课程文献中心 更多>>

关键词： Brusatol, ulcerative colitis   Intestinal mucosal injury   Interleukin 22  

摘要： Brusatol (BR) is an active compounds isolated from Brucea javanica, a Chinese herbal medicine that is famous for its anti-diarrheal effect. We have previously reported that BR mitigated inflammation in murine ulcerative colitis (UC) models. However, BR's role in intestinal mucosal healing, which is recently established as central strategy for the prevention and treatment of UC, remains unknown. In this study, the ameliorative effect of BR on intestinal mucosal damage was investigated in DSS-induced UC mice. BR significantly alleviated colitis symptoms, improved intestinal barrier function by preventing loss of goblet cells and downregulation of mucins and tight junction proteins, as well as maintained proliferative and apoptotic homeostasis in the colonic epithelium of UC mice. Mechanistically, BR enhanced the level and secretion of IL-22, but inhibited IL-22BP, an inhibitory protein of IL-22, in the blood serum and intestinal tissues of UC mice, as well as in MNK3 cells which is an effective cell model for studying ILC3s. Additionally, BR elevated the expressions of receptors for IL-22 (IL-10R2 and IL-22R1), and activated its downstream STAT3 signaling pathway. Furthermore, the involvement of IL-22 was further investigated by using recombinant IL-22 (rIL-22) and IL-22 antibody (anti-IL-22). BR demonstrated comparable effects with rIL-22 on alleviating intestinal inflammation and repairing intestinal mucosal injury. Treatment with anti-IL-22 abrogated the mucosal protective effects of BR. The present findings shed novel insights into the role of BR in intestinal mucosal healing via activating IL-22/STAT3 signaling pathway in UC.

关键词： GPR35   Kynurenic acid   Macrophage   Klebsiella pneumoniae   IL-1 beta   Glycolysis  

摘要： Carbapenemase-resistant hypervirulent Klebsiella pneumoniae (CR-hvKP) is a common pathogen that can cause severe pneumonia. The innate immune response, especially the response of macrophages, plays a crucial role in the host's defense against bacterial infections. Glycolysis is implicated in the modulation of immune functions in macrophages. Here, we provide evidence supporting the role of GPR35 in decreasing glycolysis and reducing the secretion of IL-1 beta in macrophages by inhibiting the transcription of HK2 during K. pneumoniae-induced pneumonia. Mice with GPR35 knock-out exhibit higher mortality and increased lung bacterial burdens. Mechanistically, GPR35 activation by kynurenic acid inhibits caspase-1 cleavage and reduces IL-1 beta secretion in macrophages by specifically suppressing activation of the NLRP3 inflammasome. These findings underscore the role of GPR35 in regulating inflammation during K. pneumoniae-induced pneumonia and suggest that GPR35 is a potential therapeutic target for clinical treatment.

关键词： probiotics   type 1 diabetes   glucose homeostasis   interleukin-21   interleukin-22  

摘要： Background: Probiotics alter gut microbiota and have beneficial effects on immune homeostasis. The role of probiotics in diabetes has been shown in some studies. Interleukin (IL)-21 and IL-22 have been implicated in the pathogenesis of type 1 diabetes mellitus (T1DM). Objectives: This study aimed to assess the effect of oral supplementation with probiotics on glycemic control and IL-21 and IL-22 levels in pediatric patients with T1DM. Methods: This randomized controlled trial was registered in ClinicalTrials (NCT04579341) and included 70 children and adolescents with T1DM. They were randomly assigned into two groups to receive either an oral probiotic tablet containing 0.5 mg Lactobacillus acidophilus once daily or a matching placebo. Both groups were followed up for 6 months with assessment of fasting blood glucose (FBG), lipids, hemoglobin A1c (HbA1c), and IL-21 and IL-22 levels. Results: Baseline clinical characteristics and laboratory parameters were similar between both groups (p > 0.05). After six months, probiotic supplementation for the intervention group resulted in significant decreases in FBG, HbA1c, total cholesterol, and IL-21 levels, while IL-22 was increased compared with baseline levels (p < 0.001) and compared with the placebo group (p < 0.001). No adverse reactions were reported. Baseline IL-21 was positively correlated to FBG, HbA1c, and total cholesterol while there were negative correlations between these variables and IL-22 levels. Conclusions: Probiotic supplementation improved glucose homeostasis and glycemic control, possibly through their immunomodulatory effects on cytokines IL-21 and IL-22. Thus, probiotics could be a safe adjuvant therapy to intensive insulin in pediatric patients with T1DM.

