Faculty Profiles - NAKA Shuuhei

Papers - NAKA Shuuhei

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Relationship Between the Presence of Red Complex Species and the Distribution of Other Oral Bacteria, Including Major Periodontal Pathogens in Older Japanese Individuals

Mariko Kametani, Yasuyuki Nagasawa, Momoko Usuda, Ami Kaneki, Masashi Ogawa, Kensaku Shojima, Hiromitsu Yamazaki, Kana Tokumoto, Daiki Matsuoka, Kana Suehara, Yuto Suehiro, Tatsuya Akitomo, Chieko Mitsuhata, Taro Misaki, Seigo Ito, Shuhei Naka, Michiyo Matsumoto-Nakano, Kazuhiko Nakano, Hiromitsu Kishimoto, Ken Shinmura, Ryota Nomura

International Journal of Molecular Sciences 25 ( 22 ) 12243 - 12243 2024.11

Publishing type：Research paper (scientific journal) Publisher：MDPI AG

Red complex bacteria (Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia) have high virulence in periodontal disease. In the present study, we aimed to elucidate the detailed symbiotic relationships between the red complex and other oral bacteria in older Japanese individuals. Polymerase chain reaction was performed using dental plaque from 116 subjects and specific primers for ten periodontal pathogens. The detection rate of Prevotella intermedia and Capnocytophaga sputigena was significantly higher in P. gingivalis-positive subjects than in P. gingivalis-negative subjects (p < 0.05). The detection rate of Campylobacter rectus, Prevotella nigrescens, Capnocytophaga ochracea, and Eikenella corrodens was significantly higher in T. forsythia-positive subjects than in T. forsythia-negative subjects (p < 0.01). In a comprehensive analysis of oral microbiomes, three red complex species-positive subjects had significantly higher α-diversity than only P. gingivalis-positive subjects (p < 0.05) and had significantly lower β-diversity than only T. forsythia-positive subjects (p < 0.01). In the taxonomy analysis, Porphyromonas was significantly higher in three red complex species-positive subjects than in only P. gingivalis-positive and only T. forsythia-positive subjects (p < 0.01). These results suggest that each red complex species forms a unique oral microbiome and individuals positive for all red complex bacteria may harbor oral bacteria that confer a significant advantage in developing periodontal disease.

DOI： 10.3390/ijms252212243

Contribution of collagen-binding protein Cnm of Streptococcus mutans to induced IgA nephropathy-like nephritis in rats. International journal

Shuhei Naka, Daiki Matsuoka, Taro Misaki, Yasuyuki Nagasawa, Seigo Ito, Ryota Nomura, Kazuhiko Nakano, Michiyo Matsumoto-Nakano

Communications biology 7 ( 1 ) 1141 - 1141 2024.9

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

IgA nephropathy (IgAN), the most common primary glomerulonephritis, is considered an intractable disease with unknown pathogenic factors. In our previous study, Streptococcus mutans, the major causative bacteria of dental caries, which expresses Cnm, was related to the induction of IgAN-like nephritis. In the present study, the Cnm-positive S. mutans parental strain, a Cnm-defective isogenic mutant strain, its complementation strain, and recombinant Cnm (rCnm) protein were administered intravenously to Sprague Dawley rats, and the condition of their kidneys was evaluated focusing on the pathogenicity of Cnm. Rats treated with parental and complement bacterial strains and rCnm protein developed IgAN-like nephritis with mesangial proliferation and IgA and C3 mesangial deposition. Scanning immunoelectron microscopy revealed that rCnm was present in the electron-dense deposition area of the mesangial region in the rCnm protein group. These results demonstrated that the Cnm protein itself is an important factor in the induction of IgAN in rats.

DOI： 10.1038/s42003-024-06826-x

High-performance silica-containing professional mechanical tooth-cleaning paste that effectively adsorbs pigments

Tatsuya Akitomo, Satoru Kusaka, Mariko Kametani, Chieko Mitsuhata, Shuhei Naka, Michiyo Matsumoto-Nakano, Kazuhiko Nakano, Ryota Nomura

Pediatric Dental Journal 34 ( 2 ) 62 - 69 2024.8

IgA腎症患者と習慣性扁桃炎患者の摘出扁桃における歯周病菌の検出率の比較

長澤康行, 野村良太, 三崎太郎, 伊藤誓悟, 山崎博充, 庄嶋健作, 松岡大貴, 仲周平, 仲野道代, 新村健, 仲野和彦

日本腎臓学会誌 66 ( 4 ) 591 - 591 2024.6

う蝕原性細菌cnm陽性Streptococcus mutansは扁桃を介してIgA腎症を増悪させる

伊藤誓悟, 三崎太郎, 長澤康行, 松岡大貴, 仲周平, 野村良太, 仲野道代, 仲野和彦

日本腎臓学会誌 66 ( 4 ) 637 - 637 2024.6

IgA腎症患者と習慣性扁桃炎患者の摘出扁桃における歯周病菌の検出率の比較

長澤康行, 野村良太, 三崎太郎, 伊藤誓悟, 山崎博充, 庄嶋健作, 松岡大貴, 仲周平, 仲野道代, 新村健, 仲野和彦

日本腎臓学会誌 66 ( 4 ) 591 - 591 2024.6

非アルコール性脂肪肝炎患者由来Streptococcus mutansの各臓器における分布とその特性に関する検討

田畑佳子, 仲周平, 中野聡大, 仲野道代

小児歯科学雑誌 62 ( 大会抄録号 ) 121 - 121 2024.4

非アルコール性脂肪肝炎発症に関連する鉄存在下でのStreptococcus mutansの性状変化の検討

中野聡大, 田畑佳子, 仲周平, 仲野道代

小児歯科学雑誌 62 ( 大会抄録号 ) 151 - 151 2024.4

コラーゲン結合タンパクCnmとヒト免疫グロブリンの結合に関する分子生物学的検討

末原佳奈, 松岡大貴, 仲周平, 野村良太, 仲野和彦, 仲野道代, 三崎太郎, 長澤康行, 伊藤誓悟

小児歯科学雑誌 62 ( 大会抄録号 ) 149 - 149 2024.4

ラットIgA腎症モデルにおける各種臓器での遺伝子発現の網羅的解析

松岡大貴, 末原佳奈, 仲周平, 野村良太, 仲野和彦, 仲野道代

小児歯科学雑誌 62 ( 大会抄録号 ) 153 - 153 2024.4

日本人小児口腔におけるStreptococcus mutansの陽性率と齲蝕経験歯数との関連の評価

奥田真琴, 末廣雄登, 東條文和, 又吉紗綾, 仲周平, 仲野道代, 仲野和彦

小児歯科学雑誌 62 ( 大会抄録号 ) 120 - 120 2024.4

非アルコール性脂肪肝炎患者口腔内から分離したStreptococcus mutansの各臓器における局在の検討

中野聡大, 田畑佳子, 仲周平, 仲野道代

小児歯科学雑誌 62 ( 地方会抄録号 ) 63 - 63 2024.2

廃棄される貝殻から生成したハイドロキシアパタイトのStreptococcus mutansに対する抑制効果メカニズムの検討

金木亜美, 小川将史, 臼田桃子, 亀谷茉莉子, 秋友達哉, 末廣雄登, 又吉紗綾, 仲周平, 大川玲奈, 光畑智恵子, 仲野道代, 仲野和彦, 野村良太, 八木正敏, 谷口泰造, 溝口敏郎, 藤川幸樹

小児歯科学雑誌 62 ( 地方会抄録号 ) 60 - 61 2024.2

Inhibitory Effects of Shikonin Dispersion, an Extract of Lithospermum erythrorhizon Encapsulated in β-1,3-1,6 Glucan, on Streptococcus mutans and Non-Mutans Streptococci. International journal

Ryota Nomura, Yuto Suehiro, Fumikazu Tojo, Saaya Matayoshi, Rena Okawa, Masakazu Hamada, Shuhei Naka, Michiyo Matsumoto-Nakano, Rika Unesaki, Kazuya Koumoto, Keiko Kawauchi, Takahito Nishikata, Tatsuya Akitomo, Chieko Mitsuhata, Masatoshi Yagi, Toshiro Mizoguchi, Koki Fujikawa, Taizo Taniguchi, Kazuhiko Nakano

International journal of molecular sciences 25 ( 2 ) 2024.1

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

Shikonin is extracted from the roots of Lithospermum erythrorhizon, and shikonin extracts have been shown to have inhibitory effects on several bacteria. However, shikonin extracts are difficult to formulate because of their poor water solubility. In the present study, we prepared a shikonin dispersion, which was solubilized by the inclusion of β-1,3-1,6 glucan, and analysed the inhibitory effects of this dispersion on Streptococcus mutans and non-mutans streptococci. The shikonin dispersion showed pronounced anti-S. mutans activity, and inhibited growth of and biofilm formation by this bacterium. The shikonin dispersion also showed antimicrobial and antiproliferative effects against non-mutans streptococci. In addition, a clinical trial was conducted in which 20 subjects were asked to brush their teeth for 1 week using either shikonin dispersion-containing or non-containing toothpaste, respectively. The shikonin-containing toothpaste decreased the number of S. mutans in the oral cavity, while no such effect was observed after the use of the shikonin-free toothpaste. These results suggest that shikonin dispersion has an inhibitory effect on S. mutans and non-mutans streptococci, and toothpaste containing shikonin dispersion may be effective in preventing dental caries.

DOI： 10.3390/ijms25021075

Diagnosis of maxillary lateral incisor dens invaginatus and therapeutic approach

Setsuyo Morimoto, Kana Goto, Asaumi Haruka, Tabata Keiko, Daiki Matsuoka, Shuhei Naka, Michiyo Matsumoto-Nakano

Pediatric Dental Journal 33 ( 3 ) 216 - 222 2023.12

非アルコール性脂肪肝炎患者から分離したStreptococcus mutansの増殖能に鉄イオンが及ぼす影響について

中野聡大, 田畑佳子, 仲周平, 仲野道代

岡山歯学会雑誌 42 ( 2 ) 78 - 78 2023.12

Porphyromonas gingivalis infection in the oral cavity is associated with elevated galactose-deficient IgA1 and increased nephritis severity in IgA nephropathy.

Seigo Ito, Taro Misaki, Yasuyuki Nagasawa, Ryota Nomura, Shuhei Naka, Akiko Fukunaga, Daiki Matsuoka, Saaya Matayoshi, Michiyo Matsumoto-Nakano, Kazuhiko Nakano

Clinical and experimental nephrology 2023.10

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

BACKGROUND: The relationship between the major periodontal bacteria, Porphyromonas gingivalis, and the pathogenesis of IgA nephropathy (IgAN)-particularly with respect to galactose-deficient IgA1 (Gd-IgA1)-has not been fully elucidated. METHODS: Saliva samples from 30 IgAN patients and 44 patients with chronic kidney disease (CKD) were subjected to analysis of P. gingivalis status via polymerase chain reaction using a set of P. gingivalis-specific primers. The associations between P. gingivalis presence and clinical parameters, including plasma Gd-IgA1, were analyzed in each group. RESULTS: Compared with the CKD group, the IgAN group demonstrated significantly higher plasma Gd-IgA1 levels (p < 0.05). Compared with the P. gingivalis-negative subgroup, the P. gingivalis-positive subgroup exhibited significantly higher plasma Gd-IgA1 levels in both IgAN and CKD patients (p < 0.05). Additionally, among IgAN patients, the P. gingivalis-positive subgroup displayed significantly higher plasma Gd-IgA1 and urine protein levels, compared with the P. gingivalis-negative subgroup (p < 0.05). With respect to renal biopsy findings, the frequencies of segmental glomerulosclerosis and tubular atrophy/interstitial fibrosis were significantly greater in the P. gingivalis-positive subgroup than in the P. gingivalis-negative subgroup, according to the Oxford classification of IgAN (p < 0.05). CONCLUSION: Our findings suggest an association between the presence of P. gingivalis in the oral cavity and the pathogenesis of IgAN, mediated by increased levels of Gd-IgA1.

