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关键词： childhood Sjogren's disease   SUV3   monocytes   mitochondrial double-stranded RNAs   protein kinase R  

摘要： Objectives: This study investigates the molecular and functional implications of reduced Suv3-like RNA helicase (SUV3) expression in the interferon (IFN)-enriched subset of monocytes from childhood Sjogren's disease (cSjD). SUV3 is known to unwind double-stranded RNAs (dsRNAs) for homeostatic RNA decay within mitochondria. Methods: Using single-cell RNA sequencing, we analysed highly inflammatory IFN-enriched CD14+ monocytes from cSjD patients. To model SUV3 deficiency, we performed SUV3 knockdown in monocytic cells and studied the origin, localization and accumulation of dsRNAs in the cytosol. Formaldehyde crosslinking immunoprecipitation (fCLIP)-qPCR identified an intracellular sensor of dsRNAs. We further examined patient monocytes using J2 anti-dsRNA antibodies and transmission electron microscopy (TEM) for subcellular localization. In vitro assays assessed the impact of SUV3 knockdown on oxidative stress, ATP production, migration and phagocytosis. Results: SUV3 knockdown led to the accumulation of mitochondrial-dsRNAs (mt-dsRNAs) outside of the mitochondria, where they interacted with protein kinase R (PKR). This activated PKR, triggering a type I IFN signature and upregulating proinflammatory cytokines linked to fatigue. TEM revealed mt-dsRNAs in mitochondrial-derived vesicles and multi-vesicular bodies. Notably, cSjD monocytes had a significantly higher frequency of dsRNA-positive cells compared with controls (39% vs 0.08%, P < 0.002). SUV3 depletion also increased superoxide and ROS production, while impairing ATP synthesis, migration and phagocytosis, which are key innate immune functions. These defects were partially or fully reversed by co-knockdown of PKR. Conclusion: SUV3 is the key driver for defective innate immune functions through mt-dsRNA-mediated PKR activation, which enhances cellular stress, mitochondrial dysfunction and inflammatory signatures, uncovering a novel mechanism in cSjD pathogenesis.

关键词： fetal growth restriction   gene polymorphisms   HLA-F   HLA-G   preeclampsia  

摘要： HLA-F and HLA-G may be involved in the pathogeneses of preeclampsia and fetal growth restriction (FGR). However, the functions of HLA-F and HLA-G in placental dysfunction remain unclear. The aim was to investigate differences in the prevalence of specific HLA-F and HLA-G gene allelic polymorphisms, genotypes, haplotypes, and diplotypes between controls and cases with preeclampsia or FGR. In total, blood samples from 365 pregnant females (controls, n = 192;preeclampsia, n = 164;FGR, n = 19) in their second and third trimester, and corresponding cordial blood samples (reflecting newborns, n = 160) were obtained after delivery. Genomic DNA was sequenced with a focus on the specific gene polymorphisms in the HLA-F gene locus, especially the single nucleotide polymorphisms (SNPs) rs1362126 (G/A), rs2523405 (T/G) and rs2523393 (A/G), as well as the rs371194629 (14-bp ins/del) in the 3 ' UTR of HLA-G. Haplotype and diplotype distributions were obtained using PHASE v2.1, and linkage disequilibrium analyses were performed. SNPs in the HLA-F gene locus and the 3 ' UTR of HLA-G were not associated with the risk of preeclampsia or FGR. The SNPs did not correlate with fetal-placental weight ratio, deviation of birth weight at gestational age, and placental weight. However, a trend towards an absence of certain HLA-F-HLA-G extended diplotypes in preeclampsia was observed. The current study does not support associations of the investigated HLA-F SNPs with preeclampsia or FGR. However, further studies are needed to evaluate the possible role of certain fetal HLA-F-HLA-G extended haplotypes and diplotypes in preeclampsia.

