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Periodontitis, a prevalent and chronic inflammatory disease, is intricately linked with macroautophagy/autophagy, which has a dual role in maintaining periodontal homeostasis. Despite its importance, the precise interplay between autophagy and periodontitis pathogenesis remains to be fully elucidated. In this study, our investigation revealed that the ubiquitination of RAB7A, mediated by reduced levels of the deubiquitinating enzyme USP4 (ubiquitin specific peptidase 4), disrupts normal lysosomal trafficking and autophagosome-lysosome fusion, thereby contributing significantly to periodontitis progression. Specifically, through genomic and histological analysis of clinical gingival samples, we observed a decreased RAB7A expression and impaired autophagic activity in periodontitis. This was further substantiated through experimental periodontitis mice, where RAB7A inactivation was shown to directly affect autophagy efficiency and drive periodontitis progression. Next, we explored the function of active RAB7A to promote lysosomal trafficking dynamics and autophagosome-lysosome fusion, which was inhibited by RAB7A ubiquitination in macrophages stimulated by Porphyromonas gingivalis (P. g.), one of the keystone pathogens of periodontitis. Last, by proteomics analysis, we revealed that the ubiquitination of RAB7A was mediated by USP4 and validated that upregulation of USP4 could attenuate periodontitis in vivo. In conclusion, these findings highlight the interaction between USP4 and RAB7A as a promising target for therapeutic intervention in managing periodontal diseases.Abbreviation: 3-MA: 3-methyladenine; Baf A1:bafilomycin A1; BECN1: beclin 1, autophagy related; CEJ-ABC: cementoenamel junctionto alveolar bone crest; IL1B/IL-1β: interleukin 1 beta; KD:knockdown; LPS: lipopolysaccharide; MOI: multiplicity of infection;OE: overexpression; P.g.: Porphyromonasgingivalis; RILP: Rabinteracting lysosomal protein; ScRNA-seq: single-cell RNA sequencing; SQSTM1/p62: sequestosome 1; S.s.: Streptococcus sanguinis; USP4:ubiquitin specific peptidase 4 [ABSTRACT FROM AUTHOR]

Several seminal plasma components, besides NGF, are implicated as ovulation-inducing factors in mammals. This study investigated the IL1B and its receptor IL1R1 in the testis (T), male accessory glands, prostate (P) and seminal vesicles (SV), and uterus (U) of adult rabbits using immunohistochemistry (IHC) and quantitative reverse transcription PCR (RT-qPCR). We also assessed the presence of IL1B in seminal plasma through Western blotting (WB) and examined the interaction between IL1B and NGF in vitro by measuring their production with enzyme-linked immunosorbent assay (ELISA) in the presence of NGF and IL1B alone or with their respective receptor antagonists. IHC revealed IL1B system expression in all reproductive organs studied, with IL1B and IL1R1 localized to the germinative epithelium of the T and the epithelial cells of the accessory glands and U. IL1B gene transcript levels were significantly higher (p < 0.01) in the P and SV compared to the T, while IL1R1 levels were significantly higher (p < 0.001) in the P compared to the other tissues, while IL1R1 levels were three times higher (p < 0.001) in the P. WB confirmed the presence of IL1B in seminal plasma with a 30–35 kDa band. The in vitro study demonstrated that IL1B increased (p < 0.05) basal NGF production in the U, whereas NGF had no effect on IL1B production. These findings provide evidence of the expression of the IL1B/IL1R1 system in both male and female rabbit reproductive tracts and suggest that IL1B in seminal plasma may influence uterine endocrine activity. The results propose a potential role for IL1B in ovulation, in conjunction with NGF, supporting that ovulation may involve inflammatory-like processes. [ABSTRACT FROM AUTHOR]

Abstract Background Triple‐negative breast cancer (TNBC), which is so called because of the lack of estrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor receptor 2 (HER2) receptors on the cancer cells, accounts for 10%–15% of all breast cancers. The heterogeneity of the tumor microenvironment is high. However, the role of plasma cells controlling the tumor migration progression in TNBC is still not fully understood. Methods We analyzed single‐cell RNA sequencing data from five HER2 positive, 12 ER positive/PR positive, and nine TNBC samples. The potential targets were validated by immunohistochemistry. Results Plasma cells were enriched in TNBC samples, which was consistent with validation using data from The Cancer Genome Atlas. Cell communication analysis revealed that plasma cells interact with T cells through the intercellular adhesion molecule 2–integrin–aLb2 complex, and then release interleukin 1 beta (IL1B), as verified by immunohistochemistry, ultimately promoting tumor growth. Conclusion Our results revealed the role of plasma cells in TNBC and identified IL1B as a new prognostic marker for TNBC.

Viral infections, including SARS-CoV-2, are accompanied by signs of systemic inflammation, which can cause long-term sequela for the patient. Time-stable changes in the organism may be caused by epigenetic shifts inherited in a series of cell divisions, in particular, by changes in the DNA methylation profile in cells of various organs and tissues in response to proinflammatory cytokines. IL1B is a key inflammatory factor, and it was shown that CpG methylation level in its promoter can change upon pro-inflammatory stimuli, and that it was associated with significant increase in IL1B expression. In particular, a specific CpG site in the promoter of the IL1B gene located 299 bp upstream from the transcription start site (CpG3) was previously shown to be an important player in these processes. In this study, we examined methylation/demethylation levels of this CpG3 in publicly available genome-wide methylation studies. A total of 15 dataset were analyzed that comprised data from stromal cells in normal and inflammation-associated states, immune cells of healthy young and aging donors, patients during COVID-19 and after recovery. The level of CpG3 demethylation was found to be higher in osteoarthritis samples of cartilage as compared to healthy donors in one dataset. In blood samples of patients with rheumatoid arthritis CpG3 demethylation was also found to be statistically higher than in healthy donors. In COVID-19 studies, blood samples obtained from patients with severe symptoms had higher CpG3 demethylation levels compared to samples obtained from patients with mild symptoms and controls. The level of CpG3 demethylation increased with age in healthy people as judged by whole blood samples. The same dependency was seen for in vitro cultures of mesenchymal cells obtained from healthy donors. Taken together we showed that demethylation level of a single CpG site in IL1B promoter increases in several cell types due to conditions associated with local and systemic inflammation, including SARS-CoV-2 infection, and in aging. These data suggest a possibility that a history of conditions associated with inflammation within an organism may be recorded, preserved, and encoded in its DNA methylation pattern. While the specificity of these "records of inflammation" is an open question, decoding the history of pathological events associated with inflammation that had been faced by the organism is an intriguing possibility. [ABSTRACT FROM AUTHOR]

Abstract Background Polymorphisms in IL1B play a significant role in depression, multiple inflammatory-associated disorders, and susceptibility to infection. Functional non-synonymous SNPs (nsSNPs) result in changes in the encoded amino acids, potentially leading to structural and functional alterations in the mutant proteins. So far, most genetic studies have concentrated on SNPs located in the IL1B promoter region, without addressing nsSNPs and their association with multifactorial diseases. Therefore, this study aimed to explore the impact of deleterious nsSNPs retrieved from the dbSNP database on the structure and functions of the IL1B protein. Results Six web servers (SIFT, PolyPhen-2, PROVEAN, SNPs&GO, PHD-SNP, PANTHER) were used to analyze the impact of 222 missense SNPs on the function and structure of IL1B protein. Five novel nsSNPs (E100K, T240I, S53Y, D128Y, and F228S) were found to be deleterious and had a mutational impact on the structure and function of the IL1B protein. The I-mutant v2.0 and MUPro servers predicted that these mutations decreased the stability of the IL1B protein. Additionally, these five mutations were found to be conserved, underscoring their significance in protein structure and function. Three of them (T240I, D128Y, and F228S) were predicted to be cancer-causing nsSNPs. To analyze the behavior of the mutant structures under physiological conditions, we conducted a 50 ns molecular dynamics simulation using the WebGro online tool. Our findings indicate that the mutant values differ from those of the IL1B wild type in terms of RMSD, RMSF, Rg, SASA, and the number of hydrogen bonds. Conclusions This study provides valuable insights into nsSNPs located in the coding regions of IL1B, which lead to direct deleterious effects on the functional and structural aspects of the IL1B protein. Thus, these nsSNPs could be considered significant candidates in the pathogenesis of disorders caused by IL1B dysfunction, contributing to effective drug discovery and the development of precision medications. Thorough research and wet lab experiments are required to verify our findings. Moreover, bioinformatic tools were found valuable in the prediction of deleterious nsSNPs.

