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摘要： COVID-19 is associated with diverse neurological abnormalities, but the underlying mechanisms are unclear. We hypothesized that microglia, the resident immune cells of the brain, are centrally involved in this process. To study this, we developed an autopsy platform allowing the integration of molecular anatomy, protein and mRNA datasets in postmortem mirror blocks of brain and peripheral organ samples from cases of COVID-19. We observed focal loss of microglial P2Y12R, CX3CR1-CX3CL1 axis deficits and metabolic failure at sites of virus-associated vascular inflammation in severely affected medullary autonomic nuclei and other brain areas. Microglial dysfunction is linked to mitochondrial injury at sites of excessive synapse and myelin phagocytosis and loss of glutamatergic terminals, in line with proteomic changes of synapse assembly, metabolism and neuronal injury. Furthermore, regionally heterogeneous microglial changes are associated with viral load and central and systemic inflammation related to interleukin (IL)-1 or IL-6 via virus-sensing pattern recognition receptors and inflammasomes. Thus, SARS-CoV-2-induced inflammation might lead to a primarily gliovascular failure in the brain, which could be a common contributor to diverse COVID-19-related neuropathologies.

关键词： thymic stromal lymphopoietin (TSLP)   interleukin-4   chronic rhinosinusitis (CRS)   chronic rhinosinusitis with nasal polyps (CRSwNP)   patient reported outcome measures (PROMs)   fractional exhaled nitric oxide   SNOT-22   UPSIT   endotype   functional endoscopic sinus surgery  

摘要： Background Thymic stromal lymphopoietin (TSLP) plays an important role in mediating the type-2-inflammatory response. This study examined how TSLP and interleukin (IL)-4 levels in patients with chronic rhinosinusitis with nasal polyps (CRSwNP) correlated with clinical and postoperative outcomes. Methods Solid-phase sandwich ELISA was used to analyze TSLP and IL-4 levels in mucus (n = 47), plasma (n = 17), polyp (n = 30), inferior (n = 25), and middle (n = 26) turbinate tissue collected during functional endoscopic sinus surgery (FESS) in CRSwNP patients (n = 76) and controls (n = 11). Inclusion criteria includes patients with medical treatment refractory CRSwNP confirmed by endoscopy or maxillofacial CT. Exclusion criteria include history of immunodeficiency, coagulation disorders, fungal sinusitis, or cystic fibrosis. Levels of TSLP and IL-4 were correlated with SNOT-22, UPSIT, and fractional exhaled nitric oxide (FeNO) using MannWhitney U two-tailed test and linear regression with Spearman correlation coefficient test. Results TSLP is elevated in the inferior turbinates (effect size = 2.695, p = 0.0007) of CRSwNP patients compared to controls. IL-4 is expressed at elevated levels in the inferior (effect size = 3.092, p < 0.0001) and middle turbinates (effect size = 2.041, p = 0.019) compared to controls. Mucus TSLP (r = 0.4013, p = 0.0153) and IL-4 (r = 0.6138, p < 0.0001) positively correlate with preoperative FeNO levels. Lower TSLP in the inferior (r = -0.5179, p = 0.0231) and middle turbinates (r = -0.5075, p = 0.0224) and lower IL-4 in the inferior turbinates (r = -0.5205, p = 0.0223) correlate with a greater improvement in SNOT-22 post-FESS. Conclusion TSLP and IL-4 are elevated in patients with CRSwNP and correlated with increased preoperative FeNO levels and decreased sinonasal quality of life benefit after FESS. Expression of TSLP and IL-4 may play a role in guiding postoperative expectations in patients with treatment refractory CRSwNP.

关键词： ALT   alanine aminotransferase   ASO   antisense oligonucleotide   DCA   deoxycholic acid   FDA   US Food and Drug Administration   FGF   fibroblast growth factor   FMT   fecal microbiota transplantation   FXR   farnesoid X receptor   GIP   glucose-dependent insulinotropic polypeptide   GLP-1   glucagon-like peptide 1   HCC   hepatocellular carcinoma   HFD   high-fat diet   HSD17B13   hydroxysteroid 17-   β   dehydrogenase-13   IL   interleukin   LDL   low-density lipoprotein   LPS   lipopolysaccharide   MASH   metabolic dysfunction–associated steatohepatitis   MASLD   metabolic dysfunction–associated steatotic liver disease   NAFLD   nonalcoholic fatty liver disease   NASH   nonalcoholic steatohepatitis   NF-   κ   B   nuclear factor kappa B   PAMP   pathogen-associated molecular pattern   PNPLA3   patatin-like phospholipase domain-containing 3   PPAR   peroxisome proliferator–activated receptor   RCT   randomized controlled trial   RNAi   RNA interference   ROS   reactive oxygen species   SCD-1   stearoyl-CoA desaturase 1   SCFA   short-chain fatty acid   siRNA   small interfering RNA   T2DM   type 2 diabetes mellitus   THR   thyroid hormone receptor   TLR   toll-like receptor   TMAO   trimethylamine N-oxide   VLDL   very low–density lipoprotein  

