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NF-κB and Disease

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (10 September 2020) | Viewed by 57965

Special Issue Editors

Department of Chemistry, University of Catania, Via Andrea Doria, 6, 95125 Catania, Italy
Interests: organic chemistry; synthesis; drug delivery; coniugates; hallosyte nanotubes; carrier systems; nanomaterials; biocompatible materials
Special Issues, Collections and Topics in MDPI journals
Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, 90128 Palermo, Italy
Interests: drug resistance; anticancer drug; natural compounds; essential oil

Special Issue Information

Dear Colleagues,

NF-κB proteins are members of a family that includes p52/p100, p50/p105, c-Rel, RelA/p65, and RelB. These proteins are able to dimerize to form transcription factors that regulate the expression of many targets. In the canonical pathway, stimuli as proinflammatory cytokines, LPS, growth factors, and antigen receptors activate an IKK complex (IKKβ, IKKα, and NEMO), which phosphorylates IκB proteins and consequently causes their ubiquitination and proteasomal degradation. NF-κB that in the cytoplasm is bound to IκB, can, therefore, translocate to the nucleus where alone or, in combination with other transcription factors (AP-1, Ets, and Stat), induce target gene expression. In the noncanonical pathway, p100/RelB complexes are inactive in the cytoplasm. A series of stimuli, including ligands of a subset of TNFR superfamily members such as LTβR, BAFFR, CD40, and RANK, cause the activation of the kinase NIK and, after, IKKα complexes. These phosphorylate p100 that is proteolytically processed to p52 which, together with RelB complexes, translocates to the nucleus and induces target gene expression. The pathological activation of NF-κB has been demonstrated in many diseases marked by an inflammatory process, from cancer to autoimmune diseases.

This Special Issue focuses on all diseases in which NF-κB has a role, with particular attention to molecular mechanisms involved in overexpression and/or activation of NF-κB and therapeutic implication to such events, through the use of molecules, natural and synthetic compounds, also in the form of conjugates biocompatible, which act as NF-κB inhibitors.

Dr. Paola Poma
Dr. Serena Riela
Dr. Monica Notarbartolo
Guest Editors

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Keywords

  • NF-κB
  • disease
  • pathways
  • targets
  • NF-κB inhibitors
  • drug delivery

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Published Papers (11 papers)

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Editorial

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3 pages, 164 KiB  
Editorial
NF-κB and Disease
by Paola Poma
Int. J. Mol. Sci. 2020, 21(23), 9181; https://doi.org/10.3390/ijms21239181 - 02 Dec 2020
Cited by 47 | Viewed by 3303
Abstract
The role of NF-κB in all diseases characterized by an inflammatory process, from cancer to autoimmune diseases, is known, but—precisely because it is involved in many diseases—this transcriptional factor continues to attract scientific research and the new knowledge that emerges is fundamental in [...] Read more.
The role of NF-κB in all diseases characterized by an inflammatory process, from cancer to autoimmune diseases, is known, but—precisely because it is involved in many diseases—this transcriptional factor continues to attract scientific research and the new knowledge that emerges is fundamental in highlighting the therapeutic potential that this factor can have in the various diseases in which it is involved [...] Full article
(This article belongs to the Special Issue NF-κB and Disease)

