Effects of Acute 2,3,7,8-Tetrachlorodibenzo-p-Dioxin Exposure on the Circulating and Cecal Metabolome Profile

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a polyhalogenated planar hydrocarbon belonging to a group of highly toxic and persistent environmental contaminants known as “dioxins”. TCDD is an animal teratogen and carcinogen that is well characterized for causing immunosuppression through activation of aryl hydrocarbon receptor (AHR). In this study, we investigated the effect of exposure of mice to an acute dose of TCDD on the metabolic profile within the serum and cecal contents to better define the effects of TCDD on host physiology. Our findings demonstrated that within the circulating metabolome following acute TCDD exposure, there was significant dysregulation in the metabolism of bioactive lipids, amino acids, and carbohydrates when compared with the vehicle (VEH)-treated mice. These widespread changes in metabolite abundance were identified to regulate host immunity via modulating nuclear factor-kappa B (NF-κB) and extracellular signal-regulated protein kinase (ERK1/2) activity and work as biomarkers for a variety of organ injuries and dysfunctions that follow TCDD exposure. Within the cecal content of mice exposed to TCDD, we were able to detect changes in inflammatory markers that regulate NF-κB, markers of injury-related inflammation, and changes in lysine degradation, nicotinamide metabolism, and butanoate metabolism, which collectively suggested an immediate suppression of broad-scale metabolic processes in the gastrointestinal tract. Collectively, these results demonstrate that acute TCDD exposure results in immediate irregularities in the circulating and intestinal metabolome, which likely contribute to TCDD toxicity and can be used as biomarkers for the early detection of individual exposure.

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L-Tetrahydropalmatine Inhibits the Progression of Glioblastoma Tumor by Suppressing the Extracellular-Signal-Regulated Kinase/Nuclear Factor-Kappa B Signaling Pathway

Current Topics in Nutraceutical Research ◽

10.37290/ctnr2641-452x.19:164-171 ◽

2020 ◽

Vol 19 (2) ◽

pp. 164-171

Author(s):

Feng Xue ◽

Tingting Chen

Keyword(s):

Glioblastoma Multiforme ◽

Nuclear Factor Kappa B ◽

Matrix Metalloproteinase 2 ◽

Nuclear Factor ◽

Nuclear Factor Kappa ◽

Extracellular Signal ◽

Apoptosis Protein ◽

Endothelial Growth Factor

Glioblastoma multiforme is the most common malignancy of central nervous system. Herein we have evaluated the effect of L-tetrahydropalmatine, an isoquinoline alkaloid, on the tumor growth both in vivo and in vitro using C6 glioblastoma multiforme cells and BALB/c mice injected subcutaneously with C6/luc2 cells. The results of these studies show that L-tetrahydropalmatine exhibited cytotoxic effect on C6 glioblastoma multiforme cells, suppressed nuclear factor-kappa B activity, suppressed the levels of tumor-linked proteins such as matrix metalloproteinase-2/9, Cyclin-D1, vascular endothelial growth factor, and X-linked inhibitor of apoptosis protein via ERK/nuclear factor-kappa B cascade. Further, L-tetrahydropalmatine inhibited the cell migration and invasion properties of C6 cells, and also suppressed the tumor weight and volume in mice. Immunohistochemical staining of tumor tissues suggested that L-tetrahydropalmatine inhibited the extracellular-signal-regulated kinase/nuclear factor-kappa B cascade and suppressed the levels of Cyclin-D1; matrix metalloproteinase-2/9; X-linked inhibitor of apoptosis protein; and vascular endothelial growth factor, and also the progression and growth of glioblastoma multiforme in mice. In summary, L-tetrahydropalmatine inhibits the ERK/nuclear factor-kappa B cascade, decreases the tumor volume, and inhibits the proteins responsible for tumor growth both in vivo and in vitro.

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Periplaneta americana Extracts Promote Skin Wound Healing via Nuclear Factor Kappa B Canonical Pathway and Extracellular Signal-Regulated Kinase Signaling

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2017/5821706 ◽

2017 ◽

Vol 2017 ◽

pp. 1-12 ◽

Cited By ~ 12

Author(s):

Qin Song ◽

Qiheng Gou ◽

Yuxin Xie ◽

Zhen Zhang ◽

Chaomei Fu

Keyword(s):

Wound Healing ◽

Molecular Mechanisms ◽

Periplaneta Americana ◽

Nuclear Factor Kappa B ◽

Nuclear Translocation ◽

Nuclear Factor ◽

Protective Function ◽

Extracellular Signal Regulated Kinase ◽

Nuclear Factor Kappa ◽

Extracellular Signal

Periplaneta americana extracts (PAEs) exhibit wound healing properties. However, the underlying molecular mechanisms are not well understood. Here, we treated human skin fibroblasts (HSF) with PAE and the proliferation was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The wound healing and transwell migration assays were used to detect cell migration. Nuclear factor kappa B (NF-κB) and extracellular signal-regulated kinase (ERK) pathways were analyzed by Western blot (WB). Immunofluorescence staining was used to detect the key molecular localization in the cells. The results showed that PAE enhanced the proliferation and migration of HSF cells. The expression and activation of key proteins such as RelA and p-ERK were increased in NF-κB and ERK pathways followed by nuclear translocation. In vivo, both WB and immunohistochemical (IHC) staining showed that PAE enhanced p-IκBα and p-ERK activation and the nuclear translocation of RelA. Our study suggests that the protective function of PAE is mediated via enhanced NF-κB and ERK signaling.

