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Roles of NF-kB in Inflammatory Diseases and Their Therapeutic Approaches

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Signaling".

Deadline for manuscript submissions: closed (20 March 2022) | Viewed by 19295

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Special Issue Editor

Dr. Sudhiranjan Gupta

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Guest Editor

Biomarkers and Genetics Core, VISN 17 Center of Excellence for Research on Returning War Veterans Doris Miller VAMC, Bldg. 93, Waco, TX 76711, USA
Interests: cardiac hypertrophy; myocardial infarction; pulmonary hypertension; fibrosis; traumatic brain injury; blood brain barrier; inflammation; hypoxia; NF-kB; miRNA; Thymosin beta4

Special Issue Information

Dear Colleagues,

Activation of the Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), a pivotal transcription factor discovered 35 years ago by Ranjan Sen and David Baltimore, elicits an immune, inflammatory and cellular stress response in a wide array of pathological conditions. Inflammation is the body’s natural response against infection and onset of disease or injury. NF-kB is a master regulator of inflammation. A host of debilitating diseases can result from chronic inflammation including cardiovascular, pulmonary, renal, neurological, hepatic and autoimmune diseases such as rheumatoid arthritis (RA).

The aim of this Special Issue of Cells is to publish a collection of original research findings, meta-analyses/systematic reviews, short perspective articles and reviews on NF-kB as a therapeutic target. The editor welcomes submission of original articles that are designed on broad topics including, but not limited to, the role of NF-kB in cardiac, pulmonary, vascular, metabolic and neurological disease mechanism and therapies. Each submitted manuscript will go through a rigorous peer-review process. The submitted manuscripts must not be previously published nor be under consideration with any other journal concurrently at the time of submission.

Dr. Sudhiranjan Gupta
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. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). 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

inflammation
NF-kB
cellular signaling
reactive oxygen species
diseases
therapeutic

Published Papers (5 papers)

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Research

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16 pages, 2125 KiB

Open AccessFeature PaperArticle

Role of Periostin and Nuclear Factor-κB Interplay in the Development of Diabetic Nephropathy

by Lilia Abbad, Niki Prakoura, Arthur Michon, Rym Chalghoumi, Simone Reichelt-Wurm, Miriam C. Banas and Christos Chatziantoniou

Cells 2022, 11(14), 2212; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11142212 - 15 Jul 2022

Cited by 5 | Viewed by 2445

Abstract

Diabetic nephropathy (DN) remains the most common reason for end-stage renal disease and a leading cause of kidney replacement therapy. Multifactorial pathophysiological mechanisms underlie the development of DN. Among the signalling pathways involved, nuclear factor-κB (NF-κB) plays a key role in pathogenesis triggering inflammation, oxidative stress and fibrosis. Recent evidence shows that periostin, a matricellular protein, is involved in the development of renal glomerular diseases through interaction with NF-κB signalling. The aim of the present study is to investigate the contribution of periostin and its interaction with NF-κB in DN development. To this end, we used the BTBR ob/ob mice model of diabetes type 2, and we applied transcriptomic analysis, immunostaining and methods quantifying protein and mRNA expressions. We found that increased periostin expression was correlated with decreased renal function, advanced stage renal damage and fibrosis, and NF-κB activation. Subsequently, we identified novel pathways and genes regulated by the NF-κB-periostin interaction which are involved in the mechanisms of progression of DN. Some of these genes, such as FGF1 and GDF15, have the potential to be new biomarkers and/or targets for the therapy of DN. Full article

(This article belongs to the Special Issue Roles of NF-kB in Inflammatory Diseases and Their Therapeutic Approaches)

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24 pages, 8500 KiB

Open AccessArticle

RELA∙8-Oxoguanine DNA Glycosylase1 Is an Epigenetic Regulatory Complex Coordinating the Hexosamine Biosynthetic Pathway in RSV Infection

by Xiaofang Xu, Dianhua Qiao, Lang Pan, Istvan Boldogh, Yingxin Zhao and Allan R. Brasier

Cells 2022, 11(14), 2210; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11142210 - 15 Jul 2022