Research

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16 pages, 3609 KiB  
Article
Polydeoxyribonucleotide Exerts Protective Effect Against CCl4-Induced Acute Liver Injury Through Inactivation of NF-κB/MAPK Signaling Pathway in Mice
by Il-Gyu Ko, Jun-Jang Jin, Lakkyong Hwang, Sang-Hoon Kim, Chang-Ju Kim, Jin Hee Han, Seunghwan Lee, Ha Il Kim, Hyun Phil Shin and Jung Won Jeon
Int. J. Mol. Sci. 2020, 21(21), 7894; https://doi.org/10.3390/ijms21217894 - 24 Oct 2020
Cited by 20 | Viewed by 2623
Abstract
Acute liver injury (ALI) causes life-threatening clinical problem, and its underlying etiology includes inflammation and apoptosis. An adenosine A2A receptor agonist, polydeoxyribonucleotide (PDRN), exhibits anti-inflammatory and anti-apoptotic effects by inhibiting the secretion of pro-inflammatory cytokines. In the current study, the protective effect [...] Read more.
Acute liver injury (ALI) causes life-threatening clinical problem, and its underlying etiology includes inflammation and apoptosis. An adenosine A2A receptor agonist, polydeoxyribonucleotide (PDRN), exhibits anti-inflammatory and anti-apoptotic effects by inhibiting the secretion of pro-inflammatory cytokines. In the current study, the protective effect of PDRN against carbon tetrachloride (CCl4)-induced ALI was investigated using mice. For the induction of ALI, mice received intraperitoneal injection of CCl4 twice over seven days. Mice from the PDRN-treated groups received an intraperitoneal injection of 200 μL saline containing PDRN (8 mg/kg), once a day for seven days, starting on day 1 after the first CCl4 injection. In order to confirm that the action of PDRN occurs through the adenosine A2A receptor, 8 mg/kg 3,7-dimethyl-1-propargylxanthine (DMPX), an adenosine A2A receptor antagonist, was treated with PDRN. Administration of CCl4 impaired liver tissue and increased the liver index and histopathologic score. The expression of pro-inflammatory cytokines was increased, and apoptosis was induced by the administration of CCl4. Administration of CCl4 activated nuclear factor-kappa B (NF-κB) and facilitated phosphorylation of signaling factors in mitogen-activated protein kinase (MAPK). In contrast, PDRN treatment suppressed the secretion of pro-inflammatory cytokines and inhibited apoptosis. PDRN treatment inactivated NF-κB and suppressed phosphorylation of signaling factors in MAPK. As a result, liver index and histopathologic score were reduced by PDRN treatment. When PDRN was treated with DMPX, the anti-inflammatory and anti-apoptotic effect of PDRN disappeared. Therefore, PDRN can be used as an effective therapeutic agent for acute liver damage. Full article
(This article belongs to the Special Issue NF-κB and Disease)
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15 pages, 2127 KiB  
Article
Hsp70 and NF-kB Mediated Control of Innate Inflammatory Responses in a Canine Macrophage Cell Line
by Qingkang Lyu, Magdalena Wawrzyniuk, Victor P. M. G. Rutten, Willem van Eden, Alice J. A. M. Sijts and Femke Broere
Int. J. Mol. Sci. 2020, 21(18), 6464; https://doi.org/10.3390/ijms21186464 - 04 Sep 2020
Cited by 28 | Viewed by 3841
Abstract
The pathogenesis of many inflammatory diseases is associated with the uncontrolled activation of nuclear factor kappa B (NF-κB) in macrophages. Previous studies have shown that in various cell types, heat shock protein 70 (Hsp70) plays a crucial role in controlling NF-κB activity. So [...] Read more.
