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

Simultaneous relocation of a group of pollutant sources in a heavily polluted area is a rare event. Such a relocation has been implemented in Hazaribagh, a tannery built-up area with heavy pollution, in Bangladesh. This provides a valuable opportunity to compare the changes in environmental conditions associated with the relocation of multiple putative sources. Our environmental monitoring for a period of 6 years at the stationary areas centered on Hazaribagh geographically revealed trivalent [Cr(III)], hexavalent [Cr(VI)] chromium, lead, iron, and manganese as tannery-related elements after the legal deadline for tannery relocation. The median Cr(III) level in canal water, into which wastewater from tanneries was directly discharged, after the relocation was 97% lower of that before the relocation, indicating a beneficial effect of the relocation. In contrast, the median Cr(VI) level in water samples just after the relocation and 2 years after the relocation were approximately 5-fold and 30-fold higher, respectively, than those before the relocation. These results indicate not only a harmful effect of the relocation but also the possibility of conversion from Cr(III) to Cr(VI) in nature. Although the health hazard indexes considering all of the tannery-related elements in all of the canal water samples before the relocation exceeded the safety thresholds, the percentages of samples in which the indexes exceeded their safety thresholds after the relocation decreased by 32.5%–45.0%. Treatment with our patented hydrotalcite-like compound consisting of magnesium and iron (MF-HT) resulted in decreases in the health hazard indexes in all of the water samples in which the indexes exceeded their safety thresholds to levels lower than their thresholds. Thus, this study shows the double-edged effects associated with the relocation and a potential solution.

DOI： 10.1016/j.chemosphere.2022.135098

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

DOI： 10.1038/s41598-022-08503-7

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

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Water pollution caused by tannery wastewater is an important issue in developing countries. Most studies have focused on inorganic chemicals represented by chromium as a tannery-related main pollutant. This is the first study in which pollution of water by tannery-related organic chemicals was assessed by a combination of qualitative and quantitative analyses. Our quantitative analysis showed that the maximum concentration of total phenolic compounds (phenols), consisting of phenol, bisphenol F, p-cresol and chlomcresol, in canal water in a tannery built-up area in Bangladesh was >67-fold higher than the Environmental, Health and Safety (EHS) guideline value. Mapping of our results indicated tanneries as the sources of phenols pollution. Our original depurative, a hydrotalcite-like compound consisting of magnesium and iron (MF-HT), could adsorb all kinds of phenols and exhibited the highest phenol adsorption ability (115.8 mg/g) among reported hydrotalcite-like compounds. The levels of phenols in canal water samples were reduced to levels below the guideline value by using MF-HT with assistance of a photocatalytic reaction. Moreover, the mean level of chromium (112.2 mg/L) in canal water samples was decreased by 99.7% by using the depurative. Thus, the depurative has the potential for solving the problem of tannery-related water pollution by phenols and chromium.

DOI： 10.1016/j.chemosphere.2021.130959

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

DOI： 10.1016/j.jaci.2021.05.025

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MOSBY-ELSEVIER  

Background: Air pollutants are suspected to affect pathological conditions of allergic rhinitis (AR).Objectives: After detecting Pb (375 mg/kg) in Japanese cedar pollen, the effects of intranasal exposure to Pb on symptoms of AR were investigated.Methods: Pollen counts, subjective symptoms, and Pb levels in nasal epithelial lining fluid (ELF) were investigated in 44 patients with Japanese cedar pollinosis and 57 controls from preseason to season. Effects of intranasal exposure to Pb on symptoms were confirmed by using a mouse model of AR.Results: Pb levels in ELF from patients were >40% higher than those in ELF from control subjects during the pollen season but not before the pollen season. Pb level in ELF was positively associated with pollen counts for the latest 4 days before visiting a hospital as well as scores of subjective symptoms. Intranasal exposure to Pb exacerbated symptoms in allergic mice, suggesting Pb as an exacerbation factor. Pb levels in ELF and nasal mucosa in Pb-exposed allergic mice were higher than those in Pb-exposed nonallergic mice, despite intranasally challenging the same amount of Pb. Because the increased Pb level in the nasal mucosa of Pb-exposed allergic mice was decreased after washing the nasal cavity, Pb on the surface of but not inside the nasal mucosa may have been a source of increased Pb level in ELF of allergic mice.Conclusions: Increased nasal Pb level partially derived from pollen could exacerbate subjective symptoms of AR, indicating Pb as a novel hazardous air pollutant for AR.

DOI： 10.1016/j.jaci.2021.03.019

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

Hair graying is a representative sign of aging in animals and humans. However, the mechanism for hair graying with aging remains largely unknown. In this study, we found that the microscopic appearance of hair follicles without melanocyte stem cells (MSCs) and descendant melanocytes as well as macroscopic appearances of hair graying in RET-transgenic mice carrying RET oncogene (RET-mice) are in accordance with previously reported results for hair graying in humans. Therefore, RET-mice could be a novel model mouse line for age-related hair graying. We further showed hair graying with aging in RET-mice associated with RET-mediated acceleration of hair cycles, increase of senescent follicular keratinocyte stem cells (KSCs), and decreased expression levels of endothelin-1 (ET-1) in bulges, decreased endothelin receptor B (Ednrb) expression in MSCs, resulting in a decreased number of follicular MSCs. We then showed that hair graying in RET-mice was accelerated by congenitally decreased Ednrb expression in MSCs in heterozygously Ednrb-deleted RET-mice [Ednrb(+/-);RET-mice]. We finally partially confirmed common mechanisms of hair graying with aging in mice and humans. Taken together, our results suggest that age-related dysfunction between ET-1 in follicular KSCs and endothelin receptor B (Ednrb) in follicular MSCs via cumulative hair cycles is correlated with hair graying with aging.

