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关键词： Calcitriol   Immune system   Cytokine   Vitamin D receptor   Muscle-immune-crosstalk   Immunosenescence  

摘要： Besides its classical skeletal function, vitamin D plays a critical role in both skeletal muscle and the immune system. Interleukin-15 (IL-15), which is highly expressed, and secreted complexed with its receptor, IL-15R alpha, by skeletal muscle, stimulates the development of immune cells and affects myogenesis and muscle mass. However, little is known about possible regulators of this myokine. To test whether vitamin D could be a regulator of muscle IL-15 and IL-15R alpha expression, C2C12 myotubes were treated with vitamin D3 metabolites and analysis were performed in gastrocnemius muscles of rats treated with a single intraperitoneal dose of 1,25(OH)2D3. The role of VDR was investigated by siRNA technique in C2C12 myotubes and in gastrocnemius muscles of vitamin D receptor knockout (Vdr-KO) mice. Treatment of C2C12 myotubes with 1,25(OH)2D3 or 25(OH)D3 increased Il-15 gene expression in a dose-dependent manner and 1,25(OH)2D3 also moderately increased the relative Il-15 protein amount. Rats treated with a single dose of 1,25(OH)2D3 demonstrated a higher mRNA abundance of muscle Il-15 than controls. The 1,25(OH)2D3 effect on Il-15 was considerably weaker in C2C12 myotubes treated with Vdr-specific siRNA. Vdr-KO mice showed significantly lower muscle Il-15 mRNA than WT mice. Il-15Ra mRNA and Il-15/Il-15R alpha protein abundance were unaffected by 1,25(OH)2D3-treatment or VDR functionality, and Cyp27b1 activity is not required for 25(OH)D3-mediated Il-15 gene expression. The results provide evidence for a regulatory role of hydroxyvitamin D3 metabolites on the Il-15 synthesis in skeletal muscle cells, which is largely mediated by the VDR.

关键词： Auto-inflammatory disease   Interleukin 18   Hemophagocytic lymphohistiocytosis   Actinopathies   PSTPIP1   XIAP   CDC42   Still disease  

摘要： Autoinflammatory diseases (AIDs) are conditions characterized by dysfunction of innate immunity, causing systemic inflammation and various clinical symptoms. The field of AIDs has expanded due to improved comprehension of pathophysiological mechanisms and advancements in genomics techniques. A new emerging category of AIDs is characterized by a significant increase in interleukin 18 (IL-18), a pro-inflammatory cytokine synthesized in macrophages and activated by caspase 1 via various inflammasomes. IL-18 plays a role in the regulation of innate and adaptive immunity. IL-18 is involved in various functions, such as the proliferation, survival, and differentiation of immune cells, tissue infiltration of immune cells, polarization of immune responses, and production of other pro-inflammatory cytokines. This review analyzes the literature on IL-18 regarding its functions and its implications in the diagnosis and treatment of AIDs. IL-18-associated AIDs comprise Still's disease and diseases associated with mutations in NLRC4, XIAP, CDC42, and PSTPIP1, as well as IL-18BP deficiencies. With the exception of PSTPIP1-associated diseases, these conditions all carry a risk of macrophagic activation syndrome. Measuring IL-18 levels in serum can aid in the diagnosis, prognosis, and monitoring of these diseases. Therapies targeting IL-18 and its signaling pathways are currently under investigation. (c) 2024 Societe Nationale Francaise de Medecine Interne (SNFMI). Published by Elsevier Masson SAS. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

关键词： Common cancer antigen   Cancer-specific antigen   Cytotoxic T lymphocyte (CTL)   Peptide vaccine   mRNA vaccine   HLA-A24   HLA-A2  

摘要： Targeting cancer antigens expressed in cancer cells is necessary to develop cancer-specific immunotherapy. We have performed immunohistochemical analysis of various solid cancer specimens, adding ROBO1, AFP, TGFBI, EphB4, CLDN1, and LAT1 to the previously studied glypican-3 (GPC3), HSP105 alpha, FOXM1, and SPARC, and found that these 10 common cancer antigens are sufficient to cover most solid cancers. These antigens were frequently expressed in various solid cancers but shown to be rarely ex-pressed, with some exceptions, in non-cancerous normal organs adjacent to the cancer. In this study, we predicted 72 and 73 peptides that bind to HLA-A24 and -A2 in silico from the full-length amino acid sequences of these 10 common cancer antigens and immunized each HLA transgenic mouse with a cocktail of synthesized peptides together with the poly I:CLC three times weekly to analyze the antigen-specific immune response. As a result, 68 peptide sequences (30 and 38, respectively) were identified that had higher cytotoxic T lymphocyte (CTL) induction ability than GPC3 298-306 and GPC3 144-152 used in the clinical trials. Furthermore, experiments with cocktail peptide vaccines using mouse models expressing subcutaneous tumors of each antigen showed promising results in terms of safety and efficacy. These peptides identified in this study, derived from 10 common cancer antigens covering all solid cancers, are expected to be clinically applicable as cocktail peptide vaccines.

关键词： colorectal cancer   DMH   JAK2   linagliptin   rats   STAT3  

摘要： Colorectal cancer (CRC) is a multicomponent disease and the second most frequent root of cancer-related deaths globally. Linagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor. It has been repurposed in recent experimental studies due to its marked anti-inflammatory activities. This study aimed to evaluate the ameliorative role of linagliptin in 1,2-dimethylhydrazine (DMH)-induced CRC via modulation of NFAT-mediated IL-6 and JAK2/STAT3/NF-kappa B signaling pathways. CRC model has been successfully established via a dose equal 40 mg/kg two times a week of DMH for 8-week duration. Twenty-four Wistar rats were segregated into three groups of eight rats each;normal control, DMH-induced CRC and DMH + linagliptin (10 mg/kg;p.o). Linagliptin attenuated DMH-induced oxidative stress by restoring the declined levels of some antioxidant enzymes. Linagliptin suppressed the elevated nuclear factor kappa B (NF-kappa B) induced by DMH which is highlighted using immunohistochemistry analysis. The anti-inflammatory role of linagliptin has been fortified by the decline in nuclear factor of activated T-cells (NFAT) mRNA expression level along with the reduction in vascular endothelial growth factor (VEGF), interlukin-6 (IL-6) and cyclooxygenase-2 (COX-2) levels. Linagliptin mitigate the protein expression of DMH-activated oncogenic janus-activated kinase/signal transducers and activators of transcription (JAK2/STAT3). Linagliptin exerted a proapoptotic effect to tumor cells manifested by a remarkable decline in B-cell lymphoma 2 (Bcl-2) and a significant elevation in Bcl-2-associated X protein (Bax) expression levels. The histopathological analysis revealed that linagliptin has inhibitory potential against the DMH induced dysplastic aberrant crypt foci (ACF) and adenocarcinoma. Linagliptin ameliorated CRC by modulating NFAT-mediated IL-6 with JAK2/STAT3/NF-kappa B signaling cascades.

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.