Publications by authors named "Shunsuke Sawada"

25 Publications

  • Page 1 of 1

Relationship between tooth extraction and development of medication-related osteonecrosis of the jaw in cancer patients.

Sci Rep 2021 Aug 26;11(1):17226. Epub 2021 Aug 26.

Department of Oral Health, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8588, Japan.

Tooth extraction has been avoided since it has been considered a major risk factor for medication-related osteonecrosis of the jaw (MRONJ). However, MRONJ may also develop from tooth that is an infection source. This study aimed to clarify whether tooth extraction is a risk factor for the development of MRONJ in cancer patients receiving bone-modifying agents (BMAs). This retrospective observational study included 189 patients (361 jaws) from two hospitals. The risk factors of MRONJ were identified by comparing patient characteristics between those who did and did not develop MRONJ. Furthermore, the effect of tooth extraction during BMA therapy was analyzed after adjusting for confounding factors using the propensity score matching method. MRONJ occurred in 33 patients jaws. A longer duration of BMA administration, fewer number of teeth, presence of symptoms of local infection, and infected teeth were independent risk factors of MRONJ. However, tooth extraction during BMA therapy did not increase the risk. Propensity score matching analysis showed that tooth extraction significantly lowered the risk of MRONJ development. Teeth that can be an infection source increases the risk of MRONJ, and thus, they need to be extracted even during BMA administration.
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http://dx.doi.org/10.1038/s41598-021-96480-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8390686PMC
August 2021

Surgical strategy for medication-related osteonecrosis of the jaw (MRONJ) on maxilla: A multicenter retrospective study.

J Dent Sci 2021 Jul 31;16(3):885-890. Epub 2020 Dec 31.

Department of Clinical Oral Oncology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.

Background/purpose: Because the anatomy and the nature of the bone tissue between the mandible and maxilla are largely different, more site-specific studies are required to improve the healing rate on medication-related osteonecrosis of the jaw (MRONJ). The present study assessed maxillary MRONJ that was treated by surgery to understand its clinical characteristics, and to identify critical factors that influenced outcomes.

Materials And Methods: The medical records of 54 patients with maxillary MRONJ who underwent surgery were retrospectively reviewed. Variables related to the prognosis of MRONJ were extracted from the medical records and imaging, and were statistically analyzed. We also evaluated the concomitant maxillary sinusitis (MS) after the surgical treatment of MRONJ, based on CT evaluation and change of symptoms.

Results: The healing rate of surgery for maxillary MRONJ was 85.2%, which suggested that surgical treatment is an effective strategy for treating maxillary MRONJ. Multivariate analysis revealed that postoperative residual necrotic bone was a poor prognosticator for maxillary MRONJ. Among 10 patients who did not obtain healing of MS postoperatively, 8 patients showed an improvement.

Conclusion: Our results indicate that surgical treatment is an appropriate strategy for maxillary MRONJ and complete resection of necrotic bone (i.e., extensive surgery) is needed to obtain complete healing of maxillary MRONJ. Concomitant MS tends to be healed or improved clinically in combination with the healing of maxillary MRONJ.
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http://dx.doi.org/10.1016/j.jds.2020.12.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8189890PMC
July 2021

Periosteal reaction of medication-related osteonecrosis of the jaw (MRONJ): clinical significance and changes during conservative therapy.

Support Care Cancer 2021 Apr 21. Epub 2021 Apr 21.

Department of Oral Health, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8588, Japan.

Purpose: We previously reported that the periosteal reaction (PR) in medication-related osteonecrosis of the jaw (MRONJ) is a poor prognostic factor in surgical cases, but it is not clear how PR changes during conservative therapy. The purpose of this retrospective study was to compare computed tomography (CT) findings at the first visit and during follow-up visits in MRONJ patients subjected to conservative therapy and to investigate factors associated with the exacerbation of PR during conservative therapy.

Methods: Sixteen patients with MRONJ of the lower jaw who underwent conservative therapy and experienced a PR on CT images at the first visit and underwent CT examination again after 6 months or more were enrolled in the study. Clinical features and CT findings (extent of osteolytic lesion, extent of PR, type of PR, and changes during conservative treatment) were investigated.

Results: On the second CT scan, the osteolytic lesion improved in 4 patients, had not changed in 5, and deteriorated in 7, whereas the PR improved in 5 patients, had not changed in 4, and deteriorated in 7 patients. PR was significantly deteriorated in patients who continued to receive antiresorptive agents during conservative treatment and in patients with deteriorated osteolytic lesions.

Conclusion: PR in MRONJ often expands during conservative therapy and the PR type progresses from the attached type to the gap type, and the irregular type, but discontinuation of antiresorptive agent may improve PR as well as osteolytic lesions.
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http://dx.doi.org/10.1007/s00520-021-06214-9DOI Listing
April 2021

The multiple functions and subpopulations of eosinophils in tissues under steady-state and pathological conditions.

Allergol Int 2021 Jan 24;70(1):9-18. Epub 2020 Nov 24.

Department of Otolaryngology, Head and Neck Surgery, Kansai Medical University, Osaka, Japan.