DOI： 10.1111/acel.13273

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Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1111/acel.13273

Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

Background: The process for leather material production is carried out in developing countries using a large amount of trivalent chromium [Cr(III)]. Assesment of health risks for millions of workers in tanneries worldwide that are highly polluted with Cr(III) is needed.Methods: Levels of total Cr and its chemical species in wastewater samples from tannery built-up areas of Bangladesh were investigated. Cr-mediated renal damage was assessed in 100 male tannery workers by epidemiological analysis consisting of questionnaires and measurements of levels of urinary Cr and urinary renal damage markers [urinary levels of total protein and kidney injury molecule-1 (KIM-1)].Results: High levels of total Cr (mean +/- standard deviation = 1,908,762 +/- 703,450 mu g/L) were detected in wastewater samples from 13 sites of tanneries. More than 99.99% of total Cr in the wastewater was Cr(III), indicating that workers in the tanneries were exposed to large concentrations of Cr(III). Cr levels (mean +/- standard, 2.89 +/- 4.23 mu g/g creatinine) in urine samples from the workers in tanneries were > 24-fold higher than the levels in a general population previously reported. Multivariate analysis showed significant correlations between urinary levels of Cr and urinary levels of renal damage biomarkers. Nagelkerke Pseudo R-2 values also showed that Cr level is the strongest contributor to the levels of renal damage biomarkers in the workers.Conclusion: Our results newly suggest that excess exposure to Cr(III) could be a risk for renal damage in humans.

DOI： 10.1016/j.envres.2020.109770

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

Toxic compounds from the mother's diet and medication in addition to genetic factors and infection during pregnancy remain risks for various congenital disorders and misbirth. To ensure the safety of food and drugs for pregnant women, establishment of an in vitro system that morphologically resembles human tissues has been long desired. In this study, we focused on dorsal mesoderm elongation, one of the critical early development events for trunk formation, and we established in vitro autonomous elongating tissues from human induced pluripotent stem cells (hiPSCs). This artificial tissue elongation is regulated by MYOSIN II and FGF signaling, and is diminished by methylmercury or retinoic acid (RA), similar to in vivo human developmental disabilities. Moreover, our method for differentiation of hiPSCs requires only a short culture period, and the elongation is cell number-independent. Therefore, our in vitro human tissue elongation system is a potential tool for risk assessment assays for identification of teratogenic chemicals via human tissue morphogenesis. (C) 2020 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.chemosphere.2020.126124

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

Well water could be a stable source of drinking water. Recently, the use of well water as drinking water has been encouraged in developing countries. However, many kinds of disorders caused by toxic elements in well drinking water have been reported. It is our urgent task to resolve the global issue of element-originating diseases. In this review article, our multidisciplinary approaches focusing on oncogenic toxicities and disturbances of sensory organs (skin and ear) induced by arsenic and barium are introduced. First, our environmental monitoring in developing countries in Asia showed elevated concentrations of arsenic and barium in well drinking water. Then our experimental studies in mice and our epidemiological studies in humans showed arsenic-mediated increased risks of hyperpigmented skin and hearing loss with partial elucidation of their mechanisms. Our experimental studies using cultured cells with focus on the expression and activity levels of intracellular signal transduction molecules such as c-SRC, c-RET, and oncogenic RET showed risks for malignant transformation and/or progression arose from arsenic and barium. Finally, our original hydrotalcite-like compound was proposed as a novel remediation system to effectively remove arsenic and barium from well drinking water. Hopefully, comprehensive studies consisting of (1) environmental monitoring, (2) health risk assessments, and (3) remediation will be expanded in the field of environmental health to prevent various disorders caused by environmental factors including toxic elements in drinking water.

DOI： 10.1186/s12199-020-00855-8

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Authorship：Lead author,　Last author,　Corresponding author   Language：Japanese   Publisher：The Japanese Society of Toxicology  

<p>Molybdenum has redox potential which is utilized as a cofactor of oxidoreductases including Xanthine oxidoreductase. Exess intake of molybdenum causes hepatic and neuronal toxicities. Therefore, a fine tuning of molybdenum trafficking is required. However, the storage mechanism of molybdenum remains unclear. In this study, we showed that molybdenum interacts with melanin by our in vivo and cell-free system. Melanin might be a potential storage of molybdenum. </p>

DOI： 10.14869/toxpt.47.1.0_p-206

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Authorship：Lead author,　Last author,　Corresponding author   Language：Japanese   Publisher：The Japanese Society of Toxicology  

<p>In daily and occupational environments, people have been shown to be generally exposed to low frequency noise (LFN) with frequencies below 100 Hz and sound levels of 60-110 dB. Exposure to LFN has been shown to affect balance in humans and mice. However, there is no information about prevention of LFN-mediated imbalance because of no information about the target site. In this study, we showed that excessive exposure to LFN at 100 Hz, 95 dB for only one hour induced irreversible imbalance in mice with morphological damage of the otoconial membrane in vestibule as the target site for imbalance, which can be rescued in HSP70-Tg mice.</p>

DOI： 10.14869/toxpt.47.1.0_p-151

CiNii Research

Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

Chemical leukoderma is a patchy hypopigmentation in the skin. Phenol derivatives such as raspberry ketone have been reported to cause the development of occupationally induced leukoderma. Recently, 2% (w/w) rhododenol, a reduced form of raspberry ketone used in a skin-lightning agent, also caused the development of leukoderma in >16,000 users, about 2% of all users, in Asian countries including Japan. However, a method for assessing the risk of leukoderma caused by 2% rhododenol has not been established despite the fact that the development of leukoderma caused by 30% rhododenol was previously shown in animal experiments. Establishment of a novel technique for risk assessment of leukoderma in humans caused by external treatment with chemicals is needed to prevent a possible future chemical disaster. This study demonstrated that external treatment with 2% rhododenol and the same concentration of raspberry ketone caused the development of leukoderma in murine tail skin without exception with significant decreases in the amount of melanin and number of melanocytes in the epidermis. Thus, a novel in vivo technique that can assess the risk of leukoderma caused by 2% rhododenol was developed. The unique technique using tail skin has the potential to prevent chemical leukoderma in the future. (C) 2019 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.chemosphere.2019.06.185

