Publications by authors named "Susumu Tanaka"

124 Publications

LATS kinases and SLUG regulate the transition to advanced stage in aggressive oral cancer cells.

Sci Rep 2022 Jul 20;12(1):12363. Epub 2022 Jul 20.

Department of Molecular Genetics, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.

The epithelial-to-mesenchymal transition (EMT) is a critical process by which cancer cells acquire malignant features. However, the molecular mechanism and functional implications of EMT and the mesenchymal-to-epithelial transition (MET) in tumor progression remain elusive. In this study, we established two aggressive cancer cell lines from the human oral cancer cell line SAS, mesenchymal-like SAS-m4 and epithelial-like SAS-δ. SAS-δ is a revertant cell obtained by inducing MET in SAS-m4. SAS-δ, but not SAS-m4, exhibited abnormal cell growth, including piled-up overgrowth and invasive tumor formation in the tongues of nude mice, suggesting that SAS-δ represented more advanced cancer cells than the parental SAS cells. EMT-related transcriptional factor SLUG is phosphorylated at T208 and partly stabilized by the Hippo pathway kinases, LATS1 and LATS2. Depletion of SLUG promoted the invasive activity of SAS-δ by increasing the protein levels of LATS1/2 and the proportion of the phosphorylated form among total SLUG protein. Our results suggest that the LATS1/2-SLUG axis regulates the transition of SAS cells to the advanced stage via repeated switching between EMT and MET. Therefore, an anti-SLUG-pT208 antibody would be valuable not alone as a malignant tumor marker antibody but also as a prognostic tool for patients with malignant disease.
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http://dx.doi.org/10.1038/s41598-022-16667-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9300623PMC
July 2022

Familial Hyperaldosteronism Type 3 with a Rapidly Growing Adrenal Tumor: An In Situ Aldosterone Imaging Study.

Curr Issues Mol Biol 2021 Dec 28;44(1):128-138. Epub 2021 Dec 28.

Department of Urology and Andrology, Kansai Medical University, Osaka 573-1191, Japan.

Primary aldosteronism is most often caused by aldosterone-producing adenoma (APA) and bi-lateral adrenal hyperplasia. Most APAs are caused by somatic mutations of various ion channels and pumps, the most common being the inward-rectifying potassium channel . Germ line mutations of cause familial hyperaldosteronism type 3 (FH3), which is associated with severe hyperaldosteronism and hypertension. We present an unusual case of FH3 in a young woman, first diagnosed with primary aldosteronism at the age of 6 years, with bilateral adrenal hyperplasia, who underwent unilateral adrenalectomy (left adrenal) to alleviate hyperaldosteronism. However, her hyperaldosteronism persisted. At the age of 26 years, tomography of the remaining adrenal revealed two different adrenal tumors, one of which grew substantially in 4 months; therefore, the adrenal gland was removed. A comprehensive histological, immunohistochemical, and molecular evaluation of various sections of the adrenal gland and in situ visualization of aldosterone, using matrix-assisted laser desorption/ionization imaging mass spectrometry, was performed. Aldosterone synthase (CYP11B2) immunoreactivity was observed in the tumors and adrenal gland. The larger tumor also harbored a somatic β-catenin activating mutation. Aldosterone visualized in situ was only found in the subcapsular regions of the adrenal and not in the tumors. Collectively, this case of FH3 presented unusual tumor development and histological/molecular findings.
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http://dx.doi.org/10.3390/cimb44010010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8929039PMC
December 2021

Cytoplasmic Polyadenylation Element-Binding Protein 1 Post-transcriptionally Regulates Fragile X Mental Retardation 1 Expression Through 3' Untranslated Region in Central Nervous System Neurons.

Front Cell Neurosci 2022 15;16:869398. Epub 2022 Apr 15.

Department of Anatomy, Kansai Medical University, Hirakata, Japan.

Fragile X syndrome (FXS) is an inherited intellectual disability caused by a deficiency in Fragile X mental retardation 1 () gene expression. Recent studies have proposed the importance of cytoplasmic polyadenylation element-binding protein 1 (CPEB1) in FXS pathology; however, the molecular interaction between mRNA and CPEB1 has not been fully investigated. Here, we revealed that CPEB1 co-localized and interacted with mRNA in hippocampal and cerebellar neurons and culture cells. Furthermore, CPEB1 knockdown upregulated mRNA and protein levels and caused aberrant localization of Fragile X mental retardation protein in neurons. In an FXS cell model, CPEB1 knockdown upregulated the mRNA levels of several mitochondria-related genes and rescued the intracellular heat shock protein family A member 9 distribution. These findings suggest that CPEB1 post-transcriptionally regulated expression through the 3' untranslated region, and that CPEB1 knockdown might affect mitochondrial function.
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http://dx.doi.org/10.3389/fncel.2022.869398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9051318PMC
April 2022

Sulfatide with ceramide composed of phytosphingosine (t18:0) and 2-hydroxy FAs in renal intercalated cells.

J Lipid Res 2022 06 16;63(6):100210. Epub 2022 Apr 16.

Department of Anatomy.