DOI： 10.1007/s10157-023-02411-4

Inhibitory Effect of Adsorption of Streptococcus mutans onto Scallop-Derived Hydroxyapatite. International journal

Momoko Usuda, Mariko Kametani, Masakazu Hamada, Yuto Suehiro, Saaya Matayoshi, Rena Okawa, Shuhei Naka, Michiyo Matsumoto-Nakano, Tatsuya Akitomo, Chieko Mitsuhata, Kazuya Koumoto, Keiko Kawauchi, Takahito Nishikata, Masatoshi Yagi, Toshiro Mizoguchi, Koki Fujikawa, Taizo Taniguchi, Kazuhiko Nakano, Ryota Nomura

International journal of molecular sciences 24 ( 14 ) 2023.7

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

Hydroxyapatite adsorbs various substances, but little is known about the effects on oral bacteria of adsorption onto hydroxyapatite derived from scallop shells. In the present study, we analyzed the effects of adsorption of Streptococcus mutans onto scallop-derived hydroxyapatite. When scallop-derived hydroxyapatite was mixed with S. mutans, a high proportion of the bacterial cells adsorbed onto the hydroxyapatite in a time-dependent manner. An RNA sequencing analysis of S. mutans adsorbed onto hydroxyapatite showed that the upregulation of genes resulted in abnormalities in pathways involved in glycogen and histidine metabolism and biosynthesis compared with cells in the absence of hydroxyapatite. S. mutans adsorbed onto hydroxyapatite was not killed, but the growth of the bacteria was inhibited. Electron microscopy showed morphological changes in S. mutans cells adsorbed onto hydroxyapatite. Our results suggest that hydroxyapatite derived from scallop shells showed a high adsorption ability for S. mutans. This hydroxyapatite also caused changes in gene expression related to the metabolic and biosynthetic processes, including the glycogen and histidine of S. mutans, which may result in a morphological change in the surface layer and the inhibition of the growth of the bacteria.

DOI： 10.3390/ijms241411371

Eruption cyst caused by congenital tooth in low birth weight infant

Eri Yoshida, Kana Goto, Daiki Matsuoka, Yukiko Miyai, Haruka Asaumi, Keiko Tabata, Shuhei Naka, Michiyo Matsumoto-Nakano

Pediatric Dental Journal 2023.7

口腔内のcnm遺伝子陽性S.mutansとIgA腎症患者の糖鎖異常IgA沈着の関連性

三崎太郎, 仲周平, 鈴木仁, 李明峰, 青木良輔, 長澤康行, 松岡大貴, 伊藤誓悟, 野村良太, 仲野道代, 鈴木祐介, 仲野和彦

日本腎臓学会誌 65 ( 3 ) 271 - 271 2023.5

口腔内のcnm遺伝子陽性S.mutansとIgA腎症患者の糖鎖異常IgA沈着の関連性

三崎太郎, 仲周平, 鈴木仁, 李明峰, 青木良輔, 長澤康行, 松岡大貴, 伊藤誓悟, 野村良太, 仲野道代, 鈴木祐介, 仲野和彦

日本腎臓学会誌 65 ( 3 ) 271 - 271 2023.5

腎炎のあたらしい"モデル動物"の開発ラットおよびマウスを用いた口腔細菌のIgA腎症発症への影響の検討

野村良太, 長澤康行, 三崎太郎, 仲周平, 仲野道代, 仲野和彦

日本腎臓学会誌 65 ( 3 ) 210 - 210 2023.5

Cnm陽性Streptococcus mutansの分子生物学的解析(Molecular biological analysis of Cnm positive Streptococcus mutans)

Matsuoka Daiki, Naka Shuhei, Goto Kana, Nomura Ryota, Nakano Kazuhiko, Matsumoto-Nakano Michiyo

小児歯科学雑誌 61 ( 大会抄録号 ) 274 - 274 2023.4

cnm-positive Streptococcus mutans is associated with galactose-deficient IgA in patients with IgA nephropathy. International journal

Taro Misaki, Shuhei Naka, Hitoshi Suzuki, Mingfeng Lee, Ryosuke Aoki, Yasuyuki Nagasawa, Daiki Matsuoka, Seigo Ito, Ryota Nomura, Michiyo Matsumoto-Nakano, Yusuke Suzuki, Kazuhiko Nakano

PloS one 18 ( 3 ) e0282367 2023

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

The presence of Streptococcus mutans expressing Cnm protein encoded by cnm (cnm-positive S. mutans) in the oral cavity is associated with immunoglobulin A (IgA) nephropathy (IgAN). However, the precise mechanism by which cnm-positive S. mutans is involved in the pathogenesis of IgAN remains unclear. The present study evaluated glomerular galactose-deficient IgA1 (Gd-IgA1) to clarify the association between the presence of cnm-positive S. mutans and glomerular Gd-IgA1 in patients with IgAN. The presence of S. mutans and cnm-positive S. mutans was evaluated by polymerase chain reaction in saliva specimens from 74 patients with IgAN or IgA vasculitis. Immunofluorescent staining of IgA and Gd-IgA1 using KM55 antibody in clinical glomerular tissues was then performed. There was no significant association between the glomerular staining intensity of IgA and the positive rate of S. mutans. However, there was a significant association between the glomerular staining intensity of IgA and the positive rate of cnm-positive S. mutans (P < 0.05). There was also a significant association between the glomerular staining intensity of Gd-IgA1 (KM55) and the positive rate of cnm-positive S. mutans (P < 0.05). The glomerular staining intensity of Gd-IgA1 (KM55) was not associated with the positive rate of S. mutans. These results suggest that cnm-positive S. mutans in the oral cavity is associated with the pathogenesis of Gd-IgA1 in patients with IgAN.

DOI： 10.1371/journal.pone.0282367

Distribution of periodontopathic bacterial species between saliva and tonsils.

Ryota Nomura, Yasuyuki Nagasawa, Taro Misaki, Seigo Ito, Shuhei Naka, Mieko Okunaka, Maiko Watanabe, Kenzo Tsuzuki, Michiyo Matsumoto-Nakano, Kazuhiko Nakano

Odontology 111 ( 3 ) 719 - 727 2022.12

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

Periodontopathic bacteria cause an inflammatory disease localized in the periodontal tissue and are associated with various conditions in other body parts. The distribution of periodontopathic bacterial species in the tonsils is unknown, even though the tonsils are located close to the oral cavity, and inflammation of the tonsils causes various systemic diseases. We detected the major periodontopathic bacterial species residing in saliva and tonsil specimens from 25 subjects undergoing tonsillectomy. Nine of the ten major periodontopathic bacterial species were detected by polymerase chain reaction of tonsil specimens, among which Campylobacter rectus was the most common (80.0%), followed by Porphyromonas gingivalis (36.0%). The other seven types of periodontopathic bacterial species were distributed with 0% to 25.0% abundance in the tonsil specimens. C. rectus had a high detection rate in tonsil specimens (> 75.0%), regardless of whether it was detected in the corresponding saliva specimens. However, the detection rate for P. gingivalis in tonsil specimens was significantly higher in subjects with P. gingivalis-positive saliva (77.8%) than in those with P. gingivalis-negative saliva (6.3%; P < 0.001). Furthermore, 75.0% of P. gingivalis in tonsil specimens did not have the known fimA gene that encodes the 41-kDa filamentous appendage protein FimA, which is expressed on the cell surface of the bacteria. Our results suggest that certain periodontopathic bacterial species are detected in the tonsils either independently of or depending on their distribution in the oral cavity and may be involved in tonsil-related diseases.

DOI： 10.1007/s10266-022-00776-8

Cnm of Streptococcus mutans is important for cell surface structure and membrane permeability Reviewed

Shuhei Naka, Daiki Matsuoka, Kana Goto, Taro Misaki, Yasuyuki Nagasawa, Seigo Ito, Ryota Nomura, Kazuhiko Nakano, Michiyo Matsumoto-Nakano

Frontiers in Cellular and Infection Microbiology 12 2022.9

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal) Publisher：Frontiers Media SA

Streptococcus mutans, a Gram-positive facultative anaerobic bacterium, is a major pathogen of dental caries. The protein Cnm of S. mutans is involved in collagen binding, but its other biological functions are unknown. In this study, a Cnm-deficient isogenic mutant and a complementation strain were generated from a Cnm-positive S. mutans strain to help determine the properties of Cnm. Initially, comparison of the cell surface structure was performed by electron microscopy, which demonstrated that Cnm appears to be localized on the cell surface and associated with a protruding cell surface structure. Deep RNA sequencing of the strains revealed that the defect in Cnm caused upregulated expression of many genes related to ABC transporters and cell-surface proteins, while a few genes were downregulated. The amount of biofilm formed by the Cnm-defective strain increased compared with the parental and complemented strains, but the biofilm structure was thinner because of elevated expression of genes encoding glucan synthesis enzymes, leading to increased production of extracellular polysaccharides. Particular antibiotics, including bacitracin and chloramphenicol, had a lower minimum inhibitory concentration for the Cnm-defective strain than particular antibiotics, including bacitracin and chloramphenicol, compared with the parental and complemented strains. Our results suggest that S. mutans Cnm is located on the cell surface, gives rise to the observed protruding cell surface, and is associated with several biological properties related to membrane permeability.

DOI： 10.3389/fcimb.2022.994014

Simultaneous Presence of Campylobacter rectus and Cnm-Positive Streptococcus mutans in the Oral Cavity Is Associated with Renal Dysfunction in IgA Nephropathy Patients: 5-Year Follow-Up Analysis. International journal

Taro Misaki, Shuhei Naka, Yasuyuki Nagasawa, Daiki Matsuoka, Seigo Ito, Ryota Nomura, Michiyo Matsumoto-Nakano, Kazuhiko Nakano

Nephron 147 ( 3-4 ) 1 - 10 2022.8

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

BACKGROUND: The simultaneous presence of Streptococcus mutans expressing the Cnm protein encoded by cnm (i.e., cnm-positive S. mutans) and Campylobacter rectus in the oral cavity has been associated with proteinuria in patients with IgA nephropathy (IgAN). OBJECTIVES: The present study evaluated the relationship between renal function and oral bacteria in patients with IgAN over 5 years of follow-up. METHODS: The presence of C. rectus and cnm-positive S. mutans in saliva samples of 117 patients with IgAN was initially evaluated by polymerase chain reaction. Patients were then divided into four groups according to the results of C. rectus and cnm-positive S. mutans detection: group A: C. rectus (-), cnm-positive S. mutans (-); group B: C. rectus (+), cnm-positive S. mutans (-); group C: C. rectus (-), cnm-positive S. mutans (+); and group D: C. rectus (+), cnm-positive S. mutans (+). Clinical characteristics were prospectively followed for 5 years. RESULTS: Serum creatinine levels were significantly higher in group D than in group A over 5 years of follow-up. Additionally, the proportion of patients with an estimated glomerular filtration rate <45 mL/min increased over time; it was significantly greater in group D than in group A over 5 years of follow-up. CONCLUSION: These results suggest that the simultaneous presence of C. rectus and cnm-positive S. mutans in the oral cavity is associated with renal dysfunction in IgAN patients.