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JOHN LIBBEY EUROTEXT LTD  

DOI： 10.1684/ejd.2019.3621

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

Since tannery workers in developing countries are chronically exposed to high levels of chromium (Cr), there are serious concerns about health problems. However, there has been limited study in which Cr levels were measured in tannery workers, who are chronically exposed to Cr. Our preliminary inspection showed that there was hyperpigmented skin in tannery workers. We therefore investigated the correlation between skin pigmentation levels digitally evaluated as L* values by using a reflectance spectrophotometer and Cr levels in skin appendages in 100 male tannery workers and in 49 male non-tannery workers in Bangladesh. Digitalized skin pigmentation levels of the face and feet in addition to Cr levels in hair and toenails in tannery workers were significantly higher than those in non-tannery workers in our univariate analysis. Spearman's rank correlation coefficient analysis showed significant correlation between duration of tannery work (years) and Cr levels in hair (r = 0.62) and toenails (r = 0.61). Our multivariate analysis also showed that Cr levels in hair and toenails were significantly correlated with digitalized skin pigmentation levels of the face and feet in addition to duration of tannery work in all participants. Thus, our results showed the development of hyperpigmented skin in tannery workers. Our results also suggested that hyperpigmented skin could be a useful diagnostic marker for chronic exposure to Cr. Furthermore, cutaneous L* value might be a convenient marker for detection of chronic Cr poisoning, since the digitalized values enable objective evaluation of skin pigmented levels by general people as well as dermatologists. (C) 2019 Published by Elsevier Ltd.

DOI： 10.1016/j.chemosphere.2019.04.112

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

Background: Melanin is detectable in various sense organs including the skin in animals. It has been reported that melanin adsorbs toxic elements such as mercury, cadmium, and lead. In this study, we investigated the adsorption of molybdenum, which is widely recognized as a toxic element, by melanin.Methods: Molybdenum level of the mouse skin was measured by inductively coupled plasma mass spectrometry. The pigmentation level of murine skin was digitalized as the L* value by using a reflectance spectrophotometer. An in vitro adsorption assay was performed to confirm the interaction between molybdenum and melanin.Results: Our analysis of hairless mice with different levels of skin pigmentation showed that the level of molybdenum increased with an increase in the level of skin pigmentation (L* value). Moreover, our analysis by Spearman's correlation coefficient test showed a strong correlation (r = -0.9441, p < 0.0001) between L* value and molybdenum level. Our cell- free experiment using the Langmuir isotherm provided evidence for the adsorption of molybdenum by melanin. The maximum adsorption capacity of 1 mg of synthetic melanin for molybdenum was 131 mu g in theory.Conclusion: Our in vivo and in vitro results showed a new aspect of melanin as an adsorbent of molybdenum.

DOI： 10.1186/s12199-019-0791-y

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

About 80% of young people use personal listening devices (PLDs) including MP3 players to listen to music, which consists of sound components with various frequencies. Previous studies showed that exposure to noise of high intensities affected balance in humans. However, there is no information about a frequency-dependent effect of sound components in music from a PLD on balance in young people. In this study, we determined the associations between sound component levels (dB) at 100, 1000 and 4000 Hz in music from a portable listening device (PLD) and balance objectively determined by posturography in young adults (n = 110).We divided the subjects into two groups (low and high exposure groups) based on cut-off values of sound component levels at each frequency using receiver operating characteristic (ROC) curves. Balance in the high exposure group (>= 46.6 dB) at 100 Hz was significantly better than that in low exposure group in logistic regression models adjusted for sex, BMI, smoking status and alcohol intake, while there were no significant associations at 1000 and 4000 Hz. Thus, this study demonstrated for the first time that the sound component at 100 Hz with more than 46.6 dB in music improved balance in young adults.

DOI： 10.1038/s41598-018-35244-3

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

At present, beneficial effects of melanin and harmful effects of barium have been reported. However, little is known about the adsorption of barium, and even less is known about the biological significance of adsorption of barium by melanin. In this study, we showed that there was a strong correlation between the digitalized level of skin pigmentation and barium level in murine skin compared to the correlations between skin pigmentation level and levels of homologous elements of barium (magnesium, calcium and strontium). The concentration of subcutaneously injected barium in skin with a high level of pigmentation was higher than that in skin with a low level of pigmentation. Our cell-free experiment using the Langmuir isotherm for adsorption of barium in synthetic melanin also provided direct evidence of adsorption of barium by melanin. We then investigated the biological significance of melanin mediated barium adsorption. We found barium-mediated increase in transforming activity in pig-mented melanocytes (melan-a) but not in unpigmented melanocytes (melan-c) after confirming that the barium level in melan-a melanocytes was 3.4-fold higher than that in melan-c melanocytes after culture of 5 mu M barium for 24 h. Taken together, our results not only indicate adsorption of barium by melanin in mice, cells and cell-free systems but also suggest a disadvantageous effect of adsorption of barium by melanin on transforming activity in cultured cells. (C) 2018 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.chemosphere.2018.07.022

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

Repairing injured tissues / organs is one of the major challenges for the maintenance of proper organ function in adulthood. In mammals, the central nervous system including the spinal cord, once established during embryonic development, has very limited capacity to regenerate. In contrast, salamanders such as axolotls can fully regenerate the injured spinal cord, making this a very powerful vertebrate model system for studying this process. Here we discuss the cellular and molecular requirements for spinal cord regeneration in the axolotl. The recent development of tools to test molecular function, including CRISPR-mediated gene editing, has lead to the identification of key players involved in the cell response to injury that ultimately leads to outgrowth of neural stem cells that are competent to replay the process of spinal cord development to replace the damaged/missing tissue.

DOI： 10.1016/j.ydbio.2017.09.034

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELIFE SCIENCES PUBLICATIONS LTD  

Axolotls are uniquely able to mobilize neural stem cells to regenerate all missing regions of the spinal cord. How a neural stem cell under homeostasis converts after injury to a highly regenerative cell remains unknown. Here, we show that during regeneration, axolotl neural stem cells repress neurogenic genes and reactivate a transcriptional program similar to embryonic neuroepithelial cells. This dedifferentiation includes the acquisition of rapid cell cycles, the switch from neurogenic to proliferative divisions, and the re-expression of planar cell polarity (PCP) pathway components. We show that PCP induction is essential to reorient mitotic spindles along the anterior-posterior axis of elongation, and orthogonal to the cell apical-basal axis. Disruption of this property results in premature neurogenesis and halts regeneration. Our findings reveal a key role for PCP in coordinating the morphogenesis of spinal cord outgrowth with the switch from a homeostatic to a regenerative stem cell that restores missing tissue.

