九州大学 研究者情報
論文一覧
山下 明子(やました あきこ) データ更新日:2021.06.28

助教 /  歯学研究院 歯学部門 口腔機能修復学講座


原著論文
1. Rehab Alshargabi, Takanori Shinjo, Misaki Iwashita, Akiko Yamashita, Tomomi Sano, Yuki Nishimura, Masato Hayashi , Tatsuro Zeze, Takao Fukuda, Terukazu Sanui, Fusanori Nishimura, SPOCK1 induces adipose tissue maturation: New insights into the function of SPOCK1 in metabolism, Biochem Biophys Res Commun., 17, 533(4), 1076-1082, 2020.11.
2. Taiki Sanada, Tomomi Sano, Yusuke Sotomaru, Rehab Alshargabi, Yosuke Yamawaki, Akiko Yamashita, Hiroaki Matsunaga, Misaki Iwashita, Takanori Shinjo, Takashi Kanematsu, Tomoichiro Asano, Fusanori Nishimura, Anti-inflammatory Effects of miRNA-146a Induced in Adipose and Periodontal Tissues, Biochemistry and Biophysics Reports, 2020.04.
3. Rehab Alshargabi, Tomomi Sano, Akiko Yamashita, Aiko Takano, Taiki Sanada, Misaki Iwashita, Takanori Shinjo, Takao Fukuda, Terukazu Sanui, Shosei Kishida, Fusanori Nishimura, SPOCK1 is a novel inducer of epithelial to mesenchymal transition in drug-induced gingival overgrowth, Scientific Reports, 2020.06.
4. Tomomi Sano, Taiki Sanada, Yusuke Sotomaru, Takanori Shinjo, Misaki Iwashita, Akiko Yamashita, Takao Fukuda, Terukazu Sanui, Tomoichiro Asano, Takashi Kanematsu, Fusanori Nishimura, Ccr7 null mice are protected against diet-induced obesity via Ucp1 upregulation and enhanced energy expenditure, Nutrition and Metabolism, 10.1186/s12986-019-0372-5, 16, 1, 2019.07, [URL], Background: The chemokine receptor CCR7, expressed on various immune cells, is associated with cell migration and lympho-node homing. Mice lacking Ccr7 are protected from diet-induced obesity and subsequent insulin resistance. We evaluated the mechanism underlying these protective effects from the standpoint of energy expenditure. Methods: Wild-type and Ccr7 null mice were fed a high-fat diet, and the regulation of energy metabolism and energy metabolism-related molecules, e.g., Ucp1, Cidea, and Pgc1α, were evaluated. Results: Food intake did not differ between groups. O2 consumption and CO2 production were higher in Ccr7 null mice than in wild-type mice, despite a similar respiratory quotient and glucose and lipid utilization, suggesting that energy expenditure increased in Ccr7 null mice via enhanced metabolism. In white adipose tissues of Ccr7 null mice, Prdm16, Cd137, Tmem26, Th, and Tbx1 expression increased. Similarly, in brown adipose tissues of Ccr7 null mice, Dio2, Pgc1α, Cidea, Sirt1, and Adiponectin expression increased. In both white and brown adipose tissues, Ucp1 gene and protein expression levels were higher in null mice than in wild-type mice. Conclusions: In Ccr7 null mice, browning of white adipocytes as well as the activation of brown adipocytes cause enhanced energy metabolism, resulting in protection against diet-induced obesity..
