Kyushu University Academic Staff Educational and Research Activities Database
List of Papers
Zhou Wu Last modified date:2024.04.10

Associate Professor / Department of Aging Science and Pharmacology / Department of Dental Science / Faculty of Dental Science

1. Kaige Zhang, Sijian Wang, Zihan Wang, Yiming Jiang, Minghao Huang, Nanqi Liu, Biao Wang, Xin Meng, Zhou Wu, Xu Yan and Xinwen Zhang, Critical roles of PU.1/ cathepsin S activation in regulating inflammatory responses of Macrophages in Periodontitis., J Periodontal Res. , 10.1111/jre.13153., 58, 5, 939 -947, 2023.06.
2. Zhen Xie, Jie Meng, Wei Kong, Zhou Wu, Fei Lan, Narengaowa FNU, Yoshinori Hayashi, Qinghu Yang, Zhantao Bai, Hiroshi Nakanishi, hong qing, and Junjun Ni, Microglial Cathepsin E Drives Neuroinflammation and Amyloid β Production in Alzheimer's Disease., Aging Cell. 21(3) e13565, doi: 10.1111/acel.13565., 2022.06.
3. Yicong Liu, Hui Li, Jiangqi Hu, Zhou Wu, Jie Meng, Yoshinori Hayashi, Hiroshi Nakanishi, Hong Qing, Junjun Ni, Differential Expression and Distinct Roles of Proteinase-Activated Receptor 2in Microglia and Neurons in Neonatal Mouse Brain After Hypoxia-Ischemic Injury., Mol Neurobiol., 10.1007/s12035-021-02594-5., 2021.11.
4. Muzhou Jiang, Xinwen Zhang, Xu Yan, Shinsuke Mizutani, Haruhiko Kashiwazaki, Junjun Ni† and Zhou Wu, GSK3β is involved in promoting Alzheimer’s disease pathologies following chronic systemic exposure to Porphyromonas gingivalis lipopolysaccharide in amyloid precursor proteinNL-F/NL-F knock-in mice., Brain Behav Immun., 10.1016/j.bbi.2021.08.213, 98, 1-12, 2021.09.
5. Shinichi Ishiguro*, Tetsuro Shinada*, Zhou Wu*, Mayumi Karimazawa, Michimasa Uchidate, Eiji Nishimura, Yoko Yasuno, Makiko Ebata, Piyamas Sillapakong, Hiromi Ishiguro, Nobuyoshi Ebata, Junjun Ni, Muzhou Jiang, Masanobu Goryo, Keishi Otsu, Hidemitsu Harada, Koichi Suzuki†, A novel cyclic peptide (Naturido) modulates glia-neuron interactions in vitro and reverses ageing-related deficits in senescence-accelerated mice., PLoS One,, 16, 1, 2021.05, The use of agents that target both glia and neurons may represent a new strategy for the treatment of ageing disorders. Here, we confirmed the presence of the novel cyclic peptide Naturido that originates from a medicinal fungus (Isaria japonica) grown on domestic silkworm (Bombyx mori). We found that Naturido significantly enhanced astrocyte proliferation and activated the single copy gene encoding the neuropeptide VGF and the neuron-derived NGF gene. The addition of the peptide to the culture medium of primary hippocampal neurons increased dendrite length, dendrite number and axon length. Furthermore, the addition of the peptide to primary microglial cultures shifted CGA-activated microglia towards anti-inflammatory and neuroprotective phenotypes. These findings of in vitro glia–neuron interactions led us to evaluate the effects of oral administration of the peptide on brain function and hair ageing in senescence-accelerated mice (SAMP8). In vivo analyses revealed that spatial learning ability and hair quality were improved in Naturido-treated mice compared with untreated mice, to the same level observed in the normal ageing control (SAMR1). These data suggest that Naturido may be a promising glia–neuron modulator for the treatment of not only senescence, but also Alzheimer’s disease and other neurodegenerative diseases..
6. Gongfeng L, Aiqin Zhu, Yuling Huang, Jie Meng, Lei Ji, Hongjuan Li, Xiaohong Wang, Junming Luo, Zhou Wu, Shengzheng Wu, The effect of traditional Tibetan guozhuang dance on vascular health in elderly individuals living at high altitudes, Am J Transl Res., 12, 8, 12(8):4550-4560.eCollection 2020., 2020.10.
7. Yebo Gu, Zhou Wu, Fan Zeng, Muzhou Jiang, Jessica L. Teeling, Junjun Ni, Ichiro Takahashi. ,  Systemic Exposure to Lipopolysaccharide from Porphyromonas gingivalis Induces Bone Loss-correlated Alzheimer’s Disease-like Pathologies in Middle-aged Mice, J. Alzheimer's Dis. , doi: 10.3233/JAD-200689, 2020.09.