DOI： 10.7554/eLife.10230

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

Inducing organogenesis in 3D culture is an important aspect of stem cell research. Anterior neural structures have been produced from large embryonic stem cell (ESC) aggregates, but the steps involved in patterning such complex structures have been ill defined, as embryoid bodies typically contained many cell types. Here we show that single mouse ESCs directly embedded in Matrigel or defined synthetic matrices under neural induction conditions can clonally form neuroepithelial cysts containing a single lumen in 3D. Untreated cysts were uniformly dorsal and could be ventralized to floor plate (FP). Retinoic acid posteriorized cysts to cervical levels and induced localize FP formation yielding full patterning along the dorsal/ventral (DV) axis. Correct spatial organization of motor neurons, interneurons, and dorsal interneurons along the DV axis was observed. This system serves as a valuable tool for studying morphogen action in 3D and as a source of patterned spinal cord tissue.

DOI： 10.1016/j.stemcr.2014.09.020

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

The salamander is the only tetrapod that functionally regenerates all cell types of the limb and spinal cord (SC) and thus represents an important regeneration model, but the lack of gene-knockout technology has limited molecular analysis. We compared transcriptional activator-like effector nucleases (TALENs) and clustered regularly interspaced short palindromic repeats (CRISPRs) in the knockout of three loci in the axolotl and find that CRISPRs show highly penetrant knockout with less toxic effects compared to TALENs. Deletion of Sox2 in up to 100% of cells yielded viable F0 larvae with normal SC organization and ependymoglial cell marker expression such as GFAP and ZO-1. However, upon tail amputation, neural stem cell proliferation was inhibited, resulting in spinal-cord-specific regeneration failure. In contrast, the mesodermal blastema formed normally. Sox3 expression during development, but not regeneration, most likely allowed embryonic survival and the regeneration-specific phenotype. This analysis represents the first tissue-specific regeneration phenotype from the genomic deletion of a gene in the axolotl.

DOI： 10.1016/j.stemcr.2014.06.018

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC ADVANCEMENT SCIENCE  

An amputated salamander limb regenerates the correct number of segments. Models explaining limb regeneration were largely distinct from those for limb development, despite the presence of common patterning molecules. Intercalation has been an important concept to explain salamander limb regeneration, but clear evidence supporting or refuting this model was lacking. In the intercalation model, the first blastema cells acquire fingertip identity, creating a gap in positional identity that triggers regeneration of the intervening region from the stump. We used HOXA protein analysis and transplantation assays to show that axolotl limb blastema cells acquire positional identity in a proximal-to-distal sequence. Therefore, intercalation is not the primary mechanism for segment formation during limb regeneration in this animal. Patterning in development and regeneration uses similar mechanisms.

DOI： 10.1126/science.1241796

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

The evolutionary origins of the gene network underlying cellular pluripotency, a central theme in developmental biology, have yet to be elucidated. In mammals, Oct4 is a factor crucial in the reprogramming of differentiated cells into induced pluripotent stem cells. The Oct4 and Pou2 genes evolved from a POU class V gene ancestor, but it is unknown whether pluripotency induced by Oct4 gene activity is a feature specific to mammals or was already present in ancestral vertebrates. Here we report that different vertebrate Pou2 and Oct4 homologues can induce pluripotency in mouse and human fibroblasts and that the inability of zebrafish Pou2 to establish pluripotency is not representative of all Pou2 genes, as medaka Pou2 and axolotl Pou2 are able to reprogram somatic cells into pluripotent cells. Therefore, our results indicate that induction of pluripotency is not a feature specific to mammals, but existed in the Oct4/Pou2 common ancestral vertebrate.

DOI： 10.1038/ncomms2229

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Harmful health effects of exposure to low-frequency noise (LFN) defined as noise with frequencies at ≤100 Hz on the circulatory system have been a concern. However, there has been no study on the effects of exposure to LFN on the circulatory system with consideration of its frequencies and decibels. In this study, the effects of short-term exposure to broad-band LFNs and their pure-tone components (pure-tone LFNs) on cutaneous blood flow in the extremities including the hands were investigated. In our fieldwork study, we first sampled some kinds of common broad-band LFNs. Our human study then showed that broad-band LFN with a narrower frequency range more strongly increased cutaneous blood flow than did broad-band LFN with a wider frequency range. Pure-tone LFNs of 70-100 Hz at ≤85 dB(Z), but not pure-tone LFNs exceeding 100 Hz, further increased levels of cutaneous blood flow. Our wavelet-transform spectrum analysis of cutaneous blood flow next revealed that the nitric oxide (NO)-dependent and -independent vascular activities of the vascular endothelium were specifically increased by exposure to pure-tone LFN. Our animal study again indicated that exposure to pure-tone LFN increased cutaneous blood flow in mice with impairments of bilateral inner ears as well as cutaneous blood flow in control mice, suggesting a limited effect of inner ear function on the LFN-mediated increase in cutaneous blood flow. The NO-dependent suppressive effect of pure-tone LFN on cutaneous blood flow was confirmed by inhibition of vascular endothelial activity through intravenous injection of an NO inhibitor in wild-type mice. Taken together, the results of this study demonstrated that the vascular endothelium is a target tissue of LFN and that NO is an effector of the LFN-mediated increase in cutaneous blood flow. Since improvement of peripheral circulation could generally promote human health, short-term exposure to LFN may be beneficial for health.

DOI： 10.1016/j.scitotenv.2022.158828

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Hexavalent chromium [Cr(VI)], which has a strong corrosive effect, has been reported to cause perforation of the eardrum. Trivalent chromium [Cr(III)] also has a weak corrosive effect. However, there has been no study on the effects of exposure to Cr, either Cr(VI) or Cr(III), on hearing levels in animals or humans. In this study, the effect of Cr(III) exposure on hearing levels was determined in a human study. Then the reproducibility of the results obtained in the human study and the etiology were investigated in an animal study. The mean levels of total chromium (t-Cr) in hair and toenails from 100 Bangladeshi tannery workers were >20-fold and >360-fold higher, respectively, than those in hair and toenails from 49 Bangladeshi non-tannery workers (office workers). Multivariate analysis revealed decreases of hearing levels (DHLs) at 1 k and 4 k Hz, frequencies that are crucial for understanding language, but not at 8 k and 12 k Hz, in the tannery workers. Since >99.99% of t-Cr in the wastewater that the workers were in direct contact with in the tanneries was Cr(III), the epidemiological results suggest Cr(III)-mediated DHLs in the tannery workers. The results of animal experiments in this study further showed that treatment with eardrops but not intraperitoneal injection with the same amount of Cr(III) that tannery workers might be exposed to resulted in DHL with a damaged eardrum in mice. Previous studies suggested that Cr(III) can directly reach the eardrums of tannery workers via droplets in the air. Cr(III) could also reach the eardrum via picking an ear canal with a finger contaminated with tannery wastewater including Cr(III). Taken together, the results of both human and animal studies suggest the risk of DHLs caused by damage of the eardrum through external exposure to Cr(III) via the ear canal.

