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Background Migraine belongs to the group of primary headaches, affecting 14.4% of the global population. The pathophysiological mechanisms of migraine involve the interplay between hypothalamic activation, cortical spreading depression, trigeminal stimulation, and inflammatory components with neurogenic inflammation or neuroinflammation.

BACKGROUND: Hormonal changes during the menstrual cycle play a key role in shaping immunity in the cervicovaginal tract. Cervicovaginal fluid contains cytokines, chemokines, immunoglobulins, and other immune mediators. Many studies have shown that the concentrations of these immune mediators change throughout the menstrual cycle, but the studies have often shown inconsistent results. Our understanding of immunological correlates of the menstrual cycle remains limited and could be improved by meta-analysis of the available evidence. METHODS: We performed a systematic review and meta-analysis of cervicovaginal immune mediator concentrations throughout the menstrual cycle using individual participant data. Study eligibility included strict definitions of the cycle phase (by progesterone or days since the last menstrual period) and no use of hormonal contraception or intrauterine devices. We performed random-effects meta-analyses using inverse-variance pooling to estimate concentration differences between the follicular and luteal phases. In addition, we performed a new laboratory study, measuring select immune mediators in cervicovaginal lavage samples. RESULTS: We screened 1570 abstracts and identified 71 eligible studies. We analyzed data from 31 studies, encompassing 39,589 concentration measurements of 77 immune mediators made on 2112 samples from 871 participants. Meta-analyses were performed on 53 immune mediators. Antibodies, CC-type chemokines, MMPs, IL-6, IL-16, IL-1RA, G-CSF, GNLY, and ICAM1 were lower in the luteal phase than the follicular phase. Only IL-1α, HBD-2, and HBD-3 were elevated in the luteal phase. There was minimal change between the phases for CXCL8, 9, and 10, interferons, TNF, SLPI, elafin, lysozyme, lactoferrin, and interleukins 1β, 2, 10, 12, 13, and 17A. The GRADE strength of evidence was moderate to high for all immune mediators listed here. CONCLUSIONS: Despite the variability of cervicovaginal immune mediator measurements, our meta-analyses show clear and consistent changes during the menstrual cycle. Many immune mediators were lower in the luteal phase, including chemokines, antibodies, matrix metalloproteinases, and several interleukins. Only interleukin-1α and beta-defensins were higher in the luteal phase. These cyclical differences may have consequences for immunity, susceptibility to infection, and fertility. Our study emphasizes the need to control for the effect of the menstrual cycle on immune mediators in future studies.

Atherosclerosis is an inflammatory disease of the artery walls and involves immune cells such as macrophages. Olfactory receptors (OLFRs) are G protein–coupled chemoreceptors that have a central role in detecting odorants and the sense of smell. We found that mouse vascular macrophages express the olfactory receptor Olfr2 and all associated trafficking and signaling molecules. Olfr2 detects the compound octanal, which activates the NLR family pyrin domain containing 3 (NLRP3) inflammasome and induces interleukin-1β secretion in human and mouse macrophages. We found that human and mouse blood plasma contains octanal, a product of lipid peroxidation, at concentrations sufficient to activate Olfr2 and the human ortholog olfactory receptor 6A2 (OR6A2). Boosting octanal levels exacerbated atherosclerosis, whereas genetic targeting of Olfr2 in mice significantly reduced atherosclerotic plaques. Our findings suggest that inhibiting OR6A2 may provide a promising strategy to prevent and treat atherosclerosis.

Our goal was to evaluate the effects of EC refill fluids and EC exhaled aerosol residue (ECEAR) on cultured human keratinocytes and MatTek EpiDerm™, a 3D air liquid interface human skin model. Quantification of flavor chemicals and nicotine in Dewberry Cream and Churrios refill fluids was done using GC-MS. The dominant flavor chemicals were maltol, ethyl maltol, vanillin, ethyl vanillin, benzyl alcohol, and furaneol. Cytotoxicity was determined with the MTT and LDH assays, and inflammatory markers were quantified with ELISAs. Churrios was cytotoxic to keratinocytes in the MTT assay, and both fluids induced ROS production in the medium (ROS-Glo™) and in cells (CellROX). Exposure of EpiDerm™ to relevant concentrations of Dewberry Cream and Churrios for 4 or 24 h caused secretion of inflammatory markers (IL-1α, IL-6, and MMP-9), without altering EpiDerm™ histology. Lab made fluids with propylene glycol (PG) or PG plus a flavor chemical did not produce cytotoxic effects, but increased secretion of IL-1α and MMP-9, which was attributed to PG. ECEAR derived from Dewberry Cream and Churrios did not produce cytotoxicity with Epiderm™, but Churrios ECEAR induced IL-1α secretion. These data support the conclusion that EC chemicals can cause oxidative damage and inflammation to human skin.

The aim of this study was to evaluate the possible relationships between polymorphisms in the interleukin-1 (IL-1) A, IL-1B, and IL-1RN genes and concentrations of the inflammatory mediators IL-1β, tumor necrosis factor-alpha (TNF-α), and prostaglandin E2 (PGE2) in peri-implant crevicular fluid (PICF). A cross-sectional analytical study was conducted on 51 patients with dental implants. Samples from the buccal mucosa were obtained, and genetic analysis was performed using the real-time polymerase chain reaction (PCR) technique for IL-1A and IL-1B and PCR and restriction fragment length polymorphism analysis for IL-1RN. For the biochemical analysis, the concentrations of IL-1β and TNF-α were analyzed using multiplexed fluorescent sphere immunoassays, and PGE2 by enzyme-linked immunosorbent assay. In patients with detected IL-1RN polymorphism, there was an increase in the concentration of the three mediators with statistically significant differences in the mean values of TNF-α and PGE2, regardless of peri-implant health status (p = 0.002 and p = 0.049, respectively). The concentrations of all three mediators were positively and significantly correlated (IL-1β vs. TNF-α Rho = 0.480, p < 0.001; IL-1β vs. PGE2 Rho = 0.382, p = 0.006; and TNF-α vs. PGE2 Rho = 0.528, p < 0.001). We can conclude that the IL-1RN polymorphism exerts an influence on the PICF immune response, which may explain the influence of this genetic polymorphism on the occurrence of peri-implantitis. [ABSTRACT FROM AUTHOR]

Psoriasis is a common inflammatory skin disease characterized by aberrant inflammation and epidermal hyperplasia. Molecular mechanisms that regulate psoriasis-like skin inflammation remain to be fully understood. Here, we show that the expression of Ovol1 (encoding ovo-like 1 transcription factor) is upregulated in psoriatic skin, and its deletion results in aggravated psoriasis-like skin symptoms following stimulation with imiquimod. Using bulk and single-cell RNA sequencing, we identify molecular changes in the epidermal, fibroblast, and immune cells of Ovol1-deficient skin that reflect an altered course of epidermal differentiation and enhanced inflammatory responses. Furthermore, we provide evidence for excessive full-length IL-1α signaling in the microenvironment of imiquimod-treated Ovol1-deficient skin that functionally contributes to immune cell infiltration and epidermal hyperplasia. Collectively, our study uncovers a protective role for OVOL1 in curtailing psoriasis-like inflammation and the associated skin pathology.

