Curcumin Regulates Anti-Inflammatory Responses by JAK/STAT/SOCS Signaling Pathway in BV-2 Microglial Cells

Microglia play important physiological roles in central nervous system (CNS) homeostasis and in the pathogenesis of inflammatory brain diseases. Inflammation stimulates microglia to secrete cytokines and chemokines that guide immune cells to sites of injury/inflammation. Neuroinflammation is also strongly implicated in the pathogenesis of a number of neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease, for which nutritional intervention could represent a benefit due to a lack of clinically efficacious drugs. To this end, the anti-inflammatory mechanisms of several phytochemicals, including curcumin, have been extensively studied. The present experiments show that the administration of curcumin is able to increase the production of the anti-inflammatory cytokines, IL-4 and IL-10, in murine BV-2 microglial cells treated with lipopolysaccharide (LPS). Consistent with these data, curcumin stimulation upregulates the expression of Suppressors of cytokine signaling (SOCS)-1, whereas phosphorylation of the JAK2 and STAT3 was reduced. Taken together, these results provide evidence that curcumin is able to regulate neuroinflammatory reactions by eliciting anti-inflammatory responses in microglia through JAK/STAT/SOCS signaling pathway modulation.

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Kyungheechunggan-Tang-01, a New Herbal Medication, Suppresses LPS-Induced Inflammatory Responses through JAK/STAT Signaling Pathway in RAW 264.7 Macrophages

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2017/7383104 ◽

2017 ◽

Vol 2017 ◽

pp. 1-15 ◽

Cited By ~ 4

Author(s):

Hee-Soo Han ◽

Eungyeong Jang ◽

Ji-Sun Shin ◽

Kyung-Soo Inn ◽

Jang-Hoon Lee ◽

...

Keyword(s):

Signaling Pathway ◽

Inflammatory Responses ◽

Inflammatory Diseases ◽

Molecular Data ◽

Mrna Levels ◽

Protein Levels ◽

Stat3 Phosphorylation ◽

Stat Signaling ◽

Cox 2 ◽

Anti Inflammatory

Medicinal plants have been used as alternative therapeutic tools to alleviate inflammatory diseases. The objective of this study was to evaluate anti-inflammatory properties of Kyungheechunggan-tang- (KCT-) 01, KCT-02, and Injinchunggan-tang (IJCGT) as newly developed decoctions containing 3–11 herbs in LPS-induced macrophages. KCT-01 showed the most potent inhibitory effects on LPS-induced NO, PGE2, TNF-α, and IL-6 production among those three herbal formulas. In addition, KCT-01 significantly inhibited LPS-induced iNOS and COX-2 at protein levels and expression of iNOS, COX-2, TNF-α, and IL-6 at mRNA levels. Molecular data revealed that KCT-01 attenuated the activation of JAK/STAT signaling cascade without affecting NF-κB or AP-1 activation. In ear inflammation induced by croton oil, KCT-01 significantly reduced edema, MPO activity, expression levels of iNOS and COX-2, and STAT3 phosphorylation in ear tissues. Taken together, our findings suggest that KCT-01 can downregulate the expression of proinflammatory genes by inhibiting JAK/STAT signaling pathway under inflammatory conditions. This study provides useful data for further exploration and application of KCT-01 as a potential anti-inflammatory medicine.

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Potential role of a series of lysine-/leucine-rich antimicrobial peptide in inhibiting lipopolysaccharide-induced inflammation

Biochemical Journal ◽

10.1042/bcj20180483 ◽

2018 ◽

Vol 475 (22) ◽

pp. 3687-3706 ◽

Cited By ~ 3

Author(s):

Weibing Dong ◽

Xin Zhu ◽

Xuan Zhou ◽

Ying Yang ◽

Xin Yan ◽

...

Keyword(s):