DOI： 10.1016/j.chemosphere.2022.135571

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：FRONTIERS MEDIA SA  

Vertebrate dentitions arise at various places within the oropharyngeal cavity including the jaws, the palate, or the pharynx. These dentitions develop in a highly organized way, where new tooth germs are progressively added adjacent to the initiator center, the first tooth. At the same time, the places where dentitions develop house the contact zones between the outer ectoderm and the inner endoderm, and this colocalization has instigated various suggestions on the roles of germ layers for tooth initiation and development. Here, we study development of the axolotl dentition, which is a complex of five pairs of tooth fields arranged into the typically tetrapod outer and inner dental arcades. By tracking the expression patterns of odontogenic genes, we reason that teeth of both dental arcades originate from common tooth-competent zones, one present on the mouth roof and one on the mouth floor. Progressive compartmentalization of these zones and a simultaneous addition of new tooth germs distinct for each prospective tooth field subsequently control the final shape and composition of the axolotl dentition. Interestingly, by following the fate of the GFP-labeled oral ectoderm, we further show that, in three out of five tooth field pairs, the first tooth develops right at the ecto-endodermal boundary. Our results thus indicate that a single tooth-competent zone gives rise to both dental arcades of a complex tetrapod dentition. Further, we propose that the ecto-endodermal boundary running through this zone should be accounted for as a potential source of instruction factors instigating the onset of the odontogenic program.

DOI： 10.3389/fcell.2020.622308

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

Axolotls can regenerate complex structures through recruitment and remodeling of cells within mature tissues. Accessing the underlying mechanisms at a molecular resolution is crucial to understand how injury triggers regeneration and how it proceeds. However, gene transformation in adult tissues can be challenging. Here we characterize the use of pseudotyped baculovirus (BV) as an effective gene transfer method both for cells within mature limb tissue and within the blastema. These cells remain competent to participate in regeneration after transduction. We further characterize the effectiveness of BV for gene overexpression studies by overexpressing Shh in the blastema, which yields a high penetrance of classic polydactyly phenotypes. Overall, our work establishes BV as a powerful tool to access gene function in axolotl limb regeneration.

DOI： 10.1016/j.ydbio.2017.10.008

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

Limb amputation in the newt induces myofibers to dedifferentiate and re-enter the cell cycle to generate proliferative myogenic precursors in the regeneration blastema. Here we show that bone morphogenetic proteins (BMPs) and mature BMPs that have been further cleaved by serum proteases induce cell cycle entry by dedifferentiating newt muscle cells. Protease-activated BMP4/7 heterodimers that are present in serum strongly induced myotube cell cycle reentry with protease cleavage yielding a 30-fold potency increase of BMP4/7 compared with canonical BMP4/7. Inhibition of BMP signaling via musclespecific dominant-negative receptor expression reduced cell cycle entry in vitro and in vivo. In vivo inhibition of serine protease activity depressed cell cycle re-entry, which in turn was rescued by cleaved-mimic BMP. This work identifies a mechanism of BMP activation that generates blastema cells from differentiated muscle.

DOI： 10.1016/j.devcel.2017.03.002

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

Classical grafting experiments in the Mexican axolotl had shown that the posterior neural plate of the neurula is no specified neuroectoderm but gives rise to somites of the tail and posterior trunk. The bipotentiality of this region with neuromesodermal progenitor cell populations was revealed more recently also in zebrafish, chick, and mouse. We reinvestigated the potency of the posterior plate in axolotl using grafts from transgenic embryos, immunohistochemistry, and in situ hybridization. The posterior plate is brachyury-positive except for its more anterior parts which express sox2. Between anterior and posterior regions of the posterior plate a small domain with sox2+ and bra+ cells exists. Lineage analysis of grafted GFP-labeled posterior plate tissue revealed that posterior GFP+ cells move from dorsal to ventral, form the posterior wall, turn anterior bilaterally, and join the gastrulated paraxial presomitic mesoderm. More anterior sox2+/GFP+ cells, however, are integrated into the developing spinal cord. Tail notochord is formed from axial mesoderm involuted already during gastrulation. Thus the posterior neural plate is a postgastrula source of paraxial mesoderm, which performs an anterior turn, a novel morphogenetic movement. More anterior plate cells, in contrast, do not turn anteriorly but become specified to form tail spinal cord.

DOI： 10.1016/j.ydbio.2016.12.023

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Mesenchyme is an embryonic precursor tissue that generates a range of structures in vertebrates including cartilage, bone, muscle, kidney, and the erythropoietic system. Mesenchyme originates from both mesoderm and the neural crest, an ectodermal cell population, via an epithelial to mesenchymal transition (EMT). Because ectodermal and mesodermal mesenchyme can form in close proximity and give rise to similar derivatives, the embryonic origin of many mesenchyme-derived tissues is still unclear. Recent work using genetic lineage tracing methods have upended classical ideas about the contributions of mesodermal mesenchyme and neural crest to particular structures. Using similar strategies in the Mexican axolotl (Ambystoma mexicanum), and the South African clawed toad (Xenopus laevis), we traced the origins of fin mesenchyme and tail muscle in amphibians. Here we present evidence that fin mesenchyme and striated tail muscle in both animals are derived solely from mesoderm and not from neural crest. In the context of recent work in zebrafish, our experiments suggest that trunk neural crest cells in the last common ancestor of tetrapods and ray-finned fish lacked the ability to form ectomesenchyme and its derivatives.

