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关键词： Innate lymphoid cells (ILCs)   Leprosy   ILC1   ILC3   CCR6   IL-17   IFN-g  

摘要： Leprosy is a skin disease caused by Mycobacterium leprae, characterized by both localized and generalized immune responses. Th1/17 lymphocytes play a crucial role in the immune response against M. leprae. However, adaptive immunity alone is not sufficient to completely eradicate the pathogen, suggesting the involvement of other innate immune cells in pathogen removal. Therefore, we investigated innate lymphoid cells (ILCs), which are the innate counterparts of helper T cells in adaptive immunity and are known to produce IFN-gamma and IL-17. In the present study, we evaluated the expression of ILC1 and ILC3 in borderline tuberculoid (BT) and lepromatous leprosy (LL) lesional skin by flow cytometry and real time PCR. Further, the expression of various in-situ genes, including cytokines, chemokines, cytokine receptors chemokine receptors, and transcription factors by qPCR in skin lesions of leprosy patients were analyzed. The phenotypes of ILC1 and ILC3 cells were determined as CD3negCCR6+CD19negIFN-gamma+ and CD3negCCR6+CD19negIL-17A+, respectively, by flow-cytometry analysis. BT skin lesions represents high CCR6+expression on total ILCs as compared to LL patients. Our results clearly indicate that ILC1 and ILC3 were highly expressed in skin lesions of BT as compared to LL leprosy patients. Moreover, we observed that double positive (DP) CD3negCCR6+CD19negIFN-gamma+IL-17A+ ILCs were up-regulated in LL and showed a pathogenic role. The gene expression of IL-17A and IFN-gamma were found to be significantly positively correlated with the percentage of CCR6+ ILCs. On the other hand, CCR6neg ILCs were negatively correlated with ILC1 and ILC3 associated markers. Summarily our results clearly suggest that both ILC1 and ILC3 are important and immune-protective, on the contrary DP (IFN-gamma+IL-17A+) ILCs may promote progression and immunopathology of leprosy.

关键词： Juvenile idiopathic arthritis   HLA class II alleles   treatment response   disease activity   prognostic marker  

摘要： to expedite the dissemination of scientific findings to the research community as soon as possible after acceptance following peer review and corresponding modification (where appropriate). An "Advanced Online" manuscript is published online prior to copyediting, formatting for publication and author proofreading, but is nonetheless fully citable through its Digital Object Identifier (doi (R)). Nevertheless, this "Advanced Online" version is NOT the final version of the manuscript. When the final version of this paper is published within a definitive issue of the journal with copyediting, full pagination, etc., the new final version will be accessible through the same doi and this "Advanced Online" version of the paper will disappear.

关键词： Mammary adipose tissue   Breast cancer   Inflammation   NF-kappa B   Nuclear receptor coactivator 3  

摘要： In breast cancer, adipocytes are the predominant cell type in the microenvironment, and the continuous communication between these tissues alters the adipose phenotype. However, molecular mechanisms promoting these changes are still poorly understood. Previously, we demonstrated that NCoA3 expression is increased in adipose tissue adjacent to breast cancer and that this increase is associated with an inflammatory profile. This study aimed to investigate the mechanisms underlying NCoA3 expression in adipocytes within the breast tumor microenvironment. We demonstrated that breast cancer-secreted TNF increases NCoA3 expression in adipocytes, and this upregulation is dependent on NF-kappa B transcriptional activity. Furthermore, the use of a TNF blocker prevented both coactivator overexpression and macrophages recruitment, mimicking the effects observed when NCoA3 expression was downregulated using a short hairpin RNA. These findings shed light on the molecular mechanisms by which breast cancer cells modulate adipocyte behavior, identifying NCoA3 as a key mediator in the tumor-adipose tissue crosstalk. Targeting this pathway through TNF inhibition offers promising therapeutic strategy to attenuate tumor-associated inflammation and potentially improve outcomes in breast cancer patients.

关键词： Cancer   Core/shell nanoparticles   Radio-sensitizer   Drug delivery   TNF-alpha  

