Submit to IJMS Review for IJMS Propose a Special Issue

Journal Menu

Journal Browser

NF-κB and Disease 3.0

Special Issue Editors
Special Issue Information
Keywords
Related Special Issues
Published Papers

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Immunology".

Deadline for manuscript submissions: closed (31 January 2023) | Viewed by 11955

Share This Special Issue

Special Issue Editor

Dr. Paola Poma

E-Mail Website
Guest Editor

Department of Biological, Chemical and Pharmaceutical Science and Technology (STEBICEF), University of Palermo, 90128 Palermo, Italy
Interests: anticancer pharmacology; drug resistance; natural compounds; breast cancer; leukemia; HCC
Special Issues, Collections and Topics in MDPI journals

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 such 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 biocompatible conjugates, which act as NF-κB inhibitors.

Dr. Paola Poma
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

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

Related Special Issues

NF-κB and Disease in International Journal of Molecular Sciences (11 articles)
NF-κB and Disease 2.0 in International Journal of Molecular Sciences (8 articles)

Published Papers (7 papers)

Download All Papers

Order results

Result details

Show export options Show export options

Select all

Export citation of selected articles as:

Research

Jump to: Review

21 pages, 4327 KiB

Open AccessArticle

Lost and Found: The Family of NF-κB Inhibitors Is Larger than Assumed in Salmonid Fish

by Doret R. van Muilekom, Bertrand Collet, Henrike Rebl, Kristina Zlatina, Fabio Sarais, Tom Goldammer and Alexander Rebl

Int. J. Mol. Sci. 2023, 24(12), 10229; https://doi.org/10.3390/ijms241210229 - 16 Jun 2023

Cited by 2 | Viewed by 1254

Abstract

NF-κB signalling is largely controlled by the family of ‘inhibitors of NF-κB’ (IκB). The relevant databases indicate that the genome of rainbow trout contains multiple gene copies coding for iκbα (nfkbia), iκbε (nfkbie), iκbδ (nkfbid), iκbζ (nfkbiz), and bcl3, but it lacks iκbβ (nfkbib) and iκbη (ankrd42). Strikingly, three nfkbia paralogs are apparently present in salmonid fish, two of which share a high sequence identity, while the third putative nfkbia gene is significantly less like its two paralogs. This particular nfkbia gene product, iκbα, clusters with the human IκBβ in a phylogenetic analysis, while the other two iκbα proteins from trout associate with their human IκBα counterpart. The transcript concentrations were significantly higher for the structurally more closely related nfkbia paralogs than for the structurally less similar paralog, suggesting that iκbβ probably has not been lost from the salmonid genomes but has been incorrectly designated as iκbα. In the present study, two gene variants coding for iκbα (nfkbia) and iκbε (nfkbie) were prominently expressed in the immune tissues and, particularly, in a cell fraction enriched with granulocytes, monocytes/macrophages, and dendritic cells from the head kidney of rainbow trout. Stimulation of salmonid CHSE-214 cells with zymosan significantly upregulated the iκbα-encoding gene while elevating the copy numbers of the inflammatory markers interleukin-1-beta and interleukin-8. Overexpression of iκbα and iκbε in CHSE-214 cells dose-dependently quenched both the basal and stimulated activity of an NF-κB promoter suggesting their involvement in immune-regulatory processes. This study provides the first functional data on iκbε—versus the well-researched iκbα factor—in a non-mammalian model species. Full article

(This article belongs to the Special Issue NF-κB and Disease 3.0)

► Show Figures

Figure 1

17 pages, 2204 KiB

Open AccessArticle

NF-κB Signaling Modulates miR-452-5p and miR-335-5p Expression to Functionally Decrease Epithelial Ovarian Cancer Progression in Tumor-Initiating Cells

by Rahul D. Kamdar, Brittney S. Harrington, Emma Attar, Soumya Korrapati, Jyoti Shetty, Yongmei Zhao, Bao Tran, Nathan Wong, Carrie D. House and Christina M. Annunziata

Int. J. Mol. Sci. 2023, 24(9), 7826; https://doi.org/10.3390/ijms24097826 - 25 Apr 2023

