scholarly journals Silibinin Attenuates Silica Dioxide Nanoparticles-Induced Inflammation by Suppressing TXNIP/MAPKs/AP-1 Signaling

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 678 ◽  
Author(s):  
Je-Oh Lim ◽  
Na-Rae Shin ◽  
Yun-Soo Seo ◽  
Hyeon-Hwa Nam ◽  
Je-Won Ko ◽  
...  
Keyword(s):  
Airway Inflammation ◽  
Inflammatory Responses ◽  
Underlying Mechanism ◽  
Airway Epithelial Cells ◽  
Protective Effects ◽  
Proinflammatory Mediators ◽  
Cell Counts ◽  
Silica Dioxide

Silica dioxide nanoparticles (SiONPs) have been applied to several fields, such as drug delivery and gene therapy. However, SiONPs are a constituent of fine dust and can induce excessive inflammatory responses in the lungs via the airways. Silibinin, a major component of silymarin, has been known for its anti-oxidant and anti-inflammatory effects. In the present study, we explored the protective effects of silibinin against SiONPs-induced airway inflammation and explored its underlying mechanism of action, focusing on thioredoxin-interacting protein (TXNIP)/mitogen-activated protein kinases (MAPKs) in vitro and in vivo. In SiONPs-stimulated NCI-H292 airway epithelial cells, silibinin treatment effectively suppressed the elevation of the mRNA expression of tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and IL-1β, which was accompanied by the reduction in the expression of TXNIP, MAPKs, and activator protein-1 (AP-1). In SiONPs-treated mice, silibinin administration inhibited the increase in inflammatory cell counts and proinflammatory mediators, and it alleviated airway inflammation by SiONPs exposure. In addition, silibinin administration effectively suppressed the elevation of TXNIP/MAPKs/AP-1 signaling by SiONPs exposure. Taken together, silibinin effectively inhibited SiONPs-induced inflammatory responses, and this effect was closely related to the inhibition of TXNIP/MAPK/AP-1 signaling. These results suggested that silibinin might be useful for reducing pulmonary inflammation induced by SiONPs.

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 Exosomal miR-25-3p from mesenchymal stem cells alleviates myocardial infarction by targeting pro-apoptotic proteins and EZH2

2020 ◽  
Vol 11 (5) ◽  
Author(s):  
Yi Peng ◽  
Ji-Ling Zhao ◽  
Zhi-Yong Peng ◽  
Wei-Fang Xu ◽  
Guo-Long Yu
Keyword(s):  
Myocardial Infarction ◽  
Inflammatory Responses ◽  
Luciferase Assay ◽  
Protective Effects ◽  
Functional Studies ◽  
Protein Levels ◽  
Cardioprotective Effects ◽  
Apoptotic Proteins

Abstract Mesenchymal stem cell (MSC) therapy is a promising approach against myocardial infarction (MI). Studies have demonstrated that MSCs can communicate with other cells by secreting exosomes. In the present study, we aimed to identify exosomal microRNAs that might contribute to MSC-mediated cardioprotective effects. Primary cardiomyocytes were deprived of oxygen and glucose to mimic MI in vitro. For the animal model of MI, the left anterior descending artery was ligated for 1 h, followed by reperfusion for 12 h. MSC-derived exosomes were used to treat primary cardiomyocytes or mice. Cardioprotection-related microRNAs were determined, followed by target gene identification and functional studies with quantitative PCR, western blotting, MTT assay, flow cytometry assay, chromatin immunoprecipitation and dual-luciferase assay. We found that MSC co-culture reduced OGD-induced cardiomyocyte apoptosis and inflammatory responses. Cardioprotection was also observed upon treatment with MSC-derived exosomes in vitro and in vivo. In line with this, exosome uptake led to a significant increase in miR-25-3p in cardiomyocytes. Depletion of miR-25-3p in MSCs abolished the protective effects of exosomes. Mechanistically, miR-25-3p directly targeted the pro-apoptotic genes FASL and PTEN and reduced their protein levels. Moreover, miR-25-3p decreased the levels of EZH2 and H3K27me3, leading to derepression of the cardioprotective gene eNOS as well as the anti-inflammatory gene SOCS3. Inhibition of EZH2 or overexpression of miR-25-3p in cardiomyocytes was sufficient to confer cardioprotective effects in vitro and in vivo. We concluded that exosomal miR-25-3p from MSCs alleviated MI by targeting pro-apoptotic proteins and EZH2.

scholarly journals Canagliflozin Attenuates Lipotoxicity in Cardiomyocytes and Protects Diabetic Mouse Hearts by Targeting the mTOR/HIF-1α Pathway

