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关键词： ACG   American College of Gastroenterology   ACRD   age-related cognitive decline   ACs   adenylyl cyclases   AD   Alzheimer disease   ADRD   aD-related dementias   AH   alcoholic hepatitis   AhR   aryl hydrocarbon receptor   AIPL1   aryl interacting protein-like 1   AKAPs   a-kinase anchoring proteins   ALD   alcohol-associated liver disease   ASH   alcohol-associated steatohepatitis   ASM   airways smooth muscle   AUD   alcohol use disorder   A   β   amyloid beta   BAL   bronchoalveolar lavage   bFGF   basic fibroblast growth factor   BNP   brain natriuretic peptide   cAMP   cyclic adenosine mono phosphate   CaM-PDE   calmodulin-PDE   CFP   cyan fluorescent protein   cGK-1a (also known as PKA1a)   cGMP-dependent kinase-1a   cGMP   cyclic guanosine mono phosphate   cGS-PDE   cyclic GMP-stimulated PDE   CNS   central nervous system   COPD   chronic obstructive pulmonary disease   COX   non-cyclooxygenase   CRC   colorectal cancer   CTGF   connecting tissue growth factor   DA   dopamine   DC   dendritic cell   EAR   early asthmatic response   EC   endothelial cells   ECM   extracellular matrix proteins   ERK   extracellular signal-regulated kinase   ESL   epithelial surface liquid   FAP   familial adenomatous polyposis   FDA   Food and Drug Administration   FEV₁   forced expiratory volume in 1 second   FN   fibronectin   FRET   fluorescence or Förster resonance energy transfer   FVC   forced vital capacity   GC-1   guanylyl cyclase-1   GOLD   Global Initiative for Obstructive Lung Diseases   GPCR   G-protein coupled receptor   HCL   human chromosome location   HD   Huntington’s disease   HF   heart failure   HFL-1   human fetal lung fibroblasts   HFpEF   heart failure with preserved ejection fraction   HFrEF   heart failure with reduced ejection fraction   HFS   high frequency stimulation   HNSCC   head and neck squamous cell carcinoma   HSC   hepatic stellate cells   HTNB   hypertension with brachydactyly (Bilginturan syndrome)   HUVEC   human umbilical vein endothelial cell   IBMX   isobutyl-methylxanthine   ICER   inducible cAMP early repressor   ICI   immune checkpoint inhibition   ICS   inhaled corticosteroid   Ig   immunoglobulin   ILDs   interstitial lung diseases   IPF   idiopathic pulmonary fibrosis   ITI   Intra-Cellular Therapies Inc   KRAS   Kirsten Rat  

摘要： Cyclic nucleotides are synthesized by adenylyl and/or guanylyl cyclase, and downstream of this synthesis, the cyclic nucleotide phosphodiesterase families (PDEs) specifically hydrolyze cyclic nucleotides. PDEs control cyclic adenosine-3’,5’monophosphate (cAMP) and cyclic guanosine-3’,5’-monophosphate (cGMP) intracellular levels by mediating their quick return to the basal steady state levels. This often takes place in subcellular nanodomains. Thus, PDEs govern short-term protein phosphorylation, long-term protein expression, and even epigenetic mechanisms by modulating cyclic nucleotide levels. Consequently, their involvement in both health and disease is extensively investigated. PDE inhibition has emerged as a promising clinical intervention method, with ongoing developments aiming to enhance its efficacy and applicability. In this comprehensive review, we extensively look into the intricate landscape of PDEs biochemistry, exploring their diverse roles in various tissues. Furthermore, we outline the underlying mechanisms of PDEs in different pathophysiological conditions. Additionally, we review the application of PDE inhibition in related diseases, shedding light on current advancements and future prospects for clinical intervention. Significance Statement: Regulating PDEs is a critical checkpoint for numerous (patho)physiological conditions. However, despite the development of several PDE inhibitors aimed at controlling overactivated PDEs, their applicability in clinical settings poses challenges. In this context, our focus is on pharmacodynamics and the structure activity of PDEs, aiming to illustrate how selectivity and efficacy can be optimized. Additionally, this review points to current preclinical and clinical evidence that depicts various optimization efforts and indications. © 2025 The Author(s)

