Books

1.	Nakanishi H, Wu Z, Microglia-aging and pain: Microglial cathepsin B-dependent IL-1 production, In: Interleukin-1: Genetics, Inflammatory Mechanisms and Role in Disease, Nova Science Publishers, pp. 143-156, 2013.06.
2.	Wu Z, Nakanishi H, TNF-a signaling and cathepsin B, In: Tumor Necrosis Factor: Structure. Enzyme Regulation and Role in Health and Disease, Nova Science Publisher Inc, pp. 113-128, 2013.06.
3.	Zhou Wu and Hiroshi Nakanishi, Neuroimmunology Research Focus Chapter 4 Age-Dependent Differential Activation Profiles of Glial Cell by the Leptomeninges During Systemic Inflammation, Nova Science Pulishers, Inc., pp. 101-118., 2007.09.

Reports

1.	Dehao Shang, Minghao Huang, Biyao Wang, Xu Yan, ＠Zhou Wu, Xinwen Zhang, mtDNA Maintenance and Alterations in the Pathogenesis of Neurodegenerative Diseases, Current Neuropharmacology, 10.2174/1570159X20666220810114644, 2023.04, Considerable evidence indicates that the semiautonomous organelles mitochondria play key roles in the progression of many neurodegenerative disorders. Mitochondrial DNA (mtDNA) encodes components of the OXPHOS complex but mutated mtDNA accumulates in cells with aging, which mirrors the increased prevalence of neurodegenerative diseases. This accumulation stems not only from the misreplication of mtDNA and the highly oxidative environment but also from defective mitophagy after fission. In this review, we focus on several pivotal mitochondrial proteins related to mtDNA maintenance (such as ATAD3A and TFAM), mtDNA alterations including mtDNA mutations, mtDNA elimination, and mtDNA release-activated inflammation to understand the crucial role played by mtDNA in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. Our work outlines novel therapeutic strategies for targeting mtDNA..
2.	Gregory Hook, Thomas Reinheckel, Junjun Ni, ＠Zhou Wu, Mark Kindy, Christoph Peters, and Vivian Hook, Cathepsin B Gene Knockout Improves Behavioral Deficits and Reduces Pathology in Models of Neurological Disorders, 10.1124/pharmrev.121.000527, 2022.07, Cathepsin B (CTSB) is a powerful lysosomal protease. This review evaluated CTSB gene knockout (KO) outcomes for amelioration of brain dysfunctions in neurologic diseases and aging animal models. Deletion of the CTSB gene resulted in significant improvements in behavioral deficits, neuropathology, and/or biomarkers in traumatic brain injury, ischemia, inflammatory pain, opiate tolerance, epilepsy, aging, transgenic Alzheimer’s disease (AD), and periodontitis AD models as shown in 12 studies. One study found beneficial effects for double CTSB and cathepsin S KO mice in a multiple sclerosis model. Transgenic AD models using amyloid precursor protein (APP) mimicking common sporadic AD in three studies showed that CTSB KO improved memory, neuropathology, and biomarkers; two studies used APP representing rare familial AD and found no CTSB KO effect, and two studies used highly engineered APP constructs and reported slight increases in a biomarker. In clinical studies, all reports found that CTSB enzyme was upregulated in diverse neurologic disorders, including AD in which elevated CTSB was positively correlated with cognitive dysfunction. In a wide range of neurologic animal models, CTSB was also upregulated and not downregulated. Further, human genetic mutation data provided precedence for CTSB upregulation causing disease. Thus, the consilience of data is that CTSB gene KO results in improved brain dysfunction and reduced pathology through blockade of CTSB enzyme upregulation that causes human neurologic disease phenotypes. The overall findings provide strong support for CTSB as a rational drug target and for CTSB inhibitors as therapeutic candidates for a wide range of neurologic disorders..
3.	Zhen Xie, Jie Meng, Zhou Wu, Hiroshi Nakanishi, Yoshinori Hayashi, Wei Kong, Fei Lan, Narengaowa, Qinghu Yang, Hong Qing, Junjun Ni, The Dual Nature of Microglia in Alzheimer's Disease: A Microglia-Neuron Crosstalk Perspective., Neuroscientist, doi: 10.1177/10738584211070273, 2022.03.
4.	Xu Yan;＠Zhou Wu;Biyao Wang;Tianhao Yu; Yue Hu; Sijian Wang;Chunfu Deng; Baohong Zhao; Hiroshi Nakanishi and Xinwen Zhan, Involvement of Cathepsins in Innate and Adaptive Immune Responses in Periodontitis, Evidence-Based Complementary and Alternative Medicine, doi.org/10.1155/2020/4517587, 2020.03, Periodontitis is an infectious disease whereby the chronic inflammatory process of the periodontium stimulated by bacterial products induces specific host cell responses. The activation of the host cell immune system upregulates the production of　inflammatorymediators,comprisingcytokinesandproteolyticenzymes,whichcontributetoinflammationandbonedestruction.Ithasbeenwellknownthatperiodontitisisrelatedtosystemicinflammationwhichlinkstonumeroussystemicdiseases,includingdiabetesandarteriosclerosis.Furthermore,periodontitishasbeenreportedinassociationwithneurodegenerativediseasessuchasAlzheimer’sdisease(AD)inthebrain.Regardingimmuneresponsesandinflammation,cathepsinB(CatB)playspivotalrolefortheinductionofIL-1β,cathepsinK-(CatK-)dependentactivetoll-likereceptor9(TLR9)signaling,andcathepsinS(CatS)which involves in regulating both TLR signaling and maturation of the MHC class II complex. Notably, both the production and proteolytic activities of cathepsins are upregulated in chronic inflammatory diseases, including periodontitis. In the present review, we focus on the roles of cathepsins in the innate and adaptive immune responses within periodontitis. We believe that　understandingtherolesofcathepsinsintheimmuneresponsesinperiodontitiswouldhelptoelucidatethetherapeuticstrategies of periodontitis, thus benefit for reduction of systemic diseases as well as neurodegenerative diseases in the global aging society..
5.	Wu Z, Yu J, Zhu A, Nakanishi H, Nutrients, Microglia Aging, and Brain Aging, Oxid Med Cell Longev, 2016:7498528, 2016.06.

