| 1. |
Saki Hirofuji, Yuta Hirofuji, Hiroki Kato, Keiji Masuda, Haruyoshi Yamaza, Hiroshi Sato, Fumiko Takayama, Michiko Torio, Yasunari Sakai, Shoichi Ohga, Tomoaki Taguchi, Kazuaki Nonaka, Mitochondrial dysfunction in dopaminergic neurons differentiated from exfoliated deciduous tooth-derived pulp stem cells of a child with Rett syndrome, Biochemical and Biophysical Research Communications, 10.1016/j.bbrc.2018.03.077, 498, 4, 898-904, 2018.04, Rett syndrome is an X-linked neurodevelopmental disorder associated with psychomotor impairments, autonomic dysfunctions and autism. Patients with Rett syndrome have loss-of-function mutations in MECP2, the gene encoding methyl-CpG-binding protein 2 (MeCP2). Abnormal biogenic amine signaling and mitochondrial function have been found in patients with Rett syndrome; however, few studies have analyzed the association between these factors. This study investigated the functional relationships between mitochondria and the neuronal differentiation of the MeCP2-deficient stem cells from the exfoliated deciduous teeth of a child with Rett syndrome. An enrolled subject in this study was a 5-year-old girl carrying a large deletion that included the methyl-CpG-binding domain, transcriptional repression domain, and nuclear localization signal of MECP2. Using the single-cell isolation technique, we found that the two populations of MeCP2-expressing and MeCP2-deficient stem cells kept their MECP2 expression profiles throughout the stages of cell proliferation and neuronal differentiation in vitro. Neurite outgrowth and branching were attenuated in MeCP2-deficient dopaminergic neurons. MeCP2-deficient cells showed reduced mitochondrial membrane potential, ATP production, restricted mitochondrial distribution in neurites, and lower expression of a central mitochondrial fission factor, dynamin-related protein 1 than MeCP2-expressing cells. These data indicated that MeCP2-deficiency dysregulates the expression of mitochondrial factors required for the maturation of dopaminergic neurons. This study also provides insight into the pathogenic mechanism underlying dysfunction of the intracerebral dopaminergic signaling pathway in Rett syndrome.. |
| 2. |
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, Despite a clear correlation between periodontitis and cognitive decline in Alzheimer's disease, the precise mechanism underlying the relationship remains unclear. The periodontal pathogen Porphyromonas gingivalis produces a unique class of cysteine proteinases termed gingipains that comprises Arg-gingipain (Rgp) and Lys-gingipain (Kgp). Rgp and Kgp are important in the bacterial mediated host cell responses and the subsequent intracellular signaling in infected cells. In the present study, we attempted to clarify the potential effects of Rgp and Kgp on the cellular activation of brain-resident microglia. We provide the first evidence that Rgp and Kgp cooperatively contribute to the P. gingivalis-induced cell migration and expression of proinflammatory mediators through the activation of protease-activated receptor 2. The subsequent activation of phosphoinositide 3-kinase/Akt and mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase/ERK pathways contributes to cell migration and inflammatory response of microglia.. |
| 3. |
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, A number of clinical and experimental studies have revealed a strong association between periodontitis and accelerated cognitive decline in Alzheimer's disease (AD); however, the mechanism of the association is unknown. In the present study, we tested the hypothesis that cathepsin (Cat) B plays a critical role in the initiation of neuroinflammation and neural dysfunction following chronic systemic exposure to lipopolysaccharide from Porphyromonas gingivalis (PgLPS) in mice (1 mg/kg, daily, intraperitoneally). Young (2 months old) and middle-aged (12 months old) wild-type (WT; C57BL/6N) or CatB-deficient (CatB− / −) mice were exposed to PgLPS daily for 5 consecutive weeks. The learning and memory function were assessed using the passive avoidance test, and the expression of amyloid precursor protein (APP), CatB, TLR2 and IL-1β was analyzed in brain tissues by immunohistochemistry and Western blotting. We found that chronic systemic exposure to PgLPS for five consecutive weeks induced learning and memory deficits with the intracellular accumulation of Aβ in neurons in the middle-aged WT mice, but not in young WT or middle-aged CatB− / − mice. PgLPS significantly increased the expression of CatB in both microglia and neurons in middle-aged WT mice, while increased expression of mature IL-1β and TLR2 was restricted to microglia in the hippocampus of middle-aged WT mice, but not in that of the middle-aged CatB− / − ones. In in vitro studies, PgLPS (1 µg/ml) stimulation upregulated the mean mRNA expression of IL-1β, TLR2 and downregulated the protein levels of IκBα in the cultured MG6 microglia as well as in the primary microglia from WT mice, which were significantly inhibited by the CatB-specific inhibitor CA-074Me as well as by the primary microglia from CatB− / − mice. Furthermore, the mean mRNA expression of APP and CatB were significantly increased in the primary cultured hippocampal neurons after treatment with conditioned medium from PgLPS-treated WT primary microglia, but not after treatment with conditioned medium neutralized with anti-IL-1beta, and not after treatment with conditioned medium from PgLPS-treated CatB− / − primary microglia or with PgLPS directly. Taken together, these findings indicate that chronic systemic exposure to PgLPS induces AD-like phenotypes, including microglia-mediated neuroinflammation, intracellular Aβ accumulation in neurons and impairment of the learning and memory functions in the middle-aged mice in a CatB-dependent manner. We propose that CatB may be a therapeutic target for preventing periodontitis-associated cognitive decline in AD.. |
| 4. |
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, The expression of cathepsin S (CatS), a microglia-specific lysosomal cysteine protease in the brain, is regulated by the intrinsic microglial circadian clock. We herein report that the diurnal variation of evoked synaptic responses of cortical neurons disappeared in cathepsin S-deficient (CatS−/−) mice. The dendritic spine density of the cortical neurons was significantly reduced by incubation with a recombinant CatS. Furthermore, CatS−/− mice exhibited impaired social interaction and social novelty recognition in the three-chamber test. These findings indicate that the circadian clock-regulated secretion of CatS from microglia is involved in the diurnal variation of synaptic responses and dendritic spine density through the proteolytic modification of perisynaptic ECM molecules. Therefore, a dysfunction of the diurnal synaptic responses due to CatS deficiency may lead to social behavior abnormalities.. |
| 5. |
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.. |
| 6. |
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, It has long been believed that microglia morphologically transform into the activated state by retracting their long processes and consuming pathogens when bacteria infect into the brain parenchyma. In the present study, however, we showed for the first time that murine cortical microglia extend their processes towards focally injected Porphyromonas gingivalis. This P. gingivalis-induced microglial process extension was significantly increased during the light (sleeping) phase than the dark (waking) phase. In contrast, focally injected ATP-induced microglial process extension was significantly increased during the dark phase than the light phase. Furthermore, in contrast to the P2Y 12 receptor-mediated mechanism of ATP-induced microglial process extension, the P. gingivalis-mediated microglial process extension was mediated by P2Y 6 receptors. The infection of bacteria such as P. gingivalis to the brain parenchyma may induce the secretion of UDP from microglia at the site of infection, which in turn induces the process extension of the neighboring microglia.. |
| 7. |
Hiro Take, Aiqin Zhu, Fumiko Takayama, Ryo Okada, Yicong Liu, Yuka Harada, Shizheng Wu, Hiroshi Nakanishi, Brazilian green propolis suppresses the hypoxia-induced neuroinflammatory responses by inhibiting NF- B activation in microglia, Oxidative Medicine and Cellular Longevity, 10.1155/2013/906726, 2013.09, Hypoxia has been recently proposed as a neuroinflammatogen, which drives microglia to produce proinflammatory cytokines, including interleukin-1β (IL-1β), tumor necrosis factor-α; (TNF-α;), and IL-6. Considering the fact that propolis has hepatoprotective, antitumor, antioxidative, and anti-inflammatory effects, propolis may have protective effects against the hypoxia-induced neuroinflammatory responses. In this study, propolis (50 g/mL) was found to significantly inhibit the hypoxia-induced cytotoxicity and the release of proinflammatory cytokines, including IL-1β, TNF-α;, and IL-6, by MG6 microglia following hypoxic exposure (1% O 2, 24 h). Furthermore, propolis significantly inhibited the hypoxia-induced generation of reactive oxygen species (ROS) from mitochondria and the activation of nuclear factor-B (NF-B) in microglia. Moreover, systemic treatment with propolis (8.33 mg/kg, 2 times/day, i.p.) for 7 days significantly suppressed the microglial expression of IL-1β, TNF-α;, IL-6, and 8-oxo-deoxyguanosine, a biomarker for oxidative damaged DNA, in the somatosensory cortex of mice subjected to hypoxia exposure (10% O2, 4 h). These observations indicate that propolis suppresses the hypoxia-induced neuroinflammatory responses through inhibition of the NF-B activation in microglia. Furthermore, increased generation of ROS from the mitochondria is responsible for the NF-B activation. Therefore, propolis may be beneficial in preventing hypoxia-induced neuroinflammation.. |
| 8. |
Fumiko Takayama, Hiro Take, Hong Mei Ma, Ryo Okada, Yoshinori Hayashi, Hiroshi Nakanishi, Possible involvement of aiPLA2 in the phosphatidylserine-containing liposomes induced production of PGE2 and PGD2 in microglia, Journal of Neuroimmunology, 10.1016/j.jneuroim.2013.06.011, 262, 1-2, 121-124, 2013.07, Liposomes containing phosphatidylserine (PSL) produce PGE2 after being phagocytosed by microglia, but the precise underlying mechanism behind it still remains unclear. Here, we showed that liposomes consisting of phosphatidylserine and lysophosphatidylcholine, a lipolysis product of phosphatidylcholine by PLA2, were phagocytosed by microglia, but failed to induce secretion of PGE2. Furthermore, PSL-induced PGE2 secretion was significantly inhibited by MJ33, an aiPLA2 inhibitor, but not by AACOCF3, a cPLA2 inhibitor. PSL also produced PGD2 and 15d-PGJ2 in microglia. We thus hypothesize that free arachidonic acid is supplied through aiPLA2-mediated lipolysis of phagocytosed phosphatidylcholine, leading to the production of PGH2 and its downstream metabolites.. |
| 9. |
Saki Hirofuji, Yuta Hirofuji, Hiroki Kato, Keiji Masuda, Haruyoshi Yamaza, Hiroshi Sato, Fumiko Takayama, Michiko Torio, Yasunari Sakai, Shoichi Ohga, Tomoaki Taguchi, Kazuaki Nonaka, Mitochondrial dysfunction in dopaminergic neurons differentiated from exfoliated deciduous tooth-derived pulp stem cells of a child with Rett syndrome, Biochemical and Biophysical Research Communications, 10.1016/j.bbrc.2018.03.077, 498, 4, 898-904, 2018.04, Rett syndrome is an X-linked neurodevelopmental disorder associated with psychomotor impairments, autonomic dysfunctions and autism. Patients with Rett syndrome have loss-of-function mutations in MECP2, the gene encoding methyl-CpG-binding protein 2 (MeCP2). Abnormal biogenic amine signaling and mitochondrial function have been found in patients with Rett syndrome; however, few studies have analyzed the association between these factors. This study investigated the functional relationships between mitochondria and the neuronal differentiation of the MeCP2-deficient stem cells from the exfoliated deciduous teeth of a child with Rett syndrome. An enrolled subject in this study was a 5-year-old girl carrying a large deletion that included the methyl-CpG-binding domain, transcriptional repression domain, and nuclear localization signal of MECP2. Using the single-cell isolation technique, we found that the two populations of MeCP2-expressing and MeCP2-deficient stem cells kept their MECP2 expression profiles throughout the stages of cell proliferation and neuronal differentiation in vitro. Neurite outgrowth and branching were attenuated in MeCP2-deficient dopaminergic neurons. MeCP2-deficient cells showed reduced mitochondrial membrane potential, ATP production, restricted mitochondrial distribution in neurites, and lower expression of a central mitochondrial fission factor, dynamin-related protein 1 than MeCP2-expressing cells. These data indicated that MeCP2-deficiency dysregulates the expression of mitochondrial factors required for the maturation of dopaminergic neurons. This study also provides insight into the pathogenic mechanism underlying dysfunction of the intracerebral dopaminergic signaling pathway in Rett syndrome.. |
| 10. |
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, Despite a clear correlation between periodontitis and cognitive decline in Alzheimer's disease, the precise mechanism underlying the relationship remains unclear. The periodontal pathogen Porphyromonas gingivalis produces a unique class of cysteine proteinases termed gingipains that comprises Arg-gingipain (Rgp) and Lys-gingipain (Kgp). Rgp and Kgp are important in the bacterial mediated host cell responses and the subsequent intracellular signaling in infected cells. In the present study, we attempted to clarify the potential effects of Rgp and Kgp on the cellular activation of brain-resident microglia. We provide the first evidence that Rgp and Kgp cooperatively contribute to the P. gingivalis-induced cell migration and expression of proinflammatory mediators through the activation of protease-activated receptor 2. The subsequent activation of phosphoinositide 3-kinase/Akt and mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase/ERK pathways contributes to cell migration and inflammatory response of microglia.. |
| 11. |
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, A number of clinical and experimental studies have revealed a strong association between periodontitis and accelerated cognitive decline in Alzheimer's disease (AD); however, the mechanism of the association is unknown. In the present study, we tested the hypothesis that cathepsin (Cat) B plays a critical role in the initiation of neuroinflammation and neural dysfunction following chronic systemic exposure to lipopolysaccharide from Porphyromonas gingivalis (PgLPS) in mice (1 mg/kg, daily, intraperitoneally). Young (2 months old) and middle-aged (12 months old) wild-type (WT; C57BL/6N) or CatB-deficient (CatB− / −) mice were exposed to PgLPS daily for 5 consecutive weeks. The learning and memory function were assessed using the passive avoidance test, and the expression of amyloid precursor protein (APP), CatB, TLR2 and IL-1β was analyzed in brain tissues by immunohistochemistry and Western blotting. We found that chronic systemic exposure to PgLPS for five consecutive weeks induced learning and memory deficits with the intracellular accumulation of Aβ in neurons in the middle-aged WT mice, but not in young WT or middle-aged CatB− / − mice. PgLPS significantly increased the expression of CatB in both microglia and neurons in middle-aged WT mice, while increased expression of mature IL-1β and TLR2 was restricted to microglia in the hippocampus of middle-aged WT mice, but not in that of the middle-aged CatB− / − ones. In in vitro studies, PgLPS (1 µg/ml) stimulation upregulated the mean mRNA expression of IL-1β, TLR2 and downregulated the protein levels of IκBα in the cultured MG6 microglia as well as in the primary microglia from WT mice, which were significantly inhibited by the CatB-specific inhibitor CA-074Me as well as by the primary microglia from CatB− / − mice. Furthermore, the mean mRNA expression of APP and CatB were significantly increased in the primary cultured hippocampal neurons after treatment with conditioned medium from PgLPS-treated WT primary microglia, but not after treatment with conditioned medium neutralized with anti-IL-1beta, and not after treatment with conditioned medium from PgLPS-treated CatB− / − primary microglia or with PgLPS directly. Taken together, these findings indicate that chronic systemic exposure to PgLPS induces AD-like phenotypes, including microglia-mediated neuroinflammation, intracellular Aβ accumulation in neurons and impairment of the learning and memory functions in the middle-aged mice in a CatB-dependent manner. We propose that CatB may be a therapeutic target for preventing periodontitis-associated cognitive decline in AD.. |
| 12. |
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, The expression of cathepsin S (CatS), a microglia-specific lysosomal cysteine protease in the brain, is regulated by the intrinsic microglial circadian clock. We herein report that the diurnal variation of evoked synaptic responses of cortical neurons disappeared in cathepsin S-deficient (CatS−/−) mice. The dendritic spine density of the cortical neurons was significantly reduced by incubation with a recombinant CatS. Furthermore, CatS−/− mice exhibited impaired social interaction and social novelty recognition in the three-chamber test. These findings indicate that the circadian clock-regulated secretion of CatS from microglia is involved in the diurnal variation of synaptic responses and dendritic spine density through the proteolytic modification of perisynaptic ECM molecules. Therefore, a dysfunction of the diurnal synaptic responses due to CatS deficiency may lead to social behavior abnormalities.. |
| 13. |
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.. |
| 14. |
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, It has long been believed that microglia morphologically transform into the activated state by retracting their long processes and consuming pathogens when bacteria infect into the brain parenchyma. In the present study, however, we showed for the first time that murine cortical microglia extend their processes towards focally injected Porphyromonas gingivalis. This P. gingivalis-induced microglial process extension was significantly increased during the light (sleeping) phase than the dark (waking) phase. In contrast, focally injected ATP-induced microglial process extension was significantly increased during the dark phase than the light phase. Furthermore, in contrast to the P2Y 12 receptor-mediated mechanism of ATP-induced microglial process extension, the P. gingivalis-mediated microglial process extension was mediated by P2Y 6 receptors. The infection of bacteria such as P. gingivalis to the brain parenchyma may induce the secretion of UDP from microglia at the site of infection, which in turn induces the process extension of the neighboring microglia.. |
| 15. |
Hiro Take, Aiqin Zhu, Fumiko Takayama, Ryo Okada, Yicong Liu, Yuka Harada, Shizheng Wu, Hiroshi Nakanishi, Brazilian green propolis suppresses the hypoxia-induced neuroinflammatory responses by inhibiting NF- B activation in microglia, Oxidative Medicine and Cellular Longevity, 10.1155/2013/906726, 2013.09, Hypoxia has been recently proposed as a neuroinflammatogen, which drives microglia to produce proinflammatory cytokines, including interleukin-1β (IL-1β), tumor necrosis factor-α; (TNF-α;), and IL-6. Considering the fact that propolis has hepatoprotective, antitumor, antioxidative, and anti-inflammatory effects, propolis may have protective effects against the hypoxia-induced neuroinflammatory responses. In this study, propolis (50 g/mL) was found to significantly inhibit the hypoxia-induced cytotoxicity and the release of proinflammatory cytokines, including IL-1β, TNF-α;, and IL-6, by MG6 microglia following hypoxic exposure (1% O 2, 24 h). Furthermore, propolis significantly inhibited the hypoxia-induced generation of reactive oxygen species (ROS) from mitochondria and the activation of nuclear factor-B (NF-B) in microglia. Moreover, systemic treatment with propolis (8.33 mg/kg, 2 times/day, i.p.) for 7 days significantly suppressed the microglial expression of IL-1β, TNF-α;, IL-6, and 8-oxo-deoxyguanosine, a biomarker for oxidative damaged DNA, in the somatosensory cortex of mice subjected to hypoxia exposure (10% O2, 4 h). These observations indicate that propolis suppresses the hypoxia-induced neuroinflammatory responses through inhibition of the NF-B activation in microglia. Furthermore, increased generation of ROS from the mitochondria is responsible for the NF-B activation. Therefore, propolis may be beneficial in preventing hypoxia-induced neuroinflammation.. |
| 16. |
Fumiko Takayama, Hiro Take, Hong Mei Ma, Ryo Okada, Yoshinori Hayashi, Hiroshi Nakanishi, Possible involvement of aiPLA2 in the phosphatidylserine-containing liposomes induced production of PGE2 and PGD2 in microglia, Journal of Neuroimmunology, 10.1016/j.jneuroim.2013.06.011, 262, 1-2, 121-124, 2013.07, Liposomes containing phosphatidylserine (PSL) produce PGE2 after being phagocytosed by microglia, but the precise underlying mechanism behind it still remains unclear. Here, we showed that liposomes consisting of phosphatidylserine and lysophosphatidylcholine, a lipolysis product of phosphatidylcholine by PLA2, were phagocytosed by microglia, but failed to induce secretion of PGE2. Furthermore, PSL-induced PGE2 secretion was significantly inhibited by MJ33, an aiPLA2 inhibitor, but not by AACOCF3, a cPLA2 inhibitor. PSL also produced PGD2 and 15d-PGJ2 in microglia. We thus hypothesize that free arachidonic acid is supplied through aiPLA2-mediated lipolysis of phagocytosed phosphatidylcholine, leading to the production of PGH2 and its downstream metabolites.. |
