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关键词： Cadmium   N-Acetyl cysteine   Oxidative stress   Inflammation   Immunohistochemistry  

摘要： BackgroundCadmium is known to disrupt cellular proliferation through unregulated cell division. This process leads to activation of TNF-alpha cytokines, resulting in cellular damage and increased inflammation in cells, including brain cells. This study investigates the regulation of TNF-alpha and ERK gene expression patterns mediated by N-acetylcysteine in response to cadmium exposure in Wistar rats..Methods and resultsWistar rats (n = 37) were divided into five groups: control (G1), acute cadmium exposure (G2), chronic cadmium exposure (G3), acute cadmium with N-acetylcysteine (G4), and chronic cadmium with N-acetylcysteine (G5). Brain tissue sections were prepared and stained with H&E. Then, the G-FAP was measured using immunohistochemistry. ELISA was employed to detect IL-1 beta and IL-10 levels. TNF and ERK gene expression was assessed using RT-PCR. Histopathological examination revealed increased glial inflammatory cells in groups G2 and G3. N-acetylcysteine reduced inflammatory cell infiltration, and G-FAP staining confirmed decreased astrocytic accumulation in G5. IL-1 beta levels significantly decreased in G5 after N-acetylcysteine therapy, while IL-10 levels increased after treatment but subsequently declined due to chronic cadmium exposure. TNF gene expression increased in G2 and G3 but decreased significantly in G5, demonstrating N-acetylcysteine's suppressive effect. Furthermore, ERK gene expression significantly increased in G2 and G3. However, there were notable decreases in both G4 and G5 compared to cadmium-exposed *** study demonstrated that N-acetylcysteine mitigates oxidative stress-induced tissue damage, prevents apoptosis, and exhibits anti-inflammatory properties by downregulating TNF-alpha and upregulating ERK gene expression.

关键词： Africa   HLA   Alleles   Haplotypes   Diversity indices  

摘要： Africa, being one of the most genetically diverse regions in the world, remains significantly underrepresented in high-resolution Human Leukocyte Antigen (HLA) data. The extensive genetic variation in HLA alleles across the region underscores the need for population-specific immunogenetic data to guide T-cell vaccine development. This study analysed Class I HLA data from Eastern and Southern African populations to assess regional genetic diversity. Analyses included allele and haplotype frequency distributions, deviations from Hardy-Weinberg equilibrium, linkage disequilibrium, and homozygosity test of neutrality across various populations. To further contextualise African HLA diversity, comparisons were made among African populations and also with African American and European American populations using the Hellinger diversity index and multidimensional scaling methods. The results revealed that South African populations exhibited an estimated average of 34.1% genetic diversity with respect to other African populations. Rwanda demonstrated an estimated 26.9% genetic diversity, Kenya (26.5%), Zambia (26.5%), and Uganda (24.7%). Additionally, in-country analyses revealed variations in HLA diversity among different tribes within each country. The estimated average in-country diversity was 51% in Kenya, 35.8% in Uganda, and 33.2% in Zambia. These results reveal various levels of genetic diversity among African populations. The highlighted differences in HLA Class I allele frequencies between Eastern and Southern African populations compared to US populations, demonstrate that it is inappropriate to extrapolate HLA data from US populations including that of African Americans when designing T-cell-inducing vaccines tailored to African populations. Our findings underscore the urgent need to generate high-resolution HLA data to guide vaccine development tailored to African populations.

关键词： gestational diabetes mellitus   diagnosis   biomarkers   IL-6   TNF-alpha   pregnancy  

摘要： Gestational diabetes mellitus (GDM) occurs in approximately 9-25% of pregnancies and, if left undiagnosed or inadequately controlled, can lead to adverse outcomes for both the mother and the fetus, short and long term. GDM is characterized by glucose intolerance with onset or first recognition during pregnancy and is a multifactorial condition with a pathophysiology that remains incompletely understood. It is strongly associated with a chronic low-grade inflammatory state that contributes to insulin resistance, a hallmark of GDM pathogenesis. Among the fundamental pro-inflammatory cytokines implicated in this process, TNF-alpha and IL-6 play central roles. TNF-alpha is a cytokine primarily secreted by activated macrophages, as well as by adipocytes in the context of obesity. Many studies have shown that its levels are elevated in pregnant women with GDM compared to normoglycemic pregnant individuals. IL-6 is another pro-inflammatory cytokine secreted by immune cells, adipose tissue, and the placenta. It is found in higher concentrations in the maternal circulation during pregnancies complicated by GDM. Both TNF-alpha and IL-6 act synergistically to perpetuate a pro-inflammatory intrauterine environment. Their combined effects exacerbate insulin resistance and may impair pancreatic beta-cell compensation during pregnancy, facilitating the onset of GDM in genetically or metabolically susceptible individuals. Recent research has identified various maternal serum biomarkers, such as TNF-alpha and IL-6, that may hold promise for the early detection of GDM. The aim of our study is to evaluate whether TNF-alpha and IL-6 can be used as diagnostic tools for the early diagnosis of GDM, allowing for timely intervention and reducing the risk of associated maternal and fetal complications.