One of the factors in the development of uterine fibroids is a genetic predisposition to its occurrence in some women, but the real molecular genetic mechanisms of this phenomenon remain unknown. Aim of the study was the distribution analysis of gene polymorphism of cytokines TNFα, IL-1β, IL-4, IL-6, IL-10, factors of angiogenesis (vascular endothelial growth factor, VEGF) and remodeling of extracellular matrix (metalloproteinases MMP2, MMP3, MMP9), which are associated with their levels. Material and methods. Genotyping was performed by real-time PCR using commercial test systems SYBR GreenI (Litech, Russia) and TaqMan (Syntol, Russia) in accordance with the instructions of the developer. Cytokine content in blood serum was determined by flow cytometry using microspheres coated with monoclonal antibodies to cytokines (Bio-Plex ProTM Human Cytokine 27-plex Assay), according to the instructions for Bio-Plex 200 (Bio-Rad Laboratories, USA).To evaluate the results obtained, in addition to the generally accepted methods of statistical processing for case – control studies, computational methods of bioinformatics were used for comparative analysis of the diagnostic value of various combined genetic traits. Results. It was shown that the maximum odds ratio value of uterine fibroids development are combined genetic traits that include representatives of all four regulatory factors: cytokines with pro-inflammatory activity, cytokines with anti-inflammatory activity, vascular endothelial growth factors and metalloproteinases (p = 0.002). Conclusions. The presented data reveal the real mechanisms of manifestation of the genetic predisposition of individual women to the uterine fibroids development, associated with the presence of polymorphism of certain genes in their genome, which provide features of the structure of cytokine networks with the predominance of certain activities in the regulation of tissue processes in the uterus. In addition to purely scientific interest, these results indicate the real possibility of their clinical application in the form of prognostic criteria with a certain level of prognostic significance.

BACKGROUND: Spontaneous preterm birth accounts for most preterm births and leads to significant morbidity in the newborn and childhood period. This subtype of preterm birth represents an increasing proportion of all preterm births when compared with medically indicated preterm birth, yet it is understudied in omics analyses. The placenta is a key regulator of fetal and newborn health, and the placental transcriptome can provide insight into pathologic changes that lead to spontaneous preterm birth. OBJECTIVE: This analysis aimed to identify genes for which placental expression was associated with spontaneous preterm birth (including early preterm and late preterm birth). STUDY DESIGN: The ECHO PATHWAYS consortium extracted RNA from placental samples collected from the Conditions Affecting Neurocognitive Development and Learning in Early Childhood and the Global Alliance to Prevent Prematurity and Stillbirth studies. Placental transcriptomic data were obtained by RNA sequencing. Linear models were fit to estimate differences in placental gene expression between term birth and spontaneous preterm birth (including gestational age subgroups defined by the American College of Obstetricians and Gynecologists). Models were adjusted for numerous confounding variables, including labor status, cohort, and RNA sequencing batch. This analysis excluded patients with induced labor, chorioamnionitis, multifetal gestations, or medical indications for preterm birth. Our combined cohort contained gene expression data for 14,023 genes in 48 preterm and 540 term samples. Genes and pathways were considered statistically significantly different at false discovery rate-adjusted P value of

Background: Polymorphisms in IL1B play a significant role in depression, multiple inflammatory-associated disorders, and susceptibility to infection. Functional non-synonymous SNPs (nsSNPs) result in changes in the encoded amino acids, potentially leading to structural and functional alterations in the mutant proteins. So far, most genetic studies have concentrated on SNPs located in the IL1B promoter region, without addressing nsSNPs and their association with multifactorial diseases. Therefore, this study aimed to explore the impact of deleterious nsSNPs retrieved from the dbSNP database on the structure and functions of the IL1B protein. Results: Six web servers (SIFT, PolyPhen-2, PROVEAN, SNPs&GO, PHD-SNP, PANTHER) were used to analyze the impact of 222 missense SNPs on the function and structure of IL1B protein. Five novel nsSNPs (E100K, T240I, S53Y, D128Y, and F228S) were found to be deleterious and had a mutational impact on the structure and function of the IL1B protein. The I-mutant v2.0 and MUPro servers predicted that these mutations decreased the stability of the IL1B protein. Additionally, these five mutations were found to be conserved, underscoring their significance in protein structure and function. Three of them (T240I, D128Y, and F228S) were predicted to be cancer-causing nsSNPs. To analyze the behavior of the mutant structures under physiological conditions, we conducted a 50 ns molecular dynamics simulation using the WebGro online tool. Our findings indicate that the mutant values differ from those of the IL1B wild type in terms of RMSD, RMSF, Rg, SASA, and the number of hydrogen bonds. Conclusions: This study provides valuable insights into nsSNPs located in the coding regions of IL1B, which lead to direct deleterious effects on the functional and structural aspects of the IL1B protein. Thus, these nsSNPs could be considered significant candidates in the pathogenesis of disorders caused by IL1B dysfunction, contributing to effective drug discovery and the development of precision medications. Thorough research and wet lab experiments are required to verify our findings. Moreover, bioinformatic tools were found valuable in the prediction of deleterious nsSNPs. [ABSTRACT FROM AUTHOR]

Abstract Background Emerging studies have reported the contribution of cholesterol to hepatocellular carcinoma (HCC) progression. However, the specific role and mechanism of cholesterol metabolism on spontaneous and progressive HCC development from the point of view of ferroptosis are still worth exploring. The present study aimed to reveal a novel mechanism of cholesterol metabolism-related ferroptosis in hepatocellular carcinoma cells. Methods Two microarray datasets (GSE25097, GSE22058) related to HCC were downloaded from Gene Expression Omnibus (GEO) datasets. Metabolomics analysis was performed by ultra performance liquid chromatography - tandem mass spectrometer (UPLC-MS/MS). The cholesterol-related proteins were downloaded from HMBD. Ferroptosis-related genes were extracted from FerrDb database. Data sets were separated into two groups. GSE25097 was used to identify ferroptosis-related genes, and GSE22058 was used to verify results. During these processes, chemical–protein interaction (CPI), protein–protein interaction (PPI), the Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted. Multivariate logistic regression analysis was used to test the associated pathway. Results We identified 8 differentially expressed ferroptosis-related genes (HAMP, PTGS2, IL1B, ALOX15B, CDKN2A, RRM2, NQO1 and KIF20A) and 4 differentially expressed cholesterol-related genes (LCAT, CH25H, CEL and CYP7A1). Furthermore, based on the predicted results with STITCH, we identified indomethacin and IL1B as the essential node for cholesterol-mediated ferroptosis in hepatocellular carcinoma cell. Multivariate logistic regression analysis showed the activities of plasma IL1B in liver cancer patients enrolled have been significantly affected by the level of plasma cholesterol (P

Drug repurposing is a promising approach that has the potential to revolutionize the drug discovery and development process. By leveraging existing drugs, we can bring new treatments to patients more quickly and affordably. Anti-inflammatory drugs have been shown to target multiple pathways involved in cancer development and progression. This suggests that they may be more effective in treating cancer than drugs that target a single pathway. Cell viability was measured using the MTT assay. The expression of genes related to inflammation (TNFa, IL1b, COX-1, COX-2, and 5-LOX) was measured in HepG2, MCF7, and THLE-2 cells using qPCR. The levels of TNFα, IL1b, COX-1, COX-2, and 5-LOX were also measured in these cells using an ELISA kit. An enzyme binding assay revealed that sulfadiazine expressed weaker inhibitory activity against COX-2 (IC50 = 5.27 μM) in comparison with the COX-2 selective reference inhibitor celecoxib (COX-2 IC50 = 1.94 μM). However, a more balanced inhibitory effect was revealed for sulfadiazine against the COX/LOX pathway with greater affinity towards 5-LOX (IC50 = 19.1 μM) versus COX-1 (IC50 = 18.4 μM) as compared to celecoxib (5-LOX IC50 = 16.7 μM, and COX-1 IC50 = 5.9 μM). MTT assays revealed the IC50 values of 245.69 ± 4.1 µM and 215.68 ± 3.8 µM on HepG2 and MCF7 cell lines, respectively, compared to the standard drug cisplatin (66.92 ± 1.8 µM and 46.83 ± 1.3 µM, respectively). The anti-inflammatory effect of sulfadiazine was also depicted through its effect on the levels of inflammatory markers and inflammation-related genes (TNFα, IL1b, COX-1, COX-2, 5-LOX). Molecular simulation studies revealed key binding interactions that explain the difference in the activity profiles of sulfadiazine compared to celecoxib. The results suggest that sulfadiazine exhibited balanced inhibitory activity against the 5-LOX/COX-1 enzymes compared to the selective COX-2 inhibitor, celecoxib. These findings highlight the potential of sulfadiazine as a potential anticancer agent through balanced inhibitory activity against the COX/LOX pathway and reduction in the expression of inflammatory genes. [ABSTRACT FROM AUTHOR]

