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15 pages, 18189 KiB

Open AccessArticle

Fluoxetine Induces Apoptosis through Extrinsic/Intrinsic Pathways and Inhibits ERK/NF-κB-Modulated Anti-Apoptotic and Invasive Potential in Hepatocellular Carcinoma Cells In Vitro

by Wei-Ting Chen, Fei-Ting Hsu, Yu-Chang Liu, Cheng-Hsien Chen, Li-Cho Hsu and Song-Shei Lin

Int. J. Mol. Sci. 2019, 20(3), 757; https://doi.org/10.3390/ijms20030757 - 11 Feb 2019

Cited by 37 | Viewed by 5963

Abstract

The aim of the present study was to verify the effects of fluoxetine on dysregulation of apoptosis and invasive potential in human hepatocellular carcinoma (HCC) SK-Hep1 and Hep3B cells. Cells were treated with different concentrations of fluoxetine for different times. MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide) [...] Read more.

The aim of the present study was to verify the effects of fluoxetine on dysregulation of apoptosis and invasive potential in human hepatocellular carcinoma (HCC) SK-Hep1 and Hep3B cells. Cells were treated with different concentrations of fluoxetine for different times. MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide) assays were used for testing the effects of fluoxetine on cell viability. The regulation of apoptosis signaling, and anti-apoptotic, proliferation, and metastasis-associated proteins after fluoxetine treatment were assayed by flow cytometry and Western blotting assay. The detection of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation after fluoxetine treatment was performed by NF-κB reporter gene assay. The results demonstrated that fluoxetine significantly reduced cell viability, cell migration/invasion, NF-κB, extracellular signal-regulated kinases (ERK) activation, and expression of anti-apoptotic (Cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein (C-FLIP), Myeloid cell leukemia-1 (MCL-1), X-Linked inhibitor of apoptosis protein (XAIP), and Survivin), proliferation (Cyclin-D1), angiogenesis (vascular endothelial growth factor (VEGF)), and metastasis-associated proteins (matrix metalloproteinase-9 (MMP-9)). Fluoxetine also significantly induced apoptosis, unregulated extrinsic (activation of first apoptosis signal protein and ligand (Fas/FasL), and caspase-8) and intrinsic (loss of mitochondrial membrane potential (ΔΨm) pathways and increased Bcl-2 homologous antagonist killer (BAK) apoptosis signaling. Taken together, these results demonstrated that fluoxetine induced apoptosis through extrinsic/intrinsic pathways and diminished ERK/NF-κB-modulated anti-apoptotic and invasive potential in HCC cells in vitro. Full article

(This article belongs to the Special Issue NF-κB and Cancer)

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15 pages, 16511 KiB

Open AccessArticle

Pediococcus pentosaceus-Fermented Cordyceps militaris Inhibits Inflammatory Reactions and Alleviates Contact Dermatitis

by Ha-Kyoung Kwon, Min-Jung Song, Hye-Ji Lee, Tae-Sik Park, Moon Il Kim and Hye-Jin Park

Int. J. Mol. Sci. 2018, 19(11), 3504; https://doi.org/10.3390/ijms19113504 - 7 Nov 2018

Cited by 25 | Viewed by 4880

Abstract

Cordyceps militaris is a medicinal mushroom used to treat immune-related diseases in East Asia. We investigated the anti-inflammatory effect of the extract of C. militaris grown on germinated Rhynchosia nulubilis (GRC) fermented with Pediococcus pentosaceus ON89A isolated from onion (GRC-ON89A) in vivo as [...] Read more.