Eosinophils not only play a critical role in the pathogenesis of eosinophil-associated diseases, but they also have multiple important biological functions, including the maintenance of homeostasis, host defense against infections, immune regulation through canonical Th1/Th2 balance modulation, and anti-inflammatory and anti-tumorigenic activities. Recent studies have elucidated some emerging roles of eosinophils in steady-state conditions; for example, eosinophils contribute to adipose tissue metabolism and metabolic health through alternatively activated macrophages and the maintenance of plasma cells in intestinal tissue and bone marrow. Moreover, eosinophils exert tissue damage through eosinophil-derived cytotoxic mediators that are involved in eosinophilic airway inflammation, leading to diseases including asthma and chronic rhinosinusitis with nasal polyps characterized by fibrin deposition through excessive response by eosinophils-induced. Thus, eosinophils possessing these various effects reflect the heterogenous features of these cells, which suggests the existence of distinct different subpopulations of eosinophils between steady-state and pathological conditions. Indeed, a recent study demonstrated that instead of dividing eosinophils by classical morphological changes into normodense and hypodense eosinophils, murine eosinophils from lung tissue can be phenotypically divided into two distinct subtypes: resident eosinophils and inducible eosinophils gated by Siglec-F CD62L CD101 and Siglec-F CD62L CD101, respectively. However, it is difficult to explain every function of eosinophils by rEos and iEos, and the relationship between the functions and subpopulations of eosinophils remains controversial. Here, we overview the multiple roles of eosinophils in the tissue and their biological behavior in steady-state and pathological conditions. We also discuss eosinophil subpopulations.
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http://dx.doi.org/10.1016/j.alit.2020.11.001DOI Listing
January 2021

Protein-recruiting synthetic molecules targeting the Golgi surface.

Chem Commun (Camb) 2020 Dec 25;56(98):15422-15425. Epub 2020 Nov 25.

Department of Nanopharmaceutical Sciences, Graduate School of Engineering, Nagoya Institute of Technology, Gokiso-cho, Showa-ku, Nagoya 466-8555, Japan.

Organelle-localizable small-molecule ligands are valuable tools for spatiotemporally controlling protein localization and signaling processes in living cells. Here, we present synthetic ligands that specifically localize to the Golgi surface. The ligands can rapidly recruit their target proteins from the cytoplasm to the Golgi and be applied to manipulate signaling proteins and lipids on the Golgi membrane, offering a new useful chemical tool for the study and control of Golgi/cell functions.
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http://dx.doi.org/10.1039/d0cc06908fDOI Listing
December 2020

Combination therapy with lenvatinib and radiation significantly inhibits thyroid cancer growth by uptake of tyrosine kinase inhibitor.

Exp Cell Res 2021 01 21;398(1):112390. Epub 2020 Nov 21.

Department of Otolaryngology, Head and Neck Surgery, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka, 573-1010, Japan.

Although surgical treatment cures >90% of differentiated thyroid cancer (DTC) patients, the remaining patients, including advanced DTC cases, have poor clinical outcomes. These patients with inoperable disease have only two choices of radioactive iodine therapy and tyrosine kinase inhibitors such as lenvatinib, which have a high incidence of treatment-related adverse events and can only prolong progression free survival by approximately 5-15 months. In this study, we investigated the antitumor effects of combination therapy with lenvatinib and radiation (CTLR) for DTC. CTLR synergistically inhibited cell replication and colony formation in vitro and tumor growth in nude mice without apparent toxicities and suppressed the expression of proliferation marker (Ki-67). CTLR also induced apoptosis and G2/M phase cell cycle arrest. Moreover, quantitative analysis of the intracellular uptake of lenvatinib using liquid chromatography and mass spectrometry demonstrated that intracellular uptake of lenvatinib was significantly increased 48 h following irradiation. These data suggest that increased membrane permeability caused by irradiation increases the intracellular concentration of levatinib, contributing to the synergistic effect. This mechanism-based potential of combination therapy suggests a powerful new therapeutic strategy for advanced thyroid cancer with fewer side effects and might be a milestone for developing a regimen in clinical practice.
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http://dx.doi.org/10.1016/j.yexcr.2020.112390DOI Listing
January 2021

Effect of periosteal reaction in medication-related osteonecrosis of the jaw on treatment outcome after surgery.

J Bone Miner Metab 2021 Mar 12;39(2):302-310. Epub 2020 Oct 12.

Department of Clinical Oral Oncology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8588, Japan.

Introduction: Surgical treatment in patients with medication-related osteonecrosis of the jaw (MRONJ) is superior to conservative treatment. However, treatment outcome in patients with periosteal reaction (PR) was significantly poorer than that of those without PR. The purpose of this retrospective study was to analyze the pathophysiology and clinical significance of PR in MRONJ.

Materials And Methods: Out of 181 patients with MRONJ undergoing surgery, 38 patients with PR were enrolled in the study. CT examinations, histological examinations, and bacteriological examinations using real-time polymerase chain reaction were performed, and the relationship among the opted surgical method, CT findings, and treatment outcome was investigated.

Results: The pattern of PR was classified into three types: type 1, new bone is formed parallel to the mandible, and no gap was evident between the mandible and new bone; type 2, new bone is formed parallel to the mandible, and a gap was evident between them; type 3, an irregular shape. Histological examinations revealed inflammatory tissue in the area visualized as a gap on CT. Bacteriological examination showed the presence of bacteria in the type 2 or type 3 PR. Complete cure was observed in 21 of 38 (55.3%) patients, which was lower than the cure rate of 73.4% in 143 patients without PR. The cure rate was significantly lower in cases with type 3 PR or with persistent osteolysis.