8. Zng F, Liu Y, Huang W, Qing H, Kadowaki T, Kashiwazaki H, Ni J, Wu Z, Mediates Cerebrovascular-related Amyloid β Accumulation After Porphyromonas Gingivalis Infection, Journal of Neurochemistry, 10.1111/jnc.15096, 1-13, 2020.06, Cerebrovascular-related amyloidogenesis is found in over 80% of Alzheimer’s disease (AD) cases, and amyloid β (Aβ) generation is increased in the peripheral macrophages during infection of Porphyromonas gingivalis (P. gingivalis), a causal bacterium for periodontitis. In the present study, we focused on receptor for advanced glycation end products (RAGE), the key molecule involves in Aβ influx after P. gingivalis infection to test our hypothesis that Aβ transportation from periphery into the brain, known as “Aβ influx”, is enhanced by P. gingivalis infection. Using cultured hCMEC/D3 cell line, in comparison to uninfected cells, directly infection with P. gingivalis (multiplicity of infection, MOI=5) significantly increased a time-dependent RAGE expression resulting in a dramatic increase of Aβ influx in the hCMEC/D3 cells; the P. gingivalis-upregulated RAGE expression was significantly decreased by NF-κB and Cathepsin B (CatB)-specific inhibitors, and the P.gingivalis-increased IκBα degradation was significantly decreased by CatB specific inhibitor. Furthermore, the P. gingivalis-increased Aβ influx was significantly reduced by RAGE-specific inhibitor. Using 15-month-old mice (C57BL/6JJmsSlc, female), in comparison to non-infection mice, systemic P. gingivalis infection for 3 consecutive weeks (1×108 CFU/mouse, every 3 days, intraperitoneally) significantly increased the RAGE expression in the CD31-positive endothelial cells and the Aβ loads around the CD31-positive cells in the mice’s brains. The RAGE expression in the CD31-positive cells was positively correlated with the Aβ loads. These observations demonstrate that the upregulated RAGE expression in cerebral endothelial cells mediates the Aβ influx after P. gingivalis infection, and CatB plays a critical role in regulating the NF-κB/RAGE expression..
9. Jiang M, Meng J, Zeng F, Qing H, Hook G, Hook V, Wu Z, Ni J, Cathepsin B Inhibition Blocks Neurite Outgrowth in Cultured Neurons by Regulating Lysosomal Trafficking and Remodeling, Journal of Neurochemistry, 10.1111/jnc.15032, 1-13, 2020.04.
10. Nie, Ran; Wu, Zhou; Ni, Junjun; Zeng, Fan; Yu, Weixian; Zhang, Yufeng; Kadowaki, Tomoko ; Kashiwazaki, Haruhiko; Teeling, Jessica L. ; Zhou, Yanmin, Porphyromonas gingivalis Infection Induces Amyloid-β Accumulation in Monocytes/Macrophages, Journal of Alzheimer's Disease, 72(2):479-494, 2019.11, Abnormal accumulations of amyloid-β (Aβ) in the brain is the most significant pathological hallmark of Alzheimer’s disease (AD), and we have found that chronic systemic exposure to lipopolysaccharide of P. gingivalis induces the brain Aβ accumulation in the middle-aged mice. On the other hand, recent research has shown that circulating Aβ are transferred into the brain, however, the involvement of chronic systemic P. gingivalis infection in peripheral Aβ metabolism is unknown. We hypothesized that chronic P. gingivalis infection expands the Aβ pools in peripheral inflammatory tissues which contributes to the accumulation of Aβ in the brain during periodontitis. We conducted immunofluorescence and biochemical analyses on the molecules of inflammation and Aβ metabolism in the chronic systemic P. gingivalis infected middle-aged mice and the P. gingivalis infected cultured monocyte/macrophages (RAW264.7 cells). We showed that the increased expressions of IL-1β, APP770, CatB, Aβ1-42 and Aβ3-42 were mainly co-localized with macrophages in the liver of P. gingivalis infected mice. Blocking CatB and NF-κB by their specific inhibitors significantly inhibited the P. gingivalis infection induced expressions of IL-1β, APP770, Aβ1-42 and Aβ3-42 in cultured RAW264.7 cells. Additionally, the expressions of APP770, CatB, Aβ1-42 and Aβ3-42 were determined in the macrophages of gingival tissues form patients of periodontitis. These findings indicate that chronic systemic P. gingivalis infection induces Aβ accumulation in the inflammatory monocytes/macrophages via activating CatB/NF-κB signaling, thus suggests monocytes/macrophages serve as a circulation Aβ pool during periodontitis. CatB should be a novel therapeutic target for preventing periodontitis-related AD initiation and pathology process..
11. Junjun Ni, Zhou Wu, Jie Meng, Takashi Saito, Takaomi C. Saido, Hong Qing, Hiroshi Nakanishi, An impaired intrinsic microglial clock system induces neuroinflammatory alterations in the early stage of amyloid precursor protein knock-in mouse brain, Journal of neuroinflammation, 10.1186/s12974-019-1562-9, 16, 1, 2019.08.
12. Harada Y, Zhang J, Imari K, Yamasaki R, Ni J, Wu Z, Yamamoto K, Kira JI, Nakanishi H, Hayashi Y, Cathepsin E in neutrophils contributes to the generation of neuropathic pain in experimental autoimmune encephalomyelitis., Pain, doi: 10.1097, 2019.04.
13. Junjun Ni, Hiro Take, Veronika Stoka, Jie Meng, Yoshinori Hayashi, Christoph Peters, Hong Qing, Vito Turk, Hiroshi Nakanishi, Increased expression and altered subcellular distribution of cathepsin B in microglia induce cognitive impairment through oxidative stress and inflammatory response in mice, Aging cell, 10.1111/acel.12856, 18, 1, 2019.02.
