scholarly journals Role of GADD45a in murine models of radiation- and bleomycin-induced lung injury

2015 ◽  
Vol 309 (12) ◽  
pp. L1420-L1429 ◽  
Author(s):  
Biji Mathew ◽  
Daisuke Takekoshi ◽  
Saad Sammani ◽  
Yulia Epshtein ◽  
Rajesh Sharma ◽  
...  
Keyword(s):  
Lung Injury ◽  
Inflammatory Responses ◽  
Protective Effects ◽  
Murine Models ◽  
Wild Type ◽  
Akt Inhibitor ◽  
Cell Counts ◽  
Thoracic Radiation ◽  
Novel Target

We previously reported protective effects of GADD45a (growth arrest and DNA damage-inducible gene 45 alpha) in murine ventilator-induced lung injury (VILI) via effects on Akt-mediated endothelial cell signaling. In the present study we investigated the role of GADD45a in separate murine models of radiation- and bleomycin-induced lung injury. Initial studies of wild-type mice subjected to single-dose thoracic radiation (10 Gy) confirmed a significant increase in lung GADD45a expression within 24 h and persistent at 6 wk. Mice deficient in GADD45a (GADD45a−/−) demonstrated increased susceptibility to radiation-induced lung injury (RILI, 10 Gy) evidenced by increased bronchoalveolar lavage (BAL) fluid total cell counts, protein and albumin levels, and levels of inflammatory cytokines compared with RILI-challenged wild-type animals at 2 and 4 wk. Furthermore, GADD45a−/− mice had decreased total and phosphorylated lung Akt levels both at baseline and 6 wk after RILI challenge relative to wild-type mice while increased RILI susceptibility was observed in both Akt+/− mice and mice treated with an Akt inhibitor beginning 1 wk prior to irradiation. Additionally, overexpression of a constitutively active Akt1 transgene reversed RILI-susceptibility in GADD45a−/− mice. In separate studies, lung fibrotic changes 2 wk after treatment with bleomycin (0.25 U/kg IT) was significantly increased in GADD45a−/− mice compared with wild-type mice assessed by lung collagen content and histology. These data implicate GADD45a as an important modulator of lung inflammatory responses across different injury models and highlight GADD45a-mediated signaling as a novel target in inflammatory lung injury clinically.

ID: 126: ROLE OF SYNDECAN-1 IN MECHANICAL STRESS-INDUCED LUNG ENDOTHELIAL CELL INFLAMMATORY RESPONSES MEDIATED BY INTEGRIN BETA4

2016 ◽  
Vol 64 (4) ◽  
pp. 972.2-973
Author(s):  
W Chen ◽  
RO Dull ◽  
JR Jacobson
Keyword(s):  
Endothelial Cell ◽  
Lung Injury ◽  
Mechanical Stress ◽  
Tyrosine Phosphorylation ◽  
Western Blotting ◽  
Inflammatory Responses ◽  
Cyclic Stretch ◽  
Protective Effects ◽  
Coa Reductase

RationaleSimvastatin, an HMG-CoA reductase inhibitor, has protective effects on mechanically stressed human lung endothelial cells (EC) that are mediated by the attenuation of agonist-induced integrin β4 (ITGB4) tyrosine phosphorylation. In addition, overexpression of ITGB4 constructs harboring mutations in tyrosine phosphorylation sites within the cytoplasmic tail results in decreased mechanical stress-induced inflammatory cytokine release by EC. However, the mechanisms by which ITGB4 phosphorylation is regulated is unknown. A molecule of interest in this context is syndecan-1, a cell-surface proteoglycan that binds extraceullar matrix components but also binds the ITGB4 cytoplasmic domain, is expressed by EC, and has been implicated as a mediator of acute lung injury (ALI). Thus, we hypothesized that syndecan-1 is an effector of lung endothelial cell inflammatory responses mediated by ITGB4 in response to mechanical stress.MethodsTo investigate the effects of simvastatin on ITGB4 and syndecan-1 expression human pulmonary artery EC lysates treated with simvastatin (5 µM, 16 h) were subjected to Western blotting for ITGB4 and syndecan-1. Simvastatin-treated EC were then used for immunoprecipitation (IP) of syndecan-1 followed by Western blotting for ITGB4. To study the role of syndecan-1 in EC inflammatory responses to mechanical stress mediated by ITGB4, EC were transfected with syndecan-1 siRNA prior to cyclic stretch (18% CS) and lysates were collected for immunoprecipitation of ITGB4 followed by Western blotting with a phospho-tyrosine antibody. Finally, syndecan-1-silenced EC were subjected to 18% CS and the media was collected for measurement of IL-6 and IL-8 levels.ResultsSimvastatin treatment of EC resulted in both a dramatic increase in ITGB4 and a marked decreased in syndecan-1 expression levels. In addition, syndecan-1 association with ITGB4 was markedly decreased in EC treated with simvastatin. In EC subjected to 18% CS, ITGB4 phosphorylation was significantly decreased after syndecan-1 knockdown. Finally, silencing of syndecan-1 was associated with a significant decrease in CS-induced EC IL-6 and IL-8 expression (76% and 66%, respectively, p<0.05 for both).ConclusionOur results implicate syndecan-1 as an important mediator of EC ITGB4 tyrosine phosphorylation affected by both simvastatin and mechanical-stress. These findings represent a novel area of investigation that may ultimately yield new therapeutic targets and strategies for patients with ventilator-induced lung injury, a form of ALI precipitated by excessive lung stretch.

