記述言語：英語   出版者・発行元：American Journal of Pathology  

The SF3B4 gene encodes a highly conserved protein that plays a critical role in mRNA splicing. Mutations in this gene are known to cause Nager syndrome, a rare craniofacial disorder. Although SF3B4 expression is detected in the optic vesicle before it is detected in the limb and somite, the role of SF3B4 in the eye is not well understood. This study investigated the function of sf3b4 in the retina by performing transcriptome profiles, immunostaining, and behavioral analysis of sf3b4−/− mutant zebrafish. Results from this study suggest that dysregulation of the spliceosome complex affects not only craniofacial development but also retinogenesis. Zebrafish lacking functional sf3b4 displayed characteristics similar to retinitis pigmentosa (RP), marked by severe retinal pigment epithelium defects and rod degeneration. Pathway analysis revealed altered retinol metabolism and retinoic acid signaling in the sf3b4−/− mutants. Supplementation of retinoic acid rescued key cellular phenotypes observed in the sf3b4−/− mutants, offering potential therapeutic strategies for RP in the future. In conclusion, this study sheds light on the previously unknown role of SF3B4 in retinogenesis and provides insights into the underlying mechanisms of RP.

DOI： 10.1016/j.ajpath.2023.05.008

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： DOI: 10.1016/j.jhazmat.2023.131722

記述言語：英語   出版者・発行元：Journal of Hazardous Materials  

Perfluorohexanesulfonic acid (PFHxS) is a short-chain perfluoroalkyl substance widely used to replace the banned perfluorooctanesulfonic acid (PFOS) in different industrial and household products. It has currently been identified in the environment and human bodies; nonetheless, the possible toxicities are not well-known. Zebrafish have been used as a toxicant screening model due to their fast and transparent developmental processes. In this study, zebrafish embryos were exposed to PFHxS for five days, and various experiments were performed to monitor the developmental and cellular processes. Liquid chromatography-mass spectrometry (LC/MS) analysis confirmed that PFHxS was absorbed and accumulated in the zebrafish embryos. We reported that 2.5 µM or higher PFHxS exposure induced phenotypic abnormalities, marked by developmental delay in the mid-hind brain boundary and yolk sac edema. Additionally, larvae exposed to PFHxS displayed facial malformation due to the reduction of neural crest cell expression. RNA sequencing analysis further identified 4643 differentiated expressed transcripts in 5 µM PFHxS-exposed 5-days post fertilization (5-dpf) larvae. Bioinformatics analysis revealed that glucose metabolism, lipid metabolism, as well as oxidative stress were enriched in the PFHxS-exposed larvae. To validate these findings, a series of biological experiments were conducted. PFHxS exposure led to a nearly 4-fold increase in reactive oxygen species, possibly due to hyperglycemia and impaired glutathione balance. The Oil Red O’ staining and qPCR analysis strengthens the notions that lipid metabolism was disrupted, leading to lipid accumulation, lipid peroxidation, and malondialdehyde formation. All these alterations ultimately affected cell cycle events, resulting in S and G2/M cell cycle arrest. In conclusion, our study demonstrated that PFHxS could accumulate and induce various developmental toxicities in aquatic life, and such data might assist the government to accelerate the regulatory policy on PFHxS usage.

DOI： 10.1016/j.jhazmat.2023.131722

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：mSystems  

Keng Po Lai, Peng Zhu, Delbert Almerick T. Boncan, Lu Yang, Cherry Chi Tim Leung, Jeff Cheuk Hin Ho, Xiao Lin, Ting Fung Chan, Richard Yuen Chong Kong, William Ka Fai Tse

DOI： 10.1128/msystems.00047-22

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.freeradbiomed.2020.12.455

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/1462-2920.15150

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.bbadis.2016.03.005

出版者・発行元：Comparative Biochemistry and Physiology - Part D: Genomics and Proteomics  

Gills and gut are the two primary osmoregulatory organs in fish. Recently, studies have expanded beyond the osmoregulatory mechanisms of these organs to explore the microbiota communities inhabiting them. It is now known that microbial communities in both organs shift in response to osmotic stress. However, there are limited studies identifying the major contributors and co-occurrence among these microbiota in both organs under seawater and freshwater transfer conditions. The current data mining report performed a bioinformatics analysis on two previous published datasets from our group, aiming to provide insights into host-bacteria relationships under osmotic stress. We divided the samples into four groups: control seawater gills (LSW); control seawater gut (TSW); freshwater transfer gills (LFW); and freshwater transfer gut (TFW). Our results showed that LSW had higher diversities, richness, and evenness compared to TSW. However, both the LFW and LSW did not show any significant differences after the freshwater transfer experiment. We further applied co-occurrence network analysis and, for the first time, reported on the interactions of taxa shaping the community structure in these two organs. Moreover, we identified enriched ectoine biosynthesis in seawater samples, suggesting its potential role in seawater environments. Increased mRNA expression levels of Na+/K+-atpase, and cftr, were observed in gills after 6 h of ectoine treatment. These findings provide a foundation for future studies on host-bacteria interactions under osmotic stress.