Cited by 2 | Viewed by 1398

Abstract

Epithelial ovarian cancer (EOC) remains the fifth leading cause of cancer-related death in women worldwide, partly due to the survival of chemoresistant, stem-like tumor-initiating cells (TICs) that promote disease relapse. We previously described a role for the NF-κB pathway in promoting TIC chemoresistance and survival through NF-κB transcription factors (TFs) RelA and RelB, which regulate genes important for the inflammatory response and those associated with cancer, including microRNAs (miRNAs). We hypothesized that NF-κB signaling differentially regulates miRNA expression through RelA and RelB to support TIC persistence. Inducible shRNA was stably expressed in OV90 cells to knockdown RELA or RELB; miR-seq analyses identified differentially expressed miRNAs hsa-miR-452-5p and hsa-miR-335-5p in cells grown in TIC versus adherent conditions. We validated the miR-seq findings via qPCR in TIC or adherent conditions with RELA or RELB knocked-down. We confirmed decreased expression of hsa-miR-452-5p when either RELA or RELB were depleted and increased expression of hsa-miR-335-5p when RELA was depleted. Either inhibiting miR-452-5p or mimicking miR-335-5p functionally decreased the stem-like potential of the TICs. These results highlight a novel role of NF-κB TFs in modulating miRNA expression in EOC cells, thus opening a better understanding toward preventing recurrence of EOC. Full article

(This article belongs to the Special Issue NF-κB and Disease 3.0)

► Show Figures

Figure 1

15 pages, 1333 KiB

Open AccessArticle

The Pro-Inflammatory Deletion Allele of the NF-κB1 Polymorphism Is Characterized by a Depletion of Subunit p50 in Sepsis

by Britta Marko, Paulina Heurich, Patrick Thon, Frieda Zimmer, Lars Bergmann, Hartmuth Nowak, Katharina Rump, Björn Koos, Michael Adamzik, Matthias Unterberg and Tim Rahmel

Int. J. Mol. Sci. 2022, 23(14), 7559; https://doi.org/10.3390/ijms23147559 - 08 Jul 2022

Viewed by 1223

Abstract

The functionally important NF-κB1 promoter polymorphism (−94ins/delATTG) significantly shapes inflammation and impacts the outcome of sepsis. However, exploratory studies elucidating the molecular link of this genotype-dependent pattern are lacking. Accordingly, we analyzed lipopolysaccharide-stimulated peripheral blood mononuclear cells from both healthy volunteers (n = 20) and septic patients (n = 10). All individuals were genotyped for the −94ins/delATTG NF-κB1 promoter polymorphism. We found a diminished nuclear activity of the NF-κB subunit p50 in ID/DD genotypes after 48 h of lipopolysaccharide stimulation compared to II genotypes (p = 0.025). This was associated with higher TNF-α (p = 0.005) and interleukin 6 concentrations (p = 0.014) and an increased production of mitochondrial radical oxygen species in ID/DD genotypes (p = 0.001). Although ID/DD genotypes showed enhanced activation of mitochondrial biogenesis, they still had a significantly diminished cellular ATP content (p = 0.046) and lower mtDNA copy numbers (p = 0.010) compared to II genotypes. Strikingly, these findings were mirrored in peripheral blood mononuclear cells taken from septic patients. Our results emphasize the crucial aspect of considering NF-κB subunits in sepsis. We showed here that the deletion allele of the NF-κB1 (−94ins/delATTG) polymorphism was associated with the lower nuclear activity of subunit p50, which, in turn, was associated with aggravated inflammation and mitochondrial dysfunction. Full article

(This article belongs to the Special Issue NF-κB and Disease 3.0)

► Show Figures

Figure 1

13 pages, 2193 KiB

Open AccessArticle

Dipotassium Glycyrrhizinate on Melanoma Cell Line: Inhibition of Cerebral Metastases Formation by Targeting NF-kB Genes-Mediating MicroRNA-4443 and MicroRNA-3620—Dipotassium Glycyrrhizinate Effect on Melanoma

by Gabriel Alves Bonafé, Jéssica Silva dos Santos, Jussara Vaz Ziegler, Fernando Augusto Lima Marson, Thalita Rocha and Manoela Marques Ortega

Int. J. Mol. Sci. 2022, 23(13), 7251; https://doi.org/10.3390/ijms23137251 - 29 Jun 2022

