scholarly journals Morphine promotes microglial activation by upregulating the EGFR/ERK signaling pathway

PLoS ONE ◽  
2021 ◽  
Vol 16 (9) ◽  
pp. e0256870
Author(s):  
Yaqiong Yang ◽  
Yu Sun ◽  
Rong Hu ◽  
Jia Yan ◽  
Ziheng Wang ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Proinflammatory Cytokines ◽  
Microglial Activation ◽  
Morphine Tolerance ◽  
Erk Signaling ◽  
Dependent Manner ◽  
Migration Ability ◽  
Necrosis Factor Alpha ◽  
Egfr Signaling Pathway ◽  
Egfr Expression

Although they represent the cornerstone of analgesic therapy, opioids, such as morphine, are limited in efficacy by drug tolerance, hyperalgesia and other side effects. Activation of microglia and the consequent production of proinflammatory cytokines play a key pathogenic role in morphine tolerance, but the exact mechanisms are not well understood. This study aimed to investigate the regulatory mechanism of epidermal growth factor receptor (EGFR) on microglial activation induced by morphine in mouse microglial BV-2 cells. In this research, BV-2 cells were stimulated with morphine or pretreated with AG1478 (an inhibitor of EGFR). Expression levels of cluster of differentiation molecule 11b (CD11b), EGFR, and phospho-EGFR were detected by immunofluorescence staining. Cell signaling was assayed by Western blot. The migration ability of BV-2 cells was tested by Transwell assay. The production of interleukin-1beta (IL-1β) and tumor necrosis factor-alpha (TNF-α) in the cell supernatant was determined by ELISA. We observed that the expression of CD11b induced by morphine was increased in a dose- and time- dependent manner in BV-2 cells. Phosphorylation levels of EGFR and ERK1/2, migration of BV-2 cells, and production of IL-1β and TNFα were markedly enhanced by morphine treatment. The activation, migration, and production of proinflammatory cytokines in BV-2 cells were inhibited by blocking the EGFR signaling pathway with AG1478. The present study demonstrated that the EGFR/ERK signaling pathway may represent a novel pharmacological strategy to suppress morphine tolerance through attenuation of microglial activation.

scholarly journals Reactive oxygen species rescue regeneration after silencing the MAPK–ERK signaling pathway in Schmidtea mediterranea

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
V. Jaenen ◽  
S. Fraguas ◽  
K. Bijnens ◽  
M. Heleven ◽  
T. Artois ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Signaling Pathway ◽  
Reactive Oxygen ◽  
Light Therapy ◽  
Erk Signaling ◽  
Model Organisms ◽  
Ros Production ◽  
Oxygen Species ◽  
Planarian Regeneration ◽  
Egfr Signaling Pathway

AbstractDespite extensive research on molecular pathways controlling the process of regeneration in model organisms, little is known about the actual initiation signals necessary to induce regeneration. Recently, the activation of ERK signaling has been shown to be required to initiate regeneration in planarians. However, how ERK signaling is activated remains unknown. Reactive Oxygen Species (ROS) are well-known early signals necessary for regeneration in several models, including planarians. Still, the probable interplay between ROS and MAPK/ERK has not yet been described. Here, by interfering with major mediators (ROS, EGFR and MAPK/ERK), we were able to identify wound-induced ROS, and specifically H2O2, as upstream cues in the activation of regeneration. Our data demonstrate new relationships between regeneration-related ROS production and MAPK/ERK activation at the earliest regeneration stages, as well as the involvement of the EGFR-signaling pathway. Our results suggest that (1) ROS and/or H2O2 have the potential to rescue regeneration after MEK-inhibition, either by H2O2-treatment or light therapy, (2) ROS and/or H2O2 are required for the activation of MAPK/ERK signaling pathway, (3) the EGFR pathway can mediate ROS production and the activation of MAPK/ERK during planarian regeneration.

scholarly journals Ambient Particulate Matter Induces Vascular Smooth Muscle Cell Phenotypic Changes via NOX1/ROS/NF-κB Dependent and Independent Pathways: Protective Effects of Polyphenols