DOI： 10.1016/j.cbd.2024.101285

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出版者・発行元：Toxicology  

Introduction: Growing concerns regarding the reproductive toxicity associated with daily life exposure to micro-/nano-plastics (abbreviated as MNPs) have become increasingly prevalent. In reality, MNPs exposure involves a heterogeneous mixture of MNPs of different sizes rather than a single size. Methods: In this study, an oral exposure mouse model was used to evaluate the effects of MNPs of four size ranges: 25–30 nm, 1–5 µm, 20–27 µm, and 125–150 µm. Adult male C57BL/6 J mice were administered environmentally relevant concentrations of 0.1 mg MNPs/day for 21 days. After that, open field test and computer assisted sperm assessment (CASA) were conducted. Immunohistochemical analyses of organ and cell type localization of MNPs were evaluated. Testicular transcriptome analysis was carried out to understand the molecular mechanisms. Results: Our result showed that MNPs of different size ranges all impaired sperm motility, with a decrease in progressive sperm motility, linearity and straight-line velocity of sperm movement. Alterations did not manifest in animal locomotion, body weight, or sperm count. Noteworthy effects were most pronounced in the smaller MNPs size ranges (25–30 nm and 1–5 µm). Linear regression analysis substantiated a negative correlation between the size of MNPs and sperm curvilinear activity. Immunohistochemical analysis unveiled the intrusions of 1–5 µm MNPs, but not 20–27 µm and 125–150 µm MNPs, into Leydig cells and testicular macrophages. Further testicular transcriptomic analysis revealed perturbations in pathways related to spermatogenesis, oxidative stress, and inflammation. Particularly within the 1–5 µm MNPs group, a heightened perturbation in pathways linked to spermatogenesis and oxidative stress was observed. Conclusions: Our data support the size-dependent impairment of MNPs on sperm functionality, underscoring the pressing need for apprehensions about and interventions against the escalation of environmental micro-/nano-plastics contamination. This urgency is especially pertinent to small-sized MNPs.

DOI： 10.1016/j.tox.2024.153834

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出版者・発行元：Marine Pollution Bulletin  

The COVID-19 pandemic has resulted in unprecedented plastic pollution from single-used personal protective equipment (PPE), especially face masks, in coastal and marine environments. The secondary pollutants, microplastics from face masks (mask MP), rise concern about their detrimental effects on marine organisms, terrestrial organisms and even human. Using a mouse model, oral exposure to mask MP at two doses, 0.1 and 1 mg MP/day for 21 days, caused no change in animal locomotion, total weight, or sperm counts, but caused damage to sperm motility with increased curvilinear velocity (VCL). The high-dose mask MP exposure caused a significant decrease in linearity (LIN) of sperm motility. Further testicular transcriptomic analysis revealed perturbed pathways related to spermatogenesis, oxidative stress, inflammation, metabolism and energy production. Collectively, our findings substantiate that microplastics from face masks yield adverse effects on mammalian reproductive capacity, highlighting the need for improved plastic waste management and development of environmentally friendly materials.

DOI： 10.1016/j.marpolbul.2024.116422

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： DOI: 10.1016/j.bbadis.2024.167128

記述言語：英語   出版者・発行元：Biochimica et Biophysica Acta - Molecular Basis of Disease  

Nager syndrome (NS) is a rare acrofacial dysostosis caused by heterozygous loss-of-function variants in the splicing factor 3B subunit 4 (SF3B4). The main clinical features of patients with NS are characterized by facial-mandibular and preaxial limb malformations. The migration and specification of neural crest cells are crucial for craniofacial development, and mitochondrial fitness appears to play a role in such processes. Here, by analyzing our previously published transcriptome dataset, we aim to investigate the potential involvement of mitochondrial components in the pathogenesis of craniofacial malformations, especially in sf3b4 mutant zebrafish. We identified that oxidative phosphorylation (OXPHOS) defects and overproduction of reactive oxygen species (ROS) due to decreased antioxidants defense activity, which leads to oxidative damage and mitochondrial dysfunction. Furthermore, our results highlight that fish lacking sf3b4 gene, primarily display defects in mitochondrial complex I. Altogether, our findings suggest that mitochondrial dysfunction may contribute to the development of the craniofacial anomalies observed in sf3b4-depleted zebrafish.