摘要： Metabolic dysfunction-associated steatotic liver disease (MASLD;formerly known as nonalcoholic fatty liver disease) is a chronic liver disease affecting over a billion individuals worldwide. MASLD can gradually develop into more severe liver pathologies, including metabolic dysfunction-associated steatohepatitis (MASH), cirrhosis, and liver malignancy. Notably, although being a global health problem, there are very limited therapeutic options against MASLD and its related diseases. While a thyroid hormone receptor agonist (resmetirom) is recently approved for MASH treatment, other efforts to control these diseases remain unsatisfactory. Given the projected rise in MASLD and MASH incidence, it is urgent to develop novel and effective therapeutic strategies against these prevalent liver diseases. In this article, the pathogenic mechanisms of MASLD and MASH, including insulin resistance, dysregulated nuclear receptor signaling, and genetic risk factors (eg, patatin-like phospholipase domain-containing 3 and hydroxysteroid 17-b dehydrogenase-13), are introduced. Various therapeutic interventions against MASH are then explored, including approved medication (resmetirom), drugs that are currently in clinical trials (eg, glucagon-like peptide 1 receptor agonist, fibroblast growth factor 21 analog, and PPAR agonist), and those failed in previous trials (eg, obeticholic acid and stearoyl-CoA desaturase 1 antagonist). Moreover, given that the role of gut microbes in MASLD is increasingly acknowledged, alterations in the gut microbiota and microbial mechanisms in MASLD development are elucidated. Therapeutic approaches that target the gut microbiota (eg, dietary intervention and probiotics) against MASLD and related diseases are further explored. With better understanding of the multifaceted pathogenic mechanisms, the development of innovative therapeutics that target the root causes of MASLD and MASH is greatly facilitated. The possibility of alleviating MASH and achieving be

关键词： Gout   HLA-B5801   allopurinol   characteristics   flare  

摘要： Background/Aim: Allopurinol is a standard agent used for lowering uric acid levels. Human leukocyte antigen (HLA)- B5801 positivity increases the incidence of severe cutaneous adverse reactions (SCARs) in allopurinol users. HLA alleles HLA-B27 and HLA-B51 are frequently found in patients with ankylosing spondylitis and Beh & ccedil;et's disease, showing an association with distinct clinical features. In this study, we investigated the association between the HLA- B5801 genotype and patient characteristics and outcomes in gout. Patients and Methods: We retrospectively reviewed the medical records of 263 patients with gout who were not receiving uric acid-lowering therapy and were tested for HLA-B5801 positivity between March 2020 and February 2024. Patients were classified according to their HLA-B5801 status, and patient demographics and laboratory variables were compared. The incidence of gout flares or severe flares requiring hospital care within one year was investigated. Results: A total of 37 participants were HLA-B5801 positive (37/263, 14.1%). However, no significant differences were observed in demographic or laboratory variables between the HLA-B5801 positive and negative groups. Subgroup analyses of patients with new-onset gout, males, and those with an estimated glomerular filtration rate >= 60 ml/min/1.73 m2 also demonstrated no significant differences related to HLA-B5801 genotype positivity. The incidence of disease flares or severe flares between patients in the HLA-B5801 positive and negative groups was comparable during the one-year follow-up. Conclusion: Although HLA-B5801 was a significant predictor of allopurinol-associated SCARs, the impact of HLA- B5801 positivity on the clinical characteristics or flares was not evident in this population of patients with gout.

