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关键词： Acute duodenal injury   Alcohol   Ampelopsis grossedentata   Apoptosis   Ethnopharmacology   TNF-a  

摘要： Ethnopharmacological relevance Ampelopsis grossedentata (AG) is a popular folk tea that has been used in China for more than 1000 years. It is noteworthy that AG is widely recognized for preventing alcohol hangover in folk, and its protective effects on alcohol-induced hepatic steatosis have been demonstrated. Aim of the study Alcohol overconsumption can induce acute duodenal injury (ADI) that lacks effective therapeutic strategies. This study investigated the gastrointestinal protective effects of AG on alcoholic ADI in mice. Materials and methods AG extract was chemically characterized by HPLC analysis. Institute of Cancer Research (ICR) mice were pre-administered AG extract via gavage, and then subjected to an ethanol-induced ADI. After treatment, duodenal tissues were stained with hematoxylin and eosin (H&E), and cell apoptosis was detected by TUNEL staining and immunofluorescence. Untargeted metabolomics was employed to identify the differentially expressed metabolites, and the gene expressions of duodenal tissues were determined using RNA sequencing, immunofluorescence, immunohistochemistry, and western blotting. Results Acute ethanol administration caused severe duodenal damage, characterized by necrosis and shedding of duodenal villi, hemorrhagic injury, mucosal edema, and disruption of intestinal barrier in mice, which was improved by the pre-treatment with AG extract. Notably, administration of AG aqueous extract suppressed ethanol-induced duodenal villous apoptosis in mice by inhibiting caspase-3/7. In addition, untargeted metabolomics data showed AG extract improved ethanol-induced disruption of amino acid biosynthesis and metabolism, and increased the levels of amino acids, such as L-serine, L-histidine, L-leucine, L-glutamine and L-tryptophan. RNA sequencing analysis revealed that ethanol intake activated TNF, IL-17, MAPK and apoptosis pathways, and these pathways were inhibited by AG extract pre-treatment. Immunofluorescence and immunohistochemistry r

关键词： Anti-apoptosis   Autonomous proliferation   CAR-NK cells   Membrane-bound IL-2 or IL-15   Tumor cytotoxicity  

摘要： Chimeric antigen receptor (CAR)-engineered natural killer (NK) cells hold promise for off-the-shelf cancer immunotherapy, yet their clinical application is hindered by poor persistence due to cytokine dependency and systemic toxicity from exogenous cytokine support. Here, we developed membrane-bound cytokine (mbCytokine) modules to enable autonomous survival signaling in CAR-NK cells. By fusing IL-2, IL-15, or the potent mimic Neo-2/15 to their cognate receptor α-chains (IL-2Rα or IL-15Rα), we generated self-sustaining CAR-NK92 cells that bypass reliance on external cytokines. Among these constructs, membrane-bound IL-2 (mbIL2) demonstrated superior efficacy, driving robust proliferation and resistance to apoptosis under serum-free conditions. Notably, mbIL2-armored CAR-NK cells exhibited enhanced cytotoxicity against MICA/B-expressing tumor cells. Mechanistically, mbIL2 mitigated activation-induced apoptosis and suppressed exhaustion during tumor engagement, thereby sustaining NK cell viability. These findings establish mbIL2 as a critical enhancer of CAR-NK cell persistence and antitumor function, offering a clinically translatable strategy to overcome the limitations of cytokine-dependent therapies.

关键词： Gentiana lutea   NMR spectroscopy   HPLC-DAD   Liqueurs   Traditional use   Anti-Inflammatory activity   ex vivo   study   D   2   O   Deuterated water   TSPA   3-(trimethylsilyl)-propionic-2,2,3,3   d   4   acid sodium salt   DW   dried weight   SD   standard deviation   TBZ   3,4,5-trimethoxybenzaldehyde   TUFA   tri-unsaturated fatty acids   DUFA   di-unsaturated fatty acids   MUFA   mono-unsaturated fatty acids   SFA   saturated fatty acids   STE   β   sitosterol   IL-6   interleukin 6   TNF   α   tumor necrosis alpha   IL-10   interleukin 10   IBD   Inflammatory Bowel Disease  