Antioxidants ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 782
Author(s):  
Chia-Chi Ho ◽  
Yu-Cheng Chen ◽  
Ming-Hsien Tsai ◽  
Hui-Ti Tsai ◽  
Chen-Yi Weng ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Particulate Matter ◽  
Vascular Smooth Muscle ◽  
Signaling Pathway ◽  
Proinflammatory Cytokines ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Cytokine Secretion ◽  
Ambient Particulate Matter ◽  
Migration Ability ◽  
Cytokines Secretion

Epidemiological studies have demonstrated an association between ambient particulate matter (PM) exposure and vascular diseases. Here, we observed that treatment with ambient PM increased cell migration ability in vascular smooth muscle cells (VSMCs) and pulmonary arterial SMCs (PASMCs). These results suggest that VSMCs and PASMCs transitioned from a differentiated to a synthetic phenotype after PM exposure. Furthermore, treatment with PM increased intracellular reactive oxygen species (ROS), activated the NF-κB signaling pathway, and increased the expression of proinflammatory cytokines in VSMCs. Using specific inhibitors, we demonstrated that PM increased the migration ability of VSMCs via the nicotinamide–adenine dinucleotide phosphate (NADPH) oxidase 1 (NOX1)/ROS-dependent NF-κB signaling pathway, which also partially involved in the induction of proinflammatory cytokines. Finally, we investigated whether nature polyphenolic compounds prevent PM-induced migration and proinflammatory cytokines secretion in VSMCs. Curcumin, resveratrol, and gallic acid prevented PM2.5-induced migration via the ROS-dependent NF-κB signaling pathway. However, honokiol did not prevent PM2.5-induced migration or activation of the ROS-dependent NF-κB signaling pathway. On the other hand, all polyphenols prevented PM2.5-induced cytokines secretion. These data indicated that polyphenols prevented PM-induced migration and cytokine secretion via blocking the ROS-dependent NF-κB signaling pathway in VSMCs. However, other mechanisms may also contribute to PM-induced cytokine secretion.

Scutellarin Attenuates Human-Neutrophil-Elastase-Induced Mucus Production by Inhibiting the PKC-ERK Signaling Pathway in Vitro and in Vivo

2011 ◽  
Vol 39 (06) ◽  
pp. 1193-1206 ◽  
Author(s):  
De-Peng Jiang ◽  
Qi Li ◽  
Jie Yang ◽  
Juliy M. Perelman ◽  
Victor P. Kolosov ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Neutrophil Elastase ◽  
Human Neutrophil ◽  
Erk Signaling ◽  
Control Group ◽  
Human Neutrophil Elastase ◽  
Dependent Manner ◽  
Mucus Production

The aim of this study was to investigate the influence of scutellarin on mucus production induced by human neutrophil elastase (HNE) and the possible in vitro and in vivo mechanisms. To this purpose, cells were incubated with saline, scutellarin or gefitinib for 60 min and exposed to 0.1 μM HNE for 24 h. After being pretreated respectively with saline, scutellarin or gefitinib, rats were challenged intratracheally with HNE by means of nebulization for 30 days. The expression of mucin (MUC) 5AC, protein kinase C (PKC), and extracellular signal-regulated kinase 1/2 (ERK1/2) was assessed by ELISA, RT-PCR or Western blotting. The results showed that scutellarin inhibited MUC5AC mRNA and protein expressions induced by HNE in a concentration-dependent manner in vitro. In the in vivo model, scutellarin significantly attenuated MUC5AC mRNA expression and goblet cell hyperplasia in rats treated with HNE for 30 days, as well as decreased the phosporylation of PKC and ERK1/2 compared to the HNE control group. Therefore, our study showed that scutellarin could prevent mucus hypersecretion by inhibiting the PKC-ERK signaling pathway. Inhalation scutellarin may be valuable in the treatment of chronic inflammatory lung disease.

scholarly journals Proinflammatory Responses of 1-Nitropyrene against RAW264.7 Macrophages through Akt Phosphorylation and NF-κB Pathways

