课程文献中心 更多>>

关键词： Asthma exacerbation   IL-33   Immune homeostasis   Oxidative stress   Ozone  

摘要： Short-term exposure to ozone is linked to the onset and exacerbation of asthma, yet the underlying mechanisms remain unclear. This study aims to elucidate the molecular pathways and key mediators involved in ozone-induced asthma exacerbation. In a longitudinal epidemiological study, each 10 mu g/m3 increase in ozone is associated with decreases in forced vital capacity (FVC), forced expiratory volume in one second (FEV1), and peak expiratory flow (PEF) of 26.24 ml (95 % confidence interval [CI]: 11.16 ml, 41.33 ml), 19.10 ml (95 % CI: 6.96 ml, 31.24 ml), and 41.65 ml/s (95 % CI: 3.87 ml/s, 79.43 ml/s), respectively. In asthmatic mice, ozone exposure induces oxidative stress and worsens pulmonary dysfunction, lung tissue damage, and inflammation, disrupting the balance of type 2 innate lymphoid cells (ILC2s), T helper type 2 (Th2), and T helper type 17 (Th17) cells. These effects are partially mitigated by N-acetylcysteine (NAC). Furthermore, ozone exposure significantly increases the interleukin (IL)-33 level, while treatment with an IL-33 neutralizing antibody markedly improves lung dysfunction, inflammatory cell infiltration, and immune response dysregulation. In conclusion, this study highlights that short-term exposure to ozone has deleterious effects on asthmatic patients and animals by inducing oxidative stress in lungs and disrupting immune function via IL-33.

关键词： miR-140   B7-H4   IL-10   STAT5   italic>Schistosoma japonicum  

摘要： BACKGROUND:Aflatoxin remains an under-recognized hepatocellular‑carcinoma (HCC) risk factor in the United States, where the permissible food limit (20 ppb) is five‑fold higher than in Europe. METHODS:We analyzed 350 TCGA-HCC cases with whole‑exome, RNA‑seq, and clinical data. Aflatoxin burden was quantified by single-base-substitution signature 24 (SBS24). HLA diversity was quantified from RNA‑seq reads using the Shannon diversity index. Multivariable Cox models estimated hazard ratios (HRs) for disease specific survival (DSS) with aflatoxin-virus interactions , adjusting for tumor stage, age, sex, race, alcohol use, fatty liver disease, aristolochic‑acid signature, and HLA diversity. Linear regression evaluated the association between HLA diversity and aflatoxin burden. RESULTS:Higher aflatoxin burden was associated with poorer DSS (aHR = 1.16, 95 % CI 1.01-1.33). Among HCV-positive patients, HBV infection was associated with improved DSS at low aflatoxin levels; however, this association was reversed at aflatoxin levels exceeding 30 units. HCV infection was consistently associated with worse DSS across aflatoxin levels. Asian American and Black/African American (AA) patients carried higher aflatoxin burdens than Whites (P = 0.016 and 0.014). Greater HLA diversity was independently associated with lower aflatoxin burden (P < 0.001), suggesting a protective effect. CONCLUSIONS:Somatic aflatoxin exposure, both independently and synergistically with HBV/HCV infection, adversely affects HCC prognosis, whereas greater HLA diversity may mitigate the detrimental effects of aflatoxin. Aflatoxin exposure disproportionately affected Asian-American and Black/AA patients (other minority groups not represented). IMPACT:Tightening U.S. aflatoxin food limits and expanding HBV vaccination coverage in high‑risk communities could reduce HCC disparities and improve patient survival.

关键词： CRISPR/Cas9   基因编辑   Rag1基因   Il2rg基因   双基因敲除   金黄地鼠   免疫缺陷模型  

摘要： 目的 利用成簇规律间隔短回文重复序列及其相关蛋白9（clustered regularly interspaced short palindromic repeats and CRISPR-associated protein 9， CRISPR/Cas9）技术构建Rag1/Il2rg双基因敲除金黄地鼠模型，为免疫功能低下人群中腺病毒感染研究提供参考动物模型。方法 选择金黄地鼠Rag1基因第1外显子和Il2rg基因第4外显子为靶位点，设计sgRNA并进行体外转录。将sgRNA和Cas9蛋白注射至双细胞期胚胎中，并移植至妊娠0.5 d的受体母鼠输卵管，获得F0代鼠。将F0代鼠与野生型（wild type， WT）鼠交配，基因型鉴定后筛选出F1代Rag1和Il2rg基因的单等位基因敲除杂合子（Rag1 +/-、Il2rg+/-），再通过雌雄杂合子交配，经两代繁育获得Rag1/Il2rg双基因敲除纯合子（Rag1/Il2rg-/-）。通过流式细胞术检测脾脏混合细胞中的CD3、CD4、CD8、CD19、CD20阳性群，并采用常规病理技术观察胸腺和脾脏的组织结构变化。结果 基因型鉴定成功获得Rag1/Il2rg双基因敲除纯合子（Rag1/Il2rg-/-）。流式细胞术结果显示，基因敲除鼠的CD3、CD4、CD8、CD19、CD20细胞均未出现阴阳分群。WT鼠仅CD4细胞出现阴阳分群。组织病理观察显示，与WT鼠相比，双基因敲除鼠脾脏皮质和髓质结构无明显差异；胸腺萎缩，皮质和髓质分界不清，纤维性被膜变薄，髓质中可见脂肪组织及流产型腺样结构，未见胸腺小体，细胞稀疏，上皮细胞胞质较少。结论 利用CRISPR/Cas9系统成功构建Rag1/Il2rg双基因敲除金黄地鼠模型，可为免疫功能低下人群中腺病毒感染机制的研究提供有价值的实验动物模型。