DOI： 10.1016/j.bbadis.2024.167128

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： DOI: 10.1016/j.exer.2024.109819

記述言語：英語   出版者・発行元：Experimental Eye Research  

Posterior subcapsular cataract (PSC) frequently develops as a complication in patients with retinitis pigmentosa (RP). Despite numerous scientific investigations, the intricate pathomechanisms underlying cataract formation in individuals affected by RP remain elusive. Therefore, our study aims to elucidate the potential pathogenesis of cataracts in an RP model using splicing factor subunit 3b (sf3b4) mutant zebrafish. By analyzing our previously published transcriptome dataset, we identified that, in addition to RP, cataract was listed as the second condition in our transcriptomic analysis. Furthermore, we confirmed the presence of nucleus retention in the lens fiber cells, along with abnormal cytoskeleton expression in both the lens fiber cells and lens epithelial cells in sf3b4-depleted fish. Upon closer examination, we identified 20 differentially expressed genes (DEGs) that played a role in cataract formation, with 95 % of them related to the downregulation of structural lens proteins. Additionally, we also identified that among all the DEGs, 13 % were associated with fibrotic processes. It seems that the significant upregulation of inflammatory mediators, in conjunction with TGF-β signaling, plays a central role in the cellular biology of PSC and posterior capsular opacification (PCO) in sf3b4 mutant fish. In summary, our study provides valuable insights into cataract formation in the RP model of sf3b4 mutants, highlighting its complexity driven by changes in structural lens proteins and increased cytokines/growth factors.

DOI： 10.1016/j.exer.2024.109819

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： DOI: 10.3390/genes15010093

記述言語：英語   出版者・発行元：Genes  

Perfluorohexanesulfonic acid (PFHxS) is a highly prevalent environmental pollutant, often considered to be less toxic than other poly- and perfluoroalkyl substances (PFASs). Despite its relatively lower environmental impact compared to other PFASs, several studies have suggested that exposure to PFHxS may be associated with disruptions of liver function in humans. Nevertheless, the precise pathomechanisms underlying PFHxS-induced non-alcoholic fatty liver disease (NAFLD) remain relatively unclear. Therefore, this study applied our previously published transcriptome dataset to explore the effects of PFHxS exposure on the susceptibility to NAFLD and to identify potential mechanisms responsible for PFHxS-induced NAFLD through transcriptomic analysis conducted on zebrafish embryos. Results showed that exposure to PFHxS markedly aggravated hepatic symptoms resembling NAFLD and other metabolic syndromes (MetS) in fish. Transcriptomic analysis unveiled 17 genes consistently observed in both NAFLD and insulin resistance (IR), along with an additional 28 genes identified in both the adipocytokine signaling pathway and IR. These shared genes were also found within the NAFLD dataset, suggesting that hepatic IR may play a prominent role in the development of PFHxS-induced NAFLD. In conclusion, our study suggests that environmental exposure to PFHxS could be a potential risk factor for the development of NAFLD, challenging the earlier notion of PFHxS being safer as previously claimed.

DOI： 10.3390/genes15010093

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出版者・発行元：Zoological Research  

The organ-specific toxicity resulting from microplastic (MP) exposure has been extensively explored, particularly concerning the gut, liver, testis, and lung. However, under natural conditions, these effects are not restricted to specific organs or tissues. Investigating whether MP exposure presents a systemic threat to an entire organism, impacting factors such as lifespan, sleep, and fecundity, is essential. In this study, we investigated the effects of dietary exposure to two different doses of MPs (1–5 μm) using the terrestrial model organism Drosophila melanogaster. Results indicated that the particles caused gut damage and remained within the digestive system. Continuous MP exposure significantly shortened the lifespan of adult flies. Even short-term exposure disrupted sleep patterns, increasing the length of daytime sleep episodes. Additionally, one week of MP exposure reduced ovary size, with a trend towards decreased egg-laying in mated females. Although MPs did not penetrate the brain or ovaries, transcriptome analysis revealed altered gene expression in these tissues. In the ovary, Gene Ontology (GO) analysis indicated genotoxic effects impacting inflammation, circadian regulation, and metabolic processes, with significant impacts on extracellular structure-related pathways. In the brain, GO analysis identified changes in pathways associated with proteolysis and carbohydrate metabolism. Overall, this study provides compelling evidence of the systemic negative effects of MP exposure, highlighting the urgent need to address and mitigate environmental MP pollution.

