Dysregulation Of NF-κB Research Articles

Metabolomic Effects of Liraglutide Therapy on the Plasma Metabolomic Profile of Patients with Obesity.

Liraglutide, a long-acting glucagon-like peptide-1 receptor agonist (GLP1RA), is a well-established anti-diabetic drug, has also been approved for the treatment of obesity at a dose of 3 mg. There are a limited number of studies in the literature that have looked at changes in metabolite levels before and after liraglutide treatment in patients with obesity. To this end, in the present study we aimed to explore the changes in the plasma metabolomic profile, using liquid chromatography-high resolution mass spectrometry (LC-HRMS) in patients with obesity. A single-center prospective study was undertaken to evaluate the effectiveness of 3 mg liraglutide therapy in twenty-three patients (M/F: 8/15) with obesity, mean BMI 40.81 ± 5.04 kg/m2, and mean age of 36 ± 10.9 years, in two groups: at baseline (pre-treatment) and after 12 weeks of treatment (post-treatment). An untargeted metabolomic profiling was conducted in plasma from the pre-treatment and post-treatment groups using LC-HRMS, along with bioinformatics analysis using ingenuity pathway analysis (IPA). The metabolomics analysis revealed a significant (FDR p-value ≤ 0.05, FC 1.5) dysregulation of 161 endogenous metabolites (97 upregulated and 64 downregulated) with distinct separation between the two groups. Among the significantly dysregulated metabolites, the majority of them were identified as belonging to the class of oxidized lipids (oxylipins) that includes arachidonic acid and its derivatives, phosphorglycerophosphates, N-acylated amino acids, steroid hormones, and bile acids. The biomarker analysis conducted using MetaboAnalyst showed PGP (a21:0/PG/F1alpha), an oxidized lipid, as the first metabolite among the list of the top 15 biomarkers, followed by cysteine and estrone. The IPA analysis showed that the dysregulated metabolites impacted the pathway related to cell signaling, free radical scavenging, and molecular transport, and were focused around the dysregulation of NF-κB, ERK, MAPK, PKc, VEGF, insulin, and pro-inflammatory cytokine signaling pathways. The findings suggest that liraglutide treatment reduces inflammation and modulates lipid metabolism and oxidative stress. Our study contributes to a better understanding of the drug's multifaceted impact on overall metabolism in patients with obesity.

Amicis Omnia Sunt Communia: NF-κB Inhibition as an Alternative to Overcome Osteosarcoma Heterogeneity.

Tumor heterogeneity poses a significant challenge in osteosarcoma (OS) treatment. In this regard, the "omics" era has constantly expanded our understanding of biomarkers and altered signaling pathways (i.e., PI3K/AKT/mTOR, WNT/β-catenin, NOTCH, SHH/GLI, among others) involved in OS pathophysiology. Despite different players and complexities, many commonalities have been described, among which the nuclear factor kappa B (NF-κB) stands out. Its altered activation is pervasive in cancer, with pleiotropic action on many disease-relevant traits. Thus, in the scope of this article, we highlight the evidence of NF-κB dysregulation in OS and its integration with other cancer-related pathways while we summarize the repertoire of compounds that have been described to interfere with its action. In silico strategies were used to demonstrate that NF-κB is closely coordinated with other commonly dysregulated signaling pathways not only by functionally interacting with several of their members but also by actively participating in the regulation of their transcription. While existing inhibitors lack selectivity or act indirectly, the therapeutic potential of targeting NF-κB is indisputable, first for its multifunctionality on most cancer hallmarks, and secondly, because, as a common downstream effector of the many dysregulated pathways influencing OS aggressiveness, it turns complex regulatory networks into a simpler picture underneath molecular heterogeneity.