5. Shigeki Suzuki, Takao Fukuda, Shintaro Nagayasu, Jun Nakanishi, Kazuma Yoshida, Shizu Hirata-Tsuchiya, Yuki Nakao, Tomomi Sano, Akiko Yamashita, Satoru Yamada, Kouji Ohta, Hideki Shiba, Fusanori Nishimura, Dental pulp cell-derived powerful inducer of TNF-α comprises PKR containing stress granule rich microvesicles, Scientific reports, 10.1038/s41598-019-40046-2, 9, 1, 2019.12, [URL], It is well known that dental pulp tissue can evoke some of the most severe acute inflammation observed in the human body. We found that dental pulp cells secrete a factor that induces tumor necrosis factor-α production from macrophages, and designated this factor, dental pulp cell-derived powerful inducer of TNF-α (DPIT). DPIT was induced in dental pulp cells and transported to recipient cells via microvesicles. Treatment of dental pulp cells with a PKR inhibitor markedly suppressed DPIT activity, and weak interferon signals were constitutively activated inside the cells. In recipient macrophages, stimulation with DPIT-containing supernatants from pulp cells resulted in activation of both nuclear factor-κB and MAP kinases like JNK and p38. Proteomics analyses revealed that many stress granule-related proteins were present in supernatants from dental pulp cells as well as microvesicle marker proteins like GAPDH, β-actin, HSPA8, HSPB1, HSPE1, and HSPD1. Furthermore, giant molecule AHNAK and PKR were detected in microvesicles derived from dental pulp cells, and gene silencing of AHNAK in dental pulp cells led to reduced DPIT activity. Thus, it appeared that the core protein of DPIT was PKR, and that PKR was maintained in an active state in stress granule aggregates with AHNAK and transported via microvesicles. The activity of DPIT for TNF-α induction was far superior to that of gram-negative bacterial endotoxin. Therefore, we, report for the first time, that active PKR is transported via microvesicles as stress granule aggregates and induces powerful inflammatory signals in macrophages..
6. Taiki Sanada, Tomomi Sano, Yusuke Sotomaru, Rehab Alshargabi, Yosuke Yamawaki, Akiko Yamashita, Hiroaki Matsunaga, Misaki Iwashita, Takanori Shinjo, Takashi Kanematsu, Tomoichiro Asano, Fusanori Nishimura, Anti-inflammatory effects of miRNA-146a induced in adipose and periodontal tissues, Biochemistry and Biophysics Reports, 10.1016/j.bbrep.2020.100757, 22, 2020.07, [URL], MicroRNA (miRNA) plays an important role in diverse cellular biological processes such as inflammatory response, differentiation and proliferation, and carcinogenesis. miR-146a has been suggested as a negative regulator of the inflammatory reaction. Although, it has been reported as expressed in inflamed adipose and periodontal tissues, however, miR-146a's inhibitory effects against inflammatory response in both the tissues, are not well understood. Therefore, in this study, the inhibitory effects of miR-146a on both adipose and periodontal inflammation, was investigated. In vitro study has revealed that miR-146a transfection into either adipocytes or gingival fibroblasts, has resulted in a reduced cytokine gene expression, observed on co-culturing the cells with macrophages in the presence of lipopolysaccharides (LPS), in comparison to the control miRNA transfected. Similarly, miR-146a transfection into macrophages resulted in a reduced expression of TNF-α gene and protein in response to LPS stimulation. In vivo study revealed that a continuous intravenous miR-146a administration into mice via tail vein, protected the mice from developing high-fat diet-induced obesity and the inflammatory cytokine gene expression was down-regulated in both adipose and periodontal tissues. miR-146a appeared to be induced by macrophage-derived inflammatory signals such as TNF-α by negative feed-back mechanism, and it suppressed inflammatory reaction in both adipose and periodontal tissues. Therefore, miR-146a could be suggested as a potential therapeutic molecule and as a common inflammatory regulator for both obesity-induced diabetes and related periodontal diseases..
7. Fusanori Nishimura, Misaki Iwashita, Akiko Yamashita, [Periodontal disease]., Nippon rinsho. Japanese journal of clinical medicine, 70 Suppl 5, 499-502, 2012.07.
8. 山下 明子, The inflammation-lipocalin 2 axis may contribute to the development of chronic kidney disease, NEPHROLOGY DIALYSIS TRANSPLANTATION, 10.1093/ndt/gft449, 29, 3, 611-618, 2014.03.