关键词： Chronic inflammation   Imiquimod induced psoriasis   Dihydromyricetin   IL-17   T cells   ROR gamma t  

摘要： Background and purpose: Psoriasis is a chronic inflammatory skin disorder affecting approximately 125 million people. IL-17 A secreted from Th17 cells plays a major role in elucidating psoriasis. Dihydromyricetin (DHM) is plant derived flavonoid isolated from leaves and stems of Rattan tea (Ampelopsis grossedentata). Reports indicate anti-inflammatory property of DHM but no information is currently available on its mechanism of action or effect on IL17 producing Th17 cells and exact role in psoriasis. Experimental approach: DHM shows strong anti-inflammatory properties in vitro, DHM reduced LPS-induced ROS generation, and pro-inflammatory cytokines in macrophages. The efficacy of DHM against chronic inflammatory disorder in vivo was investigated in imiquimod-induced psoriasis established in male BALB/C mice as this model closely resembles human psoriasis. Immunophenotyping and cytokine production were observed by flow cytometry, the status of gene expression was determined by real-time PCR, and nuclear co-localization and immunofluorescence of skin tissue were studied using confocal microscopy. Key results: We observed increased inflammatory parameters in imiquimod treated diseased animals and the application of DHM topically and orally reduced the inflammatory parameters and improved indicators of cardiac damage prominent in psoriatic conditions. In our study, we found that the application of DHM dose- dependently reduced the percentage of IL-17 A-producing T cell population and reduced the nuclear cotranslocation of ROR gamma t in psoriatic T cells and possibly also influenced upstream IL-6 signaling. Conclusion and implications: Our study suggests that DHM effectively alleviates psoriatic symptoms, and its mechanism of action involves the regulation of ROR gamma t pathway in T cells.

关键词： IL-6   TNF alpha   CRP   Inflammation   Mortality   Nutritional therapy   Clinical outcomes   Polymorbid   Individualization  

摘要： Background: Inflammation is a key driver of disease-related malnutrition and patients with high inflammation may not show the same benefits from nutritional therapy as other patients. We compared in an exploratory manner the prognostic ability of interleukin- 6 (IL- 6), tumor necrosis factor-alpha (TNF-alpha) and C-reactive protein (CRP) to predict outcome and response to nutritional therapy, respectively, within a large cohort of patients from a previous nutritional trial. Methods: This is a secondary analysis of the Swiss-wide, multicenter, randomized controlled Effect of early nutritional therapy on Frailty, Functional Outcomes, and Recovery of malnourished medical inpatients Trial (EFFORT) trial comparing individualized nutritional support with usual care nutrition in medical inpatients. The primary endpoint was 30-day all-cause mortality. Results: We included 996 patients with an overall mortality rate of 6% within 30 days. Compared to patients with low IL- 6 level < 11.2pg/mL, patients with high levels had a more than 3-fold increase in mortality at 30-days (adjusted HR 3.5, 95% CI 1.95-6.28, p < 0.001), but tended to have a less pronounced mortality benefit from individualized nutritional therapy as compared to usual nutritional care (hazard ratio 0.82 vs. 0.32). CRP and TNF-alpha were not associated with mortality, but patients with increased CRP levels > 100 mg/dl also showed a trend towards a diminished response to nutritional intervention (hazard ratio 1.25 vs. 0.47). Conclusion: Our findings support the thesis that a high inflammatory state is linked to reduced benefits from nutritional therapy. Apparently, CRP and IL- 6 effectively predict treatment response, but IL- 6 may additionally serve as a prognostic marker for increased mortality. This finding might help to develop improved treatment strategies for patients with elevated inflammatory profiles.

关键词： Muscle injury   Platelet-rich plasma   Inflammation   Interleukin   Peptide  

摘要： Muscle injuries are frequent in sports, necessitating therapies that reduce inflammation and enhance repair. Platelet-rich plasma (PRP), derived from autologous blood, offers high concentrations of platelets and growth factors for tissue regeneration. Interleukin-1 beta (IL-1 beta), a pro-inflammatory cytokine, is crucial in inflammation, and its inhibition may speed up healing, but the high cost of blockers limits their use. This study evaluated the effects of leukocyte-rich PRP (LR-PRP), leukocyte-poor PRP (LP-PRP), and the peptide antagonist DAP1-2 on inflammation after muscle injury. Eighty-four rats were divided into seven groups: Control;muscle injury (MI);MI + LR-PRP;MI + LP-PRP;MI + DAP1-2;MI + LR-PRP + DAP1-2;MI + LP-PRP + DAP1-2. Muscle damage was induced via contusion of the right gastrocnemius, with treatments administered 24 h post-injury. On day five, groups were euthanized for analysis. RT-qPCR measured NF-kB and IL-1 beta expression, while ELISA assessed pro- and anti-inflammatory cytokines, including TNF-alpha and IL-6. All treated groups showed reduced inflammatory and oxidative stress markers by day five, with the PRP-LP + DAP1-2 group showing the most significant effects, indicating enhanced tissue repair.