关键词： 中性粒细胞   骨折愈合   炎症   细胞因子   靶向治疗  

摘要： 背景:巨噬细胞存在特殊的促炎/抗炎表型,通过组织工程技术调节表型转变,使得其成为了在骨损伤修复中研究最多的免疫细胞。最近的研究发现中性粒细胞在骨损伤修复过程中同样发挥重要作用,但目前尚无此类综述。目的:总结目前中性粒细胞在骨折愈合中的作用方式,以及干预中性粒细胞促进骨折愈合的治疗措施。方法:检索2000年1月至2024年2月Web of Science、PubMed、中国知网及万方数据库,中文检索词为“中性粒细胞、骨折愈合、骨损伤、骨修复、骨重建”,英文检索词为“neutrophil,fracture healing,bone damage,bone repair,bone remodeling”。通过纳入排除标准筛选文献,最终纳入72篇进行综述。结果与结论:①发现中性粒细胞的历史漫长,早期由于缺乏染色技术忽视了其重要性,1900年Paul Ehrlich发明三酸染料区别出中性粒细胞,开启了研究的序幕;②正常状态下,中性粒细胞迁移到各器官辅助其发挥生理功能;病理状态下,中性粒细胞依赖吞噬作用、脱颗粒及中性粒细胞胞外陷阱发挥抗菌作用;③中性粒细胞主要参与骨折愈合早期血肿炎症阶段,通过释放细胞因子募集其他免疫细胞及间充质干细胞,同时产生纤连蛋白促进血肿形成构建局部微环境;④中性粒细胞在骨折愈合的不同阶段转化为N1/N2两种不同亚型,两者相互协调促进骨修复;⑤骨折断端募集的中性粒细胞通过分泌肿瘤坏死因子α、白细胞介素6、白细胞介素10、成纤维细胞生长因子2、单核细胞趋化蛋白1、血小板源性生长因子等细胞因子参与骨折愈合的过程;⑥中性粒细胞通过与骨折愈合不同阶段主要细胞成分的相互作用,调节成骨/破骨平衡;⑦类似于组织工程技术调节巨噬细胞极化在骨折愈合中的广泛研究与应用,未来针对干预中性粒细胞促进骨折愈合的疗法具有广阔前景。

关键词： Cerebrospinal fluid   Cigarette smoking   IL-1β   Neuroinflammation   Sleep  

摘要： Objective: Inflammatory factors and cigarette smoking have been associated with sleep disorders but molecular mechanisms that regulate sleep, specifically the role of interleukin-1β (IL-1β), remain controversial. Individuals’ cerebrospinal fluid (CSF) IL-1β, smoking behavior, and sleep data were collected to investigate how smoking may influence the relationship between CSF IL-1β and sleep via moderation analysis. Methods: A total of 191 Chinese male patients, including 104 non-smokers and 87 active smokers, scheduled for anterior cruciate ligament reconstructive surgery, were recruited. Pittsburgh Sleep Quality Index (PSQI) scores were collected prior to surgery, and CSF samples were obtained during preoperative lumbar puncture. Results: Active smokers compared to non-smokers exhibited higher scores across various subdimensions of PSQI, specifically poorer sleep quality, increased sleep latency, reduced sleep efficiency, and heightened sleep disturbance (all p < 0.05). Positive correlations were observed between CSF IL-1β levels and PSQI total scores, as well as several subdimensions of sleep (all p < 0.05) in non-smokers. In contrast, a negative correlation was observed between CSF IL-1β levels and sleep efficiency scores (p < 0.05) among active smokers. Moderation analysis revealed that smoking negatively moderated the relationship between CSF IL-1β and sleep, particularly in PSQI total scores (β = −0.95, p < 0.001), sleep latency scores (β = −1.05, p < 0.001), and sleep disturbance scores (β = −0.45, p < 0.05). Conclusions: The current study found that smoking disrupts multiple subdimensions of sleep and moderates the effect of the neuroinflammatory factor CSF IL-1β on PSQI sleep latency and sleep disturbance scores. © 2025 The Authors

关键词： HBsAg loss   Peg IFN-α   chronic hepatitis B   immunological factors   relapse  