NFκB Dysregulation in the Bone Marrow Niche Drives Epigenomic Reprogramming of Hematopoietic Stem Cells and Myeloid Bias

Introduction Aging and chronic inflammation are known to skew hematopoietic output by favoring myelopoiesis and disfavoring lymphopoiesis. In addition, the bone marrow niche plays critical roles in supporting steady-state hematopoiesis, and alterations in the microenvironment may similarly influence disordered hematopoiesis. The NFkB system is a central, pleiotropic regulator of inflammatory signaling in many cell types. Thus, we reasoned that experimental perturbations of NFκB signaling may be used to study how inflammatory dysregulation affects hematopoiesis. Methods We generated a mouse model of inflammatory immune dysregulation, the IκB - mouse ( Nfkbia +/- Nfkbib -/-Nfkbie -/-), and then compared the peripheral blood and bone marrow inflammatory proteins and cell compositions betweenyoung WT, young IκB -,and aged WT mice. Using bone marrow transplantation, we next assayed the effect of an inflamed IκB - recipient niche on the hematopoietic output of WT donor bone marrow. Finally, we performed single cell RNA sequencing (scRNA-seq) and assay for transposase-accessible chromatin sequencing (ATAC-seq) on sorted hematopoietic stem and progenitor cells (HSPC) to characterize the epigenomic and transcriptional changes occurring in WT HSPC from an immune dysregulated environment. Results We observed an increase in inflammatory cytokines in both young IκB - and aged WT mice compared to young WT controls, as well as myeloid bias in the peripheral blood leukocytes and bone marrow HPSC. Transplantation studies showed that inflammatory dysregulation in the radio-resistant microenvironment resulted in myeloid-biased hematopoiesis. However, this myeloid bias was lost upon secondary transplantation of bone marrow into a WT recipient. Performed on HSPC from an inflamed microenvironment, our scRNA-seq studies showed myeloid bias at the transcriptional level, and ATAC-seq studies further revealed epigenomic changes, with an increased transcription factor (TF) binding motif accessibility for myeloid-priming TFs in long term HSC. Conclusions Our studies establish the IκB - mouse as a new model of chronic inflammatory dysregulation that can be used to study the effects of an inflamed bone marrow microenvironment on hematopoiesis. Furthermore, our findings indicate that dysregulated NFκB signaling in the bone marrow microenvironment leads to myeloid bias in HSPC, and is associated with epigenomic reprogramming at the stem cell level. However, despite this epigenomic reprogramming, we observed that myeloid bias could be reversed upon bone marrow re-transplant into a non-dysregulated niche. Together, these data suggest that further understanding niche-derived inflammatory dysregulation may be a useful in targeting disordered hematopoiesis in chronic inflammatory states such as aging.

DNA-dependent protein kinase catalytic subunit binds to the transactivation domain 1 of NF-κB p65

Nuclear factor-kappa B (NF-κB) is a transcriptional factor that binds to the ∼10-base-pair κB motif on target genes and acts as an inflammatory regulator. Since dysregulation of NF-κB is thought to be related to various diseases, it would be very important to elucidate its post-translational modifications and binding partners in detail and to deeply understand mechanisms of the NF-κB dysregulation. NF-κB p65 is known to interact with the basic transcription factor TFIID subunit hTAFII31/TAF9 through the ФXXФФ (Ф, hydrophobic amino acid; X, any amino acid) motif in a similar fashion to p53. MDM2 is known to inhibit p53 from binding to hTAFII31/TAF9 by masking p53's ФXXФФ motif. Here, as can be rationalized from this observation, we searched for novel nuclear proteins that interact with the transactivation domain 1 (TA1) of NF-κB p65 containing a ФXXФФ motif. We prepared a GST-tagged polypeptide, GST-p65532–550, from Phe532–Ser550 of the TA1 domain and found various U937 cell nuclear proteins that bound to GST-p65532–550. The largest bound protein the size of ∼400 kDa was subjected to mass spectrometric analysis and found to be DNA-dependent protein kinase catalytic subunit (DNA-PKcs). An immunoprecipitation experiment with an antibody against p65 and nuclear extracts from TNF-α-treated A549 cells suggested that NF-κB p65 indeed binds to DNA-PKcs in human cells. Furthermore, binding assays with a series of His-tagged DNA-PKcs fragments suggested that DNA-PKcs can bind to NF-κB p65 through the interaction of the TA1 domain with the region 541−750 in the N-HEAT domain or the region 2485−2576 in the M-HEAT domain.

