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关键词： Neuroinflammation   Retinal microglia   IL-1beta   Cytokine release   NLRP3 inflammasome   Astrocyte   Age-dependent neurodegeneration   Glaucoma  

摘要： The P2X7 receptor (P2X7R) for extracellular ATP is implicated in several forms of retinal degeneration, including diabetic retinopathy, age-related macular degeneration, and glaucoma. P2X7R stimulation can trigger release of master cytokine IL-1(3 from microglia in the brain and from macrophages, but evidence of release from retinal microglia is indirect. Isolated mouse and rat retinal microglia, and wholemounts from Cx3CR1+/GFP mice, were examined to determine if ATP induced IL-1(3 release directly from retinal microglial cells and if it also primed expression of IL-1(3 on an mRNA and protein level. Isolated retinal microglia were ramified and expressed low levels of polarization markers unless provoked. Over 90% of isolated microglial cells expressed P2X7R, with cytoplasmic Ca2+ elevation following receptor stimulation. ATP induced a dose-dependent release of IL-1(3 from primed microglial cells that was blocked by P2X7R antagonist A839977 and emulated by agonist BzATP. P2X7R stimulation also primed Il1b mRNA in isolated microglia cells. BzATP increased IL-1(3 immunostaining and GFP fluorescence throughout lamina of retinal wholemounts from CX3CR1+/GFP mice. Some of the IL-1(3 and GFP signals colocalized, particularly in the outer retina, and in projections extending distally through photoreceptor layers. The inner retina had more microglia without IL-1(3, and more IL-1(3 staining without microglia. Substantial IL-1(3 release was also detected from rat retinal microglial cells, but not optic nerve head astrocytes. In summary, this study implicates microglial cells as a key source of released IL-1(3 when levels of extracellular ATP are increased following retinal damage, and suggest a greater participation in the outer retina.

关键词： plaque psoriasis   FOXP3 variants   Tregs   IL-10   TGF-beta 1  

摘要： Plaque psoriasis (PP) is a chronic immune-mediated skin disorder with a genetic basis, characterized by abnormal T-cell responses. This study investigated the role of FOXP3 gene variants rs2280883 and rs3761548 in T-cell regulation through their effects on IL-10 and TGF-beta 1 cytokine levels and their association with PP risk. A case-control study was conducted, including 101 individuals with PP and 106 healthy controls from the Mexican population. Genotyping of FOXP3 variants was performed using PCR-RFLP, and cytokine levels were measured with ELISA kits. Significant differences in allele and genotype frequencies of the rs2280883 variant were observed between PP patients and controls, suggesting an association with an increased risk of PP. IL-10 levels were found to be elevated in PP patients, regardless of FOXP3 gene variants, indicating that cytokine dysregulation in PP may involve alternative pathways independent of FOXP3-mediated regulatory T-cell (Treg) function. No significant differences were detected in TGF-beta 1 levels or rs3761548 genotype frequencies across the study groups. In conclusion, the rs2280883 variant in the FOXP3 gene is significantly associated with a higher risk of developing PP in the Mexican population, while dysregulated IL-10 levels suggest a complex cytokine interaction beyond Treg activity.

关键词： Cardiovascular progenitor cells   Inflammation   Interferon-gamma   Multi-omic analysis   Regulatory network  

摘要： The regulatory mechanisms underlying the response to pro-inflammatory cytokines in cardiac diseases are poorly understood. Here, we use iPSC-derived cardiovascular progenitor cells (CVPCs) to model the response to interferon gamma (IFN gamma) in human cardiac tissue. We generate RNA-seq and ATAC-seq for four CVPCs that were treated with IFN gamma and compare them with paired untreated controls. Transcriptional differences after treatment show that IFN gamma initiates an innate immune cell-like response, shifts the CVPC transcriptome toward coronary artery and aorta profiles, and stimulates expression of endothelial cell-specific genes. Analysis of the accessible chromatin shows that IFN gamma is a potent chromatin remodeler and establishes an IRF-STAT immune-cell like regulatory network. Finally, we show that 11 GWAS risk variants for 8 common cardiac diseases overlap IFN gamma upregulated ATAC-seq peaks. Our findings reveal insights into IFN gamma-induced activation of an immune-like regulatory network in human cardiac tissue and the potential role that regulatory elements in this pathway play in common cardiac diseases.

关键词： virus microenvironment   viral infection   intercellular communication   cell-to-cell communication   extracellular vesicles   secreted proteins   secretome   secreted metabolites   cell surface   surfaceome   extracellular matrix   spatial profiling   multiplexed imaging   proteomics   microenvironment labeling   APC   antigen presenting cell   EBV   Epstein-Barr virus   ECM   extracellular matrix   EV   extracellular vesicle   HBV   hepatitis B virus   HCMV   human cytomegalovirus   HCV   hepatitis C virus   HPV   human papilloma virus   HSV   herpes simplex virus   IAV   influenza A virus   IF   immunofluorescence   IFN   interferon   IMS   imaging MS   LCM   laser capture microdissection   LMP   latent membrane protein   MALDI   matrix-assisted laser desorption/ionization   MHC   major histocompatibility complex   MS   mass spectrometry   NK   natural killer   PPI   protein–protein interaction   sCP-mCh   secreted and cell penetrable mCherry   SIV   simian immunodeficiency virus   VME   virus microenvironment   ZIKV   Zika virus  