摘要： BACKGROUND:Emerging evidence indicates that the treatment duration of pegylated interferon-α and HBsAb may predict relapse in chronic hepatitis B (CHB) patients who achieved clinical cure. However, the host immunological mechanisms contributing to clinical relapse remain poorly characterized. OBJECTIVES:This study aimed to identify the immunological factors associated with relapse in chronic hepatitis B (CHB) patients who achieved clinical cure based on pegylated interferon-alpha treatment. METHODS:CHB patients who achieved HBsAg loss after discontinuing pegylated interferon-alpha therapy were enrolled and followed up for at least 96 weeks. HBcrAg and immunological markers, including the proportion of follicular helper T (Tfh) cells were assessed by flow cytometry. Peripheral blood cytokine levels were measured using a Luminex assay. The primary outcome was the correlation between immunological markers with relapse at the end of treatment (EOT) and end of follow-up (EOF). RESULTS:A total of 456 CHB patients were included. During the 96-week follow-up period, 37 patients (8.11%) experienced a relapse. Propensity score matching was performed at a 1:2 ratio, resulting in the inclusion of 37 relapsed (R) and 74 non-relapsed (NR) patients. The NR group exhibited higher proportions of Tfh cells than the R group in both EOT and EOF (EOT: 12.52% vs. 8.78%, p=0.008; EOF: 11.38% vs. 8.29%, p=0.008). A significantly greater proportion of CCR7loPD-1hi Tfh cells was observed in the NR group at the EOT (9.4% vs. 4.5%, p=0.009). The frequency of CCR7loPD-1hi Tfh cells was significantly and positively correlated with anti-HB levels in EOT (p=0.015, r=0.392). Serum levels (median, pg/mL) of CTLA-4 (EOT: 14.87 vs. 7.84; EOF: 14.87 vs. 7.97), PD-1 (EOT: 321.44 vs. 203.96; EOF: 288.45 vs. 166.04), and TIM-3 (EOT:4487 vs. 21254; EOF:2973 vs. 1768) were significantly higher in the R group than in the NR group at both EOT and EOF (p<0.05). At EOT, the HBcrAg level was significantly greate

关键词： Hyperphosphatemia   Sarcopenia   Inflammaging   IL-15   Myoblasts differentiation   Cellular senescence  

摘要： Aims: The association between aging-related hyperphosphatemia and sarcopenia has been documented, and evidence suggests that inflammaging is involved in the manifestation of sarcopenia. The present study investigates whether hyperphosphatemia triggers inflammation, thereby inducing the appearance of sarcopenia along with the cytokines involved in these processes. Materials and methods: RAW 264.7 macrophages were incubated with beta-glycerophosphate (BGP), as a phosphate donor, at different time intervals, to assess the production of proinflammatory markers. Conditioned medium from macrophages was collected and added to cultured C2C12 myoblasts to analyse whether proinflammatory molecules, released by macrophages, modified myogenic differentiation, cell senescence or myokine IL-15 expression. A neutralising antibody anti-TNF-alpha and recombinant IL-15 were added to evaluate the role of these cytokines in the observed effects. Additionally, TNF-alpha, IL-15, serum phosphate, and sarcopenia signs were evaluated in 5-month-old mice, 24-month-old mice and 24-month-old mice fed with a hypophosphatemic diet. Key findings: BGP increased TNF-alpha expression in macrophages through NFkB activation. Conditioned medium from BGP-treated macrophages impaired myogenic differentiation in differentiating myoblasts and promoted cellular senescence and reduced IL-15 expression in undifferentiated myoblasts. These effects were mediated by TNF-alpha. Old mice displayed reduced expression of muscle IL-15 and elevated circulating TNF-alpha, along with increased serum phosphate levels, which correlated with the appearance of sarcopenia indicators. The hypophosphatemic diet prevented these changes in old mice. Significance: Hyperphosphatemia induces TNF-alpha production in macrophages, which contributes to the reduced expression of muscular IL-15. This mechanism may play a role in inducing sarcopenia in elderly mice.

关键词： Computational tools   Diagnostic tools   HLA-typing   Inflammatory markers  

摘要： Objectives: This study aimed to determine the diverse inborn and adventitious variables that contribute to the rise of Ankylosing Spondylitis (AS) and to elucidate the genotypic study of HLA-B*27 alleles along with sub-alleles and in-silico inhibition of their respective abnormal receptor proteins by natural compounds. Methods: Case-control study was piloted. Allele-specific DNA-based HLA typing was performed after DNA extraction. Patient questionnaires and Molecular docking was applied to identify AS prognosis and potential HLA-B*27 inhibitors respectively. Results: Results revealed a 72.72% prevalence of HLA-B*27 alleles in patients versus 9.09% in controls. Sub-alleles HLA-B*27:02, 04, and 05 were identified in 87.5% of patients but were absent in controls. The chi-square (χ2) values for HLA-B*27 alleles and sub-alleles were significant, with p-values of 0.0024 and 0.0220, respectively. The study found no significant association of AS with gender, age, marital status, or environmental factors, but a strong association with family history of back pain, elevated CRP, ESR, body inflammation, and uveitis. In silico analysis identified Rutin, curcumin, and coumaroylquinic acid as natural compounds with the highest binding affinity to HLA-B27 chains A and F, suggesting their probability to modulate the structure and function of HLA-B27 proteins. Conclusions: AS is more prevalent in individuals with family history of backache, uveitis and elevated inflammatory markers, Sub-alleles of HLA-B*27 should be used as diagnostic tools alongside alleles, as they were found only in patients, not in healthy individuals. Furthermore, Rutin, curcumin, and coumaroylquinic acid may temper the function of HLA associated with AS. © 2025 American Society for Histocompatibility and Immunogenetics

关键词： non-invasive biosensor   bone cancer   electrochemical immunosensor   bone health monitoring   hydrogel   flexible biosensor   osteoporosis  

摘要： Portable biosensing is crucial for rapid detection and continuous monitoring of bone diseases such as osteoporosis and bone cancer. It is well established that such bone disorders or diseases trigger release of inflammatory cytokines including interleukin-6 (IL6), detectable in sweat by electrochemical immunosensors. To this end, this study presents a novel hydrogel nanocomposite based immunosensor with highly conductive dual-layer of thermally exfoliated graphene oxide, toward precise detection and determination of loading level of IL-6 biomarker, and in turn, developing a label-free flexible bone biosensing platform. The immunosensor employed antibody immobilization process, which was further facilitated by the modification of the dual-layer by using 1-pyrenebutyric acid N-hydroxy succinimide ester. A thorough analysis of the effects of surface modification was conducted utilizing spectroscopic, electrochemical, and morphological methods. The biosensor's response was assessed through the utilization of the cyclic voltammetry measurement, which exhibited remarkable selectivity, achieving a low limit of detection of 15.4 pg ml-1 across a wide linear range. Additionally, field emission scanning electron microscopy, Fourier transform infrared spectroscopy and Raman spectroscopy were successfully used to validate the sensing substrate in bio-fluidic samples and to understand the structure-property correlation. This innovative portable and flexible biosensor thus offers a practical and effective tool for potential application in continuous monitoring of bone health.

关键词： acute exacerbation   Asthma   IL-36   IL-6   non–type 2   pulmonary function   type 2  

摘要： Background: The IL-36 subfamily, a member of the IL-1 superfamily, is thought to promote type 2 (T2) and non-T2 inflammation and involved in autoimmune and airway disease progression. However, its role in asthma remains unclear. Objective: We sought to determine the contribution of the IL-36 subfamily to the clinical manifestation of asthma. Methods: The levels of serum IL-36α, IL-36β, and IL-36γ, recognized as IL-36 subfamily agonists, and IL-36 receptor antagonist (IL-36Ra) and IL-38, recognized as IL-36 subfamily antagonists, were measured by ELISA in 110 asthma patients (55 with nonsevere and 55 with severe asthma) aged ≥20 years and 31 healthy individuals. The association of IL-36 with clinical indices and inflammatory mediators was examined. The characteristics of high and low IL-36 subgroups were explored. Results: IL-36α, IL-36γ, and IL-36Ra levels were significantly higher in asthma patients, especially patients with severe asthma, than in healthy controls. The high IL-36γ group exhibited lower Asthma Control Test scores (P = .01), more frequent asthma exacerbations (AEs), and higher hazard ratio for AEs. The high IL-36Ra group exhibited higher values of forced expiratory volume in 1 second, more frequent severe AEs, and higher hazard ratio for severe exacerbations. The IL-36 cytokine levels, except for IL 36α, were positively correlated with IL-6, IL-13, IL-17, and/or IFN-γ levels. IL-36Ra was positively correlated with age-adjusted forced expiratory volume and forced vital capacity. Conclusion: A systemically high IL-36 level is associated with asthma severity and with both T2 and non-T2 cytokines, and it implies poor condition and enhancement of risk of AEs in asthma patients. © 2025 The Author(s)

关键词： ST段抬高型心肌梗死   经皮冠状动脉介入治疗   中性粒细胞/淋巴细胞比值   单核细胞/高密度脂蛋白胆固醇比值   造影剂肾病   预测  

摘要： 背景既往研究发现中性粒细胞、单核细胞计数增多和高密度脂蛋白胆固醇减少与ST段抬高型心肌梗死(STEMI)相关,然而中性粒细胞/淋巴细胞比值(NLR)、单核细胞/高密度脂蛋白胆固醇比值(MHR)与急诊经皮冠状动脉介入治疗(PCI)术后发生造影剂肾病(CIN)的相关性研究较少。目的探究NLR、MHR及两者联合对STEMI患者急诊PCI术后CIN的预测价值。方法选取2019—2022年在扬州大学附属苏北人民医院接受急诊PCI的437例STEMI患者为研究对象,根据入组患者术后是否发生CIN,分成CIN组(65例)和非CIN组(372例)。收集患者一般资料及实验室检查指标,计算NLR和MHR的数值,并比较2组患者临床资料。运用单因素及多因素Logistic回归分析筛选出STEMI患者PCI术后发生CIN的独立危险因素。绘制NLR、MHR及两者联合预测STEMI患者PCI术后发生CIN的受试者工作特征(ROC)曲线,并计算ROC曲线下面积(AUC)评估NLR、MHR及两者联合对CIN发生的预测效能。结果CIN组患者2型糖尿病史、利尿剂使用、白细胞计数、中性粒细胞计数、单核细胞计数、空腹血糖、NLR、MHR水平高于非CIN组,血红蛋白、淋巴细胞计数和肌酐水平低于非CIN组(P<0.05)。多因素Logistic回归分析结果显示,2型糖尿病史(OR=1.997,95%CI=1.063~3.751,P=0.032)、单核细胞计数(OR=2.372,95%CI=1.060~5.310,P=0.036)、NLR(OR=1.311,95%CI=1.171~1.468,P<0.001)、MHR(OR=7.075,95%CI=1.893~26.439,P=0.004)水平升高为STEMI患者急诊PCI术后发生CIN的独立危险因素。ROC曲线结果显示,NLR、MHR及两者联合预测STEMI患者急诊PCI术后发生CIN的AUC分别为0.733(95%CI=0.669~0.796,P<0.001)、0.706(95%CI=0.633~0.779,P<0.001)、0.796(95%CI=0.740~0.852,P<0.001);灵敏度分别为66.2%、60.0%、69.2%;特异度分别为71.8%、75.3%、73.1%。结论2型糖尿病史、单核细胞计数、NLR、MHR水平升高为STEMI患者急诊PCI术后发生CIN的独立危险因素;NLR、MHR及两者联合均可作为有效识别STEMI患者急诊PCI术后发生CIN的早期生物标志物。

关键词： Vaccination   Measles   Coverage   Mandatory  

摘要： Introduction. Measles is a highly contagious disease, but it is preventable through vaccination. Despite the availability of measles vaccines, outbreaks continue to occur, due to factors such as vaccine hesitancy. In Italy, measles vaccination has been mandatory since 2017. Methods. This study analyses vaccination coverage trends to assess the impact of this mandatory vaccination policy at regionjqal, national, and European Union levels. Results. Results show a significant increase in measles vaccination coverage within Italy following implementation of the mandate, both at the national (+5,2%) and regional levels. However, the comparison of European countries with and without mandatory vaccination policies did not reveal statistically significant differences in coverage. Conclusion. This suggests that while mandatory vaccination can improve coverage within a nation, additional strategies may be needed to address vaccine hesitancy and achieve herd immunity across broader geographical areas.