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关键词： adipocytokines   children   leptin   leptin/adiponectin ratio   obesity   overweight   sex  

摘要： Background: Childhood obesity is a major public health concern, being linked to an increased risk of metabolic disorders and cardiovascular disease. Even in childhood, obesity is associated with systemic low-grade inflammation, which is a critical factor in the development of atherosclerosis and a predictor of cardiovascular morbidity and mortality. Objectives: To describe the prevalence of obesity and examine the relationship between IL-6, TNF-alpha, adiponectin, leptin, the leptin/adiponectin (L/A) ratio, and Klotho levels with BMI in children. Methods: This cross-sectional study included children aged 10-14 years from La Rioja, Spain. Participants were selected based on BMI criteria for overweight (85th-95th percentiles) and obesity (>95th percentile). Socio-demographic and anthropometric data and blood samples were collected and analyzed for IL-6, TNF-alpha, adiponectin, leptin, and Klotho. Results: A total of 340 participants were included, with 276 (81.2%) classified as normal weight and 64 (18.8%) as overweight or obese. Mean age was similar between groups (p = 0.40). Obesity was more prevalent in males (59.4%, p = 0.048). Obese participants had higher mean birth weight (p = 0.003), current height (p = 0.04), BMI (p < 0.0001), and abdominal circumference (p < 0.0001). BMI correlated positively with leptin (r = 0.54, p = 0.0008) and the L/A ratio (r = 0.40, p = 0.025), showing sex-specific differences. Conclusions: This study underscores leptin and the L/A ratio as potential biomarkers of metabolic dysregulation in childhood obesity, particularly in females. Longitudinal studies are needed to confirm these findings and assess the clinical utility of these biomarkers in pediatric obesity management.

关键词： deubiquitination   hypoxia   IL-6 signaling   MeCP2   USP15  

摘要： Methyl-CpG binding protein 2 (MeCP2) is an important X-linked DNA methylation reader and a key heterochromatin organizer. The expression level of MeCP2 is crucial, as indicated by the observation that loss-of-function mutations of MECP2 cause Rett syndrome, whereas an extra copy spanning the MECP2 locus results in MECP2 duplication syndrome, both being progressive neurodevelopmental disorders. Our previous study demonstrated that MeCP2 protein expression is rapidly induced by renal ischemia-reperfusion injury (IRI) and protects the kidney from IRI through transcriptionally repressing the interleukin-6 (IL-6)/signal transducer and activator of transcription 3 signaling pathway. However, the mechanisms underlying the upregulation of MeCP2 have remained elusive. Here, by using two hypoxia cell models, hypoxia and reoxygenation and cobalt chloride stimulation, we confirmed that the removal of lysine 48-linked ubiquitination from MeCP2 prevented its proteasome-dependent degradation under hypoxic conditions. Through unbiased screening based on a deubiquitinating enzymes library, we identified ubiquitin-specific protease 15 (USP15) as a stabilizer of MeCP2. Further studies revealed that USP15 could attenuate hypoxia-induced MeCP2 degradation by cleaving lysine 48-linked ubiquitin chains from MeCP2, primarily targeting its C-terminal domain. Consistently, USP15 inhibited hypoxia-induced signal transducer and activator of transcription 3 activation, resulting in reduced transcription of IL-6 downstream genes. In summary, our study reveals an important role for USP15 in the maintenance of MeCP2 stability and the regulation of IL-6 signaling.

关键词： HLA new allele   HLA-DPB1   HLA-DRB1   questionable expression  

摘要： Description of two novel HLA class II alleles, DPB1*1626:01Q and DRB1*11:337 alleles.

关键词： ALKBH5   IGF2BP3   N6-methyladenosine (m(6)A)   non-small cell lung cancer (NSCLC)   XBP1  

摘要： The X-box-binding protein 1 (XBP1) is an important transcription factor during endoplasmic reticulum stress response, which was reported as an oncogene in non-small cell lung cancer (NSCLC) tumorigenesis and development. However, the regulatory mechanism of XBP1 expression in NSCLC progression was less reported. N6-methyladenosine (m(6)A) RNA modification is an emerging epigenetic regulatory mechanism for gene expression. This study aimed to investigate the regulatory role of the m(6)A modification in XBP1 expression in NSCLC. We identified XBP1 as a downstream target of ALKBH5-mediated m(6)A modification in A549 and PC9 cells. Knockdown of ALKBH5 increased the m(6)A modification and the stability of XBP1 mRNA, while overexpression of ALKBH5 had the opposite effect. Furthermore, IGF2BP3 was confirmed to be a reader of XBP1 m(6)A methylation and to enhance the stability of XBP1 mRNA. Additionally, IGF2BP3 knockdown significantly reversed the increase in XBP1 stability mediated by ALKBH5 depletion. In vivo and in vitro experiments demonstrated that ALKBH5/IGF2BP3 promotes the proliferation, migration, and invasion of NSCLC cells by upregulating XBP1 expression. In addition, we also showed that XBP1 promoted NSCLC cell proliferation, migration, and invasion by activating IL-6-JAK-STAT3 signaling. Our research suggested that ALKBH5-mediated m(6)A modification of XBP1 facilitates NSCLC progression through the IL-6-JAK-STAT3 pathway.