Conclusions: It seems that complete resection of both osteolytic area and type 3 PR is necessary to obtain complete healing in patients undergoing marginal mandibulectomy.
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http://dx.doi.org/10.1007/s00774-020-01154-6DOI Listing
March 2021

Designer Palmitoylation Motif-Based Self-Localizing Ligand for Sustained Control of Protein Localization in Living Cells and .

ACS Chem Biol 2020 04 20;15(4):837-843. Epub 2020 Mar 20.

Department of Life Science and Applied Chemistry, Nagoya Institute of Technology, Gokiso-cho, Showa-ku, Nagoya 466-8555, Japan.

Inducing protein translocation to the plasma membrane (PM) is an important approach for manipulating diverse signaling molecules/pathways in living cells. We previously devised a new chemogenetic system, in which a protein fused to dihydrofolate reductase (eDHFR) can be rapidly translocated from the cytoplasm to the PM using a trimethoprim (TMP)-based self-localizing ligand (SL), mgcTMP. However, mgcTMP-induced protein translocation turned out to be transient and spontaneously reversed within 1 h, limiting its application. Here, we first demonstrated that the spontaneous reverse translocation was caused by cellular degradation of mgcTMP, presumably by proteases. To address this problem, we newly developed a proteolysis-resistant SL, mcTMP. This mcTMP now allows sustained PM localization of eDHFR-fusion proteins (over several hours to a day), and it was applicable to inducing prolonged signal activation and cell differentiation. mcTMP also worked in live nematodes, making it an attractive new tool for probing and controlling living systems.
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http://dx.doi.org/10.1021/acschembio.0c00014DOI Listing
April 2020

Increased CD69 expression on activated eosinophils in eosinophilic chronic rhinosinusitis correlates with clinical findings.

Allergol Int 2020 Apr 10;69(2):232-238. Epub 2020 Jan 10.

Department of Otorhinolaryngology, Head & Neck Surgery, Kansai Medical University, Osaka, Japan.

Background: Eosinophilic chronic rhinosinusitis (ECRS) is a subtype of chronic rhinosinusitis associated with asthma. CD69 is an important marker of activation for eosinophils. But, whether a correlation exist between the CD69 expression on eosinophils and clinical findings is unclear.

Methods: We performed quantitative PCR and/or flow cytometry using tissue and purified eosinophils from the blood and nasal polyps of 12 patients with ECRS and from 8 patients without ECRS (controls). We assessed clinical findings including nasal polyp (NP) scores, sinus CT findings, and pulmonary function test results, and examined their possible association with the CD69 expression. We also performed CD69 cross-linking experiments in mouse eosinophils to investigate the functional role of CD69.

Results: Levels of cytokine mRNAs (IL-4, -5, -10, and -13) were significantly higher in purified NP eosinophils and tissues from patients with ECRS than the levels of those in controls. The expressions of major basic protein (MBP), eosinophilic cationic protein (ECP), eosinophilic-derived neurotoxin (EDN), eosinophil peroxidase (EPX) in cytotoxic granules, and CD69 mRNA were significantly higher in purified eosinophils from NPs than in those from blood. We also found a correlation between expression of CD69 and clinical findings. Moreover, we found EPX release from mouse eosinophils following CD69 cross-linking.

Conclusions: These data suggest that increased CD69 expression by eosinophils is not only a biomarker for nasal obstruction and pulmonary dysfunction, but also a potential therapeutic target for patients with ECRS and asthma.
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http://dx.doi.org/10.1016/j.alit.2019.11.002DOI Listing
April 2020

Multiple Biological Aspects of Eosinophils in Host Defense, Eosinophil-Associated Diseases, Immunoregulation, and Homeostasis: Is Their Role Beneficial, Detrimental, Regulator, or Bystander?

Biol Pharm Bull 2020 ;43(1):20-30

Department of Otolaryngology, Head and Neck Surgery, Kansai Medical University.

Eosinophils are innate immune leukocytes and play important roles as terminal effector cells owing to their mediators, such as tissue-destructive cationic proteins, cytokines, chemokines, and lipid mediators. Historically, they are not only considered an important player in host defense against parasitic, viral, fungal, and bacterial infections but also implicated in the pathogenesis of eosinophil-associated diseases, such as allergic rhinitis, asthma, eosinophilic chronic rhinosinusitis, esophagitis, atopic dermatitis, myopathies, and hypereosinophilic syndrome. Moreover, recent studies have shown that eosinophils have an immune regulatory and homeostatic function. Interestingly, there is emerging evidence that eosinophils are accumulated through adoptive T-helper 2 (Th2) and innate Th2 responses, mechanisms of the classical allergen-specific immunoglobulin E (IgE)-mediated response, and group 2 innate lymphoid cell-derived interleukin-5, respectively. Furthermore, in agreement with current concepts of eosinophil subtypes, it has been shown that resident and phenotypically distinct eosinophils, i.e., resident and recruited inflammatory eosinophils, exist in inflamed sites, and each has different functions. Thus, the classical and novel studies suggest that eosinophils have multiple functions, and their roles may be altered by the environment. In this article, we review multiple biological aspects of eosinophils (novel and classical roles), including their beneficial and detrimental effects, immunoregulation, and homeostatic function.
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http://dx.doi.org/10.1248/bpb.b19-00892DOI Listing
November 2020

Chemogenetic Control of Protein Anchoring to Endomembranes in Living Cells with Lipid-Tethered Small Molecules.

