BACKGROUND & AIMS: Exogenous recombinant fibroblast growth factor 20 (FGF20) protein has been proved to treat ulcerative colitis; however, its mechanism of action remains unclear. This study aimed to explore the role and mechanism of action of FGF20 in ulcerative colitis. METHODS: Data from patients with ulcerative colitis were analyzed using the Gene Expression Omnibus dataset. A murine colitis model was established by administering 2% dextran sodium sulfate. FGF20 knockout mice and Adenoassociated viruses (AAV)-FGF20-treated mice were used to elucidate the specific mechanisms. Proteomic analysis was conducted to identify differentially expressed genes. RESULTS: FGF20 levels were significantly elevated in the colonic tissues of subjects and mice with colitis. FGF20 deficiency exacerbated dextran sodium sulfate-induced colitis; in contrast, FGF20 replenishment alleviated colitis through 2 principal mechanisms: restoration of impaired intestinal epithelial barrier integrity, and inhibition of M1 macrophage polarization. Notably, S100A9 was identified as a pivotal downstream target of FGF20, which was further demonstrated by pharmacologic inhibition and overexpression experiments of S100A9 using paquinimod (a specific inhibitor of S100A9) and AAV-S100A9 in FGF20 knockout and AAV-FGF20 mice with colitis, respectively. Additionally, the nuclear factor-κB pathway was found to be involved in the process by which FGF20 regulates S100A9 to counteract colitis. CONCLUSIONS: These results suggest that FGF20 acts as a negative regulator of S100A9 and nuclear factor-κB, thereby inhibiting M1 macrophage polarization and restoring intestinal epithelial barrier integrity in mice with dextran sodium sulfate-induced colitis. FGF20 may serve as a potential therapeutic target for the treatment of ulcerative colitis.

• MeSH
• Fibroblast Growth Factors * metabolism   genetics   pharmacology   MeSH
• Calgranulin B * metabolism   genetics   MeSH
• Colitis * chemically induced   MeSH
• Humans MeSH
• Macrophages * immunology   metabolism   drug effects   MeSH
• Disease Models, Animal MeSH
• Mice, Inbred C57BL MeSH
• Mice, Knockout MeSH
• Mice MeSH
• NF-kappa B * metabolism   MeSH
• Signal Transduction MeSH
• Dextran Sulfate toxicity   MeSH
• Intestinal Mucosa * pathology   metabolism   immunology   drug effects   MeSH
• Colitis, Ulcerative * pathology   chemically induced   immunology   metabolism   drug therapy   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

BACKGROUND: Accumulating evidence suggests that spontaneous preterm labor is a syndrome caused by multiple pathological processes. The breakdown of maternal-fetal tolerance has been proposed as a key mechanism of idiopathic spontaneous preterm labor, often viewed as a chronic inflammatory process resulting from the maternal immune system's impaired tolerance of the fetus from early pregnancy. Regulatory T cells are crucial for maintaining maternal-fetal tolerance. Even a partial reduction in their levels can disrupt this tolerance, leading to adverse pregnancy outcomes such as preterm labor. Given the complexity of the T lymphocyte-mediated immune response, identifying candidate signaling pathways involved in maternal-fetal tolerance is challenging. However, current literature highlights the importance of the functional and developmental markers FoxP3, CD45RA, Helios, and CD39 due to their immunosuppressive abilities essential for maintaining pregnancy. OBJECTIVE: This study aimed to determine whether changes in numbers of selected regulatory T cell subpopulations in the first trimester are associated with subsequent spontaneous preterm labor. STUDY DESIGN: This prospective study enrolled 43 women with early singleton pregnancies, excluding those with autoimmune diseases, diabetes mellitus (type 1, type 2), primary hypertension, or who had been treated with vaginal progesterone prior to sample collection. We analyzed regulatory T cell subpopulations in maternal circulation using the DURAClone IM T cell kit, focusing on the following subsets: CD4+CD25+FoxP3+, CD4+CD25+FoxP3+CD45RA, CD4+CD25+FoxP3+Helios+, and CD4+CD25+FoxP3+CD39-. RESULTS: Among the participants, 7 experienced spontaneous preterm labor between the 23rd and 33rd weeks of gestation, while 36 delivered at term. The preterm group showed a significant reduction in numbers of all analyzed regulatory T cell subpopulations: CD4+CD25+FoxP3+ (median 0.0410×10ˆ9/L vs median 0.0550×10ˆ9/L, P=.0217), CD4+CD25+FoxP3+CD45RA- (median 0.0310×10ˆ9/L vs median 0.0420×10ˆ9/L, P=.0216), CD4+CD25+FoxP3+Helios+ (median 0.0270×10ˆ9/L vs median 0.0370×10ˆ9/L, P=.0260), CD4+CD25+FoxP3+CD39- (median 0.0300×10ˆ9/L vs median 0.0420×10ˆ9/L, P=.0427). CONCLUSION: Early first trimester alterations in specific regulatory T cell subpopulations, including diminished levels of CD4+CD25+FoxP3+, CD4+CD25+FoxP3+CD45RA-, CD4+CD25+FoxP3+Helios+, and CD4+CD25+FoxP3+CD39-, are associated with idiopathic spontaneous preterm labor. These findings suggest that early changes in these lymphocyte subpopulations may be linked to spontaneous preterm birth. This highlights the need for further research to understand the mechanisms underlying regulatory T-cell dynamics and their impact on pregnancy outcomes.

