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关键词： Newcastle Disease virus   Genotype-matched, DNA vaccine   Interferon lambda-3   IL-28b   Molecular adjuvant  

摘要： Newcastle disease virus (NDV) is an extremely contagious and deadly virus that affects numerous bird species, posing serious threats to poultry production on a global scale. In addition to implementing biosecurity practices in farming systems, vaccination remains the most effective means of controlling Newcastle disease (ND). However, while existing commercial vaccines provide some level of protection, the effectiveness of these vaccines can be questionable, particularly in field settings where the complexity of vaccination program implementation poses significant challenges, especially against virulent genotypes of NDV. A genotype-matched NDV DNA vaccine could potentially offer a more effective vaccination approach than currently available live attenuated vaccines. By being specifically tailored to match circulating strains, such a vaccine might improve efficacy and reduce the risk of vaccine failure due to genotype mismatch. To develop an alternative vaccine approach, two ND DNA vaccines were constructed in this study. Each vaccine developed in this study contains the fusion (F) and haemagglutinin-neuraminidase (HN) genes of a virulent NDV genotype VII isolate from Tanzania. Interferon lambda-3 (IFN lambda 3;IL-28b), which has demonstrated capacity to significantly enhance specific adaptive immune responses and decreased levels of inflammatory cytokines, as well as improved protective responses at a high viral challenge dose, was included in one of the developed vaccines. These plasmids were designated pTwist-F-HN-VII-IL28b and pTwist-F-HN-VII. The two plasmids differed in that pTwist-F-HN-VII-IL28b contained the cytokine adjuvant IL-28b. Transfection of cells and subsequent immunofluorescence assays indicated that both plasmids expressed high levels of NDV F-HN proteins. In vivo immunization demonstrated that chicks intramuscularly immunized with pTwist-F-HN-VII-IL28b exhibited significant immune responses compared to chicks immunized with pTwist-F-HN-VII or the

关键词： IL-17   chronic pancreatitis   immune microenvironment   pancreatic cancer   tumour-infiltrating lymphocytes  

摘要： Immunotherapy has made progress in the treatment of tumours; however, in patients with pancreatic cancer, immunotherapy has not achieved effective results. The present study investigated changes in the immune microenvironment during tumour development and progression, and the relationship between the immune microenvironment and prognosis, to clarify the mechanism of immune escape in pancreatic cancer. A total of 40 patients with pancreatic cancer (including 22 with stage I-II disease and 18 with stage III-IV disease) and 20 patients with chronic pancreatitis were included in the present study. The expression of CD3, CD4, CD8, CD56, IFN-γ, IL-17 and 4-1BBL was assessed by immunohistochemistry, and the mRNA expression levels were detected by reverse transcription-quantitative PCR (RT-qPCR). The clinicopathological characteristics and prognoses of patients with pancreatic cancer were analysed to further explore the role of IL-17, IFN-γ, 4-1BBL and tumour-infiltrating lymphocytes in pancreatic cancer. Notably, the expression levels of CD3, CD8, CD56, IFN-γ and 4-1BBL in patients with stages I-II and III-IV cancer were lower than those in patients with chronic pancreatitis (P<0.05), especially in patients with stage III-IV cancer (P<0.05). In addition, the expression of IL-17 in patients with stages I-II and III-IV cancer was greater than in patients with chronic pancreatitis (P<0.05), especially in patients with stage III-IV cancer (P<0.05). The RT-qPCR results regarding CD3, CD4, CD8, CD56, IFN-γ and IL-17 were almost the same as those obtained from immunohistochemical analysis; however, the mRNA expression levels of 4-1BBL were not significantly different between stages I-II and III-IV. Furthermore, patients with pancreatic cancer with higher expression levels of CD3, CD8, CD56, IFN-γ and 4-1BBL exhibited longer survival, whereas those with higher expression of IL-17 had a shorter survival time. The expression levels of CD3, CD8, CD56, cytokines IL-17 and IFN-γ, and c