摘要： Targeted nanostructures by local transferring the immuno-/chemo-therapy drugs to the tumor tissues and the other hand enhancing the impact of radiotherapy, can increase the efficiency of treatment. The aim of this study was to synthesize Fe3O4@Au and Fe3O4@Ag core/shell NPs and then loading them with TNF-alpha in order to overcome the systemic toxicity of TNF-alpha and then to investigate the effect of the final nano-systems in radiotherapy of MDA-MB-231 breast cancer cell-line. TNF-alpha-Fe3O4@Au and TNF-alpha-Fe3O4@Ag nano-systems were synthesized. Then, various characterization tests were performed. To investigate the anticancer effects of the nano-systems, Cell uptake, MTT, ROS, and DAPI staining tests were carried out. One-way analysis of variance was performed. The hydrodynamic diameter of Fe3O4@Au and Fe3O4@Ag NPs was 73.39 nm and 46.91 nm, and the zeta potential was-30.6 mV and-17.3 mV, respectively. Also, the TEM images showed diameters of about 24 nm and 20 nm, respectively. The correct synthesis of nanoparticles (NPs) was confirmed by FT-IR and the successful loading of TNF-alpha on the surface of NPs was confirmed by UV-vis. The results of the MTT assay showed that although TNF-alpha alone causes the proliferation of MDA-MB-231 cell-line, it increases cell death in the presence of radiation. Also, the anticancer effects and increased radiation sensitivity of NPs and final nano-systems were confirmed by MTT and DAPI tests. In this study, the final TNF-alpha-Fe3O4@Au and TNF-alpha-Fe3O4@Ag nano-systems led to a greater increase in radio-sensitivity and greater radiation effectiveness than Fe3O4@Au and Fe3O4@Ag NPs alone.

关键词： Interleukin-6   Molecularly imprinted polymer   Electrochemical sensor   Lipopolysaccharide   Point-of-care  

摘要： Interleukin-6 (IL-6) is a multifunctional cytokine that plays a key role in driving proinflammatory responses in a wide range of acute, chronic, and infectious diseases. Therefore, it is of practical importance to monitor the IL-6 level of individuals in disease diagnosis and healthcare. Currently, there is an urgent need for developing rapid, cost-effective diagnostic and prognostic sensing systems. Herein, we developed a molecularly imprinted polymer (MIP)-based electrochemical sensor for IL-6 detection. The results showed that the MIP sensor demonstrated high sensitivity in the trace of IL-6 concentration, with a limit of detection of 31.3 fM and a wide dynamic range of 100 fg/mL to 1 mu g/mL. Moreover, the MIP sensors are highly selective for IL-6, compared to other inflammatory cytokines (Interleukin-1 beta, transforming growth factor-beta 3, and tumor necrosis factor-alpha) and various interfering biomolecules (glucose, human serum albumin, fibrinogen, and lactic acid). We also confirmed that the MIP sensors maintained robust stability over three weeks without appreciable deterioration. The performance of the MIP sensors was validated using a lipopolysaccharide-induced cellular senescence model, emphasizing its potential as a point-of-care tool for IL-6 monitoring. The results suggest that our MIP-based IL-6 sensor could serve as an effective point-of-care tool in quantifying age-related physiological changes and monitoring low-grade systemic inflammation.

关键词： Chronic stress intensity   Depression severity   Behavior   Cortisol   Inflammatory factors  

摘要： Backgrounds: The etiology of depression involves chronic stress, a recognized determinant of onset and severity. This study adopts a translational approach, utilizing a mouse model and a clinical cohort to explore the relationship between chronic stress, molecular changes, and depression severity. Methods: In the mouse model, mice were exposed to varying frequencies of chronic stressors over several weeks, followed by behavioral assessments to confirm depressive-like behaviors and measurement of serum indicators to analyze their relationship with stress intensity. In the clinical cohort, we recruited 239 participants, including 137 patients with diagnosed depression and 102 healthy controls, and analyzed their plasma profiles for cortisol and inflammatory cytokines. The clinical cohort revealed distinctive plasma profiles, identifying cortisol and IL17 as potential markers. Machine learning models were developed using these markers to distinguish depression severity. Results: The study revealed subtle behavioral-molecular changes in mice subjected to varying chronic stress intensities, confirming dose-response relationships. It identified cortisol and IL-17 as potential biomarkers for distinguishing depression severity and developed machine learning models demonstrating robust diagnostic capabilities. Limitations: There is a substantial disparity in the number of individuals among different groups in the clinical participants. Conclusion: The study establishes a correlation between cortisol, IL-17, and chronic stress intensity, suggesting the latter accelerates depression progression. Cortisol and IL-17 exhibit diagnostic potential, providing insights into depression progression and guiding targeted interventions. This research advances our understanding of stress-induced molecular changes in depression, contributing to the comprehension of the intricate relationship between chronic stress, molecular alterations, and depression severity.

关键词： IL-2   IL-2 receptor alpha   IL-2 receptor beta &   gamma   Inclusion body   Refolding   Assay validation  

摘要： IL-2 is a potent cytokine that promotes multiple immune cells proliferation and activation. Accordingly, IL-2 based immunotherapies are emerging to treat cancers or AIDS by enhancing T cell growth and function. Besides, IL-2 is indispensable in in vitro cultivation of immune cells which is a critical step of CAR-T or CAR-NK immunotherapies. In bulk manufacturing of recombinant IL-2, E. coli expression system has several advantages such as low cost and rapid growth. However, high level protein expression in prokaryotic organisms often results in inactive insoluble aggregates, also known as inclusion bodies. It is crucial and most challenging work to solubilize and refold the protein of interest from inclusion bodies to generate its bioactive form. While multiple spectrum method had been applied to monitor the refolding process, the question of how to measure the refolding efficiency from the perspective of its biological function remained unaddressed. Here we present a receptor-based sandwich ELISA method to evaluate the bioactive product in samples and provide a guidance for manufacturing bioactive rhIL-2 (recombinant human IL-2) with prokaryotic expression system. Compared to traditional antibody-based ELISA method, this novel approach truly measures the presence of functional rhIL-2 and also potentially allows the detection of rhIL-2 variants with modifications like PEGylation as it doesn't rely on the exact amino acid sequence.