DOI： 10.1038/srep11428

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

Salamanders regenerate appendages via a progenitor pool called the blastema. The cellular mechanisms underlying regeneration of muscle have been much debated but have remained unclear. Here we applied Cre-loxP genetic fate mapping to skeletal muscle during limb regeneration in two salamander species, Notophthalmus viridescens (newt) and Ambystoma mexicanum (axolotl). Remarkably, we found that myofiber dedifferentiation is an integral part of limb regeneration in the newt, but not in axolotl. In the newt, myofiber fragmentation results in proliferating, PAX7(-) mononuclear cells in the blastema that give rise to the skeletal muscle in the new limb. In contrast, myofibers in axolotl do not generate proliferating cells, and do not contribute to newly regenerated muscle; instead, resident PAX7(+) cells provide the regeneration activity. Our results therefore show significant diversity in limb muscle regeneration mechanisms among salamanders and suggest that multiple strategies may be feasible for inducing regeneration in other species, including mammals.

DOI： 10.1016/j.stem.2013.11.007

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

Limb regeneration involves re-establishing a limb development program from cells within adult tissues. Identifying molecular handles that provide insight into the relationship between cell differentiation status and cell lineage is an important step to study limb blastema cell formation. Here, using single cell PCR, focusing on newly isolated Twist1 sequences, we molecularly profile axolotl limb blastema cells using several progenitor cell markers. We link their molecular expression profile to their embryonic lineage via cell tracking experiments. We use in situ hybridization to determine the spatial localization and extent of overlap of different markers and cell types. Finally, we show by single cell PCR that the mature axolotl limb harbors a small but significant population of Twist1(+) cells. (C) 2012 Published by Elsevier Inc.

DOI： 10.1016/j.ydbio.2012.10.019

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PUBLIC LIBRARY SCIENCE  

Understanding how the limb blastema is established after the initial wound healing response is an important aspect of regeneration research. Here we performed parallel expression profile time courses of healing lateral wounds versus amputated limbs in axolotl. This comparison between wound healing and regeneration allowed us to identify amputation-specific genes. By clustering the expression profiles of these samples, we could detect three distinguishable phases of gene expression - early wound healing followed by a transition-phase leading to establishment of the limb development program, which correspond to the three phases of limb regeneration that had been defined by morphological criteria. By focusing on the transition-phase, we identified 93 strictly amputation-associated genes many of which are implicated in oxidative-stress response, chromatin modification, epithelial development or limb development. We further classified the genes based on whether they were or were not significantly expressed in the developing limb bud. The specific localization of 53 selected candidates within the blastema was investigated by in situ hybridization. In summary, we identified a set of genes that are expressed specifically during regeneration and are therefore, likely candidates for the regulation of blastema formation.

DOI： 10.1371/journal.pone.0061352

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATL ACAD SCIENCES  

We show that after tail amputation in Ambystoma mexicanum (Axolotl) the correct number and spacing of dorsal root ganglia are regenerated. By transplantation of spinal cord tissue and non-clonal neurospheres, we show that the central spinal cord represents a source of peripheral nervous system cells. Interestingly, melanophores migrate from preexisting precursors in the skin. Finally, we demonstrate that implantation of a clonally derived spinal cord neurosphere can result in reconstitution of all examined cell types in the regenerating central spinal cord, suggesting derivation of a cell with spinal cord stem cell properties.

DOI： 10.1073/pnas.1116738109

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ZOOLOGICAL SOC JAPAN  

The epidermis serves as a barrier protecting organs and tissues from the environment, and comprises many types of cells. A cell renewal system is established in epidermis: old epithelial cells are replaced by newly differentiated cells, which are derived from epidermal stem cells located near basement membrane. In order to examine the mechanism of epidermal development, we isolated a novel gene expressed in Xenopus epidermis and named the gene Xenopus polka dots (Xpod) from its polka dot-like expression pattern throughout larval periods. Several immunohistochemical examinations showed that the Xpod-expressing cell type is neither p63-positive epidermal stem cells, nor the alpha-tubulin-positive ciliated cells, but a subset of the foxi1e-positive ionocytes. The forced gene expression of foxi1e caused the suppression of Xpod expression, while Xpod showed no effect on foxi1e expression. In a comparison of several osmotic conditions, we found that hypertonic culture caused the increase in number of the Xpod-expressing cell, whereas number of the foxi1e-expressing cells was reduced under the hypertonic condition. These results show the possibility that Xpod is involved in the establishment of a certain subpopulation of ionocytes under hypertonic conditions.

DOI： 10.2108/zsj.28.809

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

Mitochondria are accurately transmitted to the next generation through a female germ cell in most animals. Mitochondria produce most ATP, accompanied by the generation of reactive oxygen species (ROS). A specialized mechanism should be necessary for inherited mitochondria to escape from impairments of mtDNA by ROS. Inherited mitochondria are named germ-line mitochondria, in contrast with somatic ones. We hypothesized that germ-line mitochondria are distinct from somatic ones. The protein profiles of germ-line and somatic mitochondria were compared, using oocytes at two different stages in Xenopus laevis. Some subunits of ATP synthase were at a low level in germ-line mitochondria, which was confirmed immunologically. Ultrastructural histochemistry using 3,3'-diaminobenzidine (DAB) Showed that cytochrome c oxidase (COX) activity of germ-line mitochondria was also at a low level. Mitochondria in one oocyte were segregated into germ-line mitochondria and somatic mitochondria, during growth from stage I to VI oocytes. Respiratory activity represented by ATP synthase expression and COX activity was shown to be low during most of the long gametogenetic period. We propose that germ-line mitochondria that exhibit suppressed respiration alleviate production of ROS and enable transmission of accurate mtDNA from generation to generation. (C) 2010 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.ydbio.2010.11.021

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

We investigated the characteristics of a novel type I keratin gene in Xenopus laevis during ontogenesis. The transcript was first detected in the posterior region at the late neurula stage, and then restricted to the fin and external gill during embryogenesis. To examine the transcriptional regulation of the keratin gene in vivo, we generated transgenic lines with fluorescent reporter genes driven by its 4.2-kb upstream sequence. The promoter/enhancer activity recapitulated the endogenous gene expression during embryogenesis. Sequential deletion analyses revealed that the regions proximal to the promoter were essential for fin-specific expression. Reporter expression was detected in various organs, including the fin and gill. In particular, robust expression was observed in the developing limbs and gill. The reporter fluorescence rapidly decreased with internal gill resorption during metamorphosis. The transgenic lines carrying the promoter/enhancer should represent valuable tools for elucidating the formation, development and resorption of various organs, especially the gill. Developmental Dynamics 239:3172-3181, 2010. (C) 2010 Wiley-Liss, Inc.

