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摘要： In this article the results of genotyping of tumor necrosis factor (TNF) and Toll-like receptor 2 (TLR2) genes among 644 head of cattle of six breeds belonging to four different genetic roots are presented. The Kholmogory and Holstein breeds of black-and-white root, the Ayrshire breed of red root, the Kostroma and Brown Swiss breed of brown root, and the fawn Simmental breed were studied. The PCR-RFLP method was used to identify alleles and genotypes. Significant differences in allele frequency of the TNF and TLR2 genes were observed between breeds of different genetic roots (p < 0.001) and between breeds of dairy and dairy-meat productivity (p < 0.001). In five of the six cattle breeds studied, the predominance of the TLR2T allele was revealed. The highest frequency of the TLR2T allele (0.99) was found in the Ayrshire breed. The herd of Ayrshire cows is close to being monomorphic for the TLR2 gene; 98% of the animals have the homozygous TLR2TT genotype. A more uniform distribution of alleles and genotypes for the TLR2 gene was found in black-and-white animals: in Holstein cattle, the average frequency of the TLR2T allele was 0.78; in Kholmogory cattle, it was 0.83. The TLR2TT genotype was detected in the majority of Holstein (61%) and Kholmogory (69%) cows. The frequency of the TLR2T allele in the Simmental breed was 0.62; in the Kostroma breed, it was 0.67. In Simmental and Kostroma cows, the heterozygous TLR2TG genotype is more common (54 and 47% respectively). A different picture of the distribution of allele and genotype frequencies was revealed in Brown Swiss animals. The TLR2T allele frequency averages 0.26. More than half of Brown Swiss cows (55%) are homozygous for TLR2GG. In all breeds, the TNFB allele predominated with a frequency of occurrence ranging from 0.61 in Holstein cattle to 0.98 in the Brown Swiss breed. A high frequency of the TNFB allele was found in the Kostroma (0.94), Ayrshire (0.885), and Simmental (0.80) breeds. In the Kholmogory br

关键词： IFN-α   LADA   T1D   autoimmunity   latent autoimmune diabetes in adults   neutralizing antibody   type 1 diabetes  

摘要： CONTEXT:Autoantibodies against IFN-α (AAb-IFN-α) might be associated with the less aggressive autoimmunity in latent autoimmune diabetes in adults (LADA) compared to early-onset type 1 diabetes (T1D). OBJECTIVE:To investigate the presence and clinical relevance of the positivity to AAb-IFN-α in people with LADA compared to T1D. RESEARCH DESIGN AND METHODS:Serum levels of AAb against IFN-α isoforms were measured using a cell-based approach in 41 subjects with LADA and in 90 subjects with T1D. OUTCOMES:The primary and secondary outcomes were the difference between LADA and T1D in the proportion of participants testing positive for AAb against ≥2 and against 3 IFN-α isoforms, respectively. Presence and levels of AAb-IFN-α were related to clinical and biochemical features of participants with LADA. RESULTS:Seven (17.1%) and 5(12.2%) participants with LADA, and 3(3.3%) and 0 participants with T1D showed positivity for AAb against ≥2 and 3 IFN-α isoforms (p=0.011, and p=0.0025, respectively). Fasting blood glucose and HbA1c levels were numerically lower among people with LADA testing positive for AAb against ≥2 IFN-α isoforms, than among those who were either negative or positive for AAb against one IFN-α isoform. Among LADA-positive individuals, levels of AAb against IFN-α2 isoform were inversely correlated with GADA levels (rho= -0.513; p=0.025). CONCLUSIONS:Autoimmunity against IFN-α is peculiar to autoimmune diabetes and appears to be distinctive of its slowly progressive forms. Understanding the underlying molecular mechanisms and clinical significance of this novel autoimmunity could lead to the development of new therapeutic strategies in autoimmune diseases, advancing personalized medicine.

摘要：

Background

Macrophages play a crucial role in chronic gastritis induced by the pathogenic Helicobacter pylori (H. pylori) infection. NLRP3 inflammasome has emerged as an important component of inflammatory processes. However, the molecular mechanism by which H. pylori infection drives NLRP3 inflammasome and macrophages activation remains unclear.

Methods

Human gastritis tissues were collected for clinical significance of NLRP3. Infection with H. pylori was performed using in vitro and in vivo models. Bone marrow-derived macrophages (BMDMs) from wild-type (WT), Nlrp3-knockout (KO) and Tnfr1-KO mice were infected with H. pylori. Western blotting, qRT-PCR, immunofluorescence, immunohistochemistry and ELISA were utilized for functional and mechanistic studies.

Results

Single-cell RNA sequencing (ScRNA-seq) analysis of human gastric tissues, followed by validation, indicated that NLRP3 was primarily expressed in myeloid cells and was significantly increased in H. pylori-positive gastritis compared to H. pylori-negative gastritis. Infection with PMSS1 and NCTC11637 H. pylori strains induced NLRP3 inflammasome activation in vitro (THP1 cells) and in the insulin-gastrin (INS-GAS) transgenic mouse model. Deletion of NLRP3 in BMDMs showed marked inhibition of H. pylori-induced M1 macrophage polarization. Furthermore, NLRP3 inflammasome activation upon TNFα, or H. pylori stimulation, was partially blocked by TNFα/TNFR1 signaling inhibitors. Deletion of TNFR1 in BMDMs significantly impaired NLRP3 inflammasome activation and M1 macrophages induced by H. pylori.