DOI： 10.1159/000525511

Porphyromonas gingivalis経鼻投与によるIgA腎症モデルマウスの作製

長澤康行, 野村良太, 三崎太郎, 仲周平, 伊藤誓悟, 和唐薫子, 楠博, 山崎博充, 新村健, 仲野道代, 仲野和彦

日本腎臓学会誌 64 ( 3 ) 243 - 243 2022.5

cnm遺伝子陽性S.mutansとC.rectusの口腔内の存在は5年後のIgA腎症患者の腎機能増悪に関連する

三崎太郎, 塩崎友里子, 伊藤大介, 清水吉貴, 鈴木由美子, 仲周平, 野村良太, 長澤康行, 伊藤誓悟, 仲野道代, 仲野和彦

日本腎臓学会誌 64 ( 3 ) 243 - 243 2022.5

Title IgA Nephropathy and Oral Bacterial Species Related to Dental Caries and Periodontitis. Reviewed International journal

Yasuyuki Nagasawa, Taro Misaki, Seigo Ito, Shuhei Naka, Kaoruko Wato, Ryota Nomura, Michiyo Matsumoto-Nakano, Kazuhiko Nakano

International journal of molecular sciences 23 ( 2 ) 2022.1

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

A relationship between IgA nephropathy (IgAN) and bacterial infection has been suspected. As IgAN is a chronic disease, bacteria that could cause chronic infection in oral areas might be pathogenetic bacteria candidates. Oral bacterial species related to dental caries and periodontitis should be candidates because these bacteria are well known to be pathogenic in chronic dental disease. Recently, several reports have indicated that collagen-binding protein (cnm)-(+) Streptococcs mutans is relate to the incidence of IgAN and the progression of IgAN. Among periodontal bacteria, Treponema denticola, Porphyromonas gingivalis and Campylobacte rectus were found to be related to the incidence of IgAN. These bacteria can cause IgAN-like histological findings in animal models. While the connection between oral bacterial infection, such as infection with S. mutans and periodontal bacteria, and the incidence of IgAN remains unclear, these bacterial infections might cause aberrantly glycosylated IgA1 in nasopharynx-associated lymphoid tissue, which has been reported to cause IgA deposition in mesangial areas in glomeruli, probably through the alteration of microRNAs related to the expression of glycosylation enzymes. The roles of other factors related to the incidence and progression of IgA, such as genes and cigarette smoking, can also be explained from the perspective of the relationship between these factors and oral bacteria. This review summarizes the relationship between IgAN and oral bacteria, such as cnm-(+) S. mutans and periodontal bacteria.

DOI： 10.3390/ijms23020725

Relationship between IgA Nephropathy and Porphyromonas gingivalis; Red Complex of Periodontopathic Bacterial Species. Reviewed International journal

Yasuyuki Nagasawa, Ryota Nomura, Taro Misaki, Seigo Ito, Shuhei Naka, Kaoruko Wato, Mieko Okunaka, Maiko Watabe, Katsuya Fushimi, Kenzo Tsuzuki, Michiyo Matsumoto-Nakano, Kazuhiko Nakano

International journal of molecular sciences 22 ( 23 ) 2021.12

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

IgA nephropathy (IgAN) has been considered to have a relationship with infection in the tonsil, because IgAN patients often manifest macro hematuria just after tonsillitis. In terms of oral-area infection, the red complex of periodontal bacteria (Porphyromonas gingivalis (P. gingivalis), Treponema denticol (T. denticola) and Tannerella forsythia (T. forsythia)) is important, but the relationship between these bacteria and IgAN remains unknown. In this study, the prevalence of the red complex of periodontal bacteria in tonsil was compared between IgAN and tonsillitis patients. The pathogenicity of IgAN induced by P. gingivalis was confirmed by the mice model treated with this bacterium. The prevalence of P. gingivalis and T. forsythia in IgAN patients was significantly higher than that in tonsillitis patients (p < 0.001 and p < 0.05, respectively). A total of 92% of tonsillitis patients were free from red complex bacteria, while only 48% of IgAN patients had any of these bacteria. Nasal administration of P. gingivalis in mice caused mesangial proliferation (p < 0.05 at days 28a nd 42; p < 0.01 at days 14 and 56) and IgA deposition (p < 0.001 at day 42 and 56 after administration). Scanning-electron-microscopic observation revealed that a high-density Electron-Dense Deposit was widely distributed in the mesangial region in the mice kidneys treated with P. gingivalis. These findings suggest that P. gingivalis is involved in the pathogenesis of IgAN.

DOI： 10.3390/ijms222313022

扁桃と口腔内の歯周病菌の一致率の検討

長澤康行, 野村良太, 三崎太郎, 仲周平, 伊藤誓悟, 和唐薫子, 木田有利, 名波正義, 倉賀野隆裕, 仲野道代, 仲野和彦

日本腎臓学会誌 63 ( 4 ) 494 - 494 2021.6

Inhibitory effects of flavedo, albedo, fruits, and leaves of Citrus unshiu extracts on Streptococcus mutans. Reviewed International journal

Ryota Nomura, Jumpei Ohata, Masatoshi Otsugu, Rena Okawa, Shuhei Naka, Michiyo Matsumoto-Nakano, Kazuhiko Nakano

Archives of oral biology 124 105056 - 105056 2021.4

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

OBJECTVES: Citrus unshiu has been shown to exhibit antimicrobial effects against citrus diseases. In the present study, C. unshiu was divided into flavedo, albedo, fruits, and leaves; the inhibitory effects of these extracts on Streptococcus mutans, a major pathogen of dental caries, were investigated. DESIGN: C. unshiu specimens were separated into flavedo, albedo, fruits, and leaves. First, pH values and polyphenol amounts in Citrus extracts were measured. In addition, Citrus extract was added to the bacterial suspensions of S. mutans MT8148, and inhibitory effects of C. unshiu extracts on MT8148 for antimicrobial activity, bacterial growth, and biofilm formation were analyzed. These assays were also performed using C. sinensis extracts. RESULTS: Among these extracts, albedo exhibited a pH value closest to neutral, while the fruits exhibited the most acidic pH value; the pH values significantly differed between these extracts (P < 0.05). In addition, the amounts of polyphenols were significantly higher in albedo than in other extracts (P < 0.001). All extracts showed inhibitory effects on MT8148 for antimicrobial activity, bacterial growth and biofilm formation. These inhibitory effects were significantly stronger in flavedo, albedo, and fruits, compared with leaves (P < 0.05). Furthermore, extracts of Citrus sinensis also showed inhibitory effects on S. mutans, although these effects were weaker than the effects of C. unshiu. CONCLUSION: These results suggest that extracts from C. unshiu fruits exhibit inhibitory effects on S. mutans, among which albedo may be especially useful for dental caries prevention due to its neutral pH and abundant polyphenols, in addition to its inhibitory effects.

DOI： 10.1016/j.archoralbio.2021.105056

Streptococcus mutans induces IgA nephropathy-like glomerulonephritis in rats with severe dental caries. Reviewed International journal

Shuhei Naka, Kaoruko Wato, Taro Misaki, Seigo Ito, Daiki Matsuoka, Yasuyuki Nagasawa, Ryota Nomura, Michiyo Matsumoto-Nakano, Kazuhiko Nakano

Scientific reports 11 ( 1 ) 5784 - 5784 2021.3

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

The mechanisms underlying immunoglobulin A nephropathy (IgAN), the most common chronic form of primary glomerulonephritis, remain poorly understood. Streptococcus mutans, a Gram-positive facultatively anaerobic oral bacterium, is a common cause of dental caries. In previous studies, S. mutans isolates that express Cnm protein on their cell surface were frequently detected in IgAN patients. In the present study, inoculation of Cnm-positive S. mutans in the oral cavities of 2-week-old specific-pathogen free Sprague-Dawley rats fed a high-sucrose diet for 32 weeks produced severe dental caries in all rats. Immunohistochemical analyses of the kidneys using IgA- and complement C3-specific antibodies revealed positive staining in the mesangial region. Scanning electron microscopy revealed a wide distribution of electron dense deposits in the mesangial region and periodic acid-Schiff staining demonstrated prominent proliferation of mesangial cells and mesangial matrix. These results suggest that IgAN-like glomerulonephritis was induced in rats with severe dental caries by Cnm-positive S. mutans.

DOI： 10.1038/s41598-021-85196-4

Non-alcoholic steatohepatitis caused by oral bacteria Invited Reviewed

Shuhei Naka, Michiyo Matsumoto-Nakano

Pediatric Dental Journal 31 11 - 16 2021.2

Intravenous administration of Streptococcus mutans induces IgA nephropathy-like lesions. Reviewed

Shuhei Naka, Kaoruko Wato, Taro Misaki, Seigo Ito, Yasuyuki Nagasawa, Ryota Nomura, Michiyo Matsumoto-Nakano, Kazuhiko Nakano

Clinical and experimental nephrology 24 ( 12 ) 1122 - 1131 2020.12

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

BACKGROUND: IgA nephropathy (IgAN) is one of the most frequently occurring types of chronic glomerulonephritis. Previous analyses have revealed that a major pathogen of dental caries, Streptococcus mutans [which expresses collagen-binding protein (Cnm) on its surface], is involved in the pathogenesis of IgAN. METHODS: Cnm-positive S. mutans isolated from a patient with IgAN was intravenously administered to specific pathogen-free Sprague-Dawley rats to evaluate their kidney conditions. RESULTS: The urinary protein level of the S. mutans group reached a plateau at 30 days, with increased numbers of mesangial cells and an increased mesangial matrix. The numbers of rats with IgA-positive and/or C3-positive glomeruli were significantly greater in the S. mutans group than in the control group at 45 days (P < 0.05). Electron microscopy analyses revealed electron-dense depositions in the mesangial area among rats in the S. mutans group. There were significantly more CD68-positive cells (macrophages) in the glomeruli of the S. mutans group than in the glomeruli of the control group during the late phase (P < 0.05), similar to the findings in patients with IgAN. CONCLUSION: Our results suggested that intravenous administration of Cnm-positive S. mutans caused transient induction of IgAN-like lesions in rats.

DOI： 10.1007/s10157-020-01961-1

Potential involvement of Streptococcus mutans possessing collagen binding protein Cnm in infective endocarditis. Reviewed International journal

Ryota Nomura, Masatoshi Otsugu, Masakazu Hamada, Saaya Matayoshi, Noboru Teramoto, Naoki Iwashita, Shuhei Naka, Michiyo Matsumoto-Nakano, Kazuhiko Nakano

Scientific reports 10 ( 1 ) 19118 - 19118 2020.11

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

Streptococcus mutans, a significant contributor to dental caries, is occasionally isolated from the blood of patients with infective endocarditis. We previously showed that S. mutans strains expressing collagen-binding protein (Cnm) are present in the oral cavity of approximately 10-20% of humans and that they can effectively invade human umbilical vein endothelial cells (HUVECs). Here, we investigated the potential molecular mechanisms of HUVEC invasion by Cnm-positive S. mutans. The ability of Cnm-positive S. mutans to invade HUVECs was significantly increased by the presence of serum, purified type IV collagen, and fibrinogen (p < 0.001). Microarray analyses of HUVECs infected by Cnm-positive or -negative S. mutans strains identified several transcripts that were differentially upregulated during invasion, including those encoding the small G protein regulatory proteins ARHGEF38 and ARHGAP9. Upregulation of these proteins occurred during invasion only in the presence of serum. Knockdown of ARHGEF38 strongly reduced HUVEC invasion by Cnm-positive S. mutans. In a rat model of infective endocarditis, cardiac endothelial cell damage was more prominent following infection with a Cnm-positive strain compared with a Cnm-negative strain. These results suggest that the type IV collagen-Cnm-ARHGEF38 pathway may play a crucial role in the pathogenesis of infective endocarditis.

