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关键词： TNF   immunomodulator   molecular docking   ADMET   gene expression  

摘要： Organic acids, as natural metabolites, play crucial roles in human metabolism and health. Tumor Necrosis Factor (TNF), a pivotal mediator in immune regulation and inflammation, is a key therapeutic target. We evaluated ten organic acids as TNF modulators using in silico molecular docking, followed by detailed ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) profiling and molecular dynamics (MD) simulations for three lead candidates: gallic, aconitic, and crocetin acids. Their effects on TNF gene expression were then assessed in vivo using a mouse leukocyte model. The in silico results indicated that crocetin had the highest TNF binding affinity (-5.6 to -4.6 kcal/mol), while gallic acid formed the most stable protein-ligand complex during MD simulations, and aconitic acid established hydrogen bond interactions. ADMET analysis suggested potential pharmacokinetic limitations, including low permeability. Contrasting its high predicted binding affinity, in vivo gene expression analysis revealed that crocetin stimulated TNF synthesis, whereas gallic and aconitic acids acted as inhibitors. This research explores organic acids as potential TNF modulators, highlighting their complex interactions and providing a foundation for developing these compounds as anti-inflammatory agents targeting TNF-mediated diseases.

关键词： 阿昔洛韦   糖皮质激素   带状疱疹   有效度   细胞因子  

摘要： 探讨阿昔洛韦结合糖皮质激素治疗带状疱疹的效果影响。方法 选取76例带状疱疹患者,按照不同治疗方案分成两个小组,每组各38例。参照组(予以单纯阿昔洛韦治疗)和干预组(予以阿昔洛韦结合糖皮质激素治疗),对比两组患者的治疗有效率、症状改善时间、后遗神经痛发生率以及细胞因子水平的变化。结果 对比显示,干预组有效率显著高于参照组(P<0.05)。相较参照组,干预组症状缓解时间(止疱、结痂、止痛)更短(P<0.05)。对比显示,干预组遗神经痛发生率显著低于参照组(P<0.05)。治疗前,两组 CRP、PCT 水平无显著差异(P>0.05);治疗后,干预组较参照组显著降低(P<0.05)。结论 阿昔洛韦结合糖皮质激素治疗带状疱疹可提高临床疗效,缩短病程,降低后遗神经痛发生率,且对细胞因子水平有积极调节作用。

关键词： all-trans-retinoic acid   Gfi1   IL-4   IL-13   RAR alpha   Th2  

摘要： All-trans retinoic acid (atRA), the bioactive component of vitamin A, plays a pivotal role in various biological processes. atRA, essential for embryonic development and immune functions, primarily mediates its regulatory effects by interacting with the nuclear receptor RAR alpha (retinoic acid receptor alpha). atRA-bound RAR alpha enters the nucleus and forms a heterodimer with RXR (retinoid X receptor). This heterodimer can then interact with various transcription factors to form regulatory complexes that influence gene expression. While the role of atRA in regulating the type 2 immune response has been studied, further exploration into its specific involvement in Th2 cell differentiation is necessary to fully elucidate underlying mechanisms and assess its therapeutic potential. Our study shows that atRA suppressed the Th2 phenotype by downregulating type 2 transcription factors such as Spi1 and cMaf, without altering Gata3 expression. atRA also reduced IL-4 and IL-13 production, while enhancing IL-5 expression, potentially through upregulation of Gfi1. atRA increased the Gfi1 recruitment to the Il4 and Il13 promoters, along with the common enhancer Ecr (evolutionarily conserved region). RAR alpha, which is typically an inducer of Il4 and Il13, was observed to decrease recruitment to these loci in atRA-treated Th2 cells. Comparative gene expression analysis revealed a reduction in inflammatory responses in atRA-treated Th2 cells. Furthermore, these cells exhibited a negative correlation with epigenetic modifications and nuclear receptor activity among other biological processes. Collectively, our findings suggest that atRA can effectively suppress the Th2 phenotype in vitro, through the regulation of key type 2 transcription factors and pathways, indicating its potential therapeutic implications for limiting type 2 immune responses.