Cited by 4 | Viewed by 1748

Abstract

Glycyrrhizic acid (GA), a natural compound isolated from licorice (Glycyrrhiza glabra), has exhibited anti-inflammatory and anti-tumor effects in vitro. Dipotassium glycyrrhizinate (DPG), a dipotassium salt of GA, also has shown an anti-tumor effect on glioblastoma cell lines, U87MG and T98G. The study investigated the DPG effects in the melanoma cell line (SK-MEL-28). MTT assay demonstrated that the viability of the cells was significantly decreased in a time- and dose-dependent manner after DPG (IC₅₀ = 36 mM; 24 h). DNA fragmentation suggested that DPG (IC₅₀) induced cellular apoptosis, which was confirmed by a significant number of TUNEL-positive cells (p-value = 0.048) and by PARP-1 [0.55 vs. 1.02 arbitrary units (AUs), p-value = 0.001], BAX (1.91 vs. 1.05 AUs, p-value = 0.09), and BCL-2 (0.51 vs. 1.07 AUs, p-value = 0.0018) mRNA compared to control cells. The proliferation and wound-healing assays showed an anti-proliferative effect on DPG-IC₅₀-treated cells, also indicating an inhibitory effect on cell migration (p-values < 0.001). Moreover, it was observed that DPG promoted a 100% reduction in melanospheres formation (p-value = 0.008). Our previous microRNAs (miRs) global analysis has revealed that DPG might increase miR-4443 and miR-3620 expression levels. Thus, qPCR showed that after DPG treatment, SK-MEL-28 cells presented significantly high miR-4443 (1.77 vs. 1.04 AUs, p-value = 0.02) and miR-3620 (2.30 vs. 1.00 AUs, p-value = 0.01) expression compared to control cells, which are predicted to target the NF-kB, CD209 and TNC genes, respectively. Both genes are responsible for cell attachment and migration, and qPCR revealed significantly decreased CD209 (1.01 vs. 0.54 AUs, p-value = 0.018) and TNC (1.00 vs. 0.31 AUs, p-value = 2.38 × 10⁻⁶) mRNA expression levels after DPG compared to untreated cells. Furthermore, the migration of SK-MEL-28 cells stimulated by 12-O-tetradecanoylphorbol-13-acetate (TPA) was attenuated by adding DPG by wound-healing assay (48 h: p-value = 0.004; 72 h: p-value = 7.0 × 10⁻⁴). In addition, the MMP-9 expression level was inhibited by DPG in melanoma cells stimulated by TPA and compared to TPA-treated cells (3.56 vs. 0.99 AUs, p-value = 0.0016) after 24 h of treatment. Our results suggested that DPG has an apoptotic, anti-proliferative, and anti-migratory effect on SK-MEL-28 cells. DPG was also able to inhibit cancer stem-like cells that may cause cerebral tumor formation. Full article

(This article belongs to the Special Issue NF-κB and Disease 3.0)

► Show Figures

Figure 1

17 pages, 4010 KiB

Open AccessArticle

Cucurbitacin B Down-Regulates TNF Receptor 1 Expression and Inhibits the TNF-α-Dependent Nuclear Factor κB Signaling Pathway in Human Lung Adenocarcinoma A549 Cells

by Eiichi Kusagawa, Chiharu Okuda, Rikako Yamaguchi, Kaori Nakano, Yasunobu Miyake and Takao Kataoka

Int. J. Mol. Sci. 2022, 23(13), 7130; https://doi.org/10.3390/ijms23137130 - 27 Jun 2022

Cited by 9 | Viewed by 1829

Abstract

Pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α), induce the expression of intracellular adhesion molecule-1 (ICAM-1) by activating the nuclear factor κB (NF-κB) signaling pathway. In the present study, we found that cucurbitacin B decreased the expression of ICAM-1 in human lung adenocarcinoma A549 cells stimulated with TNF-α or interleukin-1α. We further investigated the mechanisms by which cucurbitacin B down-regulates TNF-α-induced ICAM-1 expression. Cucurbitacin B inhibited the nuclear translocation of the NF-κB subunit RelA and the phosphorylation of IκBα in A549 cells stimulated with TNF-α. Cucurbitacin B selectively down-regulated the expression of TNF receptor 1 (TNF-R1) without affecting three adaptor proteins (i.e., TRADD, RIPK1, and TRAF2). The TNF-α-converting enzyme inhibitor suppressed the down-regulation of TNF-R1 expression by cucurbitacin B. Glutathione, N-acetyl-L-cysteine, and, to a lesser extent, L-cysteine attenuated the inhibitory effects of cucurbitacin B on the TNF-α-induced expression of ICAM-1, suggesting that an α,β-unsaturated carbonyl moiety is essential for anti-inflammatory activity. The present results revealed that cucurbitacin B down-regulated the expression of TNF-R1 at the initial step in the TNF-α-dependent NF-κB signaling pathway. Full article