Role of interferon-γ in the evolution of murine bleomycin lung fibrosis

2003 ◽  
Vol 285 (6) ◽  
pp. L1255-L1262 ◽  
Author(s):  
Michael J. Segel ◽  
Gabriel Izbicki ◽  
Pazit Y. Cohen ◽  
Reuven Or ◽  
Thomas G. Christensen ◽  
...  
Keyword(s):  
Lung Injury ◽  
Lung Fibrosis ◽  
Time Course ◽  
Intratracheal Instillation ◽  
Interferon Γ ◽  
Mrna Levels ◽  
Wild Type ◽  
Cell Counts ◽  
Ifn Γ

IFN-γ production is upregulated in lung cells (LC) of bleomycin-treated C57BL/6 mice. The present study characterizes the time course, cellular source, and regulation of IFN-γ expression in bleomycin-induced lung injury. IFN-γ mRNA in LC from bleomycin-treated mice peaked 3 days after intratracheal instillation. IFN-γ protein levels were increased at 6 days, as was the percentage of LC expressing IFN-γ. CD4+, CD8+, and natural killer cells each contributed significantly to IFN-γ production. IL-12 mRNA levels were increased at 1 day in LC of bleomycin-treated mice. Anti-IL-12 and anti-IL-18 antibodies decreased IFN-γ production by these cells. To define the role of endogenous IFN-γ in the evolution of bleomycin lung injury, we compared the effect of bleomycin in mice with a targeted knockout mutation of the IFN-γ gene (IFN-γ knockout) and wild-type mice. At 14 days after intratracheal bleomycin, total bronchoalveolar lavage cell counts and lung hydroxyproline were decreased in IFN-γ knockouts compared with wild-type animals. There was no difference in morphometric parameters of fibrosis. Our data show that enhanced IFN-γ production in the lungs of bleomycin-treated mice is at least partly IL-12 and IL-18 dependent. Absence of IFN-γ in IFN-γ knockout mice does not increase pulmonary fibrosis. Endogenous IFN-γ may play a proinflammatory or profibrotic role in bleomycin-induced lung fibrosis.

scholarly journals Estrogen-related receptor alpha (ERRα) is a key regulator of intestinal homeostasis and protects against colitis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Allan Tran ◽  
Charlotte Scholtes ◽  
Mario Songane ◽  
Claudia Champagne ◽  
Luc Galarneau ◽  
...  
Keyword(s):  
Transcriptional Control ◽  
Current Knowledge ◽  
Experimental Colitis ◽  
Protective Effects ◽  
Mitochondrial Energy Metabolism ◽  
Receptor Alpha ◽  
Cell Counts ◽  
Α Diversity ◽  
Estrogen Related Receptor