DOI： 10.24272/j.issn.2095-8137.2024.038

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： DOI: 10.1016/j.scitotenv.2023.166833

記述言語：英語   出版者・発行元：Science of the Total Environment  

Perfluorohexanesulfonic acid (PFHxS) is a short-chain perfluoroalkyl substance widely used to replace the banned perfluorooctanesulfonic acid (PFOS) in various industrial and household products. It can be found in the environment and human bodies; however, its potential toxicities are not well studied. Zebrafish have been extensively used as a model for studying toxicants, and currently, two studies have reported on the toxicity of PFHxS in zebrafish from different approaches. Ulhaq and Tse (J Hazard Mater. 2023; 457: 131722) conducted general biological experiments and applied transcriptomics to demonstrate that PFHxS at a concentration of 5 μM could affect glucose and fatty acid metabolism, leading to oxidative stress, developmental defects, and cell cycle arrest. Xu et al. (Sci Total Environ. 2023; 887: 163770) employed metabolomics and showed that concentrations of various metabolites changed after exposure to 3 and 10 μM PFHxS. As we observed a match between the metabolomics data and our biochemistry experimental findings, we integrated the two studies, which enabled us to unfold the possible mechanism of the deregulated metabolites. We identified 22 differential expressed genes (DEGs) in the tricarboxylic acid (TCA) cycle, 17 DEGs in glcyolytic process, including the critical glucokinase under the carbon metabolism. Besides, genes likes aldehyde dehydrogenases, and histone-lysine N-methyltransferases that participate in lipid peroxidation and amino metabolism respectively were spotted. Lastly, we further strengthen our discoveries by undergoing the gene set enrichment analysis. This article could provide insights into the toxicity of PFHxS, as well as prospects for environmental studies.

DOI： 10.1016/j.scitotenv.2023.166833

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： DOI: 10.3389/fphar.2023.1272523

記述言語：英語   出版者・発行元：Frontiers in Pharmacology  

DOI： 10.3389/fphar.2023.1272523

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Biochemical and Biophysical Research Communications  

Fatty acid oxidation disorders (FAODs) are a group of rare genetic metabolic disorders caused by mutations in genes responsible for transporting and metabolizing fatty acids in the mitochondria. One crucial enzyme involved in this process is carnitine palmitoyltransferase I (CPT1), which transports long-chain fatty acids to the mitochondrial matrix for beta-oxidation. Defects in beta-oxidation enzymes often lead to pigmentary retinopathy; however, the underlying mechanisms are not entirely understood. To investigate FAOD and its impact on the retina, we employed zebrafish as a model organism. Specifically, we used antisense-mediated knockdown strategies to target the cpt1a gene and examined the resulting retinal phenotypes. We demonstrated that the cpt1a MO-injected fish significantly reduced the length of connecting cilia and severely affected photoreceptor cell development. Moreover, our findings highlight that the loss of functional cpt1a disrupted energy homeostasis in the retina, leading to lipid droplet deposition and promoting ferroptosis, which is likely attributed to the photoreceptor degeneration and visual impairments observed in the cpt1a morphants.

DOI： 10.1016/j.bbrc.2023.04.096

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： https://doi.org/10.18632/aging.204733

記述言語：英語   出版者・発行元：Aging  

Hepatocellular carcinoma (HCC) is the sixth most common cancer and third leading cause of cancer-related deaths worldwide. HCC is a multistep disease marked by various signaling alterations. A better understanding of the new molecular drivers of HCC could therefore provide an opportunity to develop effective diagnostic and therapeutic targets. Ubiquitin-specific protease 44 (USP44), a member of the cysteine protease family, has been reported to play a role in many cancer types. However, its contribution to HCC development remains unknown. In the present study, we observed suppression of USP44 expression in HCC tissue. Clinicopathologic analysis further showed that low USP44 expression correlated with poorer survival and a later tumor stage in HCC, suggesting that USP44 could be a predictor of poor prognosis in patients with HCC. Gain-of-function analysis in vitro demonstrated the importance of USP44 in HCC cell growth and G0/G1 cell cycle arrest. To investigate the downstream targets of USP44 and the molecular mechanisms underlying its regulation of cell proliferation in HCC, we conducted a comparative transcriptomic analysis and identified a cluster of proliferation-related genes, including CCND2, CCNG2, and SMC3. Ingenuity Pathway Analysis further delineated the gene networks controlled by USP44 through the regulation of membrane proteins and receptors, enzymes, transcriptional factors, and cyclins involved in the control of cell proliferation, metastasis, and apoptosis in HCC. To summarize, our results highlight, for the first time, the tumor-suppression role of USP44 in HCC and suggest a new prognostic biomarker in this disease.

DOI： 10.18632/aging.204733

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Biochemical and Biophysical Research Communications  

Variants in the gene encoding trafficking protein particle complex 11 (TRAPPC11) cause limb-girdle muscular dystrophy R18 (LGMD R18). Although recently several genes related to myopathies have been identified, correlations between genetic causes and signaling events that lead from mutation to the disease phenotype are still mostly unclear. Here, we utilized zebrafish to model LGMD R18 by specifically inactivating trappc11 using antisense-mediated knockdown strategies and evaluated the resulting muscular phenotypes. Targeted ablation of trappc11 showed compromised skeletal muscle function due to muscle disorganization and myofibrosis. Our findings pinpoint that fish lacking functional trappc11 suppressed FGF8, which resulted in the aberrant activation of Notch signaling and eventually stimulated epithelial-mesenchymal transition (EMT) and fibrotic changes in the skeletal muscle. In summary, our study provides the role of FGF8 in the pathogenesis and its therapeutic potential of LGMD R18.