2020 ◽  
Author(s):  
Pengbo Sun ◽  
Yipei Ding ◽  
Jingyi Luo ◽  
Jin Zhong ◽  
Weidong Xie
Keyword(s):  
Inflammatory Responses ◽  
Mammalian Target Of Rapamycin ◽  
Hypoxia Inducible Factor ◽  
Diabetic Mouse ◽  
Protective Effects ◽  
Pharmacological Mechanism ◽  
Beneficial Effects ◽  
Mtor Phosphorylation

Abstract BackgroundLipotoxicity plays an important role in the development of diabetic cardiomyopathy and heart failure (HF). Canagliflozin (CAN), a marketed sodium-glucose co-transporter 2 inhibitor, has significant beneficial effects on HF. However, the potential pharmacological mechanism is still unknown.MethodsIn this study, we evaluated the protective effects and mechanism of CAN in the hearts of a C57BL/6J diabetic mouse model induced by a high-fat diet/streptozotocin (HFD/STZ) for 12 weeks in vivo and using HL-1 cells (a type of mouse cardiomyocyte line) induced by palmitic acid (PA) in vitro.ResultsCAN could significantly alleviate lipid accumulation and inflammatory responses in the hearts of the HFD/STZ-induced diabetic mice. Furthermore, CAN significantly attenuated the inflammatory injury induced by PA in the HL-1 cells. In addition, CAN bound to the mammalian target of rapamycin (mTOR) and significantly inhibited mTOR phosphorylation and hypoxia inducible factor-1α (HIF-1α) expression.ConclusionCAN attenuated lipotoxicity in cardiomyocytes and protected diabetic mouse hearts by targeting the mTOR/HIF-1α pathway.

scholarly journals FSTL1 aggravates OVA-induced allergic airway inflammation by activating NLRP3 inflammasome

2020 ◽  
Author(s):  
Yan Wang ◽  
Tian Liu ◽  
Jun-fei Wang ◽  
Bao-yi Liu ◽  
Jin-xiang Wu ◽  
...  
Keyword(s):  
Airway Inflammation ◽  
Nlrp3 Inflammasome ◽  
Allergic Airway Inflammation ◽  
Experimental Treatment ◽  
Underlying Mechanism ◽  
Whole Body ◽  
Control Group ◽  
Asthmatic Patients

Abstract Background Asthma is a common respiratory disease characterized by chronic airway inflammation. As a novel inflammatory mediator, follistatin-like protein 1 (FSTL1) can activate immune reaction, suggesting that it may contribute to inflammatory disorders such as asthma. Besides, there are growing evidences that nucleotide-binding domain and leucine-rich repeat protein 3 (NLRP3) / Interleukin (IL)-1β axis participates in asthma. In this study, we investigated the role of FSTL1 in allergic airway inflammation and its underlying mechanism of activating NLRP3 inflammasome. Methods Circulating FSTL1 and IL-1β levels were quantified in serum of asthmatic patients and controls. Whole-body ablation Fstl1 heterozygous mice (Fstl1 +/- ) and control group were assessed after the experimental treatment. The effects of FSTL1 on NLRP3 inflammasome were also tested in primary macrophages of mice in vitro. Results The concentration of FSTL1 and IL-1β in serum of asthmatic patients were elevated compared with controls and were positively correlated. FSTL1 deficiency ameliorated infiltration of inflammatory cells,corresponding pathological changes,cytokine responses (IL-1β, IL-5,IL-13), mucous hypersecretion and hyper-responsiveness of airway after Ovalbumin (OVA) exposure in the mouse model. Additionally, inhibition of NLRP3 with MCC950 attenuated FSTL1-induced activation of NLRP3 inflammasome and airway inflammation in vivo and vitro. Conclusions Our data showed that FSTL1 played an important role in allergic airway inflammation by activating NLRP3 inflammasome, providing the possibility that FSTL1 could be applied as a therapeutic strategy on asthma.

scholarly journals Blockade of Airway Inflammation by Kaempferol via Disturbing Tyk-STAT Signaling in Airway Epithelial Cells and in Asthmatic Mice

2013 ◽  
Vol 2013 ◽  
pp. 1-13 ◽  
Author(s):  
Ju-Hyun Gong ◽  
Daekeun Shin ◽  
Seon-Young Han ◽  
Sin-Hye Park ◽  
Min-Kyung Kang ◽  
...  
Keyword(s):  
Oral Administration ◽  
Airway Inflammation ◽  
Airway Epithelium ◽  
Airway Epithelial Cells ◽  
Airway Epithelial ◽  
Bronchial Inflammation ◽  
Stat Signaling ◽  
Socs3 Expression

