCK activation by increasing serum levels of retinol and its binding protein (RBP4). The high-GPR68-expressing monocytes had increased potential for producing inflammatory cytokines, and their cardiac infiltration under CKD conditions exacerbated inflammation and fibrosis of heart. Our present study reveals an uncovered role of monocytic clock genes in CKD-induced heart failure.

Event date： 2022.12

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：横浜   Country：Japan  

Dysfunction of the circadian clock has been implicated in the pathogenesis of cardiovascular disease. Particularly, the CLOCK protein is a core molecular component of the circadian oscillator, so that mice with a mutated Clock gene (Clk/Clk) exhibit abnormal rhythms in numerous physiological processes. In this study, we analyzed the relationship between heart failure and Clock in 5/6 nephrectomy (5/6Nx) mice, which induce heart failure by chronic kidney disease (CKD). Surprisingly, cardiac inflammation and fibrosis were attenuated in Clock mutant (Clk/Clk) 5/6Nx mice even though they had high blood pressure and increased serum angiotensin II levels. A search for the underlying cause of the attenuation of heart disorder led to identification of the monocytic expression of G protein-coupled receptor 68 (GPR68) as a risk factor of CKD-induced inflammation and fibrosis of heart. 5/6Nx induced the expression of GPR68 in circulating monocytes via altered CLOCK activation by increasing serum levels of retinol and its binding protein (RBP4). The high-GPR68-expressing monocytes had increased potential for producing inflammatory cytokines, and their cardiac infiltration under CKD conditions exacerbated inflammation and fibrosis of heart. Our present study reveals an uncovered role of monocytic clock genes in CKD-induced heart failure.

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Event date： 2021.12

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：宮城   Country：Japan  

Event date： 2021.7

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Venue：沖縄 (オンライン)   Country：Japan  

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Country：Other  

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Venue：福岡 (オンラインとのハイブリッド開催)   Country：Japan  

Event date： 2019.11

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Venue：岐阜   Country：Japan  

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Venue：長崎   Country：Japan  

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Venue：Paris   Country：France  

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Venue：横浜   Country：Japan  

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Venue：横浜   Country：Japan  

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Venue：横浜   Country：Japan  

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Venue：横浜   Country：Japan  

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Venue：Sendai   Country：Japan  

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Venue：神戸   Country：Japan  

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Venue：神戸   Country：Japan  

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Venue：神戸   Country：Japan  

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Venue：神戸   Country：Japan  

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Venue：神戸   Country：Japan  

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Event date： 2023.12

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Venue：神戸   Country：Japan  

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Venue：神戸   Country：Japan  

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Venue：神戸   Country：Japan  

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Event date： 2023.10

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Venue：横浜   Country：Japan  

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Venue：横浜   Country：Japan  

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Venue：横浜   Country：Japan  

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Venue：横浜   Country：Japan  

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Event date： 2023.9

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Venue：福岡   Country：Japan  

Event date： 2023.9

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Venue：福岡   Country：Japan  

Event date： 2023.9

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Venue：福岡   Country：Japan  

Event date： 2023.9

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Venue：福岡   Country：Japan  

Event date： 2023.9

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Venue：福岡   Country：Japan  

Event date： 2023.9

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Venue：福岡   Country：Japan  

Event date： 2023.9

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Venue：福岡   Country：Japan  

Event date： 2023.9

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Venue：福岡   Country：Japan  

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Venue：福岡   Country：Japan  

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Venue：福岡   Country：Japan  

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Venue：福岡   Country：Japan  

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Event date： 2023.9

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Venue：福岡   Country：Japan  

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Venue：福岡   Country：Japan  

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Event date： 2023.9

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Venue：福岡   Country：Japan  

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Venue：北海道   Country：Japan  

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Venue：北海道   Country：Japan  

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Venue：北海道   Country：Japan  

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Venue：北海道   Country：Japan  

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Venue：北海道   Country：Japan  

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Venue：北海道   Country：Japan  

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Venue：横浜   Country：Japan  

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Venue：横浜   Country：Japan  

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Venue：横浜   Country：Japan  

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Venue：横浜   Country：Japan  

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Event date： 2022.11

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Event date： 2022.11

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Venue：長崎   Country：Japan  

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Venue：長崎   Country：Japan  

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Venue：名古屋   Country：Japan  

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Venue：名古屋   Country：Japan  

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Venue：東京   Country：Japan  

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Venue：福岡   Country：Japan  

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Venue：福岡   Country：Japan  

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Venue：福岡   Country：Japan  

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Venue：長崎   Country：Japan  

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Venue：福岡   Country：Japan  

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Venue：長崎   Country：Japan  

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Venue：熊本   Country：Japan  

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Venue：福岡   Country：Japan  

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Venue：大分   Country：Japan  

Event date： 2014.11

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Venue：福岡市   Country：Japan  

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Number of peer-reviewed articles in foreign language journals：2

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体内時計のずれ直して心疾患治療 「時間創薬」の可能性

「慢性腎臓病が心疾患の原因に」九大グループが仕組み解明 新規治療薬開発期待