Anti-Neuroinflammatory Effects of Uncaria sinensis in LPS-Stimulated BV2 Microglia Cells and Focal Cerebral Ischemic Mice

Uncaria sinensis (US) has long been used as a traditional Korean medicine to treat cardiovascular and central nervous system diseases, including hypertension and cerebral ischemia. Several recent studies have indicated that US has neuroprotective and cerebrovascular protective effects in ischemic brain injury; however, little is known about the anti-inflammatory effects of US. Therefore, the present study was designed to validate the anti-inflammatory effects of US. The anti-neuroinflammatory properties of US on pro-inflammatory mediators were investigated in lipopolysaccharide (LPS)-stimulated murine BV2 microglia and injured brains induced by photothrombotic cortical ischemia. Hexane extracts of US (HEUS) significantly suppressed the production of nitric oxide (NO) and prostaglandin E2 (PGE2) in LPS-stimulated BV2 microglia and inhibited LPS-induced expression of iNOS and COX-2 in a dose-dependent manner without causing cytotoxicity in BV2 cells. In addition, HEUS significantly reduced the generation of pro-inflammatory cytokines, including TNF-α, IL-1β, and IL-6. Moreover, HEUS treatment inhibited the transcriptional activity and nuclear translocation of NF-κB in LPS-stimulated BV2 cells. In an in vivo study, treatment of HEUS resulted in significantly reduced infarct volume and improved neurological function 48 h after ischemic brain injury, possibly through the inhibition of the production of pro-inflammatory cytokines. HEUS inhibits LPS-stimulated production of pro-inflammatory mediators and prevents cerebral ischemic damage, suggesting that US may have therapeutic potential for the prevention and treatment of ischemic stroke accompanied by microglia activation.

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The Interplay of Pro-Inflammatory Cytokines and Anti-Inflammatory Mediators during Severe Infection

Yearbook of Intensive Care and Emergency Medicine ◽

10.1007/978-3-642-79154-3_30 ◽

1995 ◽

pp. 377-384 ◽

Cited By ~ 1

Author(s):

J. W. M. van der Meer ◽

M. van Deuren ◽

B. J. Kullberg

Keyword(s):

Inflammatory Cytokines ◽

Inflammatory Mediators ◽

Severe Infection ◽

Anti Inflammatory ◽

Pro Inflammatory Cytokines

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Astilbe Chinensis ethanol extract suppresses inflammation in macrophages via NF-κB pathway

BMC Complementary Medicine and Therapies ◽

10.1186/s12906-020-03073-5 ◽

2020 ◽

Vol 20 (1) ◽

Cited By ~ 1

Author(s):

Tae-Young Gil ◽

Bo-Ram Jin ◽

Chul-Hee Hong ◽

Jong Hyuk Park ◽

Hyo-Jin An

Keyword(s):

Nitric Oxide ◽

Inflammatory Cytokines ◽

Inflammatory Mediators ◽

Ethanol Extract ◽

Nuclear Factor Κb ◽

Peritoneal Macrophages ◽

Necrosis Factor Alpha ◽

Iκb Kinase ◽

Anti Inflammatory ◽

Pro Inflammatory Cytokines

Abstract Background Macrophages play a crucial role in inflammation. Astilbe chinensis is one of perennial herbs belonging to the genus Astilbe. Plants in the genus have been used for pain, headaches, arthralgia, and chronic bronchitis. However, the effect of A.chinensis on inflammation remains unclear. To study the anti-inflammatory action of A.chinensis ethanol extract (ACE), we investigated the effect of ACE on the production of pro-inflammatory mediators and cytokines in macrophages. Methods We evaluated the effectiveness of ACE in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages and thioglycollate (TG)-elicited peritoneal macrophages from male C57BL/6 mice. We measured the levels of pro-inflammatory mediators and cytokines, and examined the anti-inflammatory actions of ACE on nuclear factor κB (NF-κB) pathway in the macrophages. Western blot analysis and immunofluorescence microscopy were used to determine protein level and translocation, respectively. Results ACE suppressed the output of nitric oxide (NO), prostaglandin E2 (PGE2), and pro-inflammatory cytokines in stimulated macrophages via inhibiting the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) proteins. ACE suppressed mRNA expression of pro-inflammatory cytokines such as interleukin (IL)-6 and tumor necrosis factor-alpha (TNF-α). We examined the efficacies of ACE on NF-κB activation by measuring the expressions including IκB kinase (IKK), inhibitor of κB (IκB), and nuclear p65 proteins. In addition, the inhibition of NF-κB p65’s translocation was determined with immunofluorescence assay. Conclusion Our findings manifested that ACE inhibited LPS or TG-induced inflammation by blocking the NF-κB signaling pathway in macrophages. It indicated that ACE is a potential therapeutic mean for inflammation and related diseases.