关键词： HLA-DQA1*03:01:19   HLA-genotyping   Illumina   next generation sequencing   novel allele  

摘要： The HLA-DQA1*03:01:19 allele differs from HLA-DQA1*03:01:01:01 by a single nucleotide substitution in exon 3.

关键词： interleukin-17A (IL-17A)   umbilical cord blood   perinatal complications   gestational diabetes mellitus (GDM)   perinatal infections  

摘要： Background/Objectives: Pregnancy complications are associated with adverse maternal-neonatal outcomes, but the underlying immune mechanisms remain unclear. Here we examined umbilical cord IL-17A levels and their link to gestational diabetes mellitus (GDM) and perinatal infections (PIs). Methods: This two-phase study analyzed 87 pregnant women (38 in the exploratory phase and 49 in the validation phase) from Shenzhen's Premature Infants Gut Microbiota Assembly and Neurodevelopment (PIGMAN) cohort, divided into perinatal complication (PC) (45 cases) and non-perinatal complication (NPC) (42 cases) groups. Cord blood IL-17A levels were measured by ELISA and analyzed as a continuous variable by Nonparametric rank-sum test and a categorical variable using Fisher's exact test. Results: Nonparametric analysis revealed consistently lower IL-17A levels in the PC group across both phases. The discovery phase median in the PC group was 0.67 pg/ml lower than the 5.68 pg/ml median in the NPC group (p = 0.001);in the validation phase, the PC and NPC group levels were 0.93 and 2.05 pg/ml (p = 0.012), respectively. Low IL-17A (<1 pg/ml) prevalence was significantly higher in PC cases (discovery: 61.9% vs. 11.8%, p = 0.002;validation: 50% vs. 36%, p = 0.031). Rank-sum test and Fisher's exact test demonstrated concordant results, confirming a robust association between reduced IL-17A levels and perinatal complications. Conclusion: Umbilical cord blood from PC pregnancies exhibited significantly lower IL-17A levels compared to that from NPC pregnancies, suggesting compromised neonatal cellular immunity. These findings implicate IL-17A deficiency in the immune dysregulation associated with GDM and PI. Conversely, the higher IL-17A levels observed in NPC pregnancies may reflect its protective role in maternal-fetal immunity during early development.

关键词： Sophocarpine   microglia   BV-2 cells   AMPK/NF-kappa B pathway   oxidative stress   neuroinflammation  

摘要： BackgroundMicroglia can be continuously activated to produce proinflammatory cytokines and reactive oxygen species, leading to progressive neurodegeneration. Sophocarpine (ScP) has been reported to exhibit neuroprotective and anti-inflammatory activities, but it remains unclear whether microglia are involved in these ***-2 cells were exposed to ScP, AMP-activated protein kinase (AMPK) agonist AICAR, and the AMPK inhibitor Compound C for 30 min before being treated with lipopolysaccharide (LPS) and IFN-gamma for 24 h. The levels of oxidative response and inflammation were detected by kits, immunofluorescence, ELISA, and western blotting. The AMPK/NF-kappa B expression was measured using western blotting. In vivo effects were next verified using LPS-induced neuroinflammatory mouse ***, 1, 2, and 4 mu M ScP had no effects on BV-2 cells. After BV-2 cells were stimulated with LPS and IFN-gamma, the levels of antioxidant enzymes were decreased, whereas the levels of allograft inflammatory factor 1 (Iba-1) and inflammatory mediators were increased. After LPS and IFN-gamma stimulation, the levels of phosphorylated (p)-AMPK protein were decreased, whilst the levels of p-I kappa B alpha and p-p65 protein were increased. ScP then reduced the levels of Iba-1, inflammatory mediators, p-I kappa B alpha, and p-p65 proteins, whilst increasing the levels of antioxidant enzymes and p-AMPK. ScP treatment reduced the extent of neuronal damage in mice, significantly improving inflammation and oxidative stress damage. The antioxidant and anti-inflammatory effects of ScP were found to be enhanced after AICAR *** can inhibit LPS and IFN-gamma-stimulated oxidative response and neuroinflammation in BV-2 cells through the AMPK/NF-kappa B axis.