AbstractThe estrogen-related receptor alpha (ERRα) is a primary regulator of mitochondrial energy metabolism, function and dynamics, and has been implicated in autophagy and immune regulation. ERRα is abundantly expressed in the intestine and in cells of the immune system. However, its role in inflammatory bowel disease (IBD) remains unknown. Here, we report a protective role of ERRα in the intestine. We found that mice deficient in ERRα were susceptible to experimental colitis, exhibiting increased colon inflammation and tissue damage. This phenotype was mediated by impaired compensatory proliferation of intestinal epithelial cells (IEC) following injury, enhanced IEC apoptosis and necrosis and reduced mucus-producing goblet cell counts. Longitudinal analysis of the microbiota demonstrated that loss of ERRα lead to a reduction in microbiome α-diversity and depletion of healthy gut bacterial constituents. Mechanistically, ERRα mediated its protective effects by acting within the radio-resistant compartment of the intestine. It promoted disease tolerance through transcriptional control of key genes involved in intestinal tissue homeostasis and repair. These findings provide new insights on the role of ERRα in the gut and extends our current knowledge of nuclear receptors implicated in IBD.

scholarly journals N-Acetylcysteine Reduces the Pro-Oxidant and Inflammatory Responses during Pancreatitis and Pancreas Tumorigenesis

Antioxidants ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1107
Author(s):  
Marie-Albane Minati ◽  
Maxime Libert ◽  
Hajar Dahou ◽  
Patrick Jacquemin ◽  
Mohamad Assi
Keyword(s):  
Nuclear Translocation ◽  
Inflammatory Responses ◽  
Acinar Cells ◽  
Pancreatic Acinar Cells ◽  
Glutathione Metabolism ◽  
Protective Effects ◽  
Wild Type ◽  
Kras Mutations ◽  
Oxidative Damages ◽  
Factor Α

Pancreatitis, an inflammation of the pancreas, appears to be a main driver of pancreatic cancer when combined with Kras mutations. In this context, the exact redox mechanisms are not clearly elucidated. Herein, we treated mice expressing a KrasG12D mutation in pancreatic acinar cells with cerulein to induce acute pancreatitis. In the presence of KrasG12D, pancreatitis triggered significantly greater redox unbalance and oxidative damages compared to control mice expressing wild-type Kras alleles. Further analyses identified the disruption in glutathione metabolism as the main redox event occurring during pancreatitis. Compared to the wild-type background, KrasG12D-bearing mice showed a greater responsiveness to treatment with a thiol-containing compound, N-acetylcysteine (NAC). Notably, NAC treatment increased the pancreatic glutathione pool, reduced systemic markers related to pancreatic and liver damages, limited the extent of pancreatic edema and fibrosis as well as reduced systemic and pancreatic oxidative damages. The protective effects of NAC were, at least, partly due to a decrease in the production of tumor necrosis factor-α (TNF-α) by acinar cells, which was concomitant with the inhibition of NF-κB(p65) nuclear translocation. Our data provide a rationale to use thiol-containing compounds as an adjuvant therapy to alleviate the severity of inflammation during pancreatitis and pancreatic tumorigenesis.

Abstract 10: The Matrix Crosslinking Enzyme Lysyl Oxidase Like-2 as a Target to Reverse Vascular Stiffness

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Jochen Steppan ◽  
Ivy Wang ◽  
Yehudit Bergman ◽  
Siqi Tan ◽  
Sandeep Jandu ◽  
...  
Keyword(s):  
Lysyl Oxidase ◽  
Vascular Stiffness ◽  
Matrix Composition ◽  
Wild Type ◽  
Matrix Deposition ◽  
Proteomic Approach ◽  
Vascular Stiffening ◽  
Group 2 ◽  
Novel Target