DOI： 10.1038/s41598-020-75933-6

Identification and functional analysis of glutamine transporter in Streptococcus mutans. Reviewed International journal

Yuko Morikawa, Setsuyo Morimoto, Eri Yoshida, Shuhei Naka, Hiroaki Inaba, Michiyo Matsumoto-Nakano

Journal of oral microbiology 12 ( 1 ) 1797320 - 1797320 2020.8

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

Background: Streptococcus mutans, a biofilm-forming bacterium, possesses several transporters that function as import/export molecules. Among them, the PII protein family is composed of members that regulate glutamine synthesis in bacterial species. Objective: In this study, we characterized the function of the glutamine transporter in S. mutans MT8148. Methods: The SMU.732 gene, corresponding to glnP in S. mutans, is homologous to the glutamine transporter gene in Bacillus subtilis. We constructed a glnP-inactivated mutant strain (GEMR) and a complement strain (comp-GEMR) and evaluated their biological functions. Results: Growth of GEMR was similar in the presence and absence of glutamine, whereas the growth rates of MT8148 and comp-GEMR were significantly lower in the presence of glutamine as compared to its absence. Furthermore, biofilms formed by MT8148 and comp-GEMR were significantly thicker than that formed by GEMR, while the GEMR strain showed a significantly lower survival rate in an acidic environment than the other strains. Addition of n-phenyl-2-naphthylamine, used to label of the membrane, led to increased fluorescence intensity of MT8148 and GEMR, albeit that was significantly lower in the latter. Conclusions: These results suggest that glnP is associated with glutamine transport in S. mutans, especially the import of glutamine involved in biofilm formation.

DOI： 10.1080/20002297.2020.1797320

Specific strains of Streptococcus mutans, a pathogen of dental caries, in the tonsils, are associated with IgA nephropathy. Reviewed International journal

Seigo Ito, Taro Misaki, Shuhei Naka, Kaoruko Wato, Yasuyuki Nagasawa, Ryota Nomura, Masatoshi Otsugu, Michiyo Matsumoto-Nakano, Kazuhiko Nakano, Hiroo Kumagai, Naoki Oshima

Scientific reports 9 ( 1 ) 20130 - 20130 2019.12

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

Streptococcus mutans is known to be a major causative agent of dental caries, and strains expressing the cell surface collagen-binding Cnm protein contribute to the development of several systemic diseases. A relationship between tonsillar immunity and glomerulonephritis has been recognized in IgA nephropathy (IgAN), and specific pathogens may have effects on tonsillar immunity (mucosal immunity). Here, we present findings showing a relationship between the presence of Cnm-positive S. mutans strains in the tonsils of IgAN patients and IgAN condition/pathogenesis. Analyses of tonsillar specimens obtained from patients with IgAN (n = 61) and chronic tonsillitis (controls; n = 40) showed that the Cnm protein-positive rate was significantly higher in IgAN patients. Among IgAN patients, the tonsillar Cnm-positive group (n = 15) had a significantly higher proportion of patients with high urinary protein (>1.5 g/gCr) and lower serum albumin level than the Cnm-negative group (n = 46). Additionally, Cnm protein and CD68, a common human macrophage marker, were shown to be merged in the tonsils of IgAN patients. These findings suggest that Cnm-positive S. mutans strains in the tonsils may be associated with severe IgAN.

DOI： 10.1038/s41598-019-56679-2

Case of autoimmune neutropenia with severe marginal periodontitis Reviewed

Setsuyo Morimoto, Keiko Hirano, Keiko Tabata, Haruka Asaumi, Yuko Morikawa, Yuki Matsumi, Shuhei Naka, Michiyo Matsumoto-Nakano

PEDIATRIC DENTAL JOURNAL 29 ( 3 ) 138 - 145 2019.12

Birooted primary canines identified in 8-year-old Japanese girl – Case report Reviewed

Kazuma Kokomoto, Rena Okawa, Shuhei Naka, Ryota Nomura, Kazuhiko Nakano

Pediatric Dental Journal 29 ( 1 ) 48 - 51 2019.4

Relationship between Streptococcus mutans expressing Cnm in the oral cavity and non-alcoholic steatohepatitis: a pilot study. Reviewed International journal

Shuichi Tonomura, Shuhei Naka, Keiko Tabata, Tasuku Hara, Kojiro Mori, Saiyu Tanaka, Yoshio Sumida, Kazuyuki Kanemasa, Ryota Nomura, Michiyo Matsumoto-Nakano, Masafumi Ihara, Nobuyuki Takahashi, Kazuhiko Nakano

BMJ open gastroenterology 6 ( 1 ) e000329 2019

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

Background: Non-alcoholic steatohepatitis (NASH) is a severe state of non-alcoholic fatty liver disease (NAFLD), which is pathologically characterised by steatosis, hepatocyte ballooning, and lobular inflammation. Host-microbial interaction has gained attention as one of the risk factors for NASH. Recently, cnm-gene positive Streptococcus mutans expressing cell surface collagen-binding protein, Cnm (cnm-positive S. mutans), was shown to aggravate NASH in model mice. Here, we assessed the detection rate of cnm-positive S. mutans in oral samples from patients with NASH among NAFLD. Methods: This single hospital cohort study included 41 patients with NAFLD. NASH was diagnosed histologically or by clinical score. The prevalence of cnm-positive S. mutans, oral hygiene and blood tests, including liver enzymes, adipocytokines and inflammatory and fibrosis markers, were assessed in biopsy-proven or clinically suspected NASH among NAFLD. Results: Prevalence of cnm-positive S. mutans was significantly higher in patients with NASH than patients without NASH (OR 3.8; 95% CI 1.02 to 15.5). The cnm-positive S. mutans was related to decreased numbers of naturally remaining teeth and increased type IV collagen 7S level (median (IQR) 10.0 (5.0-17.5) vs 20.0 (5.0-25.0), p=0.06; 5.1 (4.0-7.9) vs 4.4 (3.7-5.3), p=0.13, respectively). Conclusions: Prevalence of cnm-positive S. mutans in the oral cavity could be related to fibrosis of NASH among NAFLD.

DOI： 10.1136/bmjgast-2019-000329

Dental management of unilateral multiple impacted primary teeth

Yuki Matsumi, Yuko Morikawa, Eri Yoshida, Setsuyo Morimoto, Sho Yoshida, Tatsushi Matsumura, Seiji Iida, Yukiko Takashima, Shuhei Naka, Michiyo Matsumoto-Nakano

PEDIATRIC DENTAL JOURNAL 28 ( 3 ) 119 - 124 2018.12

A Potential New Risk Factor for Stroke: Streptococcus Mutans With Collagen-Binding Protein. Reviewed International journal

Chikanori Inenaga, Kazuya Hokamura, Kazuhiko Nakano, Ryota Nomura, Shuhei Naka, Toshihiko Ohashi, Takashi Ooshima, Nagato Kuriyama, Toshimitsu Hamasaki, Koichiro Wada, Kazuo Umemura, Tokutaro Tanaka

World neurosurgery 113 e77-e81 2018.5

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

BACKGROUND: Among human oral bacteria, particular kinds of Streptococcus mutans (SM) known as dental caries pathogens contain a collagen-binding protein, Cnm, and show platelet aggregation inhibition and matrix metalloproteinase-9 activation. We have previously reported that these strains may be a risk factor for intracerebral hemorrhage. As a major sample-providing hospital, we report the clinical details, including intracranial aneurysms and ischemic stroke. METHODS: After the study received approval from the Ethical Committee, 429 samples of whole saliva were obtained from patients who were admitted to or visited our hospital between February 16, 2010, and February 28, 2011. The study cohort comprised 48 patients with cardioembolic stroke (CES), 151 with non-CES infarct, 54 with intracerebral hemorrhage (ICH), 43 with ruptured intracranial aneurysm (RIA), and 97 with unruptured intracranial aneurysm (UIA). Cultured SM was identified as Cnm-positive when the corresponding gene was positive. The results were compared with those from 79 healthy volunteers. Relationships between Cnm-positive SM and known risk factors, including hypertension, diabetes, hyperlipidemia, smoking, and alcohol consumption, were analyzed. RESULTS: A statistically significant high Cnm-positive rate was observed in patients with CES, non-CES infarct, ICH, and RIA (P = 0.002, 0.039, 0.013, and 0.009, respectively). There were no relationships between Cnm-positive SM and known risk factors. CONCLUSIONS: Specific types of oral SM can be a risk factor for cardioembolic infarct, intracerebral hemorrhage, and intracranial aneurysm rupture. Further study is needed.

DOI： 10.1016/j.wneu.2018.01.158

Displacement of maxillary right second premolar caused by gutta percha filling in corresponding primary molar Reviewed

Shuhei Naka, Kazuma Kokomoto, Jumpei Ohata, Rena Okawa, Ryota Nomura, Kazuhiko Nakano

Pediatric Dental Journal 28 ( 1 ) 13 - 18 2018.4

Odontoma associated with unerupted primary tooth in primary dentition - Three cases

Yukiko Takashima, Yuko Morikawa, Atsushi Takagi, Yuki Matsumi, Tatsushi Matsumura, Seiji Iida, Shuhei Naka, Michiyo Matsumoto-Nakano

PEDIATRIC DENTAL JOURNAL 28 ( 1 ) 19 - 24 2018.4

Campylobacter rectus in the Oral Cavity Correlates with Proteinuria in Immunoglobulin A Nephropathy Patients. Reviewed International journal

Taro Misaki, Shuhei Naka, Kaoruko Wato, Rina Hatakeyama, Yasuyuki Nagasawa, Seigo Ito, Hiroaki Inaba, Ryota Nomura, Michiyo Matsumoto-Nakano, Kazuhiko Nakano

Nephron 139 ( 2 ) 143 - 149 2018

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

BACKGROUND: Periodontitis-related pathogens, such as Campylobacter or Treponema species, have recently been shown to be associated with immunoglobulin A nephropathy (IgAN). Some strains of Streptococcus mutans, a major pathogen of dental caries, harbour the cnm gene that encodes a collagen-binding protein (Cnm). This has also been demonstrated to be associated with urinary protein levels in IgAN patients. OBJECTIVES: The purpose of the present study was to analyse the association of IgAN with C. rectus, Treponema denticola and cnm-positive S. mutans in the oral cavity of humans. METHODS: The presence of C. rectus, T. denticola and cnm-positive S. mutans strains in saliva samples of 117 IgAN patients and 56 healthy controls was evaluated by PCR, and the subjects' clinical parameters were analysed. RESULTS: C. rectus was significantly more prevalent in the IgAN group than in the control group (p < 0.05). The C. rectus-positive group was significantly associated with proteinuria in the IgAN group (p < 0.05). In addition, the C. rectus-positive and cnm-positive S. mutans group was shown to be more closely associated with urinary protein levels than the other groups (p < 0.0083). CONCLUSION: Our results suggest that harbouring C. rectus in the oral cavity could be associated with proteinuria in IgAN patients.

DOI： 10.1159/000487103

Longitudinal comparison of Streptococcus mutans-induced aggravation of non-alcoholic steatohepatitis in mice. Reviewed International journal

Shuhei Naka, Kaoruko Wato, Rina Hatakeyama, Rena Okawa, Ryota Nomura, Kazuhiko Nakano

Journal of oral microbiology 10 ( 1 ) 1428005 - 1428005 2018

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

Background: We previously reported that intravenous administration of Streptococcus mutans strain TW871 caused typical non-alcoholic steatohepatitis (NASH)-like findings in a high-fat diet (HFD) mouse model at 16 weeks after initiating the experiment. Objective: The purpose of the present study was to analyse mice administered S. mutans TW871 fed a HFD for various periods of time. Methods: First, 6-week-old C57BL/6J mice were fed an HFD for 4 weeks, then TW871 (1 × 107 CFU) or phosphate-buffered saline (PBS) were intravenously administered. Mice were euthanized 12, 16, 20, and 48 weeks after starting the experiment, and conventional clinical and histopathological evaluations were performed. Results: Typical NASH-like findings were not identified in the mice at 12 weeks, while they were observed in the TW871 group at 16 weeks, and the severity of NASH symptoms were increased at 20 weeks. Furthermore, signs of severe NASH were also observed at 48 weeks. In contrast, in the PBS-administered group, the NASH findings were identified only at 48 weeks and no typical NASH features were observed at 12, 16, or 20 weeks. Conclusion: These results suggest that intravenous administration of a specific S. mutans strain aggravates NASH in a time-dependent manner in the mice in contrast to mice without S. mutans exposure.