关键词： Macrophages  

摘要： Mycoplasma hyopneumoniae (M. hyo), a major respiratory pathogen in swine, causes chronic respiratory diseases characterized by severe lung inflammation. Alveolar macrophages, which serve as the first line of defense in the respiratory immune system, undergo necroptosis in response to M. hyo infection. This form of programmed cell death amplifies pulmonary inflammation and leads to impaired lung function, yet the precise molecular mechanisms remain poorly understood. Long non-coding RNAs (lncRNAs), known for their regulatory roles in transcriptional and epigenetic processes, have been linked to various inflammatory and infectious diseases. In this study, we identified a novel lncRNA, lncRNA-MMTP, as a critical regulator of necroptosis during M. hyo infection. Mechanistically, lncRNA-MMTP interacts with the transcription factor TFII-I to enhance c-Fos promoter activity, leading to increased transcription of TNF-α and activation of the RIPK1/RIPK3/MLKL necroptotic pathway. Importantly, knockdown of lncRNA-MMTP or inhibition of TFII-I significantly reduced TNF-α levels and necroptosis in alveolar macrophages. These findings not only elucidate a new molecular pathway underlying M. hyo-induced lung inflammation but also suggest potential therapeutic targets for managing pathogen-induced inflammatory responses in the respiratory system. © 2024

关键词： NOX2   Rheumatoid arthritis   Pathomechanism   Anti-TNF alpha agents   Pharmacogenomics  

摘要： The aim of this research was to prospectively evaluate the impact of NOX2 gene expression profile (including NCF1, NCF2 and NCF4 genes) in peripheral blood mononuclear cells (PBMCs) on immune signatures, clinical characteristics and responsiveness to anti-TNF treatment in RA patients. Blood specimens were collected from 31 rheumatoid arthritis (RA) patients and 25 healthy controls, and 16 RA patients were followed at two timepoints during anti-TNF treatment. mRNA expression levels of selected genes and immunoregulatory cytokines concentrations were determined. We observed the significant upregulation of NCF4 and CD14 expression in RA group. The mRNA levels of NCF1 and CD14 positively correlated both in groups of RA patients and healthy controls. NOX2 gene expression profile was not associated with anti-TNF responsiveness, nor with RA clinical features. TNF alpha inhibition has not influenced NOX2 expression either. Notably, this study indicate the novel links between expression levels of NCF1 and monocyte differentiation antigen CD14.

关键词： Bone mesenchymal stem cells   Canine   Chondrocyte   Exosome   Inflammation  

摘要： Osteoarthritis is a degenerative disease of cartilage, and exosome derived from mesenchymal stem cells (MSCs) are considered promising for treating inflammatory musculoskeletal disorders, although their mechanisms are not fully understood. This study aimed to investigate the effects of exosomes derived from canine bone marrow mesenchymal stem cells (cBMSCs-Exos) on the expression of inflammatory factors and genes related cartilage matrix metabolism in IL-1β-induced canine chondrocytes. Canine BMSCs were isolated and characterized for surface markers and trilineage differentiation. Exosomes were then extracted and performed surface labeling detection. Canine chondrocytes were exposed to IL-1β to mimic osteoarthritis in vitro. Subsequently, the chondrocytes were treated with exosomes from BMSCs, and the expression levels of related genes and IL-6 protein were assessed. The mesenchymal stem cells isolated from bone marrow and cultured exhibited positive CD44 and CD90, negative expression of CD45 and HLA, and demonstrated potential to differentiate into adipocytes, osteoblasts and chondrocytes. Exosomes from BMSCs exhibited positivity expression of CD9, CD63 and CD81. Treatment with exosomes significantly reduced and mRNA levels induced by IL-1β, as well as IL-6 protein expression. Additionally, a significant decrease was observed in the mRNA levels catabolic marker genes , , and . Conversely, there was a significant increase in the mRNA levels of anti-inflammatory cytokines , , and anabolic marker genes, such as , , and . cBMSCs-Exos play a vital role in cartilage protection by suppressing the expression of pro-inflammatory and anabolic genes while simultaneously enhancing the expression of genes involved in synthesis metabolism.