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Pro-inflammatory cytokines reduce human TAFI expression via tristetraprolin-mediated mRNA destabilisation and decreased binding of HuR

Thrombosis and Haemostasis ◽

10.1160/th14-08-0653 ◽

2015 ◽

Vol 114 (08) ◽

pp. 337-349 ◽

Cited By ~ 7

Author(s):

Dragana Komnenov ◽

Corey Scipione ◽

Zainab Bazzi ◽

Justin Garabon ◽

Marlys Koschinsky ◽

...

Keyword(s):

Inflammatory Cytokines ◽

Inflammatory Mediators ◽

Hepg2 Cells ◽

Inflammatory Cells ◽

Gene Encoding ◽

Protein Levels ◽

Anti Inflammatory ◽

Mechanistic Basis ◽

Pro Inflammatory Cytokines

SummaryThrombin activatable fibrinolysis inhibitor (TAFI) is the zymogen form of a basic carboxypeptidase (TAFIa) with both anti-fibrinolytic and anti-inflammatory properties. The role of TAFI in inflammatory disease is multifaceted and involves modulation both of specific inflammatory mediators as well as of the behaviour of inflammatory cells. Moreover, as suggested by in vitro studies, inflammatory mediators are capable of regulating the expression of CPB2, the gene encoding TAFI. In this study we addressed the hypothesis that decreased TAFI levels observed in inflammation are due to post-transcriptional mechanisms. Treatment of human HepG2 cells with pro-inflammatory cytokines TNFα, IL-6 in combination with IL-1β, or with bacterial lipopolysaccharide (LPS) decreased TAFI protein levels by approximately two-fold over 24 to 48 hours of treatment. Conversely, treatment of HepG2 cells with the anti-inflammatory cytokine IL-10 increased TAFI protein levels by two-fold at both time points. We found that the mechanistic basis for this modulation of TAFI levels involves binding of tristetraprolin (TTP) to the CPB2 3′-UTR, which mediates CPB2 mRNA destabilisation. In this report we also identified that HuR, another ARE-binding protein but one that stabilises transcripts, is capable of binding the CBP2 3’UTR. We found that pro-inflammatory mediators reduce the occupancy of HuR on the CPB2 3’-UTR and that the mutation of the TTP binding site in this context abolishes this effect, although TTP and HuR appear to contact discrete binding sites. Interestingly, all of the mediators tested appear to increase TAFI protein expression in THP-1 macrophages, likewise through effects on CPB2 mRNA stability.

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Microglial VPS35 deficiency regulates microglial polarization and decreases ischemic stroke-induced damage in the cortex

Journal of Neuroinflammation ◽

10.1186/s12974-019-1633-y ◽

2019 ◽

Vol 16 (1) ◽

Cited By ~ 1

Author(s):

Shi-Yang Ye ◽

Joanna E. Apple ◽

Xiao Ren ◽

Fu-Lei Tang ◽

Ling-Ling Yao ◽

...

Keyword(s):