Melanoma differentiation associated gene-9 (MDA-9), Syntenin-1, or syndecan binding protein is a differentially regulated prometastatic gene with elevated expression in advanced stages of melanoma. MDA-9/Syntenin expression positively associates with advanced disease stage in multiple histologically distinct cancers and negatively correlates with patient survival and response to chemotherapy. MDA-9/Syntenin is a highly conserved PDZ-domain scaffold protein, robustly expressed in a spectrum of diverse cancer cell lines and clinical samples. PDZ domains interact with a number of proteins, many of which are critical regulators of signaling cascades in cancer. Knockdown of MDA-9/Syntenin decreases cancer cell metastasis, sensitizing these cells to radiation. Genetic silencing of MDA-9/Syntenin or treatment with a pharmacological inhibitor of the PDZ1 domain, PDZ1i, also activates the immune system to kill cancer cells. Additionally, suppression of MDA-9/Syntenin deregulates myeloid-derived suppressor cell differentiation via the STAT3/interleukin (IL)-1β pathway, which concomitantly promotes activation of cytotoxic T lymphocytes. Biologically, PDZ1i treatment decreases metastatic nodule formation in the lungs, resulting in significantly fewer invasive cancer cells. In summary, our observations indicate that MDA-9/Syntenin provides a direct therapeutic target for mitigating aggressive breast cancer and a small-molecule inhibitor, PDZ1i, provides a promising reagent for inhibiting advanced breast cancer pathogenesis.

Neutrophils are an important source of interleukin (IL)-1β and other cytokines because they are recruited to sites of infection and inflammation in high numbers. Although secretion of processed, bioactive IL-1β by neutrophils is dependent on NLRP3 and Gasdermin D (GSDMD), IL-1α secretion by neutrophils has not been reported. In this study, we demonstrate that neutrophils produce IL-1α following injection of Aspergillus fumigatus spores that express cell-surface β-glucan. Although IL-1α secretion by lipopolysaccharide (LPS)/ATP-activated macrophages and dendritic cells is GSDMD dependent, IL-1α secretion by β-glucan-stimulated neutrophils occurs independently of GSDMD. Instead, we found that bioactive IL-1α is in exosomes that were isolated from cell-free media of β-glucan-stimulated neutrophils. Further, the exosome inhibitor GW4869 significantly reduces IL-1α in extracellular vesicles (EVs) and total cell-free supernatant. Together, these findings identify neutrophils as a source of IL-1α and demonstrate a role for EVs, specifically exosomes, in neutrophil secretion of bioactive IL-1α.

The balance between NLRP3 inflammasome activation and mitophagy is essential for homeostasis and cellular health, but this relationship remains poorly understood. Here we found that interleukin-1α (IL-1α)-deficient macrophages have reduced caspase-1 activity and diminished IL-1β release, concurrent with reduced mitochondrial damage, suggesting a role for IL-1α in regulating this balance. LPS priming of macrophages induced pro-IL-1α translocation to mitochondria, where it directly interacted with mitochondrial cardiolipin (CL). Computational modeling revealed a likely CL binding motif in pro-IL-1α, similar to that found in LC3b. Thus, binding of pro-IL-1α to CL in activated macrophages may interrupt CL-LC3b-dependent mitophagy, leading to enhanced Nlrp3 inflammasome activation and more robust IL-1β production. Mutation of pro-IL-1α residues predicted to be involved in CL binding resulted in reduced pro-IL-1α-CL interaction, a reduction in NLRP3 inflammasome activity, and increased mitophagy. These data identify a function for pro-IL-1α in regulating mitophagy and the potency of NLRP3 inflammasome activation.

The purpose of the study is to determine the prevalence of interleukin (IL)-1A (rs1800587), IL-1B (rs1143634) and vitamin D receptor (VDR) (TaqI, rs731236) gene polymorphisms in the Turkish population and their association with Stage III Grade B/C periodontitis. Systemically and periodontally healthy individuals (N = 100) and Stage III Grade B/C periodontitis patients (N=100) based on clinical and radiographic examination were included in this research. Clinical attachment level, probing depth, bleeding on probing, plaque and gingival indices of the subjects were measured. Genotyping of IL-1A (rs1800587), IL-1B (rs1143634) and VDR (rs731236) polymorphisms was conducted by Real Time PCR. Allelic and genotypic distributions of IL-1A (rs1800587) gene polymorphism were not associated with periodontitis (p>0.05). In IL-1B (rs1143634) gene polymorphism, the C allele was detected more frequently in healthy individuals compared with the periodontitis patients (p=0.045). CC genotype and C allele in VDR (rs731236) gene polymorphism was higher in periodontitis patients (p=0.031, p=0.034, respectively). In comparison with Grade B periodontitis patients and healthy subjects, CC genotype and C allele were observed more frequently in the Grade B periodontitis in terms of alleles (C/T) and genotypes for VDR (rs731236) polymorphism (p=0.024, p=0.008, respectively). This study presents that the VDR (rs731236) polymorphism are associated with enhanced susceptibility to Stage III periodontitis in the Turkish population. Furthermore, VDR (rs731236) polymorphism may be used as an identification criteria to discriminate Grade B and Grade C in Stage III periodontitis.

Abstract Background The hair follicles (HFs) are barely regenerated after loss in injuries in mammals as well as in human beings. Recent studies have shown that the regenerative ability of HFs is age-related; however, the relationship between this phenomenon and the stem cell niche remains unclear. This study aimed to find a key secretory protein that promotes the HFs regeneration in the regenerative microenvironment. Methods To explore why age affects HFs de novo regeneration, we established an age-dependent HFs regeneration model in leucine-rich repeat G protein-coupled receptor 5 (Lgr5) + /mTmG mice. Proteins in tissue fluids were analyzed by high-throughput sequencing. The role and mechanism of candidate proteins in HFs de novo regeneration and hair follicle stem cells (HFSCs) activation were investigated through in vivo experiments. The effects of candidate proteins on skin cell populations were investigated by cellular experiments. Results Mice under 3-week-old (3W) could regenerate HFs and Lgr5 HFSCs, which were highly correlated with the immune cells, cytokines, IL-17 signaling pathway, and IL-1α level in the regeneration microenvironment. Additionally, IL-1α injection induced de novo regeneration of HFs and Lgr5 HFSCs in 3W mouse model with a 5 mm wound, as well as promoted activation and proliferation of Lgr5 HFSCs in 7-week-old (7W) mice without wound. Dexamethasone and TEMPOL inhibited the effects of IL-1α. Moreover, IL-1α increased skin thickness and promoted the proliferation of human epidermal keratinocyte line (HaCaT) and skin-derived precursors (SKPs) in vivo and in vitro, respectively. Conclusions In conclusion, injury-induced IL-1α promotes HFs regeneration by modulating inflammatory cells and oxidative stress-induced Lgr5 HFSCs regeneration as well as promoting skin cell populations proliferation. This study uncovers the underlying molecular mechanisms enabling HFs de novo regeneration in an age-dependent model.

