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The Role of NFκB in Healthy and Preeclamptic Placenta: Trophoblasts in the Spotlight.
Armistead, B, Kadam, L, Drewlo, S, Kohan-Ghadr, HR
International journal of molecular sciences. 2020;(5)
Abstract
The NFκB protein family regulates numerous pathways within the cell-including inflammation, hypoxia, angiogenesis and oxidative stress-all of which are implicated in placental development. The placenta is a critical organ that develops during pregnancy that primarily functions to supply and transport the nutrients required for fetal growth and development. Abnormal placental development can be observed in numerous disorders during pregnancy, including fetal growth restriction, miscarriage, and preeclampsia (PE). NFκB is highly expressed in the placentas of women with PE, however its contributions to the syndrome are not fully understood. In this review we discuss the molecular actions and related pathways of NFκB in the placenta and highlight areas of research that need attention.
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S-Nitrosylation in Regulation of Inflammation and Cell Damage.
Dasgupta, S, Gomez, JJ, Singh, I, Khan, M
Current drug targets. 2018;(15):1831-1838
Abstract
BACKGROUND Cell signaling through nitric oxide (NO) is a multifaceted mechanism, which regulates metabolic activities and fate in different tissues. The peroxynitrite (ONOO-) formed as reaction product of nitric oxide radical and superoxide interacts with cell membrane phospholipids and proteins causing damage. OBJECTIVE The reaction kinetics to form nitrotyrosine (ONOO-tyrosine) and/or nitrosylated cysteine (ONOO-cysteine) in protein molecules during posttranslational modification and nitration of lipids are therefore critical in determining cells' signaling mechanism for survival or apoptosis. RESULTS The nitrosylation was found to modulate GPCRs and activation of guanylate cyclase as well as regulate NF-κB activation. The recent findings have shown the neuroprotective effects of S- nitrosylation, though mechanism is unclear. CONCLUSION While keeping the background in mind, we address here the biological function of NO derivatives in medicine. We target four known compounds: SNAP, SIN- 1 chloride, SNP and GSNO to understand the effect of NO in different tissues. Here we analyze the existing findings to assess therapeutic relevance of NO-signaling during inflammation, vasodilation and tolerance.
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The Importance of Toll-like Receptors in NF-κB Signaling Pathway Activation by Helicobacter pylori Infection and the Regulators of this Response.
Hu, Y, Liu, JP, Zhu, Y, Lu, NH
Helicobacter. 2016;(5):428-40
Abstract
Helicobacter pylori (H. pylori) is a common pathogenic bacterium in the stomach that infects almost half of the population worldwide and is closely related to gastric diseases and some extragastric diseases, including iron-deficiency anemia and idiopathic thrombocytopenic purpura. Both the Maastricht IV/Florence consensus report and the Kyoto global consensus report have proposed the eradication of H. pylori to prevent gastric cancer as H.pylori has been shown to be a major cause of gastric carcinogenesis. The interactions between H. pylori and host receptors induce the release of the proinflammatory cytokines by activating proinflammatory signaling pathways such as nuclear factor kappa B (NF-κB), which plays a central role in inflammation, immune response, and carcinogenesis. Among these receptors, Toll-like receptors (TLRs) are classical pattern recognition receptors in the recognition of H. pylori and the mediation of the host inflammatory and immune responses to H. pylori. TLR polymorphisms also contribute to the clinical consequences of H. pylori infection. In this review, we focus on the functions of TLRs in the NF-κB signaling pathway activated by H. pylori, the regulators modulating this response, and the functions of TLR polymorphisms in H.pylori-related diseases.
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Histone methylation modifiers in cellular signaling pathways.
Alam, H, Gu, B, Lee, MG
Cellular and molecular life sciences : CMLS. 2015;(23):4577-92
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Abstract
Histone methyltransferases and demethylases epigenetically regulate gene expression by modifying histone methylation status in numerous cellular processes, including cell differentiation and proliferation. These modifiers also control methylation levels of various non-histone proteins, such as effector proteins that play critical roles in cellular signaling networks. Dysregulated histone methylation modifiers alter expression of oncogenes and tumor suppressor genes and change methylation states of effector proteins, frequently resulting in aberrant cellular signaling cascades and cellular transformation. In this review, we summarize the role of histone methylation modifiers in regulating the following signaling pathways: NF-κB, RAS/RAF/MEK/MAPK, PI3K/Akt, Wnt/β-catenin, p53, and ERα.
