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关键词： Anti-TNF agents   Cochrane   Psoriasis   Randomized controlled trials   adalimumab   chronic plaque psoriasis   etanercept   pediatric   tumor necrosis factor  

摘要： The transcription factor AP-2 alpha plays a crucial role in the control of tumor development and progression, and suppresses the proliferation and migration of hepatocellular carcinoma (HCC). However, the detailed function and mechanisms of AP-2 alpha in the pathogenesis of HCC are still elusive. In the current study, we investigated the role of AP-2 alpha regulation in liver injury-mediated HCC development. Downregulation of Tfap2a expression was found in the livers of DEN/CCl4-induced fibrosis and HCC mouse model. Hepatocyte (Alb-Cre), hepatic stellate cell (HSC) (Lrat-Cre) and macrophage (LysM-Cre) specific Tfap2a knockout mice were generated, respectively. Conditional knockout of Tfap2a was able to promote hepatic steatosis in Tfap2a(Delta Hep) and Tfap2a(Delta M Phi) mice, but not in Tfap2a(Delta HSC) mice fed with normal chow. Tfap2a(Delta Hep) and Tfap2a(Delta M Phi) mice treated with DEN/CCl4 for 6 months increased tumor burden compared to Tfap2a flox controls. Tfap2a-deleted macrophages or hepatocytes could enhance lipid droplet (LD) accumulation in hepatocytes. Mechanistically, AP-2 alpha binds to the promoter regions of SREBP1/ACC/FASN and inhibits hepatic lipid de novo synthesis. Deletion of Tfap2a in macrophages enhances polarization of M1 macrophages with increased iNOS expression but decreased CD206 expression, which resulted in increased pro-inflammatory cytokines and decreased anti-inflammatory factors, especially the hepatoprotective factor IL-10. The m6A modification writer WTAP could reduce the mRNA stability of AP-2 alpha in a reader YTHDC1-dependent manner, whereas knockdown of WTAP or YTHDC1 enhances AP-2 alpha expression and decreases lipid accumulation in HCC cells. Clinically, AP-2 alpha expression negatively correlates with the expression of FASN, WTAP, YTHDC1 and the development of liver disease. Taken together, hepatocyte- or macrophage-specific deletion of Tfap2a promotes hepatic steatosis, fibrosis, and the development of HCC. These re

关键词： hypertensive disorders of pregnancy   omega-3 fatty acids   oxidative stress   glutathione   metabolism   superoxide   antioxidant   lipid mediators  

摘要： Introduction Hypertensive disorders of pregnancy (HDP) are marked by elevated levels of TNF alpha, which increases reactive oxygen species (ROS) and disrupts metabolism of trophoblasts. Resolvin D2 (RvD2), an omega-3 fatty acid-derived lipid mediator, is known to resolve inflammation, but its role in protecting trophoblasts by promoting antioxidant responses to alleviate ROS remains unclear. Nuclear translocation of nuclear factor erythroid 2-related factor 2 (NRF2) controls cellular defense mechanisms against oxidative stress and helps with the maintenance of cellular redox homeostasis. Upon translocation to nucleus, NRF2 activates the antioxidant response element (ARE), inducing the expression of genes that can mitigate ROS. Hence, we hypothesized that RvD2 activates NRF2 and prevents TNF alpha-induced mitochondrial dysfunction in *** We investigated RvD2's potential protective mechanisms against TNF alpha-induced oxidative stress in trophoblasts by pretreating JEG cells with 100 nM RvD2, followed by exposure to 50 or 100 ng/mL TNF *** We also observed that placental TNF alpha levels were elevated, while NRF2 protein levels were reduced in human HDP placental tissues compared to normotensive placentas. We demonstrate that RvD2 alone enhances NRF2 nuclear translocation, increases glutathione levels and mitochondrial function, and reduces mitochondrial ROS. In contrast, TNF alpha alone decreases nuclear NRF2 levels, increases mitochondrial ROS and oxygen consumption rates, and impairs migration. Notably, pretreatment of RvD2 before TNF alpha exposure protects against mitochondrial ROS, increases NRF2 levels, and restores mitochondrial oxygen consumption rates in *** These findings demonstrate that RvD2 functions as a positive regulator of endogenous antioxidant properties by enhancing NRF2 levels and mitigating mitochondrial ROS in placental trophoblasts.