Conclusion

This s

关键词： CD4+T   IL-17   JAK/STAT   dilated cardiomyopathy  

摘要： PURPOSE:Studying the effect of interleukin-17 (IL-17) on the mechanism of CD4+ T-cell immune regulation and the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway may offer new ideas and methods for the therapy of dilated cardiomyopathy. METHODS:Naive CD4+ T cells were isolated from mice using a magnetic bead sorting reagent and manipulated by overexpression or knockdown of IL-17. Protein levels of Janus kinase 2 (JAK2), phosphorylated JAK2 (p-JAK2), signal transducer and activator of transcription 3 (STAT3), phosphorylated STAT3 (p-STAT3), matrix metalloproteinase-2 (MMP-2), and matrix metalloproteinase-9 (MMP-9) were determined by Western blotting. Quantitative polymerase chain reaction was used to assess the levels of JAK2, STAT3, MMP-2, and MMP-9. Expression of tumour necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), interleukin-4 (IL-4), and interferon-gamma (IFNγ) was determined by enzyme-linked immunosorbent assay test kits. TNF-α, IL-1β, IL-4, and IFNγ secretion was measured by flow cytometry. RESULTS:In CD4+ T cells, IL-17 overexpression increased TNF-α, IL-1β, IL-4, IFNγ, p-JAK2, p-STAT3, MMP-2, MMP-9 levels, and apoptosis. Knockdown of IL-17 reduced the levels of TNF-α, IL-1β, IL-4, IFNγ, p-JAK2, p-STAT3, MMP-2, and MMP-9, as well as the level of apoptosis. CONCLUSION:Through regulation of IL-17 expression in CD4+ T cells, this study reveals its crucial role in regulating the secretion of inflammatory factors, activation of the JAK/STAT signaling pathway, expression of matrix metalloproteinases, and apoptosis of CD4+ T cells.

摘要： Sepsis is a systemic inflammatory response caused by infection. When this inflammatory response spreads to the lungs, it can lead to acute lung injury (ALI) or more severe acute respiratory distress syndrome (ARDS). Pulmonary fibrosis is a potential complication of these conditions, and the early occurrence of pulmonary fibrosis is associated with a higher mortality rate. The underlying mechanism of ARDS-related pulmonary fibrosis remains unclear. To evaluate the role of mast cell in sepsis-induced pulmonary fibrosis and elucidate its molecular mechanism. We investigated the level of mast cell and epithelial-mesenchymal transition(EMT) in LPS-induced mouse model and cellular model. We also explored the influence of cromolyn sodium and mast cell knockout on pulmonary fibrosis. Additionally, we explored the effect of MC-derived IL-13 on the EMT and illustrated the relationship between mast cell and pulmonary fibrosis. Mast cell was up-regulated in the lung tissues of the pulmonary fibrotic mouse model compared to control groups. Cromolyn sodium and mast cell knockout decreased the expression of EMT-related protein and IL-13, alleviated the symptoms of pulmonary fibrosis in vivo and in vitro. The PI3K/AKT/mTOR signaling was activated in fibrotic lung tissue, whereas Cromolyn sodium and mast cell knockout inhibited this pathway. The expression level of mast cell is increased in fibrotic lungs. Cromolyn sodium intervention and mast cell knockout alleviate the symptoms of pulmonary fibrosis probably via the PI3K/AKT/mTOR signaling pathway. Therefore, mast cell inhibition is a potential therapeutic target for sepsis-induced pulmonary fibrosis.

摘要： Atopic dermatitis (AD) is a chronic, pruritic skin disease characterized by inflammation and skin lesion cornification. While the use of corticosteroids like dexamethasone (DXM), an antiinflammatory drug, improves symptoms temporarily and quickly, this use is not a cure. Thus, we aimed to identify a new therapeutic strategy for AD using quantum molecular resonance (QMR), a novel non-invasive technique with an electromagnetic field-based therapeutic approach as an alternative to pain killers. An AD mouse model presenting AD-like skin lesions was generated by treating BALB/c mice with dinitrochlorobenzene (DNCB), and then DNCB-induced AD mice were administered DXM or QMR, and the change of AD-like skin lesions was observed. QMR ameliorated AD-like skin lesions in DNCB-induced AD mice and reduced the numbers of infiltrated mast cells and macrophages in mouse skin. QMR also alleviated thickening of the epidermis and restored integrity of the epidermal basement membrane. Several genes regulated by DNCB and counterregulated by QMR were identified through transcriptome analysis in mouse skin, and RNA silencing experiments on these genes in TNF-α/IFN-γ- or DNCB-treated human keratinocytes revealed that IL36G and SPRR2B play important roles in inflammation and keratinization. The expression of IL36G and SPRR2B was significantly reduced by QMR in skin of DNCB-induced AD mice. These results underscore the promising role of QMR in ameliorating AD characterized by inflammation and skin lesion hyperkeratosis via targeting IL36G and SPRR2B.