Cordyceps militaris is a medicinal mushroom used to treat immune-related diseases in East Asia. We investigated the anti-inflammatory effect of the extract of C. militaris grown on germinated Rhynchosia nulubilis (GRC) fermented with Pediococcus pentosaceus ON89A isolated from onion (GRC-ON89A) in vivo as well as in vitro. The anti-inflammatory effect of GRC-ON89A was investigated in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. The total polyphenol content (TPC) and total flavonoid content (TFC) in the GRC-ON89A ethanol extract were significantly increased compared to that in GRC. GRC-ON89A hexane fraction (GRC-ON89A-Hex) inhibited the release of nitric oxide (NO) compared to that of the LPS-treated control without cytotoxicity in LPS-stimulated RAW 264.7 macrophages. GRC-ON89A-Hex decreased the inducible NO synthase (iNOS), cyclooxygenase 2 (COX2), and tumor necrosis factor (TNF)-α mRNA expression in LPS-stimulated RAW 264.7 macrophages. In addition, pre-treatment with GRC-ON89A-Hex significantly inhibited LPS-stimulated phosphorylation of mitogen-activated protein kinases (MAPKs) and nuclear factor (NF)-κB. To induce allergic contact dermatitis (ACD), 1-fluoro-2, 4-dinitrofluorobenzene (DNFB) was applied to the surface of the right ears of C57BL/6N mice. GRC-ON89A reduced the ear swelling and thickness in DNFB-induced ACD mice. This study demonstrates the potential usefulness of GRC-ON89A as an anti-inflammatory dietary supplement or drug. Full article

(This article belongs to the Special Issue NF-κB and Cancer)

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15 pages, 2773 KiB

Open AccessArticle

TRAIL/NF-κB/CX3CL1 Mediated Onco-Immuno Crosstalk Leading to TRAIL Resistance of Pancreatic Cancer Cell Lines

by Claudia Geismann, Wiebke Erhart, Frauke Grohmann, Stefan Schreiber, Günter Schneider, Heiner Schäfer and Alexander Arlt

Int. J. Mol. Sci. 2018, 19(6), 1661; https://doi.org/10.3390/ijms19061661 - 4 Jun 2018

Cited by 22 | Viewed by 4992

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignant neoplasms and registers rising death rates in western countries. Due to its late detection in advanced stages, its extremely aggressive nature and the minimal effectiveness of currently available therapies, PDAC is a [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignant neoplasms and registers rising death rates in western countries. Due to its late detection in advanced stages, its extremely aggressive nature and the minimal effectiveness of currently available therapies, PDAC is a challenging problem in the clinical field. One characteristic of PDAC is a distinct desmoplasia consisting of fibroblasts, endothelial and immune cells as well as non-cellular components, contributing to therapy resistance. It is well established that the NF-κB signaling pathway controls inflammation, cancer progression and apoptosis resistance in PDAC. This study attempts to identify NF-κB target genes mediating therapy resistance of humane PDAC cell lines towards death ligand induced apoptosis. By using a genome wide unbiased approach the chemokine CX3CL1 was established as a central NF-κB target gene mediating therapy resistance. While no direct impact of CX3CL1 expression on cancer cell apoptosis was identified in co-culture assays it became apparent that CX3CL1 is acting in a paracrine fashion, leading to an increased recruitment of inflammatory cells. These inflammatory cells in turn mediate apoptosis resistance of PDAC cells. Therefore, our data dissect a bifunctional cross-signaling pathway in PDAC between tumor and immune cells giving rise to therapy resistance. Full article

(This article belongs to the Special Issue NF-κB and Cancer)

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13 pages, 4855 KiB

Open AccessArticle

Peiminine Protects Dopaminergic Neurons from Inflammation-Induced Cell Death by Inhibiting the ERK1/2 and NF-κB Signalling Pathways

by Guangxin Chen, Juxiong Liu, Liqiang Jiang, Xin Ran, Dewei He, Yuhang Li, Bingxu Huang, Wei Wang, Dianfeng Liu and Shoupeng Fu

Int. J. Mol. Sci. 2018, 19(3), 821; https://doi.org/10.3390/ijms19030821 - 12 Mar 2018

Cited by 38 | Viewed by 4407

Abstract

Neuroinflammation, characterized marked by microglial activation, plays a very important role in the pathogenesis of Parkinson’s disease (PD). Upon activation, pro-inflammatory mediators are produced by microglia, triggering excessive inflammatory responses and ultimately damaging dopaminergic neurons. Therefore, the identification of agents that inhibit neuroinflammation [...] Read more.