Toxics ◽  
2021 ◽  
Vol 9 (11) ◽  
pp. 276
Author(s):  
Ping-Kun Tsai ◽  
Shih-Pin Chen ◽  
Rosa Huang-Liu ◽  
Chun-Jung Chen ◽  
Wen-Ying Chen ◽  
...  
Keyword(s):  
Proinflammatory Cytokines ◽  
Public Health Problem ◽  
Air Pollutant ◽  
Dependent Manner ◽  
Proinflammatory Response ◽  
Concentration Dependent Manner ◽  
Necrosis Factor Alpha ◽  
Akt Phosphorylation ◽  
Proinflammatory Mediators ◽  
Raw264.7 Macrophages

Air pollution is a major environmental and public health problem worldwide. A nitro-polycyclic aromatic hydrocarbon and the most abundant air pollutant in diesel engine exhaust, 1-nitropyrene (1-NP), is caused by the incomplete combustion of carbonaceous organic substances. Macrophages are effector cells of the innate immune cells that provide resistance in the peripheral tissue. The overactivation of macrophages results in inflammation. The generation of proinflammatory cytokines, such as interleukin (IL)-1β, IL-6, and tumour necrosis factor alpha, is induced by 1-NP in a concentration-dependent manner in macrophages. In this study, the production of proinflammatory mediators, such as nitrogen oxide and prostaglandin E2, was induced by 1-NP in a concentration-dependent manner through the expression of iNOS and COX2. The generation of proinflammatory cytokines, iNOS, and COX2 was induced by 1-NP through nuclear factor (NF)-κB p65 phosphorylation and the degradation of its upstream factor, IκB. Finally, Akt phosphorylation was induced by 1-NP in a concentration-dependent manner. These findings suggest that 1-NP exhibits a proinflammatory response through the NF-κB pathway activation due to Akt phosphorylation.

scholarly journals Giardia duodenalis Induces Proinflammatory Cytokine Production in Mouse Macrophages via TLR9-Mediated p38 and ERK Signaling Pathways

2021 ◽  
Vol 9 ◽  
Author(s):  
Xudong Pu ◽  
Xin Li ◽  
Lili Cao ◽  
Kaiming Yue ◽  
Panpan Zhao ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Signaling Pathways ◽  
Proinflammatory Cytokines ◽  
Giardia Duodenalis ◽  
Erk Signaling ◽  
Enzyme Linked Immunosorbent Assay ◽  
Dependent Manner ◽  
Mouse Macrophages ◽  
Host Inflammatory Response

Giardia duodenalis, also known as Giardia lamblia or Giardia intestinalis, is an important opportunistic, pathogenic, zoonotic, protozoan parasite that infects the small intestines of humans and animals, causing giardiasis. Several studies have demonstrated that innate immunity-associated Toll-like receptors (TLRs) are critical for the elimination of G. duodenalis; however, whether TLR9 has a role in innate immune responses against Giardia infection remains unknown. In the present study, various methods, including reverse transcriptase–quantitative polymerase chain reaction, Western blot, enzyme-linked immunosorbent assay, immunofluorescence, inhibitor assays, and small-interfering RNA interference, were utilized to probe the role of TLR9 in mouse macrophage-mediated defenses against G. lamblia virus (GLV)–free or GLV-containing Giardia trophozoites. The results revealed that in G. duodenalis–stimulated mouse macrophages, the secretion of proinflammatory cytokines, including interleukin 6 (IL-6), tumor necrosis factor α (TNF-α), and IL-12 p40, was enhanced, concomitant with the significant activation of TLR9, whereas silencing TLR9 attenuated the host inflammatory response. Notably, the presence of GLV exacerbated the secretion of host proinflammatory cytokines. Moreover, G. duodenalis stimulation activated multiple signaling pathways, including the nuclear factor κB p65 (NF-κB p65), p38, ERK, and AKT pathways, the latter three in a TLR9-dependent manner. Additionally, inhibiting the p38 or ERK pathway downregulated the G. duodenalis–induced inflammatory response, whereas AKT inhibition aggravated this process. Taken together, these results indicated that G. duodenalis may induce the secretion of proinflammatory cytokines by activating the p38 and ERK signaling pathways in a TLR9-dependent manner in mouse macrophages. Our in vitro findings on the mechanism underlying the TLR9-mediated host inflammatory response may help establish the foundation for an in-depth investigation of the role of TLR9 in the pathogenicity of G. duodenalis.