9. Shintaro Nagayasu, Shigeki Suzuki, Akiko Yamashita, Ataru Taniguchi, Mitsuo Fukushima, Yoshikatsu Nakai, Kazuko Nin, Naoya Watanabe, Shoichiro Nagasaka, Daisuke Yabe, Fusanori Nishimura, Smoking and adipose tissue inflammation suppress leptin expression in Japanese obese males
Potential mechanism of resistance to weight loss among Japanese obese smokers, Tobacco Induced Diseases, 10.1186/1617-9625-10-3, 10, 1, 2012.02, [URL], Background: The effect of smoking on leptin regulation is controversial. Smoking may induce low-grade inflammation. Recent series of studies indicated the critical role of macrophage migration in the establishment of adipose tissue inflammation. In this study, we aimed to see the effects of smoking and inflammation on leptin regulation both at cellular and epidemiological levels. Methods. We compared the concentration of inflammatory markers and serum leptin levels among Japanese male subjects. Additionally, leptin and intercellular adhesion molecule (ICAM) -1 gene expression was assessed in adipocytes co-cultured with or without macrophages in the presence or absence of nicotine and/or lipopolysaccharide (LPS). Results: In subjects with BMI below 25 kg/m 2, both WBC counts and soluble-ICAM-1 levels are significantly higher in smokers than in non-smokers. However, leptin concentration did not differ according to smoking status. However, in subjects with BMI over 25 kg/m 2, smokers exhibited significantly lower serum leptin level as well as higher WBC counts and s-ICAM-1 concentration as compared with non-smokers. Leptin gene expression was markedly suppressed in adipocytes co-cultured with macrophages than in adipocyte culture alone. Furthermore, nicotine further suppressed leptin gene expression. ICAM-1 gene expression was markedly up-regulated in adipocytes co-cultured with macrophages when stimulated with LPS. Conclusions: Adipose tissue inflammation appears to down-regulate leptin expression in adipose tissues. Nicotine further suppresses leptin expression. Thus, both smoking and inflammation may diminish leptin effect in obese subjects. Therefore, obese, but not normal weight, smokers might be more resistant to weight loss than non-smokers..
10. Yohei Sanada, Takafumi Yamamoto, Rika Satake, Akiko Yamashita, Sumire Kanai, Norihisa Kato, Fons Aj Van De Loo, Fusanori Nishimura, Philipp E. Scherer, Noriyuki Yanaka, Serum Amyloid A3 Gene Expression in Adipocytes is an Indicator of the Interaction with Macrophages, Scientific Reports, 10.1038/srep38697, 6, 2016.12, [URL], The infiltration of macrophages into adipose tissue and their interaction with adipocytes are essential for the chronic low-grade inflammation of obese adipose tissue. In this study, we identified the serum amyloid A3 (Saa3) gene as a key adipocyte-derived factor that is affected by interaction with macrophages. We showed that the Saa3 promoter in adipocytes actually responds to activated macrophages in a co-culture system. Decreasing C/EBPβ abundance in 3T3-L1 adipocytes or point mutation of C/EBPβ elements suppressed the increased promoter activity in response to activated macrophages, suggesting an essential role of C/EBPβ in Saa3 promoter activation. Bioluminescence based on Saa3 promoter activity in Saa3-luc mice was promoted in obese adipose tissue, showing that Saa3 promoter activity is most likely related to macrophage infiltration. This study suggests that the level of expression of the Saa3 gene could be utilized for the number of infiltrated macrophages in obese adipose tissue..
11. 佐野 朋美, Misaki Iwashita, Shintaro Nagaysu, Akiko Yamashita, Takanori Shinjo, Asushi Hashikata, Tomoichiro Asano, Akifumi Kushiyama, Naozumi Ishimaru, Yousuke Nishimura, Fusanori NISHIMURA, Protection from diet-induced obesity and insulin resistance in mice lacking CCL19-CCR7 signaling, OBESITY, 10.1002/oby.21127, 23, 7, 1460-1471, 2015.07.
12. Fusanori Nishimura, Misaki Iwashita, Akiko Yamashita, Periodontal disease and chronic low-grade inflammation, Journal of the Japan Diabetes Society, 54, 7, 490-492, 2011.07.