Neuroinflammation, characterized marked by microglial activation, plays a very important role in the pathogenesis of Parkinson’s disease (PD). Upon activation, pro-inflammatory mediators are produced by microglia, triggering excessive inflammatory responses and ultimately damaging dopaminergic neurons. Therefore, the identification of agents that inhibit neuroinflammation may be an effective approach for developing novel treatments for PD. In this study, we sought to investigate whether peiminine protects dopaminergic neurons by inhibiting neuroinflammation. We evaluated the effects of peiminine on behavioural dysfunction, microglial activation and the loss of dopaminergic neurons in a rat model of lipopolysaccharide (LPS)-induced PD. BV-2 cells were pretreated with peiminine for 1 h and then stimulated with LPS for different times. Then, inflammatory responses and the related signalling pathways were analysed. Peiminine markedly attenuated behavioural dysfunction and inhibited the loss of dopaminergic neurons and microglial activation in the LPS-induced PD rat model. In BV-2 cells, peiminine significantly decreased LPS-induced expression of the pro-inflammatory mediators TNF-α, IL-6 and IL-1β, COX-2 and iNOS by inhibiting the phosphorylation of ERK1/2, AKT and NF-κB p65. Based on these results demonstrated that peiminine has a role in protecting dopaminergic neurons in the LPS-induced PD rat model by inhibiting neuroinflammation. Full article

(This article belongs to the Special Issue NF-κB and Cancer)

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3190 KiB

Open AccessArticle

Quinacrine Inhibits ICAM-1 Transcription by Blocking DNA Binding of the NF-κB Subunit p65 and Sensitizes Human Lung Adenocarcinoma A549 Cells to TNF-α and the Fas Ligand

by Misuzu Harada, Kyoko Morimoto, Tetsuya Kondo, Reiko Hiramatsu, Yuji Okina, Ryo Muko, Iyo Matsuda and Takao Kataoka

Int. J. Mol. Sci. 2017, 18(12), 2603; https://doi.org/10.3390/ijms18122603 - 2 Dec 2017

Cited by 21 | Viewed by 5122

Abstract

Quinacrine has been used for therapeutic drugs in some clinical settings. In the present study, we demonstrated that quinacrine decreased the expression of intercellular adhesion molecule-1 (ICAM-1) induced by tumor necrosis factor (TNF)-α and interleukin-1 (IL-1) α in human lung adenocarcinoma A549 cells. [...] Read more.

Quinacrine has been used for therapeutic drugs in some clinical settings. In the present study, we demonstrated that quinacrine decreased the expression of intercellular adhesion molecule-1 (ICAM-1) induced by tumor necrosis factor (TNF)-α and interleukin-1 (IL-1) α in human lung adenocarcinoma A549 cells. Quinacrine inhibited ICAM-1 mRNA expression and nuclear factor κB (NF-κB)-responsive luciferase reporter activity following a treatment with TNF-α and IL-1α. In the NF-κB signaling pathway, quinacrine did not markedly affect the TNF-α-induced degradation of the inhibitor of NF-κB or the TNF-α-induced phosphorylation of the NF-κB subunit, p65, at Ser-536 and its subsequent translocation to the nucleus. In contrast, a chromatin immunoprecipitation assay showed that quinacrine prevented the binding of p65 to the ICAM-1 promoter following TNF-α stimulation. Moreover, TNF-α and the Fas ligand effectively reduced the viability of A549 cells in the presence of quinacrine only. Quinacrine down-regulated the constitutive and TNF-α-induced expression of c-FLIP and Mcl-1 in A549 cells. These results revealed that quinacrine inhibits ICAM-1 transcription by blocking the DNA binding of p65 and sensitizes A549 cells to TNF-α and the Fas ligand. Full article

(This article belongs to the Special Issue NF-κB and Cancer)

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2712 KiB

Open AccessArticle

Refined Deep-Sea Water Suppresses Inflammatory Responses via the MAPK/AP-1 and NF-κB Signaling Pathway in LPS-Treated RAW 264.7 Macrophage Cells

by So-Young Chun, Kyu-Shik Lee and Kyung-Soo Nam

Int. J. Mol. Sci. 2017, 18(11), 2282; https://doi.org/10.3390/ijms18112282 - 31 Oct 2017

Cited by 26 | Viewed by 7539

Abstract

Atopic dermatitis (AD) is a type of inflammatory skin disease caused by genetics, immune system dysfunction, and environmental stresses. It is, however, still considered to be a refractory disease. Macrophages are inflammatory immune cells that infiltrate the skin and induce inflammation. We investigated [...] Read more.