关键词： Acute psychiatric disorder   Pediatrics   T-helper 17   Streptococcus   Interleukin   Cerebral spinal fluid  

摘要： Background: Acute neuropsychiatric disorders are heterogeneous conditions resulting from interaction between genetic and environmental features. Among these, post infectious forms like Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) and Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) are common. Preclinical studies suggest a role of CNS T-helper-17/interleukin-17 (IL-17) inflammatory mediated response in the pathogenesis of these disorders. We analyze serum and cerebral-spinal fluid (CSF)-IL-17 concentrations in a cohort of patients with acute neuropsychiatric disease. Methods: We retrospectively included patients <14 years with acute neuropsychiatric symptoms from 2016 to 2020. IL-17 was determined on serum and CSF by means of quantitative sandwich enzyme immunoassay technique, and values were compared to serum and CSF controls. Variables were identified using univariate analysis with Pearson's regression test and X-2 test. Results: 58 subjects were included (67.8 % males, average age: 8.5 years). 50.8 % were classified as PANDAS, 11.8 % as PANS. Mean concentrations of serum IL-17 were higher in the study group compared to controls (p < 0.0001). We observe a trend of increasing IL-17 in post-pubertal children both on serum (p = 0.05) and on CSF (p = 0.04). Coupled IL-17 concentration were higher in the CSF than in serum (p = 0.003), with a marked significance in the PANDAS and PANS group (p < 0.001). Conclusion: IL-17 is elevated in children and adolescents with acute neuropsychiatric conditions, both on serum and CSF. IL-17 could be involved in the pathogenesis of acute neuropsychiatric disorders in childhood. Further studies are necessary to validate its potential role as a diagnostic or prognostic biomarker.

摘要： Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent metabolic disorder characterized by hepatic steatosis associated with metabolic abnormalities. Recent research has shed light on the intricate interplay among interleukin-1 receptor 1 (IL1R1), gut microbiota, and bile acids in the pathogenesis of MASLD. This review aims to provide a comprehensive overview of the current understanding of the role of IL1R1, gut microbiota, and bile acids in MASLD, exploring their interrelationships and potential mechanisms. We summarize the evidence supporting the involvement of IL1R1 in inflammation, discuss the influence of gut microbiota on bile acid metabolism and its influence on liver health, and elucidate the bidirectional interactions among IL1R1 signaling, gut microbiota composition, and bile acid homeostasis in MASLD. Furthermore, we highlight emerging therapeutic strategies targeting these interrelated pathways for the management of MASLD. Interleukin-1 receptor 1 (IL1R1), gut microbiota, and bile acids play interconnected roles in the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD). IL1R1 signaling is involved in hepatic inflammation and injury in MASLD, and genetic variations in IL1R1 can influence disease susceptibility. Gut dysbiosis, characterized by alterations in gut microbiota composition, is associated with MASLD and can affect bile acid metabolism. Bile acids, in addition to their role in digestion, have effects on hepatic lipid metabolism, inflammation, and fibrosis in MASLD. Targeting IL1R1, modulating gut microbiota through interventions like probiotics and fecal microbiota transplantation (FMT), and modulating bile acid metabolism hold promise for therapeutic interventions in MASLD. Further research is needed to elucidate the precise mechanisms underlying these interactions to develop effective targeted interventions for MASLD management. image

关键词： bladder cancer   immunotherapy   BCG   NK cells   NKG2A   HLA-E   patient outcomes  

