Inhibitory effect of withaferin A on Helicobacter pylori-induced IL-8 production and NF-κB activation in gastric epithelial cells

Kim, Green; Kim, Tae‐Hyoun; Kang, Min‐Jung; Choi, Jina; Pack, Da‐Young; Lee, Ik‐Rae; Kim, Min‐Gyu; Han, Sangsoo; Kim, Bo Yeon; Oh, Sang‐Muk; Lee, Kyung‐Bok; Kim, Dong‐Jae; Park, Jong‐Hwan

doi:10.3892/mmr.2015.4602

Cited by 16 publications

(13 citation statements)

References 39 publications

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“…In addition, upregulation of interleukin 8, vascular endothelial growth factor, angiogenin, urokinase-type plasminogen activator and MMP-9 genes by H. pylori was reported to regulate the metastasis and the invasion of gastric cancer cells (41,42). Recently, our group reported that WA inhibited the activation of NF-κB and pro-inflammatory cytokine production in gastric epithelial and immune cells infected with H. pylori (11,12). Therefore, there is evidence to suggest that the anti-inflammatory effects of WA may hinder the progression of gastric adenocarcinogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…Senthil et al (10) recently reported that an extract from W. somnifera inhibits the proliferation of AGS cells by inducing apoptosis and cell cycle arrest. Furthermore, we have recently reported that WA efficiently decreased pro-inflammatory processes in gastric epithelial cells, as well as immune cells, in response to Helicobacter pylori (11,12), which serves a pivotal role in the high incidence of gastric cancer (2). However, a complete understanding of the antitumor effects of WA in gastric cancer remains to be achieved.…”

Section: Introductionmentioning

confidence: 99%

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Withaferin A inhibits the proliferation of gastric cancer cells by inducing G2/M cell cycle arrest and apoptosis

Kim

Hwang

et al. 2017

Oncology Letters

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Abstract. Human gastric adenocarcinoma (AGS) is one of the most common types of malignant tumor and the third-leading cause of tumor-associated mortality worldwide. Withaferin A (WA), a steroidal lactone derived from Withania somnifera, exhibits antitumor activity in a variety of cancer models. However, to the best of our knowledge, the direct effect of WA on AGS cells has not previously been determined. The present study investigated the effects of WA on the proliferation and metastatic activity of AGS cells. WA exerted a dose-dependent cytotoxic effect on AGS cells. The effect was associated with cell cycle arrest at the G2/M phase and the expression of apoptotic proteins. Additionally, WA treatment resulted in a decrease in the migration and invasion ability of the AGS cells, as demonstrated using a wound healing assay and a Boyden chamber assay. These results indicate that WA directly inhibits the proliferation and metastatic activity of gastric cancer cells, and suggest that WA may be developed as a drug for the treatment of gastric cancer.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Withaferin A inhibits the proliferation of gastric cancer cells by inducing G2/M cell cycle arrest and apoptosis

Kim

Hwang

et al. 2017

Oncology Letters

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“…Ashwaganda has beneficial effects on diseases of cardiovascular nature (Ravindran et al, 2015a), obesity, diabetes, infection, cancer (Choi and Kim, 2015, Khazal et al, 2014, Rai et al, 2016), arthritis (Gupta and Singh, 2014, Khan et al, 2015) and gastric inflammation (Kim et al, 2016). The major constituent in Ashwaganda, identified as Withaferin A, itself is an inhibitor of HMG-CoA, angiotensinogen-converting enzyme, (Ravindran et al, 2015b) can lower total cholesterol, triglycerides, higher HDL/LDL ratios (Shukla et al, 2014) and reduce severity or incidence of myocardial infarction, (Khalil et al, 2015) stroke (Ahmad et al, 2015, Raghavan and Shah, 2015, Sood et al, 2015) and hypertension.…”

Section: Discussionmentioning

confidence: 99%

Natural product HTP screening for attenuation of cytokine-induced neutrophil chemo attractants (CINCs) and NO2− in LPS/IFNγ activated glioma cells