摘要： Ethnopharmacological relevance Gentiana lutea L. is a mountain herb with a long-standing use in traditional European medicine, especially for digestive disorders and for its antiseptic and anti-inflammatory properties. Its roots are also traditionally used in the preparation of regional liqueurs, particularly in Central Italy. Aim of the study This study aimed to characterize the phytochemical composition of Gentiana lutea roots from the Pollino National Park and assess the potential intestinal anti-inflammatory effects, using an ex vivo model, of an hydroalcoholic extract mimicking the traditional Italian Gentiana liqueur. Materials and methods Roots were collected from the Pollino National Park, extracted and subjected to HPLC-DAD and NMR-based metabolomic analysis for complete phytochemical characterization. A Gentiana hydroalcoholic liqueur analogue was prepared, chemically characterized and its anti-inflammatory activity was evaluated ex vivo on LPS-stimulated murine colon tissue. Results Phytochemical analyses revealed high levels of bioactive secoiridoids (gentiopicroside, swertiamarin, amarogentin, sweroside), iridoids (loganic acid), and xanthones (isogentisin). NMR metabolomics further identified sugars (sucrose predominant), organic acids (notably malate), amino acids (asparagine, glutamine, tyrosine, aspartate as major ones), and lipid components including β -sitosterol and various fatty acids. The Gentiana hydroalcoholic liqueur analogue retained relevant concentrations of swertiamarin, loganic acid, sweroside, and isogentisin, despite its milder extraction conditions. The hydroalcoholic extract significantly reduced LPS-induced expression of pro-inflammatory cytokines IL-6 and TNF- α , while upregulating IL-10 expression in colon tissues, suggesting a potent immunomodulatory effect. Conclusion These findings provide scientific support for the traditional use of Gentiana lutea roots in digestive health and highlight their potential as sources of functio

关键词： islets of Langerhans   diabetes   immune tolerance   islet organoids   HLA   CP: Immunology   CP: Metabolism  

摘要： The immune protection of pancreatic β cells has three layers: anatomical, with their distribution in 1 million islets; central, with the thymic deletion of β cell-specific T cells; and peripheral, with inhibitory cellular networks. The failure of the latter leads to most spontaneous type 1 diabetes and all diabetes induced by checkpoint inhibitor therapy. Because CD4 T cells initiate disease, major histocompatibility complex (MHC) class II-expressing cells are central to the onset. In non-diabetic mouse and human islets, two such cells were detected outside of the islet boundaries near the efferent post-capillary venules: one related to the vasculature and a fibroblast referred to as a “vascular-associated fibroblast” (VAF). Functionally, primary VAFs spontaneously presented islet antigens to CD4 T cells and expressed high levels of inhibitory B7 receptors and no costimulatory receptors. VAFs induced anergy in primary pre-activated anti-islet CD4 T cells. VAFs are likely important to protect the endocrine pancreas from autoimmunity.

关键词： Engineered exosomes   Macrophage polarization   Interferon-gamma (IFN gamma)  

摘要： Macrophages are part of the immune system and play a complex role in the development of cancer. Tumor-associated macrophages (TAMs) exhibit dynamic plasticity between pro-tumorigenic (M2) and antitumorigenic (M1) phenotypes, presenting a promising therapeutic target for cancer immunotherapy. While pharmacological modulation of M2 to M1 repolarization shows therapeutic potential, current cytokine delivery strategies face critical challenges including non-specific macrophage clearance. To address these limitations, we developed an engineered exosome system (EXO-IFN gamma) through efficient loading of interferon-gamma (IFN gamma) into THP-1 macrophage-derived exosomes. Functional investigations demonstrated that EXO-IFN gamma effectively reprogrammed human peripheral blood mononuclear cells (PBMCs) derived M2 macrophages toward the M1 phenotype, exhibiting significantly superior polarization-modulating capacity compared to free IFN gamma. To elucidate the therapeutic implications of phenotypic conversion, the bioactivity of conditioned medium (CM) derived from repolarized M1 macrophages was evaluated. The conditioned medium from repolarized M1 macrophages demonstrated potent tumor-suppressive activity, effectively inhibiting tumor cell growth and migration. Notably, the engineered exosomal delivery system demonstrated unique sustained payload release properties, endowing EXO-IFN gamma generated CM with prolonged bioactivity compared to the CM produced by using IFN gamma alone. Thus, EXO-IFN gamma is a new macrophage polarization strategy to achieve good tumor cell killing effect by combining chemotherapy and immunotherapy.

关键词： Ovarian ischemia reperfusion   Eplerenone   Aldosterone   Toll like receptor4   Fenofibrate   Peroxisome proliferator activated receptor   alpha  

摘要： Background: The immune system is deeply involved in the pathogenesis of different gynecological disorders including ovarian torsion that commonly occurs during surgical manipulation or within ovarian masses, affecting not only the ovaries, but it has remote effect on different organs particularly cardiac tissue. Early intervention and proper medical treatment are so important to preserve the ovaries and prevent distant organ damage. Accordingly, the aim of this work was to evaluate the possible ameliorative role of eplerenone (EPL) or fenofibrate (FEN) on ovarian and cardiac affection in an experimental model of ovarian ischemia/reperfusion (OIR). Method: Fifty female Wistar albino rats were divided into five groups (n = 10);control, OIR induced group, OIR plus EPL (100 mg/kg), OIR plus FEN (300 mg/kg), OIR plus EPL (100 mg/kg) plus FEN (300 mg/kg). Results: OIR could induce ovarian injury with remote cardiac damage. Data of current study revealed significant increases of the cardiac enzymes, and malondialdehyde (MDA) levels but decreases of total anti-oxidant capacity (TAC) and reduced glutathione (GSH) levels. Moreover, there were increases in toll like receptor 4 (TLR4), myeloid differentiation primary response 88 (MYD88), activation protein 1 (AP1), interleukin 6 (IL-6), nuclear factor kappa b (NF-kappa B) and cleaved caspase-3 with abnormal histological features. However, EPL or FEN co-administration alone or in combination reversed OIR damaging effects by antagonizing aldosterone action by EPL, anti-inflammatory, anti-oxidant, and anti-apoptotic features with modulation of peroxisome proliferator activated receptor alpha (PPAR alpha) by FEN and TLR4/MYD88/ NF-kappa B/AP1/IL-6 pathway. Interestingly, co-administration of both drugs showed more improvement than giving each one alone. Conclusion: EPL and/or FEN had ameliorative properties against OIR induced harmful effects.