关键词： 淋巴细胞   慢性阻塞性肺疾病(COPD)   肺淋巴系统   肺淋巴管   肺淋巴管系统   肺内三级淋巴器官   综述  

摘要： 慢性阻塞性肺疾病（COPD）简称慢阻肺病，是呼吸系统最常见的慢性气道炎症性疾病之一。肺淋巴系统在维持液体稳态、免疫应答等方面发挥重要功能。近年来，肺淋巴系统的研究热度上升，且随着科学技术的进步与发展，肺淋巴系统已被证实在肺损伤和修复，尤其是在慢性肺部炎症性疾病中具有重要作用。本文将对肺淋巴系统在慢阻肺病中的研究进展进行综述。

关键词： IL-18   Inflammation resolution   Monocyte macrophage transition   Sepsis   Recovery   Cytokine profiling  

摘要： BackgroundTimely resolution of innate immune responses activated by surgical intervention is crucial for patient recovery. While cytokines and innate immune cells are critical in inflammation resolution, the specific role of IL-18 in these processes remains controversial and *** investigate determinants of successful recovery using peripheral blood samples from orthopedic surgery (ORT) patients (n = 33) at T0 (before surgery), T1 (24 h after surgery) and T2 (3 days after surgery). Monocytes from ORT patients underwent immunophenotyping together with bulk transcriptomic analysis. We found that IL-18 strongly defines the recovery immune signature. These results were further validated in vitro by comparing IL-18 and TNF-alpha effects on monocytes, and in 3D human intestine organoids together with single cell (sc)-RNAseq *** of ORT monocytes revealed upregulation of ITG family integrins, namely ITGB3 and ITGB5, CXCL family chemokines, notably CXCL1-3, CXCL5, and SCL/TAL1 factor controlling differentiation and migration, but not pro-inflammatory genes. Similar changes were observed in IL-18 stimulated healthy donor monocytes in vitro, including an increase in CD11b, CD64, and CD86 levels, accompanied by increased phosphorylation of Akt but not NF kappa B. These changes were attenuated in the presence of TNF-alpha, thus showing a unique role of IL-18 when acting alone without its most frequent paired cytokine TNF-alpha. We further confirmed that IL-18 induces monocyte-macrophage transition and migration using human intestinal organoids. Finally, TNF-alpha/IL-18 ratio showed a high predictive value of clinical severity in septic *** propose a novel role of IL-18 on monocyte migration and macrophage transition characterizing successful orthopedic surgery recovery, as well as the ratio of IL-18/TNF-alpha as a novel marker of inflammation resolution, with potential implications for patient monitoring and thera

关键词： Atlantic cod   Vibrio anguillarum   IgM antibodies   antibody response   adaptive immunity   aquaculture  

摘要： The unique adaptive immune system of the Atlantic cod (Gadus morhua), with genetic loss of the mhc class II and cd4, poses questions about the protective role of specific antibodies in this species. We investigate the IgM response against Vibrio anguillarum, a common pathogen in aquaculture. Juvenile Atlantic cod were bath-immunized with formalin-fixed V. anguillarum serotype O2a. Vaccinated cod were fully protected against lethal vibriosis when challenged by immersion with serotype O2a and partially protected against challenge with serotype O2b. Serum IgM from immunized cod reacted specifically with V. anguillarum O2a in ELISA, with some crossreactivity towards the O2b serotype. Bath-immunized cod were also protected against intracelomic challenge with V. anguillarum O2a, supporting the induction of systemic immunity by bath vaccination. Passive transfer experiments were conducted to evaluate the protective efficacy of IgM. Naive cod that received total serum or purified IgM from immunized donors were protected against lethal vibriosis;whereas, naive cod that received naive serum were not protected. Western blotting revealed that these protective antibodies recognized a proteinase K-sensitive antigen rather than lipopolysaccharides. These insights enhance our understanding of cod immunity and provide guidance for developing future vaccination strategies in aquaculture.