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Mechanisms of Action and Clinical Application of Macrolides as Immunomodulatory Medications

Clinical Microbiology Reviews ◽

10.1128/cmr.00078-09 ◽

2010 ◽

Vol 23 (3) ◽

pp. 590-615 ◽

Cited By ~ 326

Author(s):

Soichiro Kanoh ◽

Bruce K. Rubin

Keyword(s):

Nuclear Factor Kappa B ◽

Biological Activities ◽

Mechanisms Of Action ◽

Nuclear Factor ◽

Diffuse Panbronchiolitis ◽

Extracellular Signal Regulated Kinase ◽

Extracellular Signal ◽

Regulation Of Cell Cycle ◽

Immunomodulatory Therapies

SUMMARY Macrolides have diverse biological activities and an ability to modulate inflammation and immunity in eukaryotes without affecting homeostatic immunity. These properties have led to their long-term use in treating neutrophil-dominated inflammation in diffuse panbronchiolitis, bronchiectasis, rhinosinusitis, and cystic fibrosis. These immunomodulatory activities appear to be polymodal, but evidence suggests that many of these effects are due to inhibition of extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation and nuclear factor kappa B (NF-κB) activation. Macrolides accumulate within cells, suggesting that they may associate with receptors or carriers responsible for the regulation of cell cycle and immunity. A concern is that long-term use of macrolides increases the emergence of antimicrobial resistance. Nonantimicrobial macrolides are now in development as potential immunomodulatory therapies.

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Indoxyl Sulfate Downregulates Mas Receptor via Aryl Hydrocarbon Receptor/Nuclear Factor-kappa B, and Induces Cell Proliferation and Tissue Factor Expression in Vascular Smooth Muscle Cells

Nephron ◽

10.1159/000447096 ◽

2016 ◽

Vol 133 (3) ◽

pp. 205-212 ◽

Cited By ~ 10

Author(s):

Hwee-Yeong Ng ◽

Wulaer Bolati ◽

Chien-Te Lee ◽

Yu-Shu Chien ◽

Maimaiti Yisireyili ◽

...

Keyword(s):

Cell Proliferation ◽

Smooth Muscle ◽

Aryl Hydrocarbon Receptor ◽

Vascular Smooth Muscle Cells ◽

Nuclear Factor Kappa B ◽

Nuclear Factor ◽

Tissue Factor Expression ◽

Mas Receptor ◽

Aryl Hydrocarbon ◽

Factor Expression

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4-Hydroxy-7-Methoxycoumarin Inhibits Inflammation in LPS-activated RAW264.7 Macrophages by Suppressing NF-κB and MAPK Activation

Molecules ◽

10.3390/molecules25194424 ◽

2020 ◽

Vol 25 (19) ◽

pp. 4424

Author(s):

Jin Kyu Kang ◽

Chang-Gu Hyun

Keyword(s):

Nitric Oxide ◽

Nuclear Factor Kappa B ◽

Inflammatory Diseases ◽

Raw264.7 Cells ◽

Nuclear Factor ◽

Nuclear Factor Kappa ◽

Alternative Medicines ◽

Raw264.7 Macrophages ◽

Extracellular Signal ◽

Anti Inflammatory

Coumarins are natural products with promising pharmacological activities owing to their anti-inflammatory, antioxidant, antiviral, anti-diabetic, and antimicrobial effects. Coumarins are present in many plants and microorganisms and have been widely used as complementary and alternative medicines. To date, the pharmacological efficacy of 4-hydroxy-7-methoxycoumarin (4H-7MTC) has not been reported yet. Therefore, in this study, we investigated the anti-inflammatory effects of 4H-7MTC in LPS-stimulated RAW264.7 cells as well as its mechanisms of action. Cells were treated with various concentrations of 4H-7MTC (0.3, 0.6, 0.9, and 1.2 mM) and 40 μM L-N6-(1-iminoethyl)-L-lysine (L-NIL) were used as controls. LPS-stimulated RAW264.7 cells showed that 4H-7MTC significantly reduced nitric oxide (NO) and prostaglandin E2 (PGE2) production without cytotoxic effects. In addition, 4H-7MTC strongly decreased the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX-2). Furthermore, 4H-7MTC reduced the production of proinflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6. We also found that 4H-7MTC strongly exerted its anti-inflammatory actions by downregulating nuclear factor kappa B (NF-κB) activation by suppressing inhibitor of nuclear factor kappa B alpha (IκBα) degradation in macrophages. Moreover, 4H-7MTC decreased phosphorylation of extracellular signal-regulated kinase (ERK1/2) and c-Jun N-terminal kinase/stress-activated protein kinase (JNK), but not that of p38 MAPK. These results suggest that 4H-7MTC may be a good candidate for the treatment or prevention of inflammatory diseases such as dermatitis, psoriasis, and arthritis. Ultimately, this is the first report describing the effective anti-inflammatory activity of 4H-7MTC.

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