关键词： Interleukin 21 signaling   JAK/STAT3   AKT   IgM plus B cells   Cell proliferation   Antibody secretion  

摘要： IL-21 is a type I cytokine that is produced by activated CD4+ T cells and has a significant impact on the growth, survival, and functional activation of B lymphocytes. While IL-21 has been identified in several teleost fish species, its function and associated mechanisms focus on teleost fish B cells remain largely unknown. In this study, we aimed to investigate the effects of IL-21 (OnIL-21) on IgM+ B cells from Nile tilapia (Oreochromis niloticus), as well as the intracellular signaling transduction pathway involved. Through intraperitoneal injection of recombinant OnIL-21 (rOnIL-21), we observed that IL-21 exerted significant effects on Nile tilapia IgM+ B cells, including the promotion of IgM+ B cell proliferation, induction of IgM secretion, and up-regulation of inflammatory cytokines. These findings suggest that OnIL-21 enhances the ability of IgM+ B cells in humoral immunity. Furthermore, when IgM + B cells were stimulated with rOnIL-21 in vitro, we observed a significant upregulation in antibody secretion ability (sIgM), as well as increased expression of IFN-gamma and IL-10. To further understand the regulatory mechanism of OnIL-21, we demonstrated that OnIL-21 binds to its heterodimer receptor complex (OnIL-21R/On gamma c) to exert its function. This binding triggers the conserved JAK/STAT3 and AKT pathways, which in turn regulate the expression of genes involved in B cell proliferation, antibody secretion, and cytokine expression. Collectively, our findings establish that IL-21 plays a crucial role in the regulation of humoral immunity in lower vertebrates, and this regulation is mediated through conserved signaling pathways across vertebrates.

关键词： HLA novel allele   HLA-DPB1*1781:01   nanopore sequencing  

摘要： HLA-DPB1*1781:01 differs from HLA-DPB1*03:01:01:01 by one nonsynonymous nucleotide substitution in codon 5 in exon 1.

摘要： Macrophages stimulated by lipopolysaccharide (LPS) generate mitochondria-derived reactive oxygen species (mtROS) that act as antimicrobial agents and redox signals;however, the mechanism of LPS-induced mitochondrial superoxide generation is unknown. Here we show that LPS-stimulated bone-marrow-derived macrophages produce superoxide by reverse electron transport (RET) at complex I of the electron transport chain. Using chemical biology and genetic approaches, we demonstrate that superoxide production is driven by LPS-induced metabolic reprogramming, which increases the proton motive force (triangle p), primarily as elevated mitochondrial membrane potential (Delta psi m) and maintains a reduced CoQ pool. The key metabolic changes are repurposing of ATP production from oxidative phosphorylation to glycolysis, which reduces reliance on F1FO-ATP synthase activity resulting in a higher triangle p, while oxidation of succinate sustains a reduced CoQ pool. Furthermore, the production of mtROS by RET regulates IL-1 beta release during NLRP3 inflammasome activation. Thus, we demonstrate that ROS generated by RET is an important mitochondria-derived signal that regulates macrophage cytokine production.

关键词： Head and neck squamous cell carcinoma   AIM2   STAT1   IL17   MAPK pathway  

摘要： Chronic inflammation has been recognized as one of the hallmarks of head and neck squamous cell carcinoma (HNSCC), Absent In Melanoma 2(AIM2) has emerged as important regulators of chronic inflammatory, and participated in initiation, progression of kinds of human cancers. Nonetheless, the biological functions and underlying mechanisms of AIM2 in HNSCC remain inadequately understood. Based on the bioinformatics analysis of public databases, we identified elevated AIM2 expression in HNSCC, which positively correlates with disease stage and HPV infection, thereby possessing both diagnostic and prognostic significance. Immunohistochemistry on clinical samples revealed that AIM2 expression was frequently upregulated in cancerous tissues compared to paracancerous tissues, exhibiting a significant association with Ki-67 expression. Modulating AIM2 expression in HNSCC cell lines through transfection with inhibitors or mimics demonstrated that ectopic AIM2 expression enhances cell growth, migration, tumorigenesis, and metastasis both in vitro and in vivo. A dual luciferase reporter assay indicated that the transcription factor STAT1 can bind directly to the AIM2 promoter region and activate its transcription. The STAT1 inhibitor, fludarabine, reduces AIM2 expression and subsequently diminishes cell proliferation. Mechanistically, AIM2 exerts its tumor-promoting effects through the IL17-MAPK signaling pathway. Collectively, our data demonstrate that AIM2, transcriptionally activated by STAT1, exhibits oncogenic functions by promoting the IL-17-MAPK signaling pathway, suggesting that AIM2 may be a new intervention targets for the diagnostic and treatment of HNSCC.