• MeSH
• Leukocyte Common Antigens metabolism   MeSH
• Apyrase immunology   MeSH
• Antigens, CD immunology   MeSH
• Adult MeSH
• Forkhead Transcription Factors * metabolism   MeSH
• Humans MeSH
• Young Adult MeSH
• Obstetric Labor, Premature * immunology   MeSH
• Prospective Studies MeSH
• Pregnancy Trimester, First immunology   MeSH
• T-Lymphocytes, Regulatory * immunology   MeSH
• Pregnancy MeSH
• Ikaros Transcription Factor MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Young Adult MeSH
• Pregnancy MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

The adaptive immune response critically hinges on the functionality of T cell receptors, governed by complex molecular mechanisms, including ubiquitination. In this study, we delved into the role of in T cell immunity, focusing on T cell-B cell conjugate formation and T cell activation. Using a CRISPR-Cas9 screening approach targeting deubiquitinases genes in Jurkat T cells, we identified BAP1 as a key positive regulator of T cell-B cell conjugate formation. Subsequent investigations into BAP1 knockout cells revealed impaired T cell activation, evidenced by decreased MAPK and NF-kB signaling pathways and reduced CD69 expression upon T cell receptor stimulation. Flow cytometry and qPCR analyses demonstrated that BAP1 deficiency leads to decreased surface expression of T cell receptor complex components and reduced mRNA levels of the co-stimulatory molecule CD28. Notably, the observed phenotypes associated with BAP1 knockout are specific to T cells and fully dependent on BAP1 catalytic activity. In-depth RNA-seq and mass spectrometry analyses further revealed that BAP1 deficiency induces broad mRNA and protein expression changes. Overall, our findings elucidate the vital role of BAP1 in T cell biology, especially in T cell-B cell conjugate formation and T cell activation, offering new insights and directions for future research in immune regulation.

• MeSH
• Lymphocyte Activation * immunology   MeSH
• B-Lymphocytes * immunology   metabolism   MeSH
• Jurkat Cells MeSH
• Humans MeSH
• Tumor Suppressor Proteins * metabolism   genetics   MeSH
• Receptors, Antigen, T-Cell * metabolism   MeSH
• Signal Transduction MeSH
• T-Lymphocytes * immunology   metabolism   MeSH
• Ubiquitin Thiolesterase * genetics   metabolism   deficiency   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