Cited by 4 | Viewed by 2318

Abstract

Respiratory syncytial virus (RSV), or human orthopneumovirus, is a negative-sense RNA virus that is the causative agent of severe lower respiratory tract infections in children and is associated with exacerbations of adult lung disease. The mechanisms how severe and/or repetitive virus infections cause declines in pulmonary capacity are not fully understood. We have recently discovered that viral replication triggers epithelial plasticity and metabolic reprogramming involving the hexosamine biosynthetic pathway (HBP). In this study, we examine the relationship between viral induced innate inflammation and the activation of hexosamine biosynthesis in small airway epithelial cells. We observe that RSV induces ~2-fold accumulation of intracellular UDP-GlcNAc, the end-product of the HBP and the obligate substrate of N glycosylation. Using two different silencing approaches, we observe that RSV replication activates the HBP pathway in a manner dependent on the RELA proto-oncogene (65 kDa subunit). To better understand the effect of RSV on the cellular N glycoproteome, and its RELA dependence, we conduct affinity enriched LC-MS profiling in wild-type and RELA-silenced cells. We find that RSV induces the accumulation of 171 N glycosylated peptides in a RELA-dependent manner; these proteins are functionally enriched in integrins and basal lamina formation. To elaborate this mechanism of HBP expression, we demonstrate that RSV infection coordinately induces the HBP pathway enzymes in a manner requiring RELA; these genes include Glutamine-Fructose-6-Phosphate Transaminase 1 (GFPT)-1/2, Glucosamine-Phosphate N-Acetyltransferase (GNPNAT)-1, phosphoglucomutase (PGM)-3 and UDP-N-Acetylglucosamine Pyrophosphorylase (UAP)-1. Using small-molecule inhibitor(s) of 8-oxoguanine DNA glycosylase1 (OGG1), we observe that OGG1 is also required for the expression of HBP pathway. In proximity ligation assays, RSV induces the formation of a nuclear and mitochondrial RELA∙OGG1 complex. In co-immunoprecipitaton (IP) experiments, we discover that RSV induces Ser 536-phosphorylated RELA to complex with OGG1. Chromatin IP experiments demonstrate a major role of OGG1 in supporting the recruitment of RELA and phosphorylated RNA Pol II to the HBP pathway genes. We conclude that the RELA∙OGG1 complex is an epigenetic regulator mediating metabolic reprogramming and N glycoprotein modifications of integrins in response to RSV. These findings have implications for viral-induced adaptive epithelial responses. Full article

(This article belongs to the Special Issue Roles of NF-kB in Inflammatory Diseases and Their Therapeutic Approaches)

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Review

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32 pages, 5241 KiB

Open AccessFeature PaperReview

Therapeutic Targeting of NF-κB in Acute Lung Injury: A Double-Edged Sword

by Michelle Warren Millar, Fabeha Fazal and Arshad Rahman

Cells 2022, 11(20), 3317; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11203317 - 21 Oct 2022

Cited by 33 | Viewed by 4689

Abstract

Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is a devastating disease that can be caused by a variety of conditions including pneumonia, sepsis, trauma, and most recently, COVID-19. Although our understanding of the mechanisms of ALI/ARDS pathogenesis and resolution has considerably increased in recent years, the mortality rate remains unacceptably high (~40%), primarily due to the lack of effective therapies for ALI/ARDS. Dysregulated inflammation, as characterized by massive infiltration of polymorphonuclear leukocytes (PMNs) into the airspace and the associated damage of the capillary-alveolar barrier leading to pulmonary edema and hypoxemia, is a major hallmark of ALI/ARDS. Endothelial cells (ECs), the inner lining of blood vessels, are important cellular orchestrators of PMN infiltration in the lung. Nuclear factor-kappa B (NF-κB) plays an essential role in rendering the endothelium permissive for PMN adhesion and transmigration to reach the inflammatory site. Thus, targeting NF-κB in the endothelium provides an attractive approach to mitigate PMN-mediated vascular injury, not only in ALI/ARDS, but in other inflammatory diseases as well in which EC dysfunction is a major pathogenic mechanism. This review discusses the role and regulation of NF-κB in the context of EC inflammation and evaluates the potential and problems of targeting it as a therapy for ALI/ARDS. Full article

