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关键词： periodontitis   host-pathogen interactions   Porphyromonas gingivalis   prostaglandin   inflammation  

摘要： The interaction between pathogenic microorganisms and stromal cells, in particular fibroblasts, significantly contributes to the pathogenesis of many bacterially driven diseases. In periodontitis, oral pathogens penetrate the epithelial barrier and aggravate ongoing gingival inflammation by promoting the production of inflammatory mediators, such as prostaglandin E2 (PGE2). This study aimed to investigate the functional consequences of the interplay between oral pathogens and a pro-inflammatory environment in the activation of the PGE2 pathway in primary human gingival fibroblasts (GFs). GF infection with Fusobacterium nucleatum, Porphyromonas gingivalis, or Filifactor alocis in the presence of tumor necrosis factor (TNF) led to synergistic induction of cyclooxygenase-2 (COX-2), a key enzyme in the PGE2 synthesis pathway, as well as secretion of PGE2. A similar synergy in COX-2 upregulation was observed upon GF infection with oral pathogens in the presence of IL-1 alpha, IL-1 beta, and interferon-alpha (IFN-alpha). This effect required toll-like receptor-2 (TLR2) and the p38 MAP kinase activation and was specific for fibroblasts as infection of macrophages or keratinocytes with oral pathogens in the proinflammatory environment did not cause synergistic COX-2 induction. Finally, we demonstrated that conditioned media from GFs infected with F. nucleatum under inflammatory conditions amplified the expression of the neutrophil chemokine IL8 in macrophages and confirmed that this effect was mediated by synergistic induction of PGE2 in GFs. Collectively, we identify a new mechanism of stromal-immune cross-talk that is driven by synergistic PGE2 induction by oral pathogens and inflammatory cytokines in GFs and may contribute to excessive macrophage activation and neutrophil infiltration in periodontitis. IMPORTANCE Periodontitis is a highly prevalent, dysbiosis-driven chronic inflammatory disease that not only leads to tooth loss but also is associated with severe systemic

摘要： Objective: The dualistic role of IL-6 in diseases associated with metabolic disorders (including non-alcoholic fatty liver disease, NAFLD) under oxidative stress has been repeatedly demonstrated in various studies. The aim of this work was to investigate the combined effect of IL-6 and glycoprotein 130 (gp130) on cell death pathways and mitochondrial dynamics in the HepG2 cell line in the oxidative stress model. Methods: The HepG2 cell line was used to create a model of oxidative stress in hepatocytes (hepatocytes without any additives are hereafter referred to as control) by adding tert-butyl hydroperoxide (tBHP). IL-6 (variant 1) or IL-6 + gp130 (variant 2) were added to the experimental model of oxidative stress. Cell viability was determined by flow cytometry and the expression and production of key markers of mitochondrial biogenesis, apoptosis, mitophagy and antioxidant defense were analyzed by RT-qPCR and Western blotting, respectively. Results and Discussion: The addition of IL-6 alone (variant 1) increased the relative percentage (%) of viable cells and decreased the number of dead and apoptotic cells. In the cell model, IL-6 contributed to an increase in the expression of the TFAM, MFN2, DNM1L and NF-kB1 genes and the production of MFN2 protein and, on the contrary, led to a decrease in the expression of HSP70, HSF1, BCL2L1 and SQSTM1. The addition of gp130 + IL-6 to the model of oxidative stress in hepatocytes (variant 2) increased the expression of the genes TFAM, MFN2, DNM1L, NF-kB1 and MAPLC3B, while the expression of HSP70, HSF1 and BCL2L1 decreased. Conclusions: Addition of IL-6 to the model of oxidative stress in hepatocytes promotes activation of mitochondrial dynamics, decreases apoptosis and stimulates cell viability, while gp130 mediates stimulation of the expression of genes responsible for mitoautophagy.

摘要： Although mechanical ventilation is a critical intervention for acute respiratory distress syndrome (ARDS), it can trigger an IL-1β-associated complication known as ventilator-induced lung injury. In mice, we found that LPS and high-volume ventilation, LPS-HVV, leads to hypoxemia with neutrophil extracellular traps (NETs) formation in the alveoli. Furthermore, LPS-HVV mice did not develop hypoxemia and had reduced NETs, indicating that IL-1R1 signaling is important for NETs formation and hypoxemia. Therapeutic hypothermia (TH) is known to reduce the release of inflammatory mediators. In LPS-HVV mice, TH (32 °C body temperature) prevented hypoxemia development, reducing albumin leakage, IL-1β, gasdermin D (GSDMD) and NETs formation. We also observed that LPS-primed macrophages, when stimulated at 32°C with ATP or nigericin, release less IL-1β associated with reduced GSDMD cleavage. Thus, hypothermia is an important modulating factor in the NLRP3 inflammasome activation, IL-1β release and NETs formation, preventing LPS-HVV-induced acute respiratory failure.