关键词： Oral squamous cell carcinoma   Chronic kidney disease   TNF-alpha plus neutrophils  

摘要： Background and aims: The risk of cancer in patients with chronic kidney disease (CKD), particularly in those on dialysis is high. However, the underlying mechanism remains unclear. Moreover, the involvement of CKD in the progression of oral squamous cell carcinoma (OSCC) is still not fully understood. In this study, we aimed to investigate the role and mechanism of CKD in OSCC. Methods: The correlation between peripheral blood cell analysis and clinical characteristics was tested in patients with OSCC with CKD or non-CKD. Immune cell infiltration in the tumor microenvironment of OSCC was assessed using multicolor immunofluorescences. In addition, a mouse model of OSCC under CKD conditions was established and the effect of CKD on tumor growth was examined. Single-cell RNA sequencing (scRNA-seq) was performed using fresh tumor samples obtained from the mouse model. The interactions between OSCC cells and neutrophils were evaluated in vitro. Results: A cohort of 52 patients with OSCC was included in the study, among whom 23 had CKD. Patients in the CKD group showed a significant decrease of lymphocyte counts in peripheral blood compared with those in the non-CKD group. Furthermore, patients with CKD exhibited more aggressive lymph node metastasis than did those in the non-CKD group. The subcutaneous tumor mouse model under CKD conditions showed greater proliferative capacity than did the non-CKD group. The scRNA-seq results indicated that the percentages of neutrophils and T lymphocytes were decreased in the tumor tissues of CKD mice compare to non-CKD mice. A total of five neutrophil subpopulations were identified in the tumor microenvironment, including Hexb+, tumor necrosis factor-alpha + (TNF-alpha+), Retnig+, Cxcl10, and CD74 neutrophils. Among these, the proportion of TNF-alpha + neutrophils significantly decreased, which inhibited proliferation and promoted apoptosis via releasing TNF-alpha + in OSCC cell lines. In addition, a total of ten lymphocyte subpopulati

关键词： HIV reservoir   spatial transcriptomics   lymph node immune regulation   CD8 T cell regulation   HLA-E   CP: Immunology  

摘要： B cell follicles (BCFs) in the lymph node are a major sanctuary for HIV reservoirs. Immune regulatory mechanisms hindering cytolytic CD8 + responses at these sites are poorly characterized, likely enabling HIV persistence. Spatial transcriptomics and high-dimensional histocytometry were used to define CD8 + T cell function and immune regulation in lymph node (LN) follicles of people living with HIV (PLWH), at various stages of antiretroviral therapy (ART) treatment. Histocytometry demonstrated that CD8 + T cells infiltrating BCFs mostly lacked granzyme B expression, coinciding with reduced chromatin access at cytolytic gene loci in dissociated lymph node cells. Spatial transcriptomics confirmed the immune regulatory microenvironment of HIV-infected BCFs, particularly exhibiting upregulation of HLA-E. Additional fluorescence-activated cell sorting (FACS) analysis identified a subset of LN CD8 + T cells expressing the NKG2A-interacting partner of HLA-E, with reduced granzyme B expression. These findings suggest that regulation of follicular CD8 + T cells at the HLA-E-NKG2A axis may be a key mechanism for HIV immune evasion.

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： Biochemistry   Cell biology  

摘要： trans- Fatty acids (TFAs) have been associated with various inflammatory diseases, including atherosclerosis and metabolic syndrome, such as metabolic dysfunction-associated steatotic liver disease (MASLD)/metabolic dysfunction-associated steatohepatitis (MASH). However, the underlying mechanism remains unclear. Here, we show that in response to DNA damage, elaidic acid (EA), a most common TFA, amplifies interleukin-1 receptor (IL-1R) signaling, leading to the promotion of cellular senescence and senescence-associated secretory phenotype (SASP). Upon DNA damage, EA enhanced senescence-associated β-galactosidase activity and expressions of IL-1α/6/8 through the IL-1R-transforming growth factor-β-activated kinase 1 (TAK1)-nuclear factor (NF)-κB axis in a manner dependent on mammalian target of rapamycin (mTOR). Mechanistically, EA, incorporated into lipid rafts, enhances IL-1R activation and subsequent NF-κB signaling, creating a positive feedback loop. EA consumption elevated expressions of SASP factors and cellular senescence in the livers of high-fat diet mice. Our findings provide a mechanistic insight into TFA-related inflammation and disorders, including MASLD/MASH.