Atopic dermatitis (AD) is a type of inflammatory skin disease caused by genetics, immune system dysfunction, and environmental stresses. It is, however, still considered to be a refractory disease. Macrophages are inflammatory immune cells that infiltrate the skin and induce inflammation. We investigated the effect of refined deep-sea water (RDSW) on lipopolysaccharide (LPS)-induced inflammatory response in RAW 264.7 macrophage cells. The results showed that RDSW suppressed the expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2. Furthermore, nitric oxide, a product of iNOS, and prostaglandin (PG) D₂ and PGE₂, products of COX-2, were significantly inhibited by RDSW in a hardness-dependent manner. Moreover, we found that RDSW reversed the release of histamines and regressed the mRNA expressions and production of pro-inflammatory cytokines, such as tumor necrosis factor-α, interleukin (IL)-1β, IL-6, and IL-10, and vascular endothelial growth factor, in a hardness-dependent manner. We also found that the suppressive effect of RDSW on LPS-induced inflammatory responses was regulated by the inhibition of NF-κB nuclear translocation, and ERK 1/2 and JNK 1/2 mediated the suppression of c-Jun and c-Fos expressions. In conclusion, the present investigation suggests the possibility that RDSW may be used to treat and/or prevent inflammatory diseases, including AD. Full article

(This article belongs to the Special Issue NF-κB and Cancer)

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14 pages, 571 KiB

Open AccessReview

Advancement of NF-κB Signaling Pathway: A Novel Target in Pancreatic Cancer

by Kartick C. Pramanik, Monish Ram Makena, Kuntal Bhowmick and Manoj K. Pandey

Int. J. Mol. Sci. 2018, 19(12), 3890; https://doi.org/10.3390/ijms19123890 - 5 Dec 2018

Cited by 109 | Viewed by 7490

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers and is the third highest among cancer related deaths. Despite modest success with therapy such as gemcitabine, pancreatic cancer incidence remains virtually unchanged in the past 25 years. Among the several driver mutations [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers and is the third highest among cancer related deaths. Despite modest success with therapy such as gemcitabine, pancreatic cancer incidence remains virtually unchanged in the past 25 years. Among the several driver mutations for PDAC, Kras mutation contributes a central role for its development, progression and therapeutic resistance. In addition, inflammation is implicated in the development of most human cancer, including pancreatic cancer. Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is recognized as a key mediator of inflammation and has been frequently observed to be upregulated in PDAC. Several lines of evidence suggest that NF-κB pathways play a crucial role in PDAC development, progression and resistance. In this review, we focused on emphasizing the recent advancements in the involvement of NF-κB in PADC’s progression and resistance. We also highlighted the interaction of NF-κB with other signaling pathways. Lastly, we also aim to discuss how NF-κB could be an excellent target for PDAC prevention or therapy. This review could provide insight into the development of novel therapeutic strategies by considering NF-κB as a target to prevent or treat PDAC. Full article

(This article belongs to the Special Issue NF-κB and Cancer)

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1706 KiB

Open AccessReview

KLF2 in Regulation of NF-κB-Mediated Immune Cell Function and Inflammation

by Prerana Jha and Hiranmoy Das

Int. J. Mol. Sci. 2017, 18(11), 2383; https://doi.org/10.3390/ijms18112383 - 10 Nov 2017

Cited by 105 | Viewed by 12398

Abstract

KLF2 (Kruppel-like factor 2) is a member of the zinc finger transcription factor family, which critically regulates embryonic lung development, function of endothelial cells and maintenance of quiescence in T-cells and monocytes. It is expressed in naïve T-cells and monocytes, however its level [...] Read more.

KLF2 (Kruppel-like factor 2) is a member of the zinc finger transcription factor family, which critically regulates embryonic lung development, function of endothelial cells and maintenance of quiescence in T-cells and monocytes. It is expressed in naïve T-cells and monocytes, however its level of expression decreases during activation and differentiation. KLF2 also plays critical regulatory role in various inflammatory diseases and their pathogenesis. Nuclear factor-kappaB (NF-κB) is an important inducer of inflammation and the inflammation is mediated through the transcription of several proinflammatory cytokines, chemokines and adhesion molecules. So, both transcriptional factors KLF2 and NF-κB are being associated with the similar cellular functions and their maintenance. It was shown that KLF2 regulates most of the NF-κB-mediated activities. In this review, we focused on emphasizing the involvement of KLF2 in health and disease states and how they interact with transcriptional master regulator NF-κB. Full article

(This article belongs to the Special Issue NF-κB and Cancer)

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