摘要： Bladder cancer (BC) is the second most prevalent genitourinary malignancy worldwide. Treatment options remain limited for patients with Bacillus Calmette-Gu & eacute;rin (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC). Up to 70% of NMIBC cases harbor fibroblast growth factor receptor 3 (FGFR3) alterations, and FGFR inhibition has shown potential to enhance the efficacy of immune checkpoint inhibitor (ICI). Interferon (IFN)-gamma, a cytokine produced by activated T cells and associated with better response to immunotherapy in BC, is a key inducer of PD-L1 expression in the tumor microenvironment. However, the interaction between FGFR inhibitors and IFN-gamma-induced PD-L1 expression in FGFR3-activated NMIBC cells remains unclear. Here, we show that FGFR inhibitors significantly reduced IFN-gamma-induced PD-L1 expression in NMIBC cells harboring FGFR3-TACC3 fusions. Mechanistically, FGFR inhibitors restored IFN-gamma-suppressed SIRT1 expression, promoted LC3B deacetylation and nuclear export, and enhanced autophagy-lysosomal degradation of PD-L1. Blocking autophagy, overexpression SIGMAR1, or inhibiting lysosomal activity significantly reversed PD-L1 degradation. Notably, we demonstrate for the first time that IFN-gamma-induced PD-L1 directly binds to the FGFR3 promoter and represses FGFR3-TACC3 transcription-an effect that can be rescued by FGFR inhibitors or PD-L1 knockdown. Functionally, FGFR inhibitors ameliorated PD1/PD-L1-mediated T cell suppression in co-culture assays. Together, these findings highlight a novel mechanism by which FGFR inhibitors suppress IFN-gamma-induced PD-L1 via autophagy and suggest a potential strategy to improve ICI therapy in FGFR3-altered NMIBC.

摘要： Aryl hydrocarbon receptor (AhR) interacting protein (AIP) suppresses type I IFN production by interacting with and preventing the nuclear translocation of the transcription factor IRF7. The kinase TBK1 phosphorylates AIP to promote IRF7 binding and the inhibition of the type I interferon (IFN) response. However, it is unknown if AIP expression in innate immune cells is important to suppress type I IFN in the context of RNA virus infection and . In this study we generated myeloid cell-specific AIP conditional knockout mice ( xLysM-Cre) to investigate AIP regulation of innate immune signaling in myeloid cells. Bone marrow-derived macrophages (BMDMs) from xLysM-Cre mice had diminished viral replication and increased production of IFNα/b and IL-6 in response to RNA virus infection. AIP-deficient macrophages exhibited increased IRF7 expression and impaired virus-induced IRF7 degradation. AIP interacted with the E3 ubiquitin ligase SOCS1 and enhanced SOCS1 stability and its interaction with IRF7 to promote the proteasomal degradation of IRF7. xLysM-Cre mice exhibited improved survival upon influenza A virus (IAV) infection compared to control mice. Together, these results indicate that myeloid cell-specific AIP suppresses the innate immune response by targeting IRF7.

摘要： IL-12 mediates innate and adaptive immune responses and has demonstrated therapeutic antitumor activity, but clinical development has been hindered by a narrow therapeutic window. We generated a novel IL-12-anchored drug conjugate by physiochemical linking of murine IL-12 to aluminum hydroxide (alum). The complex was designed to utilize alum as a scaffolding for durable retention of IL-12 within the tumor microenvironment as a strategy to increase the therapeutic window. To better define the systemic pharmacokinetic (PK) profile of the anchored IL-12 (mANK-101), a model-based assessment tool was developed to describe the systemic PK profile and downstream signaling factors following intratumoral injection of mANK-101. When compared with nonanchored IL-12, mANK-101 exhibited a distinct PK profile. Specifically, mANK-101 treatment was associated with a significant ninefold increase in the systemic terminal volume of distribution (Vd). Furthermore, linear mixed-effects models provided evidence that CD8+ T-cell infiltration and increased serum IFN-gamma levels were correlated with tumor regression after a single dose of mANK-101. In addition, PK/pharmacodynamic modeling confirmed a link between systemic IL-12 and serum IFN-gamma. The model also suggests that the anchored IL-12 drug conjugate is expected to prolong the absorption half-life (115 hours vs. 8 hours for the unanchored drug) with durable local retention and limited systemic absorption. In addition, serum IFN-gamma may be a surrogate marker for drug activity. The PK modeling predictions may also contribute to determining the optimal clinical dose and schedule of mANK-101 and other anchored drug conjugates in patients with solid tumors.

摘要： Immunocytokines have emerged as a promising modality in cancer therapy, capitalizing on the precision of antibodies to deliver cytokines selectively to tumours. Yet, the toxicity of the cytokine portion of these antibody-cytokine constructs remains a major dose-limiting issue. We present a new approach to control cytokine function without affecting binding of the targeting moiety. By modifying the cytokine with trans-cyclooctene carbamates at the lysine positions, we can reduce the binding to the receptor of various highly pro-inflammatory cytokines. Then, using a click-2-release (C2R)-approach, we can reactivate the cytokine activity by reacting it with a variety of tetrazines, through a Diels-Alder-pyridazine-elimination cascade. Finally, we show that the caged cytokines can be conjugated via a sortase motif to an unmodified targeting nanobody resulting in a targetable caged immunocytokine construct.