Cell Membrane ◽

Signaling Pathway ◽

Inflammatory Responses ◽

Antimicrobial Activities ◽

Host Cells ◽

Inflammatory Factors ◽

Human Macrophage ◽

U937 Cells ◽

Wide Range ◽

Anti Inflammatory

Antimicrobial peptides have broad-spectrum killing activities against bacteria, enveloped viruses, fungi and several parasites via cell membrane permeation and exhibit primarily immunomodulatory and anti-infective functions in their interactions with host cells. However, the mechanism underlying their anti-inflammatory activity remains to be elucidated. L-K6, an analog of temporin-1CEb isolated from the skin secretion of Rana chensinensis, has demonstrated a wide range of antimicrobial activities against gram-negative and gram-positive bacteria. In this study, the potent anti-inflammatory mechanism of L-K6 and its analogs in lipopolysaccharide (LPS)-stimulated human macrophage U937 cells were evaluated. We found that L-K6 suppressed the expression of inflammatory factors by two downstream signaling components in the MyD88-dependent pathway, including the mitogen-activated protein kinases (MAPKs) and the NF (nuclear factor)-κB signaling pathway, but its analog L-K5, which had the same amino acid sequence as L-K6 but no Lys residue at the –COOH terminal, only inhibited the phosphorylation of I-κB and NF-κB. Importantly, L-K6 and L-K5 were actively taken up by U937 cells through an independent cell membrane disruption mechanism and were eventually localized to the perinuclear region. The L-K6 uptake process was mediated by endocytosis, but L-K5 was specifically taken up by U937 cells via TLR4 endocytosis. Our results demonstrated that L-K6 can neutralize LPS and diassociate LPS micelles to inhibit LPS from triggering the proinflammatory signaling pathway, and by partially inhibiting inflammatory responses by the intracellular target. However, L-K5 may mainly inhibit proinflammatory responses by intracellular reporters to modulate the NF-κB signaling pathway.

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Atomistic insight into the inhibition mechanisms of suppressors of cytokine signaling on Janus kinase

Physical Chemistry Chemical Physics ◽

10.1039/c9cp02257k ◽

2019 ◽

Vol 21 (24) ◽

pp. 12905-12915 ◽

Cited By ~ 2

Author(s):

Yaru Wei ◽

Zhiyang Zhang ◽

Nai She ◽

Xin Chen ◽

Yuan Zhao ◽

...

Keyword(s):

Signaling Pathway ◽

Negative Feedback ◽

Janus Kinase ◽

Cytokine Signaling ◽

Signal Transducer ◽

Jak Kinase ◽

Stat Signaling ◽

Suppressors Of Cytokine Signaling ◽

Insight Into

Suppressors of cytokine signaling (SOCS) act as negative feedback regulators of the Janus kinase/signal transducer (JAK–STAT) signaling pathway by inhibiting the activity of JAK kinase.

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MiR-155/GSK-3β mediates anti-inflammatory effect of Chikusetsusaponin IVa by inhibiting NF-κB signaling pathway in LPS-induced RAW264.7 cell

Scientific Reports ◽

10.1038/s41598-020-75358-1 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Yi Xin ◽

Qin Yuan ◽

Chaoqi Liu ◽

Changcheng Zhang ◽

Ding Yuan

Keyword(s):

Signaling Pathway ◽

Mouse Liver ◽

Inflammatory Responses ◽

Biological Activities ◽

Raw264.7 Cells ◽

Inflammation Model ◽

Raw264.7 Cell ◽

Anti Inflammatory ◽

Gsk 3Β ◽

Inflammatory Effect

Abstract It has been demonstrated that Chikusetsusaponin IVa (CsIVa) possesses abundant biological activities. Herein, using LPS to establish acute inflammation model of mouse liver and cell line inflammation model, we investigated whether miR-155/GSK-3β regulated NF-κB signaling pathway, and CsIVa exerted anti-inflammatory effects by regulating miR-155/GSK-3β signaling pathway. Our results showed that LPS induced high expression of miR-155 and miR-155 promoted macrophage activation through GSK-3β. In addition, CsIVa inhibited inflammatory responses in LPS-induced mouse liver and RAW264.7 cells. Furthermore, we demonstrated that CsIVa improved the inflammatory response in LPS-induced RAW264.7 cells by inhibiting miR-155, increasing GSK-3β expression, and inhibiting NF-κB signaling pathway. In conclusion, our study reveals that CsIVa suppresses LPS-triggered immune response by miR-155/GSK-3β-NF-κB signaling pathway.

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Characterization and Validation of an “Acute Aerobic Exercise Load” as a Tool to Assess Antioxidative and Anti-inflammatory Nutrition in Healthy Subjects Using a Statistically Integrated Approach in a Comprehensive Clinical Trial

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/9526725 ◽

2019 ◽

Vol 2019 ◽

pp. 1-14

Author(s):

Youjin Kim ◽

Sungkyoung Choi ◽

Sungyoung Lee ◽

Saejong Park ◽

Ji Yeon Kim ◽

...

Keyword(s):