关键词： Fusobacterium nucleatum   Colorectal cancer   IL-8   Metastasis   MicroRNA  

摘要： BACKGROUND:The association between the intestinal microbiota and colorectal cancer (CRC) has been extensively studied, with Fusobacterium nucleatum (F. nucleatum, FN) being found in high abundance in colorectal cancer tissues. Previous research has emphasized the significant role of F. nucleatum in the occurrence of CRC. However, the impact of F. nucleatum on CRC liver metastasis has not been well understood. METHODS:The effects of F. nucleatum on metastasis ability of CRC cell were evaluated in vitro were examined by wound-healing assay and transwell assay. The mouse model of CRC liver metastasis was constructed by spleen injection, and the degree of liver metastasis was assessed by in vivo bioluminescence imaging. The gene expression changes in CRC cells after co-culture with F. nucleatum was analyzed through transcriptome sequencing. qRT-PCR and Western Blot assays were performed to validate the expression of related genes and proteins. RESULTS:The metastasis ability of CRC cells was significantly enhanced after co-culture with F. nucleatum in vitro. In the mouse model, F. nucleatum also promoted the development of liver metastasis in CRC. Mechanistically, F. nucleatum infection increased the expression of IL-8 by downregulated the level of miR-5692a, a regulatory microRNA of IL-8. This led to the activation of the ERK pathway and resulted in the epithelial-mesenchymal transition (EMT) of CRC cells. CONCLUSIONS:Our results suggest that F. nucleatum promotes CRC liver metastasis by inducing epithelial-mesenchymal transition through the miR-5692a/IL-8 axis. These findings provide new insights for the prevention and treatment of colorectal cancer liver metastasis.

关键词： IL-6   TNF-α   VCAM-1   cirrhosis   renal impairment   spontaneous bacterial peritonitis  

摘要： BACKGROUND:Multiple mechanisms may contribute to the occurrence of renal impairment (RI) in patients with spontaneous bacterial peritonitis (SBP). One such mechanism is systemic inflammatory response syndrome, which involves the release of pro-inflammatory cytokines (tumour necrosis factor [TNF]-α, interleukin [IL]-6 and vascular cell adhesion molecule [VCAM]-1). The goal of this research was to evaluate the role of IL-6, TNF-α and VCAM-1 as potential predictors of RI and mortality in cirrhotic patients with SBP. METHODS:This study included 90 cirrhotic patients with SBP, divided into two equal groups: group A was patients without RI and group B was patients with RI. Based on mortality outcomes, the patients were further categorized into group 1 (recovery, n=70) and group 2 (death, n=20). TNF-α, IL-6 and VCAM-1 serum levels were measured using enzyme-linked immunosorbent assay. RESULTS:RI occurred in 50% (45/90) of the study population. Among the 90 patients, 10 (11.1%) had elevated IL-6 levels, 8 (8.9%) had elevated TNF-α levels and 6 (6.7%) had elevated VCAM-1 levels. There were no significant variations in cytokine levels between groups A and B. With an area under the curve of 0.5, the three cytokines showed comparable sensitivity and specificity as predictors of RI. CONCLUSIONS:The use of TNF-α, IL-6 and VCAM-1 as predictive markers for RI and mortality in SBP patients is not recommended, as these biomarkers demonstrated limited diagnostic value.

摘要： Tumor necrosis factor alpha (TNF-α) is a well-known pro-inflammatory cytokine originally recognized for its ability to induce apoptosis and cell death. However, recent research has revealed that TNF-α also plays a crucial role as a mediator of cell survival, influencing a wide range of cellular functions. The signaling of TNF-α is mediated through two distinct receptors, TNFR1 and TNFR2, which trigger various intracellular pathways, including NF-κB, JNK, and caspase signaling cascades. Both TNFR1 and TNFR2 are expressed in astrocytes, which are specialized glial cells essential for maintaining the structural and functional integrity of the central nervous system (CNS). Astrocytes support neuronal function by regulating brain homeostasis, maintaining synaptic function, and supplying metabolic substrates. In addition, astrocytes are known to secrete a variety of growth factors and neurotrophins, such as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and NT-4/5. These neurotrophins play a critical role in supporting neuronal survival, synaptic plasticity, and myelination within the brain. The present study focuses on the role of TNF-α in modulating neurotrophin expression and secretion in rat cortical astrocytes. We demonstrate that TNF-α induces the upregulation of neurotrophins, particularly NGF and BDNF, in cultured astrocytes. This effect is accompanied by an increase in the expression of their respective receptors (TrkA & TrkB), further suggesting a functional modulation of neurotrophic signaling pathways. Notably, we show that the modulation of neurotrophin expression by TNF-α is mediated via the NF-κB signaling pathway. Additionally, we observed that TNF-α also regulates the secretion levels of NGF and BDNF into the culture media of astrocytes in a dose-dependent manner, indicating that TNF-α can modulate both the production and release of these growth factors. Taken together, our findings highlight a previously u