关键词： IL-6   PD-L1   Non-functioning pituitary adenoma   Metformin   Apoptosis  

摘要： PurposeThe aim of this study was to investigate the function and regulatory mechanism of Interleukin-6 (IL-6) in pituitary-derived folliculostellate (PDFS) cells and to explore the mechanism of metformin against PDFS cells growth through *** staining was conducted on clinical samples from non-functioning pituitary adenomas (NFPA) patients and normal individuals to assess IL-6 and Programmed Death-Ligand 1(PD-L1) expression. PDFS cells were treated with IL-6 to evaluate their effects on cell viability, proliferation, and migration through various assays. Similar assays were performed to assess the counteractive effects of metformin, focusing on the IL-6/ERK pathway and PD-L1 expression. Western blot analysis was utilized to examine apoptosis-related proteins, and Annexin V-FITC/PI double staining was used to detect cell apoptosis. It also involves assessing the effects of metformin treatment on tumor IL-6 and PD-L1 expression, tumor size, and potential toxic side effects in PDFS xenograft *** samples showed increased IL-6 and PD-L1 expression in NFPA compared to normal pituitary tissues. IL-6 treatment significantly enhanced PDFS cell viability(Increased by 46% within 48 h), proliferation(Increased by 24% within 48 h), and migration(Increased by 19% within 48 h). Metformin treatment resulted in the downregulation of IL-6 expression and mitigated IL-6-induced effects on PDFS cells. Additionally, metformin-induced apoptosis and reduced tumor size in xenograft nude mice without observable toxic side *** downregulates the expression of IL-6 in PDFS cells, inhibits the activation of the ERK pathway, thereby suppressing cell proliferation and PD-L1 expression, and induces cell apoptosis.

关键词： Liver cancer   EGR2   IL-8   PDK4   Tumor associated macrophages  

摘要： Liver tumor is a common digestive system tumor, and its development is closely related to complex cytokines, tumor microenvironment and immunoregulatory mechanisms. Tumor-associated macrophages play a great role in a series of liver cancer development by secreting various cytokines and transmitting multiple signals, but how macrophages regulate the various biological behaviors of liver cancer cells at the microscopic level is a challenge we still need to overcome. In this research, we first identified the Early Growth Response 2 (EGR2) gene, which exhibited significant expression in M2 macrophages in comparison to M0 and M1 cell types, utilizing RNA sequencing. Subsequently, we validated this finding through a battery of methodologies, including WB, qRT-PCR, and immunofluorescence assays. We further employed a co-culture model involving MHCC97L and macrophages to investigate the impact of EGR2 downregulation within M2 cells on the in vivo and in vitro metastatic and invasive capabilities of MHCC97L cells. Subsequently, we directed our attention to investigating the impact of EGR2 on the levels of interleukin-8 (IL-8). Through comprehensive analyses including RNA sequencing, CUT-and-Tag, and ChIP techniques, we demonstrated that EGR2 can bind to the promoter region of the Pyruvate Dehydrogenase Kinase 4 (PDK4) gene. Finally, we introduced a virus overexpressing PDK4 and demonstrated that EGR2 could regulate the transcriptional level of PDK4 to affect the expression of IL-8, and ultimately alter the metastatic ability of hepatocellular carcinoma cells. Our study demonstrates that EGR2 may be a valuable target for future intervention in the disease process of hepatocellular carcinoma and refines the mechanism at the microscopic level of Tumor-associated macrophages.

关键词： MHC ligands   Swiss mice   antigen presentation   flow cytometry   immunopeptidomics   major histocompatibility complex  

摘要： Antigen presentation on major histocompatibility complex (MHC) molecules is central to the initiation of immune responses, and a lot of our understanding about the antigen processing and presentation pathway has been gained through studies in mice. MHC molecules are the most genetically diverse genes; consequently, mouse strains differ substantially in their MHC make up and resulting antigen presentation. Swiss mice are commonly used in pharmacological research, yet our understanding of antigen presentation in this strain is surprisingly limited. Here, we have tested a range of anti-MHC antibodies and present a range of clones suitable to analyse MHC class I and class II molecules in Swiss mice who have the H2-q MHC haplotype. Moreover, we demonstrate using immunopeptidomics that clones 28-12-8, 34-1-2, MKD6, and N22 are also suited to isolate MHC class I and class II ligands in this mouse strain. Thus, this work also establishes a first experimental account of the H2-q-derived thymus and spleen immunopeptidome in Swiss mice which bears strong resemblance with ligands isolated from the H2-d MHC haplotype of Balb/C mice. The analysis of source proteins shows common but also organ- and function-specific antigen presentation in line with the involvement of the thymus in tolerance induction and the function of the spleen as a site of immune responses.

关键词： intramuscular fat   scRNA-seq   nuclear IL-1 alpha   pyroptosis  

摘要： Pigs are vital for meat production, and their intramuscular fat content significantly impacts pork quality and flavor. Using single-cell RNA sequencing (scRNA-seq) on porcine intramuscular fat, we found that adipose progenitor cells express highly inflammatory genes, including IL-1 alpha, during adipogenic differentiation. IL-1 alpha, a pro-inflammatory cytokine present in various cell types, can translocate to the nucleus via its nuclear localization sequence (NLS), yet its nuclear function remains unclear. By constructing an inactivated NLS carrier for IL-1 alpha, we discovered that nuclear IL-1 alpha promotes pyroptosis in porcine intramuscular adipocytes through the IRF2-NOCT-ROS pathway. This study reveals a novel role of nuclear IL-1 alpha in pyroptosis regulation, providing insights into enhancing the intramuscular fat content and improving pork quality.