Cyanobacterial harmful blooms (CyanoHABs) pose a global ecological problem, and their lipopolysaccharides (LPS) are among the bioactive compounds they release. Previous studies on CyanoHAB-LPS from single cyanobacterial species have shown varying bioactivities in different in vitro cell models. In this study, we isolated LPS from 19 CyanoHAB samples collected at 18 water bodies in the Czech Republic over two consecutive seasons. The proportions of cyanobacteria, Gram-negative bacteria (G-), and other bacteria in the biomass were determined by qPCR, while the cyanobacterial genera were identified using light microscopy. In vitro models of keratinocytes (HaCaT), the intestinal epithelium (co-culture of differentiated Caco-2 cells and peripheral blood mononuclear cells - PBMC), and PBMC alone were treated with isolated LPS at concentrations of 50, 100, and 1 μg/ml, respectively. The endotoxin activities of these concentrations were within the range measured in the aquatic environment. Approximately 85-90% of the samples displayed biological activity. However, the potency of individual LPS effects and response patterns varied across the different in vitro models. Furthermore, the observed activities did not exhibit a clear correlation with the taxonomic composition of the phytoplankton community, the relative share of microbial groups in the biomass, endotoxin activity of the LPS, or LPS migration and staining pattern in SDS-PAGE. These findings suggest that the effects of CyanoHAB-LPS depend on the specific composition and abundance of various LPS structures within the complex environmental sample and their interactions with cellular receptors.

• MeSH
• Biomass MeSH
• Caco-2 Cells MeSH
• Leukocytes, Mononuclear MeSH
• Humans MeSH
• Lipopolysaccharides * toxicity   MeSH
• Cyanobacteria * MeSH
• Harmful Algal Bloom MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

BACKGROUND: Chronic lymphocytic leukemia (CLL) is a common adult leukemia characterized by the accumulation of neoplastic mature B cells in blood, bone marrow, lymph nodes, and spleen. The disease biology remains unresolved in many aspects, including the processes underlying the disease progression and relapses. However, studying CLL in vitro poses a considerable challenge due to its complexity and dependency on the microenvironment. Several approaches are utilized to overcome this issue, such as co-culture of CLL cells with other cell types, supplementing culture media with growth factors, or setting up a three-dimensional (3D) culture. Previous studies have shown that 3D cultures, compared to conventional ones, can lead to enhanced cell survival and altered gene expression. 3D cultures can also give valuable information while testing treatment response in vitro since they mimic the cell spatial organization more accurately than conventional culture. METHODS: In our study, we investigated the behavior of CLL cells in two types of material: (i) solid porous collagen scaffolds and (ii) gel composed of carboxymethyl cellulose and polyethylene glycol (CMC-PEG). We studied CLL cells' distribution, morphology, and viability in these materials by a transmitted-light and confocal microscopy. We also measured the metabolic activity of cultured cells. Additionally, the expression levels of MYC, VCAM1, MCL1, CXCR4, and CCL4 genes in CLL cells were studied by qPCR to observe whether our novel culture approaches lead to increased adhesion, lower apoptotic rates, or activation of cell signaling in relation to the enhanced contact with co-cultured cells. RESULTS: Both materials were biocompatible, translucent, and permeable, as assessed by metabolic assays, cell staining, and microscopy. While collagen scaffolds featured easy manipulation, washability, transferability, and biodegradability, CMC-PEG was advantageous for its easy preparation process and low variability in the number of accommodated cells. Both materials promoted cell-to-cell and cell-to-matrix interactions due to the scaffold structure and generation of cell aggregates. The metabolic activity of CLL cells cultured in CMC-PEG gel was similar to or higher than in conventional culture. Compared to the conventional culture, there was (i) a lower expression of VCAM1 in both materials, (ii) a higher expression of CCL4 in collagen scaffolds, and (iii) a lower expression of CXCR4 and MCL1 (transcript variant 2) in collagen scaffolds, while it was higher in a CMC-PEG gel. Hence, culture in the material can suppress the expression of a pro-apoptotic gene (MCL1 in collagen scaffolds) or replicate certain gene expression patterns attributed to CLL cells in lymphoid organs (low CXCR4, high CCL4 in collagen scaffolds) or blood (high CXCR4 in CMC-PEG).