摘要： This study aimed to evaluate the immune-enhancing efficacy and mechanism of liposome-Rh2 as a novel vaccine adjuvant. By using an integrated preparation strategy that combined ethanol injection with high-pressure homogenization, we successfully fabricated a stable liposome-Rh2 adjuvant. Structural characterization revealed a well-defined spherical architecture with uniform particle distribution (PDI < 0.2). Notably, this formulation demonstrated exceptional colloidal stability, maintaining a unimodal size distribution and a high encapsulation efficiency exceeding 96% throughout 60 weeks of storage. In vitro experiments indicated that liposome-Rh2 could enhance the phagocytic ability of DC2.4 cells and activate the NF-kappa B signaling pathway. In the in vivo assay, liposome-Rh2 significantly enhanced humoral immunity (represented by the OD value) and simultaneously promoted cellular immune responses (reflected by the proportions of CD3(+) T cells and CD8(+) T cells). Additionally, it enhanced the activation of macrophages and the homing of dendritic cells and significantly improved the MHC-I molecule presentation pathway. These results suggested that liposome-Rh2 has the potential to be a vaccine adjuvant.

关键词： Procalcitonin (PCT)   Presepsin   Interleukin-6 (IL-6)   C-reactive protein (CRP)   Rabbit Anti-Thymocyte Globulin (rATG)   heart transplantation   inflammatory biomarkers  

摘要： Background/Objectives: Heart transplantation (HTx) is a lifesaving procedure for end-stage heart failure patients;however, postoperative infections remain a major challenge due to immunosuppressive therapy and surgical complications. Traditional biomarkers such as C-reactive protein (CRP) and procalcitonin (PCT) have limitations in distinguishing infections from systemic inflammatory response syndrome (SIRS). Emerging markers such as Presepsin and interleukin-6 (IL-6) may improve diagnostic accuracy. This study aimed to evaluate the kinetics and reliability of these four inflammatory biomarkers in heart transplant recipients in the immediate postoperative period. Methods: This retrospective observational study included 126 patients who underwent HTx at Policlinic of Bari between January 2022 and November 2024. Patients were categorized into infected (n = 26) and non-infected (n = 100) groups based on clinical and microbiological criteria. Biomarkers (CRP, PCT, Presepsin, and IL-6) were measured preoperatively and on postoperative days (PODs) 1, 2, 3, 4, 5, and 10. Statistical analyses included the Mann-Whitney U test and logistic regression to identify the independent predictors of infection. Results: CRP and PCT levels differed significantly between the groups only on day 10, limiting their use as early infection markers. In contrast, Presepsin levels were significantly elevated in infected patients from day 1 (p < 0.001), whereas IL-6 levels showed significant differences from day 3 onward. Presepsin showed the strongest association with infection in the early postoperative phase. Conclusions: Presepsin and IL-6 outperformed CRP and PCT in detecting early postoperative infections in heart transplant recipients. Their early elevation supports their use as reliable markers for guiding timely clinical intervention and improving patient outcomes. Further research is needed to validate these findings in larger cohorts and with different immunosuppressive regimens.

关键词： Adaptive immunity   Immunology   Infectious disease   Vaccines  

摘要： BACKGROUND:Anti-TNF biologics are widely used to treat patients with immune-mediated inflammatory diseases. In mouse models, the complete absence of TNF impairs germinal center (GC) responses. Less is known about the impact of anti-TNF therapy on specific immune responses in humans. Widespread vaccination against SARS-CoV-2 offered an unprecedented opportunity to investigate the effects of biological therapies on responses to specific immunization. Previous work demonstrated that inflammatory bowel disease (IBD) patients treated with anti-TNF biologics exhibit decreased Spike-specific antibody responses compared to IBD patients treated with anti-IL-12/23 or healthy controls, even after four doses of mRNA vaccine. METHODS:Here we analyzed humoral responses to SARS-CoV-2 immunization using single-cell RNA-Sequencing and flow cytometry of Spike-specific memory B cells (MBC), as well as avidity measurements of plasma antibodies from IBD patients treated with anti-TNF or anti-IL-12/23 or from healthy controls. RESULTS:We observed decreased somatic hypermutation in the B cell receptors of Spike-specific MBCs and decreased antigen-specific MBC accumulation following SARS-CoV-2 mRNA vaccination in anti-TNF treated IBD patients, compared to IBD patients treated with anti-IL-12/23 or healthy controls. This decreased somatic hypermutation in Spike-specific MBCs in anti-TNF treated patients correlated with decreased and delayed antibody affinity maturation and reduced neutralization activity. CONCLUSION:These data provide in vivo evidence that anti-TNF, but not anti-IL-12/23, therapy impairs the quantity and quality of antigen-specific GC outputs in humans. FUNDING:Juan and Stefania Speck (donation) and by Canadian Institutes of Health Research (CIHR)/COVID-Immunity Task Force (CITF) grants VR-1 172711, VS1-175545, GA2-177716, GA1-177703 and CIHR FDN 143301 &143350.

关键词： HLA-G   primary biliary cholangitis   ursodeoxicholic acid   Sardinia (Italy)   autoimmune diseases  

摘要： Introduction Primary biliary cholangitis (PBC) is a rare autoimmune liver disease involving bile duct damage and fibrosis. This study explores the role of HLA-G, an immunomodulatory molecule crucial for immune tolerance, in PBC pathogenesis and *** A cohort of 166 PBC patients from Sardinia was compared to 180 healthy controls and 205 autoimmune hepatitis type 1 (AIH-1) patients. Plasma soluble HLA-G (sHLA-G) levels, HLA-G alleles, and 3'UTR haplotypes were analyzed alongside clinical data, including therapy response to ursodeoxycholic *** The UTR-1 haplotype was significantly more frequent in PBC patients than in controls (48.2% vs 34.3%, Pc= 0.0018). The extended haplotype HLA-G*01:01:01:08/UTR-1 was also strongly associated with PBC (23.2% vs 12.5% in controls, Pc = 0.008;23.2% vs 6.6% in AIH-1, Pc= 2.6x10-9). PBC patients exhibited lower sHLA-G levels compared to controls and AIH-1 (9.1 U/mL vs 24.03 U/mL and 13.9 U/mL, respectively). Among UTR-1 carriers, sHLA-G levels were particularly reduced in PBC patients. The HLA-G*01:01:01:08/UTR-1 haplotype correlated with the lowest sHLA-G levels and poorer therapy response (60% vs 24.1%, P = 0.0001).Discussion These findings suggest HLA-G variants, especially HLA-G*01:01:01:08/UTR-1, as potential biomarkers for PBC prognosis and treatment outcomes.

关键词： Alzheimer's disease   APPswe/PS1dE9 mice   cytokines   stem cell therapy   neuroinflammation   amyloid plaques   emotionality   cognition  

摘要： Neuroinflammation is a key feature of Alzheimer's disease (AD), and stem cell therapies have emerged as promising candidates due to their immunomodulatory properties. Neuro-Cells (NC), a combination of unmodified mesenchymal stem cells (MSCs) and hematopoietic stem cells (HSCs), have demonstrated therapeutic potential in models of central nervous system (CNS) injury and neurodegeneration. Here, we studied the effects of NC in APPswe/PS1dE9 mice, an AD mouse model. Twelve-month-old APPswe/PS1dE9 mice or their wild-type littermates were injected with NC or vehicle into the cisterna magna. Five to six weeks post-injection, cognitive, locomotor, and emotional behaviors were assessed. The brain was stained for amyloid plaque density using Congo red, and for astrogliosis using DAPI and GFAP staining. Gene expression of immune activation markers (Il-1 beta, Il-6, Cd45, Tnf) and plasticity markers (Tub beta 3, Bace1, Trem2, Stat3) was examined in the prefrontal cortex. IL-6 secretion was measured in cultured human monocytes following endotoxin challenge and NC treatment. Untreated APPswe/PS1dE9 mice displayed impaired learning in the conditioned taste aversion test, reduced object exploration, and anxiety-like behavior, which were improved in the NC-treated mutants. NC treatment normalized the expression of several immune and plasticity markers and reduced the density of GFAP-positive cells in the hippocampus and thalamus. NC treatment decreased amyloid plaque density in the hippocampus and thalamus, targeting plaques of <100 mu m(2). Additionally, NC treatment suppressed IL-6 secretion by human monocytes. Thus, NC treatment alleviated behavioral deficits and reduced amyloid plaque formation in APPswe/PS1dE9 mice, likely via anti-inflammatory mechanisms. The reduction in IL-6 production in human monocytes further supports the potential of NC therapy for the treatment of AD.