OBJECTIVES: To investigate the gingival crevicular fluid (GCF) levels of interleukin (IL)-8 and IL-1α in gingivitis and periodontitis sites in the same periodontitis participant, as well as their correlation with periodontal pocket depth (PPD) and bleeding on probing (BOP). METHODS: This cross-sectional study was conducted at School of Dental Sciences, Universiti Sains Malaysia, from April 2019 to December 2021. GCF samples were collected from gingivitis (≤3 mm) and periodontitis (≥5 mm) sites of 30 periodontitis participants. In addition, the periodontal parameters (PPD and BOP) of the related sites were recorded. Enzyme-linked immunosorbent assay was used to determine IL-8 and IL-1α levels in GCF. The correlations of IL-8 and IL-1α in GCF levels with PPD and BOP were determined by the Spearman correlation test. RESULTS: Mean PPD for 180 teeth was 2.5±0.3 mm and 5.6±0.4 mm in Gingivitis and Periodontitis respectively

Colorectal cancer (CRC) is the most common cancer in the Iraqi population. Cancerous cells are stressed cells that express large amounts of intracellular and extracellular heat shock proteins to correct for distorted proteins. They also directly affect immune cells and produce large amounts of cytokines. This work aimed to study the association between serum levels of heat shock protein 70 (Hsp70), interleukin 1 (IL-1), and interleukin 10 (IL-10) in CRC patients to highlight the importance of this pathway in patients’ immune status that may affect the progression of CRC. In the current study, an enzyme-linked immune sorbent assay (ELISA) was performed in 20 Iraqi colorectal cancer patients and 20 healthy volunteers to measure serum levels of Hsp70, IL-1α, and IL-10. Serum levels of HSP70, IL-1α and IL-10 were significantly higher in the CRC group than in the healthy control group (38.83 ± 4.7 and 14.88 ± 1.74 ng mL-1), (141.4 ± 23.22 and 46.38 ± 4.4 ng mL-1) and (26.95 ± 10.14 and 1.4 ± 1.07 ng mL-1), respectively, (p < 0.0001). According to these findings of this study, Hsp70 can be used as a prognostic biomarker for CRC and may be useful in identifying patients with an increased risk of immune tolerance and CRC development in Iraqi patients. [ABSTRACT FROM AUTHOR]

Background: Although combination antiretroviral therapy has increased life expectancy in people living with HIV, it has led to a marked increase in the prevalence of hypertension, the cause of which is unknown. Despite combination antiretroviral therapy, HIV-derived proteins remain expressed and produced by CD4 + T lymphocytes in people living with HIV. However, their contribution to HIV-associated hypertension and impaired endothelium-dependent relaxation remains ill defined., Methods: Here, we tested the hypothesis that CD4 + T cells expressing viral proteins contribute to endothelial dysfunction and hypertension using the Tg26 mouse model of HIV that expresses 7 of the 9 HIV proteins under the long terminal repeat promoter. We used male and female mice, bone marrow transplantation (BMT), adoptive transfer of CD4 + T cells, and aorta specimen discarded from people living with HIV., Results: We reported that intact Tg26 mice and mice receiving BMT (Tg26→WT) or CD4 + T cells from Tg26 mice display impaired endothelium-dependent relaxation and hypertension. Conversely, BMT from WT mice into Tg26 mice, inhibition of T cell activation, and CD4 + T cell depletion restored endothelial function and blood pressure in Tg26 mice. Cytokine profiling revealed that Tg26 mice, Tg26→WT, and Tg26 CD4 + T cells consistently exhibit high interleukin 1α (IL-1α) levels with no significant increase in other cytokines, whereas BMT from WT mice into Tg26 mice reduced IL-1α levels. IL-1α neutralization reduced blood pressure and restored endothelial function in Tg26 mice. To investigate the role of CD4 + T cells and IL-1α in endothelial dysfunction, we developed an aorta-immune cell coculture system. Exposure of WT aortas to Tg26 CD4 + T cells impaired endothelium-dependent relaxation, which was blocked by IL-1α-neutralizing antibody. While investigating the mechanisms of endothelial dysfunction, we reported that Tg26 mice, Tg26→WT aorta exhibit high NADPH oxidase (NOX) 1 expression. IL-1α exposure increased NOX1 in human microvascular endothelial cells, and NOX1 blockade restored endothelial function in Tg26 and Tg26→WT arteries, whereas NOX1 deficiency protected against Tg26 BMT-induced impaired endothelium-dependent relaxation and hypertension. Aortas from people living with HIV exhibit high NOX1 levels, and exposure of human aorta to Tg26 T cells increased NOX1 expression., Conclusions: We provide the first evidence that CD4 + T cells expressing HIV viral proteins induced hypertension through IL-1α-mediated increases in vascular NOX1, which impairs endothelial function in males and females.

Asian sand dust (ASD), a significant desert sand dust, contains sub-2.5 µm fine particles and adversely affects human health, particularly exacerbating respiratory diseases. Despite this, the intricate physiological responses triggered by inhaled ASD particles remain incompletely understood. This study aimed to comprehensively examine the respiratory effects of ASD, focusing on the spatial distribution of inhaled ASD fine particles within the lungs and the immediate physiological responses they incite. Intratracheal administration of ASD fine particles in mice resulted in efficient phagocytosis by alveolar macrophages (AMs), leading to subsequent neutrophilic inflammation. A subset of ASD-phagocytosed AMs underwent necroptosis, releasing interleukin-1α (IL-1α), causing an increase in chemokines and neutrophils. These responses occurred rapidly within hours of exposure, with endotoxin in ASD particles contributing to the process. Despite variations in desert sand dust composition based on collection locale and timing, this study's findings provide a foundational basis for understanding the biological effects of desert sand dust. Insights gained into the biological responses to desert sand dust hold promise for developing preventive measures such as air purifiers, and therapeutic agents such as IL-1α neutralizing antibodies, antibacterial agents and cell death inhibitors for human diseases associated with such environmental exposures., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Hirohisa Takano reports financial support was provided by the Japan Science and Technology Agency. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Processes that have been linked to aging and cancer include an inflammatory milieu driven by senescent cells. Senescent cells lose the ability to divide, essentially irreversibly, and secrete numerous proteases, cytokines and growth factors, termed the senescence-associated secretory phenotype (SASP). Senescent cells that lack p53 tumor suppressor function show an exaggerated SASP, suggesting the SASP is negatively controlled by p53. Here, we show that increased p53 activity caused by small molecule inhibitors of MDM2, which promotes p53 degradation, reduces inflammatory cytokine production by senescent cells. Upon treatment with the MDM2 inhibitors nutlin-3a or MI-63, human cells acquired a senescence-like growth arrest, but the arrest was reversible. Importantly, the inhibitors reduced expression of the signature SASP factors IL-6 and IL-1α by cells made senescent by genotoxic stimuli, and suppressed the ability of senescent fibroblasts to stimulate breast cancer cell aggressiveness. Our findings suggest that MDM2 inhibitors could reduce cancer progression in part by reducing the pro-inflammatory environment created by senescent cells.