MiR-582-5p targets Skp1 and regulates NF-κB signaling-mediated inflammation

A well-tuned inflammatory response is crucial for an effective immune process. Nuclear factor-kappa B (NF-κB) is a key mediator of inflammatory and innate immunity responses, and its dysregulation is closely associated with immune-related diseases. MicroRNAs (miRNAs) are important inflammation modulators. However, miRNA-regulated mechanisms that implicate NF-κB activity are not fully understood. This study aimed to identify a potential miRNA that could modulate the dysregulated NF-κB signaling during inflammation. We identified miR-582-5p that was significantly downregulated in inflamed murine adipose tissues and RAW264.7 cells. S-phase kinase-associated protein 1 (SKP1), a core component of an E3 ubiquitin ligase that regulates the NF-κB pathway, was proposed as a biological target of miR-582-5p by using TargetScan. The binding of miR-582-5p to a 3′-untranslated region site on Skp1 was confirmed using a dual-luciferase reporter assay; in addition, transfection with a miR-582-5p mimic suppressed SKP1 expression in RAW264.7 cells. Importantly, exogenous miR-582-5p attenuated the production of pro-inflammatory cytokines such as tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-6 through suppressing the degradation of the NF-κB inhibitor alpha, followed by the nuclear translocation of NF-κB. Therefore, exogenously applied miR-582-5p can attenuate the NF-κB signaling pathway via targeting Skp1; this provides a prospective therapeutic strategy for treating inflammatory and immune diseases.

Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) and Nuclear Factor-Kappa B (NF- κB) Expression in Chronic Kidney Disease Patients (CKD) from South India

Aim: The present study elucidated the expression level of Nrf2 and NF-κB, in chronic kidney disease (CKD) patients from South India. Further, the expression levels of these genes are analyzed for cytokines TNF-α and IFN-γ and various subgroups of cases including dialysis, non-dialysis, diabetic and non-diabetic CKD patients, and correlation analysis performed. Methods: 133 CKD patients and 133 healthy individuals were enrolled for the evaluation of NF-κB and Nrf2 expression by qPCR. Results: Upregulated Nrf2 mRNA expression (as fold change) was observed in diabetic (Fc: 1.13), and non-diabetic (Fc: 1.30) patients. Inversely, Nrf2 mRNA expression was down regulated in non-dialysis groups (Fc: 0.80). NF-κB expression was significantly upregulated in non-diabetic (Fc:1.92), non-dialysis (Fc:1.59), dialysis (Fc: 1.36) and CKD patients (pooled) (Fc: 1.27). A dysregulated NF-κB expression was observed in diabetic groups (Fc: 0.69). Nrf2 mRNA expression were positively correlated with IFN-γ expression in diabetes (r = 0.28, p = 0.05) and non-diabetic CKD patients (r = 0.37, p < 0.002). Likewise, TNF-α expression was positively correlated with Nrf2 expression in CKD (pooled) patients (r = 0.33, p < 0.000). A negative correlation was observed in Nrf2 and NF-κB expression in CKD (pooled) (r = -0.028, p = 0.833). Conclusion: The study concluded the down regulated Nrf2 and upregulated NF-κB expressions in non-dialysis patients. On the contrary, in diabetic CKD patients, the expression level of NF-κB was downregulated and Nrf2 was upregulated. Thus, a negative correlation was observed between Nrf2 and NF-κB genes with respect to their expression patterns.

Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) and Nuclear Factor-Kappa B (NF- κB) Expression in Chronic Kidney Disease Patients (CKD) from South India

Aim: The present study elucidated the expression level of Nrf2 and NF-κB, in chronic kidney disease (CKD) patients from South India. Further, the expression levels of these genes are analyzed for cytokines TNF-α and IFN-γ and various subgroups of cases including dialysis, non-dialysis, diabetic and non-diabetic CKD patients, and correlation analysis performed. Methods: 133 CKD patients and 133 healthy individuals were enrolled for the evaluation of NF-κB and Nrf2 expression by qPCR. Results: Upregulated Nrf2 mRNA expression (as fold change) was observed in diabetic (Fc: 1.13), and non-diabetic (Fc: 1.30) patients. Inversely, Nrf2 mRNA expression was down regulated in non-dialysis groups (Fc: 0.80). NF-κB expression was significantly upregulated in non-diabetic (Fc:1.92), non-dialysis (Fc:1.59), dialysis (Fc: 1.36) and CKD patients (pooled) (Fc: 1.27). A dysregulated NF-κB expression was observed in diabetic groups (Fc: 0.69). Nrf2 mRNA expression were positively correlated with IFN-γ expression in diabetes (r = 0.28, p = 0.05) and non-diabetic CKD patients (r = 0.37, p < 0.002). Likewise, TNF-α expression was positively correlated with Nrf2 expression in CKD (pooled) patients (r = 0.33, p < 0.000). A negative correlation was observed in Nrf2 and NF-κB expression in CKD (pooled) (r = -0.028, p = 0.833). Conclusion: The study concluded the down regulated Nrf2 and upregulated NF-κB expressions in non-dialysis patients. On the contrary, in diabetic CKD patients, the expression level of NF-κB was downregulated and Nrf2 was upregulated. Thus, a negative correlation was observed between Nrf2 and NF-κB genes with respect to their expression patterns.