关键词： Asthma   secondhand smoke   IL-17 gene polymorphism   cotinine  

摘要： Background: Asthma is a multifactorial disease affecting approximately 300 million people worldwide. Multiple genes, environmental risk factors, and their interactions have been associated with asthma. Smoking triggers an IL-17-mediated inflammatory response. The IL-17-related inflammatory response may differ between individuals, and this difference is associated with IL-17 polymorphisms. Objective: Our aim was to investigate the effect of IL-17 polymorphism and its interaction with secondhand smoke on pediatric asthma Methods: The study comprised 100 pediatric asthma patients and 100 healthy children. Cotinine levels were analyzed to show SHS exposure (SHSe). A genetic study was conducted to reveal IL-17F(rs763780) and IL-17A (rs8193036, rs2275913) polymorphisms. The study participants were categorized into four groups based on the cotinine results: asthma with SHSe, asthma without SHSe, control with SHSe, and control without SHSe. Results: The median cotinine concentration was 11.06 ng/ml. Children with asthma had lower cotinine levels than healthy children (p < 0.001). Genotype distributions and allele frequencies of rs763780, rs8193036, and rs2275913 were compared among the four groups, and no significant differences were found. Conclusion: This study is the first to demonstrate the relationship between IL-17 polymorphisms and SHS interaction in childhood asthma. Neither the presence of IL-17 polymorphisms nor the interaction of these polymorphisms with SHS was found to be associated. The lower cotinine levels in asthmatic children suggest that parents are more susceptible to SHSe. Cotinine levels in our cohort were significantly greater than those found in developed countries. This demonstrates that exposure to SHS is still a serious environmental issue in our country.

关键词： allergy   eosinophilic esophagitis   IL-33   TSLP  

摘要： RationaleThymic stromal lymphopoietin (TSLP) and IL-33 are alarmins implicated in eosinophilic esophagitis (EoE) pathogenesis by activating multiple cells, including mast cells (MCs). Whether TSLP or IL-33 have a role in EoE and whether their activities are distinct requires further *** EoE was induced in wild type (WT) Il33-/- and Crlf2-/- mice. TSLP or IL-5 were neutralized using antibodies. Esophageal histopathology was determined by H&E, anti-Ki67, anti-CD31, and anti-MBP staining. Esophageal RNA was subjected to RNA sequencing. Bone marrow-derived MCs were activated with TSLP and IL-13 was determined (ELISA).ResultsTSLP and IL-33 were overexpressed in human and experimental EoE. Human and mouse esophageal MCs displayed the highest level of Crlf2 (TSLPR) compared to other immune cells. Crlf2-/- mice were nearly completely protected from EoE, and TSLP neutralization resulted in decreased basal cell proliferation, eosinophilia, lamina propria thickening, and vascularization. Induction of experimental EoE in Il33-/- mice resulted in reduced eosinophilia, but no alterations in tissue remodeling were observed compared to WT mice. RNA sequencing revealed that TSLP regulates the expression of key genes associated with human EoE (e.g., eotaxins, Il19, Klk5, Flg, Il36rn, Il1r2) and suggests a role for TSLP in regulating IL-1 signaling, barrier integrity, and epithelial cell differentiation. Experimental EoE was characterized by a MC-associated gene signature and elevated MCs. Activation of MCs with TSLP resulted in the secretion of *** and IL-33 have non-redundant functions in experimental EoE. This study highlights TSLP as an upstream regulator of IL-13 and a potential therapeutic target for EoE.