DOI： 10.1016/j.bbrc.2023.02.046

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Frontiers in Endocrinology  

DOI： 10.3389/fendo.2023.1151942

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Clinical Genetics  

Treacher Collins syndrome (TCS, OMIM: 154500) is a rare congenital craniofacial disorder that is caused by variants in the genes TCOF1, POLR1D, POLR1C, and POLR1B. Studies on the association between phenotypic variability and their relative variants are very limited. This systematic review summarized the 53 literatures from PubMed and Scopus to explore the potential TCS genotype–phenotype correlations with statistical analysis. Studies reporting both complete molecular genetics and clinical data were included. We identified that the molecular anomaly within TCOF1 (88.71%) accounted for most TCS cases. The only true hot spot for TCOF1 was detected in exon 24, with recurrent c.4369_4373delAAGAA variant is identified. While the hot spot for POLR1D, POLR1C, and POLR1B were identified in exons 3, 8, and 15, respectively. Our result suggested that the higher severity level was likely to be observed in Asian patients harboring TCOF1 variants rather than POLR1. Moreover, common 5-bp deletions tended to have a higher severity degree in comparison to any variants within exon 24 of TCOF1. In summary, this report suggested the relationship between genetic and clinical data in TCS. Our findings could be used as a reference for clinical diagnosis and further biological studies.

DOI： 10.1111/cge.14243

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Cleft Palate Craniofacial Journal  

Objective: Genetic variants in EFTUD2 were proven to influence variable phenotypic expressivity in mandibulofacial dysostosis Guion-Almeida type (MFDGA) or mandibulofacial dysostosis with microcephaly (MFDM). Yet, the association between the severity of clinical findings with variants within the EFTUD2 gene has not been established. Thus, we aim to elucidate a possible genotype–phenotype correlation in MFDM. Methods: Forty articles comprising 156 patients were evaluated. The genotype–phenotype correlation was analyzed using a chi-square or Fisher's exact test. Results: The proportion of patients with MFDM was higher in Caucasian relative to Asian populations. Although, in general, there was no apparent genotype–phenotype correlation in patients with MFDM, Asians tended to have more severe clinical manifestations than Caucasians. In addition, cardiac abnormality presented in patients with intronic variants located in canonical splice sites was a predisposing factor in affecting MFDM severity. Conclusion: Altogether, this article provides the pathogenic variants observed in EFTUD2 and possible genotype–phenotype relationships in this disease.

DOI： 10.1177/10556656221136177

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Anatomy  

Bone has multiple functions in animals, such as supporting the body for mobility. The zebrafish skeleton is composed of craniofacial and axial skeletons. It shares a physiological curvature and consists of a similar number of vertebrae as humans. Bone degeneration and malformations have been widely studied in zebrafish as human disease models. High-resolution imaging and different bone properties such as density and volume can be obtained using micro-computed tomography (micro-CT). This study aimed to understand the possible changes in the structure and bone mineral density (BMD) of the vertebrae and craniofacial skeleton with age (4, 12 and 24 months post fertilisation [mpf]) in zebrafish. Our data showed that the BMD in the vertebrae and specific craniofacial skeleton (mandibular arch, ceratohyal and ethmoid plate) of 12 and 24 mpf fish were higher than that of the 4 mpf fish. In addition, we found the age-dependent increase in BMD was not ubiquitously observed in facial bones, and such differences were not correlated with bone type. In summary, such additional information on the craniofacial skeleton could help in understanding bone development throughout the lifespan of zebrafish.

DOI： 10.1111/joa.13780

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Biology  

The fish gill is the first tissue that is exposed to the external media and undergoes continuous osmotic challenges. Recently, our group published an article entitled “Integrated Omics Approaches Revealed the Osmotic Stress-Responsive Genes and Microbiota in Gill of Marine Medaka” in the journal mSystems (e0004722, 2022), and suggested the possible host-bacterium interaction in the fish gill during osmotic stress. The previous study was performed by the progressive fresh water transfer (i.e., seawater to fresh water transfer via 50% seawater (FW)). Our group hypothesized that osmotic gradient could be a factor that determines the microbiota communities in the gill. The current 16S rRNA metagenomic sequencing study found that the direct transfer (i.e., seawater to fresh water (FWd)) could result in different gill microbiota communities in the same fresh water endpoints. Pseduomonas was the dominant bacteria (more than 55%) in the FWd gill. The Kyoto Encyclopedia of Genes and Genomes and MetaCyc analysis further suggested that the FWd group had enhanced osmosensing pathways, such as the ATP-binding cassette transporters, taurine degradation, and energy-related tricarboxylic acid metabolism compared to the FW group.