关键词： Pendulums  

摘要： The development of biomolecular sensing technologies with high sensitivity and specificity remains an important goal in modern analytical science. Molecular pendulum sensing has emerged as a new reagentless method capable of detecting a wide array of biomolecules directly in biological fluids. This sensing approach relies heavily on the modulation of hydrodynamic drag of molecular probes through solution, such that alterations in hydrodynamic diameter can transduce biomolecular interactions. Here, we explore the use of nanobodies as an alternative receptor in pendulum-based systems due to their small size and robust affinities. We compare the performance of nanobodies with that of aptamers and antibodies integrated into the molecular pendulum system by targeting the inflammatory indicator interleukin-6 (IL-6). Nanobody molecular pendulums demonstrate enhanced sensor response and sensitivity compared to those of the other receptors, enabling fine control over detection in the low physiological range of IL-6. In addition, we demonstrate the ability of nanobody sensors to function in complex biological matrices and at physiological temperature.

关键词： infliximab   adalimumab   Treg   pediatric   response biomarkers   T-lymphocytes   cytokines   inflammatory bowel disease  

摘要： Failure of anti-TNF therapy is a real concern in children with inflammatory bowel disease (IBD) owing to the limited therapeutic arsenal. Anti-TNF drugs modulate the immune response, a key driver of chronic inflammation in IBD. Accordingly, we analyzed changes in the frequency of T-lymphocyte and cytokine levels after 6 weeks of treatment to identify potential biomarkers of response to anti-TNF drugs. We recruited 77 patients under 18 years of age diagnosed with IBD and treated with an anti-TNF drug. Using flow cytometry and multiplex ELISA, we analyzed 31 T-lymphocyte populations and four cytokines. We identified changes in 10 populations of T lymphocytes after 6 weeks of treatment. Na & iuml;ve Tregs were associated with a primary response to anti-TNF drugs, while activated Tregs were associated with long-term response. Serum INF-gamma levels were decreased after anti-TNF treatment in children with Crohn's disease (CD), but not in those with ulcerative colitis (UC). The memory CD8+ Type 2 Cytotoxic T (Tc2) subset increased in non-responders with CD and the CD4+ memory Th17 cells increased in non-responders with UC. These findings could help us to understand the cellular regulation of anti-TNF therapy, to identify children at a higher risk of treatment failure, and, potentially, to develop more personalized therapeutic strategies.

关键词： 网络药理学   酒精性肝损伤   赶黄草   IL-11R/JAK/STAT通路   肠肝轴   Network Pharmacology   Alcoholic Liver Injury   Pursh   IL-11R/JAK/STAT Signaling Pathway   Gut-Liver Axis  

摘要： 目的：本研究基于“肝与大肠相通”理论，采用网络药理学预测与动物实验验证相结合的策略，探讨赶黄草–炙黄芪–生大黄复方(SHY)干预酒精性肝损伤(ALI)的作用机制。方法：网络药理学获取SHY干预ALI的活性成分及主要靶点，构建PPI网络，进行GO和KEGG富集分析筛选可能涉及的生物过程和信号通路。利用Lieber-DeCarli酒精液体饲料[5% (vol/vol)乙醇]复制野生型(WT)小鼠ALI模型，通过检测体循环血清ALT、IL-11及肝脏组织IL-11和p-STAT3蛋白表达，验证SHY对ALI的保护作用及机制。结果：通过TCMSP数据库筛选共获得15种活性成分及219个药物靶点，与ALI疾病靶点交集得到106个关键靶点。PPI网络分析显示TNF、IL6、AKT1等为核心节点，GO/KEGG富集提示其通过IL-17、TNF等信号通路调控氧化应激与炎症反应。动物实验证实SHY显著降低模型小鼠血清ALT、IL-11水平(P < 0.01)，抑制肝组织p-STAT3磷酸化。Western Blot显示SHY干预后IL-11表达下调1.8倍。结论：本研究首次揭示SHY通过调控IL-11R/JAK/STAT轴改善ALI炎症，为“肝病治肠”理论提供分子生物学依据。

关键词： methylene blue   reduced graphene oxide   polydopamine   electrochemical immunosensor   IL-6  

摘要： As an important inflammatory cytokine, interleukin-6 (IL-6) can mediate the entire pathological process of periodontitis and is closely associated with the degree of inflammation. Therefore, it is critical to develop convenient quantitative methods for monitoring IL-6 quantity in gingival crevicular fluid. In this study, methylene blue (MB)-decorated reduced graphene oxide (rGO) is employed as signal probe to further support the antibody-enabling specific recognition of IL-6. Due to pi-pi stacking and electrostatic interactions, rGO-MB nanocomposites can be stably obtained. rGO with good conductivity and large surface area characteristics promotes the redox signals of MB on the glassy carbon electrode (GCE). In addition, through the simple in situ self-polymerization of dopamine, the polydopamine (PDA) obtained can be not only directly used as a biological crosslinking agent for covalent immobilization of anti-IL-6 antibody but can also be regarded as a protective layer to enhance the stability of rGO-MB on the GCE surface. Such a designed PDA/rGO-MB/GCE-based immunosensor enables specific binding with IL-6 and produces a decreased electrochemical signal for MB, realizing the selective and sensitive quantitative measurement of IL-6. Consequently, our fabricated PDA/rGO-MB/GCE-based electrochemical immunosensor has an excellent linear relationship with IL-6 ranging from 1 pg/mL to 100 ng/mL, with a limit of detection as low as 0.48 pg/mL. Moreover, our as-prepared sensing strategy shows accurate monitoring of the IL-6 quantity in gingival crevicular fluid samples.