scholarly journals KIF15 Promotes Progression of Castration Resistant Prostate Cancer by Activating EGFR Signaling Pathway

2021 ◽  
Vol 11 ◽  
Author(s):  
Lin Gao ◽  
Ru Zhao ◽  
Junmei Liu ◽  
Wenbo Zhang ◽  
Feifei Sun ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Signaling Pathway ◽  
Growth Factor Receptor ◽  
Clinical Problem ◽  
Mitogen Activated Protein Kinase ◽  
Dependent Manner ◽  
Castration Resistant Prostate Cancer ◽  
Egfr Signaling ◽  
Castration Resistant ◽  
Egfr Signaling Pathway

Castration-resistant prostate cancer (CRPC) continues to be a major clinical problem and its underlying mechanisms are still not fully understood. The epidermal growth factor receptor (EGFR) activation is an important event that regulates mitogenic signaling. EGFR signaling plays an important role in the transition from androgen dependence to castration-resistant state in prostate cancer (PCa). Kinesin family member 15 (KIF15) has been suggested to be overexpressed in multiple malignancies. Here, we demonstrate that KIF15 expression is elevated in CRPC. We show that KIF15 contributes to CRPC progression by enhancing the EGFR signaling pathway, which includes complex network intermediates such as mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/AKT pathways. In CRPC tumors, increased expression of KIF15 is positively correlated with EGFR protein level. KIF15 binds to EGFR, and prevents EGFR proteins from degradation in a Cdc42-dependent manner. These findings highlight the key role of KIF15 in the development of CRPC and rationalize KIF15 as a potential therapeutic target.

scholarly journals Suppression of 4.1R enhances the potency of NKG2D-CAR T cells against pancreatic carcinoma via activating ERK signaling pathway

Oncogenesis ◽  
2021 ◽  
Vol 10 (9) ◽  
Author(s):  
Yaoxin Gao ◽  
Haizhen Lin ◽  
Dandan Guo ◽  
Sijia Cheng ◽  
Ying Zhou ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Pancreatic Carcinoma ◽  
Signaling Pathway ◽  
Xenograft Model ◽  
Erk Signaling ◽  
Dependent Manner ◽  
Car T Cells ◽  
Car T ◽  
Anti Tumor Activity

AbstractPancreatic carcinoma (PC) is one of the most common malignancies. Chimeric antigen receptor (CAR)-modified T cells has achieved remarkable efficacy in the treatment of hematological malignancies. However, lack of tumor-specific targets and the existence of inhibitory factors limit the function of CAR T cells when treating solid tumors. 4.1R has been reported to suppress the anti-tumor activity of T cell responses. In this study, we investigated the anti-tumor activity of 4.1R deletion in natural killer group 2D (NKG2D)-CAR T cells against PC. The CAR T cells were obtained by transfecting T cells with lentiviral vector carrying NKG2D-CAR, NC-NKG2D-CAR, or KD2-NKG2D-CAR. In vitro, NKG2D-CAR T cells showed higher cytotoxicity than Mock T cells. However, compared to NKG2D-CAR T cells, furtherly higher cytotoxicity against PC cells in a dose-dependent manner was found in KD2-NKG2D-CAR T cells. In addition, the proliferation rate and cytotoxic activity of KD2-NKG2D-CAR T cells were significantly higher than those of NKG2D-CAR T cells. Besides, the inhibitory receptors PD-1 and TIM-3 were expressed in lower level on KD2-NKG2D-CAR T cells. In vivo, KD2-NKG2D-CAR T cells suppressed tumor growth more effectively in a xenograft model compared to NKG2D-CAR T cells. Mechanistically, 4.1R regulated CAR T cell function via activating ERK signaling pathway. Therefore, the study provides a new idea to enhance the anti-tumor efficiency of CAR T therapy.

