Biology subjects

Mizukami, Y.

Publications and source records attributed to Mizukami, Y..

8 recordsLinked to original sources

bioRxiv2026

High-resolution spatial profiling identifies disease-specific molecular architecture in palmoplantar pustulosis

Palmoplantar pustulosis (PPP) and dyshidrotic eczema (DE) are chronic vesiculopustular dermatoses with overlapping clinical presentations but distinct underlying biology. Although comparative transcriptomic and proteomic analyses between PPP and DE have been reported, they remain limited in number and scope, with no comprehensive understanding of their distinct molecular signatures. Moreover, their molecular mechanisms remain unclear, and currently available therapeutic options are limited. To clarify disease-specific epidermal programs underlying vesicle formation, we conducted Visium HD spatial transcriptomic analysis of FFPE lesional skin samples obtained from patients with PPP and DE, followed by immunohistochemical validation against normal palmoplantar skin controls. Spatial clustering identified a keratinocyte subpopulation adjacent to vesicles that exhibited distinct transcriptional programs in the two diseases. In PPP, vesicle-associated keratinocytes demonstrated marked downregulation of aquaporin-3 (AQP3) and E-cadherin, together with strong, spatially localized activation of JAK-STAT3 signaling. Conversely, DE exhibited diffuse AQP3 expression and more homogeneous activation of JAK-STAT3 signaling throughout the epidermis. These results indicate that, although PPP and DE share inflammatory pathways, they differ substantially in their spatial molecular architecture. Reduced AQP3 expression and localized STAT3 activation may contribute to vesicle formation in PPP, supporting our previous hypothesis that implicates intraepidermal sweat leakage as a pathogenic mechanism in PPP. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=130 SRC="FIGDIR/small/723901v1_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@72a341org.highwire.dtl.DTLVardef@3c0beaorg.highwire.dtl.DTLVardef@325098org.highwire.dtl.DTLVardef@1493ebf_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2026

Thiol methyltransferase METTL7B coordinates lipid metabolism and promotes tumor progression in pancreatic cancer

Dysregulated lipid metabolism drives cancer progression, yet the molecular mechanisms linking lipid accumulation to pancreatic cancer remain poorly understood. Here, we identify methyltransferase-like 7B (METTL7B) as a key regulator of lipid metabolism and tumor progression in pancreatic cancer. Integrated analysis of large-scale transcriptomic datasets revealed that METTL7B is upregulated in pancreatic cancer compared with normal tissues, and elevated METTL7B expression is associated with poor patient prognosis. Functional experiments demonstrated that METTL7B is required for pancreatic cancer cell proliferation, migration, and metastasis. We identified hepatocyte nuclear factor 4 (HNF4A) and hepatocyte nuclear factor 4{gamma} (HNF4G), well-established regulators of lipid homeostasis, as transcription factors that directly upregulate METTL7B expression in pancreatic cancer cells. Moreover, we showed that METTL7B localizes around lipid droplets and promotes their accumulation in pancreatic cancer cells. Lipidomic analyses revealed that METTL7B depletion selectively reduces long-chain triacylglycerols and increases shorter-chain ceramides, while also modulating other lipid droplet-related lipid classes in a chain-length-dependent manner. Collectively, these findings suggest that METTL7B regulates lipid metabolism and malignant behavior in pancreatic cancer and may represent a potential therapeutic target.

molecular biology↗

bioRxiv2026

Dietary lipids attenuate IGF-1-Akt and injure epithelial-endothelial injury program that accelerates obstructive lung disease

Background Altered lipid metabolism is increasingly implicated in chronic obstructive pulmonary disease (COPD), but it remains unclear how a pre-existing obstructive lung state modifies the response to systemic lipid excess. We investigated whether high-fat diet (HFD) amplifies COPD-relevant lung injury and examined epithelial and vascular programs associated with this response. Methods Male wild-type (WT) and beta-epithelial sodium channel-transgenic ({beta}ENaC-Tg) mice were fed control diet or HFD for 10-11 weeks. Lung structure and function, whole-lung transcriptomes, Akt-FOXO1 signaling, apoptosis-related responses, and pulmonary vascular profiles were assessed. Streptozotocin-induced insulin-deficient diabetes and pharmacological IGF-1 receptor inhibition were used as mechanistic comparators. Palmitate responses were examined in human bronchial epithelial cells, ENaC-hyperactive epithelial cells, and endothelial cells, including conditioned-medium transfer. HFD preconditioning was also evaluated in an elastase-induced emphysema model. Statistical analyses included unpaired two-tailed Student's t tests, one-way ANOVA with Tukey-Kramer or Dunnett multiple-comparison testing, Pearson correlation, and Benjamini-Hochberg correction for RNA-sequencing analyses. Results HFD produced similar increases in body weight, glycemia, and adiposity in WT and {beta}ENaC-Tg mice, while further increasing distal-airspace enlargement and reducing FEV0.1/FVC in {beta}ENaC-Tg mice. Lung transcriptomics revealed coordinated remodeling of lipid metabolic, PI3K-Akt, and vascular programs. HFD reduced Akt phosphorylation, increased FOXO1 and Fasl, and increased TUNEL-positive cells in epithelial regions. Palmitate attenuated IGF-1-induced Akt activation in bronchial epithelial cells, whereas IGF-1 receptor inhibition reproduced Akt suppression and apoptosis-related responses without fully reproducing the HFD phenotype. HFD preconditioning also increased elastase-induced airspace enlargement, accompanied by parallel upregulation of FOXO1 and TUNEL positivity. HFD reduced pulmonary CD34-positive vascular profiles, and palmitate activated endothelial cells directly and through conditioned media from ENaC-hyperactive epithelium. In men with airflow obstruction, hepatic steatosis coincided with lower percent-predicted FEV1. Conclusions Dietary lipid stress amplifies obstructive lung injury and engages complementary epithelial and vascular responses. Impaired epithelial IGF-1-Akt signaling and epithelial-endothelial crosstalk provide a mechanistic framework linking systemic metabolic stress to reduced resilience of the obstructive lung.