Biochemistry 2020 01 15;59(2):205-211. Epub 2019 Oct 15.

Department of Life Science and Applied Chemistry , Nagoya Institute of Technology , Gokiso-cho, Showa-ku, Nagoya 466-8555 , Japan.

The self-localizing ligand-induced protein translocation (SLIPT) system is an emerging platform that controls protein localization in living cells using synthetic self-localizing ligands (SLs). Here, we report a chemogenetic SLIPT system for inducing protein translocation from the cytoplasm to the surface of the endoplasmic reticulum (ER) and Golgi membranes, referred to as endomembranes. By screening a series of lipid-trimethoprim (TMP) conjugates, we found oleic acid-tethered TMP (oleTMP) to be the optimal SL that efficiently relocated and anchored dihydrofolate reductase (eDHFR)-fusion proteins to endomembranes. We showed that oleTMP mediated protein anchoring to endomembranes within minutes and could be reversed by the addition of free TMP. We also applied the endomembrane SLIPT system to artificially activate endomembrane Ras and inhibit the active nuclear transport of extracellular signal-regulated kinase (ERK), demonstrating its applicability for manipulating biological processes in living cells. We envision that the present oleTMP-based SLIPT system, which affords rapid and reversible control of protein anchoring to endomembranes, will offer a new unique tool for the study and control of spatiotemporally regulated cell signaling processes.
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http://dx.doi.org/10.1021/acs.biochem.9b00807DOI Listing
January 2020

A Novel Approach for Investigating Upper Airway Hyperresponsiveness Using Micro-CT in Eosinophilic Upper Airway Inflammation such as Allergic Rhinitis Model.

Biomolecules 2019 06 27;9(7). Epub 2019 Jun 27.

Department of Otorhinolaryngology, Head and Neck Surgery, Kansai Medical University, Hirakata 573-1010, Japan.

Airway hyperresponsiveness (AHR) has been proposed as a feature of pathogenesis of eosinophilic upper airway inflammation such as allergic rhinitis (AR). The measurement system for upper AHR (AHR) in rodents is poorly developed, although measurements of nasal resistance have been reported. Here we assessed UAHR by direct measurement of swelling of the nasal mucosa induced by intranasal methacholine (MCh) using micro-computed tomography (micro-CT). Micro-CT analysis was performed in both naïve and ovalbumin-induced AR mice following intranasal administration of MCh. The nasal cavity was segmented into two-dimensional horizontal and axial planes, and the data for nasal mucosa were acquired for the region of interest threshold. Then, a ratio between the nasal mucosa area and nasal cavity area was calculated as nasal mucosa index. Using our novel method, nasal cavity structure was clearly identified on micro-CT, and dose-dependent increased swelling of the nasal mucosa was observed upon MCh treatment. Moreover, the nasal mucosa index was significantly increased in AR mice compared to controls following MCh treatment, while ovalbumin administration did not affect swelling of the nasal mucosa in either group. This UAHR following MCh treatment was completely reversed by pretreatment with glucocorticoids. This novel approach using micro-CT for investigating UAHR reflects a precise assessment system for swelling of the nasal mucosa following MCh treatment; it not only sheds light on the mechanism of AR but also contributes to the development of new therapeutic drugs in AR patients.
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http://dx.doi.org/10.3390/biom9070252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6681309PMC
June 2019

Clinical significance of periosteal reaction as a predictive factor for treatment outcome of medication-related osteonecrosis of the jaw.

J Bone Miner Metab 2019 Sep 4;37(5):913-919. Epub 2019 Mar 4.

Department of Otolaryngology Head and Neck Surgery, Kansai Medical University, 2-3-1 Shinmachi, Hirakata, Osaka, 573-1191, Japan.

Regarding treatment strategies for medication-related osteonecrosis of the jaw (MRONJ), surgical therapy has recently been reported to be more effective than conservative therapy. However, some patients did not achieve complete healing, even when extensive surgery was performed. Periosteal reaction in MRONJ patients is often observed by the CT examination. Tssshe purpose of this study was to investigate the relationship between periosteal reaction and treatment outcome of MRONJ. A total of 164 surgeries in 136 patients with MRONJ at two hospitals were included in the study. Correlations between various clinical and radiographic factors and treatment outcome were examined with Cox regression analysis. The results showed that the presence of periosteal reaction, as well as primary disease involving malignant tumor, were independent risk factors related to poor outcome. Furthermore, we examined factors related to the occurrence of the periosteal reaction and found that 4 variables were significantly correlated with periosteal reaction by multivariate analysis: gender (female), site (lower jaw), primary disease (malignant tumor), and osteosclerosis (severe). The present study clarified that the cure rate after surgical treatment decreased in cases with periosteal reaction, suggesting that it is necessary to review the treatment method.
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http://dx.doi.org/10.1007/s00774-019-00994-1DOI Listing
September 2019

Eosinophilic Upper Airway Inflammation in a Murine Model Using an Adoptive Transfer System Induces Hyposmia and Epithelial Layer Injury with Convex Lesions.

Med Sci (Basel) 2019 Feb 5;7(2). Epub 2019 Feb 5.

Department of Otolaryngology, Head and Neck Surgery, Kansai Medical University, Hirakata 573-1010, Japan.

Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a refractory upper airway disease, accompanied mainly by eosinophilia and/or asthma. In addition, the disease correlates with a high rate of hyposmia, following a marked infiltration of eosinophils into the inflamed site, the paranasal sinus. Although eosinophils are known to contribute to the development of hyposmia and CRSwNP pathology, the underlying mechanisms remain unclear. This study aimed to investigate whether eosinophilic upper airway inflammation induces hyposmia and CRSwNP in a murine model using an adoptive transfer system.

Methods: To induce eosinophilic rhinosinusitis, splenocytes, including a high proportion (over 50%) of activated eosinophils (SPLhEos), were collected from interleukin-5 transgenic mice following double intraperitoneal injections of antigens, such as ovalbumin, house dust mite, or fungus. Activated SPLhEos with corresponding antigens were then transferred into the nasal cavity of recipient mice, which were sensitized and challenged by the corresponding antigen four times per week. Olfactory function, histopathological, and computed tomography (CT) analyses were performed 2 days after the final transfer of eosinophils.

Results: Hyposmia was induced significantly in mice that received SPLhEos transfer compared with healthy and allergic mice, but it did not promote morphological alteration of the paranasal sinus. Pathological analysis revealed that epithelial layer injury and metaplasia similar to polyps, with prominent eosinophil infiltration, was induced in recipient tissue. However, there was no nasal polyp development with interstitial edema that was similar to those recognized in human chronic rhinosinusitis.

Conclusions: This study supports the previously unsuspected contribution of eosinophils to CRS development in the murine model and suggests that murine-activated eosinophilic splenocytes contribute to the development of hyposmia due to more mucosal inflammation than physical airway obstruction and epithelial layer injury with convex lesions.
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http://dx.doi.org/10.3390/medsci7020022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6409781PMC
February 2019

Stabilization of SF with Glyme-Coordinated Alkali Metal Cations.

Inorg Chem 2018 Dec 16;57(23):14882-14889. Epub 2018 Nov 16.

Graduate School of Energy Science , Kyoto University , Yoshida, Sakyo-ku, Kyoto , 606-8501 , Japan.

The stabilization of complex fluoroanions derived from weakly acidic parent fluorides is a significant and ongoing challenge. The [SF] anion is recognized as one such case, and only a limited number of [SF] salts are known to be stable at room temperature. In the present study, glyme-coordinated alkali metal cations (K, Rb, and Cs) are employed to stabilize [SF], which provides a simple synthetic route to a [SF] salt. The reactivities of KF and RbF with SF are significantly enhanced by complexation with G4, based on Raman spectroscopic analyses. A new room-temperature stable salt, [Cs(G4)][SF] (G4 = tetraglyme), was synthesized by stoichiometric reaction of CsF, G4, and SF. The vibrational frequencies of [SF] were assigned based on quantum chemical calculations, and the shift of the G4 breathing mode accompanying coordination to metal cations was confirmed by Raman spectroscopy. Single-crystal X-ray diffraction revealed that Cs is completely isolated from [SF] by two G4 ligands and [SF] is disordered along the crystallographic two-fold axis. Hirshfeld surface analysis reveals that the H···H interaction between two neighboring [Cs(G4)] moieties is more dominant on the Hirshfeld surface than the interaction between the H atom in glyme molecules and the F atom in [SF], providing a CsCl-type structural model where the large and spherical [Cs(G4)] cations contact each other and the [SF] anions occupy interstitial spaces in the crystal lattice. The [SF] anion, combined with [Cs(G4)], exhibits a very limited deoxofluorinating ability toward hydroxyl groups in both neat conditions and THF solutions.
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http://dx.doi.org/10.1021/acs.inorgchem.8b02655DOI Listing
December 2018

A comparison of short-term outcomes of neck dissection for head and neck cancers using Thunderbeat™, LigaSure™ or treatment without an energy-based device: A case controlled study.

Int J Surg 2018 Oct 21;58:60-64. Epub 2018 Sep 21.

Department of Otolaryngology, Head and Neck Surgery, Kansai Medical University Hospital, Japan.

Objective: The aim of this study was to evaluate the efficacy of the new energy-based device Thunderbeat in neck dissection (ND) for head and neck cancer.

Materials And Methods: We retrospectively examined 95 consecutive patients who underwent ND for head and neck squamous cell carcinoma between April 2013 and March 2018. The patients were divided into three groups: ND without the energy-based device (control group), ND using the LigaSure Small Jaw (LS group), and ND using the Thunderbeat Open Fine Jaw (TB group). The outcomes were compared among the three groups, as measured by the duration of ND (dissection time), blood loss during ND, and postoperative complications. We also analyzed the factors that may influence dissection time using multivariate analysis.

Results: Compared to the control group, dissection time was found to be significantly shorter in both energy-based device groups (LS group and TB group) (96.4, 71.1, and 66.0 min, respectively, p = 0.0015) by univariate analysis. Blood loss during ND did not differ significantly among the three groups. Multivariate analysis showed that ND using the Thunderbeat as well as elderly patients (70 years and over), less extensive surgery (3 or fewer neck levels), and absence of extracapsular invasion were independently and significantly associated with shorter dissection time (p = 0.0069, 0.0337, <0.0001, and 0.0015, respectively). The incidence of postoperative complications in the LS group (20%) tended to be higher than those in the other groups (5.6% in the control group and 3.4% in the TB group), although the differences were not significant.