DOI： 10.3390/biology11101528

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：International Journal of Molecular Sciences  

Fish gills are the major osmoregulatory tissue that contact the external water environment and have developed an effective osmoregulatory mechanism to maintain cellular function. Marine medaka (Oryzias melastigma) has the ability to live in both seawater and fresh water environments. The present study performed a seawater (SW) to 50% seawater (SFW) transfer, and the gill samples were used for comparative transcriptomic analysis to study the alteration of hypo-osmotic stress on immune responsive genes in this model organism. The result identified 518 differentiated expressed genes (DEGs) after the SW to SFW transfer. Various pathways such as p53 signaling, forkhead box O signaling, and the cell cycle were enriched. Moreover, the immune system was highlighted as one of the top altered biological processes in the enrichment analysis. Various cytokines, chemokines, and inflammatory genes that participate in the IL-17 signaling pathway were suppressed after the SW to SFW transfer. On the other hand, some immunoglobulin-related genes were up-regulated. The results were further validated by real-time qPCR. Taken together, our study provides additional gill transcriptome information in marine medaka; it also supports the notion that osmotic stress could influence the immune responses in fish gills.

DOI： 10.3390/ijms232012417

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Frontiers in Physiology  

DOI： 10.3389/fphys.2022.977185

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Cancers  

Deubiquitinases (DUBs) deconjugate ubiquitin (UBQ) from ubiquitylated substrates to regulate its activity and stability. They are involved in several cellular functions. In addition to the general biological regulation of normal cells, studies have demonstrated their critical roles in various cancers. In this review, we evaluated and grouped the biological roles of DUBs, including proliferation, metastasis, and apoptosis, in the most common cancers in the world (liver, breast, prostate, colorectal, pancreatic, and lung cancers). The current findings in these cancers are summarized, and the relevant mechanisms and relationship between DUBs and cancers are discussed. In addition to highlighting the importance of DUBs in cancer biology, this study also provides updated information on the roles of DUBs in different types of cancers.

DOI： 10.3390/cancers14143547

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Cleft Palate Craniofacial Journal  

Nager syndrome (NS) is a rare disease marked with craniofacial and preaxial limb anomalies. In this report, we summarized the current evidence to determine a possible genotype–phenotype association among NS individuals. Twenty-four articles comprising of 84 NS (including 9 patients with a severe form of NS [Rodriguez syndrome]) patients were examined, of which 76% were caused by variants in SF3B4 (OMIM *605593, Splicing Factor 3B, Subunit 4). Within the SF3B4 gene, variants located in exon 3 commonly occurred (20%) from a total identified variant, while hotspot location was identified in exon 1 (12%), and primarily occurred as frameshift variants (64%). Thirty-five distinct pathogenic variants within SF3B4 gene were identified with two common sites, c.1A > G and c.1060dupC in exons 1 and 5, respectively. Although no significant genotype–phenotype association was found, it is notable that patients with frameshift SF3B4 variants and predicted to lead to nonsense-mediated RNA decay (NMD) of the transcripts tended to have a more severe clinical manifestation. Additionally, patients harboring variants in exons 2 and 3 displayed a higher proportion of cardiac malformations. Taken together, this article summarizes the pathogenic variants observed in SF3B4 and provides a possible genotype–phenotype relationship in this disease.

DOI： 10.1177/10556656221089156

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Ecotoxicology and Environmental Safety  

2,4-dichlorophenol (2,4-DCP) is commonly found in the aquatic environment that can be formed by the conversion of triclosan, which is a high production volume endocrine disturbing chemical. The study aims to understand the potential developmental toxicity of 2,4-DCP by using the in vivo zebrafish. We exposed the 2,4-DCP to the zebrafish embryos and collected the samples at several selected developmental stages (70–85% epiboly/10–12 somite/prim-5) for the whole mount in situ hybridization. The staining is used to investigate the ventral patterning, presumptive neural formation, and brain development. Results suggested that the 2,4-DCP exposure (up to 2.5 mg/L) did not affect the tested developmental processes in the survived embryos. Further experiments on lipid accumulation and oxidative stress were carried out at 5 days post fertilization larvae. Results showed the accumulation of oil droplets and induction of reactive oxygen species (ROS) in the larvae after the highest dosage exposure (2.5 mg/L). The real-time qPCR results suggested that the alternation of lipid metabolism was due to the reduced mRNA expressions of proliferator-activated receptor alpha (ppar-α) and acetyl-CoA carboxylase (acc); while the suppressed glutathione peroxidase (gpx) mRNA expression was responsible for the induction of the ROS. To conclude, the study provided scientific merits of understanding 2,4-DCP toxicity, and suggested the possible underlying mechanism of the defects.