关键词： Diamine oxidase   IFN-gamma   NK cells   Inflammation  

摘要： Aims: Diamine oxidase (DAO), a well-established biomarker for intestinal damage, histamine intolerance or tumorigenesis, has rarely been reported in immune regulation. This study aimed to identify DAO as a critical enhancer of abnormal inflammation by promoting interferon-gamma (IFN-gamma) production from natural killer (NK) cells. Main methods: Clinical bioinformatics analyzed aoc1 (DAO-coding gene) expression in PBMCs from patients with inflammatory diseases. Murine models (LPS-induced systemic inflammation, sepsis, DSS-induced colitis) using DAO-/- mice, alongside DAO-/- NK92 cells and DAO inhibitor DIZE, were employed for phenotypic validation. Cellular profiling, bone marrow chimeras, reciprocal transplantation, RNA-sequence, non-targeted metabolomics, and flow cytometry were utilized to dissect DAO's mechanisms in NK cells. Key findings: DAO deficiency protected mice from inflammatory pathology by suppressing IFN-gamma production. NK cells were identified as the primary target cells during the process, with DAO acting intracellularly to promote IFN-gamma via a reactive oxygen species (ROS)-autophagy axis. DAO-derived ROS, distinct from mitochondrial or NOX2 sources, enhanced autophagic flux during NK activation, enabling IFN-gamma biosynthesis. DAO did not affect NK homeostasis, including maturation, proliferation, or receptor expressions. Significance: DAO is a novel risk factor in inflammatory diseases, driving IFN-gamma production through ROSautophagy signaling in NK cells. Targeting DAO may offer therapeutic strategies for conditions involving dysregulated IFN-gamma responses, including sepsis, colitis, and autoimmune disorders.

关键词： Ionic Liquid mediated green synthesis   Microwave Irradiation   Van Leusen cycloaddition   Molecular Docking   Biological evaluation   DFT studies  

摘要： A novel, efficient, and facile protocol for the green synthesis of a series of various 3,4-disubstituted pyrroles via the Van-Leusen [3+2] cycloaddition of tosyl methyl isocyanide (TosMIC) and chalcones has been demonstrated under microwave irradiation conditions using an ionic liquid system viz. [PAIM][Cl]/[BMIM][X] as an environmentally benign reaction medium. The distinctive characteristics of this work include attractive features such as IL-mediated C-C bond formation, short reaction time, energy-efficient microwave irradiation, recycling, and reuse of ionic liquids, wide substrate scope, etc. Further, the in vitro antimicrobial potential of these analogues was examined against four bacterial and six fungal strains using the broth microdilution method. Among the 26 compounds, analogues bearing peripheral chloro, fluoro, methoxy, and nitro substitutions indicated good to excellent antimicrobial activities with a minimum inhibition concentration (MIC) up to 2 mu g/mL, combating microbial infections. To understand the structure-activity relationship (SAR), molecular docking and density functional theory (DFT) studies were also carried out, and the results were in good agreement with the antimicrobial activity profiles.

关键词： 干细胞   卵巢颗粒细胞   衰老   机制   氧化应激   抑制凋亡   细胞因子   抗氧化   抗炎症反应  

摘要： 背景:干细胞疗法作为一种新兴的治疗手段,有望改善卵巢环境,延缓卵巢颗粒细胞的衰老,为高龄妊娠女性带来新的希望。目的:综述干细胞抗卵巢颗粒细胞衰老的机制及研究进展。方法:检索中国知网和PubMed数据库中关于干细胞抗卵巢颗粒细胞衰老的文献,以“干细胞,卵巢颗粒细胞,衰老”为中文检索词,以“stem cells,ovary granulosa cells,aging”为英文检索词,最终纳入67篇文献进行分析。结果与结论:①总结了5种卵巢颗粒细胞衰老的机制:DNA损伤和修复能力下降、氧化应激、线粒体功能受损、炎症反应、激素水平变化;②整理了当前干细胞治疗卵巢颗粒细胞衰老的5种机制:促进增殖和抑制凋亡、分化潜能及再生能力、分泌因子、抗氧化、抗炎症反应和免疫调节;③目前有多种类型的干细胞可通过多种方式协同治疗卵巢颗粒细胞衰老,干细胞疗法在恢复女性生育能力方面具有广阔前景。