The pathogenesis of many inflammatory diseases is associated with the uncontrolled activation of nuclear factor kappa B (NF-κB) in macrophages. Previous studies have shown that in various cell types, heat shock protein 70 (Hsp70) plays a crucial role in controlling NF-κB activity. So far, little is known about the role of Hsp70 in canine inflammatory processes. In this study we investigated the potential anti-inflammatory effects of Hsp70 in canine macrophages as well as the mechanisms underlying these effects. To this end, a canine macrophage cell line was stressed with arsenite, a chemical stressor, which upregulated Hsp70 expression as detected by flow cytometry and qPCR. A gene-edited version of this macrophage cell line lacking inducible Hsp70 was generated using CRISPR-Cas9 technology. To determine the effects of Hsp70 on macrophage inflammatory properties, arsenite-stressed wild-type and Hsp70 knockout macrophages were exposed to lipopolysaccharide (LPS), and the expression of the inflammatory cytokines IL-6, IL-1β and tumor necrosis factor-α (TNF-α) and levels of phosphorylated NF-κB were determined by qPCR and Western Blotting, respectively. Our results show that non-toxic concentrations of arsenite induced Hsp70 expression in canine macrophages; Hsp70 upregulation significantly inhibited the LPS-induced expression of the pro-inflammatory mediators TNF-α and IL-6, as well as NF-κB activation in canine macrophages. Furthermore, the gene editing of inducible Hsp70 by CRISPR-Cas9-mediated gene editing neutralized this inhibitory effect of cell stress on NF-κB activation and pro-inflammatory cytokine expression. Collectively, our study reveals that Hsp70 may regulate inflammatory responses through NF-κB activation and cytokine expression in canine macrophages. Full article
(This article belongs to the Special Issue NF-κB and Disease)
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16 pages, 1728 KiB  
Article
Canonical, Non-Canonical and Atypical Pathways of Nuclear Factor кb Activation in Preeclampsia
by Agata Sakowicz, Michalina Bralewska, Tadeusz Pietrucha, Dominika E Habrowska-Górczyńska, Agnieszka W Piastowska-Ciesielska, Agnieszka Gach, Magda Rybak-Krzyszkowska, Piotr J Witas, Hubert Huras, Mariusz Grzesiak and Lidia Biesiada
Int. J. Mol. Sci. 2020, 21(15), 5574; https://doi.org/10.3390/ijms21155574 - 04 Aug 2020
Cited by 19 | Viewed by 5804
Abstract
Although higher nuclear factor κB (NFκB) expression and activity is observed in preeclamptic placentas, its mechanism of activation is unknown. This is the first study to investigate whether the canonical, non-canonical, or atypical NFκB activation pathways may be responsible for the higher activation [...] Read more.
Although higher nuclear factor κB (NFκB) expression and activity is observed in preeclamptic placentas, its mechanism of activation is unknown. This is the first study to investigate whether the canonical, non-canonical, or atypical NFκB activation pathways may be responsible for the higher activation of NFκB observed in preeclamptic placentas. The study included 268 cases (130 preeclamptic women and 138 controls). We studied the expression of the genes coding for NFκB activators (NIK, IKKα, IKKβ, and CK2α) and inhibitors (IκBα and IκBβ) using RT-PCR in real time. The RT-PCR results were verified on the protein level using ELISA and Western blot. To determine the efficiency of the pathways, the ratios of activator(s) to one of the inhibitors (IκBα or IκBβ) were calculated for each studied pathway. The preeclamptic placentas demonstrated significantly lower IKKα and CK2α but higher IκBα and IκBβ protein levels. In addition, the calculated activator(s) to inhibitor (IκBα or IκBβ) ratios suggested that all studied pathways might be downregulated in preeclamptic placentas. Our results indicate that preeclamptic placentas may demonstrate mechanisms of NFκB activation other than the canonical, non-canonical, and atypical forms. In these mechanisms, inhibitors of NFκB may play a key role. These observations broaden the existing knowledge regarding the molecular background of preeclampsia development. Full article