THE ROLE OF LABORATORY EVALUATION IN THE DIAGNOSIS AND MANAGEMENT OF NLRP12- ASSOCIATED AUTOINFLAMMATORY DISEASE

<h3>Introduction</h3> This case highlights the relevance of including autoinflammatory diseases in the differential diagnosis of adults with recurrent fever or episodes of shock. The role of genetic testing and confirmatory functional testing in the diagnosis and therapeutic management of autoinflammatory diseases is also discussed. <h3>Case Description</h3> A 67-year-old man presented with a 2-year history of episodes of shock of unknown etiology. Symptoms included hypotension, fever and abdominal pain requiring vasopressor support and antibiotics. Extensive infectious, autoimmune and rheumatological work-up was negative. Bone marrow biopsy showed chronic myelomonocytic leukemia (CMML) that Oncology determined was non-contributory and did not require treatment. Immunological investigations demonstrated elevated IgE, CD8+ T cell lymphocytosis during episodes of shock and increased sCD163. A targeted NGS panel revealed a heterozygous VUS in the <i>NLRP12</i> gene. Functional studies were performed offline to evaluate inflammasome activity. PBMCs stimulated with LPS for 24h revealed substantially elevated levels of IL-1β, IL-6 and TNF-α compared to healthy controls suggesting inflammasome activation and NFκB dysregulation. This prompted initiation of IL-1β blockade with canakinumab, with symptom resolution. <h3>Discussion</h3> In adults presenting with a hyperinflammatory state of unknown etiology, immunological investigations should be pursued for a possible autoinflammatory syndrome. In this case, genetic testing identified a VUS in <i>NLRP12</i>. NLRP12 is an inflammasome in which LOF and GOF variants have been reported with disease manifestations, including cold-induced autoinflammatory syndrome (FCAS). NLRP12 also regulates NFκB, which may explain some of the observed hyperinflammation. This patient had complete response to IL-1β blockade. Functional evaluation of VUS may provide an opportunity for therapeutic intervention.

Uncovering incontinentia pigmenti: From DNA sequence to pathophysiology.

Incontinentia pigmenti (IP) is an X-linked dominant genodermatosis. The disease is known to be caused by recurrent deletion of exons 4–10 of the Inhibitor Of Nuclear Factor Kappa B Kinase Regulatory Subunit Gamma (IKBKG) gene located at the Xq28 chromosomal region, which encodes for NEMO/IKKgamma, a regulatory protein involved in the nuclear factor kappa B (NF-κB) signaling pathway. NF-κB plays a prominent role in the modulation of cellular proliferation, apoptosis, and inflammation. IKBKG mutation that results in a loss-of-function or dysregulated NF-κB pathway contributes to the pathophysiology of IP. Aside from typical skin characteristics such as blistering rash and wart-like skin growth presented in IP patients, other clinical manifestations like central nervous system (CNS) and ocular anomalies have also been detected. To date, the clinical genotype-phenotype correlation remains unclear due to its highly variable phenotypic expressivity. Thus, genetic findings remain an essential tool in diagnosing IP, and understanding its genetic profile allows a greater possibility for personalized treatment. IP is slowly and gradually gaining attention in research, but there is much that remains to be understood. This review highlights the progress that has been made in IP including the different types of mutations detected in various populations, current diagnostic strategies, IKBKG pathophysiology, genotype-phenotype correlation, and treatment strategies, which provide insights into understanding this rare mendelian disorder.