Dong Zhang,1,2 Siwei Duan,3 Zhangyou He,4 Zeming Zhu,3 Zhiping Li,3 Qincheng Yi,4 Tiantian Cai,1,2 Juanjuan Li,1,2 Nan Chen,1,2 Shaoju Guo1,2 1Gastrointestinal Ward, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, People’s Republic of China; 2Gastrointestinal Ward, Shenzhen Hospital of Traditional Chinese Medicine, Shenzhen, People’s Republic of China; 3Institute of Gastroenterology, Science and Technology Innovation Center of Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China; 4Institute of Gastroenterology, Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of ChinaCorrespondence: Shaoju Guo, Gastrointestinal Ward, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, People’s Republic of China, Tel +86-0755-82571384, Email gsj1080@163.comPurpose: This study was conducted to explore the mechanism of Sijunzi Decoction (SJZ) in the treatment of ulcerative colitis (UC).Methods: The study aimed to investigate the active components and targets of SJZ in the treatment of UC by screening databases such as TCMSP, GeneCards, OMIM, Distinct, TTD, and Drugbank. An online Venn tool, Cytoscape 3.7.2, and Autodock Tools were used to analyze the components and targets. The study also used a mouse model of UC to further investigate the effects of SJZ. HE staining, immunofluorescence, ELISA, qPCR, and Western blot were used to detect various indices.Results: Eighty-three active components and 112 action targets were identified from SJZ, including 67 targets for treating UC-related NETs. The five core targets identified were AKT1, JUN, IL1B, PTGS2, and TNF, and molecular docking studies indicated that the five targets were well-docked with ginsenoside Rh2, isoflavones, and formononetin. Animal experiments demonstrated that SJZ could alleviate various parameters such as weight, colon length, spleen index, disease activity index, and intestinal pathology of the UC mice. Immunofluorescence and Western blot showed that SJZ could reduce the expression of IL1B and TNF in intestinal neutrophils while increasing the expression of Occludin. Cellular immunofluorescence suggests that SJZ can reduce the expression of TNF and IL1B in NETs. The qPCR results also suggested that SJZ could inhibit TNF signal. Furthermore, ELISA results suggested that SJZ could inhibit the expression of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) while promoting the expression of anti-inflammatory cytokines (IL-10, IL-37, TGF-β).Conclusion: SJZ treats UC by reducing the content of intestinal NETs, with primary targets on the NETs being IL1B and TNFand suppress TNF signal. The practical components of SJZ may be ginsenoside Rh2, isoflavones, and formononetin.Graphical Abstract: Keywords: ulcerative colitis, Sijunzi decoction, network pharmacology, IL1B, TNF

The interleukin-1 gene cluster encodes cytokines, which modulate mesangial cell proliferation and matrix expansion, both constituting central factors in the development and progression of immunoglobulin A nephropathy (IgAN). A candidate-gene study was performed to examine the association of polymorphisms of the interleukin-1 gene cluster with the risk of progressive IgAN. To gain deeper insights into the involvement of interleukin genes in IgAN, a meta-analysis of genetic association studies (GAS) that examine the association between interleukin variants and IgAN was conducted. Association study: The case-control study consisted of 121 unrelated Caucasians with sporadic, histologically diagnosed IgAN and of 246 age- and sex-matched healthy controls. Persistent proteinuria (>2 g/24 h) and/or impaired kidney function (serum creatinine > 1.5 mg/dL) defined progressive (n = 67) vs. non-progressive (n = 54) IgAN cases. Genotypes were assessed for two promoter-region single-nucleotide polymorphisms, C-899T (rs1800587) in IL1A and C-511T (rs16944) in IL1B, and for one penta-allelic variable-length tandem repeat polymorphism (VNTR 86 bp intron 2) in IL1RN. The association of these variants with the susceptibility of IgAN and the development of progressive IgAN (healthy status, IgAN, progressive IgAN) was tested using the generalized odds ratio (ORG) metric. Linkage disequilibrium and haplotype analysis were also performed. Meta-analysis: We included in the meta-analysis 15 studies investigating association between 14 interleukin variants harbored in eight different genes and IgAN. The ORG was used to evaluate the association between interleukin variants and IgAN using random effects models. The present case-control study revealed association of IL1B C-511T (rs16944) with the progression of IgAN (p = 0.041; ORG = 2.11 (1.09–4.07)). On haplotype analysis, significant results were derived for the haplotypes C-C-1 (p = 0.005; OR = 0.456 (0.261~0.797)) and C-T-2 (p = 0.003; OR = 4.208 (1.545–11.50)). Regarding association and meta-analysis results, variants in IL1B (rs1143627 and rs16944), IL1RN (rs928940, rs439154, and rs315951) and IL10 (rs1800871) were associated with IgAN based on either genotype or allele counts. Genetic variants and haplotypes in the IL1B, IL1RN, and IL10 genes might contribute to an increased risk for development and progression of IgAN. [ABSTRACT FROM AUTHOR]

ASH2L (Absent-Small-Homeotic-2-Like protein) is a core subunit of the COMPASS (COMplex of Proteins ASsociated with Set1) complex, the most notable writer of the methylation of histone H3 lysine 4 (H3K4). The COMPASS complex regulates active promoters or enhancers for gene expression, and its dysfunction is associated with aberrant development and disease. Here, we demonstrated that ASH2L mediated the cell invasion and migration activity of triple-negative breast cancer cells through the interaction with the COMPASS components and the target genomic regions. Transcriptome analysis indicated a potential correlation between ASH2L and the genes involved in inflammatory/immune responses. Among them, we found that the intrinsic expression of IL1B (interleukin 1 beta), an essential proinflammatory gene, was directly regulated by ASH2L. These results revealed a novel role of ASH2L on the maintenance of breast cancer malignancy possibly through H3K4 methylation of the target inflammatory/immune responsive genes. • ASH2L plays an important role in cell invasion and migration of TNBC cell lines. • DNA and RBBP5 binding domains of ASH2L are critical for its oncogenic function. • ASH2L cooperates with RBBP5 and WDR5 for TNBC cell invasion and migration. • ASH2L is involved in the maintenance of global H3K4 mono- and tri-methylation. • IL1B , a pro-inflammatory cytokine, is one of the target genes regulated by ASH2L. [ABSTRACT FROM AUTHOR]

• Cortical cytokines are low at birth and increase across human brain development. • Cytokine levels peak at 2 stages: 1) toddlers and 2) adolescence. • Across development, some cytokines change coordinately while others are unique. • Cytokines appear to be regulated normally, with implications for neurodevelopmental disorders. In addition to their traditional roles in immune cell communication, cytokines regulate brain development. Cytokines are known to influence neural cell generation, differentiation, maturation, and survival. However, most work on the role of cytokines in brain development investigates rodents or focuses on prenatal events. Here, we investigate how mRNA and protein levels of key cytokines and cytokine receptors change during postnatal development of the human prefrontal cortex. We find that most cytokine transcripts investigated (IL1B , IL18 , IL6 , TNF , IL13) are lowest at birth and increase between 1.5 and 5 years old. After 5 years old, transcriptional patterns proceeded in one of two directions: decreased expression in teens and young adults (IL1B , p = 0.002; and IL18 , p = 0.004) or increased mean expression with maturation, particularly in teenagers (IL6 , p = 0.004; TNF , p = 0.002; IL13 , p < 0.001). In contrast, cytokine proteins tended to remain elevated after peaking significantly around 3 years of age (IL1B, p = 0.012; IL18, p = 0.026; IL6, p = 0.039; TNF, p < 0.001), with TNF protein being highest in teenagers. An mRNA-only analysis of cytokine receptor transcripts found that early developmental increases in cytokines were paralleled by increases in their ligand-binding receptor subunits, such as IL1R1 (p = 0.033) and IL6R (p < 0.001) transcripts. In contrast, cytokine receptor-associated signaling subunits, IL1RAP and IL6ST , did not change significantly between age groups. Of the two TNF receptors, the 'pro-death' TNFRSF1A and 'pro-survival' TNFRSF1B , only TNFRSF1B was significantly changed (p = 0.028), increasing first in toddlers and again in young adults. Finally, the cytokine inhibitor, IL13 , was elevated first in toddlers (p = 0.006) and again in young adults (p = 0.053). While the mean expression of interleukin-1 receptor antagonist (IL1RN) was highest in toddlers, this increase was not statistically significant. The fluctuations in cytokine expression reported here support a role for increases in specific cytokines at two different stages of human cortical development. The first is during the toddler/preschool period (IL1B , IL18 , and IL13), and the other occurs at adolescence/young adult maturation (IL6 , TNF and IL13). [ABSTRACT FROM AUTHOR]

Abstract Background Decidualization refers to the process of transformation of endometrial stromal fibroblast cells into specialized decidual stromal cells that provide a nutritive and immunoprivileged matrix essential for blastocyst implantation and placental development. Deficiencies in decidualization are associated with a variety of pregnancy disorders, including female infertility, recurrent implantation failure (RIF), and miscarriages. Despite the increasing number of genes reportedly associated with endometrial receptivity and decidualization, the cellular and molecular mechanisms triggering and underlying decidualization remain largely unknown. Here, we analyze single-cell transcriptional profiles of endometrial cells during the window of implantation and decidual cells of early pregnancy, to gains insights on the process of decidualization. Results We observed a unique IGF1+ stromal cell that may initiate decidualization by single-cell RNA sequencing. We found the IL1B+ stromal cells promote gland degeneration and decidua hemostasis. We defined a subset of NK cells for accelerating decidualization and extravillous trophoblast (EVT) invasion by AREG-IGF1 and AREG-CSF1 regulatory axe. Further analysis indicates that EVT promote decidualization possibly by multiply pathways. Additionally, a systematic repository of cell–cell communication for decidualization was developed. An aberrant ratio conversion of IGF1+ stromal cells to IGF1R+ stromal cells is observed in unexplained RIF patients. Conclusions Overall, a unique subpopulation of IGF1+ stromal cell is involved in initiating decidualization. Our observations provide deeper insights into the molecular and cellular characterizations of decidualization, and a platform for further development of evaluation of decidualization degree and treatment for decidualization disorder-related diseases.