Asthma is characterized by bronchial inflammation causing increased airway hyperresponsiveness and eosinophilia. The interaction between airway epithelium and inflammatory mediators plays a key role in the asthmatic pathogenesis. Thein vitrostudy elucidated inhibitory effects of kaempferol, a flavonoid found in apples and many berries, on inflammation in human airway epithelial BEAS-2B cells. Nontoxic kaempferol at ≤20 μM suppressed the LPS-induced IL-8 production through the TLR4 activation, inhibiting eotaxin-1 induction. Thein vivostudy explored the demoting effects of kaempferol on asthmatic inflammation in BALB/c mice sensitized with ovalbumin (OVA). Mouse macrophage inflammatory protein-2 production and CXCR2 expression were upregulated in OVA-challenged mice, which was attenuated by oral administration of ≥10 mg/kg kaempferol. Kaempferol allayed the airway tissue levels of eotaxin-1 and eotaxin receptor CCR3 enhanced by OVA challenge. This study further explored the blockade of Tyk-STAT signaling by kaempferol in both LPS-stimulated BEAS-2B cells and OVA-challenged mice. LPS activated Tyk2 responsible for eotaxin-1 induction, while kaempferol dose-dependently inhibited LPS- or IL-8-inflamed Tyk2 activation. Similar inhibition of Tyk2 activation by kaempferol was observed in OVA-induced mice. Additionally, LPS stimulated the activation of STAT1/3 signaling concomitant with downregulated expression of Tyk-inhibiting SOCS3. In contrast, kaempferol encumbered STAT1/3 signaling with restoration of SOCS3 expression. Consistently, oral administration of kaempferol blocked STAT3 transactivation elevated by OVA challenge. These results demonstrate that kaempferol alleviated airway inflammation through modulating Tyk2-STAT1/3 signaling responsive to IL-8 in endotoxin-exposed airway epithelium and in asthmatic mice. Therefore, kaempferol may be a therapeutic agent targeting asthmatic diseases.

scholarly journals The Protective Effects of Melittin on Propionibacterium acnes –Induced Inflammatory Responses In Vitro and In Vivo

2014 ◽  
Vol 134 (7) ◽  
pp. 1922-1930 ◽  
Author(s):  
Woo-Ram Lee ◽  
Kyung-Hyun Kim ◽  
Hyun-Jin An ◽  
Jung-yeon Kim ◽  
Young-Chae Chang ◽  
...  
Keyword(s):  
Propionibacterium Acnes ◽  
Inflammatory Responses ◽  
Protective Effects

scholarly journals Anti-Inflammatory and Immunosuppressive Effects of the A2AAdenosine Receptor

2011 ◽  
Vol 11 ◽  
pp. 320-339 ◽  
Author(s):  
Gillian R. Milne ◽  
Timothy M. Palmer
Keyword(s):  
Molecular Mechanisms ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Current Evidence ◽  
Receptor Subtypes ◽  
Protective Effects ◽  
Stress Injury ◽  
Anti Inflammatory

The production of adenosine represents a critical endogenous mechanism for regulating immune and inflammatory responses during conditions of stress, injury, or infection. Adenosine exerts predominantly protective effects through activation of four 7-transmembrane receptor subtypes termed A1, A2A, A2B, and A3, of which the A2Aadenosine receptor (A2AAR) is recognised as a major mediator of anti-inflammatory responses. The A2AAR is widely expressed on cells of the immune system and numerousin vitrostudies have identified its role in suppressing key stages of the inflammatory process, including leukocyte recruitment, phagocytosis, cytokine production, and immune cell proliferation. The majority of actions produced by A2AAR activation appear to be mediated by cAMP, but downstream events have not yet been well characterised. In this article, we review the current evidence for the anti-inflammatory effects of the A2AAR in different cell types and discuss possible molecular mechanisms mediating these effects, including the potential for generalised suppression of inflammatory gene expression through inhibition of the NF-κB and JAK/STAT proinflammatory signalling pathways. We also evaluate findings fromin vivostudies investigating the role of the A2AAR in different tissues in animal models of inflammatory disease and briefly discuss the potential for development of selective A2AAR agonists for use in the clinic to treat specific inflammatory conditions.

scholarly journals Vancomycin Acts Synergistically with Gentamicin against Penicillin-Resistant Pneumococci by Increasing the Intracellular Penetration of Gentamicin

2003 ◽  
Vol 47 (1) ◽  
pp. 144-147 ◽  
Author(s):  
P. Cottagnoud ◽  
M. Cottagnoud ◽  
M. G. Täuber
Keyword(s):  
Viable Cell ◽  
Underlying Mechanism ◽  
Intracellular Concentration ◽  
Combination Regimen ◽  
Cell Counts ◽  
Short Period ◽  
Before And After ◽  
Gentamicin Concentration