摘要： Intercellular communication is fundamental to multicellular life and a core determinant of outcomes during viral infection, where the common goals of virus and host for persistence and replication are generally at odds. Hosts rely on encoded innate and adaptive immune responses to detect and clear viral pathogens, while viruses can exploit or disrupt these pathways and other intercellular communication processes to enhance their spread and promote pathogenesis. While virus-induced signaling can result in systemic changes to the host, striking alterations are observed within the cellular microenvironment directly surrounding a site of infection, termed the virus microenvironment (VME). Mechanisms employed by viruses to condition their VMEs are emerging and are critical for understanding the biology and pathologies of viral infections. Recent advances in experimental approaches, including proteomic methods, have enabled study of the VME in unprecedented detail. In this review article, we provide a primer on proteomic approaches used to study how viral infections alter intercellular communication, highlighting the ways in which these approaches have been implemented and the exciting biology they have uncovered. First, we consider the different molecules secreted by an infected cell, including proteins, either soluble or contained within extracellular vesicles, and metabolites. We further discuss the modalities of interactions facilitated by alteration at the cell surface of infected cells, including immunopeptide presentation and interactions with the extracellular matrix. Finally, we review spatial profiling approaches that have allowed distinguishing how specific subpopulations of cells within a VME respond to infection and alter their protein composition, discussing valuable insights these methods have offered.

关键词： HLA-B*18:01:56   NGS HLA typing novel   novel HLA-B allele  

摘要： HLA-B*18:01:56 showed two synonymous nucleotide differences compared to the HLA-B*18:01:01:01 allele in codons 224 and 225.

关键词： HLA   HLA-DRB5*01:02:05   next-generation sequencing   novel allele  

摘要： HLA-DRB5*01:02:05 differs from the HLA-DRB5*01:02:01 by one synonymous nucleotide in codon 14 in exon 2.

关键词： HLA   HLA-DRB1   nanotype sequencing   novel allele   sequencing-based typing  

摘要： The novel allele HLA-DRB1*13:348 differs from HLA-DRB1*13:02:01:01 by one non-synonymous nucleotide substitution in exon 2.

关键词： C*04:NEW   HLA   IPD-IMGT/HLA  

摘要： HLA-C*04:533 differs from C*04:01:01:14 by a single non-synonymous nucleotide change in codon 216 (ACC>AAC).

关键词： Empagliflozin   SGLT-2 Inhibitors   Doxorubicin   PI3K/Akt/mTOR Pathway   Oxidative Stress   Neuroinflammation  

摘要： Chemobrain is a cognitive impairment observed in up to 75% of cancer patients treated with doxorubicin (DOX). Cognitive deficits associated with DOX are complex, and multiple interplay pathways contribute to memory impairment and the loss of concentration. Empagliflozin (EMPA), a sodium-glucose co-transporter-2 (SGLT-2) inhibitor with neuroprotective potential, has recently been elucidated because of its regulatory effects on oxidative stress and neuroinflammation. Thus, this study aimed to explore the protective mechanisms of EMPA in DOX-induced chemobrain. Rats were allocated to four groups: normal (NC), EMPA, DOX, and EMPA + DOX. Chemobrain was induced in the third and fourth groups by DOX (2 mg/kg, IP) on the 0th, 7th, 14th, and 21st days of the study, while EMPA was administered (10 mg/kg, PO) for 28 consecutive days in both the EMPA and EMPA + DOX groups. Behavioral and biochemical assessments were then performed. Rats treated with DOX exhibited significant memory, learning, and muscle coordination dysfunctions. Moreover, DOX boosted oxidative stress in the brain, as evidenced by elevated malondialdehyde (MDA) content together with decreased levels of nuclear factor-erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) and reduced glutathione (GSH). Neuroinflammation was also observed as an upsurge of tumor necrosis factor-alpha (TNF-alpha) and nuclear factor kappa B (NF-kappa B) (p65). Additionally, DOX diminished the expression of brain-derived neurotrophic factor (BDNF) and increased phosphoinositol-3-kinase (PI3K), phosphorylated-Akt (pAkt), and mammalian target of rapamycin (mTOR) content. EMPA exhibited potent neuroprotective potential in DOX-induced cognitive impairment, attributed to its antioxidant and neuroplasticity-enhancing properties and suppression of the PI3K/Akt/mTOR/NF-kappa B/TNF-alpha signaling *** AbstractDoxorubicin (DOX)-induced chemobrain may occur because of increased tumor necrosis factor-alpha (TNF-alpha) leve

关键词： inflammatory bowel disease   Crohn's disease   ulcerative colitis   early treatment   anti-TNF-alpha   biosimilar  

摘要： Data indicate that earlier initiation of anti-tumor necrosis factor alpha (anti-TNF-alpha) biologic medicines may prevent progression to irreversible bowel damage and improve outcomes for patients with inflammatory bowel disease (IBD), particularly Crohn's disease. However, the high cost of such therapies may restrict access and prevent timely treatment of IBD. Biosimilar anti-TNF-alpha medicines may represent a valuable opportunity for cost savings and optimized patient outcomes by improving access to advanced therapies and allowing earlier anti-TNF-alpha treatment initiation. Biosimilar anti-TNF-alpha medicines have been shown to offer consistent therapeutic outcomes to their reference medicines, yet despite entering the IBD treatment armamentarium over 10 years ago, their implementation in clinical practice remains suboptimal. Factors limiting the 'real' use of biosimilar anti-TNF-alpha medicines may include an ongoing lack of understanding and acceptance of biosimilars by both healthcare professionals (HCPs) and patients, as well as systemic factors such as formulary decisions outside of the control of the prescriber. In this review, an expert panel of gastroenterologists discusses HCP-level considerations to improve biosimilar anti-TNF-alpha utilization in IBD in order to support early anti-TNF-alpha initiation and maximize patient outcomes.