关键词： Two-sample Mendelian randomization   Polycystic ovary syndrome   Cytokines   GWAS   IL6R  

摘要： BackgroundPolycystic ovary syndrome is a prevalent gynecological condition affecting primarily women of childbearing age. It is characterized by elevated androgen levels, ovulatory dysfunction, and morphological abnormalities. Despite extensive research from various perspectives, the etiology and pathogenesis of PCOS remain unclear. While controversial, many believe that individuals with PCOS exhibit a chronic low-grade inflammatory state. Cytokines play diverse roles in the initiation and progression of inflammation, contributing to this inflammatory milieu. Therefore, the aim of this study was to utilize publicly available genome-wide association study data to explore the potential causal relationship between cytokines and *** accurately investigate the causal relationship between cytokines and PCOS, we initially defined cytokines using the GeneCrad and then identified cytokines in two independent large-scale plasma proteins. Subsequently, we employed a two-sample Mendelian randomization analysis framework. A series of quality control procedures were implemented to select eligible instrumental variables closely associated with the exposure. MR analysis was conducted using genome-wide association studies of PCOS in two independent European ancestry groups. Cochran, s Q test, MR-Egger and intercept test were employed to assess heterogeneity and pleiotropy in PCOS. Co-localization analysis, summary-data-based Mendelian randomization analysis, and HEIDI testing were utilized to further corroborate the relationship between positive findings and PCOS. Finally, systematical Mendelian randomization analysis between healthy lifestyle factors and PCOS-related proteins was conducted to identify which proteins could act as interventional targets by lifestyle *** our investigation, we performed Mendelian randomization analysis on 33 cytokines in relation to PCOS using data from the deCODE and the Fenland. Our findings revealed that the plasma level of

关键词： IGF-1   IL-1 beta   LPS   microglia   neurodegenerative diseases   neuroinflammation   NLRP3   sex differences   TREM2  

摘要： BackgroundNeurodegenerative diseases (NDs) have caused serious health issues worldwide. A growing body of evidence suggests a correlation between neuroinflammation and abnormal microglial activity with ND symptoms. Microglia survey play crucial roles in CNS during health and the injury. It is proposed that sex affects microglial roles during inflammation, resulting in mouse behavioural changes and expression alterations in key markers related to microglia *** and female C57BL/6 mice were injected with a single dose of LPS (5 mg/kg, i.p.) or saline. After 48 h, an open field test was conducted, followed by brain tissues collection for measuring the expression of IGF-1, IL-1 beta and TREM2 and Immunohistochemistry (IHC) analysis for NLRP3 *** displayed greater depressive-like behaviour in the OFT, with lower levels of IGF-1, IL-1 beta, and NLRP3 and high TREM2 expression. Female mice did not exhibit this behaviour, in contrast to male mice, they exhibited increased IL-1 beta and NLRP3 expressionDiscussionThis study revealed that LPS-induced sex-specific changes in genes involved in neuronal cell survival caused behavioural alterations in male mice. Moreover, females had observed inflammatory responses that had no impact on behavioural alterations. Overall, both sexes exhibited sex-specific microglial activation states.

关键词： diagnostics   peri-implant bone loss   peri-implant health   peri-implantitis  

摘要： PURPOSE:Peri-implantitis is a progressive inflammatory condition characterized by peri- implant bone loss and clinical signs of inflammation. Traditional diagnostic methods, including clinical and radiographic evaluations, have limitations in detecting the disease in its early stages. Salivary biomarkers, including interleukin-1β (IL-1β), have been identified as potential non-invasive indicators for diagnosing peri-implantitis. This study aimed to investigate the relationship between salivary IL-1β levels, radiographic bone loss, and clinical peri-implant parameters. MATERIALS AND METHODS:60 patients enrolled in this cross-sectional study (24 peri-implant health [PIH] and 36 with peri-implantitis [PI]), accounting for a total of 152 implants. Clinical parameters, including peri-implant pocket depth (PIPD), modified plaque index (mPI), and bleeding on probing (BOP), were recorded. Periapical radiographs were obtained to assess peri-implant bone loss in mesial (PIBLm) and distal (PIBLd) aspects. Unstimulated whole saliva samples were analyzed for IL-1β expression using quantitative real-time polymerase chain reaction (PCR). The correlations between IL-1β expression levels in saliva and peri-implant clinical and radiographic findings were analyzed using Pearson's correlation coefficient. RESULTS:IL-1β expression levels in saliva were significantly higher in the PI compared to PIH (p<0.001). A strong positive correlation was observed between IL-1β levels and peri-implant bone loss (PIBLm: r=0.515, p<0.01; PIBLd: r=0.535, p<0.01), as well as with clinical parameters including PIPD (r=0.59, p<0.01) and BOP (r=0.792, p<0.001). CONCLUSION:The significant correlation between salivary IL-1β levels and peri-implant disease parameters suggests its potential as a non-invasive biomarker for early peri- implantitis detection. Further large-scale studies with standardized methodologies are required to validate these findings and enhance diagnostic accuracy.