14. Junko Hatakeyama, Hisashi Anan, Yuji Hatakeyama, Noriyoshi Matsumoto, Fumiko Takayama, Hiro Take, Etsuko Matsuzaki, Masahiko Minakami, Toshio Izumi, Hiroshi Nakanishi, Induction of bone repair in rat calvarial defects using a combination of hydroxyapatite with phosphatidylserine liposomes, Journal of Oral Science, 10.2334/josnusd.17-0488, 61, 1, 111-118, 2019.01, Phosphatidylserine (PS)―normally present on the inner leaflet of the plasma membrane― translocates to the outer leaflet at an early stage of apoptosis. PS-containing liposomes (PSLs) can mimic the effect of apoptotic cells in inducing the secretion of prostaglandin E2 from phagocytes and inhibiting the maturation of dendritic cells and osteoclast precursors. The present study attempted to evaluate the effect of calcium phosphate (in the form of hydroxyapatite [HAP]) in the presence or absence of PSLs for repair of rat calvarial bone defects. The defects, each 5 mm in diameter, were created in the calvaria parietal bone of 8-week-old Wistar rats and subjected to one of the following treatments: no augmentation (Sham), HAP alone, or a mixture of HAP and PSL (HAP+PSL). Micro-computed tomography data showed that the HAP+PSL complexes promoted greater bone regeneration in comparison with either the Sham procedure or HAP alone at 4 and 8 weeks after implantation. The regeneration of calvarial bone defects induced by PSLs was mediated partly through upregulation of the osteogenic marker Alkaline Phosphatase, Type I collagen, osteocalcin, Runx2, and Osterix mRNAs. These data are the first to show that PSLs can influence bone regeneration by regulating osteoblast differentiation..
15. Jie Meng, Junjun Ni, Wu Z, Muzhou Jiang, Aiqin Zhu, Hong Qing, and Hiroshi Nakanishi, The Critical Role of IL-10 in the Antineuroinflammatory and Antioxidative Effects of Rheum tanguticum on Activated Microglia, OXIDATIVE MEDICINE AND CELLULAR LONGEVITY, 10.1155/2018/1083596, 2018.09.
16. Zhu A, Wu Z, Zhong X, Ni J, Li Y, Meng J, Du C, Zhao X, Nakanishi H, Wu S, Brazilian Green Propolis Prevents Cognitive Decline into Mild Cognitive Impairment in Elderly People Living at High Altitude, J. Alzheimer's Dis, 63(2), 551-560, 2018.06.
17. Ryo Okada, Xinwen Zhang, Yuka Harada, Hiro Take, Hiroshi Nakanishi, Cathepsin H deficiency in mice induces excess Th1 cell activation and early-onset of EAE though impairment of toll-like receptor 3 cascade, Inflammation Research, 10.1007/s00011-018-1136-9, 67, 5, 371-374, 2018.05, Objective: The objective of this study is to investigate the role of cathepsin H (CatH), a lysosomal cysteine protease, in the development of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. Methods: EAE was induced in CatH-deficient mice (CatH−/−) and wild-type littermates (+/+) using myelin oligodendrocyte glycoprotein (MOG) 35–55. The effects of CatH deficiency were determined by clinical scoring, mRNA expression levels of Tbx21, Rorc and FoxP3, protein levels of poly(I:C)-induced toll-like receptor 3 (TLR3) and phosphorylation of IRF3, and secretion of interferon-β (IFN-β) by splenocytes. Results and conclusions: CatH−/− showed a significantly earlier disease onset of EAE and increased Th1 cell differentiation in splenocytes. Splenocytes prepared from immunized CatH−/− showed a significant decrease in poly(I:C)-induced increased TLR3 expression, interferon regulatory factor 3 (IRF3) phospholylation and IFN-β secretion. Therefore, CatH deficiency impaired TLR3-mediated activation of IRF3 and consequent secretion of IFN-β from dendritic cells, leading to the enhancement of Th1 cell differentiation and consequent early disease onset of EAE..
18. Zhu Aiqin *,Wu Z*, Zhong, Xin, Ni, Junjun, Li, Yinglan, Meng, Jie, Du, Can, Zhao Xue, Nakanishi, Hiroshi, Wu Shizheng, Brazilian Green Propolis Prevents Cognitive Decline into Mild Cognitive Impairment in Elderly People Living at High Altitude, JOURNAL OF ALZHEIMERS DISEASE, 10.3233/JAD-170630, 63, 2, 551-560, 2018.03.
19. Yicong Liu, Hiro Take, Yurika Nakanishi, Junjun Ni, Yoshinori Hayashi, Fumiko Takayama, Yanmin Zhou, Tomoko Kadawaki, Hiroshi Nakanishi, Infection of microglia with Porphyromonas gingivalis promotes cell migration and an inflammatory response through the gingipain-mediated activation of protease-activated receptor-2 in mice, Scientific Reports, 10.1038/s41598-017-12173-1, 7, 1, 2017.12.
20. Hiro Take, Junjun Ni, Yicong Liu, Jessica L. Teeling, Fumiko Takayama, Alex Collcutt, Paul Ibbett, Hiroshi Nakanishi, Cathepsin B plays a critical role in inducing Alzheimer's disease-like phenotypes following chronic systemic exposure to lipopolysaccharide from Porphyromonas gingivalis in mice, Brain, Behavior, and Immunity, 10.1016/j.bbi.2017.06.002, 65, 350-361, 2017.10.
21. Fumiko Takayama, Xinwen Zhang, Yoshinori Hayashi, Hiro Take, Hiroshi Nakanishi, Dysfunction in diurnal synaptic responses and social behavior abnormalities in cathepsin S-deficient mice, Biochemical and Biophysical Research Communications, 10.1016/j.bbrc.2017.06.061, 490, 2, 447-452, 2017.08.