DOI： 10.1002/dvdy.22451

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

Primordial germ cells (PGCs) in Xenopus embryo are specified in the endodermal cell mass and migrate dorsally toward the future gonads. The role of the signal mediated by Notch and Suppressor of Hairless [Su(H)] was analyzed on the migrating PGCs at the tailbud stage. X-Notch-1 and X-Delta-1 are expressed in the migrating PGCs and surrounding endodermal cells, whereas X-Delta-2 and X-Serrate-1 are expressed preferentially in the PGCs. Suppression and constitutive activation of the Notch/Su(H) signaling in the whole endoderm region or selectively in the PGCs resulted in an increase in ectopic PGCs located in lateral or ventral regions. Knocking down of the Notch ligands by morpholino oligonucleotides revealed that X-Delta-2 was indispensable for the correct PGC migration. The ectopic PGCs seemed to have lost their motility in the Notch/Su(H) signal-manipulated embryos. Our results suggest that a cell-to-cell interaction via the Notch/Su(H) pathway has a significant role in the PGC migration by regulating cell motility.

DOI： 10.1111/j.1440-169X.2009.01164.x

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

Amputation of the larval tail of Xenopus injures the notochord, spinal cord, muscle masses, mesenchyme, and epidermis, induces the growth and differentiation of cells in those tissues, and results in tail regeneration. A dorsal incision in the larval tail injures the same tissues and induces cell growth and differentiation, but never results in the formation of any extra appendages. The first sign of tail regeneration is the multilayered wound epidermis and Xwnt-5a expression in the distal region, neither of which is observed in the recovering region after a dorsal incision. To evaluate the role of Xwnt-5a in tail regeneration, Xwnt-5a was overexpressed in the recovering region. When an animal cap injected with Xwnt-5a mRNA was grafted into the dorsal incision, an ectopic protrusion was formed. Morphological and molecular analyses revealed that the protrusion was an ectopic larval tail, which was equivalent to the regenerating tail but different from the tail that develops from the embryonic tail bud. Lineage labeling revealed that the major differentiated structures of the ectopic tail were formed from host cells, suggesting that Xwnt-5a induced host cells to make a complete tail. The ectopic tail was not induced by Xwnt-8 or Xwnt-11, demonstrating the specificity of Xwnt-5a in this process. A pharmacological study showed that JNK signaling is required in tail regeneration. These results support the proposition that Xwnt-5a plays an instructive role in larval tail regeneration via Wnt/JNK signaling. (C) 2008 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.mod.2008.10.002

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

Background information. The results of water permeability measurements suggest the presence of an AQP (aquaporin) in the membrane of the CV (contractile vacuole) in Amoeba proteus [Nishihara, Shimmen and Sonobe (2004) Cell Struct. Funct. 29, 85-90].Results. In the present study, we cloned an AQP gene from A. proteus [ApAQP (A. proteus AQP)] that encodes a 295-amino-acid protein. The protein has six putative TMs (transmembrane domains) and two NPA (Asn-Pro-Ala) motifs, which are conserved among various AQPs and are thought to be involved in the formation of water channels that span the lipid bilayer. Using Xenopus oocytes, we have demonstrated that the ApAQP protein product can function as a water channel. Immuncifluorescence microscopy with anti-ApAQP antibody revealed that ApAQP is detected on the CV membrane and on the vesicles around the CV. The presence of V-ATPase (vacuolar H+-ATPase) on the vesicle membrane around the CV was also detected.Conclusions. Our data on ApAQP allow us to provide the first informed explanation of the high water permeability of the CV membrane in amoeba. Moreover, the results suggest that vesicles possessing V-ATPase are involved in generating an osmotic gradient. Based on our findings, we propose a new hypothesis for the mechanism of CV function.

DOI： 10.1042/BC20070091

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

Tail regeneration in urodeles is dependent on the spinal cord (SC), but it is believed that anuran larvae regenerate normal tails without the SC. To evaluate the precise role of the SC in anuran tail regeneration, we developed a simple operation method to ablate the SC completely and minimize the damage to the tadpole using Xenopus laevis. The SC-ablated tadpole regenerated a twisted and smaller tail. These morphological abnormalities were attributed to defects in the notochord (NC), as the regenerated NC in the SC-ablated tail was short, slim and twisted. The SC ablation never affected the early steps of the regeneration, including closure of the amputated surface with epidermis and accumulation of the NC precursor cells. The proliferation rate of the NC precursor cells, however, was reduced, and NC cell maturation was retarded in the SC-ablated tail. These results show that the SC has an essential role in the normal tail regeneration of Xenopus larvae, especially in the proliferation and differentiation of the NC cells. Gene expression analysis and implantation of a bead soaked with growth factor showed that fibroblast growth factor-2 and -10 were involved in the signaling molecules, which were expressed in the SC and stimulated growth of the NC cells.

DOI： 10.1111/j.1440-169X.2007.00981.x

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

We succeeded in visualization of the primordial germ cells (PGCs) in a living Xenopus embryo. The mRNA of the reporter Venus protein, fused to the 3' untranslated region (UTR) of DEADSouth, which is a component of the germ plasm in Xenopus eggs, was micro-injected into the vegetal pole of fertilized eggs and then the cells with Venus fluorescence were monitored during development. The behavior of the cells was identical to that previously described for PGCs. Almost all Venus-expressing cells were Xdazl-positive in the stage 48 tadpoles, indicating that they were PGCs. In addition, we found three sub-regions (A, B and C) in the 3' UTR, which were involved in the PGC-specific expression of the reporter protein. Sub-region A, which was identified previously as a localization signal for the germ plasm during oogenesis, participated in anchoring of the mRNA at the germ plasm and the degradation of the mRNA in the somatic cells. Sub-regions B and C were also involved in anchoring of the mRNA at the germ plasm. Sub-region B participated in the enhancement of translation. (c) 2006 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.mod.2006.07.006