molecular biology↗

bioRxiv2025

Trehalose promotes wound healing in vitro by enhancing the migration of human keratinocytes via the VEGF/JNK/PI3K pathway

BackgroundTrehalose is a naturally occurring disaccharide found in invertebrates but cannot be synthesized by vertebrates. We previously reported that high-concentration trehalose induces a transient senescent-like state in fibroblasts, leading to cell cycle arrest and growth factor secretion via CDKN1A/p21, and this process promoted keratinocyte proliferation, enhancing capillary formation and wound closure in vivo. ObjectiveThis study aimed to investigate the effect of trehalose on human keratinocytes. MethodsPreviously published RNA-seq data of cytokine-untreated samples from our group of trehalose-treated human keratinocytes were re-analyzed, and an in vitro scratch assay was performed using cells treated with mitomycin C. ResultsThe trehalose-treated group exhibited increased wound closure. A significantly increased secretion of vascular endothelial growth factor (VEGF) was observed in keratinocytes treated with high-concentration trehalose, which is one of the most crucial molecules inducing angiogenesis in the skin. Significant upregulation of mRNA level and protein secretion of VEGF was confirmed using qPCR and ELISA, respectively. Furthermore, treatment with axitinib, a VEGF receptor inhibitor, significantly suppressed trehalose-induced activation of keratinocyte migration. Additionally, the increase in trehalose-induced migration activity was significantly inhibited by the Jun N-terminal kinase (JNK) inhibitor SP600125 and the PI3K inhibitor LY294002. ConclusionTrehalose promotes wound healing via VEGF secretion from keratinocytes and the PI3K and JNK pathways. The findings of this study may lead to the development of novel therapeutic agents that can alter the wound healing process. IMPORTANTO_LIManuscripts submitted to Review Commons are peer reviewed in a journal-agnostic way. C_LIO_LIUpon transfer of the peer reviewed preprint to a journal, the referee reports will be available in full to the handling editor. C_LIO_LIThe identity of the referees will NOT be communicated to the authors unless the reviewers choose to sign their report. C_LIO_LIThe identity of the referee will be confidentially disclosed to any affiliate journals to which the manuscript is transferred. C_LI GUIDELINESO_LIFor reviewers: https://www.reviewcommons.org/reviewers C_LIO_LIFor authors: https://www.reviewcommons.org/authors C_LI CONTACTThe Review Commons office can be contacted directly at: office@reviewcommons.org

cell biology↗

bioRxiv2025

Mycn Reactivates the Cell Cycle in Adult Cardiomyocytes and Promotes Cardioprotection in Myocardial Infarction

BackgroundAdult mammalian cardiomyocytes are terminally differentiated and possess minimal capacity for cell cycle re-entry. However, recent studies have shown that a rare population of cycling cardiomyocytes may confer cardioprotective effects following myocardial infarction (MI). The Myc family--Myc, Mycl, and Mycn--plays central roles in regulating cell cycle progression and cellular plasticity. This raises the possibility that specific Myc isoforms could reactivate the cardiomyocyte cell cycle and promote cardioprotective responses in the ischemic heart. This study aimed to systematically evaluate the effects of Myc, Mycl, and Mycn on cardiomyocyte cell cycle activation and cardiac outcomes following MI. MethodsCardiomyocyte-specific overexpression of Myc, Mycl, or Mycn was achieved in adult mice via adeno-associated virus 9 vectors driven by the cardiac troponin T promoter. Cardiomyocyte cell cycle activity, structural remodeling, and functional outcomes were assessed using RNA sequencing, immunohistochemistry, and transthoracic echocardiography. Cardioprotective effects were evaluated in MI model mice. ResultsWhile all three Myc family members activated cell cycle-related gene expression to varying degrees, Mycn elicited the most robust response. Mycn overexpression significantly enhanced cardiomyocyte cell cycle re-entry, as demonstrated by increased 5-bromo-2-deoxyuridine incorporation and phosphorylation of histone H3. Mycn also induced hypertrophic growth, reflected by increased cardiomyocyte size and heart mass. Transcriptomic analyses revealed that Mycn uniquely upregulated genes associated with extracellular matrix remodeling and paracrine signaling, typically enriched in neonatal cardiomyocytes and previously linked to cardioprotection. Functionally, Mycn expression preserved cardiac contractility after MI, reduced infarct size, and increased capillary density in peri-infarct regions. ConclusionsThese findings identify Mycn as a functionally distinct member of the Myc family in the adult heart, capable of reactivating the cardiomyocyte cell cycle and promoting cardiac protection after ischemic injury. The cardioprotective effects appear to be mediated, in part, by the induction of a neonatal-like gene expression program supporting a stress-adaptive cardiac microenvironment.