Introduction: Stiffening of the central vasculature is a strong and independent predictor of adverse cardiovascular events. Vascular stiffening is a complex process that involves changes in the vessel wall composition and smooth muscle cell (SMC) function. We recently used an unbiased proteomic approach to identify Lysyl oxidase like 2 (LOXL2) as a potential new target in vascular stiffness. The goal of this study is to characterize the role of LOXL2 in vascular stiffening and its potential as a target to reverse vascular stiffness associated with hypertension. Results: We demonstrate that decreased nitric oxide (NO) bioavailability results in increased secretion and activity of LOXL2 in SMCs. LOXL2 knockdown markedly attenuates SMC adhesion, motility, and proliferation and results in diminished matrix deposition. LOXL2 knockdown also results in striking changes in the stiffness and cytoskeletal remodeling events in CMSs. Tensile testing shows that intact aortas of LOXL2+/- animals are stiffer when compared with those from wild type mice, while there is no difference in decellularized vessels. We next investigated the role of LOXL2 in the development of hypertension using angiotensin II (AngII) infusion in LOXL2+/- (group 1) and wild type (WT; group 2) mice. BP and pulse wave velocity (PWV) increased significantly with AngII infusion in both groups during the study period, without a significant change in heart rate. Compared to WT animals, contractile responsiveness was markedly diminished in LOXL2+/- animals at baseline as well as with AngII infusion when compared with untreated controls. The NO- dependent vasodilatory response to acetylcholine was identical at baseline and diminished significantly with AngII infusion in both groups of animals. There was no difference between the groups in the endothelium-independent response to sodium nitroprusside. Conclusion: In this study, we demonstrated the role of NO in the regulation of LOXL2. Interestingly, LOXL2 appears to have a dual role in vascular stiffness by affecting both SMC function as well as matrix composition. We therefore conclude that LOXL2 is a novel target involved in vascular stiffness that requires further characterization to elicit the possibility of therapeutic intervention.

3-methyadenine inhibits lipopolysaccharides-induced pulmonary inflammation at the early stage of silicosis via blocking NF-κB signaling pathway

2021 ◽  
pp. 074823372110394
Author(s):  
Yujing Zhang ◽  
Shuai Huang ◽  
Shiyi Tan ◽  
Mingke Chen ◽  
Shang Yang ◽  
...  
Keyword(s):  
Lung Injury ◽  
Late Stage ◽  
Caspase 3 ◽  
Inflammatory Responses ◽  
Early Stage ◽  
Pulmonary Inflammation ◽  
Mechanism Study ◽  
Silica Dust ◽  
Tnf Α

Occupational exposure to silica dust is related to pulmonary inflammation and silicosis. Lipopolysaccharides (LPSs) could aggravate apoptosis in alveolar macrophages (AMs) of human silicosis through autophagy, yet how the reduction of autophagy attenuated LPS-induced lung injury and the related mechanisms need to be investigated. In the study, we aim to understand the role of 3-methyladenine (3-MA), an inhibitor of autophagy, in LPS-mediated inflammatory responses and fibrosis. We collected AMs from observers/silicosis patients. The results showed that LPS induced NF-κB-related pulmonary inflammation in observers and silicosis patients, as confirmed by an increase in the expression of IL-1β, IL-6, TNF-α, and p65, which could be inhibited by 3-MA treatment. In mice models, at the early stage (7d) of silicosis, but not the late (28d) stage, blocking autophagy reversed the increased levels of IL-1β, IL-6, TNF-α, and p65 caused by LPS. Mechanism study revealed that LPS triggered the expression of LC3 II, p62, and cleaved caspase-3 at the early stage exposed to silica, which could be restored by 3-MA, while there was no difference in the expression of LAMP1 either at the early or late stage of silicosis in different groups. Similarly, 3-MA treatment did not prevent fibrosis characterized by destroyed alveoli, collagen deposition, and increased expression of α-SMA and Col-1 induced by LPS at the late stage of silicosis. The results suggested that 3-MA has a role in the protection of lung injury at the early stage of silicosis and provided an experimental basis for preventive strategies of pulmonary inflammation and silicosis.

A Role of Plasminogen in Atherosclerosis and Restenosis Models in Mice

1999 ◽  
Vol 82 (S 01) ◽  
pp. 4-7 ◽  
Author(s):  
Victoria A. Ploplis ◽  
Steven Busuttil ◽  
Peter Carmeliet ◽  
Desire Collen ◽  
Edward F. Plow
Keyword(s):  
Vessel Wall ◽  
Inflammatory Responses ◽  
Leukocyte Migration ◽  
Early Event ◽  
Macrophage Migration ◽  
Murine Models ◽  
Response Models ◽  
Deficient Mice