Scutellarin combined with Lidocaine: a new combination of anti-glioma drugs

2021 ◽  
Author(s):  
Xiu-Ying He ◽  
Xiao-Ming Zhao ◽  
Qing-Jie Xia ◽  
Lei Zhou ◽  
Ting-Hua Wang
Keyword(s):  
Glioma Cells ◽  
Cell Counting ◽  
New Combination ◽  
Dependent Manner ◽  
Human Glioma ◽  
Human Glioma Cells ◽  
Migration Ability ◽  
Egfr Expression ◽  
And Migration ◽  
Proliferation And Migration

Abstract Background Glioma is the most common primary intracranial tumors. Although great achievements in the treatment have been made, the efficacy is still not satisfactory, which imposes a great burden on patients and society. Therefore, the exploration of new and effective anti-glioma drugs is urgent. Methods Human glioma cells U251 and LN229 cells were included in the study. The proliferation was detected by cell counting kit-8, plate clone formation assay, EdU incorporation assay and xCELLigence real-time cell analyzer. The cell apoptosis was evaluated by TUNEL assay and flow cytometry. The transwell assay was for assessing the migration. Moreover, Western blot was performed to detect the protein level of Epidermal growth factor receptor (EGFR). Results In present study, we found that Scutellarin(SCU) and Lidocaine suppressed the proliferation and migration, and induced the apoptosis of human glioma cells, including U251 and LN229 cells, in a dose-dependent manner. Moreover, the combination of Scutellarin and Lidocaine further restrained the proliferation and migration ability of U251 and LN229 cells, while induced their apoptosis. Mechanistically, the effect of Scutellarin and its combination with Lidocaine on glioma cells was partially associated with the downregulation of EGFR protein. Conclusions Scutellarin and Lidocaine exert a synergistic effect on suppressing the proliferation and migration and induce the apoptosis of glioma cells partly via repressing the EGFR expression.

scholarly journals Protective Effect of Iridoid Glycosides of the Leaves of Syringa oblata Lindl. on Dextran Sulfate Sodium-Induced Ulcerative Colitis by Inhibition of the TLR2/4/MyD88/NF-κB Signaling Pathway

2020 ◽  
Vol 2020 ◽  
pp. 1-13
Author(s):  
Yifang Zhang ◽  
Dandan Han ◽  
Shen Yu ◽  
Chiying An ◽  
Xin Liu ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Protective Effect ◽  
Signaling Pathway ◽  
Proinflammatory Cytokines ◽  
Dextran Sulfate ◽  
Dextran Sulfate Sodium ◽  
Activity Index ◽  
Iridoid Glycosides ◽  
Mrna Levels ◽  
Dependent Manner

Iridoid glycoside (IG) is the major active fraction extracted from the leaves of Syringa oblata Lindl. In view of its antimicrobial and antidiarrheal potential, it could be beneficial for the treatment of ulcerative colitis (UC). In the present study, IG (20, 40, and 80 mg/kg) was administered orally for 14 days to dextran sulfate sodium- (DSS-) induced colitis rats. The anti-inflammatory effects of IG on DSS-induced UC were evaluated by comparing observations in DSS-induced colitis and drug-treated groups using disease activity index (DAI), macroscopic score, histological analysis, and apoptosis assay. To elucidate the antioxidant mechanisms of IG on NOX-dependent ROS production, the activities of 8-OHdG, NOX1, and NOX2 in DSS-induced colitis were determined. The levels of proinflammatory cytokines such as IL-2, IL-4, IL-5, IL-12p40, and IL-13 were detected. The inflammation-associated protein and mRNA expressions of TLR-2, TLR-4, MyD88, and NF-κBp65 were assessed by immunohistochemistry and real-time quantitative PCR, respectively. The results suggested that IG treatment significantly reduced DAI, macroscopic score, and histological damage compared to untreated animals (p<0.01), whereas administration of IG remarkably attenuated the upregulation of 8-OHdG, NOX1, and NOX2 and the expression of proinflammatory cytokines such as IL-2, IL-4, IL-5, IL-12p40, and IL-13 in DSS-treated rats in a concentration-dependent manner. In addition, IG treatment could dose dependently suppress the protein and mRNA levels of TLR-2, TLR-4, MyD88, and NF-κBp65. The dose of IG that produced the most significant protective effect was 80 mg/kg. The above results demonstrate that IG exerts its inhibitory effect on cell apoptosis, oxidative stress, and proinflammatory cytokines in DSS-induced colitis through modulation of the TLR2/4/MyD88/NF-κB signaling pathway.

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