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Chemoprevention of head and neck squamous cell carcinoma through inhibition of NF-κB signaling.
Vander Broek, R, Snow, GE, Chen, Z, Van Waes, C
Oral oncology. 2014;(10):930-41
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Abstract
Nuclear factor-kappa B (NF-κB) transcription factors regulate cellular processes such as inflammation and cell survival. The NF-κB pathway is often activated with development and progression of head and neck squamous cell carcinoma (HNSCC). As such, NF-κB represents an attractive target for chemoprevention. HNSCC involves progression of lesions from premalignant to malignant, providing a window of opportunity for intervention with chemopreventive agents. Appropriate chemopreventive agents should be inexpensive, nontoxic, and target important pathways involved in the development of HNSCC. Several such agents that inhibit the NF-κB pathway have been investigated in HNSCC. Retinoids have been studied most extensively but have shown limited potential in human trials. Epidermal growth factor receptor inhibitors and PI3K-mTOR inhibitors may benefit a subset of patients. Other agents such as green tea extract and curcumin are appealing because they are generally regarded as safe. In contrast, there is evidence that Vitamin E supplementation may actually increase mortality of cancer patients. Repurposed drugs such as cyclooxygenase (COX) inhibitors and antidiabetic drugs are an emerging area of interest. Future research to develop agents with lower toxicity and higher specificity for the NF-κB pathway, and to target these therapies to individual patient genetic signatures should help to increase the utility of chemoprevention in HSNCC.
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1α,25OH2D3 down-regulates HBp17/FGFBP-1 expression via NF-κB pathway.
Rosli, SN, Shintani, T, Hayashido, Y, Toratani, S, Usui, E, Okamoto, T
The Journal of steroid biochemistry and molecular biology. 2013;:98-101
Abstract
The heparin binding protein 17/fibroblast growth factor-binding protein-1 (HBp17/FGFBP-1, GenBank accession no. NP-005121) has been reported to enhance angiogenesis as well as promotes tumor growth in vivo. Furthermore, this molecule was found to be highly expressed in the tissue and cell lines of oral squamous cell carcinoma (OSCC). 1α,25(OH)2D3 is used to study its potential to curb the expression of HBp17/FGFBP-1 in cancer cells. Consequently, we found that HBp17/FGFBP-1 mRNA and protein levels were significantly down-regulated. In this present study, we show that this event takes place via the NF-κB pathway since mRNA and protein levels of this pathway regulator, IκBα, were found to be significantly up-regulated. Furthermore, the promoter activity of HBp17/FGFBP-1 (region between -217 and +61) measured by a luciferase reporter assay was down-regulated following treatment. Silencing of VDR with siRNA showed the effect of 1α,25(OH)2D3 on HBp17/FGFBP-1. Based on these findings, we concluded that 1α,25(OH)2D3 down-regulated HBp17/FGFBP-1 expression via NF-κB. This article is part of a Special Issue entitled 'Vitamin D Workshop'.
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Phytochemicals suppress nuclear factor-κB signaling: impact on health span and the aging process.
Salminen, A, Kauppinen, A, Kaarniranta, K
Current opinion in clinical nutrition and metabolic care. 2012;(1):23-8
Abstract
PURPOSE OF REVIEW We will briefly review the current knowledge on the major molecular targets of plant-derived phytochemicals, particularly their connections to nuclear factor-κB (NF-κB) signaling, and accordingly link these observations to their anti-inflammatory properties and beneficial effects on the aging process and age-related degenerative diseases. RECENT FINDINGS Many of the major phytochemicals, for example, flavonoids and terpenoids, possess significant therapeutic properties including anti-inflammatory and anticancer effects. Although phytochemicals have multiple molecular targets, recent studies have indicated that many of them can activate signaling pathways driven by AMP-activated protein kinase and nuclear factor-erythroid 2-related factor 2. These pathways are potent inhibitors of NF-κB signaling, a crucial inducer of inflammatory responses and cancer formation. Current opinion suggests that inflammation has a critical role in the aging process and in the pathogenesis of age-related degenerative diseases and, thus, anti-inflammatory properties of phytochemicals could explain their beneficial effects on health span and lifespan. SUMMARY Plant-derived phytochemicals are promising lead compounds helping modern drug discovery to develop potent and safe inhibitors for age-related inflammatory disorders driven by NF-κB signaling.
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Insights into iron and nuclear factor-kappa B (NF-kappaB) involvement in chronic inflammatory processes in peritoneal endometriosis.