DOI： 10.1080/20002297.2018.1428005

The in vivo Inhibition of Oral Biofilm Accumulation and Streptococcus mutans by Ceramic Water. Reviewed International journal

Ryota Nomura, Risa Yoneyama, Shuhei Naka, Masatoshi Otsugu, Yuko Ogaya, Rina Hatakeyama, Yumiko Morita, Jumpei Maruo, Michiyo Matsumoto-Nakano, Osamu Yamada, Kazuhiko Nakano

Caries research 51 ( 1 ) 58 - 67 2017

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

Combustion-synthesized titanium carbide ceramics uniformly disperse silver, producing silver ions and hydroxyl radicals in water. This generates antimicrobial activity against various bacteria. One such bacterium is Streptococcus mutans, a gram-positive anaerobic bacterium known as a major pathogen of dental caries. In this study, we analyzed the inhibition of oral biofilms and S. mutans by ceramic water in in vitro and human studies. S. mutans strains showed significantly lower antimicrobial and sucrose-dependent adhesion activity in the presence of ceramic powder compared with untreated culture medium. Confocal microscopy revealed that S. mutans biofilm structures with ceramic powder were thin and coarse. Twenty-seven volunteers (13 males, 14 females; 18-37 years old, mean 25.2 years) were enrolled for subsequent studies. After each meal, one group was asked to rinse with ceramic water while the other rinsed with untreated water for 1 week. After 1 week, the rinsing contents were switched between the groups and the same protocol was followed for an additional week. After rinsing with ceramic water, the average plaque score was 43.0 ± 3.7, which was significantly lower than the baseline value (74.1 ± 5.7, p < 0.001). However, no significant difference was observed when rinsing with untreated water. In addition, the total number of S. mutans in saliva was significantly reduced after rinsing with ceramic water compared with untreated water (p < 0.05). These results suggest that ceramic water possesses antimicrobial activity against S. mutans and inhibits biofilm formation. Rinsing with ceramic water can also inhibit dental plaque formation and S. mutans colonization in humans.

DOI： 10.1159/000452343

Oral Cnm-positive Streptococcus Mutans Expressing Collagen Binding Activity is a Risk Factor for Cerebral Microbleeds and Cognitive Impairment. Reviewed International journal

Isao Watanabe, Nagato Kuriyama, Fumitaro Miyatani, Ryota Nomura, Shuhei Naka, Kazuhiko Nakano, Masafumi Ihara, Komei Iwai, Daisuke Matsui, Etsuko Ozaki, Teruhide Koyama, Masaru Nishigaki, Toshiro Yamamoto, Aiko Tamura, Toshiki Mizuno, Kentaro Akazawa, Akihiro Takada, Kazuo Takeda, Kei Yamada, Masanori Nakagawa, Tokutaro Tanaka, Narisato Kanamura, Robert P Friedland, Yoshiyuki Watanabe

Scientific reports 6 38561 - 38561 2016.12

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

Cerebral microbleeds (CMBs) are an important risk factor for stroke and dementia. We have shown that the collagen binding surface Cnm protein expressed on cnm-positive Streptococcus mutans is involved in the development of CMBs. However, whether the collagen binding activity of cnm-positive S. mutans is related to the nature of the CMBs or to cognitive impairment is unclear. Two-hundred seventy nine community residents (70.0 years) were examined for the presence or absence of cnm-positive S. mutans in the saliva by PCR and collagen binding activity, CMBs, and cognitive function were evaluated. Cnm-positive S. mutans was detected more often among subjects with CMBs (p < 0.01) than those without. The risk of CMBs was significantly higher (odds ratio = 14.3) in the group with S. mutans expressing collagen binding activity, as compared to the group without that finding. Deep CMBs were more frequent (67%) and cognitive function was lower among subjects with cnm-positive S. mutans expressing collagen binding activity. This work supports the role of oral health in stroke and dementia and proposes a molecular mechanism for the interaction.

DOI： 10.1038/srep38561

Contributions of Streptococcus mutans Cnm and PA antigens to aggravation of non-alcoholic steatohepatitis in mice. Reviewed International journal

Shuhei Naka, Rina Hatakeyama, Yukiko Takashima, Michiyo Matsumoto-Nakano, Ryota Nomura, Kazuhiko Nakano

Scientific reports 6 36886 - 36886 2016.11

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

Streptococcus mutans, a major pathogen of dental caries, can cause infective endocarditis after invading the bloodstream. Recently, intravenous administration of specific S. mutans strains was shown to aggravate non-alcoholic steatohepatitis (NASH) in a mouse model fed a high-fat diet. Here, we investigated the mechanism of this aggravation in a NASH mouse model by focusing on the S. mutans cell surface collagen-binding protein (Cnm) and the 190-kDa protein antigen (PA). Mice that were intravenously administered a S. mutans strain with a defect in Cnm (TW871CND) or PA (TW871PD) did not show clinical or histopathological signs of NASH aggravation, in contrast to those administered the parent strain TW871. The immunochemical analyses demonstrated higher levels of interferon-γ and metallothionein expression in the TW871 group than in the TW871CND and TW871PD groups. Analysis of bacterial affinity to cultured hepatic cells in the presence of unsaturated fatty acids revealed that the incorporation rate of TW871 was significantly higher than those of TW871CND and TW871PD. Together, our results suggest that Cnm and PA are important cell surface proteins for the NASH aggravation caused by S. mutans adhesion and affinity for hepatic cells.

DOI： 10.1038/srep36886

Presence of Streptococcus mutans strains harbouring the cnm gene correlates with dental caries status and IgA nephropathy conditions. International journal

Taro Misaki, Shuhei Naka, Rina Hatakeyama, Akiko Fukunaga, Ryota Nomura, Taisuke Isozaki, Kazuhiko Nakano

Scientific reports 6 36455 - 36455 2016.11

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

Streptococcus mutans is a major pathogen of human dental caries. Strains harbouring the cnm gene, which encodes Cnm, a collagen-binding protein, contribute to the development of several systemic diseases. In this study, we analysed S. mutans strains isolated from the oral cavity of immunoglobulin (Ig)A nephropathy (IgAN) patients to determine potential relationships between cnm and caries status as well as IgAN conditions. Saliva specimens were collected from 109 IgAN patients and the cnm status of isolated S. mutans strains was determined using PCR. In addition, the dental caries status (decayed, missing or filled teeth [DMFT] index) in patients who agreed to dental consultation (n = 49) was evaluated. The DMFT index and urinary protein levels in the cnm-positive group were significantly higher than those in the cnm-negative group (p < 0.05). Moreover, the urinary protein levels in the high DMFT (≥15) group were significantly higher than those in the low DMFT (<15) group (p < 0.05). Our results show that isolation of cnm-positive S. mutans strains from the oral cavity may be associated with urinary protein levels in IgAN patients, especially those with a high dental caries status.

DOI： 10.1038/srep36455

Lowe syndrome oral findings: Case report Reviewed

Rena Okawa, Shuhei Naka, Kanae Saga, Kazuhiko Nakano

Pediatric Dental Journal 26 ( 1 ) 34 - 37 2016.4

Distribution of Streptococcus mutans strains with collagen-binding proteins in the oral cavity of IgA nephropathy patients.

Taro Misaki, Shuhei Naka, Keiko Kuroda, Ryota Nomura, Tempei Shiooka, Yoshitaka Naito, Yumiko Suzuki, Hideo Yasuda, Taisuke Isozaki, Kazuhiko Nakano

Clinical and experimental nephrology 19 ( 5 ) 844 - 50 2015.10

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

BACKGROUND: IgA nephropathy (IgAN) is the most common primary chronic glomerulonephritis; however, its precise initiating pathogenesis remains unclear. Streptococcus mutans is a major pathogen of human dental caries. S. mutans strains with the cnm gene encoding Cnm, a collagen-binding protein, have been reported to contribute to the development of systemic diseases. However, the contribution of S. mutans with Cnm in the development of IgAN has not been reported. The aim of this study was to investigate the prevalence of cnm-positive S. mutans in IgAN patients and clarify the effects of cnm-positive S. mutans on the histological pathology of IgAN. METHODS: We identified the cnm gene in S. mutans isolated in saliva specimens, which were collected from IgAN patients (n = 53) and control subjects (n = 50). We evaluated the collagen-binding properties of S. mutans in IgAN patients and controls. The clinical parameters and histological scores were also assessed in IgAN patients. RESULTS: The rates of S. mutans isolation in IgAN and control groups were 84.0 and 84.9 %, respectively, not significantly dfferent. cnm-positive strains were significantly more prevalent in the IgAN group than in controls (32.1 vs. 14.0 %, p < 0.05). With regard to collagen-binding assays, the binding rates of cnm-positive strains were significantly higher in the IgAN group than in controls (96.6 vs. 30.0, p < 0.05). In addition, the segmental glomerulosclerosis scores were significantly higher in cnm-positive patients with IgAN than in cnm-negative patients with IgAN (0.94 vs. 0.57, p < 0.05). CONCLUSION: cnm-positive S. mutans strains are potentially associated with the pathogenesis of IgAN.

DOI： 10.1007/s10157-014-1072-0

Epulis appeared after exfoliation of natal tooth in infant Japanese boy Reviewed

Rena Okawa, Kazuyo Fujita, Shuhei Naka, Ryota Nomura, Kazuhiko Nakano

Pediatric Dental Journal 24 ( 3 ) 189 - 191 2014.12

Contribution of the interaction of Streptococcus mutans serotype k strains with fibrinogen to the pathogenicity of infective endocarditis. Reviewed International journal

Ryota Nomura, Masatoshi Otsugu, Shuhei Naka, Noboru Teramoto, Ayuchi Kojima, Yoshinori Muranaka, Michiyo Matsumoto-Nakano, Takashi Ooshima, Kazuhiko Nakano

Infection and immunity 82 ( 12 ) 5223 - 34 2014.12

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

Streptococcus mutans, a pathogen responsible for dental caries, is occasionally isolated from the blood of patients with bacteremia and infective endocarditis (IE). Our previous study demonstrated that serotype k-specific bacterial DNA is frequently detected in S. mutans-positive heart valve specimens extirpated from IE patients. However, the reason for this frequent detection remains unknown. In the present study, we analyzed the virulence of IE from S. mutans strains, focusing on the characterization of serotype k strains, most of which are positive for the 120-kDa cell surface collagen-binding protein Cbm and negative for the 190-kDa protein antigen (PA) known as SpaP, P1, antigen I/II, and other designations. Fibrinogen-binding assays were performed with 85 clinical strains classified by Cbm and PA expression levels. The Cbm(+)/PA(-) group strains had significantly higher fibrinogen-binding rates than the other groups. Analysis of platelet aggregation revealed that SA31, a Cbm(+)/PA(-) strain, induced an increased level of aggregation in the presence of fibrinogen, while negligible aggregation was induced by the Cbm-defective isogenic mutant SA31CBD. A rat IE model with an artificial impairment of the aortic valve created using a catheter showed that extirpated heart valves in the SA31 group displayed a prominent vegetation mass not seen in those in the SA31CBD group. These findings could explain why Cbm(+)/PA(-) strains are highly virulent and are related to the development of IE, and the findings could also explain the frequent detection of serotype k DNA in S. mutans-positive heart valve clinical specimens.