22. Yuka Harada, Fumiko Takayama, Kazunari Tanabe, Junjun Ni, Yoshinori Hayashi, Kenji Yamamoto, Hiro Take, Hiroshi Nakanishi, Overexpression of Cathepsin E Interferes with Neuronal Differentiation of P19 Embryonal Teratocarcinoma Cells by Degradation of N-cadherin, Cellular and Molecular Neurobiology, 10.1007/s10571-016-0376-x, 37, 3, 437-443, 2017.04, Cathepsin E (CatE), an aspartic protease, has a limited distribution in certain cell types such as gastric cells. CatE is not detectable in the normal brain, whereas it is increasingly expressed in damaged neurons and activated microglia of the pathological brain. Neurons expressing high levels of CatE showed apparent morphological changes, including a marked shrinkage of the cytoplasmic region and beading of neurites, suggesting neuronal damage. The intracellular level of CatE in neurons is strictly regulated at both transcriptional and translational levels. Although the up-regulation of CatE may cause pathological changes in neurons, little information is available about the precise outcome of the increased expression of CatE in neurons. In this study, we have attempted to clarify the outcome of up-regulated CatE gene expression in neurons using the P19 cell neuronal differentiation after the overexpression of CatE. We unexpectedly found that the overexpression of CatE interfered with neuronal differentiation of P19 cells through an impairment of cell aggregate formation. Pepstatin A, an aspartic protease inhibitor, restored the impaired cell aggregation of P19/CatE cells. The small number of P19 cells differentiated into neurons had abnormal morphology characterized by their fusiform cell bodies with short processes. Furthermore, CatE proteolytically cleaved the extracellular domain of N-cadherin. These observations suggest that the overexpression of CatE interferes with neuronal differentiation of P19 cells through an impairment of cell aggregate formation, possibly through proteolytic degradation of N-cadherin..
23. Xinwen Zhang, Hiro Take, Yicong Liu, Junjun Ni, Chunfu Deng, Baohong Zhao, Hiroshi Nakanishi, Jing He, Xu Yan, Boi-ogi-to (TJ-20), a Kampo Formula, Suppresses the Inflammatory Bone Destruction and the Expression of Cytokines in the Synovia of Ankle Joints of Adjuvant Arthritic Rats, Evidence-based Complementary and Alternative Medicine, 10.1155/2017/3679295, 2017, 2017.01.
24. Junjun Ni, Hiro Take, Jie Meng, Aiqin Zhu, Xin Zhong, Shizheng Wu, Hiroshi Nakanishi, The Neuroprotective Effects of Brazilian Green Propolis on Neurodegenerative Damage in Human Neuronal SH-SY5Y Cells, Oxidative Medicine and Cellular Longevity, 10.1155/2017/7984327, 2017, 2017.01.
25. Fumiko Takayama, Yoshinori Hayashi, Hiro Take, Yicong Liu, Hiroshi Nakanishi, Diurnal dynamic behavior of microglia in response to infected bacteria through the UDP-P2Y 6 receptor system, Scientific Reports, 10.1038/srep30006, 6, 2016.07.
26. Yoshinori Hayashi, Saori Morinaga, Jing Zhang, Yasushi Satoh, Andrea L. Meredith, Takahiro Nakata, Hiro Take, Shinichi Kohsaka, Kazuhide Inoue, Hiroshi Nakanishi, BK channels in microglia are required for morphine-induced hyperalgesia, Nature Communications, 10.1038/ncomms11697, 7, 2016.05.
27. Xue Li, Hiro Take, Junjun Ni, Yicong Liu, Jie Meng, Weixian Yu, Hiroshi Nakanishi, Yanmin Zhou, Cathepsin B Regulates Collagen Expression by Fibroblasts via Prolonging TLR2/NF-κB Activation, Oxidative Medicine and Cellular Longevity, 10.1155/2016/7894247, 2016, 2016.01.
28. Hiro Take, Janchun Yu, Aiqin Zhu, Hiroshi Nakanishi, Nutrients, Microglia Aging, and Brain Aging, Oxidative Medicine and Cellular Longevity, 10.1155/2016/7498528, 2016, 2016.01.
29. Xue Li, Hiro Take, Junjun Ni, Yicong Liu, Jie Meng, Weixian Yu, Hiroshi Nakanishi, Yanmin Zhou, Cathepsin B Regulates Collagen Expression by Fibroblasts via Prolonging TLR2/NF-κB Activation, Oxidative Medicine and Cellular Longevity, 10.1155/2016/7894247, 2016, 2016.01, Fibroblasts are essential for tissue repair due to producing collagens, and lysosomal proteinase cathepsin B (CatB) is involved in promoting chronic inflammation. We herein report that CatB regulates the expression of collagens III and IV by fibroblasts in response to a TLR2 agonist, lipopolysaccharide from Porphyromonas gingivalis (P.g. LPS). In cultured human BJ fibroblasts, mRNA expression of CatB was significantly increased, while that of collagens III and IV was significantly decreased at 24 h after challenge with P.g. LPS (1 μg/mL). The P.g. LPS-decreased collagen expression was completely inhibited by CA-074Me, the specific inhibitor of CatB. Surprisingly, expression of collagens III and IV was significantly increased in the primary fibroblasts from CatB-deficient mice after challenge with P.g. LPS. The increase of CatB was accompanied with an increase of 8-hydroxy-2′-deoxyguanosine (8-OHdG) and a decrease of IκBα. Furthermore, the P.g. LPS-increased 8-OHdG and decreased IκBα were restored by CA-074Me. Moreover, 87% of CatB and 86% of 8-OHdG were colocalized with gingival fibroblasts of chronic periodontitis patients. The findings indicate the critical role of CatB in regulating the expression of collagens III and IV by fibroblasts via prolonging TLR2/NF-κB activation and oxidative stress. CatB-specific inhibitors may therefore improve chronic inflammation-delayed tissue repair..