关键词： Chronic rhinosinusitis with nasal polyps   SNOT-22   T2 inflammation   asthma   comorbidity   nasal polyps   real world   severe asthma  

摘要： Background:Chronic rhinosinusitis with nasal polyps (CRSwNP) and severe asthma (SA) are 2 frequently coexisting conditions that are, in most cases, associated with eosinophilic inflammation. The concurrence of both diseases has a negative synergistic impact on disease severity and patients' health-related quality of life. Thus, a holistic, collaborative management of these patients is a critical unmet need. Mepolizumab, a systemic anti-IL-5 therapy, has been shown to be effective as an add-on treatment in both SA and CRSwNP, with more literature available on asthma outcomes than on CRSwNP. Objectives:The primary objective of the study is to evaluate the real-world effectiveness of mepolizumab in improving the health-related quality of life of comorbid patients at 12 months using the SNOT-22 questionnaire. Secondary objectives include safety and efficacy outcomes of mepolizumab treatment in the 2 populations, which are expected to have variable severity of the respective comorbid conditions. Methods:RESPONSE is a European real-world prospective cohort study designed to assess the effectiveness of mepolizumab in 2 cohorts of adult patients: one with SA as primary diagnosis with (secondary diagnosis) comorbid CRSwNP, and another with CRSwNP as primary diagnosis with (secondary diagnosis) comorbid asthma. Up to 350 patients receiving newly prescribed mepolizumab will be followed up for 12 months as per the investigators' standard of care. Conclusion:This study will report the effects of anti-IL-5 therapy in both diseases investigated and the respective comorbidity, as well as the consequence of treating milder forms of asthma and CRSwNP with mepolizumab, supporting the emerging evidence on early treatment optimization.

关键词： ABPA   allergic bronchopulmonary aspergillosis   asthma biologics   dupilumab   severe asthma  

摘要： Background:Allergic bronchopulmonary aspergillosis (ABPA) is a disease resulting from an overactive type 2 response to . Initial studies suggest that asthma biologics can effectively treat ABPA, but it is unclear which biologic class is superior. Objective:We sought to compare the effectiveness of asthma biologics in the treatment of ABPA. Methods:We performed a retrospective analysis of patients with ABPA treated with asthma biologics, and measured outcomes of respiratory exacerbations, daily oral corticosteroids, and antifungals. We assessed these variables while individuals were treated with 1 of 3 biologic classes: anti-IgE, anti-IL-5/IL-5 receptor alpha (IL-5Ra), anti-IL-4 receptor alpha (IL-4Ra). Results:A total of 21 patients were included in our analysis. Anti-IL-4Ra was associated with a significantly lower number of exacerbations and oral corticosteroid use compared with anti-IgE or anti-IL-5/IL-5Ra therapies. Anti-IL-4Ra also had significantly lower antifungal use than anti-IgE, and there was a trend toward lower antifungal use when compared with anti-IL-5/IL-5Ra. In a subgroup of 10 patients treated with 2 or more biologics sequentially, we found that 8 of them achieved clinical control on anti-IL-4Ra therapy after failing anti-IgE and/or anti-IL-5/IL-5Ra therapies. Conclusions:Dupilumab blocks the IL-4Ra, resulting in the downstream inhibition of both IL-4 and IL-13 effector pathways. Dupilumab may benefit patients with ABPA by inhibiting the generation of airway mucus (IL-13), and by reducing local B-cell differentiation into IgE antibody-secreting cells (IL-4). On the basis of our findings and with the known molecular mechanisms of dupilumab, we believe that anti-IL-4Rα-targeted therapy may be more effective than anti-IgE or anti-IL-5/IL-5Rα therapies to treat ABPA.

关键词： Shaoyao decoction   Ulcerative colitis   IL-17a   M1 macrophage polarization   PPAR/NF-kappa B pathway  

摘要： Ethnopharmacological relevance: The efficacy of Shaoyao decoction (SYD), a traditional Chinese medicine prescription, in alleviating colonic mucosal inflammation in ulcerative colitis (UC) has been established. However, the specific mechanism underlying the therapeutic effects of SYD on UC is not clear. Aim of study: In this study, we demonstrated the therapeutic effect of SYD on the polarization of M1 macrophages and elucidated the underlying mechanism. Materials and methods: UC mice were induced with 3% DSS for one week and subsequently treated with SYD for another week. The composition of SYD was determined by HPLC. To assess the therapeutic efficacy of SYD, key parameters, including body weight changes, DAI scores, colon length, and histological alterations in colonic tissues, were monitored. ELISA was performed to quantify inflammatory cytokines, while Western blotting and immunofluorescence analyses were performed to quantify tight junction protein expression and M1 macrophage infiltration, respectively. Functional assessments focused on lysosomal activity and glucose oxidation in primary macrophages and RAW 264.7 cells exposed to LPS, IL-17a, and SYD using dedicated kits. To elucidate the mechanisms underlying the action of SYD, the data derived from TMT-based proteomics were analyzed to screen and predict its potential targets and regulated pathways. Results: After treatment for seven days, SYD significantly mitigated colitis symptoms in mice, as determined by a decrease in body weight loss, an increase in colon length, and a decrease in disease activity index (DAI) score. The results of histopathological analysis showed substantial improvements in the integrity of colonic tissue. Additionally, SYD treatment significantly decreased the levels of proinflammatory cytokines, including IL-17a, IL-6, IL-1 beta, and TNF-alpha. This effect was accompanied by a reduction in the infiltration of CD86+ macrophages and restoration of occludin and ZO-1 levels, thus impro