DOI： 10.1128/IAI.02164-14

A specific Streptococcus mutans strain aggravates non-alcoholic fatty liver disease. Reviewed International journal

S Naka, R Nomura, Y Takashima, R Okawa, T Ooshima, K Nakano

Oral diseases 20 ( 7 ) 700 - 6 2014.10

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

OBJECTIVE: Streptococcus mutans, a major dental caries pathogen, has shown to be associated with the aggravation of cerebral hemorrhage and inflammatory bowel diseases. In this study, we evaluated the effects ofS. mutans on the development of non-alcoholic steatohepatitis (NASH) in a mouse model. MATERIALS AND METHODS: Streptococcus mutans oral strain MT8148 (serotype c) and a blood isolate TW871 (k) were used. C57BL/6J mice (6 weeks old)were fed a high-fat diet for 4 weeks; the test strains or phosphate-buffered saline was then intravenously administered. Mice were euthanized after 8 or 12 weeks. Whole body, extirpated liver, and visceral fat weights were determined, and histopathological evaluations of the liver specimens were performed. RESULTS: Mice infected with TW871 showed significantly greater body and liver weights than those administered MT8148 or phosphate-buffered saline. Histopathological analyses revealed prominent infiltration of inflammatory cells and adipocellular deposition in livers extirpated 8 weeks after an infection with TW871; fibrosis was also observed in livers extirpated after 12 weeks. CONCLUSION: These results suggest that a specific strain of S. mutans could induce NASH.

Delayed eruption of mandibular primary central incisors in a child with severe lingual inclination and their spontaneous movement to appropriate positions Reviewed

Rena Okawa, Shuhei Naka, Miharu Higashino, Ryota Nomura, Kazuhiko Nakano

Pediatric Dental Journal 24 ( 2 ) 120 - 123 2014.8

Hypoplasia in crown of primary mandibular left lateral incisor identified in infant Japanese girl Reviewed

Rena Okawa, Shuhei Naka, Kanae Saga, Ryota Nomura, Kazuhiko Nakano

Pediatric Dental Journal 24 ( 2 ) 129 - 131 2014.8

Aggravation of inflammatory bowel diseases by oral streptococci. Reviewed International journal

A Kojima, R Nomura, S Naka, R Okawa, T Ooshima, K Nakano

Oral diseases 20 ( 4 ) 359 - 66 2014.5

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

OBJECTIVES: Streptococcus mutans can aggravate colitis in mice. We evaluated the virulence of colitis using type strains as well as blood isolates of several oral streptococcal species. MATERIALS AND METHODS: We investigated the susceptibility of blood isolates of several oral streptococci to phagocytosis, adhesion to and invasion of hepatic cells and interferon-γ secretion. A mouse model of dextran sodium sulphate-induced colitis was used to evaluate bacterial aggravation of colitis. In addition, interferon-γ antibody was administered to mice with prominent aggravation of colitis. RESULTS: In vitro analyses showed that Streptococcus sanguinis ATCC 10556 was a possible virulent strain among type strains of several oral streptococci, and that analysis of blood isolates of S. sanguinis TW289 revealed a potential virulent strain. Intravenous administration of ATCC 10556 and TW289 caused prominent aggravation of dextran sodium sulphate-induced colitis, and histopathological examinations showed that interferon-γ secretion due to infection of hepatic cells caused colitis aggravation. Administration of interferon-γ antibody suppressed TW289-induced colitis. CONCLUSION: These results suggest that some virulent oral streptococcal strains are associated with the aggravation of colitis induced by enhanced secretion of interferon-γ when they invade the bloodstream.

DOI： 10.1111/odi.12125

Potential high virulence for infective endocarditis in Streptococcus mutans strains with collagen-binding proteins but lacking PA expression. Reviewed International journal

R Nomura, S Naka, H Nemoto, M Otsugu, S Nakamura, T Ooshima, K Nakano

Archives of oral biology 58 ( 11 ) 1627 - 34 2013.11

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

OBJECTIVE: Streptococcus mutans, an aetiologic agent of dental caries, is a pathogen for infective endocarditis (IE). We investigated strains that express collagen-binding proteins (CBPs) with further classification based on expression of the 190-kDa protein antigen (PA). METHOD: Zeta-potential values of strains TW871 (CBP+/PA+) and MT8148 (CBP-/PA+), and their respective PA-defective mutant strains TW871PD (CBP+/PA-) and MT8148PD (CBP-/PA-), were analysed, as were their adhesion to and invasion of human umbilical vein endothelial cells (HUVECs). The distribution of strains from the oral cavities of 200 healthy individuals was analysed for CBP and/or PA expression and the strains were characterised for their adhesion and invasion properties. RESULTS: TW871PD and MT8148PD showed significantly lower zeta-potential values than TW871 and MT8148, respectively. Collagen-binding rates were significantly higher for TW871PD than for TW871 but nearly negligible for MT8148 and MT8148PD. The adhesion and invasion rates of HUVECs were significantly higher for TW871PD than for TW871 and significantly higher for TW871 than for MT8148 and MT8148PD. The prevalence of CBP+ strains was ~10% and ~3% in the case of CBP+/PA- strains. Analyses of 200 clinical strains showed the CBP+/PA- group to have higher adhesion and invasion rates than other groups. CONCLUSIONS: CBP+/PA- S. mutans strains, despite their low distribution frequency, may be highly virulent for infective endocarditis.

DOI： 10.1016/j.archoralbio.2013.06.008

Multilocus sequence typing of Streptococcus mutans strains with the cbm gene encoding a novel collagen-binding protein. Reviewed International journal

Jinthana Lapirattanakul, Ryota Nomura, Hirotoshi Nemoto, Shuhei Naka, Takashi Ooshima, Kazuhiko Nakano

Archives of oral biology 58 ( 8 ) 989 - 96 2013.8

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

OBJECTIVE: Streptococcus mutans, an oral pathogen associated with infective endocarditis (IE), possesses two genes encoding collagen-binding proteins, namely cnm and cbm. In this study, we used multilocus sequence typing (MLST) of S. mutans with the cbm gene. DESIGN: Forty-five S. mutans strains including 15 strains with the cnm gene, 15 strains with the cbm gene, and 15 strains without these two genes were analysed by MLST. In addition, the collagen-binding properties as well as the abilities to adhere to and invade human umbilical vein endothelial cells (HUVEC) were also evaluated for all strains. RESULTS: In the groups of cnm-positive and cbm-positive strains, all properties, including collagen binding, adhesion, and invasion were significantly greater than those of the cnm-cbm-negative group. Moreover, MLST revealed three clonal complexes of S. mutans possessing the cbm gene. These three clones showed no close relatedness with clones of strains containing the cnm gene. Among three clones harbouring the cbm gene, two clones belong to serotype k, and appeared to be associated with the pathogenesis of IE due to their strong collagen binding and relatively enhanced abilities to adhere to and invade endothelial cells. However, such properties were relatively weak in the other non-serotype k clone possessing the cbm gene. CONCLUSIONS: MLST indicated a difference in evolution between S. mutans strains with the cbm gene and those with the cnm gene. In addition, this technique also suggested the importance of cbm-positive S. mutans clones relative to the pathogenesis of IE.

DOI： 10.1016/j.archoralbio.2013.02.007

Potential involvement of collagen-binding proteins of Streptococcus mutans in infective endocarditis. Reviewed International journal

R Nomura, S Naka, H Nemoto, S Inagaki, K Taniguchi, T Ooshima, K Nakano

Oral diseases 19 ( 4 ) 387 - 93 2013.5

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

OBJECTIVE: Streptococcus mutans, a major pathogen of dental caries, is considered to be one of the causative agents of infective endocarditis (IE). Two types of cell surface collagen-binding proteins, Cnm and Cbm, have been identified in the organism. The aim of the present study was to analyze these proteins as possible etiologic factors for IE. MATERIALS AND METHODS: The binding activities of S. mutans strains to collagen types I, III, and IV were analyzed relative to the presence of Cnm and Cbm, as were their adhesion and invasion properties with human umbilical vein endothelial cells (HUVEC). In addition, distributions of the genes encoding Cnm and Cbm in S. mutans-positive heart valve specimens extirpated from IE and non-IE patients were analyzed by PCR. RESULTS: Most of the Cbm-positive strains showed higher levels of binding to type I collagen as well as higher rates of adhesion and invasion with HUVEC as compared to the Cnm-positive strains. Furthermore, the gene encoding Cbm was detected significantly more frequently in heart valve specimens from IE patients than from non-IE patients. CONCLUSIONS: These results suggest that the collagen-binding protein Cbm of S. mutans may be one of the potential important factor associated with the pathogenesis of IE.

DOI： 10.1111/odi.12016

Horizontal impaction of primary mandibular bilateral central incisors identified in 2-year-8-month-old girl Reviewed

Rena Okawa, Shuhei Naka, Kazuyo Fujita, Suguru Sakashita, Ryota Nomura, Kazuhiko Nakano

Pediatric Dental Journal 23 ( 1 ) 66 - 69 2013.4

Long-term follow-up of delayed development of maxillary right second premolar with inversely positioned corresponding primary molar Reviewed

Rena Okawa, Shuhei Naka, Ayuchi Kojima, Hidekazu Sasaki, Ryota Nomura, Kazuhiko Nakano

Pediatric Dental Journal 23 ( 1 ) 62 - 65 2013.4

Distribution and molecular characterization of Porphyromonas gulae carrying a new fimA genotype. Reviewed International journal

Yoshie Yamasaki, Ryota Nomura, Kazuhiko Nakano, Hiroaki Inaba, Masae Kuboniwa, Norihiko Hirai, Mitsuyuki Shirai, Yukio Kato, Masaru Murakami, Shuhei Naka, Soichi Iwai, Michiyo Matsumoto-Nakano, Takashi Ooshima, Atsuo Amano, Fumitoshi Asai

Veterinary microbiology 161 ( 1-2 ) 196 - 205 2012.12

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

Porphyromonas gulae is a gram-negative black-pigmented anaerobe which is known to be a pathogen for periodontitis in dogs. Approximately 41kDa filamentous appendages on the cell surface (FimA) encoded by the fimA gene are regarded as important factors associated with periodontitis. The fimA genotype was classified into two major types and strains in type B were shown to be more virulent than those in type A. In the present study, we characterized a strain with a novel fimA genotype and designated it as type C. The putative amino acid sequence was shown to be similar to the genotype IV fimA of Porphyromonas gingivalis, a major pathogen of human periodontitis. Analyses using an oral squamous cell carcinoma cell line derived from tongue primary lesions revealed that the type C strain inhibited proliferation and scratch closure more than genotype A and B strains. In addition, experiments using a mouse abscess model demonstrated that the type C strain could induce much higher systemic inflammation when compared with strains of the other genotypes. Furthermore, molecular analyses of oral swab specimens collected from dogs demonstrated that the detection frequencies of P. gulae and the genotype C in the periodontitis group were significantly higher than those in the periodontally healthy group. These results suggest that FimA of P. gulae is diverse with the virulence of genotype C strains the highest and that molecular identification of genotype C P. gulae could be a possible useful marker for identifying dogs at high risk of developing periodontitis.