(This article belongs to the Special Issue NF-κB and Disease 3.0)

► Show Figures

Figure 1

20 pages, 2934 KiB

Open AccessArticle

Synthesis, In Vitro and In Silico Analysis of New Oleanolic Acid and Lupeol Derivatives against Leukemia Cell Lines: Involvement of the NF-κB Pathway

by Gianfranco Fontana, Natale Badalamenti, Maurizio Bruno, Davide Castiglione, Monica Notarbartolo, Paola Poma, Alberto Spinella, Marco Tutone and Manuela Labbozzetta

Int. J. Mol. Sci. 2022, 23(12), 6594; https://doi.org/10.3390/ijms23126594 - 13 Jun 2022

Cited by 2 | Viewed by 1953

Abstract

Oleanolic acid (OA) and Lupeol (LU) belong to the class of natural triterpenes and are endowed with a wide range of biological activities, including cytotoxicity toward several cancer cell lines. In this context, we investigated a set of compounds obtained from the two natural precursors for the cytotoxicity against leukemia HL60 cells and the multidrug-resistant (MDR) variant HL60R. Six new semi-synthetic triterpenes have been synthetized, fully characterized, and were investigated together with other triterpenes compounds for their pharmacological mechanism of action. The interaction of the more cytotoxic compounds with the nuclear factor kappa B (NF-κB) pathway has been also evaluated with the aid of docking. The lupane-like compounds were more active than the precursor, while the oleane-like compounds showed more complex behavior. Both OA and LU derivatives possess a similar interaction pattern with the p65 subunit of NF-κB, justifying the similar trend in their ability to inhibit the binding of p65 to DNA. Further, some of the derivatives tested were able to increase IκB-α levels preventing the translocation of NF-κB to the nucleus. In conclusion, this study offers a deeper insight on the pharmacological action of triterpenes toward leukemia cells, and it improves the background useful for the development of new anti-cancer drugs. Full article

(This article belongs to the Special Issue NF-κB and Disease 3.0)

► Show Figures

Figure 1

Review

Jump to: Research

16 pages, 1810 KiB

Open AccessReview

Role of NF-κB Signaling in the Interplay between Multiple Myeloma and Mesenchymal Stromal Cells

by Marco Cippitelli, Helena Stabile, Andrea Kosta, Sara Petillo, Lorenzo Lucantonio, Angela Gismondi, Angela Santoni and Cinzia Fionda

Int. J. Mol. Sci. 2023, 24(3), 1823; https://doi.org/10.3390/ijms24031823 - 17 Jan 2023

Cited by 7 | Viewed by 1901

Abstract

Nuclear factor-κB (NF-κB) transcription factors play a key role in the pathogenesis of multiple myeloma (MM). The survival, proliferation and chemoresistance of malignant plasma cells largely rely on the activation of canonical and noncanonical NF-κB pathways. They are triggered by cancer-associated mutations or by the autocrine and paracrine production of cytokines and growth factors as well as direct interaction with cellular and noncellular components of bone marrow microenvironment (BM). In this context, NF-κB also significantly affects the activity of noncancerous cells, including mesenchymal stromal cells (MSCs), which have a critical role in disease progression. Indeed, NF-κB transcription factors are involved in inflammatory signaling that alters the functional properties of these cells to support cancer evolution. Moreover, they act as regulators and/or effectors of pathways involved in the interplay between MSCs and MM cells. The aim of this review is to analyze the role of NF-κB in this hematologic cancer, focusing on NF-κB-dependent mechanisms in tumor cells, MSCs and myeloma–mesenchymal stromal cell crosstalk. Full article

(This article belongs to the Special Issue NF-κB and Disease 3.0)

► Show Figures

Journal Menu

Journal Browser

NF-κB and Disease 3.0

Share This Special Issue

Special Issue Editor

Special Issue Information

Keywords

Related Special Issues

Published Papers (7 papers)

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI