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摘要： The two most clinically important members of the flavivirus genus, Zika virus (ZIKV) and dengue virus (DENV) pose a significant public health challenge. They cause a range of diseases in humans, from hemorrhagic to neurological manifestations, leading to economic and social burden worldwide. Nevertheless, there are no approved antiviral drugs to treat these infections. Zafirlukast is an orally available Food and Drug Administration (FDA) approved drug for the prophylaxis and treatment of chronic asthma. It is a leukotriene receptor antagonist (LTRA) with high selectivity of the cysteinyl leukotriene-1 receptor (CYSLTR1) that acts as an immune modulator. Thus, we evaluated the antiviral potential of Zafirlukast against ZIKV and DENV in SK-N-SH cells. We showed that Zafirlukast exhibited potent antiviral activity against ZIKV, which could be linked to Zafirlukast's immune blockade of TNF signaling pathways and its downstream signaling pathways such as MAPK and ERK1/2. In addition, our results showed that Zafirlukast also counteracts ZIKV-induced changes in key genes involved in cellular lipid metabolism. Thus, these findings highlight the translational potential of optimizing Zafirlukast as a therapeutic agent for the treatment of ZIKV and DENV.

关键词： Macroinvertebrates  

摘要： IFN-λs hold promise as therapeutic candidates against mutable respiratory viruses, but their efficacy against porcine reproductive and respiratory syndrome virus (PRRSV) remains unclear. In this study, we expressed a recombinant fusion protein consisting of porcine ISG15 linked porcine IFN-λ3 (ISG15-IFN-λ3) via a rigid protein linker in Escherichia coli (E. coli). In vitro experiments demonstrated that treatment of porcine alveolar macrophage (PAM)-derived CRL-2843 cells with ISG15-IFN-λ3 induced upregulation of several Interferon-stimulated Genes (ISGs) proteins, including ISG15, ISG56, and HERC5. CRL-2843 cells pretreated with ISG15-IFN-λ3 exhibited heightened resistance to Newcastle disease virus infection, while PRRSV-permissive cells treated with ISG15-IFN-λ3 before and during PRRSV exposure showed significantly inhibited PRRSV replication as well. In animal experiments, at 21 days post-infection, ISG15-IFN-λ3-treated piglets displayed milder lung tissue pathology and significantly reduced serum PRRSV-RNA, indicating enhanced viral clearance and faster recovery. Additionally, PAMs collected from ISG15-IFN-λ3-treated piglets showed significantly reduced mRNA expression of representative cytokines, chemokines, suggesting that ISG15-IFN-λ3 treatment may mitigate pneumonia severity by reducing the levels of these inflammatory mediators. These findings indicate that recombinant ISG15-IFN-λ3 expressed in E. coli may serve as a novel, effective, and affordable agent for treating severe PRRSV infection in piglets, potentially benefiting the pork industry. © 2024 Elsevier B.V.

关键词： Acute therapy   Edaravone   Genetics   Intracerebral hemorrhage  

摘要： Objective: Edaravone is utilized in intra-cerebral hemorrhage (ICH) patients for years, while personalized variances were observed in clinic. To explore the precision medicine strategy for Edaravone, this study investigated the association between genetic polymorphisms and Edaravone efficacy in ICH patients. Methods: We genotyped 7 SNPs in 4 potential genes, including COL4A2, TNF, WNK2 and IL6, from the peripheral blood of 217 ICH patients with or without Edaravone utilizations. PLINK and SPSS were utilized for association tests, Student's t tests, Mann-Whitney U tests and Chi-square tests. Results: Rs1800796 (C>G) in IL6 (OR: 0.41, 95 % CI: 0.18-0.94, p-value = 0.03) and rs16936752 (G>T) in WNK2 (OR: 0.28, 95 % CI: 0.09-0.88, p-value = 0.02) were found to be significantly associated with Edaravone efficacy. The association of rs1800796 and rs16936752 were found to be different in patients with or without smoking habit, alcohol drinking habit, hypertension history and hyperlipemia history were found to be different. Both of these two SNPs were found to be associated with the concentration of high-density lipoprotein cholesterol (HDL) in ICH patients. Conclusions: The IL6 rs1800796 and the WNK2 rs16936752 could be useful biomarkers for prognosis prediction during Edaravone treatment. These SNPs should be considered in the personalized medicine strategy for Edaravone in the future.

关键词： Monocytic HLA-DR   Sepsis   Infection   Diagnosis   Severity   Prognosis  

摘要： Objective: Sepsis is characterized by high incidence and mortality rates, making early recognition and risk stratification critical for preventing delayed treatment and overtreatment. This study investigated the potential of monocytic (m) HLA-DR as a diagnostic and prognostic biomarker of sepsis. Methods: In this prospective study, we collected blood in EDTA-anticoagulated tubes within 48 h from patients diagnosed with sepsis or infection and analyzed the percentage of mHLA-DR in peripheral blood mononuclear cells, C-reactive protein, and procalcitonin within 2 h of collection. We gathered clinical and laboratory data, including sex, age, and comorbidities, calculated the number of dysfunctional organs and sequential organ failure assessment (SOFA) score, and recorded the survival status of patients with sepsis on the 30th day after admission. Results: mHLA-DR levels were lower in patients with sepsis (median 46.60 [interquartile range 23.86-66.51]%) than infection (75.44 [52.13-91.50]%). mHLA-DR could distinguish sepsis from infection with an area under the curve (AUC) of 0.724 (95 %CI 0.624-0.824). Decreased mHLA-DR levels have been found in septic patients with shock or secondary infections. mHLA-DR expression decreased with an increasing number of dysfunctional organs and higher SOFA score. In 30-day non-survivors, mHLA-DR levels were 26.94 (12.06-44.45)%, significantly lower than in survivors (55.20 [24.83-72.37]%). mHLA-DR predicted sepsis prognosis with an AUC of 0.750 (95 %CI 0.623-0.877). When the cut-off value was <52.29 %, the sensitivity and specificity of mHLA-DR for prognosis were 100 % and 52.83 %, respectively. The 30-day survival rate of septic patients with mHLA-DR >= 52.29 % was 6.798 (95 %CI 2.075-22.27) times higher than that of patients with mHLA-DR < 52.29 %. Conclusion: mHLA-DR negatively correlates with the severity of sepsis and could be used as a diagnostic and prognostic biomarker for sepsis.

关键词： Daphne mezereum   Thymelaeaceae   Coumarins   Flavonoids   Immune cells  

摘要： Daphne mezereum L. (Thymelaeaceae) was an important medicinal plant in Norway during the 18th and 19th centuries and used against diseases such as diarrhea, swelling, stomach pain, and tuberculosis. Five previously undescribed phenolic compounds, including two biflavonoids with a catechin core structure, two tricoumarins, and one bicoumarin, together with ten known compounds were isolated from a 50% EtOH extract of the bark of D. mezereum. Using NMR, HRESIMS, acid hydrolysis, and circular dichroism spectra, the biflavonoids were identified as 3 '-hydroxygenkwanol A and 3 '-hydroxydihydrodaphnodorin B, and the coumarins were identified as 3"-O-acetyltriumbellin, triumbellin 4"-O-beta-D-glucopyranoside, and daphnogitin-7-O-beta-D-glucopyranoside. The absolute configuration of dihydrodaphnodorin B was for the first time established as 2R, 3S, 2 '' S, 3 '' S. Daphnin, syringin, 3 '-hydroxydihydrodaphnodorin B, dihydrodaphnodorin B, and neochamaejasmin A and B were identified as the major secondary metabolites in the extract. Neochamaejasmin A and B showed the most potent inhibition of TNF-alpha secretion in Con A stimulated peripheral blood mononuclear cells (PBMCs) with 71.3 +/- 3.4 and 83.5 +/- 11.5% inhibition, respectively, at 50 mu M.

关键词： ADHD   ASD   cerebellum   Interleukin-4   microglia   prefrontal cortex  

摘要： Microglia are crucial for brain development and their function can be impacted by postnatal insults, such as early-life allergies. These are characterized by an upregulation of interleukin (IL)-4 levels. Allergies share a strong comorbidity with Autism Spectrum Disorders (ASD) and Attention-Deficit/Hyperactivity Disorder (ADHD). We previously showed that early-life allergic asthma induces hyperactive and impulsive behaviors in mice. This phenotype was reproduced in animals administered with IL-4 in the second postnatal week. Mechanistically, elevated IL-4 levels prevented microglia-mediated engulfment of neurons in the cerebellum, resulting in a surplus of granule cells and consequent dysfunction in cerebellar connectivity. Here, we aimed to further understand the impact of early IL-4 administration in microglia of the cerebellum and the prefrontal cortex (PFC), two brain regions with protracted developmental programs and susceptible to immune system malfunction after birth. While IL-4 administration induced differential short-term effects on microglia in the cerebellum and PFC, both regions presented similar microglial features in adult mice. Although Sholl analysis did not reveal significant alterations in overall microglia morphology at postnatal day (P)10, the density of microglia was decreased in the cerebellum at this age, especially in the granular layer (GL), but remained unaltered in the PFC. Interestingly, the presence of microglia with phagocytic cups, morphological features important for whole-cell engulfment, was decreased in both regions. When assessing the long-term consequences of IL-4 administration, cerebellar and PFC microglia were hypo-ramified and exhibited increased overall density. Importantly, microglia alterations were exclusive to the GL of the cerebellum and the infralimbic region of the PFC. Our results show that postnatal elevated levels of IL-4 impair the percentage of microglia engaged in cell clearing in two brain regions with protrac

关键词： clinically relevant acute rejection   functional single-nucleotide polymorphisms   genetics   mismatch score   transmembrane and secreted proteins  

摘要： Background:Acute cellular rejection (ACR) remains a common complication causing significant morbidity post-liver transplantation. Non-human leukocyte antigen (non-HLA) mismatches were associated with an increased risk of ACR in kidney transplantation. Therefore, we hypothesized that donor-recipient non-HLA genetic mismatch is associated with increased ACR incidence post-liver ***:We conducted an international multicenter case-control genome-wide association study of donor-recipient liver transplant pairs in 3 independent cohorts, totaling 1846 pairs. To assess genetic mismatch burden, we calculated sum scores for single-nucleotide polymorphism (SNP) mismatch based on all non-HLA functional SNPs, specifically SNPs coding for transmembrane or secreted proteins as they more likely affect the immune system. We analyzed the association between the non-HLA mismatch scores and ACR in a multivariable Cox regression model per cohort, followed by a weighted ***:During the first year post-transplantation, 90 of 689 (13%), 161 of 720 (22%), and 48 of 437 (11%) recipients experienced ACR in cohorts 1-3, respectively. Weighted meta-analyses showed that higher mismatch in functional non-HLA SNPs was associated with an increased incidence of ACR (HR 5.99;95% CI: 1.39-20.08;p=0.011). Moreover, we found a larger effect of mismatch in SNPs coding for transmembrane or secreted proteins on ACR (HR 7.54;95% CI 1.95-28.79;p=0.003). Sensitivity analyses showed that imputed HLA mismatch did not affect the associations between both non-HLA mismatch scores and ***:Donor-recipient mismatch of functional non-HLA SNPs overall and, especially, of SNPs encoding transmembrane or secreted proteins correlated with 1-year ACR post-liver transplantation. Identifying high-risk immunological burdens between pairs may prevent early graft rejection and aid in personalizing immunosuppressive therapy. Future studies are, however, needed to validate our findin