• MeSH
• Cell Culture Techniques methods   MeSH
• Leukemia, Lymphocytic, Chronic, B-Cell * pathology   metabolism   MeSH
• Gels chemistry   MeSH
• Collagen * chemistry   pharmacology   MeSH
• Humans MeSH
• Polyethylene Glycols * chemistry   MeSH
• Receptors, CXCR4 metabolism   MeSH
• Carboxymethylcellulose Sodium * chemistry   pharmacology   MeSH
• Cell Culture Techniques, Three Dimensional methods   MeSH
• Tissue Scaffolds * chemistry   MeSH
• Cell Survival drug effects   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

Vysokoškolská učebnice, která se zaměřuje na histologii.; Komplexní a srozumitelný zdroj histologických poznatků v novém vydání učebnice. Text je výsledkem spolupráce histologů, anatomů, patologů, studentů, klinických lékařů i andragogů.Strukturovaný text s důrazem na důležité informace z cytologie, obecné histologie a mikroskopické anatomie je kombinován s jednoduchým designem a velkým množstvím barevných obrázků a mikrofotografií. Novinkou jsou rozhodovací algoritmy, které studentům velmi pomohou při určování preparátů, a kapitola o mikroskopovacích technikách.

• MeSH
• Histology MeSH

• Conspectus
• Anatomie člověka a srovnávací anatomie
• Učební osnovy. Vyučovací předměty. Učebnice
• NML Fields
• histologie
• NML Publication type
• učebnice vysokých škol

The mammalian body possesses remarkable adaptability to cold exposure, involving intricate adjustments in cellular metabolism, ultimately leading to thermogenesis. However, cold-induced stress can impact immune response, primarily through noradrenaline-mediated pathways. In our study, we utilized a rat model subjected to short-term or long-term mild cold exposure to investigate systemic immune response during the cold acclimation. To provide human relevance, we included a group of regular cold swimmers in our study. Our research revealed complex relationship between cold exposure, neural signaling, immune response, and thermogenic regulation. One-day cold exposure triggered stress response, including cytokine production in white adipose tissue, subsequently activating brown adipose tissue, and inducing thermogenesis. We further studied systemic immune response, including the proportion of leukocytes and cytokines production. Interestingly, γδ T cells emerged as possible regulators in the broader systemic response, suggesting their possible contribution in the dynamic process of cold adaptation. We employed RNA-seq to gain further insights into the mechanisms by which γδ T cells participate in the response to cold. Additionally, we challenged rats exposed to cold with the Toll-like receptor 2 agonist, showing significant modulation of immune response. These findings significantly contribute to understanding of the physiological acclimation that occur in response to cold exposure.

• MeSH
• Acclimatization immunology   MeSH
• Cytokines metabolism   MeSH
• Adipose Tissue, Brown immunology   metabolism   MeSH
• Rats MeSH
• Humans MeSH
• Cold Temperature * MeSH
• Receptors, Antigen, T-Cell, gamma-delta immunology   metabolism   MeSH
• T-Lymphocytes immunology   MeSH
• Thermogenesis immunology   MeSH
• Toll-Like Receptor 2 * metabolism   genetics   immunology   MeSH
• Inflammation * immunology   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Humans MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

Early identification of resistant cancer cells is currently a major challenge, as their expansion leads to refractoriness. To capture the dynamics of these cells, we made a comprehensive analysis of disease progression and treatment response in a chronic lymphocytic leukemia (CLL) patient using a combination of single-cell and bulk genomic methods. At diagnosis, the patient presented with unfavorable genetic markers, including notch receptor 1 (NOTCH1) mutation and loss(11q). The initial and subsequent treatment lines did not lead to a durable response and the patient developed refractory disease. Refractory CLL cells featured substantial dysregulation in B-cell phenotypic markers such as human leukocyte antigen (HLA) genes, immunoglobulin (IG) genes, CD19 molecule (CD19), membrane spanning 4-domains A1 (MS4A1; previously known as CD20), CD79a molecule (CD79A) and paired box 5 (PAX5), indicating B-cell de-differentiation and disease transformation. We described the clonal evolution and characterized in detail two cell populations that emerged during the refractory disease phase, differing in the presence of high genomic complexity. In addition, we successfully tracked the cells with high genomic complexity back to the time before treatment, where they formed a rare subpopulation. We have confirmed that single-cell RNA sequencing enables the characterization of refractory cells and the monitoring of their development over time.