摘要： Host effector CD4(+) T cells emerge as critical mediators for tumor regression but whether they can be activated by adoptively transferred CD8(+) T cells remains unknown. We previously reported that adoptive transfer of interleukin 9 (IL-9)-producing cytotoxic CD8(+) T (Tc9) cells achieved long-term control of tumor growth. Here, we demonstrate that murine tumor-specific Tc9 cells control the outgrowth of antigen-loss relapsed tumors by recruiting and activating host effector CD4(+) T cells. Tc9 cells secreted IL-24 and recruited CCR7-expressing conventional type 2 dendritic cells (cDC2 cells) into tumor-draining lymph nodes to prime host CD4(+) T cells against relapsed tumors. Host CD4(+) T cell or cDC2 deficiency impaired the ability of Tc9 cells to control relapsed tumor outgrowth. Additionally, intratumoral IL24 expression correlates with cDC2 and CD4(+) T cell gene signatures in human cancers and their expression is associated with better patient survival. This study reports a mechanism for activation of tumor-specific CD4(+) T cells in vivo.

关键词： MHC   aquaculture   artificial selection   domestication   ohnolog  

摘要： Domestication and artificial selection for desirable traits have driven significant phenotypic changes and left detectable genomic footprints in farmed animals. Since the 1960s, intensive breeding has led to the rapid domestication of Atlantic salmon (Salmo salar), with multiple independent events that make it a valuable model for studying early domestication stages and the parallel evolution of populations of different origins subjected to similar selection pressures. Some aquatic species, including Atlantic salmon, have undergone whole-genome duplication (WGD), raising the possibility that genetic redundancy resulting from WGD has contributed to adaptation in captive environments, as seen in plants. Here, we examined the genomic responses to domestication in Atlantic salmon, focusing on potential signatures of parallel selection, including those associated with WGD. Candidate genomic regions under selection were identified by comparing whole-genome sequences from aquaculture and wild populations across 2 independently domesticated lineages (Western Norway and North America) using a genome-wide scan that combined 3 statistical methods: allele frequencies (FST), site frequency (Tajima's D), and haplotype differentiation (XP-EHH). These analyses revealed shared selective sweeps on identical SNPs in major histocompatibility complex (MHC) genes across aquaculture populations. This suggests that a combination of long-term balancing selection and recent human-induced selection has shaped MHC gene evolution in domesticated salmon. Additionally, we observed selective sweeps on a small number of gene pairs in homeologous regions originating from WGD, offering insights into how historical genome duplication events may intersect with recent selection pressures in aquaculture species.

关键词： hysteresis   synthetic biology   bacterial immunotherapy   solid tumor microenvironment   CD8+ T cells   IL-10R  

摘要： Bacterial immunotherapy holds promising cancer-fighting potential. However, unlocking its power requires a mechanistic understanding of how bacteria both evade antimicrobial immune defenses and stimulate antitumor immune responses within the tumor microenvironment (TME). Here, by harnessing an engineered Salmonella enterica strain with this dual proficiency, we unveil an underlying singular mechanism. Specifically, the hysteretic nonlinearity of interleukin-10 receptor (IL-10R) expression drives tumor-infiltrated immune cells into a tumor-specific IL-10Rhi state. Bacteria leverage this to enhance tumor-associated macrophages producing IL-10, evade phagocytosis by tumor-associated neutrophils, and coincidently expand and stimulate the preexisting exhausted tumor-resident CD8+ T cells. This effective combination eliminates tumors, prevents recurrence, and inhibits metastasis across multiple tumor types. Analysis of human samples suggests that the IL-10Rhi state might be a ubiquitous trait across human tumor types. Our study unveils the unsolved mechanism behind bacterial immunotherapy's dual challenge in solid tumors and provides a framework for intratumoral immunomodulation.

关键词： Red-light LED   Wound healing   Collagen production   Angiogenesis  

摘要： This study examines the effects of 630 nm red-light laser therapy on wound healing, with a focus on VEGF-mediated angiogenesis and collagen production. The effectiveness of red-light therapy is influenced by critical parameters, including treatment duration and distance, which often lack standardization across protocols. To address this, we conducted cell viability and scratch wound assays using NIH/3T3 cells in-vitro to identify optimal treatment conditions. Treatment durations of 10 s, 30 s, 60 s, and 5 min, along with distances of 3 cm and 5 cm, were evaluated. Following parameter optimization, the wound-healing efficacy of red-light therapy was assessed in-vivo using nude mice. Standardized 4 mm wounds were created using a biopsy punch, and healing was evaluated at 7 and 21-days post-intervention. Histological analysis was performed, and gene and protein expression levels of COL1A1, COL2A1, VEGF, and IL-1 beta, which are implicated in wound healing, were assessed via RT-PCR, western blotting, and immunohistochemistry. Results demonstrated that red-light laser therapy significantly upregulated collagen and VEGF expression while reducing IL-1 beta levels at the three-week time point (p < 0.05). Notably, these effects were comparable to hydrogel treatment, which served as a positive control to assess the efficacy of light-emitting diode (LED)-based therapy. These findings indicate that red-light therapy effectively promotes wound healing by enhancing collagen synthesis and VEGF-mediated angiogenesis within the wound bed.