关键词： Mitochondrial uncoupling proteins 1   TLR4/NLRP3/IL-1 beta signaling pathway   Aortic dissection/aneurysms   Inflammation   Phenotype switching  

摘要： Thoracic aortic aneurysms and dissection (TAAD) is a life-condition associated with high morbidity and mortality. Research has proven that inflammation contributes to the progression of TAAD. Mitochondrial uncoupling protein 1 (UCP1) can inhibit the release of inflammatory factors in perivascular adipose tissue (PVAT), regulate fat and inflammation, to confer vascular protection. However, whether UCP1 can ameliorate TAAD has not been clarified. In this study, aortas were harvested from organ donors and TAAD patients to explore the expression of UCP1 and Toll-like receptor 4 (TLR4)/NOD-like receptor thermal protein domain associated protein 3 (NLRP3)/ interleukin-1(3 (IL-1(3) signaling pathway. Meanwhile, in vitro and in vivo models of TAAD were constructed to clarify the impact of UCP1 expression on VSMCs and TAAD. UCP1 expression was significantly downregulated and the TLR4/NLRP3/IL-1(3 signaling pathway was activated in TAAD in vivo. Moreover, UCP1 inhibited the migration, invasion, apoptosis, and phenotype switching of VSMCs in vitro. UCP1 significantly blocked the (3-aminopropionitrile (BAPN)-induced TAAD formation and rupture in mice, suppressed aortic dilation, elastic fiber fragmentation, and apoptosis in the aorta. It also activated the TLR4/NLRP3/IL-1(3 signaling pathway to alleviate aortic inflammation and prevent the degradation of systolic phenotype proteins and phenotype switching of VSMCs. These effects suggest that UCP1 may inhibit TAAD formation by blocking the TLR4/NLRP3/ IL-1(3 signaling pathway and VSMC phenotype switching.

关键词： Gene delivery   Genetically engineered cells   Cell-based delivery   Interleukin-6   Gene therapeutics   Anti-cytokine therapy   IL-6 trans-signaling  

摘要： Interleukin-6 (IL-6) is a highly pro-inflammatory cytokine involved in the etiopathology of several inflammatory diseases and cancer. As so, the inhibition of IL-6 signaling pathways has emerged as an attractive therapeutic avenue for the treatment of several chronic diseases. Since IL-6 trans-signaling was described as the pathological branch of IL-6, selective inhibitors were developed. Next-generation variants with increased trans-signaling specificity and potency emerged as great candidates for the treatment of several diseases, with reduced off-target effects. The highly time-consuming and costly processes involving recombinant protein production, however, have hampered the progress of anti-cytokine pharmaceuticals in clinic so far. Herein, we developed gene therapeutic modalities of IL-6-trans-signaling inhibitors as alternatives for sustained recombinant protein secretion. By using an IL-6-dependent lymphoma cell line and xenograft tumor model, we demonstrated the superior inhibitory potential of second-generation anti-IL-6 trans-signaling therapeutic. We compared the efficiency of distinct gene delivery modalities using a bioluminescent biomarker probe and observed consistent protein production via cell-based delivery. When delivered intratumorally, genetically engineered sgp130FlyRFc-secreting cells significantly reduced tumor burden and increased animal survival, representing a promising therapeutic avenue to be explored in clinically relevant gene delivery applications.

关键词： corneal fibroblast   transforming growth factor-beta (TGF-beta)   interleukin-beta (IL-beta)   urokinase-type plasminogen activator (uPA)   alpha-smooth muscle actin (alpha-SMA)  