Papers

1.	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.
2.	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..
3.	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.
4.	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..
5.	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.
6.	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.
7.	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.
8.	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.
9.	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.
10.	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.
11.	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..
12.	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.

Presentations

1.	Yebo Gu, Junjun Ni, Zhou Wu, Ichiro Takahashi, Chronic systemic exposure of Lipopolysaccharide from Porphyromonas gingivalis induces memory decline through the upregulation of the bone loss promotion molecule IL-17 in middle-aged mice, 第72回日本薬理学会西南部会, 2019.11.
2.	Yebo Gu, Junjun Ni, Zhou Wu, Ichiro Takahashi, Chronic systemic exposure of PgLPS induces long bone loss and cognitive decline in middle-aged mice, 第78回日本矯正歯科学会, 2019.11.
3.	Yebo Gu, Junjun Ni, Muzhou Jiang, Zhou Wu, Ichiro Takahashi, Chronic systemic exposure of Lipopolysaccharide from Porphyromonas gingivalis induces Memory decline and Bone loss in Middle-aged Mice, 6th Congress of ASCNP, 2019.10.
4.	Fan Zeng, Junjun Ni, Zhou Wu , Porphyromonas gingivalis infection increases RAGE production in hCMEC/D3 cell line, 6th Congress of ASCNP, 2019.10.
5.	Wanyi Huang, Junjun Ni, Zhou Wu,, Porphyromonas gingivalis infected Leptomeningeal Cells Reduces Synapses Proteins in Primary Cultured Neurons, 6th Congress of AsCNP, 2019.10.
6.	Muzhou Jiang, Junjun Ni, Yebo Gu, Zhou Wu, Microglia induces tau hyperphosphorylation of cultured neurons after exposure to Porphyromonas gingivalis LPS, 6th Congress of ASCNP, 2019.10.
7.	Zhou WU, Inflammation and Lysosomal Enzymes: Prevention Approach of Cognitive Decline, Neurology Conference , 2019.06.
8.	Wu Z, Cathepsin B, novel therapeutic target for microglia-mediated neuroinflammation, special seminar in University of Southampton, 2017.02.
9.	Hiro Take, Oral health and healthy life expectancy, The 1st International Symposium for Women Researchers on Advanced Science and Technology conjugated with Seminar for Young Researchers, 2016.07.
10.	Hiro Take, Oral health, Nutrition and healthy life expectancy, 9th CASPN, 2015.05.

Enforce the lectures for undergraduate and graduate students school as a faculty member, conducte research guidance for undergraduates and graduate studentsand write the research papers as PI (principle investigator).

As a member of the Japan BPW (Business & Professional Woman) Federation Fukuoka Club (Niji no Kai), I strive to improve the social status and vocational standards of working women and educate female students through various activities. I had served as an officer of the Niji no Kai from 2019 to 2021(planning and international affairs), and I has been a member of the International and Development Committee of the International Women's Year Liaison Committee since 2021. We also hold seminars for citizens all over the country through the Private Grant Foundation. He is in charge of managing and giving lectures on international symposiums held at the Institute of Dentistry, giving lectures overseas, and conducting joint research with overseas..