Cutaneous melanoma is one of the most aggressive types of cancer and often proves fatal in metastatic stages. Few treatment options are available, and its global incidence is quickly increasing. In order to gain an improved understanding of the molecular features regarding melanoma progression, we have compared gene and small non-coding RNA expression profiles from cell lines derived from primary melanoma (MelJuSo), lymph node metastasis (MNT-1) and brain metastasis (VMM1), representing distinct stages of malignant progression. Our preliminary results highlighted the aberrant regulation of molecular markers involved in several processes that aid melanoma progression and metastasis development, including extracellular matrix remodeling, migratory potential and angiogenesis. Moreover, bioinformatic analysis revealed potential targets of the microRNAs of interest. Confocal microscopy and immunohistochemistry analysis were used for validation at the protein level. Exploring the molecular landscape of melanoma may contribute to the achievement of future efficient targeted therapy, as well as better prevention, diagnosis and clinical management. [ABSTRACT FROM AUTHOR]

This study investigated the anti-arthritic potential of novel mannich-based derivatives of 2-mercaptobenzimidazole (AK7 and AK9) in rats. The compounds were characterized by NMR and FTIR spectroscopies and their acute anti-inflammatory effects were measured by carrageenan (CRG)-induced paw edema model. The most potent doses of AK7 and AK9 were subsequently evaluated in the complete Freund's adjuvant (CFA)–induced inflammatory arthritis model. AK7 and AK9 inhibited CRG-induced inflammation in a dose-dependent fashion and a similar reduction in CFA-induced paw inflammation was observed. Moreover, X-ray and histopathological analyses of AK7-treated animals displayed normal joint structure whereas AK9, despite of its anti-inflammatory effects, failed to protect against cartilage destruction. Interestingly, biochemical analysis revealed a better safety profile for AK7 than for AK9 and methotrexate. Both compounds suppressed mRNA levels of pro-inflammatory mediators (IRAK1, NF-κB1, TNF-α, IL1B) while only AK7 reduced the transcript levels of interstitial collagenase (MMP1). Molecular docking analysis of AK7 and AK9 with TNF-α and MMP1 also supported the experimental data. These findings clearly highlight the beneficial effects of AK7 in the prevention and/or treatment of inflammatory arthritis. [ABSTRACT FROM AUTHOR]

ABSTRACT Macrophages are innate immune cells that patrol tissues and are the first responders to detect infection. They orchestrate the host immune response in eliminating invading pathogens and the subsequent transition from inflammation to tissue repair. Macrophage dysfunction contributes to age-related pathologies, including low-grade inflammation in advanced age that is termed “inflammaging.” Our laboratory has previously identified that macrophage expression of a fatty acid desaturase, stearoyl-CoA desaturase 2 (SCD2), declines with age. Herein, we delineate the precise cellular effects of SCD2 deficiency in murine macrophages. We found that deletion of Scd2 from macrophages dysregulated basal and bacterial lipopolysaccharide (LPS)-stimulated transcription of numerous inflammation-associated genes. Specifically, deletion of Scd2 from macrophages decreased basal and LPS-induced expression of Il1b transcript that corresponded to decreased production of precursor IL1B protein and release of mature IL1B. Furthermore, we identified disruptions in autophagy and depletion of unsaturated cardiolipins in SCD2-deficient macrophages. To assess the functional relevance of SCD2 in the macrophage response to infection, we challenged SCD2-deficient macrophages with uropathogenic Escherichia coli and found that there was impaired clearance of intracellular bacteria. This increased burden of intracellular bacteria was accompanied by increased release of pro-inflammatory cytokines IL6 and TNF but decreased IL1B. Taken together, these results indicate that macrophage expression of Scd2 is necessary for maintaining the macrophage response to inflammatory stimuli. This link between fatty acid metabolism and fundamental macrophage effector functions may potentially be relevant to diverse age-related pathologies. IMPORTANCE Macrophages are immune cells that respond to infection, but their dysfunction is implicated in many age-related diseases. Recent evidence showed that macrophage expression of a fatty acid enzyme, stearoyl-CoA desaturase 2, declines in aged organisms. In this work, we characterize the effects when stearoyl-CoA desaturase 2 is deficient in macrophages. We identify aspects of the macrophage inflammatory response to infection that may be affected when expression of a key fatty acid enzyme is decreased, and these findings may provide cellular insight into how macrophages contribute to age-related diseases.

Drug repurposing is a promising approach that has the potential to revolutionize the drug discovery and development process. By leveraging existing drugs, we can bring new treatments to patients more quickly and affordably. Anti-inflammatory drugs have been shown to target multiple pathways involved in cancer development and progression. This suggests that they may be more effective in treating cancer than drugs that target a single pathway. Cell viability was measured using the MTT assay. The expression of genes related to inflammation (TNFa, IL1b, COX-1, COX-2, and 5-LOX) was measured in HepG2, MCF7, and THLE-2 cells using qPCR. The levels of TNFα, IL1b, COX-1, COX-2, and 5-LOX were also measured in these cells using an ELISA kit. An enzyme binding assay revealed that sulfadiazine expressed weaker inhibitory activity against COX-2 (IC50 = 5.27 μM) in comparison with the COX-2 selective reference inhibitor celecoxib (COX-2 IC50 = 1.94 μM). However, a more balanced inhibitory effect was revealed for sulfadiazine against the COX/LOX pathway with greater affinity towards 5-LOX (IC50 = 19.1 μM) versus COX-1 (IC50 = 18.4 μM) as compared to celecoxib (5-LOX IC50 = 16.7 μM, and COX-1 IC50 = 5.9 μM). MTT assays revealed the IC50 values of 245.69 ± 4.1 µM and 215.68 ± 3.8 µM on HepG2 and MCF7 cell lines, respectively, compared to the standard drug cisplatin (66.92 ± 1.8 µM and 46.83 ± 1.3 µM, respectively). The anti-inflammatory effect of sulfadiazine was also depicted through its effect on the levels of inflammatory markers and inflammation-related genes (TNFα, IL1b, COX-1, COX-2, 5-LOX). Molecular simulation studies revealed key binding interactions that explain the difference in the activity profiles of sulfadiazine compared to celecoxib. The results suggest that sulfadiazine exhibited balanced inhibitory activity against the 5-LOX/COX-1 enzymes compared to the selective COX-2 inhibitor, celecoxib. These findings highlight the potential of sulfadiazine as a potential anticancer agent through balanced inhibitory activity against the COX/LOX pathway and reduction in the expression of inflammatory genes.

Introduction: It is necessary to explore a noninvasive method to stratify head and neck squamous cell carcinoma (HNSCC)'s prognosis and to seek new indicators for individualized precision treatment. As a vital inflammatory cytokine, IL1B might drive a new tumor subtype that could be reflected in overall survival (OS) and predicted using the radiomics method. Methods: A total of 139 patients with RNA-Seq data from The Cancer Genome Atlas (TCGA) and matched CECT data from The Cancer Image Archive (TCIA) were included in the analysis. The prognostic value of IL1B expression in patients with HNSCC was analyzed using Kaplan-Meier analysis, Cox regression analysis and subgroup analysis. Furthermore, the molecular function of IL1B on HNSCC was explored using function enrichment and immunocytes infiltration analyses. Radiomic features were extracted with PyRadiomics and processed using maxrelevance minredundancy, recursive feature elimination, and gradient boosting machine algorithm to construct aradiomics model for predicting IL1B expression. The area under the receiver operating characteristic curve (AUC), calibration curve, precision recall (PR) curve, and decision curve analysis (DCA) curve were used to examine the performance of the model. Results: Increased IL1B expression in patients with HNSCC indicated a poor prognosis (hazard ratio [HR] = 1.56, P = 0.003) and was harmful in patients who underwent radiotherapy (HR = 1.87, P = 0.007) or chemotherapy (HR = 2.514, P < 0.001). Shape_Sphericity, glszm_SmallAreaEmphasis, and firstorder_Kurtosis were included in the radiomics model (AUC: training cohort, 0.861; validation cohort, 0.703). The calibration curves, PR curves and DCA showed good diagnostic effect of the model. The rad-score was close related to IL1B (P = 4.490*10-9), and shared the same corelated trend to EMT-related genes with IL1B. A higher rad-score was associated with worse overall survival (P = 0.041). Frontiers Discussion: The CECT-based radiomics model provides preoperative IL1B expression predictionand offers non-invasive instructions for the prognosis and individualized treatment of patients withHNSCC. [ABSTRACT FROM AUTHOR]

While a low level of ROS plays a role in cellular regulatory processes, a high level can lead to oxidative stress and cellular dysfunction. Insulin resistance (IR) is one of the dysfunctions in which oxidative stress occurs and, until now, the factors underlying the correlation between oxidative stress and IR were unclear and incomplete. This study aims to explore this correlation in skeletal muscle, a tissue relevant to insulin-mediated glucose disposal, using the hyperthyroid rat as a model of oxidative stress. The development of IR in the liver from hyperthyroid animals has been widely reported, whereas data concerning the muscle are quite controversial. Thus, we investigated whether hyperthyroidism induces IR in skeletal muscle and the role of oxidative stress in this process. Particularly, we compared the effects of hyperthyroidism on IR both in the absence and presence of vitamin E (Vit E), acting as an antioxidant. Putative correlations between ROS production, oxidative stress markers, antioxidant capacity and changes in intracellular signalling pathways related to insulin action (AKT) and cellular stress response (EIF2α; JNK; PGC1α; BIP; and NRF1) were investigated. Moreover, we assessed the effects of hyperthyroidism and Vit E on the expression levels of genes encoding for glucose transporters (Slc2a1; Slc2a4), factors involved in lipid homeostasis and insulin signalling (Pparg; Ppara, Cd36), as well as for one of the IR-related inflammatory factors, i.e., interleukin 1b (Il1b). Our results suggest that hyperthyroidism-linked oxidative stress plays a role in IR development in muscle and that an adequate antioxidant status, obtained by vitamin E supplementation, that mitigates oxidative stress, may prevent IR development. [ABSTRACT FROM AUTHOR]