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

In many organisms, proper embryo development depends on the asymmetrical distribution of mRNA in the cytoplasm of the egg. Here we report comprehensive screening of RNA localized in the animal or vegetal hemisphere of the Xenopus egg. Macroarrays including over 40000 independent embryonic cDNA clones, representing at least 17000 unigenes, were differentially hybridized with labeled probes synthesized from the mRNA of animal or vegetal blastomeres. After two rounds of screening, we identified 33 clones of transcripts that may be preferentially distributed in the vegetal region of the early stage embryo, but transcripts localized in the animal region were not found. To assess the array results, we performed northern blot and quantitative real-time reverse transcription-polymerase chain reaction analysis. As a result, 21 transcripts of the 33 were confirmed to be localized in the vegetal region of the early stage embryo. Whole-mount in situ hybridization analysis revealed that 11 transcripts, including 7 previously reported genes, were localized in the vegetal hemisphere of the egg. These 11 transcripts were categorized into three groups according to their expression patterns in the egg. The first group, which contained four transcripts, showed uniform expression in the vegetal hemisphere, similar to VegT. The second group, which contained three transcripts, showed gradual expression from the vegetal pole to the equator, similar to Vg1. The last group, which contained three transcripts, was expressed at the germ plasm, similar to Xdazl. One transcript, Xwnt11, showed both the second and the third expression patterns.

DOI： 10.1111/j.1440-169X.2005.00826.x

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Language：English   Publisher：ELSEVIER SCIENCE BV  

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-LISS  

Xenopus larvae possess a remarkable ability to regenerate their tails after they have been severed. To gain an understanding of the molecular mechanisms underlying tail regeneration, we performed a cDNA macroarray-based analysis of gene expression. A Xenopus cDNA macroarray representing 42,240 independent clones was differentially hybridized with probes synthesized from the total RNA of normal and regenerating tails. Temporal expression analysis revealed that the up-regulated genes could be grouped into early or late responding genes. A comparative expression analysis revealed that most genes showed similar expression patterns between tail development and regeneration. However, some genes showed regeneration-specific expression. Finally, we identified 48 up-regulated genes that fell into several categories based on their putative functions. These categories reflect the various processes that take place during regeneration, such as inflammation response, wound healing, cell proliferation, cell differentiation, and control of cell structure. Thus, we have identified a panel of genes that appear to be involved in the process of regeneration. (c) 2005 Wiley-Liss, Inc.

DOI： 10.1002/dvdy.20472

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Authorship：Lead author,　Last author,　Corresponding author  

DOI： 10.1111/j.1440-169x.2004.00727.x

PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

In addition to the chief function of erythropoietin (Epo) in promoting erythropoiesis, some other roles have been found in the brain and uterus. We have reported that signalling pathways of Epo and Epo receptor (EpoR) are involved in the tumourigenesis of ovarian and uterine cancers. To determine whether Epo plays a similar role in other malignancies, we studied the expression of Epo in several malignant human cell lines. We found that 24 malignant human cell lines examined express Epo and EpoR regardless of their origins, types, genetic characteristics and biological properties and secrete a very small amount of Epo individually and that most of them respond to hypoxic stimuli by enhanced secretion of Epo. To determine whether the Epo-EpoR pathway operates in tumours of these cell lines, we transplanted several cell lines into nude mice and confirmed the presence of Epo-responsive sites in xenografts in which the phosphorylation of the STAT5 (signal transducer and activator of transcription) is detectable. Furthermore, in nude mice we blocked the Epo signalling in xenografts of two representative cell lines, stomach choriocarcinoma and melanoma, by i.p. injections of EpoR antagonist and found inhibition of angiogenesis and survival of tumour cells leading to destruction of tumour masses and disturbances of phosphorylation of STAT5. In contrast, Epo mimetic peptide promotes angiogenesis and tumour cell survival. These findings suggest that Epo is indispensable for the growth and viability of malignant tumour and also that the deprivation of Epo signalling may be a promising therapy for human malignancy.

DOI： 10.1093/carcin/bgg060

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER-VERLAG  

We have cloned and sequenced a cDNA encoding an intermediate filament protein (IF) from the planarian Dugesia japonica named DjIFb. The deduced amino acid sequence of DjIFb has similarity to those of protostomic IFs and lamins, supporting a previous hypothesis that the protostomic IFs, including DjIFb, are evolutionarily closer to lamins than to vertebrate cytoplasmic IFs. In addition, analysis of the exon/intron organization revealed that 8 out of 10 introns of DjIFb were coincident in their position, even in the codon phase, with those of the non-neuronal IF of the snail Helix aspersa. This suggests that the Platyhelminthes are not the most primitive Bilateria but instead are evolutionarily close to the Mollusca. The DjIFb gene was expressed in particular cells, probably a kind of adhesive gland cell, which were present in the marginal region encircling the planarian body. The localization of DjIFb protein suggests that it plays an important role in the secretion of an adhesive substance. The specific expression pattern of the DjIFb gene enabled us to monitor how the body margin forms during planarian regeneration.

DOI： 10.1007/s00427-002-0253-0

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC  

In order to investigate the neural connection. of planarian, it is imperative to produce an antibody that specifically stains axons. To identify axon-specific genes, we constructed a cDNA library from a single eye by using a single cell PCR method, in which visual neurons are major components, and sequenced one thousand independent clones. We succeeded in the identification of a planarian homologue of synaptotagmin, Djsyt, whose specific expression in neurons was confirmed by in situ hybridization. The antibody against DjSYT specifically stained axons although its mRNA is distributed in the cell bodies. By using anti-DjSYT, we succeeded in the visualization of neural connections in planarians by whole mount staining. The anti-DjSYT antibody will become a powerful tool to analyze the molecular mechanisms underlying neural network formation in planarian. (C) 1999 Academic Press.

DOI： 10.1006/bbrc.1999.0933

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ZOOLOGICAL SOC JAPAN  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ELSEVIER SCIENCE BV  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ELSEVIER SCIENCE BV  

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Language：English   Publisher：OXFORD UNIV PRESS  

DOI： 10.1093/carcin/bgg126

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