Conclusion: ND for head and neck cancers using the Thunderbeat is a safe and reliable method in terms of duration of dissection without increasing postoperative complications.
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http://dx.doi.org/10.1016/j.ijsu.2018.09.009DOI Listing
October 2018

Enhancement of Anti-Inflammatory and Osteogenic Abilities of Mesenchymal Stem Cells via Cell-to-Cell Adhesion to Periodontal Ligament-Derived Fibroblasts.

Stem Cells Int 2017 12;2017:3296498. Epub 2017 Jan 12.

Division of Cellular Biosignal Sciences, Department of Biochemistry, Iwate Medical University, Yahaba, Iwate 028-3694, Japan.

Mesenchymal stem cells (MSCs) are involved in anti-inflammatory events and tissue repair; these functions are activated by their migration or homing to inflammatory tissues in response to various chemokines. However, the mechanism by which MSCs interact with other cell types in inflammatory tissue remains unclear. We investigated the role of periodontal ligament fibroblasts (PDL-Fs) in regulating the anti-inflammatory and osteogenic abilities of bone marrow-derived- (BM-) MSCs. The expression of monocyte chemotactic protein- (MCP-)1 was significantly enhanced by stimulation of PDL-Fs with inflammatory cytokines. MCP-1 induced the migratory ability of BM-MSCs but not PDL-Fs. Expression levels of anti-inflammatory and inflammatory cytokines were increased and decreased, respectively, by direct-contact coculture between MSCs and PDL-Fs. In addition, the direct-contact coculture enhanced the expression of MSC markers that play important roles in the self-renewal and maintenance of multipotency of MSCs, which in turn induced the osteogenic ability of the cells. These results suggest that MCP-1 induces the migration and homing of BM-MSCs into the PDL inflammatory tissue. The subsequent adherence of MSCs to PDL-Fs plays an immunomodulatory role to terminate inflammation during wound healing and upregulates the expression stem cell markers to enhance the stemness of MSCs, thereby facilitating bone formation in damaged PDL tissue.
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http://dx.doi.org/10.1155/2017/3296498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5266859PMC
January 2017

VEGF-C and TGF-β reciprocally regulate mesenchymal stem cell commitment to differentiation into lymphatic endothelial or osteoblastic phenotypes.

Int J Mol Med 2016 Apr 25;37(4):1005-13. Epub 2016 Feb 25.

Division of Cellular Biosignal Sciences, Department of Biochemistry, Iwate Medical University, Yahaba, Iwate 028-3694, Japan.

The direction of mesenchymal stem cell (MSC) differentiation is regulated by stimulation with various growth factors and cytokines. We recently established MSC lines, [transforming growth factor-β (TGF-β)-responsive SG‑2 cells, bone morphogenetic protein (BMP)-responsive SG‑3 cells, and TGF-β/BMP-non-responsive SG‑5 cells], derived from the bone marrow of green fluorescent protein-transgenic mice. In this study, to compare gene expression profiles in these MSC lines, we used DNA microarray analysis to characterize the specific gene expression profiles observed in the TGF-β-responsive SG‑2 cells. Among the genes that were highly expressed in the SG‑2 cells, we focused on vascular endothelial growth factor (VEGF) receptor 3 (VEGFR3), the gene product of FMS-like tyrosine kinase 4 (Flt4). We found that VEGF-C, a specific ligand of VEGFR3, significantly induced the cell proliferative activity, migratory ability (as shown by Transwell migration assay), as well as the phosphorylation of extracellular signal-regulated kinase (ERK)1/2 in the SG‑2 cells. Additionally, VEGF-C significantly increased the expression of prospero homeobox 1 (Prox1) and lymphatic vessel endothelial hyaluronan receptor 1 (Lyve1), which are lymphatic endothelial cell markers, and decreased the expression of osteogenic differentiation marker genes in these cells. By contrast, TGF-β significantly increased the expression of early-phase osteogenic differentiation marker genes in the SG‑2 cells and markedly decreased the expression of lymphatic endothelial cell markers. The findings of our study strongly suggest the following: i) that VEGF-C promotes the proliferative activity and migratory ability of MSCs; and ii) VEGF-C and TGF-β reciprocally regulate MSC commitment to differentiation into lymphatic endothelial or osteoblastic phenotypes, respectively. Our findings provide new insight into the molecular mechanisms underlying the regenerative ability of MSCs.
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http://dx.doi.org/10.3892/ijmm.2016.2502DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4790684PMC
April 2016

Establishment of mesenchymal stem cell lines derived from the bone marrow of green fluorescent protein-transgenic mice exhibiting a diversity in intracellular transforming growth factor-β and bone morphogenetic protein signaling.

Mol Med Rep 2016 Mar 18;13(3):2023-31. Epub 2016 Jan 18.

Division of Cellular Biosignal Sciences, Department of Biochemistry, Iwate Medical University, Yahaba, Iwate 028‑3694, Japan.