Aerobic Exercise ◽

Healthy Subjects ◽

Inflammatory Responses ◽

Integrated Approach ◽

Nutritional Intervention ◽

Nutritional Interventions ◽

Exercise Load ◽

Pathway Network ◽

Treatment Data ◽

Anti Inflammatory

The homeostatic challenge may provide unique opportunities for quantitative assessment of the health-promoting effects of nutritional interventions in healthy individuals. Objective. The present study is aimed at characterizing and validating the use of acute aerobic exercise (AAE) on a treadmill at 60% of VO2max for 30 min, in assessing the antioxidative and anti-inflammatory effects of a nutritional intervention. In a controlled, randomized, parallel trial of Korean black raspberry (KBR) (n=24/group), fasting blood and urine samples collected before and following the AAE load at either baseline or 4-week follow-up were analyzed for biochemical markers, 1H-NMR metabolomics, and transcriptomics. The AAE was characterized using the placebo data only, and either the placebo or the treatment data were used in the validation. The AAE load generated a total of 50 correlations of 44 selected markers, based on Pearson’s correlation coefficient analysis of 105 differential markers. Subsequent mapping of selected markers onto the KEGG pathway dataset showed 127 pathways relevant to the AAE load. Of these, 54 pathways involving 18 key targets were annotated to be related to oxidative stress and inflammation. The biochemical responses were amplified with the AAE load as compared to those with no load, whereas, the metabolomic and transcriptomic responses were downgraded. Furthermore, target-pathway network analysis revealed that the AAE load provided more explanations on how KBR exerted antioxidant effects in healthy subjects (29 pathways involving 12 key targets with AAE vs. 12 pathways involving 2 key targets without AAE). This study provides considerable insight into the molecular changes incurred by AAE and furthers our understanding that AAE-induced homeostatic perturbation could magnify oxidative and inflammatory responses, thereby providing a unique opportunity to test functional foods for antioxidant and anti-inflammatory purposes in clinical settings with healthy subjects.

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Fermented ginseng attenuates lipopolysaccharide-induced inflammatory responses by activating the TLR4/MAPK signaling pathway and remediating gut barrier

Food & Function ◽

10.1039/d0fo02404j ◽

2021 ◽

Author(s):

Jingjing Fan ◽

Sitong Liu ◽

Zhiyi Ai ◽

Yiying Chen ◽

Yonghong Wang ◽

...

Keyword(s):

Signaling Pathway ◽

Inflammatory Responses ◽

Mapk Signaling ◽

Physiological Effect ◽

Mapk Signaling Pathway ◽

Gut Barrier ◽

Fermented Ginseng ◽

Anti Inflammatory

Generally, ginsenosides have the physiological effect of an anti-inflammatory immunity.

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Ethanol Extract of Lilium Bulbs Plays an Anti-Inflammatory Role by Targeting the IKKα/β-Mediated NF-κB Pathway in Macrophages

The American Journal of Chinese Medicine ◽

10.1142/s0192415x18500672 ◽

2018 ◽

Vol 46 (06) ◽

pp. 1281-1296 ◽

Cited By ~ 9

Author(s):

Sang Yun Han ◽

Young-Su Yi ◽

Seong-Gu Jeong ◽

Yo Han Hong ◽

Kang Jun Choi ◽

...

Keyword(s):

Nitric Oxide ◽

Signaling Pathway ◽

Nuclear Translocation ◽

Inflammatory Responses ◽

Inflammatory Activity ◽

Raw264.7 Cells ◽

No Production ◽

Dependent Manner ◽

Bioactive Components ◽

Anti Inflammatory

Lilium bulbs have long been used as Chinese traditional medicines to alleviate the symptoms of various human inflammatory diseases. However, mechanisms of Lilium bulb-mediated anti-inflammatory activity and the bioactive components in Lilium bulbs remain unknown. In the present study, the anti-inflammatory activity of Lilium bulbs and the underlying mechanism of action were investigated in macrophages using Lilium bulb ethanol extracts (Lb-EE). In a dose-dependent manner, Lb-EE inhibited nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated RAW264.7 cells and bone marrow-derived macrophages (BMDMs) without causing significant cytotoxicity. Lb-EE also down-regulated mRNA expression of inflammatory genes in LPS-stimulated RAW264.7 cells, which included inducuble nitric oxide synthase (iNOS), cyclooxygenase-2 (COX2), and tumor necrosis factor-[Formula: see text] (TNF-[Formula: see text]). Furthermore, Lb-EE markedly restored LPS-induced morphological changes in RAW264.7 cells to a normal morphology. HPLC analysis identified quercetin, luteolin, and kaempferol as bioactive components contained in Lb-EE. Mechanistic studies in LPS-stimulated RAW264.7 cells revealed that Lb-EE suppressed MyD88- and TRIF-induced NF-[Formula: see text]B transcriptional activation and the nuclear translocation of NF-[Formula: see text]B transcription factors. Moreover, Lb-EE inhibited IKK[Formula: see text]/[Formula: see text]-induced activation of the NF-[Formula: see text]B signaling pathway and IKK inhibition significantly reduced NO production in LPS-stimulated RAW264.7 cells. Taken together, these results suggest that Lb-EE plays an anti-inflammatory role by targeting IKK[Formula: see text]/[Formula: see text]-mediated activation of the NF-[Formula: see text]B signaling pathway during macrophage-mediated inflammatory responses.

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Activation of the Nrf2/HO-1 Pathway by Amomum villosum Extract Suppresses LPS-Induced Oxidative Stress In Vitro and Ex Vivo

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2020/2837853 ◽

2020 ◽

Vol 2020 ◽

pp. 1-13

Author(s):

Dong-Woo Lim ◽

Hee-Jin Choi ◽

Sun-Dong Park ◽

Hyuck Kim ◽

Ga-Ram Yu ◽

...

