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关键词： IgG4-Related Ophthalmic Disease   IL-33/ST2 signaling   MMP-12   Lat(Y136F) knock-in C57BL/6 mouse model   M2 macrophages  

摘要： IgG4-Related Ophthalmic Disease (IgG4-ROD) is a chronic autoimmune-mediated fibrotic disease that predominantly affects the lacrimal glands, often leading to loss of function in the involved tissues or organs. Recent studies have demonstrated that MMP-12 is highly expressed in IgG4-ROD and plays a significant role in regulating immune responses. In this study, we reviewed nine patients diagnosed with IgG4-ROD based on clinical manifestations and histological analysis, and we investigated the expression of IL-33/ST2 and MMP-12 in IgG4-ROD lacrimal gland tissues using IHC. We found that IL-33 interacts with its specific receptor ST2, both of which are significantly overexpressed in IgG4-ROD tissues. Additionally, we successfully constructed a mouse model by introducing the Lat(Y136F) mutation into C57BL/6 mice to mimic IgG4-ROD lacrimal gland involvement, which helped elucidate the mechanisms involved in the induction of MMP-12. Furthermore, immunofluorescence staining confirmed that most MMP-12(+) cells were derived from M2 macrophages, and an ELISA assay demonstrated that IL-33 upregulates MMP-12 in IgG4-ROD. Collectively, these data suggest that the IL-33/ST2/MMP-12 signaling pathway is activated in IgG4-ROD, with IL-33/ST2 potentially promoting M2 macrophage polarization and activation to produce MMP-12, which may serve as a novel therapeutic target for IgG4-ROD.

关键词： SARS-CoV-2   COVID-19   HLA gene variants   next-generation sequencing   genetic association study   biological sex differences   immune system modulation   genetic architecture   case-control study  

摘要： Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection, responsible for Coronavirus Disease 2019 (COVID-19), exhibits a spectrum of clinical manifestations, ranging from asymptomatic to severe pulmonary dysfunction or death. The variability in COVID-19 severity has largely been attributed to the host's genetic characteristics, suggesting a polygenic genetic architecture, without significant strong evidence of sex-related genetic differences. In this Italian retrospective case-control study, we investigated the association between COVID-19 severity (severe vs. asymptomatic/oligosymptomatic healed individuals) and HLA gene variants, analyzed by next-generation sequencing (NGS). We identified significant HLA alleles (according to the conventional nomenclature), SNPs and haplotypes in the HLA-B, -C, -F, -DQA1, -DRB1, and -DRB5 genes associated with COVID-19 severity. Interestingly, these variants showed biological sex-related effects. Also, we identified specific haplotypes associated with COVID-19 severity that are shared by different conventional HLA alleles, indicated here as "super-haplotypes". These haplotypes had a biological sex-specific impact on disease severity and markedly increased the risk of severe COVID-19 compared to the conventional HLA alleles (odds ratio of up to 15). Our data suggest that the revision of the current HLA nomenclature may help to identify variants with a stronger effect on disease susceptibility and that association studies could benefit from the stratification of patients by biological sex. If replicated in other disease models, these findings could help to define the functional diversity in immune response between sexes, also based on the HLA system. Finally, due to the global pandemic's mortality rate, we hypothesize here that SARS-CoV-2 may have acted as a natural selection trigger, leading to a drift in HLA allelic frequencies in the general population.

关键词： barefoot walking exercise   CRP   NK-cell   interferon gamma   IFN gamma   serotonin  

摘要： Background/Objectives: This study investigated the effects of barefoot walking on an urban forest path on participants' C-reactive protein (CRP), interferon gamma (IFN gamma), and serotonin levels, which are associated with feelings of well-being. Methods: Participants in the walking program included 62 consenting adults, divided into a sneaker-wearing and barefoot group (each N = 31). The program comprised 20 sessions, each consisting of a 90 min 4.4 km walk at a 50-70% target heart rate, held four times per week for 5 weeks. Physiological measurements were taken from pre-program saliva samples and after 10 and 20 sessions, respectively. Results: The sneaker-wearing group showed a consistent CRP increase, with levels reaching statistical significance after 20 sessions. In the barefoot group, CRP increased up to Session 10 but was lower than at the end of Session 20. The analysis of those with an initial CRP above 100 pg/mL showed that CRP was statistically significantly lower in the barefoot (N = 14) than in the sneaker-wearing (t = -0.048, p = 0.963) group after 20 sessions compared to before the program (t = 3.027, p = 0.010). IFN gamma increased in both groups up to Session 10 but showed minimal change between Sessions 10 and 20. Serotonin was statistically significantly higher after 20 sessions than before the program in the barefoot group (t = -2.081, p = 0.046). Conclusions: Barefoot walking on forest trails is effective for people with above-normal inflammation, increasing serotonin levels.

关键词： HLA-DPA1   HLA-DRB1   new allele   next-generation sequencing  

摘要： Two novel alleles, HLA-DRB1*14:270 and HLA-DPA1*01:222, were discovered in Russian individuals.