Diverse molecular species of sulfatide with differences in FA lengths, unsaturation degrees, and hydroxylation statuses are expressed in the kidneys. However, the physiological functions of specific sulfatide species in the kidneys are unclear. Here, we evaluated the distribution of specific sulfatide species in the kidneys and their physiological functions. Electron microscopic analysis of kidneys of Cst-deficient mice lacking sulfatide showed vacuolar accumulation in the cytoplasm of intercalated cells in the collecting duct, whereas the proximal and distal tubules were unchanged. Immunohistochemical analysis revealed that vacuolar H-ATPase-positive vesicles were accumulated in intercalated cells in sulfatide-deficient kidneys. Seventeen sulfatide species were detected in the murine kidney by iMScope MALDI-MS analysis. The distribution of the specific sulfatide species was classified into four patterns. Although most sulfatide species were highly expressed in the outer medullary layer, two unique sulfatide species of m/z 896.6 (predicted ceramide structure: t18:0-C22:0h) and m/z 924.6 (predicted ceramide structure: t18:0-C24:0h) were dispersed along the collecting duct, implying expression in intercalated cells. In addition, the intercalated cell-enriched fraction was purified by fluorescence-activated cell sorting using the anti-vacuolar H-ATPase subunit 6V0A4, which predominantly contained sulfatide species (m/z 896.6 and 924.6). The Degs2 and Fa2h genes, which are responsible for ceramide hydroxylation, were expressed in the purified intercalated cells. These results suggested that sulfatide molecular species with ceramide composed of phytosphingosine (t18:0) and 2-hydroxy FAs, which were characteristically expressed in intercalated cells, were involved in the excretion of NH and protons into the urine.
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http://dx.doi.org/10.1016/j.jlr.2022.100210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9157219PMC
June 2022

Preoperative nutritional evaluation, surgical site infection, and prognosis in patients with oral cancer.

Oral Surg Oral Med Oral Pathol Oral Radiol 2022 08 16;134(2):168-175. Epub 2022 Jan 16.

First Department of Oral and Maxillofacial Surgery, Graduate School of Dentistry, Osaka University, Suita, Osaka, Japan.

Objectives: The risk of postoperative infection after reconstructive oral cancer surgery is high and poses a problem in perioperative management. The objective of this study was to verify the association between preoperative nutritional indicators, surgical site infection (SSI), and long-term prognosis after reconstruction for oral cancer.

Study Design: Sixty-seven patients admitted to a dental hospital were enrolled. The following nutritional indicators were examined: serum albumin level, modified Glasgow Prognostic Score, Miki's Glasgow Prognostic Score, prognostic nutritional index, platelet/lymphocyte ratio, neutrophil/lymphocyte ratio, lymphocyte/monocyte ratio, and the Controlling Nutritional Status tool. Statistical analyses were conducted to determine potential risk factors for SSI.

Results: The Cox proportional hazards model demonstrated that SSI and platelet/lymphocyte ratio ≥211.4 were independent prognostic factors affecting survival. The results demonstrated that albumin <4.0 and platelet/lymphocyte ratio ≥211.4 were risk factors for SSI. Furthermore, albumin <4.0, platelet/lymphocyte ratio ≥211.4, and SSI were correlated with prognosis. Preoperative nutritional indicators were associated with SSI and prognosis in patients with oral cancer after reconstructive surgery.

Conclusion: Preoperative nutritional therapy is crucial for improving therapeutic outcomes in patients with oral cancer who require reconstructive surgery.
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http://dx.doi.org/10.1016/j.oooo.2022.01.009DOI Listing
August 2022

A rare genetic variant in the cleavage site of prepro-orexin is associated with idiopathic hypersomnia.

NPJ Genom Med 2022 Apr 12;7(1):29. Epub 2022 Apr 12.

Department of Neurology, Junwakai Memorial Hospital, Miyazaki, Japan.

Idiopathic hypersomnia (IH) is a rare, heterogeneous sleep disorder characterized by excessive daytime sleepiness. In contrast to narcolepsy type 1, which is a well-defined type of central disorders of hypersomnolence, the etiology of IH is poorly understood. No susceptibility loci associated with IH have been clearly identified, despite the tendency for familial aggregation of IH. We performed a variation screening of the prepro-orexin/hypocretin and orexin receptors genes and an association study for IH in a Japanese population, with replication (598 patients and 9826 controls). We identified a rare missense variant (g.42184347T>C; p.Lys68Arg; rs537376938) in the cleavage site of prepro-orexin that was associated with IH (minor allele frequency of 1.67% in cases versus 0.32% in controls, P = 2.7 × 10, odds ratio = 5.36). Two forms of orexin (orexin-A and -B) are generated from cleavage of one precursor peptide, prepro-orexin. The difference in cleavage efficiency between wild-type (Gly-Lys-Arg; GKR) and mutant (Gly-Arg-Arg; GRR) peptides was examined by assays using proprotein convertase subtilisin/kexin (PCSK) type 1 and PCSK type 2. In both PCSK1 and PCSK2 assays, the cleavage efficiency of the mutant peptide was lower than that of the wild-type peptide. We also confirmed that the prepro-orexin peptides themselves transmitted less signaling through orexin receptors than mature orexin-A and orexin-B peptides. These results indicate that a subgroup of IH is associated with decreased orexin signaling, which is believed to be a hallmark of narcolepsy type 1.
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http://dx.doi.org/10.1038/s41525-022-00298-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9005711PMC
April 2022

Labial Vestibular Flap Closure of the Cleft Palate Is Advantageous for Maxillary Development.

Cleft Palate Craniofac J 2022 Jan 19:10556656211065944. Epub 2022 Jan 19.

136081st Department of Oral and Maxillofacial Surgery, 314275Osaka University Graduate School of Dentistry, Suita, Japan.

Using labial vestibular flap was performed to close the primary alveolar and hard palate cleft at the second stage of early 2-stage closure surgery for unilateral cleft lip and palate for minimizing the damage to the maxillary periosteum. We analyzed maxillary development to clarify the influence of cleft palate surgery. : Retrospective longitudinal study in 5 years after primary palatal closure. Institutional study Patients: Study subjects included 214 patients with nonsyndromic complete unilateral cleft lip and palate who were consecutively treated in our clinic. : We used a 3D dental model scanner to assess maxillary development in patients aged 3 months to 5 years after using either the conventional pushback method (PB) (51 cases) or 2-stage closure (Local palatal flap closure: LF [67 cases] and Labial vestibular flap closure: VF [96 cases]). : Comparing the measurement results, the major axis of maxilla, width, intercanine distance, and intermolar distance was significantly larger in the LF group compared to the PB group. After the age of 3, the cleft side of VF group had grown significantly to compare with LF group in width. It was also confirmed that the inserted labial mucosal flap itself grew. Enlargement of the labial mucosal flap was observed at all sites except the canine. : Good maxillary growth occurred in the following order: VF groups > LF group > PB group. Poor growth was correlated with the extent of periosteal damage during surgery and the degree of postoperative bone surface exposure.
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http://dx.doi.org/10.1177/10556656211065944DOI Listing
January 2022

Functional assessment of miR‑1291 in colon cancer cells.