Cytokines and their intercellular signals regulate the multipotency of mesenchymal stem cells (MSCs). The present study established the MSC lines SG‑2, ‑3, and ‑5 from the bone marrow of green fluorescent protein (GFP)‑transgenic mice. These cell lines clearly expressed mouse MSC markers Sca‑1 and CD44, and SG‑2 and ‑5 cells retained the potential for osteogenic and adipogenic differentiation in the absence of members of the transforming growth factor (TGF)‑β superfamily. By contrast, SG‑3 cells only retained adipogenic differentiation potential. Analysis of cytokine and cytokine receptor expression in these SG cell lines showed that bone morphogenetic protein (BMP) receptor 1B was most highly expressed in the SG‑3 cells, which underwent osteogenesis in response to BMP, while TGF‑β receptor II was most highly expressed in SG‑3 and ‑5 cells. However, it was unexpectedly noted that phosphorylation of Smad 2, a major transcription factor, was induced by TGF‑β1 in SG‑2 cells but not in SG‑3 or ‑5 cells. Furthermore, TGF‑β1 clearly induced the expression of Smad‑interacting transcription factor CCAAT/enhancer binding protein‑β in SG‑2 but not in SG‑3 or ‑5 cells. These results demonstrated the establishment of TGF‑β‑responsive SG‑2 MSCs, BMP‑responsive SG‑3 MSCs and TGF‑β/BMP‑unresponsive SG‑5 MSCs, each of which was able to be traced by GFP fluorescence after transplantation into in vivo experimental models. In conclusion, the present study suggested that these cell lines may be used to explore how the TGF‑β superfamily affects the proliferation and differentiation status of MSCs in vivo.
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http://dx.doi.org/10.3892/mmr.2016.4794DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4768972PMC
March 2016

Novel SCRG1/BST1 axis regulates self-renewal, migration, and osteogenic differentiation potential in mesenchymal stem cells.

Sci Rep 2014 Jan 13;4:3652. Epub 2014 Jan 13.

Division of Cellular Biosignal Sciences, Department of Biochemistry, Iwate Medical University, Yahaba, Iwate 028-3694, Japan.

Human mesenchymal stem cells (hMSCs) remodel or regenerate various tissues through several mechanisms. Here, we identified the hMSC-secreted protein SCRG1 and its receptor BST1 as a positive regulator of self-renewal, migration, and osteogenic differentiation. SCRG1 and BST1 gene expression decreased during osteogenic differentiation of hMSCs. Intriguingly, SCRG1 maintained stem cell marker expression (Oct-4 and CD271/LNGFR) and the potentials of self-renewal, migration, and osteogenic differentiation, even at high passage numbers. Thus, the novel SCRG1/BST1 axis determines the fate of hMSCs by regulating their kinetic and differentiation potentials. Our findings provide a new perspective on methods for ex vivo expansion of hMSCs that maintain native stem cell potentials for bone-forming cell therapy.
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http://dx.doi.org/10.1038/srep03652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3888969PMC
January 2014

PDGF-induced PI3K-mediated signaling enhances the TGF-β-induced osteogenic differentiation of human mesenchymal stem cells in a TGF-β-activated MEK-dependent manner.

Int J Mol Med 2014 Mar 27;33(3):534-42. Epub 2013 Dec 27.

Division of Cellular Biosignal Sciences, Department of Biochemistry, Iwate Medical University, Yahaba, Iwate 028‑3694, Japan.

Transforming growth factor-β (TGF-β) is a critical regulator of osteogenic differentiation and the platelet-derived growth factor (PDGF) is a chemoattractant or mitogen of osteogenic mesenchymal cells. However, the combined effects of these regulators on the osteogenic differentiation of mesenchymal cells remains unknown. In this study, we investigated the effects of TGF-β and/or PDGF on the osteogenic differentiation of human mesenchymal stem cells (hMSCs). The TGF-β-induced osteogenic differentiation of UE7T-13 cells, a bone marrow-derived hMSC line, was markedly enhanced by PDGF, although PDGF alone did not induce differentiation. TGF-β induced extracellular signal-regulated kinase (ERK) phosphorylation and PDGF induced Akt phosphorylation. In addition, the mitogen-activated protein kinase (MAPK)/ERK kinase (MEK) inhibitor, U0126, suppressed the osteogenic differentiation induced by TGF-β alone. Moreover, U0126 completely suppressed the osteogenic differentiation synergistically induced by TGF-β and PDGF, whereas the phosphoinositide-3-kinase (PI3K) inhibitor, LY294002, only partially suppressed this effect. These results suggest that the enhancement of TGF-β-induced osteogenic differentiation by PDGF-induced PI3K/Akt-mediated signaling depends on TGF-β-induced MEK activity. Thus, PDGF positively modulates the TGF-β-induced osteogenic differentiation of hMSCs through synergistic crosstalk between MEK- and PI3K/Akt-mediated signaling.
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http://dx.doi.org/10.3892/ijmm.2013.1606DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3926498PMC
March 2014

Enhancement of gingival inflammation induced by synergism of IL-1β and IL-6.

Biomed Res 2013 Feb;34(1):31-40

Division of Periodontics, Department of Conservative Dentistry and Oral Rehabilitation, Iwate Medical University School of Dentistry, Morioka, Iwate, Japan.