ABSTRACT Vancomycin and gentamicin act synergistically against penicillin-resistant pneumococci in vitro and in experimental rabbit meningitis. The aim of the present study was to investigate the underlying mechanism of this synergism. The intracellular concentration of gentamicin was measured by using the following experimental setting. Bacterial cultures were incubated with either gentamicin alone or gentamicin plus vancomycin for a short period (15 min). The gentamicin concentration was determined before and after grinding of the cultures by using the COBAS INTEGRA fluorescence polarization system (Roche). The grinding efficacies ranged between 44 and 54%, as determined by viable cell counts. In the combination regimen the intracellular concentration of gentamicin increased to 186% compared to that achieved with gentamicin monotherapy. These data suggest that the synergy observed in vivo and in vitro is based on an increased intracellular penetration of the aminoglycoside, probably due to the effect of vancomycin on the permeability of the cell wall.

Diesel exhaust particulate-induced activation of Stat3 requires activities of EGFR and Src in airway epithelial cells

2007 ◽  
Vol 292 (2) ◽  
pp. L422-L429 ◽  
Author(s):  
Dongsun Cao ◽  
Tamara L. Tal ◽  
Lee M. Graves ◽  
Ian Gilmour ◽  
William Linak ◽  
...  
Keyword(s):  
Growth Factor ◽  
Diesel Exhaust ◽  
Inflammatory Responses ◽  
Critical Role ◽  
Airway Epithelial Cells ◽  
Diesel Exhaust Particles ◽  
Diesel Exhaust Particulate ◽  
Stat3 Phosphorylation

In vivo exposure to diesel exhaust particles (DEP) elicits acute inflammatory responses in the lung characterized by inflammatory cell influx and elevated expression of mediators such as cytokines and chemokines. Signal transducers and activators of transcription (STAT) proteins are a family of cytoplasmic transcription factors that are key transducers of signaling in response to cytokine and growth factor stimulation. One member of the STAT family, Stat3, has been implicated as a regulator of inflammation but has not been studied in regard to DEP exposure. The results of this study show that DEP induces Stat3 phosphorylation as early as 1 h following stimulation and that phosphorylated Stat3 translocates into the nucleus. Inhibition of epidermal growth factor receptor (EGFR) and Src activities by the inhibitors PD-153035 and PP2, respectively, abolished the activation of Stat3 by DEP, suggesting that Stat3 activation by DEP requires EGFR and Src kinase activation. The present study suggests that oxidative stress induced by DEP may play a critical role in activating EGFR signaling, as evidenced by the fact that pretreatment with antioxidant prevented the activation of EGFR and Stat3. These findings demonstrate that DEP inhalation can activate proinflammatory Stat3 signaling in vitro.

Carpesium macrocephalum Attenuates Lipopolysaccharide-Induced Inflammation in Macrophages by Regulating the NF-κB/IκB-α, Akt, and STAT Signaling Pathways

2013 ◽  
Vol 41 (04) ◽  
pp. 927-943 ◽  
Author(s):  
Sushruta Koppula ◽  
Wan-Jae Kim ◽  
Jun Jiang ◽  
Do-Wan Shim ◽  
Na-Hyun Oh ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
In Vivo Studies ◽  
Raw264.7 Cells ◽  
Traditional Use ◽  
Necrosis Factor Alpha ◽  
Proinflammatory Mediators ◽  
Raw264.7 Macrophages ◽  
Anti Inflammatory

Carpesium macrocephalum (CM) Fr. et Sav. (Compositae) has been used in Chinese folk medicine as an analgesic, hemostatic, antipyretic, and to suppress inflammatory conditions. In the present study we aimed to provide scientific evidence for the anti-inflammatory properties of CM extract and evaluate the intrinsic mechanisms involved in both in vitro and in vivo experimental models. In in vitro findings, CM significantly inhibited the LPS-stimulated release of proinflammatory mediators such as nitric oxide, tumor necrosis factor-alpha, prostaglandin E2, and interleukin-6 in RAW264.7 macrophages in a concentration-dependent fashion. The attenuation of inflammatory responses in LPS-activated RAW264.7 cells by CM was closely associated with the suppression of nuclear factor-kappa B (NF-κB) phosphorylation, IκB-α degradation, and phosphorylation of Akt. CM treatment also attenuated the phosphorylation of STAT through TRIF dependent pathways in LPS-activated RAW264.7 cells. In vivo studies revealed that CM extract concentration dependently suppressed the acetic acid-induced vascular permeability in mice. Considering the data obtained regulation of multiple signaling mechanisms involving TRIF and Akt/NF-κB pathways might be responsible for the potent anti-inflammatory action of CM, substantiating its traditional use in inflammatory diseases.

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