molecular biology↗

bioRxiv2025

Altered laminin signaling destinates melanocyte reprogramming in vitiligo

Vitiligo is an acquired depigmenting skin disorder characterized by progressive melanocyte loss, but the cellular mechanisms driving this process remain unclear. Here, we identify melanocyte dedifferentiation as a central and reversible pathogenic mechanism in vitiligo. In healthy human skin, melanocytes reside within a basement membrane niche defined by dystroglycan-laminin-211 adhesion. In contrast, vitiligo lesions exhibit aberrant extracellular matrix remodeling, leading to an adhesion switch to integrin 3{beta}1-laminin-332 interactions. This shift promotes melanocyte dedifferentiation via Rho-F-actin-dependent activation of Hippo and MAPK pathways, resulting in c-Jun-mediated transcriptional changes. Dedifferentiated melanocytes lose their pigment-producing identity and acquire neural crest-like features with multilineage potential. Importantly, this process is reversible. Pharmacological inhibition of involved pathways restores melanocyte differentiation and induces repigmentation in both vitiligo mouse models and ex vivo patient skin. Notably, JAK inhibitors also promote redifferentiation independently of immune modulation. These findings uncover melanocyte dedifferentiation as a fundamental driver of vitiligo and a tractable therapeutic target, offering new opportunities for therapeutic intervention.

cell biology↗

bioRxiv2023

Akr1b7 functions as a master regulator in ovarian aging

At the beginning of ovarian aging, the ovulation of immature oocytes is accelerated, leading to the arrest of ovulation despite the remaining oocytes. Here, RNA expression in the ovarian aging of mice is comprehensively analyzed during the estrous cycle after ovulation stimulation. The aldo-keto reductase Akr1b7 pathway transiently activated in the ovaries of young mice disappears in those of old mice. Akr1b7--/-- mice attenuate oocyte Akt activation essential for the follicular development in primordial follicles, and enhanced ovulation in immature oocytes. The estrous cycle is extended because of the prolonged diestrous stage by a sustained progesterone level in Akr1b7--/--mice ovaries, which is caused by the decline of Cyp17a1, a major metabolic enzyme of progesterone in Akr1b7-expressed theca cell layers. In summary, the decreased Akr1b7 pathway causes ovulation of immature oocytes and a prolonged estrous cycle, typical symptoms of ovarian aging.

molecular biology↗

bioRxiv2021

Highly concentrated trehalose induces transient senescence-associated secretory phenotype in fibroblasts via CDKN1A/p21

Trehalose is the nonreducing disaccharide of glucose, evolutionarily conserved in invertebrates, but does not exist in vertebrates. The living skin equivalent (LSE) is an organotypic coculture containing keratinocytes cultivated on fibroblast-populated dermal substitutes. We demonstrated that human primary fibroblasts treated with highly concentrated trehalose promote significantly extensive spread of the epidermal layer of LSE without any deleterious effects. The RNA-seq analysis data and Ingenuity pathway analysis of the differentially expressed genes of trehalose-treated 2D and 3D fibroblasts at early time points revealed the involvement of the CDKN1A pathway, which is necessary for the marked upregulation of growth factors including DPT. By contrast, the mRNA-seq data of LSEs 2-weeks after air exposure indicated that gene expression profiles are similar for untreated and trehalose-treated cells in both keratinocytes and fibroblasts. The trehalose-treated fibroblasts were positive for senescence-associated {beta}-galactosidase with the significantly downregulated expressions of LMNB1. Finally, we demonstrated that transplantation of the dermal substitute with trehalose-treated fibroblasts accelerated wound closure and increased capillary formation significantly in the experimental mouse wounds in vivo. These data indicate that high-concentration trehalose can induce the beneficial senescence-associated secretory phenotype in fibroblasts via CDKN1A/p21, which may be therapeutically useful for optimal wound repair.

cell biology↗