摘要： Background: Immunotherapy is gaining great relevance in both non-muscle-invasive bladder cancer (NMIBC), with the use of bacille Calmette-Guerin (BCG), and in muscle-invasive BC (MIBC) with anti-checkpoint therapies blocking PD-1/PD-L1, CTLA-4/CD80-CD86, and, more recently, NKG2A/HLA-E interactions. Biomarkers are necessary to optimize the use of these therapies. Methods: We evaluated killer-cell immunoglobulin-like receptors (KIRs) and HLA-I genotyping and the expression of NK cell receptors in circulating T and NK lymphocytes at diagnosis in 325 consecutive BC patients (151 treated with BCG and 174 treated with other therapies), as well as in 648 patients with other cancers and 973 healthy donors as controls. The proliferation and production of cytokines and cytotoxicity were evaluated in peripheral blood mononuclear cells, stimulated in vitro with anti-CD3/CD28 or BCG, from selected patients based on HLA-B -21M/T dimorphism (NKG2A ligands). Results: The HLA-B -21M/T genotype showed opposing results in BC patients treated with BCG or other therapies. The MM genotype, compared to MT and TT, was associated with a longer 75th-percentile overall survival (not reached vs. 68.0 +/- 13.7 and 52.0 +/- 8.3 months, p = 0.034) in BCG, but a shorter (8.0 +/- 2.4 vs. 21.0 +/- 3.4 and 19.0 +/- 4.9 months, p = 0.131) survival in other treatments. The HLA-B -21M/T genotype was an independent predictive parameter of the progression-free survival (HR = 2.08, p = 0.01) and the OS (HR = 2.059, p = 0.039) of BC patients treated with BCG, together with age and tumor histopathologic characteristics. The MM genotype was associated with higher counts of circulating CD56bright, fewer KIR2DL1/L2+ NK cells, and lower NKG2A expression, but not with differential in vitro NK cell functionality. Conclusions: The HLA-B -21M/T is independently associated with BC patient outcomes and can help to optimize the use of new immunotherapies in these patients.

关键词： TNF-Alpha   HERV-K Env   Inflammatory disease   Tissue microarray   Immunofluorescence  

摘要： BackgroundHuman endogenous retroviruses (HERVs) were integrated into the human genome millions of years ago and have since proliferated to comprise about 8% of the human genome. For a long time, HERVs were thought to be remnants of ancient viruses, rendered inactive over the ages. However, recent studies have revealed that HERVs are involved in various diseases, including cancer. Notably, HERVs have been found to play a crucial role in immune responses and inflammatory processes, indicating their significant influence on the regulation of immune-related *** reported in previous reports that HERV-K119 env Knockout (KO) and inflammatory response were associated. In this study, we identified the correlation between inflammatory disease and HERV-K Env and TNF-Alpha protein expression in multiple types of colon disease tissue and lung disease spectrum *** performed Immunofluorescence (IF) using multiple types of colon disease and lung disease spectrum tissue microarray (TMAs) and compared and analyzed the patient clinical data *** a result, we identified that the expression of HERV-K Env and TNF-Alpha proteins in certain colorectal inflammatory diseases and certain lung inflammatory diseases showed specific expression. And through the analysis of the clinical data provided, environmental factors could be *** study demonstrates that the relationship between TNF-Alpha and HERV-K Env expression in inflammation disease and clinical significance of disease tissues.

关键词： HLA-C*03:681   novel allele   sequencing-based typing  

摘要： The HLA-C*03:681 allele differs from HLA-C*03:02:02:01 by a single non-synonymous nucleotide change in exon 3.

关键词： Available online xxx   Adventitial injection   Hydrogel   IL-33   Local drug administration   Neointimal hyperplasia   Vascular injury   Wire injury  

摘要： Introduction: Neointimal hyperplasia is one of the persistent complications after vascular interventions, and is the major cause of treatment failure. Interleukin-33 (IL-33) emerges as a crucial factor in many biological processes and plays an important role in vascular diseases. Adventitial injection is catching attention for its effectiveness and fewer side effects. We hypothesize that targeting IL-33 by adventitial injection can be a therapeutic method to inhibit neointimal hyperplasia. Method: IL-33 expression was examined in human vein graft. The hydrogel was fabricated by the interaction of hyaluronic acid, sodium alginate, and CaCO3;and phosphate buffered saline (PBS) or IL-33 antibody or recombinant IL-33 was mixed within the hydrogel uniformly. A rat aortic wire injury-induced neointimal hyperplasia model was developed;rats were divided into three groups and received an adventitial injection of a hydrogel loaded with PBS or IL-33 antibody or recombinant IL-33 after wire injury. Tissues were harvested at day 21 and analyzed by histology and immunohistochemical staining. Hydrogel loaded with PBS, IL-33 antibody, or IL-33 was also used in a mouse carotid artery ligation neointimal hyperplasia model. Result: There was a high expression of IL-33 in human vein graft neointima. Hydrogel can be successfully injected into the aortic wall and is encapsulated by the adventitia. The hydrogel could be seen beneath the adventitia after adventitial injection and was partly degraded at day 21. There was a significantly thinner neointimal thickness and less proliferation and inflammation in the IL-33 antibody group compared to the control group. On the contrary, the IL-33 group has a thicker neointima, increased proliferation, and inflammation. The mouse carotid artery ligation model showed similar results. Conclusions: IL-33 plays a role in arterial neointimal hyperplasia in both human and rodent models;adventitial injection of hydrogel loaded with IL-33 antibody can effec