Ischemic Stroke ◽

Brain Injury ◽

Brain Damage ◽

Hippocampal Neurogenesis ◽

Conditional Knockout ◽

Microglial Cells ◽

Ischemic Brain Injury ◽

Ischemic Brain ◽

Sensorimotor Deficits ◽

Anti Inflammatory

Abstract Background Vacuolar sorting protein 35 (VPS35), a critical component of retromer, is essential for selective endosome-to-Golgi retrieval of membrane proteins. It is highly expressed in microglial cells, in addition to neurons. We have previously demonstrated microglial VPS35’s functions in preventing hippocampal, but not cortical, microglial activation, and in promoting adult hippocampal neurogenesis. However, microglial VPS35’s role in the cortex in response to ischemic stroke remains largely unclear. Methods We used mice with VPS35 cKO (conditional knockout) in microglial cells and examined and compared their responses to ischemic stroke with control mice. The brain damage, cell death, changes in glial cells and gene expression, and sensorimotor deficits were assessed by a combination of immunohistochemical and immunofluorescence staining, RT-PCR, Western blot, and neurological functional behavior tests. Results We found that microglial VPS35 loss results in an increase of anti-inflammatory microglia in mouse cortex after ischemic stroke. The ischemic stroke-induced brain injury phenotypes, including brain damage, neuronal death, and sensorimotor deficits, were all attenuated by microglial VPS35-deficiency. Further analysis of protein expression changes revealed a reduction in CX3CR1 (CX3C chemokine receptor 1) in microglial VPS35-deficient cortex after ischemic stroke, implicating CX3CR1 as a potential cargo of VPS35 in this event. Conclusion Together, these results reveal an unrecognized function of microglial VPS35 in enhancing ischemic brain injury-induced inflammatory microglia, but suppressing the injury-induced anti-inflammatory microglia. Consequently, microglial VPS35 cKO mice exhibit attenuation of ischemic brain injury response.

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Fisetin has Inhibitory Effects on the TLR 4/NF-κB-Mediated Inflammatory Pathway After Traumatic Brain Injury in Mice: A Potential Neuroprotective Role

10.21203/rs.3.rs-776980/v1 ◽

2021 ◽

Author(s):

Chenhui Zhou ◽

Sheng Nie ◽

Zhepei Wang ◽

Fanyong Gong ◽

Jingmi Wu ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Brain Edema ◽

Inflammatory Cytokines ◽

Nuclear Factor Κb ◽

Neuroprotective Effects ◽

Inflammatory Pathway ◽

Mortality And Morbidity ◽

Anti Inflammatory ◽

Pro Inflammatory Cytokines

Abstract Inflammatory response contributes to the high mortality and morbidity of traumatic brain injury (TBI). Potent anti-inflammatory effects can alleviate brain injury after TBI. Fisetin has anti-inflammatory properties in several brain injury models, but the effects of fisetin on inflammation after TBI is still unclear. Our study aimed to investigate the neuroprotective effects of fisetin against inflammation after TBI in mice.Fisetin (25 mg/kg, 50 mg/kg or 75 mg/kg) or equal volume of vehicle was given via intraperitoneal injection 30 min after TBI. The neurological severity score, brain edema and blood brain barrier (BBB) permeability were assayed after TBI. In further mechanistic studies, changes in the toll-like receptor 4 (TLR 4)/nuclear factor-κB (NF-κB) pathway and the expression of pro-inflammatory cytokines were measured. Fisetin significantly improved behavioral outcomes and reduced brain edema after TBI. These changes were associated with significant reductions in TLR 4 expression and NF-κB activity. In addition, changes in the expression of pro-inflammatory cytokines were detected 24 h after TBI. Our study provided the first evidence that fisetin exerted neuroprotective effects by inhibiting the TLR 4/NF-κB–mediated inflammatory pathway after TBI in mice.

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Abstract P448: Interaction Between Ischemic Brain Injury and Amyloid-β Deposition in Cognitive Decline; Possible Cognitive Protection by AT 2 Receptor Activation

Hypertension ◽

10.1161/hyp.70.suppl_1.p448 ◽

2017 ◽

Vol 70 (suppl_1) ◽

Author(s):

Li-Juan Min ◽

Masaki Mogi ◽

Kana Tsukuda ◽

Hui-Yu Bai ◽

Bao-Shuai Shan ◽

...

Keyword(s):