Mazzio

Bauer

Mendonca

et al. 2017

Journal of Neuroimmunology

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Chronic or acute central nervous system (CNS) inflammation is carried out by glial cells, which can contribute to neurological injuries associated with head trauma, stroke, and infection, Parkinson’s or Alzheimer ’s disease. The process of aging combined with inflammation are also risk factors for developing glioblastoma multiforme (GBM) as well as perpetuating its malignant aggression. With growing public curiosity in complementary and alternative medicines (CAMs), in this work we conduct a high throughput (HTP) screening of >1400 natural herbs, plants and over the counter (OTC) products for anti-inflammatory effects on lipopolysaccharide (LPS)/interferon gamma (IFNγ) activated C6 glioma cells. Validation studies suggest a pro-inflammatory profile mediated by LPS [3μg/ml/IFNγ 3ng/ml] is consistent with elevation [> 8.5 fold] of MCP-1 and cytokine-induced neutrophil chemo-attractants (CINC) 1, CINC 2a and CINC3. The data show no evidence of changes to the following, IL-13, TNF-a, fracktaline, leptin, LIX, GM-CSF, ICAM1, L-Selectin, activin A, agrin, IL-1α, MIP-3a, B72/CD86, NGF, IL-1b, MMP-8, IL-1 R6, PDGF-AA, IL-2, IL-4, prolactin R, RAGE, IL-6, Thymus Chemokine-1, CNTF,IL-10 or TIMP-1. The data also show a LPS/IFNγ mediated rise in iNOS and NO2− as often reported. A HTP screening was conducted, where we employ an in vitro efficacy index (iEI) defined as the ratio of toxicity (LC50)/anti-inflammatory potency (IC50) to ensure biological effects were occurring in fully viable cells (ratio > 3.8). Using NO2− as a guideline molecule, the data show that 1.77 % (25 of 1410 tested) (at <250μg/ml) had anti-inflammatory effects with an iEI ratio >3.8. These include reference drugs (hydrocortisone, dexamethasone N6-(1-iminoethyl)-L-lysine and NSAIDS : diclofenac, tolfenamic acid), a histone deacetylase inhibitor (apicidin) and the following natural products; Ashwaganda (Withania somnifera), Elecampagne Root (Inula helenium), Feverfew (Tanacetum parthenium), Green Tea (Camellia sinensis), Turmeric Root (Curcuma Longa) Ganthoda (Valeriana wallichii), Tansy (Tanacetum vulgare), Maddar Root (Rubia tinctoria), Red Sandle wood (Pterocarpus santalinus), Bay Leaf (Laurus nobilis, Lauraceae), quercetin, cardamonin, fisetin, EGCG, biochanin A, galangin, apigenin and curcumin. The herb with the largest iEI was Ashwaganda where the IC50/LC50 was 11.1/>1750.0 μg/mL, and the compound with the greatest iEI was quercetin where the IC50/LC50 was 10.0/>363.6 ug/mL. These substances also downregulate the production of iNOS expression and attenuate CINC-3 release. In summary, this HTP screening provides guideline information as to efficacy of natural products that in the long term, could prevent inflammatory processes associated with neurodegenerative disease and aggressive glioma tumor growth.

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“…Macrophages are important players in the host's defense against H. pylori infections (Yamauchi et al, 2008;Ansari et al, 2014). H. pylori infections trigger nuclear factor (NF)-kB-mediated pro-inflammatory signaling pathway in epithelial cells and macrophages (Ahmed et al, 2014;Kim et al, 2016). Inflammatory stimuli up-regulate inducible nitric oxide synthase (iNOS) expression in macrophages to produce nitric oxide (NO), which can kill H. pylori (Chaturvedi et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

LECT2 association with macrophage-mediated killing of Helicobacter pylori by activating NF-κB and nitric oxide production

Shen

Chen

et al. 2016

Genet. Mol. Res.

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ABSTRACT. Helicobacter pylori employs unique methods to colonize the stomach, which induces chronic inflammation. It is also able to avoid eradication by macrophages and other immune cells. Leukocyte cell-derived chemotaxin 2 (LECT2), a multi-functional cytokine involved in many pathological conditions, has recently been shown to activate macrophages via the CD209a receptor. Therefore, we aimed to investigate the effects of LECT2 on H. pylori-infected macrophages. Macrophages were treated with recombinant LECT2, and both their ability to kill H. pylori and produce nitric oxide were analyzed. Western blot was performed to determine nuclear translocation and protein phosphorylation of p65, a subunit of nuclear factor (NF)-kB. Transfection experiments were performed to analyze the signaling pathway of LECT2 in macrophages. We found that treatment with LECT2 enhanced H. pylori killing and nitric oxide production in macrophages. In addition, DNA-binding activity and nuclear translocation of p65 were up-regulated by LECT2 treatment. Furthermore, we found that NFkB activation by LECT2 was mediated by Raf-1 in macrophages, and Raf-1 phosphorylation was specifically altered in response to LECT2. Moreover, LECT2 induced Ser28 phosphorylation in the intracellular domain of CD209a. CD209a Ser28 phosphorylation was required for LECT2-induced Raf-1 and NF-kB activation in RAW264.7 macrophages. Our study showed that the effects of LECT2 on H. pylori killing and nitric oxide production were dependent on CD209a phosphorylation, Raf-1, and NF-kB activation. Together, these results demonstrate for the first time that exposure to LECT2 can modulate specific intracellular mechanisms downstream of CD209a to enhance H. pylori killing and nitric oxide production in macrophages.

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Inhibitory effect of withaferin A on Helicobacter pylori-induced IL-8 production and NF-κB activation in gastric epithelial cells

Cited by 16 publications

References 39 publications

Withaferin A inhibits the proliferation of gastric cancer cells by inducing G2/M cell cycle arrest and apoptosis

Withaferin A inhibits the proliferation of gastric cancer cells by inducing G2/M cell cycle arrest and apoptosis

Natural product HTP screening for attenuation of cytokine-induced neutrophil chemo attractants (CINCs) and NO2− in LPS/IFNγ activated glioma cells

LECT2 association with macrophage-mediated killing of Helicobacter pylori by activating NF-κB and nitric oxide production

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