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[This corrects the article DOI: 10.3389/fimmu.2021.767188.].

Background Type 2 diabetes mellitus (T2DM) and chronic periodontitis share a bidirectional relationship, with T2DM exacerbating periodontal inflammation and periodontitis impairing glycemic control. We aim to identify the diagnostic potential of NFKB1, hsa-miR-(342–5192, and 15b) in serum as well as gingival crevicular fluid (GCF) in individuals with T2DM+chronic periodontitis. Methods A total of 140 participants (Healthy controls, individuals with chronic periodontitis, and those with T2DM+chronic periodontitis) were involved in the study. The NFKB1 protein levels were analyzed by ELISA, and the differential miRNA expression was analyzed using In silico bioinformatics analysis, followed by Quantitative polymerase chain reaction(qPCR) in both serum and GCF. Periodontitis parameters, such as probing pocket depth (PPD), clinical attachment loss (CAL), and metabolic markers, were also assessed. Forty-eight male rats were used to validate the molecular findings in a controlled environment. Periodontitis was induced using sterile silk ligatures placed subgingivally, and after two weeks, rats were sacrificed for histological analysis of inflammatory cell infiltration in both periodontitis and control groups. Results Levels of NFKB1 and the selected miRNAs were significantly heightened in T2DM with periodontitis cases compared to controls. These biomarkers exhibited strong positive correlations with periodontal parameters such as CAL and PPD. Receiver Operating Characteristic (ROC) curve analysis revealed excellent diagnostic performance for NFKB1 and miRNAs in both serum and GCF, with hsa-miR-15b(G) showing the highest Area under the curve (AUC) of 0.995. The animal model confirmed these findings, showing significant inflammatory cell infiltration in the periodontitis group. Conclusions NFKB1 and miRNAs hsa-miR-342-5p -5192, and − 15b exhibit strong potential biomarkers for diagnosing periodontitis and T2DM-associated periodontitis. Their non-invasive nature and robust clinical associations make them promising candidates for personalized management strategies.

Abstract Rationale Albuterol, a bronchodilator medication, is the first-line therapy for asthma worldwide. There are significant racial/ethnic differences in albuterol drug response. Objectives To identify genetic variants important for bronchodilator drug response (BDR) in racially diverse children. Methods We performed the first whole-genome sequencing pharmacogenetics study from 1,441 children with asthma from the tails of the BDR distribution to identify genetic association with BDR. Measurements and Main Results We identified population-specific and shared genetic variants associated with BDR, including genome-wide significant (P < 3.53 × 10−7) and suggestive (P < 7.06 × 10−6) loci near genes previously associated with lung capacity (DNAH5), immunity (NFKB1 and PLCB1), and β-adrenergic signaling (ADAMTS3 and COX18). Functional analyses of the BDR-associated SNP in NFKB1 revealed potential regulatory function in bronchial smooth muscle cells. The SNP is also an expression quantitative trait locus for a neighboring gene, SLC39A8. The lack of other asthma study populations with BDR and whole-genome sequencing data on minority children makes it impossible to perform replication of our rare variant associations. Minority underrepresentation also poses significant challenges to identify age-matched and population-matched cohorts of sufficient sample size for replication of our common variant findings. Conclusions The lack of minority data, despite a collaboration of eight universities and 13 individual laboratories, highlights the urgent need for a dedicated national effort to prioritize diversity in research. Our study expands the understanding of pharmacogenetic analyses in racially/ethnically diverse populations and advances the foundation for precision medicine in at-risk and understudied minority populations.

NF-κB1 deficiency is suggested to be the most common cause of common variable immunodeficiency (CVID). NFKB1 encodes for the p105 precursor protein of NF-κB1, which is converted into the active transcriptional subunit p50 through proteasomal processing of its C-terminal half upon stimulation and is implicated in the canonical NF-kB pathway. Rare monoallelic NFKB1 variants have been shown to cause (haplo) insufficiency. Our report describes a novel NFKB1 missense variant (c.691C>T, p.R230C; allele frequency 0.00004953) in a family vulnerable to meningitis, sepsis, and late-onset hypogammaglobulinemia. We investigated the pathogenic relevance of this variant by lymphocyte stimulation, immunophenotyping, overexpression study and immunoblotting. The ectopic expression of p50 for c.691 C>T restricted transcriptionally active p50 in the cytoplasm, and immunoblotting revealed reduced p105/50 expression. This study shows that the deleterious missense variant in NFKB1 adversely affects the transcriptional and translational activity of NFκB1, impairing its function. Patients immunological parameters show a progressive course of hypogammaglobulinemia, which may partially account for the incomplete disease penetrance and suggest the need for closer immunological monitoring of those mutation carriers.