Int J Oncol 2022 Feb 4;60(2). Epub 2022 Jan 4.

Department of Molecular Pathology, Division of Health Sciences, Osaka University, Suita, Osaka 565‑0871, Japan.

miR‑1291 exerts an anti‑tumor effect in a subset of human carcinomas, including pancreatic cancer. However, its role in colorectal cancer (CRC) is largely unknown. In the present study, the expression and effect of miR‑1291 in CRC cells was investigated. It was identified that miR‑1291 significantly suppressed the proliferation, invasion, cell mobility and colony formation of CRC cells. Additionally, miR‑1291 induced cell apoptosis. A luciferase reporter assay revealed that miR‑1291 directly bound the 3'‑untranslated region sequence of doublecortin‑like kinase 1 (DCLK1). miR‑1291 also suppressed DCLK1 mRNA and protein expression in HCT116 cells that expressed DCLK1. Furthermore, miR‑1291 suppressed cancer stem cell markers BMI1 and CD133, and inhibited sphere formation. The inhibitory effects on sphere formation, invasion and mobility in HCT116 cells were also explored and verified using DCLK1 siRNAs. Furthermore, miR‑1291 induced CDK inhibitors p21 and p27 in three CRC cell lines, and the overexpression of DCLK1 in HCT116 cells led to a decrease of p21 and p27. Intravenous administration of miR‑1291 loaded on the super carbonate apatite delivery system significantly inhibited tumor growth in the DLD‑1 xenograft mouse model. Additionally, the resultant tumors exhibited significant upregulation of the p21 and p27 protein with treatment of miR‑1291. Taken together, the results indicated that miR‑1291 served an anti‑tumor effect by modulating multiple functions, including cancer stemness and cell cycle regulation. The current data suggested that miR‑1291 may be a promising nucleic acid medicine against CRC.
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http://dx.doi.org/10.3892/ijo.2022.5303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8759348PMC
February 2022

Matrix Metalloproteinases in Human Decidualized Endometrial Stromal Cells.

Curr Issues Mol Biol 2021 Nov 26;43(3):2111-2123. Epub 2021 Nov 26.

Department of Obstetrics and Gynecology, Kansai Medical University, Osaka 573-1010, Japan.

Cyclic changes, such as growth, decidualization, shedding, and regeneration, in the human endometrium are regulated by the reciprocal action of female hormones, such as estradiol (E), and progesterone (P). Matrix metalloproteases (MMPs) and tissue inhibitors of MMPs (TIMPs) control the invasion of extravillous trophoblast cells after implantation. Several MMPs and TIMPs function in the decidua and endometrial stromal cells (ESCs). Here, we aimed to systematically investigate the changes in MMPs and TIMPs associated with ESC decidualization. We evaluated the expression of 23 MMPs, four TIMPs, and four anti-sense non-coding RNAs from MMP loci. Primary ESC cultures treated with E + medroxyprogesterone acetate (MPA), a potent P receptor agonist, showed significant down-regulation of , , , , , and in decidualized ESCs, as assessed by quantitative reverse transcription PCR. Further, and were significantly upregulated in decidualized ESCs. siRNA-mediated silencing of Heart and Neural Crest Derivatives Expressed 2 (HAND2), a master transcriptional regulator in ESC decidualization, significantly increased expression in untreated human ESCs. These results collectively indicate the importance of and in ESC decidualization and highlight the role of HAND2 in repressing transcription, thereby regulating decidualization.
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http://dx.doi.org/10.3390/cimb43030146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8929033PMC
November 2021

Ras signaling and RREB1 are required for the dissociation of medial edge epithelial cells in murine palatogenesis.

Dis Model Mech 2022 02 15;15(2). Epub 2022 Feb 15.

Department of Orthodontics and Dentofacial Orthopedics, Osaka University Graduate School of Dentistry, Osaka 5650871, Japan.

Cleft palate is one of the major congenital craniofacial birth defects. The etiology underlying the pathogenesis of cleft palate has yet to be fully elucidated. Dissociation of the medial edge epithelium (MEE) at the contacting region of palatal shelves and subsequent migration or apoptosis of MEE cells is required for proper MEE removal. Ras-responsive element-binding protein 1 (RREB1), a RAS transcriptional effector, has recently been shown to play a crucial role in developmental epithelial-mesenchymal transition (EMT), in which loss of epithelial characteristics is an initial step, during mid-gastrulation of embryonic development. Interestingly, the involvement of RREB1 in cleft palate has been indicated in humans. Here, we demonstrated that pan-Ras inhibitor prevents the dissociation of MEE during murine palatal fusion. Rreb1 is expressed in the palatal epithelium during palatal fusion, and knockdown of Rreb1 in palatal organ culture resulted in palatal fusion defects by inhibiting the dissociation of MEE cells. Our present findings provide evidence that RREB1-mediated Ras signaling is required during palatal fusion. Aberrant RREB1-mediated Ras signaling might be involved in the pathogenesis of cleft palate.
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http://dx.doi.org/10.1242/dmm.049093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8862740PMC
February 2022

Efficient cell transplantation combining injectable hydrogels with control release of growth factors.

Regen Ther 2021 Dec 25;18:372-383. Epub 2021 Sep 25.

Laboratory of Biomaterials, Department of Regeneration Science and Engineering, Institute for Frontier Life and Medical Sciences, Kyoto University, 53 Kawara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.

Introduction: The objective of this study is to investigate the effect of gelatin microspheres incorporating growth factors on the therapeutic efficacy in cell transplantation. The strength of this study is to combine gelatin hydrogel microspheres incorporating basic fibroblast growth factor and platelet growth factor mixture (GM/GF) with bioabsorbable injectable hydrogels (iGel) for transplantation of adipose-derived stem cells (ASCs).