13. Hideo Nakarai, Akiko Yamashita, Mikimasa Takagi, Masataka Adachi, Masaharu Sugiyama, Haruhiko Noda, Masafumi Katano, Ryuji Yamakawa, Keiji Nakayama, Hitomi Takumiya, Yoshikatsu Nakai, Ataru Taniguchi, Fusanori Nishimura, Periodontal disease and hypertriglyceridemia in Japanese subjects
Potential association with enhanced lipolysis, Metabolism: Clinical and Experimental, 10.1016/j.metabol.2010.07.034, 60, 6, 823-829, 2011.06, [URL], Although periodontal disease may be associated with increased risk for atherosclerosis, the mechanism by which the disease causes atherosclerosis is still unknown. The candidates contributing to atherosclerosis in periodontal disease include low-grade inflammation such as C-reactive protein (CRP) and insulin resistance. A previous study demonstrated that periodontal therapy leads to an improvement in CRP as well as insulin resistance, indicating the relationship between periodontal disease and low-grade inflammation or insulin resistance. On the other hand, we previously demonstrated that serum triglyceride (TG) per se is independently associated with CRP or insulin resistance in Japanese populations with a body mass index (BMI) of 21.5 to 27.0 (midrange BMI). To the best of our knowledge, however, the relationship between periodontal disease and serum TG is not fully clarified. The first aim of the present study is to investigate whether periodontal disease is associated with serum TG in Japanese subjects with midrange BMI. If so, another aim of the study is to determine which mechanism is responsible for the association between periodontal disease and serum TG in these subjects. We have performed a periodontal examination in the Ogaki metabolic syndrome medical examination. One hundred sixty-two participants from 40 to 74 years old (56 men and 106 women; mean age, 66.43 ± 6.25 years) were enrolled in the study. Besides medical examination, oral panoramic radiograph was taken for all participants. Average bone score was also calculated. Periodontal bone destruction increased according to the age of the participants (r = 0.227, P < .004, Spearman correlation coefficient). Periodontal bone destruction was also associated with serum TG levels (r = 0.299, P = .000). This association was more evident in subjects with midrange BMI (r = 0.332, P < .001). In subjects with midrange BMI, TG was not correlated with BMI or waste circumstances. Furthermore, TG was not associated with age itself in the midrange BMI group. We then investigated the lipolytic activity of endotoxin in cocultures of adipocytes and macrophages. Low-dose lipopolysaccharide dose-dependently increased lipolytic activity in cocultures, and this activity was neutralized by anti-tumor necrosis factor α neutralizing antibodies. These results suggest that periodontal infection, especially bacterial endotoxinemia, is associated with enhanced lipolysis and subsequent up-regulation of circulating TG in Japanese with midrange BMI..
14. Mitsudai Tsuruta, Misaki Iwashita, Takanori Shinjo, Hiroaki Matsunaga, Akiko Yamashita, Fusanori Nishimura, Metabolic Endotoxemia-Activated Macrophages Promote Pancreatic β Cell Death via IFNβ-Xaf1 Pathway, Hormone and Metabolic Research, 10.1055/s-0043-121467, 50, 2, 160-167, 2018.02, [URL], Metabolic endotoxemia has been implicated in the pathogenesis of type 2 diabetes. In addition to adipose tissue inflammation, inflammatory cell infiltration is also observed in islets, although its effect on islets is largely unknown. We hypothesized that macrophage infiltration into islets leads to impairment of α or β cell function, which ultimately act to exacerbate the pathophysiology of diabetes. Gene expression in a murine α cell line, αTC1, and β cell line, βTC6, was investigated by DNA microarray after co-culturing the cells with a murine macrophage cell line, RAW 264.7, in the presence or absence of bacterial endotoxin. Among the genes showing highly upregulated expression, genes specifically upregulated only in β cells were evaluated to determine the roles of the gene products on the cellular function of β cells. In both α and β cells, expression of type I interferon-responsive genes was highly upregulated upon endotoxin stimulation. Among these genes, expression of the X-linked inhibitor of apoptosis (Xiap)-associated factor 1 (Xaf1) gene, which is associated with the induction of apoptosis, was specifically enhanced in β cells by endotoxin stimulation. This upregulation appeared to be mediated by macrophage-derived interferon β (IFNβ), as endotoxin-stimulated macrophages produced higher amounts of IFNβ, and exogenous addition of IFNβ into βTC6 cultures resulted in increased Xaf1 protein production and cleaved caspase 3, which accelerated β-cell apoptosis. Macrophages activated by metabolic endotoxemia infiltrated into islets and produced IFNβ, which induced β-cell apoptosis by increasing the expression of Xaf1..