关键词： Delayed hypersensitivity reactions   Maculopapular exanthema   Drug reaction with eosinophilia and systemic symptoms   Iodinated contrast media   In vivo diagnostic tools   Ex vivo diagnostic tools  

摘要： Background The use of in vivo and ex vivo diagnostic tools for delayed hypersensitivity reactions (DHRs) associated with iodinated contrast media (ICM) is currently ill-defined. Objective To evaluate the role of in vivo and ex vivo diagnostic tools for DHRs occurring >6 h following intravenous low-osmolality ICM. Methods We conducted a prospective, multicenter, international cohort study. The patients were recruited from two tertiary care adult allergy clinics, Austin Health, Australia and the McGill University Health Centre, Canada. Eligible participants were adults who reported a DHR after receiving ICM. In vivo testing (skin testing and intravenous challenge) was performed to identify an alternative agent. Ex vivo testing using interferon-gamma enzyme-linked ImmunoSpot assay was performed in four Australian patients to explore its diagnostic performance. Results The culprit ICM was identified by dIDT in 17/20 (85%) while in 3/20 (15%) a challenge was necessary to confirm delayed hypersensitivity. All patients with a positive dIDT to iohexol were positive to iodixanol (15/15;100%) while 3/4 (75%), 3/4 (75%), 4/6 (67%), and 3/5 (60%) were positive to iopromide, ioversol, iopamidol, and iobitridol, respectively. Overall, 7/20 (35%) patients tolerated a challenge with an alternative ICM. The IFN-gamma release assay was negative for the implicated ICM in 4 patients with confirmed DHR through a positive dIDT. Conclusion dIDT allowed confirmation of T cell-mediated allergy to the implicated ICM in 85% of patients with a strong clinical suspicion of DHR and identification of non-cross-reactive ICM in 35% of patients. The IFN-y ELISpot was not useful in the four patients tested.

关键词： Dyslipidaemia   TNF-alpha   SNP   Genetic association  

摘要： TNF-alpha polymorphisms may influence dyslipidaemia, but their role remains unclear. This case-control study investigated associations between TNF-alpha gene polymorphisms (-1031T/C, -863C/A, -857C/T, -308G/A and -238G/A) and dyslipidaemia in 595 participants (162 cases, 433 controls) from the Chaoshan region of China. Anthropometric, biochemical and genetic data were analysed using chi 2 tests and logistic regression, with the false discovery rate (FDR) method applied to correct for multiple comparisons. Results revealed that only the -1031T/C and -863C/A polymorphisms were significantly associated with dyslipidaemia. Carriers of the TC + CC genotype for -1031T/C (OR = 048;95 % CI: 030, 078;P FDR = 0006) and the CA + AA genotype for -863C/A (OR = 041;95 % CI: 024, 070;P FDR = 0004) had lower odds of dyslipidaemia. Protective effects were observed for the C allele at -1031T/C (OR = 058, P FDR = 0012) and the A allele at -863C/A (OR = 047, P FDR = 0004). Stratified analyses showed that these associations were significant in males but not females. Functional annotation linked these TNF-alpha gene polymorphisms to transcription factors (e.g. HNF-1A, STAT1 beta) in the adipogenesis pathway. This study reveals genetic associations between TNF-alpha polymorphisms and dyslipidaemia, particularly in males, and provides mechanistic insights into their role in transcriptional regulation.

关键词： Cancer   Neoplasm   Malignancy   Tumor necrosis factor alpha inhibitors   Inflammation   Immunosuppression   Adalimumab   Infliximab   Etanercept  

摘要： BackgroundTumor necrosis factor-alpha (TNF) is an inflammatory cytokine implicated in the development of many chronic inflammatory diseases and TNF-alpha inhibitors (TNF-I) are frequently prescribed as treatment. Their malignancy risk is debated, with pro-oncogenic effects of decreased immune surveillance and anti-oncogenic effects of decreasing chronic inflammation. As such, the literature is inconclusive in the malignancy risk of these medications. Here we investigate the malignancy risk in patients with chronic TNF-I *** is a single health system, retrospective non-matched cohort study of patients with chronic inflammatory conditions between 1996 and 2023. Patients exposed to TNF-I were identified using the generic medication names and the chronic inflammatory disease indication. The unmatched control cohort consisted of patients with the same chronic inflammatory conditions but without TNF-I exposure. Malignancies in this population were identified using ICD-9 and ICD-10 codes. TNF-I exposure was analyzed as a time-varying covariate prior to model fitting. Hazard ratios (HR) for TNF-I exposure on overall and individual cancer risk were estimated using two-sided Cox proportional hazards *** were 12,941 patients exposed to TNF-I and 37,402 patients unexposed to TNF-I. TNF-I exposure was not associated with overall cancer risk (HR 1.05, 95% CI 0.92-1.19). TNF-I exposure was positively associated with melanoma (HR 1.45, 95% CI 1.01-2.08), basal cell carcinoma (BCC) (HR 1.6, 95% CI 1.18-2.15) and squamous cell carcinoma (SCC) (HR 1.8, 95% CI 1.15-2.83), and negatively associated with prostate cancer (PCa) (HR = 0.51, 95% CI 0.29-0.91), leukemia (HR 0.12, 95% CI 0.02-0.83), and non-Hodgkin lymphoma (NHL) (HR 0.36, 95% CI 0.13-0.98). There was an increased risk of overall malignancy in TNF-I exposed patients with Psoriasis (HR 1.53, 95% CI 1.15-2.03, p = 0.003) but not in other inflammatory *** with TNF-I