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关键词： Diabetic Nephropathy   Acute Hyperglycemia   Inflammation   Monocyte   TNF alpha   Podocyte   Apoptosis   Vitamin D   GLP-1R Agonists  

摘要： Targeting optimal glycemic control based on hemoglobin A1c (A1c) values reduces but does not abolish the onset of diabetic kidney disease and its progression to chronic kidney disease (CKD). This suggests that factors other than the average glucose contribute to the residual risk. Vitamin D deficiency and frequent episodes of acute hyperglycemia (AH) are associated with the onset of albuminuria and CKD progression in diabetes. This study aimed to determine if moderate levels of AH harm podocytes directly or promote a pro-inflammatory monocyte/ macrophage phenotype that leads to podocyte apoptosis, and whether vitamin D deficiency accelerates these processes. We found that AH (16.7 mM D- glucose) didn't induce podocyte apoptosis directly, but it did promote a pro-inflammatory response in human monocytes and macrophages, resulting in an increased TNF-alpha secretion causing podocyte apoptosis. The AH-induced monocyte TNF-alpha secretion was inversely correlated with healthy donors' serum 25(OH)D levels. AH induced monocyte TNF-alpha release by increasing oxidative and ER stress, which in turn increased ADAM17 (A Disintegrin And Metalloprotease 17) and iRhom2 (inactive Rhomboid protein 2) expression, both essential for TNF-alpha secretion. Additionally, monocyte activation of glucagon-like peptide-1 receptor (GLP-1R), using a GLP-1R agonist, downregulated ADAM17/iRhom2 expression, decreasing TNF-alpha release and reducing podocyte apoptosis. These results show that a normal vitamin D status may attenuate a mechanism by which AH contributes to podocyte apoptosis and CKD progression and might enhance a novel antiinflammatory role of GLP-1 to prevent AH-driven CKD progression in diabetes.

关键词： Huntington's disease   Interleukin 8   CXCL8   IL-8   Cytokines   Chemokines   Neuroinflammation   Inflammation-related markers  

摘要： Objectives: Huntington's Disease (HD) is a debilitating neurodegenerative condition characterized by motor, cognitive and psychiatric abnormalities. Immune hyperactivity and dysregulation are common in HD. In addition to the central nervous system, HD patients exhibit systemic innate immune activation and inflammation, which has been shown to contribute to the pathogenic effects of the Huntingtin gene mutation. Upregulation of inflammatory mediators including interferon gamma (IFN-gamma) and interleukin (IL)-8 has been observed in animal Huntington's disease models. However, studies on HD patients remain limited. Methods: In this study, serum samples from 58 HD patients and 59 age- and gender-matched healthy control individuals were analysed using a bead-based assay, that enabled simultaneous measurement of 13 cytokines and chemokines. Additionally, publicly available transcriptomic data from brain tissues of HD patients and controls were examined. Results: Our results confirm that IL-8 protein levels are significantly higher in HD patients compared to non-HD controls, with the highest levels observed in the moderate HD group. In the control group, we found significant positive correlations between IL-8 levels and both IL-17A and IL-10. However, these correlations were not observed in HD patients, where IL-8 levels were notably positively correlated with pro-inflammatory markers including IFN gamma and IL-23. Interestingly, IL-17A levels demonstrated a negative correlation with disease parameters, including CAG trinucleotide repeat expansion and disease burden score. Furthermore, cytokines and chemokines such as IFN gamma and monocyte chemoattractant protein 1 (MCP-1;CCL2) demonstrated positive correlations with the same disease parameters. In-depth analysis of publicly available bulk RNAseq, and singlenucleus RNA-sequencing (snRNAseq) data from two key HD-affected brain regions- the prefrontal cortex and striatum revealed that IL-8 expression is significantly incre

关键词： IL-10RA   Energy metabolism   FAO   NSCLC   STAT3 signaling pathway  

摘要： Metabolic reprogramming in tumor cells plays a crucial role in promoting cell proliferation and metastasis, and is currently recognized as a significant marker of tumor progression. Interleukin-10 receptor subunit alpha (IL10RA), a member of the type II cytokine receptor family, is predominantly expressed on macrophages and T cells and plays a crucial role in regulating immune cell metabolism and immune response. However, its role in the energy metabolic pathways of tumor cells remains unclear. In this study, we found increased expression of IL10RA in human non-small cell lung cancer (NSCLC), and a correlation between increased IL-10RA expression and tumor stage, tumor size, and short overall survival of patients with NSCLC. IL-10RA overexpression significantly promoted the proliferation of NSCLC cell lines and enhanced glycolysis and fatty acid oxidation (FAO), thereby boosting energy production. Correspondingly, the downregulation of IL-10RA inhibited proliferation, glycolysis, and FAO in NSCLC cell lines. Bioinformatic analyses indicated that IL-10RA upregulates the signal transducer and activator of transcription 3 (STAT3) signaling pathway. STAT3 inhibitor effectively blocked the increase in FAO levels and cell proliferation induced by IL-10RA overexpression. These findings suggest that IL-10RA accelerates NSCLC cell proliferation by increasing FAO levels via the STAT3 pathway, highlighting IL-10RA as a potential therapeutic target for NSCLC.