15. Akiko Yamashita, Yoshihiko Soga, Yoshihiro Iwamoto, Sayuri Yoshizawa, Hirotaka Iwata, Susumu Kokeguchi, Shogo Takashiba, Fusanori Nishimura, Macrophage-adipocyte interaction
Marked interleukin-6 production by lipopolysaccharide, Obesity, 10.1038/oby.2007.305, 15, 11, 2549-2552, 2007.11, [URL], Objective: Recent studies suggested macrophages were integrated in adipose tissues, interacting with adipocytes, thereby exacerbating inflammatory responses. Persistent low-grade infection by gram-negative bacteria appears to promote atherogenesis. We hypothesized a ligand for toll-like receptor 4 (TLR4), bacterial lipopolysaccharide (LPS), would further exaggerate macrophage-adipocyte interaction. Research Methods and Procedures: RAW264.7 macrophage cell line and differentiated 3T3-L1 preadipocytes were co-cultured using transwell system. As a control, each cell was cultured independently. After incubation of the cells with or without Escherichia coli LPS, tumor necrosis factor (TNF)-α and interleukin (IL)-6 production was evaluated. Results: Co-culture of macrophages and adipocytes with low concentration of Escherichia coli LPS (1 ng/mL) markedly up-regulated IL-6 production (nearly 100-fold higher than that of adipocyte culture alone, p < 0.01), whereas TNF-α production was not significantly influenced. This increase was partially inhibited by anti-TNF-α neutralizing antibody. Recombinant TNF-α and LPS synergistically up-regulated IL-6 production in adipocytes. However, this increase did not reach the level of production observed in co-cultures stimulated with LPS. Discussion: A ligand for TLR-4 stimulates macrophages to produce TNF-α. TNF-α, thus produced, cooperatively up-regulates IL-6 production with other soluble factors secreted either from adipocytes or macrophages in these cells. Markedly up-regulated IL-6 would greatly influence the pathophysiology of diabetes and its vascular complications..
16. Takanori Shinjo, Misaki Iwashita, Akiko Yamashita, Tomomi Sano, Mitsudai Tsuruta, Hiroaki Matsunaga, Terukazu Sanui, Tomoichiro Asano, Fusanori Nishimura, IL-17A synergistically enhances TNFα-induced IL-6 and CCL20 production in 3T3-L1 adipocytes, Biochemical and Biophysical Research Communications, 10.1016/j.bbrc.2016.06.049, 477, 2, 241-246, 2016.08, [URL], Interleukin-17A (IL-17A) is known to induce inflammatory responses and to be involved in the pathogenesis of not only autoimmune diseases, but also several metabolic and infectious diseases. In this study, IL-17A is shown to induce IL-6 expression in 3T3-L1 mature adipocytes. Interestingly, we found that IL-17A synergistically amplified TNFα-induced secretion of IL-6 and upregulation of IL-17RA expression in 3T3-L1 adipocytes. Its synergistic effects on IL-6 production were inhibited by pre-treatment with inhibitors of IκBα and JNK. Furthermore, IL-17A cooperatively enhanced LPS-mediated IL-6 production in 3T3-L1 adipocytes co-cultured with RAW264.7 macrophages. In addition, IL-17A also enhanced CCL20 production in 3T3-L1 adipocytes stimulated with TNFα or co-cultured with LPS-stimulated RAW macrophages. In high-fat diet-fed mouse epididymal adipose tissues, IL-17RA and RORγt mRNA levels were significantly increased and the serum level of CCL20 was also upregulated. Taken together, these data show that, in adipose tissues, IL-17A contributes to exacerbating insulin resistance-enhancing IL-6 production and promotes the infiltration of Th17 cells in cooperation with TNFα; these findings represent a novel hypothesis for the association between IL-17A-producing cells and type 2 diabetes..