Inflammation involves a coordinated, sequential, and self limiting sequence of events controlled by positive and negative regulatory mechanisms. Recent studies have shown that microRNAs (miRNAs), an evolutionarily conserved class of endogenous 22-nucleotide noncoding RNAs, contribute to the regulation of inflammation by repressing gene expression at the posttranscriptional level. In this study, we characterize the profile of miRNAs induced by LPS in human polymorphonuclear neutrophils (PMN) and monocytes. In particular, we identify miR-9 as the only miRNA (among 365 analyzed) up-regulated in both cell types after TLR4 activation. miR-9 is also induced by TLR2 and TLR7/8 agonists and by the proinflammatory cytokines TNF-α and IL-1β, but not by IFNγ. Among the 3 different genes encoding miR-9 precursors in humans, we show that LPS selectively induces the transcription of miR-9-1 located in the CROC4 locus, in a MyD88- and NF-κB-dependent manner. In PMN and monocytes, LPS regulates NFKB1 at both the transcriptional and posttranscriptional levels, and a conserved miR-9 seed sustained a miR-9-dependent inhibition of the NFKB1 transcript. Overall, these data suggest that TLR4-activated NF-κB rapidly increases the expression of miR-9 that operates a feedback control of the NF-κB-dependent responses by fine tuning the expression of a key member of the NF-κB family.

Current evidence strongly suggests that aberrant activation of the NF-κB signalling pathway is associated with carcinogenesis. A number of key cellular processes are governed by the effectors of this pathway, including immune responses and apoptosis, both crucial in the development of cancer. Therefore, it is not surprising that dysregulated and chronic NF-κB signalling can have a profound impact on cellular homeostasis. Here we discuss NFKB1 (p105/p50), one of the five subunits of NF-κB, widely implicated in carcinogenesis, in some cases driving cancer progression and in others acting as a tumour-suppressor. The complexity of the role of this subunit lies in the multiple dimeric combination possibilities as well as the different interacting co-factors, which dictate whether gene transcription is activated or repressed, in a cell and organ-specific manner. This review highlights the multiple roles of NFKB1 in the development and progression of different cancers, and the considerations to make when attempting to manipulate NF-κB as a potential cancer therapy.

BackgroundInborn errors of immunity (IEIs) encompass various diseases with diverse clinical and immunological symptoms. Determining the genotype–phenotype of different variants in IEI entity precisely is challenging, as manifestations can be heterogeneous even in patients with the same mutated gene.ObjectiveIn the present study, we conducted a systematic review of patients recorded with NFKB1 and NFKB2 mutations, two of the most frequent monogenic IEIs.MethodsThe search for relevant literature was conducted in databases including Web of Science, PubMed, and Scopus. Information encompassing demographic, clinical, immunological, and genetic data was extracted from cases reported with mutations in NFKB1 and NFKB2. The comprehensive features of manifestations in patients were described, and a comparative analysis of primary characteristics was conducted between individuals with NFKB1 loss of function (LOF) and NFKB2 (p52-LOF/IκBδ-gain of function (GOF)) variants.ResultsA total of 397 patients were included in this study, 257 had NFKB1 mutations and 140 had NFKB2 mutations. There were 175 LOF cases in NFKB1 and 122 p52LOF/IκBδGOF cases in NFKB2 pivotal groups with confirmed functional implications. NFKB1LOF and p52LOF/IκBδGOF predominant cases (81.8% and 62.5% respectively) initially presented with a CVID-like phenotype. Patients with NFKB1LOF variants often experienced hematologic autoimmune disorders, whereas p52LOF/IκBδGOF patients were more susceptible to other autoimmune diseases. Viral infections were markedly higher in p52LOF/IκBδGOF cases compared to NFKB1LOF (P-value < 0.001). NFKB2 (p52LOF/IκBδGOF) patients exhibited a greater prevalence of ectodermal dysplasia and pituitary gland involvement than NFKB1LOF patients. Most NFKB1LOF and p52LOF/IκBδGOF cases showed low CD19 + B cells, with p52LOF/IκBδGOF having more cases of this type. Low memory B cells were more common in p52LOF/IκBδGOF patients.ConclusionsPatients with NFKB2 mutations, particularly p52LOF/IκBδGOF, are at higher risk of viral infections, pituitary gland involvement, and ectodermal dysplasia compared to patients with NFKB1LOF mutations. Genetic testing is essential to resolve the initial complexity and confusion surrounding clinical and immunological features. Emphasizing the significance of functional assays in determining the probability of correlations between mutations and immunological and clinical characteristics of patients is crucial.