Inflammatory cytokines play a dominant role in the pathogenesis of disc degeneration. Pulsed electromagnetic fields (PEMF) are noninvasive biophysical stimulus that has been used extensively in the orthopaedic field for many years. However, the specific cellular responses and mechanisms involved are still unclear. The objective of this study was to assess the time-dependent PEMF effects on pro-inflammatory factor IL-6 expression in disc nucleus pulposus cells using a novel green fluorescence protein (GFP) reporter system. An MS2-tagged GFP reporter system driven by IL-6 promoter was constructed to visualize PEMF treatment effect on IL-6 transcription in single living cells. IL-6-MS2 reporter-labeled cells were treated with IL-1α to mimic the in situ inflammatory environment of degenerative disc while simultaneously exposed to PEMF continuously for 4 h. Time-lapse imaging was recorded using a confocal microscope to track dynamic IL-6 transcription activity that was demonstrated by GFP. Finally, real-time RT-PCR was performed to confirm the imaging data. Live cell imaging demonstrated that pro-inflammatory factor IL-1α significantly promoted IL-6 transcription over time as compared with DMEM basal medium condition. Imaging and PCR data demonstrated that the inductive effect of IL-1α on IL-6 expression could be significantly inhibited by PEMF treatment in a time-dependent manner (early as 2 h of stimulus initiation). Our data suggest that PEMF may have a role in the clinical management of patients with chronic low back pain. Furthermore, this study shows that the MS2-tagged GFP reporter system is a useful tool for visualizing the dynamic events of mechanobiology in musculoskeletal research. © 2017 The Authors. Journal of Orthopaedic Research® Published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society. J Orthop Res 35:778-787, 2018.

Variants in the gene locus encoding protein tyrosine phosphatase non-receptor type 2 (PTPN2) are associated with inflammatory disorders, including inflammatory bowel diseases, rheumatoid arthritis, and type 1 diabetes. The anti-inflammatory role of PTPN2 is highlighted by the fact that PTPN2-deficient mice die a few weeks after birth because of systemic inflammation and severe colitis. However, the tissues, cells, and molecular mechanisms that contribute to this phenotype remain unclear. Here, we demonstrate that myeloid cell-specific deletion of PTPN2 in mice (PTPN2-LysMCre) promotes intestinal inflammation but protects from colitis-associated tumor formation in an IL-1β-dependent manner. Elevated levels of mature IL-1β production in PTPN2-LysMCre mice are a consequence of increased inflammasome assembly due to elevated phosphorylation of the inflammasome adaptor molecule ASC. Thus, we have identified a dual role for myeloid PTPN2 in directly regulating inflammasome activation and IL-1β production to suppress pro-inflammatory responses during colitis but promote intestinal tumor development.

Apigenin (4',5,7,-trihydroxyflavone) is a flavonoid found in certain herbs, fruits, and vegetables. Apigenin can attenuate inflammation, which is associated with many chronic diseases of aging. Senescent cells-stressed cells that accumulate with age in mammals-display a pro-inflammatory senescence-associated secretory phenotype (SASP) that can drive or exacerbate several age-related pathologies, including cancer. Flavonoids, including apigenin, were recently shown to reduce the SASP of a human fibroblast strain induced to senesce by bleomycin. Here, we confirm that apigenin suppresses the SASP in three human fibroblast strains induced to senesce by ionizing radiation, constitutive MAPK (mitogen-activated protein kinase) signaling, oncogenic RAS, or replicative exhaustion. Apigenin suppressed the SASP in part by suppressing IL-1α signaling through IRAK1 and IRAK4, p38-MAPK, and NF-κB. Apigenin was particularly potent at suppressing the expression and secretion of CXCL10 (IP10), a newly identified SASP factor. Further, apigenin-mediated suppression of the SASP substantially reduced the aggressive phenotype of human breast cancer cells, as determined by cell proliferation, extracellular matrix invasion, and epithelial-mesenchymal transition. Our results support the idea that apigenin is a promising natural product for reducing the impact of senescent cells on age-related diseases such as cancer.

Hematopoietic stem cells (HSCs) are considered one of the most promising therapeutic targets for the treatment of various blood disorders. However, due to difficulties in establishing stable maintenance and expansion of HSCs in vitro, their insufficient supply is a major constraint to transplantation studies. To solve these problems we have developed a fully defined, all-recombinant protein-based culture system. Through this system, we have identified hemopexin (HPX) and interleukin-1α as responsible for HSC maintenance in vitro. Subsequent molecular analysis revealed that HPX reduces intracellular reactive oxygen species levels within cultured HSCs. Furthermore, bone marrow immunostaining and 3D immunohistochemistry revealed that HPX is expressed in non-myelinating Schwann cells, known HSC niche constituents. These results highlight the utility of this fully defined all-recombinant protein-based culture system for reproducible in vitro HSC culture and its potential to contribute to the identification of factors responsible for in vitro maintenance, expansion, and differentiation of stem cell populations.

The purpose of the study is to determine the prevalence of interleukin (IL)-1A (rs1800587), IL-1B (rs1143634) and vitamin D receptor (VDR) (TaqI, rs731236) gene polymorphisms in the Turkish population and their association with Stage III Grade B/C periodontitis. Systemically and periodontally healthy individuals (N = 100) and Stage III Grade B/C periodontitis patients (N=100) based on clinical and radiographic examination were included in this research. Clinical attachment level, probing depth, bleeding on probing, plaque and gingival indices of the subjects were measured. Genotyping of IL-1A (rs1800587), IL-1B (rs1143634) and VDR (rs731236) polymorphisms was conducted by Real Time PCR. Allelic and genotypic distributions of IL-1A (rs1800587) gene polymorphism were not associated with periodontitis (p>0.05). In IL-1B (rs1143634) gene polymorphism, the C allele was detected more frequently in healthy individuals compared with the periodontitis patients (p=0.045). CC genotype and C allele in VDR (rs731236) gene polymorphism was higher in periodontitis patients (p=0.031, p=0.034, respectively). In comparison with Grade B periodontitis patients and healthy subjects, CC genotype and C allele were observed more frequently in the Grade B periodontitis in terms of alleles (C/T) and genotypes for VDR (rs731236) polymorphism (p=0.024, p=0.008, respectively). This study presents that the VDR (rs731236) polymorphism are associated with enhanced susceptibility to Stage III periodontitis in the Turkish population. Furthermore, VDR (rs731236) polymorphism may be used as an identification criteria to discriminate Grade B and Grade C in Stage III periodontitis. [ABSTRACT FROM AUTHOR]

Diabetes is a metabolic disorder caused by insulin resistance and/or deficiency and impairs bone quality and bone healing due to altered gene expression, reduced vascularization, and prolonged inflammation. No effective treatments for diabetic bone healing are currently available, and most existing treatments do not directly address the diabetic complications that impair bone healing. We recently demonstrated that sustained and localized delivery of salicylic acid (SA) via an SA-based polymer provides a low-cost approach to enhance diabetic bone regeneration. Herein, we report mechanistic studies that delve into the biological action and local pharmacokinetics of SA-releasing polymers shown to enhance diabetic bone regeneration. The results suggest that low SA concentrations were locally maintained at the bone defect site for more than 1 month. As a result of the sustained SA release, a significantly reduced inflammation was observed in diabetic animals, which in turn, yielded reduced osteoclast density and activity, as well as increased osteoblastogenesis. Based upon these results, localized and sustained SA delivery from the SA-based polymer effectively improved bone regeneration in diabetic animals by affecting both osteoclasts and osteoblasts, thereby providing a positive basis for clinical treatments. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 2595-2603, 2016.