DOI： 10.1016/j.ecoenv.2021.113133

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Frontiers in Marine Science  

Recent studies have shown hypoxia to be an endocrine disruptor that impairs sex differentiation and reproductive function, leading to male-biased F1 populations in fish. However, the molecular mechanisms through which hypoxia alters fish sex differentiation and therefore sex ratios remain poorly understood. In order to understand the potential role of miRNAs in mediating hypoxia-altered sex determination and differentiation in fish, we conducted small RNA sequencing and transcriptome sequencing on marine medaka (Oryzias melastigma) embryos that were exposed to hypoxia (2.0 ± 0.2 mg O2 L–1) for 40 h (encompassing a critical window of sex determination). We identified dysregulated miRNAs and mRNAs in the hypoxia-exposed embryo, and bioinformatic analysis of the integrative small RNA sequencing and transcriptome sequencing results revealed hypoxia to cause alterations of genes related to embryonic development through miRNA regulation. Importantly, we have identified miRNA-mRNA pairs that were reported to play roles in gonad development (novel miR-145-col9a3 and novel miRNA-94- arid5b), in sex hormone response (novel miRNA-210-ca2, novel miRNA-106-nr2f2, nbr-miR-29c-nr4a1, and ola-miR-92b-akr1d1), and in sex characteristic development (novel miRNA-145-mns1, nle-miR-20-sord, and ipu-miR-219b-abcc8). Our findings highlighted the possible roles of miRNA–mRNA in regulation of embryonic development and sex determination in response to hypoxic stress.

DOI： 10.3389/fmars.2021.736362

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出版者・発行元：Biomolecules  

Unlike mammals, zebrafish are capable to regenerate many of their organs, however, the response of tissue damage varies across tissues. Understanding the molecular mechanism behind the robust regenerative capacity in a model organism may help to identify and develop novel treatment strategies for mammals (including humans). Hence, we systematically analyzed the current literature on the proteome profile collected from different regenerated zebrafish tissues. Our analyses underlining that several proteins and protein families responsible as a component of cytoskeleton and structure, protein synthesis and degradation, cell cycle control, and energy metabolism were frequently identified. Moreover, target proteins responsible for the initiation of the regeneration process, such as inflammation and immune response were less frequently detected. This highlights the limitation of previous proteomic analysis and suggested a more sensitive modern proteomics analysis is needed to unfold the mechanism. This brief report provides a list of target proteins with predicted functions that could be useful for further biological studies.

DOI： 10.3390/biom12010035

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/lam.13539

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.aquatox.2021.105813

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3389/fmars.2021.618489

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.marpolbul.2021.112090

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3390/cancers12051288

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3390/ijms21072548

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.chemosphere.2019.124810

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1096/fj.201902557RRR

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.ajpath.2017.10.004

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.fsi.2017.12.026

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.gene.2017.11.016

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/s41598-018-19327-9

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1002/cbin.10799

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.bbrc.2017.04.132

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.chemosphere.2016.08.073

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.biocel.2016.10.016

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.chemosphere.2016.05.060

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.aquatox.2016.01.001

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1186/s12864-015-2271-0

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.dib.2015.02.012

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/srep10673

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/srep09836

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1186/s12864-015-1325-7

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.jprot.2014.01.025

記述言語：英語  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1186/s12983-014-0086-5

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.ydbio.2013.06.012

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.jprot.2013.05.026

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background Osmotic stress transcription factor 1/transforming growth factor-β-stimulated clone 22 domain 3 (Ostf1/Tsc22d3) is a transcription factor that plays an osmoregulatory role in euryhaline fishes. Its mRNA and protein levels are up-regulated under hyperosmotic stress. However, its osmoregulatory and developmental functions have not been studied in any stenohaline freshwater fishes. Zebrafish is an excellent model to perform such study to unfold the functional role of Tsc22d3. Methods We identified the zebrafish Tsc22d3 and performed knockdown studies using morpholino antisense oligonucleotide (MO). Results Zebrafish Tsc22d3 did not response to hypertonic stress and ts22d3 knockdown or overexpression by injecting MO or capped RNA did not change the transcriptional levels of any of the known ionocyte markers. To reveal the unknown function of zebrafish Tsc22d3, we performed several in situ molecular marker studies on tsc22d3 morphants and found that Tsc22d3 plays multi-functional roles in dorsoventral (DV) patterning, segmentation, and brain development. We then aimed to identify the mechanism of Tsc22d3 in the earliest stages of DV patterning. Our results demonstrated that tsc22d3 is a ventralizing gene that can stimulate the transcription of bone morphogenetic protein 4 (bmp4) and, thus, has a positive effect on the Bmp signaling pathway. Furthermore, we showed that Tsc22d3 interacts with deubiquitylating enzymes, ubiquitin-specific protease 15 (Usp15) and ovarian tumor domain containing protein 4 (Otud4). In addition, the interruption of Bmp4 signaling by double knockdown of usp15 and otud4 reduced the ventralized effects in tsc22d3-overexpressing embryos. Conclusions This is the first study to identify new developmental functions of Tsc22d3 in zebrafish. General significance Zebrafish tsc22d3 is a ventralizing gene and plays a role in early embryogenesis.