Defrère, S, González-Ramos, R, Lousse, JC, Colette, S, Donnez, O, Donnez, J, Van Langendonckt, A
Histology and histopathology. 2011;(8):1083-92
Abstract
Endometriosis is a chronic pelvic inflammatory process. Local inflammation is known to play a role in pain and infertility associated with the disease, and may be extensively involved in molecular and cellular processes leading to endometriosis development. In this review, we focus on two inflammatory mediators clearly implicated in the pathogenesis of endometriosis, iron and NF-kappaB, and their potential association. Iron is essential for all living organisms, but excess iron results in toxicity and is linked to pathological disorders. In endometriosis patients, iron overload has been demonstrated in the different compartments of the peritoneal cavity (peritoneal fluid, endometriotic lesions, peritoneum and macrophages). This iron overload affects numerous mechanisms involved in endometriosis development. Moreover, iron can generate free radical species able to react with a wide range of cellular constituents, inducing cellular damage. Overproduction of reactive oxygen species also impairs cellular function by altering gene expression via regulation of redox-sensitive transcription factors such as NF-kappaB, which is clearly implicated in endometriosis. Indeed, NF-kappaB is activated in endometriotic lesions and peritoneal macrophages of endometriosis patients, which stimulates synthesis of proinflammatory cytokines, generating a positive feedback loop in the NF-kappaB pathway. NF-kappaB-mediated gene transcription promotes a variety of processes, including endometriotic lesion establishment, maintenance and development. In conclusion, iron and NF-kappaB appear to be linked and both are clearly involved in endometriosis development, making these pathways an attractive target for future treatment and prevention of this disease.
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The role of chalcones in suppression of NF-κB-mediated inflammation and cancer.
Yadav, VR, Prasad, S, Sung, B, Aggarwal, BB
International immunopharmacology. 2011;(3):295-309
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Abstract
Although consumption of fruits, vegetables, spices, cereals and pulses has been associated with lower incidence of cancer and other chronic diseases, how these dietary agents and their active ingredients minimize these diseases, is not fully understood. Whether it is oranges, kawa, hops, water-lilly, locorice, wax apple or mulberry, they are all connected by a group of aromatic ketones, called chalcones (1,3-diaryl-2-propen-1-ones). Some of the most significant chalcones identified from these plants include flavokawin, butein, xanthoangelol, 4-hydroxyderricin, cardamonin, 2',4'-dihydroxychalcone, isoliquiritigenin, isosalipurposide, and naringenin chalcone. These chalcones have been linked with immunomodulation, antibacterial, antifungal, antiviral, anti-inflammatory, antioxidant, anticancer, and antidiabetic activities. The current review, however, deals with the role of various chalcones in inflammation that controls both the immune system and tumorigenesis. Inflammatory pathways have been shown to mediate the survival, proliferation, invasion, angiogenesis and metastasis of tumors. How these chalcones modulate inflammatory pathways, tumorigenesis and immune system is the focus of this review.
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Role of nuclear factor κB-mediated inflammatory pathways in cancer-related symptoms and their regulation by nutritional agents.
Gupta, SC, Kim, JH, Kannappan, R, Reuter, S, Dougherty, PM, Aggarwal, BB
Experimental biology and medicine (Maywood, N.J.). 2011;(6):658-71
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Abstract
Cancer is a disease characterized by dysregulation of multiple genes and is associated with symptoms such as cachexia, anorexia, fatigue, depression, neuropathic pain, anxiety, cognitive impairment, sleep disorders and delirium (acute confusion state) in medically ill patients. These symptoms are caused by either the cancer itself or the cancer treatment. During the past decade, increasing evidence has shown that the dysregulation of inflammatory pathways contributes to the expression of these symptoms. Cancer patients have been found to have higher levels of proinflammatory cytokines such as interleukin-6. The nuclear factor (NF)-κB is a major mediator of inflammatory pathways. Therefore, anti-inflammatory agents that can modulate the NF-κB activation and inflammatory pathways may have potential in improving cancer-related symptoms in patients. Because of their multitargeting properties, low cost, low toxicity and immediate availability, natural agents have gained considerable attention for prevention and treatment of cancer-related symptoms. How NF-κB and inflammatory pathways contribute to cancer-related symptoms is the focus of this review. We will also discuss how nutritional agents such as curcumin, genistein, resveratrol, epigallocatechin gallate and lycopene can modulate inflammatory pathways and thereby reduce cancer-related symptoms in patients.