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      Pristimerin Inhibits MMP-9 Expression and Cell Migration Through Attenuating NOX/ROS-Dependent NF-κB Activation in Rat Brain Astrocytes Challenged with LPS

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          Abstract

          Purpose

          Neuroinflammation plays a crucial role in neurodegenerative diseases. Matrix metalloproteinases (MMPs) are a landmark of neuroinflammation. Lipopolysaccharide (LPS) has been demonstrated to induce MMP-9 expression. The mechanisms underlying LPS-induced MMP-9 expression have not been completely elucidated in astrocytes. Nuclear factor-kappaB (NF-κB) is well known as one of the crucial transcription factors in MMP-9 induction. Moreover, reactive oxygen species (ROS) could be an important mediator of neuroinflammation. Here, we differentiated whether ROS and NF-κB contributed to LPS-mediated MMP-9 expression in rat brain astrocytes (RBA-1). Besides, pristimerin has been revealed to possess antioxidant and anti-inflammatory effects. We also evaluated the effects of pristimerin on LPS-induced inflammatory responses.

          Methods

          RBA-1 cells were used for analyses. Pharmacological inhibitors and siRNAs were used to evaluate the signaling pathway. Western blotting and gelatin zymography were conducted to evaluate protein and MMP-9 expression, respectively. Real-time PCR was for mRNA expression. Wound healing assay was for cell migration. 2ʹ,7ʹ-dichlorodihydrofluorescein diacetate (H 2DCF-DA) and dihydroethidium (DHE) staining were for ROS generation. Immunofluorescence staining was conducted to assess NF-κB p65. Promoter-reporter gene assay and chromatin immunoprecipitation (ChIP) assay were used to detect promoter activity and the association of nuclear proteins with the promoter.

          Results

          Our results showed that the increased level of ROS generation was attenuated by edaravone (a ROS scavenger), apocynin (APO; an inhibitor of p47 Phox), diphenyleneiodonium (DPI; an inhibitor of NOX), and pristimerin in RBA-1 cells exposed to LPS. Besides, pretreatment with APO, DPI, edaravone, Bay11-7082, and pristimerin also inhibited the phosphorylation, nuclear translocation, promoter binding activity of NF-κB p65 as well as upregulation of MMP-9 expression-mediated cell migration in RBA-1 cells challenged with LPS.

          Conclusion

          These results suggested that LPS enhances the upregulation of MMP-9 through nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX)/ROS-dependent NF-κB activity. These results also provide new insights into the mechanisms by which pristimerin attenuates LPS-mediated MMP-9 expression and neuroinflammatory responses.

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          Most cited references28

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          The endotoxin hypothesis of neurodegeneration

          Guy Brown (2019)
          The endotoxin hypothesis of neurodegeneration is the hypothesis that endotoxin causes or contributes to neurodegeneration. Endotoxin is a lipopolysaccharide (LPS), constituting much of the outer membrane of gram-negative bacteria, present at high concentrations in gut, gums and skin and in other tissue during bacterial infection. Blood plasma levels of endotoxin are normally low, but are elevated during infections, gut inflammation, gum disease and neurodegenerative disease. Adding endotoxin at such levels to blood of healthy humans induces systemic inflammation and brain microglial activation. Adding high levels of endotoxin to the blood or body of rodents induces microglial activation, priming and/or tolerance, memory deficits and loss of brain synapses and neurons. Endotoxin promotes amyloid β and tau aggregation and neuropathology, suggesting the possibility that endotoxin synergises with different aggregable proteins to give different neurodegenerative diseases. Blood and brain endotoxin levels are elevated in Alzheimer’s disease, which is accelerated by systemic infections, including gum disease. Endotoxin binds directly to APOE, and the APOE4 variant both sensitises to endotoxin and predisposes to Alzheimer’s disease. Intestinal permeability increases early in Parkinson’s disease, and injection of endotoxin into mice induces α-synuclein production and aggregation, as well as loss of dopaminergic neurons in the substantia nigra. The gut microbiome changes in Parkinson’s disease, and changing the endotoxin-producing bacterial species can affect the disease in patients and mouse models. Blood endotoxin is elevated in amyotrophic lateral sclerosis, and endotoxin promotes TDP-43 aggregation and neuropathology. Peripheral diseases that elevate blood endotoxin, such as sepsis, AIDS and liver failure, also result in neurodegeneration. Endotoxin directly and indirectly activates microglia that damage neurons via nitric oxide, oxidants and cytokines, and by phagocytosis of synapses and neurons. The endotoxin hypothesis is unproven, but if correct, then neurodegeneration may be reduced by decreasing endotoxin levels or endotoxin-induced neuroinflammation.
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            Lipopolysaccharide Associates with Amyloid Plaques, Neurons and Oligodendrocytes in Alzheimer’s Disease Brain: A Review

            This review proposes that lipopolysaccharide (LPS, found in the wall of all Gram-negative bacteria) could play a role in causing sporadic Alzheimer’s disease (AD). This is based in part upon recent studies showing that: Gram-negative E. coli bacteria can form extracellular amyloid; bacterial-encoded 16S rRNA is present in all human brains with over 70% being Gram-negative bacteria; ultrastructural analyses have shown microbes in erythrocytes of AD patients; blood LPS levels in AD patients are 3-fold the levels in control; LPS combined with focal cerebral ischemia and hypoxia produced amyloid-like plaques and myelin injury in adult rat cortex. Moreover, Gram-negative bacterial LPS was found in aging control and AD brains, though LPS levels were much higher in AD brains. In addition, LPS co-localized with amyloid plaques, peri-vascular amyloid, neurons, and oligodendrocytes in AD brains. Based upon the postulate LPS caused oligodendrocyte injury, degraded Myelin Basic Protein (dMBP) levels were found to be much higher in AD compared to control brains. Immunofluorescence showed that the dMBP co-localized with β amyloid (Aβ) and LPS in amyloid plaques in AD brain, and dMBP and other myelin molecules were found in the walls of vesicles in periventricular White Matter (WM). These data led to the hypothesis that LPS acts on leukocyte and microglial TLR4-CD14/TLR2 receptors to produce NFkB mediated increases of cytokines which increase Aβ levels, damage oligodendrocytes and produce myelin injury found in AD brain. Since Aβ1–42 is also an agonist for TLR4 receptors, this could produce a vicious cycle that accounts for the relentless progression of AD. Thus, LPS, the TLR4 receptor complex, and Gram-negative bacteria might be treatment or prevention targets for sporadic AD.
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              The Potential Role of the NLRP3 Inflammasome Activation as a Link Between Mitochondria ROS Generation and Neuroinflammation in Postoperative Cognitive Dysfunction

              Postoperative cognitive dysfunction (POCD) is commonly observed in perioperative care following major surgery and general anesthesia in elderly individuals. No preventive or interventional agents have been established so far. Although the role of interleukin-1β (IL-1β)-mediated neuroinflammation following surgery and anesthesia is strongly implicated in POCD, the exact mechanism of action remains to be explored. Growing evidence has shown that mitochondria-derived reactive oxygen species (mtROS) are closely linked to IL-1β expression through a redox sensor known as the nod-like receptor pyrin domain-containing 3 (NLRP3) inflammasome. Therefore, we hypothesize that the mechanisms underlying POCD involve the mtROS/NLRP3 inflammasome/IL-1β signaling pathway. Furthermore, we speculate that cholinergic anti-inflammatory pathway induced by α7 nicotinic acetylcholine receptor (a7nAChR) may be the potential upstream of mtROS/NLRP3 inflammasome/IL-1β signaling pathway in POCD. For validating the hypotheses, we provide experimental plan involving different paradigms namely; microglial cells and behavioral studies. The link between mtROS, the NLRP3 inflammasome, and IL-1β within and between these different stages in combination with mtROS and NLRP3 inflammasome agonists and inhibitors could be explored using techniques, such as knockout mice, small interference ribonucleic acid, flow cytometry, co-immunoprecipitation, and the Morris Water Maze test. We conclude that the NLRP3 inflammasome is a new preventive and therapeutic target for POCD.
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                Author and article information

                Journal
                J Inflamm Res
                J Inflamm Res
                JIR
                jinres
                Journal of Inflammation Research
                Dove
                1178-7031
                20 July 2020
                2020
                : 13
                : 325-341
                Affiliations
                [1 ]Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital at Tao-Yuan , Tao-Yuan 33302, Taiwan
                [2 ]School of Traditional Chinese Medicine, College of Medicine, Chang Gung University , Tao-Yuan 33302, Taiwan
                [3 ]Department of Pharmacology, College of Medicine, China Medical University , Taichung 40402, Taiwan
                [4 ]Department of Post-Baccalaureate Veterinary Medicine, College of Medical and Health Science, Asia University , Taichung 41354, Taiwan
                Author notes
                Correspondence: Chuen-Mao Yang Tel +886 4-22053366 (Ext. 2229) Email chuenmao@mail.cmu.edu.tw
                Article
                252659
                10.2147/JIR.S252659
                7381777
                32765041
                20d5ecdf-6f5e-427b-8aeb-cdbb0b070601
                © 2020 Yang et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                History
                : 05 March 2020
                : 10 June 2020
                Page count
                Figures: 8, References: 41, Pages: 17
                Funding
                Funded by: the Ministry of Science and Technology, Taiwan
                Funded by: China Medical University, Taiwan
                Funded by: Chang Gung Medical Research Foundation, Taiwan
                This work was supported by the Ministry of Science and Technology, Taiwan [Grant numbers: MOST107-2320-B-182-020-MY2, MOST108-2320-B-039-061, and MOST108-2320-B-182-014]; China Medical University, Taiwan [Grant numbers: CMU108-MF-08]; and Chang Gung Medical Research Foundation, Taiwan [Grant numbers: CMRPG5F0203 and CMRPG5I0041].
                Categories
                Original Research

                Immunology
                neuroinflammation,nox,ros,lps,mmp-9,pristimerin,astrocytes
                Immunology
                neuroinflammation, nox, ros, lps, mmp-9, pristimerin, astrocytes

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