DOI： 10.1016/j.bbagen.2013.05.006

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Osmosensing and osmoregulatory processes undertaken in gills of euryhaline fish are coordinated by integrative actions of various signaling molecules/transcriptional factors. Considerable numbers of studies report the hyper- and hypoosmoregulatory functions of fish gills, by illustrating the process of gill cell remodeling and the modulation of the expression of ion channels/transporters. Comparatively mechanistic information relayed from signal integration to transcriptional regulation in mediating gill cell functions has not yet been elucidated. In this study we demonstrate the functional links from cortisol stimulation, to Akt activation, to the expression of the transcriptional factor, Ostf1. Using the synthetic glucocorticoid receptor agonist, dexamethasone (DEX), Ostf1 expression is found to be activated via glucocorticoid receptor (GR) and mediated by the Akt-GSK3β signaling pathway. Pharmacological experiments using kinase inhibitors reveal that the expression of Ostf1 is negatively regulated by Akt activation. The inhibition of PI3K or Akt activities, by the specific kinase inhibitors (wortmannin, LY294002 or SH6), stimulates Ostf1 expression, while a reduction of GSK3β activity by LiCl reduces Ostf1 expression. Collectively, our report for the first time indicates that DEX can induce Ostf1 via GR, with the involvement of the Akt-GSK3β signaling pathway in primary eel gill cell cultures. The data also suggest that Ostf1 may play different roles in gill cell survival during seawater acclimation.

DOI： 10.1242/bio.20134135

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1242/bio.20134283

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.biocel.2013.05.023

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1186/1742-9994-9-3

記述言語：英語  

DOI： 10.1007/978-1-61779-424-7_24

記述言語：英語  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.biocel.2011.08.013

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1002/jez.681

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1139/z11-009

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1387/ijdb.103089wt

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1186/1471-2164-10-637

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1242/jeb.017368

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1242/jeb.004101

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.bbrc.2006.06.028

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1080/15376520500194692

開催年月日： 2019年8月

記述言語：英語  

国名：中華人民共和国  

開催年月日： 2019年5月

記述言語：英語  

国名：日本国  

開催年月日： 2018年8月

記述言語：英語  

国名：日本国  

開催年月日： 2018年6月

記述言語：英語  

国名：日本国  

開催年月日： 2017年8月

記述言語：英語  

国名：日本国  

開催年月日： 2017年5月

記述言語：英語  

国名：日本国  

開催年月日： 2015年7月

記述言語：英語   会議種別：口頭発表（一般）  

開催年月日： 2015年6月

記述言語：英語  

国名：日本国  

開催年月日： 2015年6月

記述言語：英語  

国名：日本国  

開催年月日： 2014年5月

記述言語：英語  

国名：日本国  

開催年月日： 2014年5月

記述言語：英語  

国名：日本国  

開催年月日： 2013年5月

記述言語：英語   会議種別：口頭発表（一般）  

国名：日本国  

開催年月日： 2012年11月

記述言語：英語  

開催年月日： 2009年7月

記述言語：英語  

国名：アメリカ合衆国  

開催年月日： 2009年5月

記述言語：英語  

国名：日本国  

開催年月日： 2008年6月

記述言語：英語  

国名：アメリカ合衆国  

開催年月日： 2006年7月

記述言語：英語  

国名：カナダ  

開催年月日： 2006年2月

記述言語：英語   会議種別：口頭発表（一般）  

国名：タイ王国  

開催年月日： 2005年3月

記述言語：英語  

開催地：New Orleans   国名：アメリカ合衆国  

種別：査読等 

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種別：学会・研究会等 

種別：査読等 

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種別：学会・研究会等 

種別：査読等 

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種別：査読等 

外国語雑誌　査読論文数：30

種別：学会・研究会等 

種別：査読等 

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種別：大会・シンポジウム等 

種別：査読等 

外国語雑誌　査読論文数：50

種別：学会・研究会等 

種別：査読等 

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種別：査読等 

外国語雑誌　査読論文数：26

種別：学会・研究会等 

種別：査読等 

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種別：査読等 

外国語雑誌　査読論文数：24

種別：その他

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