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with a high probability of metastasis and a lack of specific targets and targeted therapeutics. Previously, we have reported that COL8A1, which is highly expressed in the mesenchymal stem-like (MSL) subtype of TNBC, facilitates TNBC growth via FAK/Src activation. Furthermore, we have found that COL8A1 enhances the invasion and metastasis of MDA-MB-231 cells, classified into MSL. However, the mechanism of invasion and metastasis by COL8A1 remains unclear. Here, we investigated the biological function of COL8A1 on the invasion and metastasis of MDA-MB-231 cells. The invasion and metastasis of MDA-MB-231 cells were evaluated using three-dimensional (3D) culture methods and xenograft mouse models. DNA microarray analysis examined the gene expression in COL8A1-overexpressing MDA-MB-231 cells and control cells. Gene expression was verified using RT-qPCR. COL8A1-deficient cells showed little or no metastasis, whereas forced expression of COL8A1 in MDA-MB-231 cells, the MSL subtype of TNBC cell lines, significantly promoted distant metastasis after tumor resection. As with in vivo , 3D invasion assay revealed that COL8A1 increased the invasion capacity of MDA-MB-231 and Hs578T cells, classified into the MSL subtype of TNBC. DNA microarray analysis for COL8A1-overexpressing cells indicated that COL8A1 induces interleukin 1B (IL1B) and matrix metalloproteinase-1 (MMP1) expression, both of which are correlated with COL8A1 expression in the mesenchymal subtypes of TNBC, and the Kaplan–Meier plotter provided evidence that the prognosis in the MSL subtype was strongly associated with both gene expressions and COL8A1 expression. Pharmacological inhibitor treatment showed that COL8A1 regulated IL1B and MMP1 expression through a different pathway. Moreover, the knockdown of each gene expression reduced the invasion capacity of COL8A1-overexpressing MDA-MB-231 and Hs578T cells. Our findings indicate that COL8A1-induced IL1B and MMP1 enhanced the invasion and metastasis of the MSL subtype of TNBC. Considering our previous findings that COL8A1 promotes tumor growth, COL8A1 may be a prognostic and practical therapeutic target in TNBC. [Display omitted] • COL8A1 enhances the invasion and metastasis of MDA-MB-231 cells, classified into MSL. • COL8A1 induces IL1B and MMP1 expression in MDA-MB-231 cells. • Poor prognosis in the MSL subtype was strongly associated with IL1B and MMP1.. • COL8A1 regulated IL1B and MMP1 expression through a different pathway. • Knockdown experiment revealed COL8A1-induced IL1B and MMP1 increased the invasion. [ABSTRACT FROM AUTHOR]

The SYNTAX score is clinically validated to stratify number of lesions and pattern of CAD. A better understanding of the underlying molecular mechanisms influencing the pattern and complexity of coronary arteries lesions among CAD patients is needed. Human arterial biopsies from 49 patients (16 low-SYNTAX-score (LSS, <23), 16 intermediate-SYNTAX-score (ISS, 23 to 32) and 17 high-SYNTAX-score (HSS, >32)) were evaluated using Affymetrix GeneChip® Human Genome U133 Plus 2.0 microarray. The data were validated by Next-Generation Sequencing (NGS). Primary VSMC from patients with low and high SYNTAX scores were isolated and compared using immunohistochemistry, qPCR and immunoblotting to confirm mRNA and proteomic results. The IL1B was verified as the top upstream regulator of 47 inflammatory DEGs in LSS patients and validated by another sets of patient samples using NGS analysis. The upregulated expression of IL1B was translated to increased level of IL1β protein in the LSS tissue based on immunohistochemical quantitative analysis. Plausibility of idea that IL1B in the arterial wall could be originated from VSMC was checked by exposing culture to proinflammatory conditions where IL1B came out as the top DEG (logFC = 7.083, FDR = 1.38 × 10−114). The LSS patient-derived primary VSMCs confirmed higher levels of IL1B mRNA and protein. LSS patients could represent a group of patients where IL1B could play a substantial role in disease pathogenesis. The LSS group could represent a plausible cohort of patients for whom anti-inflammatory therapy could be considered. [Display omitted] • IL1B expression in the arterial wall correlates with the low-SYNTAX-score (LSS) pattern of coronary artery disease. • IL1B was verified as the top upstream regulator in LSS samples, directly connected with 47 inflammatory differentially expressed genes (DEGs). • IL1B was the top DEG under proinflammatory conditions in vascular smooth muscle cell (VSMC) culture. • LSS patient-derived VSMCs showed higher levels of IL1B at the mRNA and protein levels compare to high-SYNTAX score. • LSS patients with elevated levels of IL1B represent a specific group where inflammation could play a substantial role in disease pathogenesis. [ABSTRACT FROM AUTHOR]

Haohan Zhou,1,2,&ast; Jiayi Tian,3,&ast; Hongyu Sun,1 Jiaying Fu,1 Nan Lin,1 Danni Yuan,1 Li Zhou,3 Meihui Xia,3 Liankun Sun1 1Key Laboratory of Pathobiology, Ministry of Education, Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, 130021, People’s Republic of China; 2Department of Orthopaedic Oncology, Changzheng Hospital, Second Military Medical University, Shanghai, 200000, People’s Republic of China; 3First Hospital, Jilin University, Changchun, 130021, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Liankun Sun, Key Laboratory of Pathobiology, Ministry of Education, Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, 130021, People’s Republic of China, Email sunlk@jlu.edu.cn Meihui Xia, First Hospital, Jilin University, Changchun, 130021, People’s Republic of China, Email xiamh@jlu.edu.cnPurpose: Magnetic iron oxide nanoparticle (MNP) drug delivery system is a novel promising therapeutic option for cancer treatment. Material issues such as fabrication and functionalized modification have been investigated; however, pharmacologic mechanisms of bare MNPs inside cancer cells remain obscure. This study aimed to explore a systems pharmacology approach to understand the reaction of the whole cell to MNPs and suggest drug selection in MNP delivery systems to exert synergetic or additive anti-cancer effects.Methods: HeLa and SiHa cell lines were used to estimate the properties of bare MNPs in cervical cancer through 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) and enzyme activity assays and cellular fluorescence imaging. A systems pharmacology approach was utilized by combining bioinformatics data mining with clinical data analysis and without a predefined hypothesis. Key genes of the MNP onco-pharmacologic mechanism in cervical cancer were identified and further validated through transcriptome analysis with quantitative reverse transcription PCR (qRT-PCR).Results: Low cytotoxic activity and cell internalization of MNP in HeLa and SiHa cells were observed. Lysosomal function was found to be impaired after MNP treatment. Protein tyrosine kinase 2 beta (PTK2B), liprin-alpha-4 (PPFIA4), mothers against decapentaplegic homolog 7 (SMAD7), and interleukin (IL) 1B were identified as key genes relevant for MNP pharmacology, clinical features, somatic mutation, and immune infiltration. The four key genes also exhibited significant correlations with the lysosome gene set. The qRT-PCR results showed significant alterations in the expression of the four key genes after MNP treatment in HeLa and SiHa cells.Conclusion: Our research suggests that treatment of bare MNPs in HeLa and SiHa cells induced significant expression changes in PTK2B, PPFIA4, SMAD7, and IL1B, which play crucial roles in cervical cancer development and progression. Interactions of the key genes with specific anti-cancer drugs must be considered in the rational design of MNP drug delivery systems.Keywords: drug delivery, anti-cancer drugs, PTK2B, PPFIA4, SMAD7, IL1B

Turner syndrome (TS) is associated with an increased susceptibility to inflammatory and autoimmune diseases. This study investigates the association between genetic polymorphisms in the IL1B and NLRP3 genes, as well as the expression profiles of IL1B , NLRP3 , and NLRP1 , and the risk of inflammatory and autoimmune conditions in TS patients compared to healthy controls. The genetic association analysis included 92 TS patients (case) and 146 healthy controls (HC), evaluating IL1B rs16944, NLRP3 rs10754558 and rs4925659 using TaqMan genotyping assays. In addition, mRNA expression levels of IL1B , NLRP3 , and NLRP1 were also compared in 17 TS patients and 17 healthy females (control group) using qPCR-based fluorogenic probes. The study found significant associations with the G allele of rs16944 (p = 0.001) and the GG genotype (p = 0.002) in TS patients, though these were not associated with inflammatory disorders in this group., On the other hand, rs4925659 exhibited a significantly higher frequency of the A allele (p = 0.02) and AA genotype (p = 0.0001) in HC, while the A allele and GA genotype were more common in the TS group (p = 0.0001). Expression analysis revealed a downregulation of IL1B and NLRP3 (fold change: FC = −6.78 and −15.73, respectively) and an upregulation of NLRP1 (FC = 21.5) in TS patients compared to HC. These results indicate a differential distribution of IL1B and NLRP3 polymorphisms in TS patients, and suggest that alterations in the expression of IL1B , NLRP3 , and NLRP1 may contribute to an inflammatory imbalance in the Turner syndrome. [ABSTRACT FROM AUTHOR]