Methods: The rats ASCs suspended in various solutions were transplanted in masseter muscle. Rats were euthanized 2, 7, 14 days after injection for measurement of the number of ASCs retention in the muscle and morphological evaluation of muscle fibers and the inflammation of the injected tissue by histologic and immunofluorescent stain.

Results: Following the injection into the skeletal muscle, the GM/GF allowed the growth factors to release at the injection site over one week. When ASCs were transplanted into skeletal muscle using iGel incorporating GM/GF (iGel+GM/GF), the number of cells grafted was significantly high compared with other control groups. Moreover, for the groups to which GM/GF was added, the cells transplanted survived, and the Myo-D expression of a myoblast marker was observed at the region of cells transplanted.

Conclusions: The growth factors released for a long time likely enhance the proliferative and differentiative capacity of cells. The simple combination with iGel and GM/GF allowed ASCs to enhance their survival at the injected site and consequently achieve improved therapeutic efficacy in cell transplantation.
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http://dx.doi.org/10.1016/j.reth.2021.09.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8479297PMC
December 2021

Osteopontin-derived synthetic peptide SVVYGLR upregulates functional regeneration of oral and maxillofacial soft-tissue injury.

Jpn Dent Sci Rev 2021 Nov 28;57:174-181. Epub 2021 Sep 28.

The 1st Department of Oral and Maxillofacial Surgery, Graduate School of Dentistry, Osaka University, Osaka, Japan.

Wound healing in the oral and maxillofacial region is a complicated and interactive process. Severe mucosal or skeletal muscle injury by trauma or surgery induces worse healing conditions, including delayed wound closure and repair with excessive scar tissue. These complications lead to persistent functional impairment, such as digestive behavior or suppression of maxillofacial growth in infancy. Osteopontin (OPN), expressed in a variety of cells, is multifunctional and comprises a number of functional domains. Seven amino acids sequence, SVVYGLR (SV peptide), exposed by thrombin cleavage of OPN, has angiogenic activity and promotes fibroblast differentiation into myofibroblasts and increased expression of collagen type III. Additionally, synthetic SV peptide shows faster dermal and oral mucosal wound closure by facilitating cell motility and migratory activities in dermal- or mucosal-derived keratinocytes and fibroblasts. Moreover, cell motility and differentiation in myogenic cell populations are accelerated by SV peptide, which contributes to the facilitation of matured myofibers and scarless healing and favorable functional regeneration after skeletal muscle injury. SV peptide has high affinity with TGF-β, with potential involvement of the TGF-β/Smad signaling pathway. Clinical application of single-dose SV peptide could be a powerful alternative treatment option for excessive oral and maxillofacial wound care to prevent disadvantageous events.
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http://dx.doi.org/10.1016/j.jdsr.2021.09.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8487951PMC
November 2021

Transcriptional regulation of LGALS9 by HAND2 and FOXO1 in human endometrial stromal cells in women with regular cycles.

Mol Hum Reprod 2021 11;27(11)

Department of Obstetrics and Gynecology, Kansai Medical University, Hirakata, Osaka, Japan.

Uterine natural killer cells are regulated via surface inhibitory receptors for IL15 and galectin-9 (LGALS9) secreted by endometrial stromal cells (ESCs). However, the mechanism that regulates LGALS9 mRNA levels in ESCs is unclear. The aim of this study is to clarify the transcriptional regulation of LGALS9 in ESCs. Here, LGALS9 mRNA expression levels significantly decreased in the endometrial tissue in the early- to mid-secretory phase, and recovered in the mid- to late-secretory phase, compared to that in the proliferative phase. In ESCs, LGALS9 mRNA expression significantly decreased following estradiol + medroxyprogesterone acetate treatment for 1 day and increased after 12 days compared to that in the control. The transcriptional activity of the LGALS9 upstream region was upregulated by heart and neural crest derivatives expressed 2 (HAND2) and downregulated by forkhead box O1 (FOXO1). In ESCs, HAND2 expression significantly increased throughout the 12 days treatment with steroid hormones, whereas FOXO1 expression significantly increased on Day 1, reached a plateau, and significantly increased again after 6 days of treatment. Levels of FOXO1 phosphorylation (pFOXO1) remained unchanged after a 3-day treatment of ESCs with steroid hormones, but significantly increased following a 12-day treatment. pFOXO1 could not bind to the DNA and was thus unable to directly suppress LGALS9 transcription. Therefore, expression level of HAND2 and phosphorylation status of FOXO1 may determine LGALS9 mRNA expression. This study provides a novel molecular mechanism underlying the transcriptional regulation of LGALS9 mRNA in ESCs, which could be valuable in the treatment of diseases associated with decidualization failure.
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http://dx.doi.org/10.1093/molehr/gaab063DOI Listing
November 2021

Distribution, fine structure, and three-dimensional innervation of lamellar corpuscles in rat plantar skin.

Cell Tissue Res 2021 Dec 25;386(3):477-490. Epub 2021 Sep 25.

Department of Anatomy, Meiji University of Integrative Medicine, Nantan City, Kyoto, Japan.