Internleukin-1 (IL-1) and IL-6 are the most potent proinflammatory cytokines being involved in inflammatory diseases such as periodontitis. The objective of this study was to examine the synergistic effects of IL-1β and IL-6 on gingival inflammation by targeting cultured human gingival fibroblasts (HGFs). HGFs were treated with IL-1β or IL-6/soluble IL-6R (sIL-6R), and total RNA and total cell lysate were collected to examine expression of gp130 known as a signal transducer of IL-6 using qRT-PCR and Western blotting. IL-1β-mediated IL-6 productivity in HGFs was examined using ELISA method. Likewise, after HGFs and THP-1 macrophages were treated with IL-1β, TNF-α and IL-6, sIL-6R productivity was examined. Next, HGFs were treated with IL-6/ sIL-6R after pretreatment of IL-1β, and the intracellular signals were examined using Western blotting. Finally, various mRNA/protein expressions in HGFs treated with IL-6/sIL-6R after pretreatment of IL-1β were examined using qRT-PCR and ELISA method. IL-1β increased significantly both gp130 and IL-6 expression in HGFs. IL-6 increased significantly sIL-6R production in THP-1 macrophages but not HGFs. Co-stimulation with IL-1β and IL-6/sIL-6R induced dramatically the phosphorylation of Stat3, ERK and JNK in HGFs. Interestingly, expression of various inflammation- related molecules such as MMP-1, MCP-1, IL-1ra, bFGF and VEGF were enhanced by co-stimulation with IL-1β and IL-6/sIL-6R in HGFs. Gingival inflammation is regulated by HGFs affected by both IL-1β and IL-6/sIL-6R synergistically through induction of gp130 expression, resulting in progression of periodontitis.
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http://dx.doi.org/10.2220/biomedres.34.31DOI Listing
February 2013

Secreted caveolin-1 enhances periodontal inflammation by targeting gingival fibroblasts.

Biomed Res 2013 Feb;34(1):1-11

Division of Periodontics, Department of Conservative Dentistry and Oral Rehabilitation, Iwate Medical University School of Dentistry, Morioka, Iwate, Japan.

Caveolin-1 (Cav-1) is a membrane protein. Recently, it has been reported that secreted Cav-1 induces angiogenesis in inflammatory microenvironment. However, it is unclear that Cav-1 regulates gingival inflammation. Therefore, we investigated the Cav-1 function to periodontal cells. Expression of Cav-1 in human periodontitis tissues was examined pathologically. Secretion of Cav-1 from human gingival fibroblasts (HGFs) or human periodontal ligament cells (HPLFs) treated with IL-1β and TNF-α was examined using Western blotting. Likewise, intracellular signals induced by Cav-1 were examined. Finally, we examined whether the secreted Cav-1 induces production of inflammatory mediators in HGFs using ELISA or qRT-PCR. Pathologically, high expression of Cav-1 was observed in human periodontitis tissues. Cav-1 secretion increased in both cultured HGFs and HPLFs treated with IL-1β and TNF-α. Cav-1 induced phosphorylation of JNK and ERK, but not Stat3 in HGFs. Furthermore, Cav-1 increased proMMP-1 and VEGF secretion in HGFs, and the VEGF secretion was statistically suppressed by JNK inhibitor SP600125, but not ERK inhibitor PD98059. ProMMP-1 secretion was suppressed statistically by both SP600125 and PD98059. In addition, Cav-1 increased significantly MMP-1, -10 and -14 mRNA expressions, whereas no increase of TIMPs mRNA was observed in HGFs treated with Cav-1. These data suggest that secreted Cav-1 derived from periodontal fibroblastic cells enhances inflammation-related several proteases and VEGF secretion in HGFs via MAPKs pathway, resulting in progression of periodontitis through induction of tissue degradation or angiogenesis.
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http://dx.doi.org/10.2220/biomedres.34.1DOI Listing
February 2013

Transforming growth factor-β1 induces epithelial-mesenchymal transition and integrin α3β1-mediated cell migration of HSC-4 human squamous cell carcinoma cells through Slug.

J Biochem 2013 Mar 17;153(3):303-15. Epub 2012 Dec 17.

Division of Cellular Biosignal Sciences, Department of Biochemistry, Iwate Medical University, Nishitokuta, Yahaba-cho, Iwate 028-3694, Japan.

We investigated whether transforming growth factor (TGF)-β1 promoted epithelial-mesenchymal transition (EMT) and migration of human oral squamous cell carcinoma (hOSCC) cells. Among 6 hOSCC cell lines investigated, Smad2 phosphorylation and TGF-β target genes expression were most clearly upregulated following TGF-β1 stimulation in HSC-4 cells, indicating that HSC-4 cells were the most responsive to TGF-β1. In addition, the expression levels of the mesenchymal markers N-cadherin and vimentin were most clearly induced in HSC-4 cells among the hOSCC cell lines by TGF-β1 stimulation. Interestingly, E-cadherin and β-catenin at the cell surface were internalized in HSC-4 cells stimulated with TGF-β1. In addition, the expression levels of the EMT-related transcription factor Slug was significantly upregulated on TGF-β1 stimulation. Moreover, the downregulation of Slug by RNA interference clearly inhibited the TGF-β1-induced expression of mesenchymal marker and the migration of HSC-4 cells. Proteomics analysis also revealed that the expression levels of integrin α3β1-targeted proteins were upregulated in TGF-β1-stimulated HSC-4 cells. Neutral antibodies against integrin α3 and β1, as well as a focal adhesion kinase (FAK) inhibitor, clearly suppressed TGF-β1-induced cell migration. These results suggest that the EMT and integrin α3β1/FAK pathway-mediated migration of TGF-β1-stimulated HSC-4 hOSCC cells is positively controlled by Slug.
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http://dx.doi.org/10.1093/jb/mvs144DOI Listing
March 2013
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