DOI： 10.1016/j.vetmic.2012.07.026

Distribution of periodontopathic bacterial species in dogs and their owners Reviewed

Y. Yamasaki, R. Nomura, K. Nakano, S. Naka, M. Matsumoto-Nakano, F. Asai, T. Ooshima

Archives of Oral Biology 57 ( 9 ) 1183 - 1188 2012.9

Identification and characterization of a collagen-binding protein, Cbm, in Streptococcus mutans. Reviewed International journal

R Nomura, K Nakano, S Naka, H Nemoto, K Masuda, J Lapirattanakul, S Alaluusua, M Matsumoto, S Kawabata, T Ooshima

Molecular oral microbiology 27 ( 4 ) 308 - 23 2012.8

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

Streptococcus mutans, a major pathogen of dental caries, is occasionally isolated from the blood of patients with infective endocarditis. Bacterial attachment of exposed collagen tissue in the impaired endothelium is an important step in the onset of infective endocarditis. In our previous studies, some S. mutans strains were shown to possess collagen-binding activities and most of them had an approximately 120-kDa cell-surface collagen-binding protein called Cnm. However, several strains without Cnm proteins show collagen-binding properties. In the present study, another collagen-binding protein, Cbm, was characterized and its coding gene cbm was sequenced in these strains. The amino acid alignment in the putative collagen-binding domain of Cbm was shown to have approximately 80% identity and 90% similarity to the comparable region of Cnm. Cbm-deficient isogenic mutant strains constructed by insertional inactivation of the cbm gene, lacked collagen-binding properties, which were recovered in the complemented mutant. Analyses of a large number of clinical isolates from Japan, Thailand and Finland revealed that cbm-positive strains were present in all of these countries and that cnm-positive and cbm-positive strains were detected in the oral cavity of approximately 10 and 2% of systemically healthy subjects, respectively. In addition, cnm-positive strains were predominantly identified in the serotype f group, whereas cbm-positive strains were frequently detected in serotype k. These results suggest that Cbm as well as Cnm are major cell surface proteins of S. mutans associated with binding to type I collagen and predominantly identified in serotype k strains.

DOI： 10.1111/j.2041-1014.2012.00649.x

Diversity of fimbrillin among Porphyromonas gulae clinical isolates from Japanese dogs. Reviewed

Ryota Nomura, Mitsuyuki Shirai, Yukio Kato, Masaru Murakami, Kazuhiko Nakano, Norihiko Hirai, Tetsuya Mizusawa, Shuhei Naka, Yoshie Yamasaki, Michiyo Matsumoto-Nakano, Takashi Ooshima, Fumitoshi Asai

The Journal of veterinary medical science 74 ( 7 ) 885 - 91 2012.7

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

Porphyromonas gulae, a gram-negative black-pigmented anaerobe, is a pathogen for periodontitis in dogs. An approximately 41-kDa fimbrial subunit protein (FimA) encoded by fimA is regarded as associated with periodontitis. In the present study, the fimA genes of 17 P. gulae strains were sequenced, and classified into two major types. The generation of phylogenetic trees based on the deduced amino acid sequence of FimA of P. gulae strains along with sequences from several strains of Porphyromonas gingivalis, a major cause of human periodontitis, revealed that the two types of FimA (types A and B) of P. gulae were similar to type I FimA and types II and III FimA of P. gingivalis, respectively. A PCR system for classification was established based on differences in the nucleotide sequences of the fimA genes. Analysis of 115 P. gulae-positive oral swab specimens from dogs revealed that 42.6%, 22.6%, and 26.1% of them contained type A, type B, and both type A and B fimA genes, respectively. Experiments with a mouse abscess model demonstrated that the strains with type B fimA caused significantly greater systemic inflammation than those with type A. These results suggest that the FimA proteins of P. gulae are diverse with two major types and that strains with type B fimA could be more virulent.

Amoxicillin-resistant oral streptococci identified in dental plaque specimens from healthy Japanese adults. Reviewed International journal

Katsuhiko Masuda, Hirotoshi Nemoto, Kazuhiko Nakano, Shuhei Naka, Ryota Nomura, Takashi Ooshima

Journal of cardiology 59 ( 3 ) 285 - 90 2012.5

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

BACKGROUND: Infective endocarditis (IE) is known to be a life-threatening disease and invasive dental procedures are considered to be important factors. Oral amoxicillin (AMPC) is widely used for prophylaxis in patients with heart disorders who are at risk for IE. However, there is only limited information regarding the inhibition of oral bacteria by AMPC. METHODS AND RESULTS: Dental plaque specimens were obtained from 120 healthy Japanese adult subjects, then diluted and streaked onto selective medium for oral streptococci. The minimum inhibitory concentration (MIC) of AMPC was evaluated using a macro-dilution method by Clinical Laboratory Standard Institute (2006). Seven strains with an MIC of AMPC of 16μg/mL or more were isolated from 5 subjects. The bacterial species were confirmed by sequence analysis of 16S rRNA from each strain, which demonstrated that most were Streptococcus sanguinis, followed by Streptococcus oralis. Dental plaque specimens collected from these 5 subjects again after an interval of 2-3 months possessed no strains with an MIC of AMPC of 16μg/mL or more. CONCLUSIONS: These findings suggest that strains with a high MIC of AMPC are present in the oral cavities of Japanese adults, though they may be transient rather than inhabitants.

DOI： 10.1016/j.jjcc.2011.12.004

Involvement of a periodontal pathogen, Porphyromonas gingivalis on the pathogenesis of non-alcoholic fatty liver disease. Reviewed International journal

Masato Yoneda, Shuhei Naka, Kazuhiko Nakano, Koichiro Wada, Hiroki Endo, Hironori Mawatari, Kento Imajo, Ryota Nomura, Kazuya Hokamura, Masafumi Ono, Shogo Murata, Iwai Tohnai, Yoshio Sumida, Toshihide Shima, Masae Kuboniwa, Kazuo Umemura, Yoshinori Kamisaki, Atsuo Amano, Takeshi Okanoue, Takashi Ooshima, Atsushi Nakajima

BMC gastroenterology 12 16 - 16 2012.2

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

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a hepatic manifestation of metabolic syndrome that is closely associated with multiple factors such as obesity, hyperlipidemia and type 2 diabetes mellitus. However, other risk factors for the development of NAFLD are unclear. With the association between periodontal disease and the development of systemic diseases receiving increasing attention recently, we conducted this study to investigate the relationship between NAFLD and infection with Porphyromonas gingivalis (P. gingivalis), a major causative agent of periodontitis. METHODS: The detection frequencies of periodontal bacteria in oral samples collected from 150 biopsy-proven NAFLD patients (102 with non-alcoholic steatohepatitis (NASH) and 48 with non-alcoholic fatty liver (NAFL) patients) and 60 non-NAFLD control subjects were determined. Detection of P. gingivalis and other periodontopathic bacteria were detected by PCR assay. In addition, effect of P. gingivalis-infection on mouse NAFLD model was investigated. To clarify the exact contribution of P. gingivalis-induced periodontitis, non-surgical periodontal treatments were also undertaken for 3 months in 10 NAFLD patients with periodontitis. RESULTS: The detection frequency of P. gingivalis in NAFLD patients was significantly higher than that in the non-NAFLD control subjects (46.7% vs. 21.7%, odds ratio: 3.16). In addition, the detection frequency of P. gingivalis in NASH patients was markedly higher than that in the non-NAFLD subjects (52.0%, odds ratio: 3.91). Most of the P. gingivalis fimbria detected in the NAFLD patients was of invasive genotypes, especially type II (50.0%). Infection of type II P. gingivalis on NAFLD model of mice accelerated the NAFLD progression. The non-surgical periodontal treatments on NAFLD patients carried out for 3 months ameliorated the liver function parameters, such as the serum levels of AST and ALT. CONCLUSIONS: Infection with high-virulence P. gingivalis might be an additional risk factor for the development/progression of NAFLD/NASH.

DOI： 10.1186/1471-230X-12-16

The collagen-binding protein of Streptococcus mutans is involved in haemorrhagic stroke. Reviewed International journal

Kazuhiko Nakano, Kazuya Hokamura, Naho Taniguchi, Koichiro Wada, Chiho Kudo, Ryota Nomura, Ayuchi Kojima, Shuhei Naka, Yoshinori Muranaka, Min Thura, Atsushi Nakajima, Katsuhiko Masuda, Ichiro Nakagawa, Pietro Speziale, Nobumitsu Shimada, Atsuo Amano, Yoshinori Kamisaki, Tokutaro Tanaka, Kazuo Umemura, Takashi Ooshima

Nature communications 2 485 - 485 2011.9

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

Although several risk factors for stroke have been identified, one-third remain unexplained. Here we show that infection with Streptococcus mutans expressing collagen-binding protein (CBP) is a potential risk factor for haemorrhagic stroke. Infection with serotype k S. mutans, but not a standard strain, aggravates cerebral haemorrhage in mice. Serotype k S. mutans accumulates in the damaged, but not the contralateral hemisphere, indicating an interaction of bacteria with injured blood vessels. The most important factor for high-virulence is expression of CBP, which is a common property of most serotype k strains. The detection frequency of CBP-expressing S. mutans in haemorrhagic stroke patients is significantly higher than in control subjects. Strains isolated from haemorrhagic stroke patients aggravate haemorrhage in a mouse model, indicating that they are haemorrhagic stroke-associated. Administration of recombinant CBP causes aggravation of haemorrhage. Our data suggest that CBP of S. mutans is directly involved in haemorrhagic stroke.

DOI： 10.1038/ncomms1491

Characterization of aortic aneurysms in cardiovascular disease patients harboring Porphyromonas gingivalis Reviewed

K Nakano, K Wada, R Nomura, H Nemoto, H Inaba, A Kojima, S Naka, K Hokamura, T Mukai, A Nakajima, K Umemura, Y Kamisaki, H Yoshioka, K Taniguchi, A Amano, T Ooshima

Oral Diseases 17 ( 4 ) 370 - 378 2011.5

Successful application of atelocollagen for treatment of perforated teeth. Reviewed International journal

Katsuhiko Masuda, Kazuhiko Nakano, Rena Okawa, Shuhei Naka, Michiyo Matsumoto, Takashi Ooshima

The Journal of clinical pediatric dentistry 36 ( 1 ) 1 - 4 2011

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

OBJECTIVE: Cervical or furcal root perforation is a serious clinical problem and one of its treatment modalities is perforation repair with composite resin. However, many cases still progress in inevitable extraction. When primary teeth are affected, early tooth loss can cause problems related to the eruption space for the permanent successors. The aim of the present study was to evaluate a novel clinical treatment method for perforated teeth. STUDY DESIGN: Atelocollagen was applied to perforated furcal and cervical areas of 13 primary teeth in 13 children aged 4-9 years and 8 permanent teeth in 8 adults aged 35-69 years after debridement with an electric knife. Thereafter the final restorations were performed after confirming good tooth conditions. Clinical evaluations were performed at follow-up examinations at approximately 3-month intervals. RESULTS: None of the treated primary teeth showed any clinical problems throughout the observation period, with eruption of the permanent successors noted in 7 cases. In the permanent teeth, no clinical problems were identified in any of the cases during follow-up periods of 10-60 months. CONCLUSION: This novel method may enable preservation of perforated primary teeth for a longer duration.