摘要： PURPOSE. Corneal fibroblasts appear to differentiate into cells with opposing functions of collagen degradation and collagen synthesis in response to various stimuli during corneal wound healing process. Interleukin-1 beta (IL-1 beta) is a proinflammatory cytokine and promotes collagen degradation by corneal fibroblasts by upregulating their production of urokinase-type plasminogen activator (uPA). Transforming growth factor-beta (TGF-beta) induces the differentiation of corneal fibroblasts into myofibroblasts that express a-smooth muscle actin (a-SMA) and increase collagen synthesis, resulting in tissue contraction and remodeling. To investigate how these two factors might cooperatively regulate collagen metabolism during stromal wound healing, we investigated the potential interaction between IL-1 beta and TGF-beta in the regulation of uPA and a-SMA expression by corneal fibroblasts. METHODS. Human corneal fibroblasts were cultured in a three-dimensional gel of type collagen. The uPA was detected by fibrin zymography and immunofluorescence staining, whereas a-SMA was detected by immunoblot analysis and immunofluorescence staining. Collagen gel contraction was assessed by measurement of gel diameter. RESULTS. TGF-beta not only downregulated uPA abundance in corneal fibroblasts under the basal condition, but also attenuated the upregulation of uPA expression by IL-1 beta. Conversely, IL-1 beta inhibited both the upregulation of a-SMA expression in these cells and the cell-mediated collagen gel contraction induced by TGF-beta. CONCLUSIONS. Our results show that IL-1 beta and TGF-beta interact to regulate the expression of uPA and a-SMA as well as collagen gel contraction mediated by corneal fibroblasts cultured in a collagen gel. They highlight the phase-dependent effects of cytokines and growth factors on collagen metabolism during corneal wound healing.

关键词： freckles   GWAS   meta-analysis   MHC   vitiligo  

摘要： BackgroundVitiligo and freckles are both pigmentary disorders of the skin. The high prevalence of these conditions also places substantial strain on social healthcare systems. While vitiligo shows genetic predisposition, freckles exhibit autosomal dominant inheritance. Both conditions are closely linked to the immune system, potentially involving immune irregularities and autoimmune *** study aimed to investigate the correlation between vitiligo and freckles in relation to major histocompatibility complex (MHC) regions to better understand the genetic factors influencing these chronic pigmentation *** from 3315 vitiligo patients, 7168 healthy controls, 524 freckle patients, and 4280 healthy controls were collected. A genome-wide association study (GWAS) utilizing the Infinium Global Screening Array-24 v2.0 BeadChip (GSA) and MHC region imputation was conducted, followed by *** stepwise conditional analysis, five single-nucleotide polymorphisms (SNPs) associated with both vitiligo and freckles were identified. These genetic markers shed light on common susceptibility factors between the two *** findings of this study provide insights into the genetic basis of vitiligo and freckles, suggesting potential associations and shared pathways. Understanding these genetic correlations can aid in disease diagnosis, prevention strategies, and further exploration of biological mechanisms underlying these pigmentation disorders.

关键词： Ammonia detoxication   Functional amino acids   Gut health   Inflammatory cytokine   Microbiota   Nile tilapia fingerlings   Nutrigenomics  

摘要： This study aimed to evaluate the effects of dietary glutamine (Gln) and glutamic acid (Glu) blend on growth performance, plasmatic biochemical parameters, intestinal bacteriome composition, short-chain fatty acids (SCFAs) production, digestive enzyme activity, and histomorphometry of Nile tilapia fingerlings. The study also aimed to evaluate the effects of this blend on liver antioxidant status and gene expression of anti-inflammatory interleukin 10 (IL-10), pre-inflammatory interleukin 1 beta (IL-1 beta), glutamine synthetase (GS), and peroxisome proliferator-activated receptor alpha (PPAR-alpha). Fish (n = 408;1.0 +/- 0.0 g) were randomly distributed into eight aquaria (51 fish each) and fed micro-extruded diets either unsupplemented (CON) or supplemented with 20 g kg-1 of Gln and Glu (1:1) blend (AMG). Fish were hand-fed six times daily until apparent satiety for 30 days. Fish fed AMG diet showed higher body weight gain (+3.0 %) than those fed CON diet. Additionally, these fish exhibited a higher abundance of Staphylococcus saprophyticus, a SCFA-producing bacterium known for its probiotic-like potential in fish. Consequently, fish fed AMG diet exhibited higher intestinal butyric acid production and increased intestinal fold height relative to fish fed CON diet. The upregulation of PPAR-alpha and GS genes suggested that fish fed AMG diet exhibited improved energy metabolism and ammonia excretion, respectively. Furthermore, the upregulated expression of the anti-inflammatory cytokine IL-10 gene in fish fed AMG diet indicated enhanced immune responses. Fish fed AMG diet showed increased activity of superoxide dismutase and glutathione-S-transferase and decreased malondialdehyde concentration in the liver. Dietary supplementation with 20 g kg-1 of Gln plus Glu promoted fish growth and survival through beneficial modulation of the bacteriome, improving intestinal health and function, supporting nutrient absorption and metabolism, strengthening innate immunity, and red