(This article belongs to the Special Issue NF-κB and Disease)
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19 pages, 2939 KiB  
Article
HIF-1β Positively Regulates NF-κB Activity via Direct Control of TRAF6
by Laura D’Ignazio, Dilem Shakir, Michael Batie, H. Arno Muller and Sonia Rocha
Int. J. Mol. Sci. 2020, 21(8), 3000; https://doi.org/10.3390/ijms21083000 - 24 Apr 2020
Cited by 12 | Viewed by 3858
Abstract
NF-κB signalling is crucial for cellular responses to inflammation but is also associated with the hypoxia response. NF-κB and hypoxia inducible factor (HIF) transcription factors possess an intense molecular crosstalk. Although it is known that HIF-1α modulates NF-κB transcriptional response, very little is [...] Read more.
NF-κB signalling is crucial for cellular responses to inflammation but is also associated with the hypoxia response. NF-κB and hypoxia inducible factor (HIF) transcription factors possess an intense molecular crosstalk. Although it is known that HIF-1α modulates NF-κB transcriptional response, very little is understood regarding how HIF-1β contributes to NF-κB signalling. Here, we demonstrate that HIF-1β is required for full NF-κB activation in cells following canonical and non-canonical stimuli. We found that HIF-1β specifically controls TRAF6 expression in human cells but also in Drosophila melanogaster. HIF-1β binds to the TRAF6 gene and controls its expression independently of HIF-1α. Furthermore, exogenous TRAF6 expression is able to rescue all of the cellular phenotypes observed in the absence of HIF-1β. These results indicate that HIF-1β is an important regulator of NF-κB with consequences for homeostasis and human disease. Full article
(This article belongs to the Special Issue NF-κB and Disease)
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20 pages, 2567 KiB  
Article
Celastrol Alleviates Gamma Irradiation-Induced Damage by Modulating Diverse Inflammatory Mediators
by Hong Wang, Kwang Seok Ahn, Sulaiman Ali Alharbi, Omar H. M. Shair, Frank Arfuso, Gautam Sethi, Arunachalam Chinnathambi and Feng Ru Tang
Int. J. Mol. Sci. 2020, 21(3), 1084; https://doi.org/10.3390/ijms21031084 - 06 Feb 2020
Cited by 20 | Viewed by 3390
Abstract
The present study aimed to explore the possible radioprotective effects of celastrol and relevant molecular mechanisms in an in vitro cell and in vivo mouse models exposed to gamma radiation. Human keratinocytes (HaCaT) and foreskin fibroblast (BJ) cells were exposed to gamma radiation [...] Read more.
The present study aimed to explore the possible radioprotective effects of celastrol and relevant molecular mechanisms in an in vitro cell and in vivo mouse models exposed to gamma radiation. Human keratinocytes (HaCaT) and foreskin fibroblast (BJ) cells were exposed to gamma radiation of 20 Gy, followed by treatment with celastrol for 24 h. Cell viability, reactive oxygen species (ROS), nitric oxide (NO) and glutathione (GSH) production, lipid peroxidation, DNA damage, inflammatory cytokine levels, and NF-κB pathway activation were examined. The survival rate, levels of interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) in