Keyword(s):

Oxidative Stress ◽

Signaling Pathway ◽

Inflammatory Responses ◽

Ethanol Extract ◽

Peritoneal Macrophages ◽

Raw 264.7 Cells ◽

Heme Oxygenase 1 ◽

Raw 264.7 ◽

Related Factor ◽

Anti Inflammatory

Despite its deleterious effects on living cells, oxidative stress plays essential roles in normal physiological processes and provides signaling molecules for cell growth, differentiation, and inflammation. Macrophages are equipped with antioxidant mechanisms to cope with intracellular ROS produced during immune response, and Nrf2 (NF-E2-related factor 2)/HO-1 (heme oxygenase-1) pathway is an attractive target due to its protective effect against ROS-induced cell damage in inflamed macrophages. We investigated the effects of ethanol extract of A. villosum (AVEE) on lipopolysaccharide- (LPS-) stimulated inflammatory responses generated via the Nrf2/HO-1 signaling pathway in murine peritoneal macrophages and RAW 264.7 cells. AVEE was found to suppress the NF-κB signaling pathway, thus, to reduce proinflammatory cytokine, nitric oxide, and prostaglandin levels in peritoneal macrophages and Raw 264.7 cells treated with LPS, and to enhance HO-1 expression by activating Nrf2 signaling. Furthermore, these anti-inflammatory effects of AVEE were diminished when cells were pretreated with SnPP (a HO-1 inhibitor). HPLC analysis revealed AVEE contained quercetin, a possible activator of the Nrf2/HO-1 pathway. These results show A. villosum ethanol extract exerts anti-inflammatory effects by activating the Nrf2/HO-1 pathway in LPS-stimulated macrophages.

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Zerumbone ameliorates behavioral impairments and neuropathology in transgenic APP/PS1 mice by suppressing MAPK signaling

10.21203/rs.2.17060/v1 ◽

2019 ◽

Author(s):

Lei Li ◽

Xiang-Hui Wu ◽

Xiao-Jing Zhao ◽

Lu Xu ◽

Cai-Long Pan ◽

...

Keyword(s):

Signaling Pathway ◽

Mapk Pathway ◽

Mapk Signaling ◽

Amyloid Deposition ◽

Microglial Cells ◽

Therapeutic Effects ◽

Inflammatory Phenotype ◽

Β Amyloid ◽

Anti Inflammatory ◽

Behavioral Impairments

Abstract Background: Alzheimer’s disease (AD) is a major clinical problem, but there is a distinct lack of effective therapeutic drugs for this disease. We investigated the potential therapeutic effects of zerumbone, a subtropical ginger sesquiterpene, in transgenic APP/PS1 mice, rodent models of AD which exhibit cerebral amyloidosis and neuroinflammation. Methods: The N9 microglial cell line and primary microglial cells were cultured to investigate the effects of zerumbone on microglia. APP/PS1 mice were treated with zerumbone, and non-cognitive and cognitive behavioral impairments were assessed and compared between the treatment and control groups. The animals were then sacrificed, and tissues were collected for further analysis. The potential therapeutic mechanism of zerumbone and the signaling pathways involved were also investigated. Results: Zerumbone suppressed the expression of pro-inflammatory cytokines and induced a switch in microglial phenotype from the classic inflammatory phenotype to the alternative anti-inflammatory phenotype by inhibiting the mitogen-activated protein kinase (MAPK)/nuclear factor-kappa B signaling pathway in vitro. After a treatment period of 20 days, zerumbone significantly ameliorated deficits in both non-cognitive and cognitive behaviors in transgenic APP/PS1 mice. Zerumbone significantly reduced β-amyloid deposition and attenuated pro-inflammatory microglial activation in the cortex and hippocampus. Interestingly, zerumbone significantly increased the proportion of anti-inflammatory microglia among all activated microglia, potentially contributing to reduced β-amyloid deposition by enhancing phagocytosis. Meanwhile, zerumbone also reduced the expression of key molecules of the MAPK pathway, such as p38 and extracellular signal-regulated kinase. Conclusions: Overall, zerumbone effectively ameliorated behavioral impairments, attenuated neuroinflammation, and reduced β-amyloid deposition in transgenic APP/PS1 mice. Zerumbone exhibited substantial anti-inflammatory activity in microglial cells and induced a phenotypic switch in microglia from the pro-inflammatory phenotype to the anti-inflammatory phenotype by inhibiting the MAPK signaling pathway, which may play an important role in its neuroprotective effects. Our results suggest that zerumbone is a potential therapeutic agent for human neuroinflammatory and neurodegenerative diseases, in particular AD.

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