Abstract Background Obesity has been recognized as a worldwide growing problem, producing many pathologies including the promotion of “proinflammatory state.” The etiology of human obesity is still only partially understood; however, the genetic background has been proved. Its nature is complex, and currently, it appears that the combined effects of the interactions among multiple genes should receive more attention. Due to the fact that obesity promotes proinflammatory conditions, in this study, we investigated the genetic polymorphism of IL-1 family genes in healthy people with normal and elevated body mass index (BMI) and fat %. Results The single-nucleotide polymorphisms (SNPs) within the IL1A -889C > T (rs1800587), IL1B + 3954 T > C (rs1143634), and IL1RN -87G > A (rs2234677) genes alone were associated neither with BMI nor fat % values in tested group. The associations between SNP–SNP interaction and BMI for the IL1B × IL1RN interactions were significant for dominant model (p = 0.02) and codominant model (p = 0.03). The same SNP-SNP interaction (IL1B × IL1RN) was associated also with fat % for codominant (p = 0.01) and recessive (p = 0.002) models. Conclusions This study further confirmed that IL-1 family genes are involved in genetic background of obesity. It has been shown that interaction IL1B × IL1RN was associated with both BMI and fat % with rare T allele protecting form higher values. Thus, even if certain polymorphisms in single genes of IL-1 family cannot be defined as related to obesity in examined population, the genetic interrelationships should be analyzed.

Background: Decidualization refers to the process of transformation of endometrial stromal fibroblast cells into specialized decidual stromal cells that provide a nutritive and immunoprivileged matrix essential for blastocyst implantation and placental development. Deficiencies in decidualization are associated with a variety of pregnancy disorders, including female infertility, recurrent implantation failure (RIF), and miscarriages. Despite the increasing number of genes reportedly associated with endometrial receptivity and decidualization, the cellular and molecular mechanisms triggering and underlying decidualization remain largely unknown. Here, we analyze single-cell transcriptional profiles of endometrial cells during the window of implantation and decidual cells of early pregnancy, to gains insights on the process of decidualization. Results: We observed a unique IGF1+ stromal cell that may initiate decidualization by single-cell RNA sequencing. We found the IL1B+ stromal cells promote gland degeneration and decidua hemostasis. We defined a subset of NK cells for accelerating decidualization and extravillous trophoblast (EVT) invasion by AREG-IGF1 and AREG-CSF1 regulatory axe. Further analysis indicates that EVT promote decidualization possibly by multiply pathways. Additionally, a systematic repository of cell–cell communication for decidualization was developed. An aberrant ratio conversion of IGF1+ stromal cells to IGF1R+ stromal cells is observed in unexplained RIF patients. Conclusions: Overall, a unique subpopulation of IGF1+ stromal cell is involved in initiating decidualization. Our observations provide deeper insights into the molecular and cellular characterizations of decidualization, and a platform for further development of evaluation of decidualization degree and treatment for decidualization disorder-related diseases. [ABSTRACT FROM AUTHOR]

Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD). Its etiology is unclear. Much evidence suggests that the death of abnormal intestinal epithelial cells (IECs) leads to intestinal barrier disruption, and the subsequent inflammatory response plays a vital role in UC. Pyroptosis is a form of programmed inflammatory cell death, and the role of pyroptosis in UC etiology remains to be explored. This study identified 10 hub genes in pyroptosis by gene expression profiles obtained from the GSE87466 dataset. Meanwhile, the biomarkers were screened based on gene significance (GS) and module membership (MM) through the Weighted Gene Co-Expression Network Analysis (WGCNA). The following analysis indicated that hub genes were closely associated with the UC progression and therapeutic drug response. The single-cell RNA (scRNA) sequencing data from UC patients within the GSE162335 dataset indicated that macrophages were most related to pyroptosis. Finally, the expression of hub genes and response to the therapeutic drug [5-aminosalicylic acid (5-ASA)] were verified in dextran sulfate sodium (DSS)-induced colitis mice. Our study identified IL1B as the critical pyroptosis-related biomarker in UC. The crosstalk between macrophage pyroptosis and IEC pyroptosis may play an essential role in UC, deserving further exploration. [ABSTRACT FROM AUTHOR]

Background: The main aim of this study was to evaluate whether selected polymorphic variants in genes from the inflammatory pathway can be predictors of pulmonary or digestive manifestation of cystic fibrosis, as well as of severity of lung disease. Materials and methods: Using pyrosequencing and sequencing we have genotyped 12 variants in TNF (rs361525, rs1800629), CXCL8 (rs4073, rs2227306, rs2227307, rs188378669), IL1B (rs16944, rs1143634, rs1142639, rs1143627), IL6 (rs1800795) and IL10 (rs1800896) genes in a cohort of 55 Polish patients with diagnosed cystic fibrosis and controls. In our study group, a pulmonary manifestation of disease revealed 44 of subjects (80%), and digestive symptoms dominated in 11 (20%) of analyzed individuals. Severe lung dysfunction has occurred in 20 (36.4%) of patients. Results: We proved, that two promoter variants of IL1B, rs1143627 (c.-118G > A) and rs16944 (c.-598T > C) are presented significantly more often in patients with severe character of lung disease compared to mild (82.5% vs. 62.8%, p-value 0.030, and 87.5% vs. 64.3%, p-value 0.008, respectively) in cystic fibrosis course. Haplotype AC formed by both changes had also a higher frequency (80%) in patients with severe course compared to the mild character (61.4%) of disease. However, the frequency of promoter variant TNF c.-308C > T (rs1800629) was presented at a significantly lower level in the patient’s group compared to healthy controls (2.7% vs. 15%, p-value 0.001). Furthermore, the presence of methicillin-resistant Staphylococcus aureus significantly correlated with the lower FEV1% in patients (p-value 0.01). Conclusions: Genetic variants, rs1143627 and rs16944, of IL1B are promising candidates as predictors of the severe character of lung disease in Polish patients with cystic fibrosis.

Background: Triple-negative breast cancer (TNBC), which is so called because of the lack of estrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor receptor 2 (HER2) receptors on the cancer cells, accounts for 10%-15% of all breast cancers. The heterogeneity of the tumor microenvironment is high. However, the role of plasma cells controlling the tumor migration progression in TNBC is still not fully understood., Methods: We analyzed single-cell RNA sequencing data from five HER2 positive, 12 ER positive/PR positive, and nine TNBC samples. The potential targets were validated by immunohistochemistry., Results: Plasma cells were enriched in TNBC samples, which was consistent with validation using data from The Cancer Genome Atlas. Cell communication analysis revealed that plasma cells interact with T cells through the intercellular adhesion molecule 2-integrin-aLb2 complex, and then release interleukin 1 beta (IL1B), as verified by immunohistochemistry, ultimately promoting tumor growth., Conclusion: Our results revealed the role of plasma cells in TNBC and identified IL1B as a new prognostic marker for TNBC., (© 2024 The Author(s). Animal Models and Experimental Medicine published by John Wiley & Sons Australia, Ltd on behalf of The Chinese Association for Laboratory Animal Sciences.)

Background: The main aim of this study was to evaluate whether selected polymorphic variants in genes from the inflammatory pathway can be predictors of pulmonary or digestive manifestation of cystic fibrosis, as well as of severity of lung disease. Materials and methods: Using pyrosequencing and sequencing we have genotyped 12 variants in TNF (rs361525, rs1800629), CXCL8 (rs4073, rs2227306, rs2227307, rs188378669), IL1B (rs16944, rs1143634, rs1142639, rs1143627), IL6 (rs1800795) and IL10 (rs1800896) genes in a cohort of 55 Polish patients with diagnosed cystic fibrosis and controls. In our study group, a pulmonary manifestation of disease revealed 44 of subjects (80%), and digestive symptoms dominated in 11 (20%) of analyzed individuals. Severe lung dysfunction has occurred in 20 (36.4%) of patients. Results: We proved, that two promoter variants of IL1B, rs1143627 (c.-118G > A) and rs16944 (c.-598T > C) are presented significantly more often in patients with severe character of lung disease compared to mild (82.5% vs. 62.8%, p-value 0.030, and 87.5% vs. 64.3%, p-value 0.008, respectively) in cystic fibrosis course. Haplotype AC formed by both changes had also a higher frequency (80%) in patients with severe course compared to the mild character (61.4%) of disease. However, the frequency of promoter variant TNF c.-308C > T (rs1800629) was presented at a significantly lower level in the patient’s group compared to healthy controls (2.7% vs. 15%, p-value 0.001). Furthermore, the presence of methicillin-resistant Staphylococcus aureus significantly correlated with the lower FEV1% in patients (p-value 0.01). Conclusions: Genetic variants, rs1143627 and rs16944, of IL1B are promising candidates as predictors of the severe character of lung disease in Polish patients with cystic fibrosis.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD). Its etiology is unclear. Much evidence suggests that the death of abnormal intestinal epithelial cells (IECs) leads to intestinal barrier disruption, and the subsequent inflammatory response plays a vital role in UC. Pyroptosis is a form of programmed inflammatory cell death, and the role of pyroptosis in UC etiology remains to be explored. This study identified 10 hub genes in pyroptosis by gene expression profiles obtained from the GSE87466 dataset. Meanwhile, the biomarkers were screened based on gene significance (GS) and module membership (MM) through the Weighted Gene Co-Expression Network Analysis (WGCNA). The following analysis indicated that hub genes were closely associated with the UC progression and therapeutic drug response. The single-cell RNA (scRNA) sequencing data from UC patients within the GSE162335 dataset indicated that macrophages were most related to pyroptosis. Finally, the expression of hub genes and response to the therapeutic drug [5-aminosalicylic acid (5-ASA)] were verified in dextran sulfate sodium (DSS)-induced colitis mice. Our study identified IL1B as the critical pyroptosis-related biomarker in UC. The crosstalk between macrophage pyroptosis and IEC pyroptosis may play an essential role in UC, deserving further exploration.