关键词： Saffron   Colorectal cancer   IL-17   Immunotherapy  

摘要： Ethnopharmacological relevance: Saffron is one of the traditional medicinal herbs, which contains various active ingredients, such as safranal, crocin, saffron acid, etc. It has anti-inflammatory, antioxidant, and anti-cancer properties, and is widely used in clinical practice. The anti-cancer efficacy of saffron has been previously confirmed, but its anti-cancer mechanism in colorectal cancer remains unclear. Objective: We investigated the effect of active compounds of saffron on the efficacy of immunotherapy for colorectal cancer. Methods: TCMSP and liquid chromatography-mass spectrometry analysis (LC-MS), GeneCards, and DisGeNET databases were used to identify the active compounds of saffron, drug targets and the disease targets of colorectal cancer. They were then subjected to Gene Ontology Enrichment (GO) and Signalling Pathway Enrichment (KEGG) analyses. The core targets and corresponding compounds were selected for molecular docking. The effect of active components of saffron on the proliferation of CT26 and HCT116 cells was investigated using the cell counting kit-8 (CCK-8). In vitro experiments were conducted by subcutaneous injection of CT26 cells to establish a colon cancer model. Enzyme-linked immunosorbent assay (ELISA), western blotting (WB), real-time polymerase chain reaction (RT-PCR), immunohistochemistry (IHC), and flow cytometry (FCM) were employed to validate the effects of saffron on colorectal cancer immunotherapy. Results: 1. LC-MS analysis revealed that the main active component of saffron extract was crocin. The active chemicals of saffron intersected with 170 colorectal cancer targets, with 17 predicting targets for saffron treatment. GO and KEGG enrichment analyses revealed that the active components of saffron can prevent colorectal cancer development by enhancing Th17 cell differentiation and the IL-17 signaling pathway. 2. In vitro studies revealed that saffron alcohol extract, crocin, and safranal can suppress the proliferation of CT26

关键词： Diabetic mice   Mudan granules   TMT proteomics   FBN2   TNF-alpha  

摘要： Ethnopharmacological relevance: Mudan granules (MuD), a time-honored traditional Chinese patent medicine (TCPM), are widely utilized in the clinical treatment of diabetic peripheral neuropathy (DPN). In the field of biomedical diagnostics, both diabetic retinopathy (DR) and DPN are recognized as critical microvascular complications associated with diabetes. According to the principles of traditional Chinese medicine (TCM), these conditions are primarily attributed to a deficiency in Qi and the obstruction of collaterals. Despite this, the protective effects of MuD on DR and the underlying mechanisms remain to be comprehensively elucidated. Aims of the study: The purpose of this study was to investigate the effect of MuD on DR and to further explore the promising therapeutic targets. Methods: A diabetic mouse model was established by administering 60 mg/kg of streptozotocin (STZ) via intraperitoneal injection for five consecutive days. The therapeutic efficacy of MuD was evaluated using a comprehensive approach, which included electroretinogram (ERG) analysis, histopathological examination, and assessment of serum biochemical markers. Then, the pharmacodynamic mechanisms of MuD were systematically analyzed using Tandem Mass Tags-based proteomics. Meanwhile, the candidate compounds of MuD were analyzed by ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS) and molecular docking was applied to estimate the affinity of the active ingredient to their potential key targets. In addition, the functional mechanisms identified through bioinformatics analysis were confirmed by molecular biological methods. Results: We demonstrated that MuD provided significant protection to retinal function and effectively mitigated the reduction in retinal thickness observed in the animal model. Through proteomic analysis, we identified a substantial regulation by MuD of 70 biomarkers associated with diabetic retinal damage. These proteins were n