SummaryIn addition to its preeminent role in fibrinolysis, the plasminogen system is believed to play a key role in mediating cell migration. Leukocyte migration into the vessel wall is a key and early event in the development of the lesions of atherosclerosis and restenosis, pathologies which may be viewed as specific examples of vascular inflammatory responses. The development of mice in which the plasminogen gene has been inactivated affords an opportunity to test the contribution of plasminogen in leukocyte migration during in vivo. This article summarizes recent studies conducted in murine models of the inflammatory repsonse, restenosis and atherosclerosis in which leukocyte migration, and in particular monocyte/macrophage migration, has been evaluated in plasminogen-deficient mice. Recruitment of these cells through the vessel wall in inflammatory response models and into the vessel wall in restenosis and transplant atherosclerosis models is substantially blunted. These data implicate plasminogen in the migration of leukocytes in these murine models. With the numerous correlations between components and/or activation of the plasminogen system in restenosis and atherosclerosis, these results also support a role of plasminogen in the corresponding human pathologies.

scholarly journals Crocin Improves Insulin Sensitivity and Ameliorates Adiposity by Regulating AMPK-CDK5-PPARγ Signaling

2020 ◽  
Vol 2020 ◽  
pp. 1-8
Author(s):  
Kai Fang ◽  
Ming Gu
Keyword(s):  
Protein Level ◽  
Biological Activities ◽  
Protective Effects ◽  
Metabolic Dysfunction ◽  
Ampk Activation ◽  
Diabetic Mice ◽  
Wild Type ◽  
Ampk Signaling ◽  
Beneficial Effects

Crocin is a carotenoid compound which possesses multiple biological activities. Our and other laboratory’s previous findings show that crocin alleviates obesity and type 2 diabetes-related complications. We have found that crocin activates AMP-activated protein kinase (AMPK) signaling and inhibition of AMPK suppresses crocin-induced protective effects. However, the causal role of AMPK activation in the biological role of crocin is still not verified. In the present study, we showed that crocin markedly inhibits the changes of glucose metabolic parameters and serum lipid profiles in wild type diabetic mice. In AMPKα KO diabetic mice, those protective effects of crocin against glucose and lipid metabolic dysfunction were abolished. These results demonstrated AMPK activation was responsible for the beneficial effects of crocin on metabolic dysfunction. Moreover, we have shown that the antiobese effect of crocin has been abolished by the deficiency of AMPKα. We also showed that crocin induced a significant decrease of CDK5 protein level in wild type diabetic mice, while this effect was abolished in AMPKα KO diabetic mice. The regulation of downstream targets of CDK5/PPARγ by crocin was abolished by the deficiency of AMPK. In conclusion, our study verified that activation of AMPK is involved in crocin-induced protective effects against glucose and lipid metabolic dysfunction. Activation of AMPK downregulates the protein level of CDK5, followed by the decrease of PPARγ phosphorylation, leading to the inhibition of adipose formation and metabolic dysfunction. Our study provides new insights into the mechanism of protective effects of crocin and interaction of AMPK and CDK5/PPARγ signaling.

Polar head groups are important for barrier-protective effects of oxidized phospholipids on pulmonary endothelium

2007 ◽  
Vol 292 (4) ◽  
pp. L924-L935 ◽  
Author(s):  
Anna A. Birukova ◽  
Panfeng Fu ◽  
Santipongse Chatchavalvanich ◽  
Dylan Burdette ◽  
Olga Oskolkova ◽  
...  
Keyword(s):  
Protective Effects ◽  
Oxidized Phospholipids ◽  
Barrier Dysfunction ◽  
Polar Head ◽  
Cell Counts ◽  
Head Groups ◽  
Stimulation Of

We have previously described protective effects of oxidized 1-palmitoyl-2-arachidonoyl- sn-glycero-3-phosphocholine (OxPAPC) on pulmonary endothelial cell (EC) barrier function and demonstrated the critical role of cyclopentenone-containing modifications of arachidonoyl moiety in OxPAPC protective effects. In this study we used oxidized phosphocholine (OxPAPC), phosphoserine (OxPAPS), and glycerophosphate (OxPAPA) to investigate the role of polar head groups in EC barrier-protective responses to oxidized phospholipids (OxPLs). OxPAPC and OxPAPS induced sustained barrier enhancement in pulmonary EC, whereas OxPAPA caused a transient protective response as judged by measurements of transendothelial electrical resistance (TER). Non-OxPLs showed no effects on TER levels. All three OxPLs caused enhancement of peripheral EC actin cytoskeleton. OxPAPC and OxPAPS completely abolished LPS-induced EC hyperpermeability in vitro, whereas OxPAPA showed only a partial protective effect. In vivo, intravenous injection of OxPAPS or OxPAPC (1.5 mg/kg) markedly attenuated increases in the protein content, cell counts, and myeloperoxidase activities detected in bronchoalveolar lavage fluid upon intratracheal LPS instillation in mice, although OxPAPC showed less potency. All three OxPLs partially attenuated EC barrier dysfunction induced by IL-6 and thrombin. Their protective effects against thrombin-induced EC barrier dysfunction were linked to the attenuation of the thrombin-induced Rho pathway of EC hyperpermeability and stimulation of Rac-mediated mechanisms of EC barrier recovery. These results demonstrate for the first time the essential role of polar OxPL groups in blunting the LPS-induced EC dysfunction in vitro and in vivo and suggest the mechanism of agonist-induced hyperpermeability attenuation by OxPLs via reduction of Rho and stimulation of Rac signaling.