Diminished noncanonical NF-κB signaling induces colitis-associated colorectal cancer susceptibility upon de-differentiation of epithelial cells

Abstract Patients with a medical history of Inflammatory Bowel Disease are predisposed to developing colitis-associated colorectal cancer (CAC), with greater than 20% developing CAC within 30 years of disease onset. CAC is a form of inflammation-induced tumorigenesis, where unregulated inflammation causes cells in the colon to accumulate mutations poising them for neoplasia. We demonstrate that NF-κB inducing kinase (NIK) is a critical regulator of intestinal epithelial cell (IEC) regeneration. We hypothesize that IECs exposed to chronic inflammatory conditions mitigated by dysregulated noncanonical NF-κB signaling are most prone to mutagenesis and cancer-initiating events termed Top-down tumorigenesis. In CAC, NIK depletion results in the accumulation of mature IECs that are increasingly susceptible to mutation and neoplastic transformation. This suggests that terminally differentiated IECs dedifferentiate into a stem-like phenotype. Our work has clinical relevancy, where human CAC biopsy samples have diminished noncanonical NF-κB signaling and NIK (MAP3K14) gene expression. Murine models with NIK deletion in IECs have increased susceptibility to inflammation-induced tumorigenesis following the chemical induction of AOM/DSS to induce colitis. Our mechanistic studies evaluating crypts demonstrate accumulation of mature, non-dividing IECs, which are more susceptible to mutations and malignant transformation. Here, we present a novel role for noncanonical NF-κB signaling in regulating intestinal epithelial cell turnover in protecting against CAC development. Focusing on the key niche signaling interplay following noncanonical NF-κB dysregulation gives greater insight into the CAC tumor microenvironment. Supported by grants from the iTHRIVE Pilot Translational and Clinical Studies Program, VCOM Center for One Health Research, Virginia Tech Carilion Research Acceleration Program, and the Virginia-Maryland College of Veterinary Medicine.

NF-κB Signaling and Inflammation-Drug Repurposing to Treat Inflammatory Disorders?

Simple SummarySince its first description 35 years ago, the transcription factor NF-κB (nuclear factor κ-light-chain-enhancer of activated B cells) has been shown to be a key mediator of immune cell responses to inflammatory mediators, oxidative stress and genotoxic injury. Dysregulated NF-κB signalling drives inflammation in inflammatory disorders such as multiple sclerosis, rheumatoid arthritis or inflammatory bowel disease. Thus, re-establishing the appropriate regulation of NF-κB activity seems like a promising approach to treat inflammatory diseases. Current anti-inflammatory drugs have many, often serious, side effects. Thus, there is an unmet clinical need for safe and effective anti-inflammatory medicines that both decrease inflammatory mediator production and enhance endogenous anti-inflammatory and prorepair pathways. So far, traditional de novo drug discovery has fallen short of satisfying this need. Drug repurposing is a cost- and time-effective alternative to de novo drug development for the identification of novel applications and has already resulted in the identification of effective anti-inflammatories in the ongoing COVID-19 pandemic. In this paper we critically review NF-κB as a potential target for the development of anti-inflammatory drugs with an emphasis on drug repurposing as a strategy to identify new approaches to treat inflammatory diseases.NF-κB is a central mediator of inflammation, response to DNA damage and oxidative stress. As a result of its central role in so many important cellular processes, NF-κB dysregulation has been implicated in the pathology of important human diseases. NF-κB activation causes inappropriate inflammatory responses in diseases including rheumatoid arthritis (RA) and multiple sclerosis (MS). Thus, modulation of NF-κB signaling is being widely investigated as an approach to treat chronic inflammatory diseases, autoimmunity and cancer. The emergence of COVID-19 in late 2019, the subsequent pandemic and the huge clinical burden of patients with life-threatening SARS-CoV-2 pneumonia led to a massive scramble to repurpose existing medicines to treat lung inflammation in a wide range of healthcare systems. These efforts continue and have proven to be controversial. Drug repurposing strategies are a promising alternative to de novo drug development, as they minimize drug development timelines and reduce the risk of failure due to unexpected side effects. Different experimental approaches have been applied to identify existing medicines which inhibit NF-κB that could be repurposed as anti-inflammatory drugs.

Neuroinflammation Associated With Inborn Errors of Immunity.

The advent of high-throughput sequencing has facilitated genotype-phenotype correlations in congenital diseases. This has provided molecular diagnosis and benefited patient management but has also revealed substantial phenotypic heterogeneity. Although distinct neuroinflammatory diseases are scarce among the several thousands of established congenital diseases, elements of neuroinflammation are increasingly recognized in a substantial proportion of inborn errors of immunity, where it may even dominate the clinical picture at initial presentation. Although each disease entity is rare, they collectively can constitute a significant proportion of neuropediatric patients in tertiary care and may occasionally also explain adult neurology patients. We focus this review on the signs and symptoms of neuroinflammation that have been reported in association with established pathogenic variants in immune genes and suggest the following subdivision based on proposed underlying mechanisms: autoinflammatory disorders, tolerance defects, and immunodeficiency disorders. The large group of autoinflammatory disorders is further subdivided into IL-1β-mediated disorders, NF-κB dysregulation, type I interferonopathies, and hemophagocytic syndromes. We delineate emerging pathogenic themes underlying neuroinflammation in monogenic diseases and describe the breadth of the clinical spectrum to support decisions to screen for a genetic diagnosis and encourage further research on a neglected phenomenon.

Peripheral NF-\u03baB dysregulation in people with schizophrenia drives inflammation: putative anti-inflammatory functions of NF-\u03baB kinases

Elevations in plasma levels of pro-inflammatory cytokines and C-reactive protein (CRP) in patient blood have been associated with impairments in cognitive abilities and more severe psychiatric symptoms in people with schizophrenia. The transcription factor nuclear factor kappa B (NF-κB) regulates the gene expression of pro-inflammatory factors whose protein products trigger CRP release. NF-κB activation pathway mRNAs are increased in the brain in schizophrenia and are strongly related to neuroinflammation. Thus, it is likely that this central immune regulator is also dysregulated in the blood and associated with cytokine and CRP levels. We measured levels of six pro-inflammatory cytokine mRNAs and 18 mRNAs encoding NF-κB pathway members in peripheral blood leukocytes from 87 people with schizophrenia and 83 healthy control subjects. We then assessed the relationships between the alterations in NF-κB pathway genes, pro-inflammatory cytokine and CRP levels, psychiatric symptoms and cognition in people with schizophrenia. IL-1β and IFN-γ mRNAs were increased in patients compared to controls (both p < 0.001), while IL-6, IL-8, IL-18, and TNF-α mRNAs did not differ. Recursive two-step cluster analysis revealed that high levels of IL-1β mRNA and high levels of plasma CRP defined ‘high inflammation’ individuals in our cohort, and a higher proportion of people with schizophrenia were identified as displaying ‘high inflammation’ compared to controls using this method (p = 0.03). Overall, leukocyte expression of the NF-κB-activating receptors, TLR4 and TNFR2, and the NF-κB subunit, RelB, was increased in people with schizophrenia compared to healthy control subjects (all p < 0.01), while NF-κB-inducing kinase mRNAs IKKβ and NIK were downregulated in patients (all p < 0.05). We found that elevations in TLR4 and RelB appear more related to inflammatory status than to a diagnosis of schizophrenia, but changes in TNFR2 occur in both the high and low inflammation patients (but were exaggerated in high inflammation patients). Further, decreased leukocyte expression of IKKβ and NIK mRNAs was unique to high inflammation patients, which may represent schizophrenia-specific dysregulation of NF-κB that gives rise to peripheral inflammation in a subset of patients.

Novel Treatments Targeting the Dysregulated Cell Signaling Pathway during Sepsis

Previously characterized as a purely immune mediated disease, sepsis is now recognized as a dysregulated multisystem response against a pathogen. Recognition of the infectious agent by pathogen recognition receptors (PRRs) can initiate activation of the NF-κB signaling pathway and promote the secretion of proinflammatory cytokines. During sepsis, the activation of NF-κB is dysregulated and results in cytokine storm, or the pathologic release of cytokines. Current treatments for sepsis rely on broad spectrum antimicrobial medications and fluid replacement therapy, to neutralize the inciting pathogen and maintain adequate blood pressure. The addition of vasopressor therapy is also utilized when sepsis progresses to septic shock, which is defined by treatment resistant hypotension. Even though modern treatment guidelines have improved clinical outcomes, the mortality rate of sepsis and septic shock is still 15-20% and 20-50%, respectively. To reduce mortality, recent sepsis treatment research has focused on investigating novel therapeutics that can attenuate the dysregulated NF-κB signaling pathway. Antioxidants, such as Retinoic acid and Oxytocin, can reduce activation of the NF-κB pathway by neutralizing stimulatory reactive oxygen species (ROS). Likewise, anti-inflammatory agents can also affect the NF-κB pathway by decreasing the secretion of proinflammatory cytokines, such as TNFα and IL-6. Novel anti-inflammatory cytokines, such as IL-37 and IL-38, have recently been characterized and shown to reduce inflammation in mice with bacterial sepsis. Separately, antioxidants and anti-inflammatory cytokines show promise as potential therapies for sepsis, however, a combined therapy including both agents may prove more beneficial in further improving clinical outcomes.

The canonical and non-canonical NF-κB pathways and their crosstalk: A comparative study based on Petri nets

NF-κB is a protein complex that occurs in almost all animal cell types. It regulates the cellular immune responses to stimuli in the nucleus. Dysregulation of NF-κB can cause severe diseases like chronic inflammation, autoimmune diseases or cancer. We modeled the two major pathways leading from the external cellular stimulation of the CD40 receptor to the nuclear translocation of NF-κB dimers, the canonical and non-canonical pathway. Based on literature data, we developed two Petri net models describing these pathways. In a third Petri net, we combined the two models, introducing crosstalk specific in CD40L-stimulated B cells. In terms of structural properties, we checked the Petri nets for their consistency and correctness. To explore differences and similarities, we compared structural properties and the simulation behavior of the models. The non-canonical NF-κB pathway exhibited a more diverse regulation than the canonical pathway. Applying in silico knockout analyses, we were able to quantify the relevance of individual biochemical processes. We predicted interrelationships, e.g., between the synthesis of the protein NF-κB-inducing kinase and the processing of the precursor protein p100. The activation of the transcription factors, p50-RelA and p52-RelB, was affected by most of the knockouts. The results of the in silico knockout were in accordance with experimental studies. The Petri net models provide a basis for further analyses and could be extended to include gene expression, additional pathways, molecular processes, and kinetic data.

NF-κB and Pancreatic Cancer; Chapter and Verse.

Simple SummaryThe incidence of pancreatic cancer is increasing but there has been little progress in the diagnosis and survival rates of this lethal cancer for decades. Understanding the biological mechanisms and defining how pancreatic cancer develops from normal pancreas tissue, to early lesions and then tumor is vital in developing better treatment options. Unrelenting inflammation in the pancreas significantly increases the risk of developing precursor lesions which result in pancreatic cancer. This inflammatory environment can result in the “switching on” of signaling pathways in the pancreas that influences many factors such as cell survival and turnover involved in tumor initiation, development and spread. In this review we discuss in detail how components of one such pathway, the NF-κB signaling network, are involved at various stages of pancreatic cancer development and in the cellular milieu of this cancer. We also discuss how this signaling pathway could be potentially “switched off” or regulated using new inhibitors and how these agents may be coupled with conventional and/or other therapies for better patient treatment outcomes.Pancreatic Ductal Adenocarcinoma (PDAC) is one of the world’s most lethal cancers. An increase in occurrence, coupled with, presently limited treatment options, necessitates the pursuit of new therapeutic approaches. Many human cancers, including PDAC are initiated by unresolved inflammation. The transcription factor NF-κB coordinates many signals that drive cellular activation and proliferation during immunity but also those involved in inflammation and autophagy which may instigate tumorigenesis. It is not surprising therefore, that activation of canonical and non-canonical NF-κB pathways is increasingly recognized as an important driver of pancreatic injury, progression to tumorigenesis and drug resistance. Paradoxically, NF-κB dysregulation has also been shown to inhibit pancreatic inflammation and pancreatic cancer, depending on the context. A pro-oncogenic or pro-suppressive role for individual components of the NF-κB pathway appears to be cell type, microenvironment and even stage dependent. This review provides an outline of NF-κB signaling, focusing on the role of the various NF-κB family members in the evolving inflammatory PDAC microenvironment. Finally, we discuss pharmacological control of NF-κB to curb inflammation, focussing on novel anti-cancer agents which reinstate the process of cancer cell death, the Smac mimetics and their pre-clinical and early clinical trials.

NF-κB in Gastric Cancer Development and Therapy.