The neuropathogenesis of HIV-associated neurocognitive disorders (HAND) remains puzzling. We interrogated several levels of data (host genetic, histopathology, brain viral load, and neurocognitive) to identify histopathological changes most relevant to HAND. The design of the study is a clinicopathological study employing genetic association analyses. Data and brain tissue from 80 HIV-infected adults were used. Markers in monocyte chemoattractant protein-1 (MCP-1), interleukin 1-alpha (IL1-α), macrophage inflammatory protein 1-alpha (MIP1-α), DRD3, DRD2, and apolipoprotein E (ApoE) were genotyped. Microtubule associated protein 2 (MAP2), synaptophysin (SYP), human leukocyte antigen-DR (HLA-DR), glial fibrillary acidic protein (GFAP), amyloid beta (A-Beta), and ionized calcium-binding adaptor molecule-1 (Iba-1) immunoreactivity were quantified in the frontal cortex, putamen, and hippocampus. A composite score for each marker (mean of the three brain regions) was used. Neurocognitive functioning and other clinical variables were determined within 1 year of death. Brain HIV RNA viral load was available for a subset of cases. MAP2 and SYP proved most relevant to neurocognitive functioning. Immunoreactivity of these markers, as well as A-Beta and Iba-1, was correlated with brain HIV RNA viral load. Several genetic markers in combination with other factors predicted histopathology: HIV blood viral load, MIP1-α genotype, and DRD3 genotype predicted Iba-1 immunoreactivity; the duration of infection and IL1-α genotype predicted GFAP immunoreactivity; ApoE genotype and age at death predicted A-Beta immunoreactivity. These data indicate that HIV replication in the brain is the primary driving force leading to neuroinflammation and dysfunctional protein clearance, as reflected by A-Beta and Iba-1. Downstream to these changes are synaptodendritic degeneration, which is the immediate histopathological substrate of the neurocognitive impairment characteristic of HAND. These intermediate histopathological phenotypes are influenced by host genetic polymorphisms in genes encoding cytokines/chemokines, neuronal protein clearance pathways, and dopaminergic factors.

ObjectiveKawasaki disease (KD) is the most common cause of acquired cardiac disease in US children. In addition to coronary artery abnormalities and aneurysms, it can be associated with systemic arterial aneurysms. We evaluated the development of systemic arterial dilatation and aneurysms, including abdominal aortic aneurysm (AAA) in the Lactobacillus casei cell-wall extract (LCWE)-induced KD vasculitis mouse model.Methods and resultsWe discovered that in addition to aortitis, coronary arteritis and myocarditis, the LCWE-induced KD mouse model is also associated with abdominal aorta dilatation and AAA, as well as renal and iliac artery aneurysms. AAA induced in KD mice was exclusively infrarenal, both fusiform and saccular, with intimal proliferation, myofibroblastic proliferation, break in the elastin layer, vascular smooth muscle cell loss, and inflammatory cell accumulation in the media and adventitia. Il1r(-/-), Il1a(-/-), and Il1b(-/-) mice were protected from KD associated AAA. Infiltrating CD11c(+) macrophages produced active caspase-1, and caspase-1 or NLRP3 deficiency inhibited AAA formation. Treatment with interleukin (IL)-1R antagonist (Anakinra), anti-IL-1α, or anti-IL-1β mAb blocked LCWE-induced AAA formation.ConclusionsSimilar to clinical KD, the LCWE-induced KD vasculitis mouse model can also be accompanied by AAA formation. Both IL-1α and IL-1β play a key role, and use of an IL-1R blocking agent that inhibits both pathways may be a promising therapeutic target not only for KD coronary arteritis, but also for the other systemic arterial aneurysms including AAA that maybe seen in severe cases of KD. The LCWE-induced vasculitis model may also represent an alternative model for AAA disease.

Simple Summary: This study is the first study comparing the same parameters of inflammation in two periodontal disease experimental models proposed by the literature and used in the research. The importance of the method used to induce periodontitis in animals resides in the efficacy of proposed technologies and treatments used in preclinical trials. The inflammatory markers Interleukin-1 alpha(IL-1α), Tumor Necrosis Factor-alpha (TNF-α), and high sensitive C reactive protein (hsCRP), the hematological analyses, and the histological probes showed a similar and reproducible periodontal inflammation for the molar induced periodontitis model. Ligation-induced periodontitis in rats has limitations and will never reproduce all aspects of periodontal disease in humans. The findings of this study with the complex association between clinical, biochemical, and histological aspects of the two experimental models of periodontal pathology induction in rats suggest that a similar periodontal pathology to the one we find in humans is best replicated in rats with the molar induced periodontitis model. Experimental animal models for studying the mechanisms of periodontitis and its links are a better alternative to in vitro studies. The aim of this study is to compare two ligature induced periodontitis models and validate the best one for further use in research. An experimental study was performed on male Wistar rats that were divided into three groups: Test 1 (n = 10), incisor ligated, Test 2 (n = 10), molar ligated, and Control (n = 10). The animals were clinically evaluated at the beginning and at the end of the experiment by recording body weight, gingival bleeding index, tooth mobility score, changes in color, and consistency of gingival tissue. Two blood samples were obtained for each animal at baseline and at the end of the experiment. The hematological parameters Interleukin-1 alpha (IL-1 α), high sensitive C Reactive Protein (hsCRP), and Tumor Necrosis Factor-alpha (TNF-α) were measured. Seven days after the induction of periodontitis, the animals were sacrificed, and samples were prepared for histological evaluation. The results of this research demonstrated that the association between clinical, histological, and biochemical parameters initiate a periodontal pathology in the molar induced model in rats while the incisor experimental model initiates only a moderate and incomplete periodontal inflammation, mainly due to mechanical irritation. [ABSTRACT FROM AUTHOR]

ObjectiveKawasaki disease (KD) is the most common cause of acute vasculitis and acquired cardiac disease among US children. We have previously shown that both TLR2/MyD88 and interleukin (IL)-1β signaling are required for the Lactobacillus casei cell wall extract-induced KD vasculitis mouse model. The objectives of this study were to investigate the cellular origins of IL-1 production, the role of CD11c(+) dendritic cells and macrophages, and the relative contribution of hematopoietic and stromal cells for IL-1 responsive cells, as well the MyD88 signaling, in Lactobacillus casei cell wall extract-induced KD mouse model of vasculitis.Approach and resultsUsing mouse knockout models and antibody depletion, we found that both IL-1α and IL-1β were required for Lactobacillus casei cell wall extract-induced KD. Both dendritic cells and macrophages were necessary, and we found that MyD88 signaling was required in both hematopoietic and stromal cells. However, IL-1 response and signaling were critically required in nonendothelial stromal cells, but not in hematopoietic cells.ConclusionsOur results suggest that IL-1α and IL-1β, as well as CD11c(+) dendritic cells and macrophages, are essential for the development of KD vasculitis and coronary arteritis in this mouse model. Bone marrow chimera experiments suggest that MyD88 signaling is important in both hematopoietic and stromal cells, whereas IL-1 signaling and response are required only in stromal cells, but not in endothelial cells. Determining the role of IL-1α and IL-1β and of specific cell types in the KD vasculitis mouse model may have important implications for the design of more targeted therapies and understanding of the molecular mechanisms of KD immunopathologies.

Natural antisense transcripts (NATs) are a class of long noncoding RNAs (lncRNAs) that are complementary to other protein-coding genes. Although thousands of NATs are encoded by mammalian genomes, their functions in innate immunity are unknown. In this study, we identified and characterized a novel NAT, AS-IL1α, which is partially complementary to IL-1α. Similar to IL-1α, AS-IL1α is expressed at low levels in resting macrophages and is induced following infection with Listeria monocytogenes or stimulation with TLR ligands (Pam3CSK4, LPS, polyinosinic-polycytidylic acid). Inducible expression of IL-1α mRNA and protein were significantly reduced in macrophages expressing shRNA that target AS-IL1α. AS-IL1α is located in the nucleus and did not alter the stability of IL-1α mRNA. Instead, AS-IL1α was required for the recruitment of RNA polymerase II to the IL-1α promoter. In summary, our studies identify AS-IL1α as an important regulator of IL-1α transcription during the innate immune response.

Acute lung injury (ALI) remains a serious health issue with little improvement in our understanding of the pathophysiology and therapeutic approaches. We investigated the mechanism that lipopolysaccharide (LPS) induces early neutrophil recruitment to lungs and increases pulmonary vascular permeability during ALI. Intratracheal LPS induced release of pro-interleukin-1α (IL-1α) from necrotic alveolar macrophages (AM), which activated endothelial cells (EC) to induce vascular leakage via loss of vascular endothelial (VE)-cadherin. LPS triggered the AM purinergic receptor P2X7(R) to induce Ca(2+) influx and ATP depletion, which led to necrosis. P2X7R deficiency significantly reduced necrotic death of AM and release of pro-IL-1α into the lung. CD14 was required for LPS binding to P2X7R, as CD14 neutralization significantly diminished LPS induced necrotic death of AM and pro-IL-1α release. These results demonstrate a key role for pro-IL-1α from necrotic alveolar macrophages in LPS-mediated ALI, as a critical initiator of increased vascular permeability and early neutrophil infiltration.

The harsh inflammatory environment associated with injured and arthritic joints represents a major challenge to articular cartilage repair. In this study, we report the effect of cerium oxide nanoparticles, or nanoceria, in modulating development of engineered cartilage and in combating the deleterious effects of interleukin-1α. Nanoceria was found to be biocompatible with bovine chondrocytes up to a concentration of 1000 μg/mL (60,000 cells/μg of nanoceria), and its presence significantly improved compressive mechanical properties and biochemical composition (i.e., glycosaminoglycans) of engineered cartilage. Raman microspectroscopy revealed that individual chondrocytes with internalized nanoceria have increased concentrations of proline, procollagen, and glycogen as compared with cells without the nanoparticles in their vicinity. The inflammatory response due to physiologically relevant quantities of interluekin-1α (0.5 ng/mL) is partially inhibited by nanoceria. To the best of the authors' knowledge, these results are the first to demonstrate a high potential for nanoceria to improve articular cartilage tissue properties and for their long-term treatment against an inflammatory reaction.

A missense single-nucleotide polymorphism (SNP) in the immune modulatory gene IL1A has been associated with ovarian cancer risk (rs17561). Although the exact mechanism through which this SNP alters risk of ovarian cancer is not clearly understood, rs17561 has also been associated with risk of endometriosis, an epidemiologic risk factor for ovarian cancer. Interleukin-1α (IL1A) is both regulated by and able to activate NF-κB, a transcription factor family that induces transcription of many proinflammatory genes and may be an important mediator in carcinogenesis. We therefore tagged SNPs in more than 200 genes in the NF-κB pathway for a total of 2,282 SNPs (including rs17561) for genotype analysis of 15,604 cases of ovarian cancer in patients of European descent, including 6,179 of high-grade serous (HGS), 2,100 endometrioid, 1,591 mucinous, 1,034 clear cell, and 1,016 low-grade serous, including 23,235 control cases spanning 40 studies in the Ovarian Cancer Association Consortium. In this large population, we confirmed the association between rs17561 and clear cell ovarian cancer [OR, 0.84; 95% confidence interval (CI), 0.76-0.93; P = 0.00075], which remained intact even after excluding participants in the prior study (OR, 0.85; 95% CI, 0.75-0.95; P = 0.006). Considering a multiple-testing-corrected significance threshold of P < 2.5 × 10(-5), only one other variant, the TNFSF10 SNP rs6785617, was associated significantly with a risk of ovarian cancer (low malignant potential tumors OR, 0.85; 95% CI, 0.79-0.91; P = 0.00002). Our results extend the evidence that borderline tumors may have a distinct genetic etiology. Further investigation of how these SNPs might modify ovarian cancer associations with other inflammation-related risk factors is warranted.

The immune mechanisms for neonatal susceptibility to respiratory pathogens are poorly understood. Given that mucosal surfaces serve as a first line of host defense, we hypothesized that the innate immune response to infectious agents may be developmentally regulated in airway epithelium. To test this hypothesis, we determined whether the expression of IL-8 and IL-6 in airway epithelium after LPS exposure is dependent on chronological age. Tracheas from infant, juvenile, and adult rhesus monkeys were first exposed to LPS ex vivo, and then processed for air-liquid interface primary airway epithelial cell cultures and secondary LPS treatment in vitro. Compared with adult cultures, infant and juvenile cultures expressed significantly reduced concentrations of IL-8 after LPS treatment. IL-8 protein in cultures increased with animal age, whereas LPS-induced IL-6 protein was predominantly associated with juvenile cultures. Toll-like receptor (TLR) pathway RT-PCR arrays showed differential expressions of multiple mRNAs in infant cultures relative to adult cultures, including IL-1α, TLR10, and the peptidoglycan recognition protein PGLYRP2. To determine whether the age-dependent cytokine response to LPS is reflective of antecedent exposures, we assessed primary airway epithelial cell cultures established from juvenile monkeys housed in filtered air since birth. Filtered air-housed animal cultures exhibited LPS-induced IL-8 and IL-6 expression that was discordant with age-matched ambient air-housed animals. A single LPS aerosol in vivo also affected this cytokine profile. Cumulatively, our findings demonstrate that the innate immune response to LPS in airway epithelium is variable with age, and may be modulated by previous environmental exposures.

The pulmonary innate immune system is heavily implicated in the perpetual airway inflammation and impaired host defense characterizing Chronic Obstructive Pulmonary Disease (COPD). The airways of patients suffering from COPD are infiltrated by various immune and inflammatory cells including macrophages, neutrophils, T lymphocytes, and dendritic cells. While the role of macrophages, neutrophils and T lymphocytes is well characterized, the contribution of dendritic cells to COPD pathogenesis is still the subject of emerging research. A paper by Botelho and colleagues in the current issue of Respiratory Research investigates the importance of dendritic cell recruitment in cigarette-smoke induced acute and chronic inflammation in mice. Dendritic cells of the healthy lung parenchyma and airways perform an important sentinel function and regulate immune homeostasis. During inflammatory responses the function and migration pattern of these cells is dramatically altered but the underlying mechanisms are incompletely understood. Botelho and colleagues demonstrate here the importance of IL-1R1/IL-1α related mechanisms including CCL20 production in cigarette-smoke induced recruitment of dendritic cells and T cell activation in the mouse lung.

BackgroundEndotoxin induced chorioamnionitis increases IL-1 and provokes an inflammatory response in the fetal ileum that interferes with intestinal maturation. In the present study, we tested in an ovine chorioamnionitis model whether IL-1 is a major cytokine driving the inflammatory response in the fetal ileum.MethodSheep bearing singleton fetuses received a single intraamniotic injection of recombinant ovine IL-1α at 7, 3 or 1 d before caesarian delivery at 125 days gestational age (term = 150 days).Results3 and 7 d after IL-1α administration, intestinal mRNA levels for IL-4, IL-10, IFN-γ and TNF-α were strongly elevated. Numbers of CD3+ and CD4+ T-lymphocytes and myeloidperoxidase+ cells were increased whereas FoxP3+ T-cells were detected at low frequency. This increased proinflammatory state was associated with ileal mucosal barrier loss as demonstrated by decreased levels of the intestinal fatty acid binding protein and disruption of the tight junctional protein ZO-1.ConclusionIntraamniotic IL-1α causes an acute detrimental inflammatory response in the ileum, suggesting that induction of IL-1 is a critical element in the pathophysiological effects of endotoxin induced chorioamnionitis. A disturbed balance between T-effector and FoxP3+ cells may contribute to this process.

BackgroundMuscle wasting and weight loss were observed when carcinomas were induced in a murine model of head and neck squamous cell carcinomas. Our hypothesis was C3H/HeN mice would develop evidence of cachexia when injected with tumor cellsMethodsAge- and weight-matched female mice were injected with SCCF/VII cells. Daily food intake and weights were measured. Body composition and analysis of circulating cytokines was performed. At the completion of experiments, hind legs were weighed. Muscle atrophy was detected using analysis for muscle ring finger 1 (MuRF1). The tumor-derived lipid mobilizing factor (LMF) was measured.ResultsDespite increased food intake, tumor-bearing mice lost weight and experienced reduced hind leg weights. Interleukin-1beta (IL-1beta) was increased and MuRF1 was present in tumor-bearing mice but not controls. LMF was present in SCCF/VII cells.ConclusionIn this immunocompetent murine model, we demonstrated the development of cancer cachexia in mice inoculated with SCCF cells, which express LMF. There was increased serum IL-1beta, weight loss, and muscle wasting and atrophy in tumor-bearing mice.

Respiratory viral infections remain a major cause of hospitalization and death worldwide. Patients with respiratory infections often lose weight. While acute weight loss is speculated to be a tolerance mechanism to limit pathogen growth, severe weight loss following infection can cause quality of life deterioration. Despite the clinical relevance of respiratory infection-induced weight loss, its mechanism is not yet completely understood. We utilized a model of CD 8 + T cell-driven weight loss during respiratory syncytial virus (RSV) infection to dissect the immune regulation of post-infection weight loss. Supporting previous data, bulk RNA sequencing indicated significant enrichment of the interleukin (IL)-1 signaling pathway after RSV infection. Despite increased viral load, infection-associated weight loss was significantly reduced after IL-1α (but not IL-1β) blockade. IL-1α depletion resulted in a reversal of the gut microbiota changes observed following RSV infection. Direct nasal instillation of IL-1α also caused weight loss. Of note, we detected IL-1α in the brain after either infection or nasal delivery. This was associated with changes in genes controlling appetite after RSV infection and corresponding changes in signaling molecules such as leptin and growth/differentiation factor 15. Together, these findings indicate a lung-brain-gut signaling axis for IL-1α in regulating weight loss after RSV infection., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Intracellular protein complexes, known as inflammasomes, activate caspase-1 and induce the secretion of pro-inflammatory cytokines, namely interleukin (IL)-1β and -18. Korean Red Ginseng extract (RGE) is a known immunomodulator and a potential candidate for the regulation of inflammasomes. The saponins, such as ginsenosides, of RGE inhibit inflammasome signaling, while non-saponin substances containing amino sugars promote the priming step, up-regulating inflammasome components (pro-IL-1β, NLRP3, caspase-1, and Asc). In this study, the amino sugar-enriched fraction (ASEF), which increases only non-saponin components, including amino sugars, without changing the concentration of saponin substances, was used to investigate whether saponin or non-saponin components of RGE would have a greater impact on the priming step. When murine macrophages were treated with ASEF, the gene expression of inflammatory cytokines ( IL-1α , TNFα , IL-6 , and IL-10 ) increased. Additionally, ASEF induced the priming step but did not affect the inflammasome activation step, such as the secretion of IL-1β, cleavage of caspase-1, and formation of Asc pyroptosome. Furthermore, the upregulation of gene expression of inflammasome components by ASEF was blocked by inhibitors of Toll-like receptor 4 signaling. Maltol, the main constituent of ASEF, promoted the priming step but inhibited the activation step of the inflammasome, while arginine, sugars, arginine-fructose-glucose, and fructose-arginine, the other main constituents of ASEF, had no effect on either step. Thus, certain amino sugars in RGE, excluding maltol, are believed to be the components that induce the priming step. The priming step that prepares the NLRP3 inflammasome for activation appears to be induced by amino sugars in RGE, thereby contributing to the immune-boosting effects of RGE.

Background: Rilonacept, a once-weekly interleukin-1 alpha and beta cytokine trap, reduced pericarditis recurrence in the phase 3 study, RHAPSODY (Rilonacept Inhibition of Interleukin-1 Alpha and Beta for Recurrent Pericarditis: A Pivotal Symptomatology and Outcomes Study). The RHAPSODY long-term extension further explored recurrent pericarditis natural history and treatment duration decision-making during 24 additional months of open-label rilonacept treatment., Methods and Results: Seventy-four patients commenced the long-term extension, with a median (maximum) total rilonacept duration of 22 (35) months. Individually, 18 months after the most proximal pericarditis recurrence, investigators decided to continue rilonacept on study, suspend rilonacept for off-treatment observation (rescue allowed), or discontinue the study. The annualized incidence of pericarditis recurrence on rilonacept up to the 18-month decision milestone was 0.04 events/patient-year versus 4.4 events/patient-year prestudy while on oral therapies. At the 18-month decision milestone, 64% (33/52) continued rilonacept, 15% (8/52) suspended rilonacept for observation, and 21% (11/52) discontinued the study. Among the 33 patients (1/33; 3.0%) continuing rilonacept (median time to recurrence could not be estimated due to too few events), a single recurrence occurred 4 weeks after a treatment interruption. Among patients suspending rilonacept, 75% (6/8) experienced recurrence (median time to recurrence, 11.8 weeks [95% CI, 3.7 weeks to not estimable]). There was a 98% reduction in risk of pericarditis recurrence among patients continuing rilonacept treatment after the 18-month decision milestone versus those suspending treatment for observation (hazard ratio, 0.02; P <0.0001)., Conclusions: In the RHAPSODY long-term extension, continued rilonacept treatment resulted in continued response; treatment suspension at the 18-month decision milestone was associated with pericarditis recurrence., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03737110.

Background: A case-control study was performed to explore eight pro-inflammatory and anti-inflammatory cytokines, namely interleukin (IL)-1α, IL-1Ra (IL-1 receptor antagonist), IL-12, IL-17A, IL-31, IL-33, CXCL10 (C-X-C motif chemokine ligand 10), and CXCL16, with the aim to understand their role in ankylosing spondylitis (AS) pathogenesis and evaluate their utility as markers to differentiate between diseased and healthy individuals. Among these cytokines, IL-31 and CXCL16 have not been well studied in AS., Patients and Methods: The study included 94 male patients with AS and 91 age-matched control males. Interleukin and chemokine levels were measured using ELISA kits., Results: Serum levels of IL-17A, CXCL10, and CXCL16 were significantly elevated in patients compared to controls, while IL-31 levels were significantly decreased in patients. IL-17A, CXCL10, and CXCL16 were associated with an increased risk of AS, while IL-31 was associated with a decreased risk of disease (odds ratio = 1.22, 1.78, 1.14, and 0.89, respectively). As indicated by the area under the curve (AUC), IL-17A, IL-31, CXCL10, and CXCL16 were potential markers to differentiate between AS patients and controls (AUC = 0.877, 0.735, 0.8, and 0.7, respectively). IL-1α, IL-1Ra, IL-12, and IL-33 levels showed no significant variations between patients and controls., Conclusions: Among the eight cytokines examined, IL-17A, CXCL10, and CXCL16 were up-regulated in the serum of AS patients, while IL-31 was down-regulated. The levels of IL-1α, IL-1Ra, IL-12, and IL-33 showed no significant differences between patients and controls. Serum levels of all cytokines were not affected by disease duration, HLA-B27 positivity, or disease activity., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background/Aim. Apical periodontitis is mainly caused by bacterial infection within the root canal and periapical bone destruction which are prominent features of this lesion. The aim of this study was to determine the quantity of interleukin-1β in the tissues of periapical lesions and to analyze its relationships with: lesion size, previous treatments and pathohistological finding of involved teeth. Methods. Periapical tissues were obtained from patients undergoing periapical surgery. Out of all 80 cases included in the study, 24 had no previous endodontic treatment (open lesions), 37 were with endodontic failure (closed lesion) and in 15 cases root canal retreatment was performed few months before the surgery. By excluding four samples, the total of 76 samples, consisted of periapical lesions and the apical part of the tooth root, was collected. Each periapical tissue sample was divided into two equal parts. The one half of each lesion was used for quantification of interleukin-1β in tissue homogenates by the enzyme-linked immunosorbent assay (ELISA) method. The other part of each lesion was used for histopathological evaluation. Results. For each of the tissue homogenates, the quantity of interleukin-1β was measured, and it ranged from 0.6 pg/mg up to 74 pg/mg. There was no significant difference between the symptomatology and amount of interleukin-1β. Statistical data analysis showed a moderate correlation between lesion size and interleukin-1β measured values. The highest levels of interleukin-1β corresponded with chronic lesions in the stages of acute exacerbation and granulomas in early developing stages. Persistant granulomas, scar tissues, non-inflamed cysts and teeth with recently finished endodontic treatments showed a significantly lower level of interleukin-1β. Conclusion. The study results suggest that the differences in quantity of interleukin-1β correlate to lesion progression and phases of development.

Epidemiological studies have reported a positive association between chronic inflammation and cancer risk. However, the causal association between chronic inflammation and breast cancer (BC) risk remains unclear. Here, we performed a Mendelian randomization study to investigate the etiological role of chronic inflammation in BC risk. We acquired data regarding C-reactive protein (CRP), interleukin (IL)-1a, IL-1b, and IL-6 expression and BC related to single nucleotide polymorphisms (SNPs) from two larger consortia (the genome-wide association studies and the Breast Cancer Association Consortium). Next, we conducted the two-sample Mendelian randomization study to investigate the relationship of the abovementioned inflammatory factors with the incidence of BC. We found that genetically predicted CRP, IL-6, and IL-1a levels did not increase BC incidence (odds ratio (OR) CRP 1.06, 95% confidence interval (CI) 0.98-1.12, P = 0.2059, OR IL-6 1.05, 95% CI 0.95-1.16, P = 0.3297 and OR IL-1a 1.01, 95% CI 0.99-1.03, P = 0.2167). However, in subgroup analysis, genetically predicted IL-1b levels increased ER + BC incidence (OR 1.15, 95% CI 1.03-1.27, P = 0.0088). Our study suggested that genetically predicted IL-1b levels were found to increase ER + BC susceptibility. However, due to the support of only one SNP, heterogeneity and pleiotropy tests cannot be performed, which deserves further research., (© 2024. The Author(s).)

Introduction: The global shortage of human blood for medical use has prompted the development of alternative blood sources. Nonhuman primates (NHPs) are commonly used owing to their physiological similarities to humans. The objective of the current study was to establish a controlled-blood-loss model in NHPs to explore their clinical and biological responses., Methods: Blood was sequentially withdrawn from 10 cynomolgus monkeys (10, 14, 18, 22, and 25% of the total blood volume); their vital signs were monitored, and blood parameters were serially analyzed. Humoral mediators in the blood were measured using flow cytometry and enzyme-linked immunosorbent assays., Results: In NHPs subjects to 25% blood loss and presenting with related clinical symptoms, the systolic blood pressure ratio on day 0 after bleeding was significantly lower than that of the animals from the other groups (median: 0.65 vs. 0.88, P = 0.0444). Red blood cell counts from day 0-14 and hematocrit levels from day 0-7 were markedly decreased relative to the baseline ( P < 0.01). These parameters showed a direct correlation with the extent of blood loss. The levels of creatine phosphokinase, aspartate aminotransferase, and alanine aminotransferase exhibited increases in response to blood loss and had a stronger correlation with the hemoglobin ratio than the volume of blood loss. The levels of C3a and C4a, as well as interleukin (IL)-1α and IL-15, displayed a strong correlation, with no apparent association with blood loss., Conclusion: The findings of the present study showed that only NHPs with 25% blood loss exhibited clinical decompensation and significant systolic blood pressure reduction without fatalities, suggesting that this level of blood loss is suitable for evaluating blood transfusion efficacy or other treatments in NHP models. In addition, the ratio of hemoglobin may serve as a more dependable marker for predicting clinical status than the actual volume of blood loss. Thus, our study could serve as a basis for future xenotransfusion research and to predict biological responses to massive blood loss in humans where controlled experiments cannot be ethically performed., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Roh, Park, Lee, Hwang, Kim, Park and Kang.)