scholarly journals GPR110 (ADGRF1) mediates anti-inflammatory effects of N-docosahexaenoylethanolamine

2019 ◽  
Vol 16 (1) ◽  
Author(s):  
Taeyeop Park ◽  
Huazhen Chen ◽  
Hee-Yong Kim
Keyword(s):  
Inflammatory Cytokine ◽  
Inflammatory Responses ◽  
Cytokine Expression ◽  
Regulatory Function ◽  
Enzyme Linked Immunosorbent Assay ◽  
Inflammatory Condition ◽  
Wild Type ◽  
Knock Out ◽  
The Brain

Abstract Background Neuroinflammation is a widely accepted underlying condition for various pathological processes in the brain. In a recent study, synaptamide, an endogenous metabolite derived from docosahexaenoic acid (DHA, 22:6n-3), was identified as a specific ligand to orphan adhesion G-protein-coupled receptor 110 (GPR110, ADGRF1). Synaptamide has been shown to suppress lipopolysaccharide (LPS)-induced neuroinflammation in mice, but involvement of GPR110 in this process has not been established. In this study, we investigated the possible immune regulatory role of GPR110 in mediating the anti-neuroinflammatory effects of synaptamide under a systemic inflammatory condition. Methods For in vitro studies, we assessed the role of GPR110 in synaptamide effects on LPS-induced inflammatory responses in adult primary mouse microglia, immortalized murine microglial cells (BV2), primary neutrophil, and peritoneal macrophage by using quantitative PCR (qPCR) and enzyme-linked immunosorbent assay (ELISA) as well as neutrophil migration and ROS production assays. To evaluate in vivo effects, wild-type (WT) and GPR110 knock-out (KO) mice were injected with LPS intraperitoneally (i.p.) or TNF intravenously (i.v.) followed by synaptamide (i.p.), and expression of proinflammatory mediators was measured by qPCR, ELISA, and western blot analysis. Activated microglia in the brain and NF-kB activation in cells were examined microscopically after immunostaining for Iba-1 and RelA, respectively. Results Intraperitoneal (i.p.) administration of LPS increased TNF and IL-1β in the blood and induced pro-inflammatory cytokine expression in the brain. Subsequent i.p. injection of the GPR110 ligand synaptamide significantly reduced LPS-induced inflammatory responses in wild-type (WT) but not in GPR110 knock-out (KO) mice. In cultured microglia, synaptamide increased cAMP and inhibited LPS-induced proinflammatory cytokine expression by inhibiting the translocation of NF-κB subunit RelA into the nucleus. These effects were abolished by blocking synaptamide binding to GPR110 using an N-terminal targeting antibody. GPR110 expression was found to be high in neutrophils and macrophages where synaptamide also caused a GPR110-dependent increase in cAMP and inhibition of LPS-induced pro-inflammatory mediator expression. Intravenous injection of TNF, a pro-inflammatory cytokine that increases in the circulation after LPS treatment, elicited inflammatory responses in the brain which were dampened by the subsequent injection (i.p.) of synaptamide in a GPR110-dependent manner. Conclusion Our study demonstrates the immune-regulatory function of GPR110 in both brain and periphery, collectively contributing to the anti-neuroinflammatory effects of synaptamide under a systemic inflammatory condition. We suggest GPR110 activation as a novel therapeutic strategy to ameliorate inflammation in the brain as well as periphery.

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