Gastric cancer is considered one of the most common causes of cancer-related death worldwide and, thus, a major health problem. A variety of environmental factors including physical and chemical noxae, as well as pathogen infections could contribute to the development of gastric cancer. The transcription factor nuclear factor kappa B (NF-κB) and its dysregulation has a major impact on gastric carcinogenesis due to the regulation of cytokines/chemokines, growth factors, anti-apoptotic factors, cell cycle regulators, and metalloproteinases. Changes in NF-κB signaling are directed by genetic alterations in the transcription factors themselves, but also in NF-κB signaling molecules. NF-κB actively participates in the crosstalk of the cells in the tumor micromilieu with divergent effects on the heterogeneous tumor cell and immune cell populations. Thus, the benefits/consequences of therapeutic targeting of NF-κB have to be carefully evaluated. In this review, we address recent knowledge about the mechanisms and consequences of NF-κB dysregulation in gastric cancer development and therapy.

MicroRNA: Could It Play a Role in Bovine Endometritis?

Endometritis in dairy cows is a major economic problem worldwide; without advances in lifestyle management and drug treatment, it causes high morbidity and death. Micro ribonucleic acid (miRNAs) these days is seen as an important part of gene control networks. It is a class of small nucleotides 20-25, single-stranded RNA molecules. In endometritis, the inflammatory response caused by the gram-negative bacteria Escherichia coli (E. coli) alters the expression of miRNA which can regulate the innate immune system. This manuscript reviews (1) the interaction of miRNAs with the signaling of NF-κB and dysregulation of miRNAs and NF-κB activity in endometritis and (2) the activity of miR-let-7c, miR-148a, and miR-488 in NF-κB activation and their effect on endometritis. Cows with reduced immunity are more vulnerable to transition diseases, such as endometritis. During post-partum, cows undergo stress, metabolic disorders, hormonal imbalance, negative energy balance, and changes in diet. One of the many categories of regulatory molecules, which explain its natural function and pathological impact on NF-κB dysregulation, is important to inform the complexity of the immune system and to develop treatments for endometritis. It shows that miRNAs could have multiple applications in veterinary medicine. Nevertheless, a comprehensive study of is essential which should be aimed at exploring the role of microRNA at physiological level and its effect due to dysfunction and dysregulation.

Phosphorylation of the Regulators, a Complex Facet of NF-κB Signaling in Cancer.

The nuclear factor kappa B (NF-κB) is a ubiquitous transcription factor central to inflammation and various malignant diseases in humans. The regulation of NF-κB can be influenced by a myriad of post-translational modifications (PTMs), including phosphorylation, one of the most popular PTM formats in NF-κB signaling. The regulation by phosphorylation modification is not limited to NF-κB subunits, but it also encompasses the diverse regulators of NF-κB signaling. The differential site-specific phosphorylation of NF-κB itself or some NF-κB regulators can result in dysregulated NF-κB signaling, often culminating in events that induce cancer progression and other hyper NF-κB related diseases, such as inflammation, cardiovascular diseases, diabetes, as well as neurodegenerative diseases, etc. In this review, we discuss the regulatory role of phosphorylation in NF-κB signaling and the mechanisms through which they aid cancer progression. Additionally, we highlight some of the known and novel NF-κB regulators that are frequently subjected to phosphorylation. Finally, we provide some future perspectives in terms of drug development to target kinases that regulate NF-κB signaling for cancer therapeutic purposes.

Loss of NF-kB1 and c-Rel accelerates oral carcinogenesis in mice.

This article is protected by copyright. All rights reserved. Oral squamous cell carcinoma (OSCC) is a major subcategory of head and neck squamous cell carcinomas (HNSCC) and is currently the 6th highest cause of cancer mortality world-wide (Bray et al., 2018; Siegel, Miller, & Jemal, 2019). Despite current treatments such as surgery with adjunctive radiation and chemotherapy, the 5-year survival has remained at 50% for decades (Kumar, Nanavati, Modi, & Dobariya, 2016; Rivera, 2015). Most human solid cancers are believed to be driven by chronic inflammation that instigates nascent tumour proliferation (dysplasia), transformation and metastasis while conversely suppressing anti-tumour immune responses (Taniguchi & Karin, 2018). Inflammation promoted by dysregulated NF-κB (nuclear factor of kappa B) is also a hallmark of early OSCC (Cancer Genome Atlas, 2015; Tang et al., 2015). Lack of knowledge of this molecular driver is a key feature limiting curative outcomes.