Lamellar corpuscles function as mechanoreceptors in the skin, composed of axon terminals and lamellae constructed by terminal Schwann cells. They are classified into Pacinian, Meissner, and simple corpuscles based on histological criteria. Lamellar corpuscles in rat dermal papilla cells have been reported; however, the morphological aspects have yet to be thoroughly investigated. In the present study, we analyzed the enzyme activity, distribution, fine structure, and three-dimensional innervation of lamellar corpuscles in rat plantar skin. The lamellar corpuscles exhibiting non-specific cholinesterase were densely distributed in rat footpads, evident as notable skin elevations, especially at the apex, the highest portion of the ridges in each footpad. In contrast, only a few lamellar corpuscles were found in other plantar skin areas. Lamellar corpuscle was considered composed of a flat axon terminal Schwann cell lamellae, which were roughly concentrically arranged in the dermal papilla. These histological characteristics correspond to those of the simple corpuscle. Moreover, the axon tracing method revealed that one trunk axon innervated several simple corpuscles. The territory of the trunk axons overlapped with each other. Finally, the animals' footprints were analyzed. During the pausing and walking phases, footpads are often in contact with the floor. These results demonstrate that the type of lamellar corpuscles in the dermal papillae of rat plantar skin is a simple corpuscle and implies that their distribution pattern in the plantar skin is convenient for efficient sensing and transmission of mechanical stimuli from the ground.
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http://dx.doi.org/10.1007/s00441-021-03525-5DOI Listing
December 2021

A Novel Surgical Approach for the Successful Removal of Overextruded Separated Endodontic Instruments.

J Endod 2021 Dec 3;47(12):1942-1946. Epub 2021 Sep 3.

The 1st Department of Oral and Maxillofacial Surgery, Osaka University Graduate School of Dentistry, Suita, Osaka, Japan.

Endodontic procedures can result in various complications. Separation of the endodontic instrument is a common complication of incorrect use or overuse of the instrument. However, a separated endodontic instrument may hinder cleaning and shaping during endodontic treatment procedures, which can potentially impact prognosis. Therefore, it is necessary to manage this complication by removal of the separated instruments from inside the root canal. Although several devices are used, nonsurgical removal for retreatment remains difficult. We report the case of a failed attempt to manage a separated endodontic instrument nonsurgically by a private dentist, which resulted in extrusion of the instrument beyond the root apex and its migration into the mandible. We describe a novel surgical approach involving intentional tooth replantation combined with alveolar osteotomy. There have been few reports on the management of separated endodontic instruments that were pushed out beyond the root apex. Our novel surgical approach suggests a technique for the potential removal of a separated endodontic instrument extruded beyond the root apex.
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http://dx.doi.org/10.1016/j.joen.2021.08.012DOI Listing
December 2021

Cpeb1 expression is post-transcriptionally regulated by AUF1, CPEB1, and microRNAs.

FEBS Open Bio 2022 01 8;12(1):82-94. Epub 2021 Nov 8.

Department of Anatomy, Kansai Medical University, Hirakata, Japan.

Cytoplasmic polyadenylation element binding protein 1 (CPEB1) regulates the translation of numerous mRNAs. We previously showed that AU-rich binding factor 1 (AUF1) regulates Cpeb1 expression through the 3' untranslated region (3'UTR). To investigate the molecular basis of the regulatory potential of the Cpeb1 3'UTR, here we performed reporter analyses that examined expression levels of Gfp reporter mRNA containing the Cpeb1 3'UTR. Our findings indicate that CPEB1 represses the translation of Cpeb1 mRNA and that miR-145a-5p and let-7b-5p are involved in the reduction in Cpeb1 expression in the absence of AUF1. These results suggest that Cpeb1 expression is post-transcriptionally regulated by AUF1, CPEB1, and microRNAs.
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http://dx.doi.org/10.1002/2211-5463.13286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8727934PMC
January 2022

Various Stacking Patterns of Two-Dimensional Molecular Assemblies in Hydrogen-Bonded Cocrystals: Insight into Competitive Intermolecular Interactions and Control of Stacking Patterns.

Angew Chem Int Ed Engl 2021 Oct 9;60(42):22839-22848. Epub 2021 Sep 9.

Division of Chemistry, Graduate School of Science, Kyoto University, Kitashirakawa-Oiwakecho, Sakyo-ku, Kyoto, 606-8502, Japan.

Control over the stacking patterns in 2D molecular assemblies is demonstrated using chemical modification. A target system is a hydrogen-bonded cocrystal (2:1) composed of 2-pyrrolidone (Py) and chloranilic acid (CA) (PyCA). X-ray crystallography showed that weak intersheet interactions give rise to a variety of metastable overlapping patterns comprised of the 2D assemblies mainly formed via hydrogen bonds, affording reversible and irreversible structural phase transitions. We prepared cocrystals of Py and anilic acids bearing different halogens, in which 2D assemblies isostructural with those observed in PyCA exhibit various overlapping patterns. The order of stability for each overlapping pattern estimated using calculations of the intermolecular interactions did not completely coincide with those indicated by our experimental results, which can be explained by considering the entropic effect: the molecular motion of Py as detected using nuclear quadrupole resonance spectroscopy.
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http://dx.doi.org/10.1002/anie.202107784DOI Listing
October 2021

Diarsine- vs diphosphine-protected Au clusters: Effect of subtle geometric differences on optical property and electronic structure.

J Chem Phys 2021 Aug;155(5):054301

Graduate School of Environmental Science, Hokkaido University, North 10 West 5, Sapporo 060-0810, Japan.

In the design of ligand-protected metal clusters, the choice of protecting ligands is a critical factor because they can profoundly affect the nuclearity, geometry, and electronic structures to afford a diverse range of cluster compounds. Here, we report the synthesis of two novel diarsine-protected Au clusters ([AuLCl], L = diarsine) and compare these clusters with diphosphine analogs in terms of the core geometry and optical properties. In the crystal structure, the cluster bearing C3-bridged diarsines {[Au(dpap)Cl], 3} had an apparently identical icosahedral Au core to [Au(dppe)Cl] (1) with C2-bridged diphosphines, but slight structural differences associated with the bridging unit of the ligands were found. Despite similar icosahedral Au cores 1 and 3, their absorption and photoluminescence profiles were evidently different. Theoretical calculations revealed that the subtle deformation of the Au icosahedron, rather than the coordinating atoms (As or P), notably influences the electronic structure to cause the difference in the absorption profiles.
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http://dx.doi.org/10.1063/5.0059607DOI Listing
August 2021

Progression of melanoma is suppressed by targeting all transforming growth factor‑β isoforms with an Fc chimeric receptor.

Oncol Rep 2021 Sep 23;46(3). Epub 2021 Jul 23.

Department of Biochemistry, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Bunkyo, Tokyo 113‑8549, Japan.

Melanoma is an aggressive type of cancer originating from the skin that arises from neoplastic changes in melanocytes. Transforming growth factor‑β (TGF‑β) is a pleiotropic cytokine and is known to contribute to melanoma progression by inducing the epithelial‑mesenchymal transition (EMT) program and creating an environment that favors tumor progression. There are three TGF‑β isoforms, TGF‑β1, TGF‑β2 and TGF‑β3, all of which engage in pro‑tumorigenic activities by activating SMAD signaling pathways. All TGF‑β isoforms activate signaling pathways by binding to their TGF‑β type I (TβRI) and type II (TβRII) receptors. Thus, effective targeting of all TGF‑β isoforms is of great importance. In the present study, chimeric proteins comprising the extracellular domains of TβRI and/or TβRII fused with the Fc portion of human immunoglobulin (IgG) were validated in the melanoma context. The Fc chimeric receptor comprising both TβRI and TβRII (TβRI‑TβRII‑Fc) effectively trapped all TGF‑β isoforms. Conversely, TβRII‑Fc chimeric receptor, that comprises TβRII only, was able to interact with TGF‑β1 and TGF‑β3 isoforms, but not with TGF‑β2, which is a poor prognostic factor for melanoma patients. Accordingly, it was revealed that TβRI‑TβRII‑Fc chimeric receptor suppressed the EMT program in melanoma cells induced by any of the three TGF‑β isoforms, as revealed by decreased expression of mesenchymal markers. Conversely, TβRII‑Fc chimeric receptor inhibited the EMT program induced by TGF‑β1 and TGF‑β3. In addition, it was established that tumor growth in subcutaneous mouse melanoma was inhibited by TβRI‑TβRII‑Fc chimeric receptor indicating that Fc chimeric receptor could be applied to modify the tumor microenvironment (TME) of melanoma. Therefore, designing of Fc chimeric receptors targeting TGF‑β signals that affect various components of the TME may result in the development of effective anti‑melanoma agents.
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http://dx.doi.org/10.3892/or.2021.8148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8317165PMC
September 2021

Membrane excitabilities in neonatal rat mesencephalic trigeminal neurons under dietary zinc deficiency.

J Oral Sci 2021 Jun 13;63(3):242-246. Epub 2021 May 13.

First Department of Oral and Maxillofacial Surgery, Graduate School of Dentistry, Osaka University.

Purpose: The present study aimed to evaluate the effects of zinc deprivation on the properties of membrane and spike-discharge features of mesencephalic trigeminal neurons (MTNs), which are important sensory neurons for oral-motor reflexes and rhythmical jaw movements.

Methods: Neonatal Sprague Dawley rats (P10-12) were distributed equally into a normal diet group and a zinc-deficient diet (ZD) group. Whole cell patch-clamp recordings were obtained from MTNs from coronal brain slices.

Results: Passive membrane properties showed a modest depolarized membrane potential and decreased cell capacitance in the ZD group. Zinc deprivation decreased the minimal current amplitude, which induced an action potential and increased the amplitude of afterhyperpolarization following the action potential. Negligible changes were observed for other action potential properties. A decreased burst duration was observed, accompanied by hastened spike frequency adaptation in the burst discharge. There was no difference in the resonant properties at both the subthreshold depolarized potential and hyperpolarized membrane potential between the control and ZD groups.

Conclusion: These results suggests that neither the persistent sodium conductance nor slow inwardly rectifying conductance were altered; however, there appeared to be an increase in Ca-dependent K conductance in zincdeficient MTNs.
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http://dx.doi.org/10.2334/josnusd.20-0566DOI Listing
June 2021

Salivary duct carcinoma of the submandibular gland presenting a diagnostic challenge: A case report.

World J Clin Cases 2021 Apr;9(12):2908-2915

First Department of Oral and Maxillofacial Surgery, Osaka University Graduate School of Dentistry, Suita 565-0871, Osaka, Japan.

Background: Salivary duct carcinoma (SDC) is a rare, extremely aggressive malignancy that arises in the submandibular gland. It can metastasize locally early and therefore is an important differential diagnosis of metastatic disease in cervical lymph nodes or specific lymphadenitis such as tuberculous cervical lymphadenitis.

Case Summary: We report a case of SDC in the submandibular gland that presented diagnostic difficulty. The lesion was coincidentally discovered through examination of the radiolucent area of the maxilla. Imaging failed to confirm the possibility of specific inflammation, leading us to execute an open biopsy to verify the diagnosis. The surgical specimen showed that the submandibular gland was primarily replaced with a calcified body. Following histological analysis and confirmation, we performed surgical resection, radiotherapy, and various chemotherapies.

Conclusion: Radiographic imaging characteristics of lymph node metastases of salivary gland cancer, especially of SDC, may resemble other cervical lymphadenitis; calcification at the submandibular gland is the landmark of SDC occurring at the subman-dibular gland.
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http://dx.doi.org/10.12998/wjcc.v9.i12.2908DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8058683PMC
April 2021

Primary Alveolar Soft Part Sarcoma of Cheek: Report of a Case and Review of the Literature.

Head Neck Pathol 2021 Dec 11;15(4):1426-1431. Epub 2021 Apr 11.

Department of Oral Pathology, Osaka University Graduate School of Dentistry, 1-8 Yamadaoka, Suita, Osaka, 565-0871, Japan.

Alveolar soft part sarcoma (ASPS) is a rare soft tissue sarcoma characterized by an alveolar or organoid arrangement of polygonal tumour cells separated by fibrovascular septa. A specific fusion gene [ASPS critical region 1 (ASPSCR1)-TFE3] was detected in ASPS. Despite being a slow-growing tumour without pain and dysfunction, ASPS is characterized by early metastasis, which leads to poor prognosis. Herein, we report a rare case of primary ASPS of the cheek harbouring ASPSCR1 (exon 7)-TFE3 (exon 5) fusion gene in a 21 year-old woman. This tumour was a well-circumscribed, smooth, round mass that was clinically suspected as a benign tumour. However, histologically, it was observed that the polygonal tumour cells were arranged in solid and alveolar growth patterns. Post-operative examination of the whole body excluded the possibility of metastasis at other sites. Thus, careful immunohistochemical and genetic analyses, as well as whole-body examination, demonstrated that the tumour was a primary ASPS of the cheek.
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http://dx.doi.org/10.1007/s12105-021-01324-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8633199PMC
December 2021

Persistent sodium conductance contributes to orexin-A-mediated modulation of membrane excitability in neonatal rat mesencephalic V neurons.

Neurosci Lett 2021 05 24;753:135846. Epub 2021 Mar 24.

First Department of Oral and Maxillofacial Surgery, Graduate School of Dentistry, Osaka University, 1-8 Yamadaoka, Suita, Osaka, 565-0871, Japan.

Orexins are multifunctional hypothalamic neuropeptides that participate in the stimulation of feeding behavior and energy expenditure. However, little is known about their neuromodulatory effects in lower brainstem effector regions, including in the trigeminal neuronal system. The aim of this study was to examine the effects of orexin-A (Ox-A) on the membrane properties of mesencephalic trigeminal (Mes V) neurons that are critically involved in the generation and control of rhythmical oral motor activities. Whole-cell patch clamp recordings were obtained from Mes V neurons in coronal brain slices prepared from Sprague-Dawley rats (postnatal day 12-17). Bath application of Ox-A (100 nM) shortened the duration of the after-hyperpolarization following the action potential, while the interspike frequency of firings during repetitive discharge increased, together with a shift in the frequency-current relationship toward the left. In addition, Ox-A amplified the resonance at the depolarized membrane potential, accompanied with an increase in both Q-value and resonant frequency. A further voltage-clamp experiment demonstrated that Ox-A increased the peak current density of the persistent sodium current (I) and shifted its activation curve to the hyperpolarization direction. These results suggested that Ox-A may increase Mes V neuronal excitability by enhancing I, possibly sharing a common mechanism with another orexigenic hypothalamic neuropeptide, neuropeptide Y.
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http://dx.doi.org/10.1016/j.neulet.2021.135846DOI Listing
May 2021

The synthetic peptide SVVYGLR promotes myogenic cell motility via the TGFβ1/Smad signaling pathway and facilitates skeletal myogenic differentiation in vitro.

Dent Mater J 2021 Jul 13;40(4):957-963. Epub 2021 Mar 13.

The 1st Department of Oral and Maxillofacial Surgery, Graduate School of Dentistry, Osaka University.

In the present study, we investigated the possible involvement of the TGF-β/Smad signaling pathway in the osteopontin-derived SVVYGLR (SV) peptide-mediated migratory activities of myogenic cells and evaluated the facilitative effects of the SV peptide on the differentiation of myogenic cells in vitro. The SV peptide-induced migration in both human-derived satellite cells and myoblasts was substantially suppressed by the TGF-β1 receptor inhibitor SB431542 or SB505124. Besides, the expression level of the Smad3 phosphorylation was further enhanced by the addition of the SV peptide in comparison with control groups. Furthermore, an increase in the expression of myogenin-positive nuclei and a higher number of nascent myotubes with myosin heavy chain expression was confirmed in cultured myoblasts supplemented with the SV peptide. These results suggest that the involvement of the TGF-β/Smad signaling pathway in the SV peptide-mediated migration and the facilitative effect of the SV peptide on the differentiation of myogenic cells into myotubes.
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http://dx.doi.org/10.4012/dmj.2020-354DOI Listing
July 2021

Validity of the combined use of two esthetic rating systems, the infant index and 5-point aesthetic index, for pre- and postsurgical evaluation of cleft lip repair.

J Craniomaxillofac Surg 2021 Apr 24;49(4):304-311. Epub 2020 Sep 24.

The 1st Department of Oral and Maxillofacial Surgery, Osaka University Graduate School of Dentistry, 1-8 Yamadaoka, Suita, Osaka, 565-0871, Japan.

Objective: The present study was designed to investigate the usefulness of combining two different ordinal scaling indices, infant index (I-I) and 5-point aesthetic index (5-PAI), for the assessment and prediction of esthetic outcome of primary lip repair for patients with unilateral cleft lip.

Materials And Methods: The nasolabial appearance of the patients was evaluated before primary lip repair and at 5 years of age using cropped facial photographs with frontal and oblique views. The I-I and 5-PAI employ expanded reference photographs and objective esthetic variables for judgment.

Results: The inter- and intrarater Kappa values of both I-I and 5-PAI demonstrated good to very good agreement (range: 0.74-0.84 for I-I and 0.62-0.77 for 5-PAI). Furthermore, both the declination of the columella and the deformity of the alar cartilage in I-I showed a correlation with nasal rating score of 5-PAI and were identified as predictable independent parameters (declination of the columella: Rs = 0.37, P = 0.04; deformity of the alar cartilage: Rs = 0.35, P = 0.02).

Conclusion: The combined use of I-I and 5-PAI with expanded reference photographs and objective variables could be useful for obtaining greater accuracy of the esthetic assessment and predicting postsurgical nasolabial esthetics at infancy.
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http://dx.doi.org/10.1016/j.jcms.2020.09.009DOI Listing
April 2021

The synthetic peptide SVVYGLR promotes cell motility of myogenic cells and facilitates differentiation in skeletal muscle regeneration.

Dent Mater J 2021 May 10;40(3):766-771. Epub 2021 Mar 10.

The 1st Department of Oral and Maxillofacial Surgery, Graduate School of Dentistry, Osaka University.