关键词： Sj & ouml   gren's disease   polygenic risk score (PRS)   single nucleotide variant (SNV)   genome-wide association studies (GWAS)   HLA   antinuclear antibodies   SSA   SSB  

摘要： Objectives To calculate a polygenic risk score (PRS) based on single nucleotide variants (SNVs) previously associated with primary Sj & ouml;gren's disease (SjD) with genome-wide significance and determine the genetic risk for SjD stratified by antibodies, sex and age at diagnosis. Methods Patients with SjD (n = 1065) were genotyped using Illumina OmniExpressExome chip. Control genotype data were available (n = 7742). Two PRSs were constructed, one including HLA gene variants (n = 21 SNVs), and one without HLA (n = 18 SNVs). High PRS quartile (Q4) individuals were compared with low PRS (Q1-3). Results A high PRS was associated with SSA antibody-positive SjD (OR 9.16, 95% CI 7.75-10.85, P = 3.7 x 10(-146)), and strengthened in SjD positive for both SSA/SSB antibodies (OR 13.67, 95% CI 10.88-17.32, P = 4.6 x 10(-108)). High PRS classified SSA/SSB antibody-positive SjD with very good accuracy (AUC 0.86). PRS without HLA showed a weaker association with SSA/SSB positive SjD (OR 2.09, 95% CI 1.71-2.55, P = 6.4 x 10(-13)). Antibody negative SjD displayed a PRS similar to controls. Patients in the high PRS quartile were significantly younger at diagnosis, 48.9 +/- 14.9 vs 53.4 +/- 13.4 years in the low PRS quartiles (Q1-3), P = 2.2 x 10(-6), and presented higher frequencies of ANA, SSA and SSA/SSB antibodies, P < 1 x 10(-5). Conclusion A high PRS is associated with SSA/SSB antibody positivity and early disease onset, both largely attributed to the weight of the HLA alleles. Integration of PRS with other biomarkers applied to clinical phenotypes could be a useful tool for disease risk stratification and treatment decisions.

关键词： Cytomegalovirus   HLA   Stem Cell Transplantation   Antigen Loand  

摘要： Among the complications occurring after allogeneic hematopoietic stem cell transplantation (HSCT), infection by human Cytomegalovirus (CMV) represents one of the most relevant in terms of morbidity/mortality and specific management is required by either monitoring viral load and administer anti-CMV therapies. Due to the physiological role of the Human Leucocyte Antigen (HLA) system in presenting foreign antigens to the adaptive immune system to enhance viral clearance, we measured here the HLA antigen load for two immunodominant CMV peptides and correlate with transplant outcome in 238 consecutive adult patients undergoing haploidentical HSCT at a single center. Interestingly, a higher class I antigen load (i.e. above the median) for protein IE1 correlated with an inferior absolute incidence of CMV infection;moreover, a statistically significant correlation with lower non-relapse mortality and higher overall survival was observed (HR: 0.32, 0.12-0.84, p = 0.02;0.34 (0.17-0.69, p = 0.003;respectively), with a protective effect in patients with high antigen load values. Despite additional research is needed, our exploratory data support the role of the HLA polymorphism on CMV infection and survival after HSCT. The introduction of CMV antigen load as a new potential predictive factor might contribute to further define the post-transplant risk on an individualised basis.