blood, and p65 and phospho-p65 expression were also evaluated in mice after exposure to gamma radiation and celastrol treatment. The gamma irradiation of HaCaT cells induced decreased cell viability, but treatment with celastrol significantly blocked this cytotoxicity. Gamma irradiation also increased free radical production (e.g., ROS and NO), decreased the level of GSH, and enhanced oxidative DNA damage and lipid peroxidation in cells, which were effectively reversed by celastrol treatment. Moreover, inflammatory responses induced by gamma irradiation, as demonstrated by increased levels of IL-6, TNF-α, and IL-1β, were also blocked by celastrol. The increased activity of NF-κB DNA binding following gamma radiation was significantly attenuated after celastrol treatment. In the irradiated mice, treatment with celastrol significantly improved overall survival rate, reduced the excessive inflammatory responses, and decreased NF-κB activity. As a NF-κB pathway blocker and antioxidant, celastrol may represent a promising pharmacological agent with protective effects against gamma irradiation-induced injury. Full article
(This article belongs to the Special Issue NF-κB and Disease)
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15 pages, 2225 KiB  
Article
Protective Effect of PBCA Nanoparticles Loaded with Thymulin Against the Relapsing-Remitting Form of Experimental Autoimmune Encephalomyelitis in Mice
by Sergey M. Lunin, Maxim O. Khrenov, Olga V. Glushkova, Svetlana B. Parfenyuk, Tatyana V. Novoselova and Elena G. Novoselova
Int. J. Mol. Sci. 2019, 20(21), 5374; https://doi.org/10.3390/ijms20215374 - 29 Oct 2019
Cited by 9 | Viewed by 2932
Abstract
Relapsing–remitting experimental autoimmune encephalomyelitis (rEAE) in mice is a model that closely resembles relapsing–remitting multiple sclerosis in humans. This study aims to investigate a new approach to modulation of the inflammatory response in rEAE mice using a thymic peptide thymulin bound to polybutylcyanoacrylate [...] Read more.
Relapsing–remitting experimental autoimmune encephalomyelitis (rEAE) in mice is a model that closely resembles relapsing–remitting multiple sclerosis in humans. This study aims to investigate a new approach to modulation of the inflammatory response in rEAE mice using a thymic peptide thymulin bound to polybutylcyanoacrylate (PBCA) nanoparticles. PBCA nanoparticles were used to prolong the presence of thymulin in the blood. Cytokine levels in blood were measured by ELISA; NF-κB and SAPK/JNK cascade activation, as well as Hsp72 and p53 protein expression, were measured by Western blotting. Animal health statuses were estimated using severity scores. Results showed that the cytokine response in rEAE was multi-staged: an early phase was accompanied by an increase in plasma interferon-γ, while the interleukin (IL)-17 response was markedly increased at a later stage. The stages were attributed to rEAE induction and maintenance phases. Thymulin significantly alleviated symptoms of rEAE and lowered plasma cytokine levels both in early and later stages of rEAE, and decreased NF-κB and SAPK/JNK cascade activation. Thymulin modulated NF-kappaB pathway activity via site-specific phosphorylation of RelA/p65 protein (at Ser276 and Ser536). The effect of nanoparticle-bound thymulin was more pronounced than the effect of free thymulin. Therefore, PBCA–thymulin can be considered a prospective treatment for this pathology. Full article
(This article belongs to the Special Issue NF-κB and Disease)
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Review