In recent years, studies on circadian control in immunity have been actively conducted in mammals, but little is known about circadian rhythms in the field of fish immunology. In this study, we aimed to analyse the regulation of the diel oscillation of inflammatory cytokine interleukin-1β (il1b) gene expression by core components of the circadian clock in Japanese medaka (Oryzias latipes). The expression of il1b and clock genes (bmal1 and clock1) in medaka acclimated to a 12:12 light (L): dark (D) cycle showed diel rhythm. Additionally, higher expression of il1b was detected in medaka embryo cells (OLHdrR-e3) overexpressing bmal1 and clock1. A significant decrease in il1b expression was observed in OLHdrR-e3 cells after bmal1 knockdown using morpholino oligos. These changes may be mediated by transcriptional regulation via clock proteins, which target the E-box sequence in the cis -element of il1b as identified using luciferase reporter assays. Moreover, LPS stimulation and pathogenic bacterial infection at different zeitgeber time (ZT) under LD12:12 conditions affected the degree of il1b expression, which showed high and low responsiveness to both immuno-stimulations at ZT2 and ZT14, respectively. These results suggested that fish IL-1β exhibited diel oscillation regulated by clock proteins, and its responsiveness to immune-stimulation depends on the time of day. • Medaka il1b is expressed in a circadian rhythm. • Medaka clock genes bmal1 and clock1 regulate il1b expression. • Immuno-stimulation at different time point impacts il1b expression magnitude. [ABSTRACT FROM AUTHOR]

In this study, we determined to interpret the effects of the interleukin (IL)1B gene rs1143634 C/T polymorphism on myocardial infarction (MI) risk. This study, conducted in a Chinese Han population, recruited 369 MI patients and 465 controls. The variant of IL1B gene (rs1143634 C/T polymorphism) was genotyped by PCR-RFLP method. In this study, a significant link was shown between the IL1B rs1143634 C/T polymorphism and MI risk. We found that the IL1B rs1143634 C/T polymorphism enhanced the risk of MI in this population. Subgroup analysis detected that the IL1B rs1143634 C/T polymorphism associated with MI susceptibility in males, smokers, and individuals with diabetes mellitus. In addition, the IL1B rs1143634 C/T polymorphism was related with the levels of blood lipids including low-density lipoprotein (LDL), and total cholesterol (TC). This study uncovers that the IL1B rs1143634 C/T polymorphism may associate with the risk and blood lipid levels of MI in an Eastern Chinese Han population. Abbreviations: MI: myocardial infarction; IL-1: Interleukin-1; SNP: single nucleotide polymorphism; BMI: Body Mass Index; HDL: high-density lipoprotein; TC: total cholesterol; TG: triglyceride; LDL: low-density lipoprotein; PCR: polymerase chain reaction; 95% CI: 95% confidence interval; OR: odds ratio [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICI) for early-stage non-small cell lung cancer (NSCLC) have been approved to improve outcomes and reduce recurrence. Biomarkers for patient selection are needed. In this paper, we proposed an inflammasome-based risk score (IRS) system for prognosis and prediction of ICI response for early-stage NSCLC. Cox regression analysis was used to identify significant genes (from 141 core inflammasome genes) for overall survival (OS) in a microarray discovery cohort (n = 467). IRS was established and independently validated by other datasets (n = 1320). We evaluated the inflammasome signaling steps based on five gene sets, which were IL1B-, CASP-1-, IL18-, GSDMD-, and inflammasome-regulated genes. Gene set enrichment analysis, the Kaplan–Meier curve, receiver operator characteristic with area under curve (AUC) analysis, and advanced bioinformatic tools were used to confirm the ability of IRS in prognosis and classification of patients into ICI responders and non-responders. A 30-gene IRS was developed, and it indicated good risk stratification at 10-year OS (AUC = 0.726). Patients were stratified into high- and low-risk groups based on optimal cutoff points, and high-risk IRS had significantly poorer OS and relapse-free survival. In addition, the high-risk group was characterized by an inflamed immunophenotype and higher proportion of ICI responders. Furthermore, expression of SLAMF8 was the key gene in IRS and indicated good correlation with biomarkers associated with immunotherapy. It could serve as a therapeutic target in the clinical setting of immunotherapy. [ABSTRACT FROM AUTHOR]

Zhongqiu Zhang,1,2,&ast; Yanping Mei,3,&ast; Mengqiu Xiong,3 Fang Lu,1,2 Xianghong Zhao,1,2 Junrong Zhu,1,2 Bangshun He1,3 1School of Basic Medicine & Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211198, Jiangsu Province, People’s Republic of China; 2Department of Pharmacy, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, Jiangsu Province, People’s Republic of China; 3Department of Laboratory Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, Jiangsu Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Bangshun HeDepartment of Laboratory Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, 210006, People’s Republic of ChinaEmail bhe@njmu.edu.cnJunrong ZhuDepartment of Pharmacy, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing, Jiangsu Province, 210006, People’s Republic of ChinaEmail junrong_zhu@aliyun.comBackground: Inflammation proteins play an important role in stroke occurrence. IL1A, IL1B, PTGS2, MMP2, and MMP9 were the mediators involved in the immune response, and the association of these genetic variations with ischemic stroke (IS) risk was still unclear.Methods: To investigate the susceptibility of genetic variations of IL1A, IL1B, PTGS2, MMP2, and MMP9 to IS risk, we performed a case–control study involving 299 patients and 300 controls in a Chinese population. Thirteen genetic variations of investigated genes of all participants were genotyped using an improved multiplex ligase detection–reaction technique.Results: No SNP in all genes showed an association with overall IS. However, in subgroup analysis, PTGS2 rs689466 (dominant model: CT vs TT – ORadjusted= 2.51, 95% CI: 1.22– 5.16, p = 0.012; co-dominant model: CT/CC vs TT – ORadjusted= 2.53, 95% CI: 1.26– 5.07, p = 0.009; additive model – ORadjusted= 2.26, 95% CI: 1.19– 4.28, p = 0.013) and rs5275 (dominant model: GG vs AA – ORadjusted= 0.31, 95% CI: 0.12– 0.80, p = 0.016; co-dominant model: GA/GG vs AA – ORadjusted= 0.45, 95% CI: 0.21– 0.95, p = 0.036; additive model – ORadjusted= 0.60, 95% CI: 0.39– 0.92, p = 0.020) were associated with IS type of small-vessel occlusion.Conclusion: Our study suggested that PTGS2 rs689466 C and rs5275 A were potentially associated with IS subtype of small-vessel occlusion. Our result should be confirmed with further large sample sized studies.Keywords: ischemic stroke, genetic variation, IL1A, IL1B, PTGS2, MMP2, MMP9, risk

Background: The main aim of this study was to evaluate whether selected polymorphic variants in genes from the inflammatory pathway can be predictors of pulmonary or digestive manifestation of cystic fibrosis, as well as of severity of lung disease. Materials and methods: Using pyrosequencing and sequencing we have genotyped 12 variants in TNF (rs361525, rs1800629), CXCL8 (rs4073, rs2227306, rs2227307, rs188378669), IL1B (rs16944, rs1143634, rs1142639, rs1143627), IL6 (rs1800795) and IL10 (rs1800896) genes in a cohort of 55 Polish patients with diagnosed cystic fibrosis and controls. In our study group, a pulmonary manifestation of disease revealed 44 of subjects (80%), and digestive symptoms dominated in 11 (20%) of analyzed individuals. Severe lung dysfunction has occurred in 20 (36.4%) of patients. Results: We proved, that two promoter variants of IL1B, rs1143627 (c.-118G > A) and rs16944 (c.-598T > C) are presented significantly more often in patients with severe character of lung disease compared to mild (82.5% vs. 62.8%, p-value 0.030, and 87.5% vs. 64.3%, p-value 0.008, respectively) in cystic fibrosis course. Haplotype AC formed by both changes had also a higher frequency (80%) in patients with severe course compared to the mild character (61.4%) of disease. However, the frequency of promoter variant TNF c.-308C > T (rs1800629) was presented at a significantly lower level in the patient’s group compared to healthy controls (2.7% vs. 15%, p-value 0.001). Furthermore, the presence of methicillin-resistant Staphylococcus aureus significantly correlated with the lower FEV1% in patients (p-value 0.01). Conclusions: Genetic variants, rs1143627 and rs16944, of IL1B are promising candidates as predictors of the severe character of lung disease in Polish patients with cystic fibrosis.

Abstract Background Helicobacter pylori (H. pylori) infects nearly half of the world’s population with a variation in incidence among different geographic regions. Genetic variants in the promoter regions of the IL1B gene can affect cytokine expression and creates a condition of hypoacidity which favors the survival and colonization of H. pylori. Therefore, the aim of this study was to characterize the polymorphic sites in the 5′- region [−687_ + 297] of IL1B in H. pylori infection using in silico tools. Results A total of five nucleotide variations were detected in the 5′-regulatory region [−687_ + 297] of IL1B which led to the addition or alteration of transcription factor binding sites (TFBSs) or composite regulatory elements (CEs). Genotyping of IL1B − 31 C > T revealed a significant association between -31 T and susceptibility to H. pylori infection in the studied population (P = 0.0363). Comparative analysis showed conservation rates of IL1B upstream [−368_ + 10] region above 70% in chimpanzee, rhesus monkey, a domesticated dog, cow and rat. Conclusions In H. pylori-infected patients, three detected SNPs (− 338, − 155 and − 31) located in the IL1B promoter were predicted to alter TFBSs and CE, which might affect the gene expression. These in silico predictions provide insight for further experimental in vitro and in vivo studies of the regulation of IL1B expression and its relationship to H. pylori infection. However, the recognition of regulatory motifs by computer algorithms is fundamental for understanding gene expression patterns.

The aim. To evaluate the association of fibrinogen (FGB), tumor necrosis factor α (TNFα), interleukin 1β (IL-1β), lipoprotein lipase (LPL), platelet glycoprotein (ITGB3), and transforming growth factor β (TGFB1) genes with the incidence of recurrent myocardial infarction (MI) in patients living in the middle Volga region.Materials and methods. The study included 104 people with recurrent MI compared to 280 people who had just one episode of MI. TNFα (rs1800629), IL1B (rs16944), TGFB1b (rs1800469), FGB (rs1800788), ITGB3 (rs5918) and LPL (rs328) gene polymorphism was determined in all patients using competing TaqMan probes. Association estimation was performed with multivariate logistic regression analysis.Results. Patients with recurrent MI much more often had TNFα, IL1B, TGFB1b, FGB, ITGB3 and LPL allele and genotype polymorphism. Moreover the risk of MI increased significantly in a case of combination of FGB (alleles and genotypes) and TNFα (alleles and genotypes) gene polymorphisms (OR = 4.04, 95% CI = (1.895–8.615), p = 0.0001).Conclusion. Thus, FGB, LPL, TNFα, TGFB1b and ITGB3 gene polymorphism are associated with more severe coronary heart disease and may be a risk factor of recurrent MI development. The dominant total contribution of the FGB (rs1800788) and TNFα (rs1800629) polymorphic genes to the development of recurrent MI in the population of the middle Volga region was revealed.

Background: The main aim of this study was to evaluate whether selected polymorphic variants in genes from the inflammatory pathway can be predictors of pulmonary or digestive manifestation of cystic fibrosis, as well as of severity of lung disease. Materials and methods: Using pyrosequencing and sequencing we have genotyped 12 variants in TNF (rs361525, rs1800629), CXCL8 (rs4073, rs2227306, rs2227307, rs188378669), IL1B (rs16944, rs1143634, rs1142639, rs1143627), IL6 (rs1800795) and IL10 (rs1800896) genes in a cohort of 55 Polish patients with diagnosed cystic fibrosis and controls. In our study group, a pulmonary manifestation of disease revealed 44 of subjects (80%), and digestive symptoms dominated in 11 (20%) of analyzed individuals. Severe lung dysfunction has occurred in 20 (36.4%) of patients. Results: We proved, that two promoter variants of IL1B, rs1143627 (c.-118G > A) and rs16944 (c.-598T > C) are presented significantly more often in patients with severe character of lung disease compared to mild (82.5% vs. 62.8%, p-value 0.030, and 87.5% vs. 64.3%, p-value 0.008, respectively) in cystic fibrosis course. Haplotype AC formed by both changes had also a higher frequency (80%) in patients with severe course compared to the mild character (61.4%) of disease. However, the frequency of promoter variant TNF c.-308C > T (rs1800629) was presented at a significantly lower level in the patient’s group compared to healthy controls (2.7% vs. 15%, p-value 0.001). Furthermore, the presence of methicillin-resistant Staphylococcus aureus significantly correlated with the lower FEV1% in patients (p-value 0.01). Conclusions: Genetic variants, rs1143627 and rs16944, of IL1B are promising candidates as predictors of the severe character of lung disease in Polish patients with cystic fibrosis.

Background: Obesity has been recognized as a worldwide growing problem, producing many pathologies including the promotion of "proinflammatory state." The etiology of human obesity is still only partially understood; however, the genetic background has been proved. Its nature is complex, and currently, it appears that the combined effects of the interactions among multiple genes should receive more attention. Due to the fact that obesity promotes proinflammatory conditions, in this study, we investigated the genetic polymorphism of IL-1 family genes in healthy people with normal and elevated body mass index (BMI) and fat %. Results: The single-nucleotide polymorphisms (SNPs) within the IL1A -889C > T (rs1800587), IL1B + 3954 T > C (rs1143634), and IL1RN -87G > A (rs2234677) genes alone were associated neither with BMI nor fat % values in tested group. The associations between SNP–SNP interaction and BMI for the IL1B × IL1RN interactions were significant for dominant model (p = 0.02) and codominant model (p = 0.03). The same SNP-SNP interaction (IL1B × IL1RN) was associated also with fat % for codominant (p = 0.01) and recessive (p = 0.002) models. Conclusions: This study further confirmed that IL-1 family genes are involved in genetic background of obesity. It has been shown that interaction IL1B × IL1RN was associated with both BMI and fat % with rare T allele protecting form higher values. Thus, even if certain polymorphisms in single genes of IL-1 family cannot be defined as related to obesity in examined population, the genetic interrelationships should be analyzed. [ABSTRACT FROM AUTHOR]

Time course of changes in neuroinflammatory processes in the dorsal and ventral hippocampus was studied during the early period after lateral fluid percussion-induced neocortical traumatic brain injury (TBI) in the ipsilateral and contralateral hemispheres. In the ipsilateral hippocampus, neuroinflammation (increase in expression of pro-inflammatory cytokines) was evident from day 1 after TBI and ceased by day 14, while in the contralateral hippocampus, it was mainly limited to the dorsal part on day 1. TBI induced an increase in hippocampal corticosterone level on day 3 bilaterally and an accumulation of Il1b on day 1 in the ipsilateral hippocampus. Activation of microglia was observed from day 7 in different hippocampal areas of both hemispheres. Neuronal cell loss was detected in the ipsilateral dentate gyrus on day 3 and extended to the contralateral hippocampus by day 7 after TBI. The data suggest that TBI results in distant hippocampal damage (delayed neurodegeneration in the dentate gyrus and microglia proliferation in both the ipsilateral and contralateral hippocampus), the time course of this damage being different from that of the neuroinflammatory response. [ABSTRACT FROM AUTHOR]

Abstract Background The aim of the study was to investigate the genetic risk factors of essential tremor (ET) in Chinese Population. Methods A total of 225 ET patients (25 ET patients also had restless legs syndrome (RLS) and were excluded from final analysis) and 229 controls were recruited. The diagnosis of ET was based on the Consensus Statement of the Movement Disorders Society on tremor. Polymerase chain reaction (PCR) and sequencing were used to detect 12 single nucleotide polymorphisms (SNPs) in seven candidate genes for RLS (HMOX1, HMOX2, VDR, IL17A, IL1B, NOS1 and ADH1B). Results We found that one SNP was associated with the risk of ET in Chinese population after adjusting for age and gender: rs1143633 of IL1B (odds ratio [OR] =2.57, p = 0.003, recessive model), and the statistical result remained significant after Bonferroni correction. Then, we performed a query in Genotype-tissue Expression (GTEx), Brain eQTL Almanac (Braineac) databases and Blood expression quantitative trait loci (eQTL) browser. The significant association was only found between genotype at rs1143633 and IL1B expression level of putamen and white matter in Braineac database, which was more prominent with homozygous (GG) carriers. Conclusions Our study firstly reported the association of IL1B polymorphism with the risk of ET in Chinese population. However, the association might only suggest a marker of IL1B SNP associated with ET instead of the casual variant. Further studies are needed to confirm our finding.

Wnt proteins comprise a large family of highly conserved glycoproteins known for their role in development, cell fate specification, tissue regeneration, and tissue homeostasis. Aberrant Wnt signaling is linked to developmental defects, malignant transformation, and carcinogenesis as well as to inflammation. Mounting evidence from recent research suggests that a dysregulated activation of Wnt signaling is involved in the pathogenesis of chronic inflammatory diseases, such as neuroinflammation, cancer-mediated inflammation, and metabolic inflammatory diseases. Recent findings highlight the role of Wnt in the modulation of inflammatory cytokine production, such as NF-kB signaling and in innate defense mechanisms as well as in the bridging of innate and adaptive immunity. This sparked the development of novel therapeutic treatments against inflammatory diseases based on Wnt modulation. Here, we summarize the role and function of the Wnt pathway in inflammatory diseases and focus on Wnt signaling as underlying master regulator of inflammation that can be therapeutically targeted.