[...]STRING's reliance on existing annotations and curated data may not capture newly discovered or less well-studied protein interactions, leading to potential gaps in coverage. [...]while it offers extensive flexibility, the complexity of the software may present a steep learning curve for users unfamiliar with network analysis tools. [...]Cytoscape's performance may degrade when handling large-scale networks with thousands of nodes and edges, requiring substantial computational resources. [...]the reliance on pre-existing databases and computational algorithms means that GeneMANIA's results may not capture emerging or context-specific gene associations, potentially leading to incomplete or biased interpretations.

NFKB1, a core transcription factor critical in various biological process (BP), is increasingly studied for its role in tumors. This research combines literature reviews, meta-analyses, and bioinformatics to systematically explore NFKB1's involvement in tumor initiation and progression. A unique focus is placed on the NFKB1-94 ATTG promoter polymorphism, highlighting its association with cancer risk across diverse genetic models and ethnic groups, alongside comprehensive analysis of pan-cancer expression patterns and drug sensitivity. The study reveals the intricate connections between NFKB1 and tumors, highlighting its significant roles in invasion, metastasis, genomic stability, and metabolic changes. Through meta-analysis, it is evidenced that tumor specimens exhibit increased NFKB1 expression when compared to non-tumor specimens, although its association with cancer incidence requires further investigation. Analysis from the Gene Expression Omnibus (GEO) database suggests that high NFKB1 gene expression may not markedly impact tumor patient prognosis. The noticeable correlation between the NFKB1-94 ATTG promoter polymorphic sequence and elevated cancer susceptibility is highlighted across different genetic models. Furthermore, bioinformatics analysis uncovers NFKB1's association with the sensitivity to various anticancer drugs and its central involvement in crucial BP like the cell cycle, cytoskeleton assembly, and cellular senescence. Overall, NFKB1's expression and polymorphisms are significantly linked to tumor risk, prognosis, and treatment response, highlighting its prospect as a forthcoming aim for cancer treatment. This study offers a robust foundation for further exploration of NFKB1's mechanisms and the development of innovative therapeutic strategies.

Background Overactivated microglia are a key contributor to Parkinson’s disease (PD) by inducing neuroinflammation. CD200R1, a membrane glycoprotein mainly found on microglia, is crucial for maintaining quiescence with its dysregulation linked to microglia’s abnormal activation. We and other groups have reported a decline in CD200R1 levels in several neurological disorders including PD. However, the mechanism regulating CD200R1 expression and the specific reasons for its reduction in PD remain largely unexplored. Given the pivotal role of transcription factors in gene expression, this study aimed to elucidate the transcriptional regulation of CD200R1 and its implications in PD. Methods The CD200R1 promoter core region was identified via luciferase assays. Potential transcription factors were predicted using the UCSC ChIP-seq database and JASPAR. NFKB1 binding to the CD200R1 core promoter was substantiated through electrophoretic mobility shift and chromatin immunoprecipitation assays. Knocking-down or overexpressing NFKB1 validated its regulatory effect on CD200R1. Correlation between decreased CD200R1 and deficient NFKB1 was studied using Genotype-Tissue Expression database. The clinical samples of the peripheral blood mononuclear cells were acquired from 44 PD patients (mean age 64.13 ± 9.78, 43.2% male, median Hoehn-Yahr stage 1.77) and 45 controls (mean age 64.70 ± 9.41, 52.1% male). NFKB1 knockout mice were utilized to study the impact of NFKB1 on CD200R1 expression and to assess their roles in PD pathophysiology. Results The study identified the CD200R1 core promoter region, located 482 to 146 bp upstream of its translation initiation site, was directly regulated by NFKB1. Significant correlation between NFKB1 and CD200R1 expression was observed in human PMBCs. Both NFKB1 and CD200R1 were significantly decreased in PD patient samples. Furthermore, NFKB1-/- mice exhibited exacerbated microglia activation and dopaminergic neuron loss after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment. Conclusion Our study identified that NFKB1 served as a direct regulator of CD200R1. Reduced NFKB1 played a critical role in CD200R1 dysregulation and subsequent microglia overactivation in PD. These findings provide evidence that targeting the NFKB1-CD200R1 axis would be a novel therapeutic strategy for PD.