• MeSH
• Single-Cell Analysis * methods   MeSH
• Drug Resistance, Neoplasm genetics   MeSH
• Leukemia, Lymphocytic, Chronic, B-Cell * genetics   pathology   MeSH
• Humans MeSH
• Sequence Analysis, RNA MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Publication type
• Journal Article MeSH
• Case Reports MeSH

Neutrophils play a Janus-faced role in the complex landscape of cancer pathogenesis and immunotherapy. As immune defense cells, neutrophils release toxic substances, including reactive oxygen species and matrix metalloproteinase 9, within the tumor microenvironment. They also modulate the expression of tumor necrosis factor-related apoptosis-inducing ligand and Fas ligand, augmenting their capacity to induce tumor cell apoptosis. Their involvement in antitumor immune regulation synergistically activates a network of immune cells, bolstering anticancer effects. Paradoxically, neutrophils can succumb to the influence of tumors, triggering signaling cascades such as JAK/STAT, which deactivate the immune system network, thereby promoting immune evasion by malignant cells. Additionally, neutrophil granular constituents, such as neutrophil elastase and vascular endothelial growth factor, intricately fuel tumor cell proliferation, metastasis, and angiogenesis. Understanding the mechanisms that guide neutrophils to collaborate with other immune cells for comprehensive tumor eradication is crucial to enhancing the efficacy of cancer therapeutics. In this review, we illuminate the underlying mechanisms governing neutrophil-mediated support or inhibition of tumor progression, with a particular focus on elucidating the internal and external factors that influence neutrophil polarization. We provide an overview of recent advances in clinical research regarding the involvement of neutrophils in cancer therapy. Moreover, the future prospects and limitations of neutrophil research are discussed, aiming to provide fresh insights for the development of innovative cancer treatment strategies targeting neutrophils.

• MeSH
• Immunotherapy * methods   MeSH
• Humans MeSH
• Tumor Microenvironment * immunology   MeSH
• Neoplasms * immunology   therapy   metabolism   pathology   MeSH
• Neutrophils * immunology   metabolism   MeSH
• Signal Transduction MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

The objective of this study was to evaluate whether RSV inhibits neutrophil extracellular traps (NETs) that induce joint hyperalgesia in C57BL/6 mice after adjuvant-induced arthritis. A subplantar injection of Freund's complete adjuvant was administered to C57BL/6 mice on day 0 for immunization in the AIA model. Resveratrol (RSV, 25 mg/kg) was administered intraperitoneally once daily starting on day 22 and continuing for two weeks. The effects of mechanical hyperalgesia and edema formation have been assessed in addition to histopathological scoring. Mice were sacrificed on day 35 to determine cytokine levels and PADI4 and COX-2 expression levels. ELISA was used to quantify neutrophil extracellular traps (NETs) along with neutrophil elastase-DNA and myeloperoxidase-DNA complexes in neutrophils. An immunohistochemical stain was performed on knee joints to determine the presence of nuclear factor kappa B p65 (NF-kappaB p65). AIA mice were found to have higher levels of NET in joints and their joint cells demonstrated an increased expression of the PADI4 gene. Treatment with RSV in AIA mice (25 mg/kg, i.p.) significantly (P<0.05) inhibited joint hyperalgesia, resulting in a significant increase in mechanical threshold, a decrease in articular edema, a decrease in the production of inflammatory cytokines, increased COX-2 expression, and a decrease in the immunostaining of NF-kappaB. Furthermore, treatment with RSV significantly reduced the amount of neutrophil elastase (NE)-DNA and MPO-DNA complexes, which were used as indicators of NET formation (P<0.05). This study indicates that RSV reduces NET production and hyperalgesia by reducing inflammation mediated by PADI4 and COX-2. According to these data, NETs contribute to joint pain and resveratrol can be used to treat pain in RA through this pathway.

• MeSH
• Cyclooxygenase 2 MeSH
• Cytokines metabolism   MeSH
• DNA metabolism   MeSH
• Edema metabolism   MeSH
• Extracellular Traps * metabolism   MeSH
• Hyperalgesia drug therapy   metabolism   MeSH
• Leukocyte Elastase metabolism   pharmacology   MeSH
• Mice, Inbred C57BL MeSH
• Mice MeSH
• Neutrophils metabolism   MeSH
• NF-kappa B metabolism   MeSH
• Resveratrol pharmacology   therapeutic use   metabolism   MeSH
• Arthritis, Rheumatoid * metabolism   MeSH
• Toll-Like Receptor 4 metabolism   MeSH
• Inflammation metabolism   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH