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关键词： COVID-19   HLA   Bulgarian population   SARS-CoV-2  

摘要： AbstractThe SARS-CoV-2 outbreak represents a global health problem. The different infection rates are heavily influenced by host genetic factors, such as variability in the HLA region. The aim of our study was to investigate whether certain HLA alleles in the Bulgarian population contribute to COVID-19 progression and their role in anti-SARS-CoV-2 immunity. We evaluated 76 patients diagnosed with COVID-19 and classified them according to severity as mild, moderate, and severe. Data from a population cohort ( n = 539), representative of the Bulgarian population, was used for comparisons. We found that the HLA-DQB1*05:03 (OR = 3.13, pc = 0.0008) allele was significantly associated with COVID-19 severity. Several other class I and class II alleles showed a promising association with a predisposition to disease severity or a protective role in its progression. This is the first study to assess the association between HLA and COVID-19 progression in the Bulgarian population. Despite some limitations, our results suggest that certain HLA alleles play a role in the severity of SARS-CoV-2 infection and it would be interesting to further trace their effect in the context of long COVID.

关键词： 结肠炎,溃疡性   白细胞介素-6受体   白细胞介素-22   病情严重程度   临床结局  

摘要： 目的探究血清白细胞介素-6受体(IL-6R)和白细胞介素-22(IL-22)表达与溃疡性结肠炎严重程度及临床结局的关系。方法选取监利市人民医院2017年12月至2022年6月治疗的212例溃疡性结肠炎病人为研究对象,根据其病情严重程度分为轻症组与重症组,根据治疗2个月的预后情况分为预后良好组与预后不良组,采用酶联免疫吸附测定检测IL-6R、IL-22水平并收集病人临床资料,logistic多因素回归分析影响溃疡性结肠炎病人预后的相关因素;绘制受试者操作特征曲线(ROC曲线)预测IL-6R和IL-22对溃疡性结肠炎严重程度以及预后的临床诊断及预测价值。结果与轻症组[(11.10±1.21)ng/L、(50.24±6.35)ng/L]相比,重症组在入院时的血清IL-6R[(15.32±2.62)ng/L]、IL-22水平[(63.61±6.95)ng/L]显著增加(P<0.05),通过绘制ROC曲线发现IL-6R、IL-22以及两者联合诊断重症溃疡性结肠炎的曲线下面积(AUC)分别为0.85、0.85、0.92,并且二者联合诊断显著优于IL-6R、IL-22单独诊断(Z=3.58,3.42;P=0.003,0.006);通过分析病人一般临床资料发现,溃疡性结肠炎病人的预后与病人是否有肠外表现、C反应蛋白(CRP)、降钙素原(PCT)、红细胞沉降率(ESR)、粪便钙卫蛋白(FC)、粪便乳铁蛋白(FL)、IL-6R以及IL-22水平有关(P<0.05),与性别、年龄无关(P>0.05),logistic多因素回归分析发现,CRP、PCT、ESR、FC、FL、IL-6R以及IL-22均为影响溃疡性结肠炎病人预后的危险因素(P<0.05)。绘制ROC曲线发现IL-6R、IL-22以及两者联合预测溃疡性结肠炎病人预后的AUC分别为0.81、0.83、0.90,并且二者联合预测显著优于IL-6R、IL-22单独预测(Z=3.70,3.18;P<0.001,P=0.002)。结论溃疡性结肠炎病人血清IL-6R、IL-22水平随病人病情严重程度增加,均为影响溃疡性结肠炎病人预后的危险因素,并且对病人的病情严重程度及临床结局预测具有辅助诊断价值。

关键词： 结膜松弛症   肝肾阴虚型   杞精明目汤   Th17   IL-17  

摘要： 目的:观察中药杞精明目汤联合人工泪液治疗对肝肾阴虚型结膜松弛症(CCH)患者泪液中Th17相关细胞因子的改变。方法:收集56例56眼Ⅱ-Ⅲ级肝肾阴虚型CCH患者,随机分为治疗组(杞精明目汤联合人工泪液)26例26眼和对照组(单纯人工泪液)30例30眼,疗程1 mo,观察治疗前后患者的国际眼表疾病指数(OSDI)、泪膜破裂时间(BUT)、泪河高度(TMH)、球结膜充血指数。采集治疗前后CCH患者的泪液,通过流式免疫荧光发光法对患者泪液中Th17相关细胞因子进行检测和分析。结果:治疗组与对照组CCH患者治疗后OSDI、BUT、球结膜充血指数均较治疗前均明显改善(均P<0.01);治疗后治疗组患者TMH较治疗前显著降低(P<0.01),对照组患者治疗前后TMH无差异(P=0.41)。治疗组CCH患者在治疗后泪液中Th17相关细胞因子IL-17A、IL-22、IFN-γ、IL-17F、IL-1β水平较治疗前明显降低(均P<0.01),且治疗组的变化更为显著(均P<0.05);而对照组治疗前后泪液中Th17相关细胞因子无差异(均P>0.05)。治疗后两组CCH患者泪液中IL-6、TNF-α均较治疗前降低(均P<0.05),但治疗组的变化更为显著(均P<0.01)。结论:杞精明目汤联合人工泪液治疗可有效改善肝肾阴虚型结膜松弛症患者眼表微环境,提高泪膜稳定性,抑制眼表炎症,可能与其降低泪液中Th17相关细胞因子的分泌相关。

关键词： 帕金森病   普拉克索   司来吉兰   脑源性神经营养因子   神经生长因子   胶质细胞源性神经营养因子  

摘要： 目的探讨中晚期帕金森病患者在司来吉兰治疗的基础上,联合普拉克索的临床疗效,以及对其血清脑源性神经营养因子、神经生长因子、胶质细胞源性神经营养因子水平的影响。方法回顾性分析扬州大学附属泰州第二人民医院2021年1月至2024年1月收治的80例中晚期帕金森病患者的临床资料,根据治疗方法不同分为常规组(40例,接受司来吉兰治疗)和联合组(40例,接受普拉克索联合司来吉兰治疗)。两组患者均连续治疗60 d。比较两组患者临床疗效,治疗前后血清脑源性神经营养因子、神经生长因子、胶质细胞源性神经营养因子水平及认知功能、精神状态、综合症状评分,以及治疗期间不良反应发生情况。结果联合组临床疗效高于常规组;与治疗前比,两组患者治疗后血清脑源性神经营养因子、神经生长因子、胶质细胞源性神经营养因子水平及蒙特利尔认知评估量表(MOCA)、简易精神状态量表(MMSE)评分均升高,且联合组均高于常规组,统一帕金森评分量表(UPDRS)评分均降低,且联合组低于常规组(均P<0.05);两组患者不良反应总发生率比较,差异无统计学意义(P>0.05)。结论在司来吉兰治疗的基础上联合普拉克索治疗中晚期帕金森病患者的疗效更显著,可有效改善其神经细胞因子水平,缓解患者综合症状,有助于改善其认知功能与精神状态,且安全性良好。

关键词： Fibroblasts   Interleukin-33   Orofacial neuropathic pain   Transient receptor potential ankyrin 1   Trigeminal ganglion neurons  

摘要： Damage to the peripheral nerves of trigeminal ganglion (TG) neurons leads to intractable orofacial neuropathic pain through the induction of neuroinflammation. However, the details of this process are not yet fully understood. Here, we found that fibroblast-derived interleukin (IL)-33 was required for the development of mechanical allodynia in whisker pad skin following infraorbital nerve injury (IONI). The amount of IL-33 in the TG increased after IONI when the mice exhibited mechanical allodynia. Neutralization of IL-33 in the TG inhibited the development of IONI-induced mechanical allodynia. Conversely, intra-TG administration of recombinant human IL-33 (rhIL-33) elicited mechanical allodynia in na & iuml;ve mice. IL-33 and its receptor were exclusively expressed in fibroblasts and neurons, respectively, in the TG. Fibroblast ablation caused the loss of IL-33 in the TG and delayed the development of mechanical allodynia after IONI. rhIL-33 elicited an increase in intracellular Ca2+ concentration and subsequent enhancement of Ca2+ influx via transient receptor potential ankyrin 1 (TRPA1) in primary cultured TG neurons. Additionally, rhIL-33 facilitated membrane translocation of TRPA1 in the TG. Mechanical allodynia caused by intra-TG administration of rhIL-33 was significantly inhibited by pharmacological blockade or gene silencing of TRPA1 in the TG. Inhibition of protein kinase A abrogated TRPA1 membrane translocation and delayed mechanical allodynia after IONI. Substance P stimulation caused upregulation of IL-33 expression in primary cultured fibroblasts. Preemptive administration of a neurokinin-1 receptor antagonist in the TG attenuated mechanical allodynia and IL-33 expression following IONI. Taken together, these results indicate that fibroblast-derived IL-33 exacerbates TG neuronal excitability via suppression of tumorigenicity 2 (ST2)-TRPA1 signaling, ultimately leading to orofacial neuropathic pain.

关键词： IL-17A   IL-17RA   alpha-Synuclein   Parkinson's disease   Senescence  

摘要： Parkinson's disease (PD) pathogenesis is characterized by alpha-synuclein (alpha-syn) pathology, which is influenced by various factors such as neuroinflammation and senescence. Increasing evidence has suggested a pivotal role for Interleukin-17A(IL-17A) and Interleukin-17 Receptor A (IL-17RA) in PD, yet the trigger and impact of IL-17A/IL17RA activation in PD remains elusive. This study observed an age-related increase in IL-17A and IL-17RA in the human central nervous system, accompanied by increased alpha-syn and senescence biomarkers. Interestingly, both levels of IL-17A and IL-17RA in PD patients were significantly elevated compared to age-matched controls, wherein the IL-17A was mainly present in neurons. This abnormal neuronal IL-17A activation in the PD brain was recapitulated in alpha-syn mouse models. Correspondingly, administration of recombinant IL-17A exacerbated pathological alpha-syn in both neuron and mouse models. Furthermore, IL-17A/IL-17RA pathway interventions via blocking antibody or shRNA-mediated knockdown can mitigate the effects of pathological alpha-syn. This study reveals an interplay between dysregulation of the IL-17A/IL-17RA pathway and alpha-syn, suggesting that regulating the IL-17A/IL-17RA pathway could modify PD progression by disrupting the detrimental cycle.

关键词： TNF-alpha   Fear conditioning   Anxiety   Adverse outcome pathway   Physiological map   Neurotoxicology   Glutamate   Serotonin   Cell death   Psychoneuroimmunology  

摘要： Background: The pathophysiology of several neurodegenerative and neuropsychiatric disorders is linked to an altered immune system. However, it is often unclear how the immune system specifically affects these disorders since neuroimmune interactions are very complex. In this paper, we introduce an adjusted version of the adverse outcome pathway (AOP) approach from toxicology to the field of neuroimmunology. A review of the effect of TNF-alpha on fear learning deficits is used as a worked example to demonstrate how an AOP approach can help identify gaps of knowledge and crucial steps in the pathophysiology of neuroimmunological disorders. Methods: The AOP was constructed in five steps. First, the adverse outcome was formulated clearly and specifically. Second, the link between the molecular initiating event and the adverse outcome was established with a preliminary literature search in the Medline database. Third, a systematic literature search was performed in which we identified 95 relevant articles. Fourth, the main biological processes and relevant key events were identified. Fifth, the links between key events were determined and an AOP network was constructed. Results: We identified three pathways through which TNF-alpha may affect fear learning. First, TNF-alpha receptor activation increases NF-kappa B levels which increases oxidative stress levels and reduces the activity of glutamate transporters. This alters the synaptic plasticity which is associated with impaired fear acquisition, consolidation, and fear extinction. Second, activation of TNF-alpha receptors increases the expression and capacity of the serotonin transporter which is linked to impaired fear acquisition, expression, and extinction. Third, TNF-alpha receptor 1 activation can induce necroptosis, leading to neuroinflammation which is linked to fear learning deficits. Conclusion: To successfully apply the AOP approach in neuroimmunology we recommend defining adverse outcomes more precisely, esta

关键词： MIP3 alpha/CCL20   IFN alpha/interferon alpha/type I interferon   5-Aza-2 '-deoxycytidine/decitabine   CD11c   tumor microenvironment   CD11c+CD8+T cell   DNA therapeutic cancer vaccine  

摘要： Previous studies in the B16F10 mouse melanoma model have demonstrated that combining a DNA vaccine comprised of regions of gp100 and tyrosinase-related protein 2 fused to macrophage-inflammatory protein 3-alpha (MIP3 alpha) with recombinant interferon alpha (IFN) and 5-Aza-2 '-deoxycytidine (5Aza) treatments resulted in significantly greater antitumor activity and immunogenicity in the tumor microenvironment (TME). This brief report details that the combination of vaccine with treatments IFN and 5Aza results in an increase in the TME of a distinct CD11c+ CD8+ T-cell population. This cell population correlates with tumor size, is primarily comprised of effector or effector memory T cells, and has a more robust response to ex vivo stimulation as compared with CD11c- CD8+ T cells. In conclusion, this combination therapy results in a greater presence of highly active effector CD8+ T cells expressing CD11c in the TME, which are likely primary contributors to treatment efficacy.

关键词： Major histocompatibility complex   Hucho bleekeri   Tissue distribution   Immune response   Polymorphism  

摘要： The major histocompatibility complex (MHC) is involved in antigen presentation and plays an essential role in regulating immune function. In the present study, we identified two MHC class II genes and investigated their potential roles in Hucho bleekeri. The MHC II alpha and MHC II (3 of H. bleekeri had typical leading peptides, extracellular domains, connecting peptides, transmembrane region, and cytoplasmic region. Amino acid sequence comparison revealed that MHC II of H. bleekeri has high homology with other vertebrates, among which homology with salmonid fish was the highest. Phylogenetic analysis showed that H. bleekeri MHC II clustered with salmonid fish;moreover they clustered with orthologous genes of other fish, whereas mammalian MHC II clustered into a separate branch. Tissue distribution analysis revealed MHC II was widely expressed in all tested tissues, with both MHC II alpha and MHC II beta highly expressed in the spleen, gill, kidney, and hindgut. After lipopolysaccharide (LPS) and polyinosinic:polycytidylic acid (poly(I:C)) stimulation, the expression of MHC II in the head kidney and spleen of H. bleekeri was significantly upregulated. Compared with MHC II alpha, MHC II beta acted faster in response to the stimulation. Polymorphism analysis of MHC II revealed that all the different alleles belonged to the same major type, and very limited polymorphisms were found in H. bleekeri MHC II alpha and II beta. Selection pressure analysis showed signs of weak and non-significant positive selection in the MHC II alpha and MHC II beta extracellular region. Our study reveals the potential role of MHC II in the immune response of H. bleekeri and provides a reference for studying the evolutionary model of teleost MHC II.

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.