17. Hirotaka Iwata, Yoshihiko Soga, Michio Meguro, Sayuri Yoshizawa, Yuka Okada, Yoshihiro Iwamoto, Akiko Yamashita, Shogo Takashiba, Fusanori Nishimura, High glucose up-regulates lipopolysaccharide-stimulated inflammatory cytokine production via c-jun N-terminal kinase in the monocytic cell line THP-1, Innate Immunity, 10.1177/0968051907082608, 13, 4, 227-234, 2007.08, [URL], Diabetic subjects are susceptible to atherosclerosis. It has been postulated that inflammation plays a crucial role in atherogenesis. Since previous studies suggested persistent low-grade infection by Gram-negative bacteria such as Chlamydia spp. and/or periodontal infection is associated with increased atherogenesis among diabetic subjects, we hypothesized that macrophages under hyperglycemia respond to lipopolysaccharide (LPS) challenge in a more exaggerated manner than under normal glucose conditions. Therefore, we examined cytokine productivity and associated signal transduction molecules in LPS-stimulated the monocytic cell line THP-1, under conditions of hyperglycemia. Differentiated THP-1 cells were cultured under normal and high glucose conditions without fetal bovine serum, and were stimulated with Escherichia coli LPS in the presence of LPS binding protein. Following stimulation, activated signal transduction molecules were detected by protein microarray and confirmed thereafter. Results indicated that c-jun N-terminal kinase (JNK) was highly-phosphorylated at high glucose concentrations, and this was confirmed by Western-immunoblotting. Tumor necrosis factor-α and monocyte chemo-attractant protein-1 production were significantly enhanced under these conditions. SP600125, a selective inhibitor of JNK, dose-dependently suppressed the production of these cytokine. Therefore, we suggest that this may be one of the mechanisms by which sub-clinical infection by Gram-negative bacteria promotes atherosclerosis in diabetic subjects..
18. J. Yonehiro, Y. Yoshida, Akiko Yamashita, S. Yoshizawa, K. Ohta, N. Kamata, T. Okihara, Fusanori Nishimura, Flavonol-containing phosphorylated pullulan may attenuate pulp inflammation, International Endodontic Journal, 10.1111/j.1365-2591.2012.02095.x, 46, 2, 119-127, 2013.02, [URL], Aim: To find possible reagents to minimize inflammatory responses by using an established pulpitis models for the purpose of developing new pulp-capping materials, and to test the possible use of phosphorylated pullulan as a carrier for such an anti-inflammatory reagent. Methodology: Co-culturing was performed using transwell systems. Inflammatory responses were evaluated by measuring cytokines produced by the cells. The effects of two flavonoids, luteolin and quercetin, as anti-inflammatory reagents, and phosphorylated pullulan, which potentially achieves a sufficient marginal sealing to hydroxyapatite and slowly releases luteolin, as a carrier for flavonoids, were tested. Results: Flavonols, particularly luteolin, dramatically attenuated inflammatory cytokine production, which was augmented by co-cultures. Luteolin was successfully enclosed by phosphorylated pullulan. Finally, it was confirmed that luteolin released from phosphorylated pullulan was effective in reducing cytokine production by co-cultures. Conclusions: Combination of phosphorylated pullulan and luteolin could be potentially used in the treatment of dental pulp inflammation..
19. J. Yonehiro, Akiko Yamashita, Y. Yoshida, S. Yoshizawa, K. Ohta, N. Kamata, T. Okihara, Fusanori Nishimura, Establishment of an ex vivo pulpitis model by co-culturing immortalized dental pulp cells and macrophages, International Endodontic Journal, 10.1111/j.1365-2591.2012.02074.x, 45, 12, 1103-1108, 2012.12, [URL], Aim To establish an ex vivo pulpitis model by co-culturing dental pulp cells with macrophages. Methodology As dental pulp cells, immortalized human dental pulp cells, named DP-1, were used, whilst as macrophage cell lines, the differentiated human monocytic cell line, THP-1, was used. In some experiments, primary dental pulp cells were isolated and used to confirm the results obtained in the experiments using immortalized cells. Co-culturing was performed using transwell systems. Inflammatory responses were evaluated by measuring cytokines produced by the cells. Results Co-culturing both cell types markedly up-regulated inflammatory cytokine production as compared with the cells cultured independently, suggesting that both cell types interact with each other to synergistically produce higher amounts of inflammatory cytokines. Interestingly, both DP-1 and primary dental pulp cells appeared to produce molecules stimulating macrophages to produce tumour necrosis factor-α- Conclusion Co-culturing immortalized dental pulp cells and macrophages may be a new ex vivo model for studying the pathophysiology of reversible pulpitis..
20. Tomomi Sano, S. Nagayasu, S. Suzuki, Misaki Iwashita, Akiko Yamashita, T. Shinjo, Terukazu Sanui, A. Kushiyama, T. Kanematsu, T. Asano, Fusanori Nishimura, Epicatechin downregulates adipose tissue CCL19 expression and thereby ameliorates diet-induced obesity and insulin resistance, Nutrition, Metabolism and Cardiovascular Diseases, 10.1016/j.numecd.2016.11.008, 27, 3, 249-259, 2017.03, [URL], Background and aims Epicatechin (EC) intake has been suggested to be beneficial for the prevention of cardiovascular disorders, and it is well known that adipose tissue inflammation is one of the major risk factors for coronary heart diseases. The purpose of the present study was to determine the in vitro and in vivo effects of EC on adipose tissue inflammation and obesity. Methods and results DNA microarray analysis was performed to evaluate the effects of EC on gene expression in adipocytes co-cultured with bacterial endotoxin-stimulated macrophages. To determine the in vivo effects of the catechin, C57BL/6 mice were fed either a high-fat diet (HFD) or HFD combined with EC, and metabolic changes were observed EC suppressed the expression of many inflammatory genes in the adipocytes co-cultured with endotoxin-stimulated macrophages. Specifically, EC markedly suppressed chemokine (C–C motif) ligand 19 (CCL19) expression. The target cell of EC appeared to macrophages. The in vivo study indicated that mice fed the EC-supplemented HFD were protected from diet-induced obesity and insulin resistance. Accordingly, the expression levels of genes associated with inflammation in adipose tissue and in the liver were downregulated in this group of mice. Conclusions EC exerts beneficial effects for the prevention of adipose tissue inflammation and insulin resistance. Since we previously reported that mice deficient in the CCL19 receptor were protected from diet-induced obesity and insulin resistance, it can be concluded that the beneficial effects of EC could be mediated, at least in part, by marked suppression of CCL19 expression..
21. Suzuki S, Fukuda T, Nagayasu S, Nakanishi J, Yoshida K, Hirata-Tsuchiya S, Nakao Y, Sano T, Yamashita A, Yamada S, Ohta K, Shiba H, Nishimura F., Dental pulp cell-derived powerful inducer of TNF-α comprises PKR containing stress granule rich microvesicles., Sci Rep. , 2019 Mar 7;9(1):3825., 2019.03.
22. Akiko Yamashita, Y. Soga, Y. Iwamoto, T. Asano, Y. Li, Y. Abiko, Fusanori Nishimura, DNA microarray analyses of genes expressed differentially in 3T3-L1 adipocytes co-cultured with murine macrophage cell line RAW264.7 in the presence of the toll-like receptor 4 ligand bacterial endotoxin, International Journal of Obesity, 10.1038/ijo.2008.153, 32, 11, 1725-1729, 2008.11, [URL], Recent studies have suggested that macrophages were integrated into adipose tissues to interact with adipocytes, thereby exacerbating inflammatory responses. Furthermore, both adipocytes and macrophages appear to express toll-like receptor-4 (TLR-4), and free fatty acids may stimulate cells through TLR-4. Herein, we analyzed genes differentially expressed in adipocytes when co-cultured with macrophages in the presence of a ligand for TLR-4, bacterial lipopolysaccharide (LPS). RAW264.7, a murine macrophage cell line and differentiated 3T3-L1 adipocytes were co-cultured using a transwell system. Genes differentially expressed in adipocytes were analyzed by the DNA microarray method following 4, 8, 12 and 24 h stimulation with 1 ng ml-1 of Escherichia coli LPS. Randomly selected genes with high expressions were confirmed by quantitative methods at both the gene and the protein level. Co-culture of macrophages and adipocytes with a low LPS concentration (1 ng ml-1) markedly upregulated gene expressions associated with inflammation and/or angiogenesis, such as those of interleukin-6 (IL-6), MCP-1, RANTES and CXCL1/KC, in adipocytes. Furthermore, several genes associated with insulin resistance were differentially expressed. Upregulations of genes encoding MCP-1, RANTES and CXC/KC were confirmed by quantitative methods. These results suggest that ligands for TLR-4 stimulate both adipocytes and macrophages to upregulate the expressions of many genes associated with inflammation and/or angiogenesis..
23. Sano T, Sanada T, Sotomaru Y, Shinjo T, Iwashita M, Yamashita A, Fukuda T, Sanui T, Asano T, Kanematsu T, Nishimura F., Ccr7 null mice are protected against diet-induced obesity via Ucp1 upregulation and enhanced energy expenditure., Nutr Metab (Lond), 2019 Jul 4;16:43, 2019.07.
24. Hiroaki Matsunaga, Misaki Iwashita, Takanori Shinjo, Akiko Yamashita, Mitsudai Tsuruta, Shoichiro Nagasaka, Ataru Taniguchi, Mitsuo Fukushima, Naoya Watanabe, Fusanori Nishimura, Adipose tissue complement factor B promotes adipocyte maturation, Biochemical and Biophysical Research Communications, 10.1016/j.bbrc.2017.11.069, 495, 1, 740-748, 2018.01, [URL], Objectives It is well-known that the complement system plays an essential role in host immunity. Observational studies have indicated that complement system-related molecules such as complement factor B (CfB) and other components are correlated with obesity and/or insulin resistance parameters. In this study, we investigated the role of adipocyte-derived CfB in adipose tissue metabolism. Methods We investigated the expression level of complement system-related genes in adipocytes. To understand the role of CfB in adipocyte, we performed Cfb overexpression in 3T3-L1 preadipocytes and generated adipocyte-specific Cfb transgenic mice. Results Cfb expression was markedly enhanced in 3T3-L1 adipocytes co-cultured with macrophages following endotoxin stimulation. In Cfb-overexpressing cells, the expression of adipocyte differentiation/maturation-related genes encoding peroxisome proliferator-activated receptor γ (Pparγ), adipocyte Protein 2 and perilipin was significantly enhanced. Cfb transgenic mice showed a marked increase in the expression of genes encoding Pparγ, perilipin, sterol regulatory element-binding protein 1 c, and Cd36 in the subcutaneous adipose tissue. Conclusions CfB plays a crucial role in late-phase of adipocyte differentiation and subsequent lipid droplet formation..
25. Hideo Nakarai, Akiko Yamashita, Shintaro Nagayasu, Misaki Iwashita, Sonoko Kumamoto, Hideki Ohyama, Masaki Hata, Yoshihiko Soga, Akifumi Kushiyama, Tomoichiro Asano, Yoshimitsu Abiko, Fusanori Nishimura, Adipocyte-macrophage interaction may mediate LPS-induced low-grade inflammation
Potential link with metabolic complications, Innate Immunity, 10.1177/1753425910393370, 18, 1, 164-170, 2012.02, [URL], Chronic low-grade infection has been suggested to be associated with metabolic disorder such as diabetes. However, the molecular mechanism underlying this important association is largely unknown. The only clue established so far is that many subjects exhibit elevated levels of C-reactive protein as measured by highly sensitive assay. Here, we hypothesized that adipocyte-macrophage interaction plays a key role in amplifying such low grade infection to the level of influencing metabolic disorders. The presence of macrophages in abdominal adipose tissues was investigated by immunohistochemistry. To see whether molecules associated with acute phase protein, LPS signaling, and persistent recruitment of monocytes, are produced at higher amounts in adipocytes co-cultured with macrophages stimulated with low concentration of LPS (1 ng/ml), we measured serum amyloid A (SAA), LPS binding protein (LBP), soluble CD14 (sCD14), and RANTES levels in culture supernatant of co-cultures. Lastly, we investigated in vivo effect of low-grade LPS infusion on the production of these molecules using obese model mice. The macrophages were certainly identified in abdominal adipose tissues. Investigated molecules, especially LBP, SAA, and RANTES were produced at higher amounts in co-cultures stimulated with LPS compared with the cells without LPS. The ob/ob, and high-fat diet-induced obesity mice produced higher amounts of LBP, SAA, and RANTES one day after LPS infusion (1 ng/ml/g body weight) compared with ob/- and normal-fat fed control mice. Thus, adipocytes and infiltrated macrophages, and their interaction with low endotoxin stimulation appear to play an important role in amplifying and maintaining LPS-induced low-grade inflammation..
26. Matsunaga H, Iwashita M, Shinjo T, Yamashita A, Tsuruta M, Nagasaka S, Taniguchi A, Fukushima M, Watanabe N, Nishimura F., Adipose tissue complement factor B promotes adipocyte maturation., Biochem Biophys Res Commun. , 495(1):740-748, 2018.01.

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