摘要： Tumor-specific HLA class I expression is required for cytotoxic T-cell elimination of cancer cells expressing tumor-associated antigens or neoantigens. Cancers downregulate antigen presentation to avoid adaptive immunity. The highly polymorphic nature of the genes encoding these proteins, coupled with quaternary-structure changes after formalin fixation, complicates detection by IHC. In this study, we determined recognition of 16 specific HLA-A, -B, and -C alleles by 15 antibodies commercially available for IHC use, identifying and validating pan and specific HLA-A, -B, and -C antibodies, providing a validated method that can be applied to investigate HLA-A, -B, and -C molecule-specific loss in cancer. We applied this approach to a series of breast cancers as a proof of utility, identifying differential HLA-A, -B, and -C loss, with a higher incidence of HLA-A and -B loss in hormone-driven breast cancers, HLA-B loss in HER2+ cancers, and an equal loss of all three molecules in triple-negative disease. Additionally, we found that at the protein level, HLA-A and -B loss were early events prevalent in premalignant lesions, whereas HLA-C loss was less common throughout tumor evolution. Effective response to immunotherapies such as checkpoint inhibitors and MHC-I-targeted cancer vaccines, which hinge on the carriage of specific allele groups, requires MHC-I expression on tumor cells. These findings have implications for the success of checkpoint inhibitors and vaccine strategies.

关键词： Ionic liquids   hydrophobicity   octanol-water distribution coefficient   metal ion extraction  

摘要： Three measures of ionic liquid (IL) hydrophobicity - water solubility, the hydrophilicity index (HI), and the octanol-water distribution coefficient (D-ow) - have been evaluated as a means to correlate the observed balance between solvation and cation-exchange pathways in the extraction of alkaline earth cations by a macrocyclic polyether into a series of 1-alkyl-3-methylimidazolium, N-alkylpyridinium, and quaternary ammonium bis[(trifluoromethyl)sulfonyl]imides with IL hydrophobicity. Of the three, D-ow values are shown to provide the most satisfactory results, with data indicating that cation exchange is largely suppressed for ionic liquids exhibiting an octanol-water distribution coefficient of ca. 40 or greater. Higher distribution coefficients are required to achieve suppression in analogous systems involving alkali metal ion extraction, as had been anticipated from prior work demonstrating the importance of high metal ion charge density in minimizing undesirable ion-exchange processes in these systems.

关键词： antibody mediated rejection   donor-specific antibodies   non-HLA antibodies   autoantibodies   heart transplant  

摘要： Introduction Humoral autoimmune response may play a significant role in stimulating the alloimmune response, leading to antibody-mediated rejection (ABMR). This study investigated whether the development of IgG de novo donor-specific antibodies (dnDSA) could serve as an independent marker for ABMR diagnosis. Subsequently, we evaluated the synergistic effects of non-HLA anti-nuclear antibodies (ANA) and circulating IgG anti-HLA dnDSA in the development of *** This retrospective study included 285 patients who underwent heart transplants between January 2007 to November 2020 at the University of Chicago Medical Center and who had sufficient serum collected at the time of protocol or indication biopsy available for antibody *** We observed a 23% incidence of ABMR in heart transplant patients at our center. Kaplan-Meier survival analysis revealed the lowest ABMR free survival in recipients that were positive for both ANA and circulating IgG dnDSA (Log rank p = 2 x 10-16), indicating a synergistic effect of ANA and circulating IgG dnDSA. A univariate stepwise cox proportional hazard model establishes the presence of IgG dnDSA as an independent marker to predict ABMR diagnosis (HR = 8.70, p = 6.15 x 10-9). Similarly, a synergistic effect was found in the presence of a positive ANA titer and IgG dnDSA for ABMR diagnosis in a univariate model (HR = 13.1, p = 2.73 x 10-14). A multivariate stepwise cox proportional hazard model showed an almost seven-fold increased risk for ABMR in patients that have developed IgG dnDSA (HR = 6.96, p = 2.33 x 10-6). Similarly, nearly an eleven-fold enhanced risk for ABMR was found in heart transplant recipients who were positive for ANA and had developed de novo IgG DSA (HR = 10.7, p = 1.25 x 10-10), suggesting the synergistic effect of ANA and IgG dnDSA in ABMR *** This study establishes circulating IgG dnDSA as an independent biomarker for ABMR diagnosis in heart transplantation and confirms the previou