The present study was designed to evaluate the effects of the osteopontin-derived multifunctional short peptide, SVVYGLR (SV) peptide on the biological properties of skeletal muscle-specific myogenic cells. We employed human-derived satellite cells (HSkMSC) and skeletal muscle myoblasts (HSMM) and performed a series of biochemical experiments. The synthetic SV peptide showed no influence on the proliferation and adhesion properties of HSkMSC and HSMM, while it showed a significant increase in cell motility, including migration activities upon treatment with the SV peptide. In a rat model with volumetric loss of masticatory muscle, immunohistochemical staining of regenerating muscle tissue immediately after injury demonstrated an increase of the number of both MyoD- and myogenin-positive cells in SV peptide-treated group. These results suggest that SV peptide plays a potent role in facilitating skeletal muscle regeneration by promoting the migration, and differentiation of myogenic precursor and progenitor cells.
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http://dx.doi.org/10.4012/dmj.2020-317DOI Listing
May 2021

Crossover of Rate-Limiting Process in Plasma Gel Growth by Contact with Source of Gelator.

Gels 2021 Jan 28;7(1). Epub 2021 Jan 28.

Division of Molecular Science, Graduate School of Science and Technology, Gunma University, Kiryu 376-8515, Gunma, Japan.

Plasma is regarded as a solution of precursor polymers specifically transformed to gel-forming polymers by a reaction with initiators. We developed a theory for the gel growth dynamics of plasma induced by contact with a source of gelators that are yielded by the initiation. In developing the theory, we combined the Ginzburg-Landau type dynamics with the gelator diffusion dynamics expressed by the moving boundary picture. The theory predicts the crossover of the rate-limiting process in the time course of the thickness of the gel layer from the energy-limited process expressed by X∼t to the diffusion-limited process expressed by X∼t, where is the time elapsed from when the plasma comes into contact with the source of gelators. A demonstration experiment was performed by placing a tissue factor coating plate as the initiator in plasma. Log-log plot of vs. showed a crossover as predicted by the theory, and the parameters characterizing plasma were determined.
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http://dx.doi.org/10.3390/gels7010011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7931059PMC
January 2021

Immune Tolerance of the Human Decidua.

J Clin Med 2021 Jan 18;10(2). Epub 2021 Jan 18.

Department of Obstetrics and Gynecology, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka 573-1010, Japan.

The endometrium is necessary for implantation, complete development of the placenta, and a successful pregnancy. The endometrium undergoes repeated cycles of proliferation, decidualization (differentiation), and shedding during each menstrual cycle. The endometrium-including stromal, epithelial, vascular endothelial, and immune cells-is both functionally and morphologically altered in response to progesterone, causing changes in the number and types of immune cells. Immune cells make up half of the total number of endometrial cells during implantation and menstruation. Surprisingly, immune tolerant cells in the endometrium (uterine natural killer cells, T cells, and macrophages) have two conflicting functions: to protect the body by eliminating pathogenic microorganisms and other pathogens and to foster immunological change to tolerate the embryo during pregnancy. One of the key molecules involved in this control is the cytokine interleukin-15 (IL-15), which is secreted by endometrial stromal cells. Recently, it has been reported that IL-15 is directly regulated by the transcription factor heart- and neural crest derivatives-expressed protein 2 in endometrial stromal cells. In this review, we outline the significance of the endometrium and immune cell population during menstruation and early pregnancy and describe the factors involved in immune tolerance and their involvement in the establishment and maintenance of pregnancy.
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http://dx.doi.org/10.3390/jcm10020351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7831321PMC
January 2021

2,3-Diarylbenzo[b]arsole: Structural Modification and Polymerization for Tuning of Photophysical Properties.

Chemistry 2021 Mar 9;27(14):4676-4682. Epub 2021 Feb 9.

Faculty of Molecular Chemistry and Engineering, Graduate School of, Science and Technology, Kyoto Institute of Technology, Goshokaido-cho, Matsugasaki, Sakyo-ku, Kyoto, 606-8585, Japan.

2,3-Diarylbenzo[b]arsoles were synthesized from zirconacycles and diiodophenylarsine. The structural modification to the luminophore was attained through diarylacetylene precursors, Suzuki-Miyaura coupling, and oxidation of the arsenic atom. The emission properties were controlled according to these modifications. The 2,3-diarylbenzo[b]arsoles showed aggregation-induced emission enhancement; the stronger emission was observed in the solid states than in solutions. In addition, Suzuki-Miyaura polycondensation and olefin metathesis polymerization produced main- and side-chain polymers, respectively. The resultant polymers showed different emission behaviors such as aggregation caused quenching and aggregation induced emission enhancement.
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http://dx.doi.org/10.1002/chem.202005001DOI Listing
March 2021

AUF1, an mRNA decay factor, has a discordant role in Cpeb1 expression.

Biochem Biophys Res Commun 2021 01 19;534:491-497. Epub 2020 Nov 19.

Department of Anatomy, Kansai Medical University, Hirakata, Osaka, 573-1010, Japan.

Cytoplasmic polyadenylation element binding protein 1 (CPEB1) regulates polyadenylation and subsequent translation of CPE-containing mRNAs involved in various physiological and pathological phenomena. Although the significance of CPEB1-mediated translational regulation has recently been reported, the detailed regulatory mechanism of Cpeb1 expression remains unclear. To elucidate the post-transcriptional regulatory mechanisms of Cpeb1 expression, we constructed reporter plasmids containing various deletions or mutations in the Cpeb1 mRNA 3' untranslated region (3'UTR). We investigated their expression levels in Neuro2a neuroblastoma cells. We found that Cpeb1 expression is regulated through an AU-rich element in its 3'UTR. Furthermore, the mRNA decay factor AU-rich binding factor 1 (AUF1) regulates Cpeb1 expression, and knockdown of AUF1 upregulates Cpeb1 mRNA expression but results in a decrease in CPEB1 protein levels. These findings indicate that AUF1 has a discordant role in the expression of Cpeb1.
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http://dx.doi.org/10.1016/j.bbrc.2020.11.054DOI Listing
January 2021
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