(This article belongs to the Special Issue Roles of NF-kB in Inflammatory Diseases and Their Therapeutic Approaches)

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14 pages, 343 KiB

Open AccessReview

Involvement of Nuclear Factor-κB in Inflammation and Neuronal Plasticity Associated with Post-Traumatic Stress Disorder

by Sudhiranjan Gupta and Rakeshwar S. Guleria

Cells 2022, 11(13), 2034; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11132034 - 27 Jun 2022

Cited by 12 | Viewed by 2368

Abstract

Post-traumatic stress disorder (PTSD) is a debilitating psychiatric condition which develops either due to stress or witnessing a traumatic situation. PTSD is characterized by acute and chronic stress response exhibit anxiety, fear, and an increased inflammatory etiology. Inflammation contributes a critical role in several parts of the brain that control fear and flashback cognatic function. It is known that impairment of the neurological circuit leads to the development of PTSD. Evidence has suggested that dysregulation of the sympathetic nervous system and hypothalamic-pituitary adrenal (HPA) axis and inflammatory responsiveness are pivotal and a greater risk in PTSD. NF-κB, a master regulator for inflammation, has been showed to modulate memory reconsolidation and synaptic plasticity; however, NF-κB’s association with PTSD remain elusive. In this review, we provide relevant findings regarding NF-κB activity in various components of brain and describe a potential mechanism linking PTSD using preclinical and clinical models. We envisage NF-κB signaling as a crucial mediator for inflammation, cognitive function, memory restoration and behavioral actions of stress and suggest that it could be used for therapeutic intervention in PTSD. Full article

(This article belongs to the Special Issue Roles of NF-kB in Inflammatory Diseases and Their Therapeutic Approaches)

16 pages, 1153 KiB

Open AccessReview

Interleukin-1 and Nuclear Factor Kappa B Signaling Promote Breast Cancer Progression and Treatment Resistance

by Sydney Diep, Mahita Maddukuri, Stephanie Yamauchi, Ganamee Geshow and Nikki A. Delk

Cells 2022, 11(10), 1673; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11101673 - 18 May 2022

Cited by 22 | Viewed by 6765

Abstract

While meant for wound healing and immunity in response to injury and infection, inflammatory signaling is usurped by cancerous tumors to promote disease progression, including treatment resistance. The interleukin-1 (IL-1) inflammatory cytokine family functions in wound healing and innate and adaptive immunity. Two major, closely related IL-1 family members, IL-1α and IL-1β, promote tumorigenic phenotypes and contribute to treatment resistance in cancer. IL-1 signaling converges on transactivation of the Nuclear Factor Kappa B (NF-κB) and Activator protein 1 (AP-1) transcription factors. NF-κB and AP-1 signaling are also activated by the inflammatory cytokine Tumor Necrosis Factor Alpha (TNFα) and microbe-sensing Toll-Like Receptors (TLRs). As reviewed elsewhere, IL-1, TNFα, and TLR can promote cancer progression through NF-κB or AP-1. In this review, we focus on what is known about the role of IL-1α and IL-1β in breast cancer (BCa) progression and therapeutic resistance, and state evidence for the role of NF-κB in mediating IL-1-induced BCa progression and therapeutic resistance. We will present evidence that IL-1 promotes BCa cell proliferation, BCa stem cell expansion, angiogenesis, and metastasis. IL-1 also regulates intracellular signaling and BCa cell hormone receptor expression in a manner that confers a growth advantage to the tumor cells and allows BCa cells to evade therapy. As such, the IL-1 receptor antagonist, anakinra, is in clinical trials to treat BCa and multiple other cancer types. This article presents a review of the literature from the 1990s to the present, outlining the evidence supporting a role for IL-1 and IL-1-NF-κB signaling in BCa progression. Full article

(This article belongs to the Special Issue Roles of NF-kB in Inflammatory Diseases and Their Therapeutic Approaches)

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