30. Hiro Take, Janchun Yu, Aiqin Zhu, Hiroshi Nakanishi, Nutrients, Microglia Aging, and Brain Aging, Oxidative Medicine and Cellular Longevity, 10.1155/2016/7498528, 2016, 2016.01, As the life expectancy continues to increase, the cognitive decline associated with Alzheimer's disease (AD) becomes a big major issue in the world. After cellular activation upon systemic inflammation, microglia, the resident immune cells in the brain, start to release proinflammatory mediators to trigger neuroinflammation. We have found that chronic systemic inflammatory challenges induce differential age-dependent microglial responses, which are in line with the impairment of learning and memory, even in middle-aged animals. We thus raise the concept of "microglia aging." This concept is based on the fact that microglia are the key contributor to the acceleration of cognitive decline, which is the major sign of brain aging. On the other hand, inflammation induces oxidative stress and DNA damage, which leads to the overproduction of reactive oxygen species by the numerous types of cells, including macrophages and microglia. Oxidative stress-damaged cells successively produce larger amounts of inflammatory mediators to promote microglia aging. Nutrients are necessary for maintaining general health, including the health of brain. The intake of antioxidant nutrients reduces both systemic inflammation and neuroinflammation and thus reduces cognitive decline during aging. We herein review our microglia aging concept and discuss systemic inflammation and microglia aging. We propose that a nutritional approach to controlling microglia aging will open a new window for healthy brain aging..
31. Yoshinori Hayashi, Saori Morinaga, Xia Liu, Jing Zhang, Hiro Take, Takeshi Yokoyama, Hiroshi Nakanishi, An EP2 Agonist Facilitates NMDA-Induced Outward Currents and Inhibits Dendritic Beading through Activation of BK Channels in Mouse Cortical Neurons, Mediators of Inflammation, 10.1155/2016/5079597, 2016, 2016.01.
32. NI JUNJUN, Wu Z, Christoph Peterts, Kenji, Yamamoto, Hong Qin, Hiroshi Nakanishi, The critical role of proteolytic relay through cathepsins B and E in the phenotypic change of microglia/macrophage, Journal of Neuroscience, 10.1523/JNEUROSCI.1599-15.2015, 35, 12488-501, 2015.09.
33. NI JUNJUN, Wu Z, Christoph Peterts, Kenji, Yamamoto, Hong Qin, Hiroshi Nakanishi, The critical role of proteolytic relay through cathepsins B and E in the phenotypic change of microglia/macrophage, J. Neurosci, 10.1523/JNEUROSCI.1599-15.2015, 35, 36, 12488-501, 2015.09.
34. Wu Z, Hiroshi Nakanishi, Lessons from Microglia Aging for the Link between Inflammatory Bone Disorders and Alzheimer’s Disease,, Journal of Immunology Research , Volume 2015 (2015),, 1-10, Article ID 471342, 2015.03.
35. Aiqin Zhu, Wu Z, Jie Meng, Patrick L. McGeer, Yi Zhu, Hiroshi Nakanishi, Shizheng Wu, The Neuroprotective Effects of Ratanasampil on Oxidative Stress-Mediated Neuronal Damage in Human Neuronal SH-SY5Y Cells, Oxidative Medicine and Cellular Longevity, Volume 2015 (2015), , 1-9, 2015.03.
36. Zhou Wu, Hiroshi Nakanishi, Lessons from Microglia Aging for the Link between Inflammatory Bone Disorders and Alzheimer's Disease, Journal of Immunology Research, 10.1155/2015/471342, 2015, 2015.01, Bone is sensitive to overactive immune responses, which initiate the onset of inflammatory bone disorders, such as rheumatoid arthritis and periodontitis, resulting in a significant systemic inflammatory response. On the other hand, neuroinflammation is strongly implicated in Alzheimer's disease (AD), which can be enhanced by systemic inflammation, such as that due to cardiovascular disease and diabetes. There is growing clinical evidence supporting the concept that rheumatoid arthritis and periodontitis are positively linked to AD, suggesting that inflammatory bone disorders are risk factors for this condition. Recent studies have suggested that leptomeningeal cells play an important role in transducing systemic inflammatory signals to brain-resident microglia. More importantly, senescent-type, but not juvenile-type, microglia provoke neuroinflammation in response to systemic inflammation. Because the prevalence of rheumatoid arthritis and periodontitis increases with age, inflammatory bone disorders may be significant sources of covert systemic inflammation among elderly people. The present review article highlights our current understanding of the link between inflammatory bone disorders and AD with a special focus on microglia aging..
37. Aiqin Zhu, Hiro Take, Jie Meng, Patrick L. McGeer, Yi Zhu, Hiroshi Nakanishi, Shizheng Wu, The Neuroprotective Effects of Ratanasampil on Oxidative Stress-Mediated Neuronal Damage in Human Neuronal SH-SY5Y Cells, Oxidative Medicine and Cellular Longevity, 10.1155/2015/792342, 2015, 2015.01.
38. Hiroshi Nakanishi, Hiro Take, The downward spiral of periodontitis and diabetes in Alzheimer's disease
Extending healthy life expectancy through oral health, Journal of Oral Biosciences, 10.1016/j.job.2015.05.002, 57, 3, 139-142, 2015.01.
39. Aiqin Zhu, Hiro Take, Jie Meng, Patrick L. McGeer, Yi Zhu, Hiroshi Nakanishi, Shizheng Wu, The Neuroprotective Effects of Ratanasampil on Oxidative Stress-Mediated Neuronal Damage in Human Neuronal SH-SY5Y Cells, Oxidative Medicine and Cellular Longevity, 10.1155/2015/792342, 2015, 2015.01.
40. Okada Ryo, Wu Z, junjun Ni, J Zhang, Yoshito Yoshimine, Christoph Peters, Paul Saftig, Hiroshi Nakanishi, Cathepsin D deficiency induces oxidative damage in brain pericytes and impairs the blood-brain barrier, Molecular and Cellular Neuroscience, 10.1016/j.mcn.2014.12.002, 64, 51-60, 2014.12.
41. Wu Z, Hiroshi Nakanishi, Connection between periodontitis and Alzheimer's disease: possible roles of microglia and leptomeningeal cells, Journal of Pharmacological Sciences,, 10.1254/jphs.14 R11CP, 126, 1, 8-13, 2014.12.
42. Yoshinori Hayashi, yuka Koga, Xinwen Zhang, Christoph Peters, Yanagawa Y, Wu Z, Takeshi Yokoyama, Hiroshi Nakanishi, “Autophagy in superficial spinal dorsal horn accelerates the cathepsin B-dependent morphine antinociceptive tolerance”, Neuroscience,, 10.1016/j.neuroscience.2014.06.037, 275, 384-394, 2014.05.
43. Zhang XW, Wu Z, Yoshinori Hayashi, Okada Ryo, Hiroshi Nakanishi, Peripheral role of cathepsin S in Th1 cell-dependent transition of nerve injury-induced acute pain to a chronic pain state., J Neurosci., 10.1523/JNEUROSCI.3681-13.2014, 34(8):3013-22, 2014.02.
44. Liu Y, Wu Z, Zhang XW, Ni J, Yu W, Zhou Y, Hiroshi Nakanishi, Leptomeningeal cells transduce peripheral macrophages inflammatory signal to microglia in reponse to Porphyromonas gingivalis LPS., Mediators Inflamm., 10.1155/2013/407562, 2013:407562, 2013.12.
45. Hiro Take, Li Sun, Sadayuki Hashioka, Sheng Yu, Claudia Schwab, Ryo Okada, Yoshinori Hayashi, Patrick L. McGeer, Hiroshi Nakanishi, Differential pathways for interleukin-1β production activated by chromogranin A and amyloid β in microglia, Neurobiology of Aging, 10.1016/j.neurobiolaging.2013.05.018, 34, 12, 2715-2725, 2013.12, Although chromogranin A (CGA) is frequently present in Alzheimer's disease (AD), senile plaques associated with microglial activation, little is known about basic difference between CGA and fibrillar amyloid-β (fAβ) as neuroinflammatory factors. Here we have compared the interleukin-1β (IL-1β) production pathways by CGA and fAβ in microglia. In cultured microglia, production of IL-1β was induced by CGA, but not by fAβ. CGA activated both nuclear factor-κB (NF-κB) and pro-caspase-1, whereas fAβ activated pro-caspase-1 only. For the activation of pro-caspase-1, both CGA and fAβ needed the enzymatic activity of cathepsin B (CatB), but only fAβ required cytosolic leakage of CatB and the NLRP3 inflammasome activation. In contrast, fAβ induced the IL-1β secretion from microglia isolated from the aged mouse brain. In AD brain, highly activated microglia, which showed intense immunoreactivity for CatB and IL-1β, surrounded CGA-positive plaques more frequently than Aβ-positive plaques. These observations indicate differential pathways for the microglial IL-1β production by CGA and fAβ, which may aid in better understanding of the pathological significance of neuroinflammation in AD..
46. Yoshinori Hayashi, Koyanagi Satoru, Naoki Kusunose, Ryo Okada, Hiro Take, Hidetoshi Saitoh, Kiyoharu Ukai, Shinichi Kohsaka, Kazuhide Inoue, Shigehiro Ohdo, Hiroshi Nakanishi, The intrinsic microglial molecular clock controls synaptic strength via the circadian expression of cathepsin S, Scientific Reports, 10.1038/srep02744, 3, 2013.10.
47. Wu Z, Zhu A, Takayama F, Okada Ryo, Liu Y, Yoshinori Hayashi, Wu S, Hiroshi Nakanishi, Brazilian green propolis suppresses the hypoxia-induced neuroinflammatory responses by inhibiting NF-κB activation in microglia., Oxid Med Cell Longev, 10.1155/2013/906726, 2013;2013:906726, 2013.09.
48. Takayama F, Wu Z, Ma HM, Okada Ryo, Yoshinori Hayashi, Hiroshi Nakanishi, Possible involvement of aiPLA2 in the phosphatidylserine-containing liposomes induced production of PGE2 and PGD2 in microglia., J Neuroimmunol., 10.1016/j.jneuroim.2013.06.011. , 262(1-2):121-4, 2013.09.
49. Lui X, Wu Z, Yoshinori Hayashi, Hiroshi Nakanishi, Age-dependent neuroinflammatory responses and deficits in long-term potentiation in the hippocampus during systemic inflammation., Neuroscience., 10.1016/j.neuroscience.2012.04.050., 216:133-42, 2012.08.
50. Sun Li, Wu Z, Yoshinori Hayashi, Peter C, TSUDA MAKOTO, Kazuhide Inoue, Hiroshi Nakanishi, Microglial cathepsin B contributes to the initiation of peripheral inflammation-induced chronic pain., J Neurosci, 32(33):11330-42., 2012.08.
51. Ma HM, Wu Z, Nakanishi H. , Phosphatidylserine-containing liposomes: potential pharmacological interventions against inflammatory and immune diseases through the production of prostaglandin E(2) after uptake by myeloid derived phagocytes., Lab Invest. , 91, 6, 921-31, 2011.01.
52. Zhang R, Sun L, Yoshinori Hayashi, Liu X, Koyama S, Wu Z, Hiroshi Nakanishi, Acute p38-mediated inhibition of NMDA-induced outward currents in hippocampal CA1 neurons by interleukin-1beta., Neurobiol Dis, 10.1016/j.nbd.2009.12.028, 38(1):68-77, 2010.08.
53. Sun L, Wu Z, Baba M, Peters C, Uchiyama Y, Nakanishi H., Cathepsin B-dependent motor neuron death after nerve injury in the adult mouse, Biochem Biophys Res Commun, 399, 3, 391-5, 2010.08.
54. Terada K, Yamada J, Hayashi Y, Wu Z, Uchiyama Y, Peters C, Nakanishi H, Involvement of cathepsin B in the processing and secretion of interleukin-1beta in chromogranin A-stimulated microglia., Glia., 58(1):114-24.  , 2010.01.
55. Li Y. J., Kukita A., Teramachi J., Nagata K., Wu Z., Akamine A., and Kukita T. , A possible suppressive role of galectin-3 in upregulated osteoclastogenesis accompanying adjuvant-induced arthritis in rats., Lab. Invest., 89: 26-37., 2009.05.
56. Wu, Z., Tokuda, Y., Zhang, X-W., Nakanishi, H., Age-dependent responses of glial cells and leptomeninges during sytemic inflammation., Neurobiology of Disease, 32, 543-551, 2008.10.
57. Hayashi Y., Yoshida M., Yamato M., Ide T., Wu Z., Ochi-Shindou M., Kanki T., Kang D., Sunagawa K., Tsutsui H., and Nakanishi H., Reverse of brain aging by an overexpression of human mitochondrial transcription factor A in mice., J. Neurosci, 28: 8624-8634., 2008.05.
58. Zhang R., Yamada J., Hayashi Y., Wu Z., Koyama S., Nakanishi H., Inhibition of NMDA-induced outward currents by interleukin-1beta
in hippocampal neurons., Biochem. Biophys. Res. Commun, 372: 816-820 , 2008.05.
59. Yamada J., Hayashi Y., Jinno S., Wu Z., Inoue K., Kohsaka S., Nakanishi H, Reduced synaptic acticity precedes synaptic stripping in vagal motoneurons after axotomy, Glia , 56: 1448-1462, 2007.09.
60. Yamasaki R., Zhang J., Koshiishi I., Sastradipura Suniarti D.F.,Wu Z., Peters C., Schwake M., UchiyamaY., Kira J. I., Saftig P., Utsumi H., and Nakanishi H, Involvement of lysosomal storage-induced p38 MAP kinase activation in the overproduction of nitric oxide by microglia in cathepsin D- deficient mice, Mol. Cell. Neurosci., 35: 573-584, 2007.07.
61. Wu Z, Hayashi Y, Jian Zhang, Nakanishi H., Involvement of Prostaglandin E2 Released from Leptomeningeal Cells in Increased Expression of TGF-beta1 in Glial Cells and Cortical Neurons during Systemic Inflammation., J Neurosci Res., 85:184-192, 2007.01.
62. Yoshinori Hayashi, Y. Tomimatsu, H. Suzuki, Jun Yamada, Hiro Take, H. Yao, Y. Kagamiishi, N. Tateishi, M. Sawada, Hiroshi Nakanishi, The intra-arterial injection of microglia protects hippocampal CA1 neurons against global ischemia-induced functional deficits in rats, Neuroscience, 10.1016/j.neuroscience.2006.06.003, 142, 1, 87-96, 2006.09, In the present study, we have attempted to elucidate the effects of the intra-arterial injection of microglia on the global ischemia-induced functional and morphological deficits of hippocampal CA1 neurons. When PKH26-labeled immortalized microglial cells, GMIR1, were injected into the subclavian artery, these exogenous microglia were found to accumulate in the hippocampus at 24 h after ischemia. In hippocampal slices prepared from medium-injected rats subjected to ischemia 48 h earlier, synaptic dysfunctions including a significant reduction of synaptic responses and a marked reduction of long-term potentiation (LTP) of the CA3-CA1 Schaffer collateral synapses were observed. At this stage, however, neither significant neuronal degeneration nor gliosis was observed in the hippocampus. At 96 h after ischemia, there was a total loss of the synaptic activity and a marked neuronal death in the CA1 subfield. In contrast, the basal synaptic transmission and LTP of the CA3-CA1 synapses were well preserved after ischemia in the slices prepared from the microglia-injected animals. We also found the microglial-conditioned medium (MCM) to significantly increase the frequency of the spontaneous postsynaptic currents of CA1 neurons without affecting the amplitude, thus indicating that MCM increased the provability of the neurotransmitter release. The protective effect of the intra-arterial injected microglia against the ischemia-induced neuronal degeneration in the hippocampus was substantiated by immunohistochemical and immunoblot analyses. Furthermore, the arterial-injected microglia prevented the ischemia-induced decline of the brain-derived neurotrophic factor (BDNF) levels in CA1 neurons. These observations strongly suggest that the arterial-injection of microglia protected CA1 neurons against the ischemia-induced neuronal degeneration. The restoration of the ischemia-induced synaptic deficits and the resultant reduction of the BDNF levels in CA1 neurons, possibly by the release of diffusible factor(s), might thus contribute to the protective effect of the arterial-injection of microglia against ischemia-induced neuronal degeneration..
63. Hayashi Y, Tomimatsu Y, Suzuki H, Yamada J, Wu Z, Yao H, Kagamiishi Y, Tateishi N, Sawada M, Nakanishi H., The intra-arterial injection of microglia protects hippocampal CA1 neurons against global ischemia-induced functional deficits in rats., Neuroscience, 142(1):87-96, 2006.04.
64. Jian Zhang, Shunsuke Fujii, Zhou Wu, Sadayuki Hashioka, Yoshitaka Tanaka, Akiko Shiratsuchi, Yoshinobu Nakanishi, Hiroshi Nakanishi, Involvement of COX-1 and up-regulated prostaglandin e synthases in phosphatidylserine liposome-induced prostaglandin E2 production by microglia, Journal of Neuroimmunology, 10.1016/j.jneuroim.2005.11.008, 172, 1-2, 112-120, 2006.03.
65. Zhang J, Fujii S, Wu Z, Hashioka S, Tanaka Y, Shiratsuchi A, Nakanishi Y, Nakanishi H., Involvement of COX-1 and up-regulated prostaglandin E synthases in phosphatidylserine liposome-induced prostaglandin E2 production by microglia., J Neuroimmunol., 172(1-2):112-20, 2006.01.
66. Takahiro Nakamura, Toshio Kukita, Takeo Shobuike, Kengo Nagata, Hiro Take, Kenji Ogawa, Takao Hotokebuchi, Osamu Kohashi, Akiko Kukita, Inhibition of histone deacetylase suppresses osteoclastogenesis and bone destruction by inducing IFN-β production, Journal of Immunology, 175, 9, 5809-5816, 2005.11.
67. Wu Z, Zhang J, Nakanishi H., Leptomeningeal cells activate microglia and astrocytes to induce IL-10 production by releasing pro-inflammatory cytokines during systemic inflammation., J Neuroimmunol., 10.1016/j.jneuroim.2005.06.025, 167, 1-2, 90-98, 167 (1-2):90-8., 2005.09.
68. Nakamura T, Kukita T, hobuike T, Nagata K, Wu Z, Ogawa K, Hotokebuchi T, Kohashi O, Kukita A.,  Inhibition of Histone Deacetylase Suppresses Osteoclastogenesis and Bone Destruction by Inducing IFN-{beta} Production., J Immunol., 175, 9, 5809-5816, 175(9):5809-16, 2005.07.
69. Tang QY, Kukita T, Ushijima Y, Kukita A, Nagata K, Sandra F, Watanabe T, Toh K, Okuma Y, Kawasaki S, Rasubala L, Teramachi J, Miyamoto I, Wu Z, Iijima T., Regulation of osteoclastogenesis by Simon extracts composed of caffeic acid and related compounds: successful suppression of bone destruction accompanied with adjuvant-induced arthritis in rats., Histochem Cell Biol, 10.1007/s00418-005-0062-4, 125, 3, 215-225, 125(3): 1-11, 2005.02.
70. Toh K, Kukita T, Wu Z, Kukita A, Sandra F, Tang QY, Nomiyama H, Iijima T., Possible involvement of MIP-1alpha in the recruitment of osteoclast progenitors to the distal tibia in rats with adjuvant-induced arthritis, Lab Invest., 10.1038/labinvest.3700132, 84, 9, 1092-1102, 84(9):1092-102, 2004.09.
71. Wu Z, Toh K, Nagata K, Kukita T, Iijima T., Effect of the resection of the sciatic nerve on the Th1/Th2 balance in the synovia of the ankle joint of adjuvant arthritic rats., Histochem Cell Biol., 10.1007/s00418-003-0614-4, 121, 2, 141-147, 121(2):141-7., 2004.01.
72. Wu Z, Kengo Nagata, Tadahiko Iijima, Involvement of sensory nerves and immune cells in osteophyte formation in the ankle joint of adjuvant arthritic rats, Histochemistry and Cell Biology, 118, 3, 213-220, 2002.10.
73. Wu Z, Nagata K, Iijima T., Involvement of sensory nerves and immune cells in osteophyte formation in the ankle joint of adjuvant arthritic rats., Histochem Cell Biol., 10.1007/s00418-002-0443-x, 118, 3, 213-220, 118(3):213-20., 2002.05.
74. Wu Z, Nagata K, Iijima T., Immunohistochemical study of NGF and it receptors in the synovial membrane of the ankle joint of adjuvant-induced arthritic rats., Histochem Cell Biol., 114, 6, 453-459, 114(6):453-9, 2000.12.