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19 pages, 2125 KiB  
Review
Targeting NF-κB-Inducing Kinase (NIK) in Immunity, Inflammation, and Cancer
by Kathryn M. Pflug and Raquel Sitcheran
Int. J. Mol. Sci. 2020, 21(22), 8470; https://doi.org/10.3390/ijms21228470 - 11 Nov 2020
Cited by 82 | Viewed by 9488
Abstract
NF-κB-inducing kinase (NIK), the essential upstream kinase, which regulates activation of the noncanonical NF-κB pathway, has important roles in regulating immunity and inflammation. In addition, NIK is vital for maintaining cellular health through its control of fundamental cellular processes, including differentiation, growth, and [...] Read more.
NF-κB-inducing kinase (NIK), the essential upstream kinase, which regulates activation of the noncanonical NF-κB pathway, has important roles in regulating immunity and inflammation. In addition, NIK is vital for maintaining cellular health through its control of fundamental cellular processes, including differentiation, growth, and cell survival. As such aberrant expression or regulation of NIK is associated with several disease states. For example, loss of NIK leads to severe immune defects, while the overexpression of NIK is observed in inflammatory diseases, metabolic disorders, and the development and progression of cancer. This review discusses recent studies investigating the therapeutic potential of NIK inhibitors in various diseases. Full article
(This article belongs to the Special Issue NF-κB and Disease)
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43 pages, 2318 KiB  
Review
Small Molecule NF-κB Pathway Inhibitors in Clinic
by Venkataramanan Ramadass, Thamilselvan Vaiyapuri and Vinay Tergaonkar
Int. J. Mol. Sci. 2020, 21(14), 5164; https://doi.org/10.3390/ijms21145164 - 21 Jul 2020
Cited by 109 | Viewed by 12188
Abstract
Nuclear factor kappa B (NF-κB) signaling is implicated in all major human chronic diseases, with its role in transcription of hundreds of gene well established in the literature. This has propelled research into targeting the NF-κB pathways for modulating expression of those genes [...] Read more.
Nuclear factor kappa B (NF-κB) signaling is implicated in all major human chronic diseases, with its role in transcription of hundreds of gene well established in the literature. This has propelled research into targeting the NF-κB pathways for modulating expression of those genes and the diseases mediated by them. In-spite of the critical, but often promiscuous role played by this pathway and the inhibition causing adverse drug reaction, currently many biologics, macromolecules, and small molecules that modulate this pathway are in the market or in clinical trials. Furthermore, many marketed drugs that were later found to also have NF-κB targeting activity were repurposed for new therapeutic interventions. Despite the rising importance of biologics in drug discovery, small molecules got around 76% of US-FDA (Food and Drug Administration-US) approval in the last decade. This encouraged us to review information regarding clinically relevant small molecule inhibitors of the NF-κB pathway from cell surface receptor stimulation to nuclear signaling. We have also highlighted the underexplored targets in this pathway that have potential to succeed in clinic. Full article
(This article belongs to the Special Issue NF-κB and Disease)
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20 pages, 1063 KiB  
Review
NF-κB and Its Role in Checkpoint Control
by Annika C. Betzler, Marie-Nicole Theodoraki, Patrick J. Schuler, Johannes Döscher, Simon Laban, Thomas K. Hoffmann and Cornelia Brunner
Int. J. Mol. Sci. 2020, 21(11), 3949; https://doi.org/10.3390/ijms21113949 - 31 May 2020
Cited by 43 | Viewed by 6191
Abstract
Nuclear factor-κB (NF-κB) has been described as one of the most important molecules linking inflammation to cancer. More recently, it has become clear that NF-κB is also involved in the regulation of immune checkpoint expression. Therapeutic approaches targeting immune checkpoint molecules, enabling the [...] Read more.
Nuclear factor-κB (NF-κB) has been described as one of the most important molecules linking inflammation to cancer. More recently, it has become clear that NF-κB is also involved in the regulation of immune checkpoint expression. Therapeutic approaches targeting immune checkpoint molecules, enabling the immune system to initiate immune responses against tumor cells, constitute a key breakthrough in cancer treatment. This review discusses recent evidence for an association of NF-κB and immune checkpoint expression and examines the therapeutic potential of inhibitors targeting either NF-κB directly or molecules involved in NF-κB regulation in combination with immune checkpoint blockade. Full article
(This article belongs to the Special Issue NF-κB and Disease)
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20 pages, 598 KiB  
Review
Can NF-κB Be Considered a Valid Drug Target in Neoplastic Diseases? Our Point of View
by Manuela Labbozzetta, Monica Notarbartolo and Paola Poma
Int. J. Mol. Sci. 2020, 21(9), 3070; https://doi.org/10.3390/ijms21093070 - 27 Apr 2020
Cited by 40 | Viewed by 3462
Abstract
Multidrug resistance (MDR), of the innate and acquired types, is one of major problems in treating tumor diseases with a good chance of success. In this review, we examine the key role of nuclear factor-kappa B (NF-κB) to induce MDR in three tumor [...] Read more.
Multidrug resistance (MDR), of the innate and acquired types, is one of major problems in treating tumor diseases with a good chance of success. In this review, we examine the key role of nuclear factor-kappa B (NF-κB) to induce MDR in three tumor models characterized precisely by innate or acquired MDR, in particular triple negative breast cancer (TNBC), hepatocellular carcinoma (HCC), and acute myeloid leukemia (AML). We also present different pharmacological approaches that our group have employed to reduce the expression/activation of this transcriptional factor and thus to restore chemo-sensitivity. Finally, we examine the latest scientific evidence found by other groups, the most significant clinical trials regarding NF-κB, and new perspectives on the possibility to consider this transcriptional factor a valid drug target in neoplastic diseases. Full article
(This article belongs to the Special Issue NF-κB and Disease)
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