关键词： cholesteatoma   IL-6   Middle Ear Risk Index   miRNA-21  

摘要： Background: Cholesteatoma, a destructive middle ear condition, poses challenges due to its variable clinical presentation and propensity for recurrence. Understanding its molecular underpinnings could enhance prognostication and guide therapeutic interventions. This study investigates the association between cholesteatoma aggressiveness, as assessed by the Middle Ear Risk Index (MERI), and the expression of miRNA-21 and IL-6 genes. Methods: A cross-sectional observational study involving 30 patients with cholesteatoma undergoing tympanomastoid exploration was conducted. MERI scores were calculated preoperatively, and cholesteatoma tissue was analyzed for miRNA-21 and IL-6 gene expression using RT-PCR. Statistical analysis was performed to correlate MERI scores with gene expression levels. Results: The majority (80%) of patients exhibited severe MERI scores, correlating with extensive middle ear pathology and necessitating canal wall-down (CWD) mastoidectomy. Higher miRNA-21 and IL-6 gene expression levels were observed in cholesteatoma tissues, indicating local aggressiveness and inflammatory activity. Significant moderate correlations were found between MERI scores and miRNA-21 (Pearson correlation = 0.579, p = 0.001) and IL-6 gene expression (Pearson correlation = 0.388, p = 0.034). Patients with severe MERI scores had elevated miRNA-21 and IL-6 levels, suggesting a more aggressive disease phenotype. Conclusion: MERI scores demonstrated utility in predicting cholesteatoma aggressiveness, with higher scores correlating with elevated miRNA-21 and IL-6 expression. These findings suggest a potential role for MERI in guiding surgical decision-making and prognostication. Future research on targeted therapies based on molecular mechanisms holds promise for improving cholesteatoma management.

关键词： T cell exhaustion   Mucosal immunity   CD8+T   Gut   Ischemia reperfusion  

摘要： Currently, impairments in gut mucosal immunity following intestinal ischemia reperfusion (IR) remain unclear. Mucosal CD8+T cells are critical for host defense against bacterial translocation from the gut lumen, and exhausted T cells lose robust effector functions. The present study was designed to verify the hypothesis that intestinal IR leads to mucosal CD8+T cell exhaustion, and that reinvigoration of exhausted CD8+T cell attenuates IR-induced bacterial translocation and liver damage. The intestinal IR model was performed through clamping the superior mesenteric artery in mice. The percent of exhausted CD8+T cells and the effector function of CD8+T cells were examined to determine the occurrence of intestinal mucosal CD8+T cell exhaustion. Subsequently, PD1 blockade or combined PD-1 and IL-10 blockade was respectively used to reinvigorate exhausted CD8+T cells. Serum biomarkers, bacterial RNA and colonies, and inflammatory factors were examined to determine bacterial translocation and liver damage. The results indicated that intestinal IR induced CD8+T cell exhaustion in mucosal tissues, as evidenced by increased PD-1+ and PD-1+LAG-3+CD8+T cells and decreased IL-2 and TNF-alpha expression in CD8+T cells. Combined PD-1 and IL-10 blockade, but not PD-1 blockade alone, reinvigorated CD8+T cell exhaustion, as evidenced by increased generation of exhausted CD8+T cells with cytotoxicity and effector function, and elevated production of IFN-gamma. Moreover, combined blockade significantly reduced the translocation of gut bacteria and injury to the liver after IR. In conclusion, intestinal IR leads to mucosal CD8+T cell exhaustion. Combined PD-1 and IL-10 blockade reinvigorates exhausted CD8+T cells, and ameliorates bacterial translocation and liver damage following IR.

关键词： Clinical study   Diabetes   IL-1 beta   Inflammasome   Inflammation   Insulin   NLRP3   Obesity   Pancreatic islet   Review  

摘要： Increased activity of the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome-IL-1 beta pathway is observed in obesity and contributes to the development of type 2 diabetes and its complications. In this review, we describe the pathological activation of IL-1 beta by metabolic stress, ageing and the microbiome and present data on the role of IL-1 beta in metabolism. We explore the physiological role of the IL-1 beta pathway in insulin secretion and the relationship between circulating levels of IL-1 beta and the development of diabetes and associated diseases. We highlight the paradoxical nature of IL-1 beta as both a friend and a foe in glucose regulation and provide details on clinical translation, including the glucose-lowering effects of IL-1 antagonism and its impact on disease modification. We also discuss the potential role of IL-1 beta in obesity, Alzheimer's disease, fatigue, gonadal dysfunction and related disorders such as rheumatoid arthritis and gout. Finally, we address the safety of NLRP3 inhibition and IL-1 antagonists and the prospect of using this therapeutic approach for the treatment of type 2 diabetes and its comorbidities.