关键词： Chinese propolis   Caffeic acid phenethyl ester   IL-2   Spleen cells   IL-4   IL-10  

摘要： Objectives: Interleukin (IL)-2 production by mouse spleen cells stimulated with an anti-CD3 antibody is significantly enhanced by caffeic acid phenethyl ester (CAPE), a major constituent of Chinese propolis (CP). In this study, we evaluated the functional significance of IL-2 in CAPE-treated activated spleen cells. Methods: Mouse spleen cells were stimulated with an anti-CD3 monoclonal antibody in the presence of CAPE. Cytokine production was examined using an enzyme-linked immunosorbent assay (ELISA). Messenger RNA expression was examined via reverse transcription quantitative polymerase chain reaction (RT-PCR). IL-2 function was assessed using IL-2 and a neutralizing antibody. Spleen cell subsets were identified and characterized using flow cytometry. Results: CAPE treatment of anti-CD3 antibody-stimulated spleen cells reduced IFN-gamma production, then enhanced IL-2 production, followed by enhancement of IL-4 and IL-10 production. The Th2 cytokine production enhancing effects of CAPE were completely abolished by addition of an anti-IL-2 neutralizing antibody. In the absence of CAPE, exogenously added IL-2 could enhance IL-4 production to a lesser degree, but did not stimulate IL-10 production, in stimulated spleen cells. Interestingly, CAPE significantly reduced the proportions of CD4+ and CD8+ cells, and increased those of CD4-CD8- cells among anti-CD3 stimulated spleen cells, in the presence or absence of anti-IL-2 neutralizing antibody treatment. Conclusion: CAPE reduced IFN-gamma production, then enhanced IL-4 and IL-10 production via the activity of specifically elevated IL-2 in stimulated spleen cells. CAPE exerted these effects in a CD4- CD8- cell specific manner.

关键词： SARS-CoV-2   NSP16   IL-6   HIF-1 alpha   Ubiquitination  

摘要： Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiologic agent of coronavirus disease 2019 (COVID-19). Severe and fatal COVID-19 cases often display cytokine storm i.e. significant elevation of pro-inflammatory cytokines and acute respiratory distress syndrome (ARDS) with systemic hypoxia. Understanding the mechanisms of these pathogenic manifestations would be essential for the prevention and especially treatment of COVID-19 patients. Here, using a dual luciferase reporter assay for hypoxia-response element (HRE), we initially identified SARS-CoV-2 nonstructural protein 5 (NSP5), NSP16, and open reading frame 3a (ORF3a) to upregulate hypoxia-inducible factor-1 alpha (HIF-1 alpha) signaling. Further experiments showed NSP16 to have the most prominent effect on HIF-1 alpha, thus contributing to the induction of COVID-19 associated pro-inflammatory response. We demonstrate that NSP16 interrupts von Hippel-Lindau (VHL) protein interaction with HIF-1 alpha, thereby inhibiting ubiquitin-dependent degradation of HIF-1 alpha and allowing it to bind HRE region in the IL-6 promoter region. Taken together, the findings imply that SARS-CoV-2 NSP16 induces HIF-1 alpha expression, which in turn exacerbates the production of IL-6.

关键词： Inflammatory bowel diseases   IL10RB gene   Whole exome sequencing   Iran   Mutation  

摘要： BackgroundInfantile-onset inflammatory bowel disease (IOIBD) is a gastrointestinal inflammatory condition often associated with monogenic disorders and is frequently caused by Interleukin-10 deficiencies. This study aimed to identify the mutation responsible for IBD in an 8-year-old patient from an Iranian family with consanguineous ***-exome sequencing (WES) was employed to identify disease-causing variations. Furthermore, we utilized integrated experimental data of HADDOCK molecular docking platform, including NMR spectroscopy, to characterize the mutant protein and elucidate the underlying functional mechanism of the identified mutation's *** findings revealed a novel 19-bp deletion mutation (c.25_43del, ***9CysfsTer15) in the IL10RB gene. Sanger sequencing confirmed that this variant was inherited in homozygous state within this family, marking the first mutation identified in exon 1 of this gene. Molecular docking simulation demonstrated that the mutant form of IL10RB exhibited reduced affinity for binding to the Interleukin-10 ligand, leading to disruptions in downstream cellular signaling *** identification of this novel genetic variant as a causative factor for IOIBD highlights the clinical value of utilizing genetic testing, such as WES, as a reliable diagnostic approach for patients affected by this condition.

关键词： Endogenous oxalate synthesis   Il-6-jak/stat signaling pathway   Kukoamine a   Nephrolithiasis   Fruit fly   Kidney stone  

摘要： Background: The recurrent nature and socioeconomic burden of nephrolithiasis demand effective treatments. Delineating the crosstalk between inflammatory processes and the endogenous oxalate metabolism pathway, which underpins nephrolithiasis pathogenesis, is essential for advancing treatment strategies. Purpose: We aim to screen therapeutic Chinese herbal remedies and their bioactive constituents for kidney stone treatment using a fruit fly model, followed by efficacy and mechanism validation in a rodent nephrolithiasis model as well as in vitro human cell culture model. Study design and methods: We developed a fruit fly model to screen for efficient traditional Chinese medicine herbs and their active compounds for kidney stone treatment. Candidate active compounds from efficient herbs were separated and identified by solid-phase chromatography coupled with LC-MS analysis. Fruit fly genetic tools were employed to manipulate the expression of related genes to explore the therapeutic mechanisms of the Lycii Cortex and kukoamine A (KuA). To confirm the therapeutic effects and mechanisms of KuA for mammalian nephrolithiasis, mouse model of glyoxylate-induced kidney stone and human renal tubular cells were used. The therapeutic role of kukoamine A in nephrolithiasis was evaluated by assessing tubular injury, crystal deposition, and adhesion. The level of expression and phosphorylation in cells and mice was assessed using RT-qPCR and western blot. Results: Our findings indicate that Lycii Cortex potently inhibits calcium oxalate stone formation via activation of the JNK/Upd3/JAK/STAT signaling cascade, resulting in diminished endogenous oxalate synthesis by downregulating D-amino acid oxidase (DAO) gene expression, predominantly in fruit fly Malpighian tube stellate cells. KuA was identified as the principal bioactive constituent mediating these effects. Both mouse models and human cell assays confirmed KuA's efficacy in preventing calcium oxalate nephrolithiasis in mamma