Cognitive Impairment ◽

Brain Injury ◽

Cognitive Function ◽

Nadph Oxidase ◽

Inflammatory Cytokines ◽

Amyloid Β ◽

Receptor Activation ◽

Ischemic Brain Injury ◽

Ischemic Brain ◽

Aβ Clearance

Objectives: Cerebrovascular damage could breakdown amyloid-β (Aβ) clearance and accelerate Aβ deposition. We examined the interaction between ischemic brain damage and Aβ deposition in cognitive function, focusing on the roles of angiotensin II type 2 (AT 2 ) receptor in vascular smooth muscle cells (VSMC). Methods: Male wild-type mice (WT) or the mice with VSMC-specific AT 2 receptor overexpression (smAT 2 ) were used. Mice were subjected to ICV injection of Aβ1-40. Ischemic brain injury was induced by bilateral common carotid artery occlusion (BCCAO) 24 hours after Aβ1-40 injection. Three weeks after Aβ1-40 injection, cognitive function was evaluated by the Morris water maze test. Brain samples obtained 8 days after Aβ1-40 injection were used to study the related signals. Results: ICV injection of Aβ1-40 in WT showed impaired cognitive function (arriving time to platform at day 5: control, 26.53±4.46 sec; Aβ, 65.35±7.44 sec), whereas BCCAO alone did not decline significantly cognitive function. In contrast, BCCAO following Aβ1-40 injection exhibited more marked cognitive impairment (84.27±8.00 sec) compared to Aβ injection alone with the increase in expressions of NADPH oxidase subunits such as p22phox and p67phox in the hippocampus of mice. Aβ1-40 injection with BCCAO tended to increase the mRNA levels of inflammatory cytokines such as MCP-1 and TNFα. BCCAO significantly enhanced the expression of Aβ clearance factor, RAGE (receptor for advanced glycation end product). Aβ1-40 injection did not increase the neuron pyknosis in the hippocampus, whereas the number of neuron pyknosis was increased significantly with BCCAO (control, 6.33±0.88/field; Aβ with BCCAO, 46.33±4.10/field). On the other hand, smAT 2 did not show cognitive impairment, the changes of the expression for NADPH oxidase subunits and inflammatory cytokines, and neuron pyknosis, which were induced by BCCAO with/without Aβ1-40 injection in WT. Conclusion: Ischemic brain injury could enhance Aβ-induced cognitive impairment with possible involvement of enhanced oxidative stress, neuron degeneration, and breakdown of RAGE-mediated Aβ clearance. AT 2 receptor activation in VSMC could play inhibitory roles in the cognitive decline induced by ischemic brain damage and Aβ deposition.

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Propofol attenuates BV2 microglia inflammation via NMDA receptor inhibition

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2017-0243 ◽

2018 ◽

Vol 96 (3) ◽

pp. 241-248 ◽

Cited By ~ 14

Author(s):

Qichao Wu ◽

Yanjun Zhao ◽

Xiangyuan Chen ◽

Minmin Zhu ◽

Changhong Miao

Keyword(s):

Nmda Receptor ◽

Inflammatory Cytokines ◽

Inflammatory Cytokine ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Underlying Mechanism ◽

Enzyme Expression ◽

Bv2 Cells ◽

Bv2 Microglia ◽

Pro Inflammatory Cytokines

Activated microglia, involved in the occurrence and improvement of sepsis-associated encephalopathy, can induce the expression of pro-inflammatory cytokines and pro-inflammatory enzymes, resulting in inflammation-mediated neuronal cell death. It was reported that propofol could inhibit lipopolysaccharide (LPS) induced pro-inflammatory cytokine and pro-inflammatory enzyme expression in BV2 and primary microglial cells. However, the underlying mechanism is not well known. In the present study, we investigated whether and how propofol inhibited LPS-induced the expression of pro-inflammatory cytokines and pro-inflammatory enzymes in BV2 cells. LPS induced pro-inflammatory cytokine and pro-inflammatory enzyme expression, NF-κB, extracellular regulated kinase 1/2 (ERK), calcium (Ca2+)/calmodulin-dependent protein kinase II (CaMK II) phosphorylation, and BV2 cell Ca2+ accumulation. Propofol could reverse these effects induced by LPS. MK801, an inhibitor of the NMDA receptor, could attenuate LPS-induced Ca2+ accumulation, the expression of pro-inflammatory cytokines and pro-inflammatory enzymes, and phosphorylation of NF-κB, ERK, and CaMK II, which was similar to propofol. Moreover, these effects of propofol could be counteracted by rapastinel, an activator of the NMDA receptor. The present study suggested that propofol, via inhibiting the NMDA receptor, attenuating Ca2+ accumulation, and inhibiting CaMK II, ERK1/2, and NF-κB phosphorylation, down-regulated LPS-induced pro-inflammatory cytokine and pro-inflammatory enzyme expression.

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