Successful application of molecular biological technique for evaluation of changes in periodontopathic bacteria in Japanese children with developmental disabilities Reviewed

Ardin Arifah Chieko, Nakano Kazuhiko, Yamana Aki, Okawa Rena, Naka Shuhei, Matsumoto Michiyo, Ooshima Takashi

Ped Dent J 21 ( 1 ) 56 - 62 2011

Language：English Publisher：The Japanese Society of Pediatric Dentistry

Developments in molecular biological techniques enables rapid and easy identification of periodontopathic bacterial species in clinical specimens. However, there are few reports regarding their application for community dentistry. The aim of this study was to show successful application of a molecular biological technique for evaluation of changes in periodontal bacterial species in children at daycare centers. We studied 187 children who received oral examinations in 2009 and 186 who received examinations in 2010, among whom 102 were examined in both years. Clinical parameters regarding periodontal conditions were evaluated and the distribution of 10 periodontopathic species in dental plaque specimens were determined by polymerase chain reaction. Periodontal pocket depth values in the 2010 group were significantly smaller than those in 2009. When the subjects were divided into those with (positive group) and without (negative group) Porphyromonas gingivalis, Treponema denticola, Tannerella forsythia, or Campylobacter rectus in 2009, the positive group had significantly smaller periodontal pocket values than the negative group. In addition, the rate of subjects with P.gingivalis, T.denticola, T.forsythia, or C.rectus in the positive group in 2010 was significantly reduced. Our findings demonstrate that molecular biological methods provide more information as compared to a standard clinical examination when evaluating changes of periodontal conditions in the field of community dentistry.

DOI： 10.11411/pdj.21.56

A case of incidental identification of mesiodens in 1-year-old boy followed for 6 years Reviewed

Nakano Kazuhiko, Naka Shuhei, Kojima Ayuchi, Nemoto Hirotoshi, Inagaki Satoko, Ooshima Takashi

Pediatric Dental Journal 21 ( 1 ) 73 - 77 2011

Language：English Publisher：The Japanese Society of Pediatric Dentistry

We present a case of mesiodens identified in a 1-year 9-month-old boy. The patient visited our clinic after receiving a traumatic injury, which caused intrusion of the maxillary right and left primary central incisors. A periapical radiograph revealed no root fractures, though a mesiodens was incidentally found. The intruded teeth naturally moved into their original positions and periodical examinations were scheduled. At 4Y2M, uncommon mesial inclination of the maxillary right primary central incisor was noted. A radiographic examination showed the enlarged dental follicle of the mesiodens, which appeared to cause the inclination, and we planned fenestration when enlargement of the lesion was identified. At 5Y1M, he received another traumatic injury and the maxillary right primary central incisor was exfoliated. At 5Y5M, the mesiodens spontaneously emerged into the oral cavity and a radiographic examination showed prominent rotation of the maxillary right central incisor. Two-thirds of the crown of the mesiodens could be seen at 6Y4M. At 6Y11M, the patient again received a traumatic injury, and intrusion of the maxillary left primary central incisor was observed. At 7Y0M, the mesiodens and maxillary left primary central incisor were extracted under infiltration anesthesia, after which inclination of the axis of the adjacent maxillary right central incisor gradually improved.

DOI： 10.11411/pdj.21.73

Detection of oral streptococci with collagen-binding properties in saliva specimens from mothers and their children. Reviewed International journal

Ryota Nomura, Shuhei Naka, Kazuhiko Nakano, Naho Taniguchi, Michiyo Matsumoto, Takashi Ooshima

International journal of paediatric dentistry 20 ( 4 ) 254 - 60 2010.7

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

BACKGROUND: Approximately 10-20% of Streptococcus mutans strains have been reported to possess collagen-binding properties, whereas other species in the oral cavity with those properties remain to be elucidated. Aim. To identify strains with collagen-binding properties and analyse their characteristics in comparison with S. mutans. DESIGN: A total of 110 expectorated saliva specimens were collected from 55 pairs of mothers and their children. Bacterial strains with collagen-binding properties were isolated and the species specified. In addition, strains with collagen-binding properties isolated from mother-child pairs were analysed using molecular biological approaches. RESULTS: The detection frequency of strains with collagen-binding properties was shown to be 40.9%, among which S. salivarius was the most frequently detected, followed by S. mutans. The collagen-binding activity of the S. mutans group was the highest, followed by S. salivarius. In addition, S. mutans and S. salivarius strains from 3 and 1 mother-child pairs, respectively, were shown to be the same clones. CONCLUSIONS: Our results indicate that S. mutans and S. salivarius are major species with collagen-binding properties in the oral cavity, and that strains with such properties may be related to mother-child transmission.

DOI： 10.1111/j.1365-263X.2010.01047.x

Defect of glucosyltransferases reduces platelet aggregation activity of Streptococcus mutans: analysis of clinical strains isolated from oral cavities. Reviewed International journal

N Taniguchi, K Nakano, R Nomura, S Naka, A Kojima, M Matsumoto, T Ooshima

Archives of oral biology 55 ( 6 ) 410 - 6 2010.6

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

OBJECTIVE: Streptococcus mutans is a major pathogen of dental caries and occasionally isolated from the blood of patients with infective endocarditis, though the association of its cell-surface glucosyltransferases (GTFB, GTFC, and GTFD) with pathogenicity for infective endocarditis remains to be elucidated. In this study, we investigated the contribution of S. mutans GTFs to platelet aggregation and analysed GTF expression profiles in a large number of clinical oral isolates. DESIGN: The platelet aggregation properties of GTF-defective isogenic mutant strains constructed from S. mutans reference strain MT8148 were evaluated using whole blood and platelet-rich plasma (PRP) taken from mice, as well as human PRP. In addition, GTF expression profiles for 396 S. mutans strains isolated from the oral cavities of 396 subjects were analysed by western blotting using antisera specific for each GTF. RESULTS: The platelet aggregation activities of the GTF-defective isogenic mutants were significantly lower than that of MT8148 when added to a large number of cells. Western blotting revealed no strains without GTF expression, though six strains had alterations of GTFB and GTFC as compared to MT8148. PCR analyses indicated that the gtfB-gtfC region length was approximately 4.5 kb shorter in those strains as compared to MT8148. These were designated as "GTFBC-fusion" strains and they demonstrated lower levels of platelet aggregation. CONCLUSIONS: Our findings indicate that GTFs are associated with platelet aggregation. Although the clinical detection frequency of S. mutans strains with altered expressions is extremely low, GTFBC-fusion strains have activities similar to GTF-defective mutant strains.

DOI： 10.1016/j.archoralbio.2010.03.017

Molecular characterization of Streptococcus mutans strains containing the cnm gene encoding a collagen-binding adhesin. Reviewed International journal

K Nakano, R Nomura, N Taniguchi, J Lapirattanakul, A Kojima, S Naka, P Senawongse, R Srisatjaluk, L Grönroos, S Alaluusua, M Matsumoto, T Ooshima

Archives of oral biology 55 ( 1 ) 34 - 9 2010.1

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

OBJECTIVE: Streptococcus mutans, known to be a major pathogen of dental caries, is also considered to cause infective endocarditis. Its 120-kDa Cnm protein binds to type I collagen, which may be a potential virulence factor. In this study, we characterized S. mutans clinical strains focusing on the cnm gene encoding Cnm. DESIGN: A total of 528 S. mutans strains isolated from Japanese, Finnish, and Thai subjects were investigated. Using molecular techniques, the distribution frequency of cnm-positive strains and location of the inserted cnm were analyzed. Furthermore, isogenic mutant strains were constructed by inactivation of the cnm gene, then their biological properties of collagen-binding and glucan-binding were evaluated. Southern hybridization of the genes encoding glucan-binding proteins was also performed. RESULTS: The distribution frequency of cnm-positive strains from Thai subjects was 12%, similar to that previously reported for Japanese and Finnish subjects. Furthermore, the location of insertion of cnm was the same in all cnm-positive clinical isolates. As for the cnm-inactivated mutant strains constructed from 28 clinical isolates, their collagen-binding activity was negligible. In addition, glucan-binding activity in the cnm-positive clinical isolates was significantly reduced and corresponded to a lack of gbpA encoding glucan-binding protein A. CONCLUSIONS: Our results indicate that strains with cnm genes, the most crucial factor for the collagen-binding property of S. mutans, are detectable at similar frequencies over several different geographic locations. In addition, the common properties of these strains are a high level of collagen-binding activity and tendency for a low level of glucan-binding activity.

DOI： 10.1016/j.archoralbio.2009.11.008

Suspected cerebral gigantism diagnosed by dental examination Reviewed

OKAWA Rena, MASUDA Katsuhiko, NAKANO Kazuhiko, NAKA Shuhei, MATSUMOTO Michiyo, OOSHIMA Takashi

Pediatric Dental Journal 19 ( 2 ) 247 - 251 2009.9

Language：English Publisher：The Japanese Society of Pediatric Dentistry

Cerebral gigantism is an overgrowth disorder that occurs from the prenatal stage through childhood and features such clinical symptoms as advanced bone age, macrocephaly, characteristic facial appearance, and learning difficulties. A 4-year 3-month-old girl was referred to our clinic for consultation regarding anterior crossbite and occlusal pain in the molar region. An intraoral examination showed that the mandible was considerably larger than the maxilla. The dental age of the entire dentition estimated from orthopantomogram images was approximately 1 year ahead of chronological age. Cephalometrics analysis demonstrated maxillary protrusion, prominent mandibular protrusion, and vertically severe short face. The size of maxilla was slightly small, whereas that of mandible was above the average. Since height and body weight were above the 97 percentile, the patient was referred to a pediatrician for a general examination prior to dental treatment and diagnosed with suspected cerebral gigantism. As for occlusal pain in the molar region, we considered that it was caused by excessive occlusal pressure. Following application of splinting and several adjustments, the pain gradually disappeared.

DOI： 10.11411/pdj.19.247

Distribution of periodontopathic bacterial species in Japanese children with developmental disabilities. Reviewed International journal

Shuhei Naka, Aki Yamana, Kazuhiko Nakano, Rena Okawa, Kazuyo Fujita, Ayuchi Kojima, Hirotoshi Nemoto, Ryota Nomura, Michiyo Matsumoto, Takashi Ooshima

BMC oral health 9 24 - 24 2009.9

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

BACKGROUND: Recent developments in molecular biological techniques have enabled rapid detection of periodontopathic bacterial species in clinical specimens. Accumulated evidence suggests that detection of specific bacterial species enables identification of subjects at high risk for the onset of periodontitis. We investigated the distribution of 10 selected periodontopathic bacterial species in dental plaque specimens obtained from children with disabilities who were attending daycare centers. METHODS: A total of 187 children (136 boys, 51 girls) aged 1-6 years old and diagnosed with such disabilities as mental retardation, cerebral palsy, and autism, participated in the study. Subgingival dental plaque specimens were collected from the buccal side of the maxillary left second primary molar after a clinical examination. Bacterial DNA was extracted from the specimens and PCR analyses were carried out to detect 10 selected periodontopathic species using specific primers for each. In addition, statistical analyses were performed to analyze the correlations among clinical parameters and the detected species. RESULTS: The most frequently detected species was Capnocytophaga sputigena (28.3%), followed by Aggregatibacter actinomycetemcomitans (20.9%) and Campylobacter rectus (18.2%). Eikenella corrodens, Capnocytophaga ochracea, and Prevotella nigrescence were detected in approximately 10% of the specimens, whereas Treponema denticola, Tannerella forsythia, and Prevotella intermedia were rarely found, and Porphyromonas gingivalis was not detected in any of the subjects. The total numbers of detected species were positively correlated with the age of the subjects. There were 10 subjects with positive reactions for T. denticola and/or T. forsythia, in whom the total number of bacterial species was significantly higher as compared to the other subjects. Furthermore, subjects possessing C. rectus showed significantly greater values for periodontal pocket depth, gingival index, and total number of species. CONCLUSION: We found that approximately one-fourth of the present subjects with disabilities who possessed at least one of T. denticola, T. forsythia, and C. rectus were at possible risk for periodontitis. Follow-up examinations as well as preventive approaches should be utilized for such individuals.

DOI： 10.1186/1472-6831-9-24

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