关键词： oncotherapy   exosome   IL24   NKG2D  

摘要： Natural killer (NK) cell-derived exosomes (NK-Exos) are emerging as a promising avenue in cancer immunotherapy due to their inherent tumor-targeting properties and their capacity to deliver therapeutic agents directly to malignant cells. This research delves into the boosted anti-tumor potency of NK-Exos that has been genetically enhanced to overexpress NKG2D, a vital activating receptor, along with interleukin-24 (IL24), a cytokine renowned for its selective suppressive impact on tumor cells. NKG2D facilitates the recognition of tumor cells by binding to stress-induced ligands, while IL24 induces apoptosis and modulates immune responses to enhance tumor destruction. The NK-Exos engineered to express both NKG2D and IL24 significantly enhanced tumor targeting and increased the apoptosis rate of tumor cells by 30% in A549 and by 20% in HELA at 48 h compared with non-modified NK-Exos, respectively. Furthermore, this enhancement also impacted cell proliferation, with inhibition rates increasing by 30%, 15%, and 15% in A549, HELA, and MCF-7 cells, respectively, and it reduced A549 cell migration by 10%. The integration of NKG2D and IL24 within NK-Exos confers a dual therapeutic mechanism, synergistically amplifying their efficacy in cancer treatment. The utility of NK-Exos co-expressing NKG2D and IL24 offers a novel approach to overcome the limitations of current therapies, providing prolonged tumor suppression and precise targeting of malignant cells and holding great promise for clinical application.

关键词： HLA   HLA-B   new allele   sequencing-based typing  

摘要： The new allele HLA-B*38:114 differs from HLA-B*38:32 by three nucleotide substitutions in exon 3.

关键词： hesperidin   CPT-11   CPT-11-induced diarrhea   metabolomics   16S rRNA sequencing   transcriptomics  

摘要： Irinotecan (CPT-11) is a chemotherapy agent commonly used for the treatment of gastrointestinal tumors, with diarrhea being a frequent adverse effect. Hesperidin is a flavonoid abundant in citrus fruits and has shown potential in managing CPT-11-induced diarrhea (CID). However, the mechanisms underlying its effects remain unclear. This study established a mouse model of CID using CPT-11 administration to evaluate the effects of hesperidin on diarrhea severity, intestinal pathology, gut microbiota composition, and metabolite profiles by conducting biochemical analysis, histopathology, immunohistochemistry, 16S rRNA sequencing, and untargeted metabolomics. In addition, transcriptomic analysis, molecular docking, and molecular dynamics simulations were conducted to investigate potential mechanisms of action. Hesperidin supplementation was found to significantly alleviate CID in mice. Analysis of gut microbiota using 16S rRNA sequencing revealed that hesperidin improved microbial composition, with key taxa such as Alistipes, Limosilactobacillus, Rikenella, and Mucispirillum playing a central role in ameliorating CID. Furthermore, hesperidin enhanced intestinal barrier function by upregulating tight junction proteins, mitigating epithelial damage, and reducing the expression of IL-17A, TARF6, p38, phosphorylated-p38 (P-p38), and AP-1 proteins in the colon. These findings suggest that hesperidin supplementation mitigates CID by modulating gut microbiota and inhibiting the IL-17 signaling pathway, thereby improving intestinal barrier integrity.

摘要： izae282.02

关键词： Ancient DNA   European Neolithic   Population genetics   Admixture   Immune genes   HLA diversity  

摘要： BackgroundThe northern European Neolithic is characterized by two major demographic events: immigration of early farmers from Anatolia at 7500 years before present, and their admixture with local western hunter-gatherers forming late farmers, from around 6200 years before present. The influence of this admixture event on variation in the immune-relevant human leukocyte antigen (HLA) region is *** analyzed genome-wide data of 125 individuals from seven archeological early farmer and late farmer sites located in present-day Germany. The late farmer group studied here is associated with the Wartberg culture, from around 5500-4800 years before present. We note that late farmers resulted from sex-biased admixture from male western hunter-gatherers. In addition, we observe Y-chromosome haplogroup I as the dominant lineage in late farmers, with site-specific sub-lineages. We analyze true HLA genotypes from 135 Neolithic individuals, the majority of which were produced in this study. We observe significant shifts in HLA allele frequencies from early farmers to late farmers, likely due to admixture with western hunter-gatherers. Especially for the haplotype DQB1*04:01-DRB1*08:01, there is evidence for a western hunter-gatherer origin. The HLA diversity increased from early farmers to late farmers. However, it is considerably lower than in modern *** early farmers and late farmers exhibit a relatively narrow HLA allele spectrum compared to today. This coincides with sparse traces of pathogen DNA, potentially indicating a lower pathogen pressure at the time.

关键词： Polyvinylidene fluoride composites   Fused deposition molding   Electrical properties  

摘要： The polar n phase of polyvinylidene fluoride (PVDF) is a desirable material for the fabrication of smart sensor devices, given that PVDF typically exists in its alpha phase under standard conditions. In this study, we developed a method to fabricate high dielectric PVDF composites by incorporating an ionic liquid (IL) modified barium titanate BaTiO3 (BT). This was achieved by leveraging the filling effect of F atoms in PVDF and oxygen vacancies in BT, as well as the ion-dipole interaction between the CF2 of PVDF and the imidazolium cation of IL. These synergistic effects induced a crystalline phase transition in the PVDF, leading to an increase in the content of the polar n-phase to 84.01 % and a peak dielectric constant of 36.3 (100 HZ), which is 4.5 times that of the pure PVDF. Furthermore, it was demonstrated that the n phase content of the composite material remains high during the Fused deposition molding(FDM) process, thereby providing a material foundation for one-time molding of the dielectric material. Based on the above method, the fully 3D printed triboelectric nanogenerator (TENG) has a stable signal output and achieves a balance between device structure and performance. These findings indicate that PVDF/BT/IL holds promise as an electronegative material in the realm of triboelectricity.