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关键词： Solute carrier family 7 member 11   Interleukin-1 beta   Combined therapy   T cell exhaustion   Oral carcinogenesis  

摘要： Oral squamous cell carcinoma (OSCC), one of the most prevalent and aggressive forms of head and neck squamous cell carcinoma, has a five-year survival rate of about 50% similar to 60%, emphasizing the urgent need for more effective therapeutic strategies. Solute carrier family 7 member 11 (SLC7A11) is overexpressed in various cancers and represents a potential therapeutic target. Sulfasalazine (SAS), a Food and Drug Administration-approved drug, is a potent inhibiter of SLC7A11. However, SAS can also increase the levels of pro-inflammatory cytokines such as IL-1 beta, which may suppress the immune response. Here, we investigate the effect of SAS combined with anti-IL-1 beta monoclonal antibody (anti-IL-1 beta mAb) as a novel treatment strategy for OSCC. In this study, SLC7A11 was markedly increased in OSCC tissues, and high SLC7A11 expression predicted poor prognosis. SAS treatment was shown to suppress OSCC cell proliferation and trigger ferroptosis, as evidenced by elevated reactive oxygen species, reduced glutathione and enhanced lipid peroxidation. SAS also elevated IL-1 beta levels, leading to T cell exhaustion. Combining SAS with anti-IL-1 beta mAb reversed T cell exhaustion and amplified the anti-tumor effects in vitro. In the 4-nitroquinoline-1-oxide-induced oral cancergenisis model, the combination treatment significantly inhibited oral carcinogenesis compared to monotherapy. Our results suggest that combining SAS with anti-IL-1 beta mAb enhances the anti-tumor efficacy against OSCC through tumor growth inhibition and immune modulation, offering a promising therapeutic strategy.

摘要： Background:Co-trimoxazole is a leading global cause of severe cutaneous adverse drug reactions (SCAR) including Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS). Co-trimoxazole-induced SCAR are associated with HLA class I alleles including HLA-B*13:01 and HLA-B*38:02 in Southeast Asian (SEA) populations. However, the global generalizability of these associations is unknown but critical for population-appropriate risk stratification and diagnosis. Objective:To determine HLA risk factors associated with co-trimoxazole-induced SJS/TEN and DRESS in populations from the United States (US) and South Africa (SA). Methods:We performed high-resolution HLA typing on dermatologist-adjudicated co-trimoxazole-induced SCAR patients in the US (n=63) and SA (n=26) compared to population controls. Peptide binding and docking analyses were performed using MHCcluster2.0 and CB-Dock2. Results:In a multiple logistic regression model, HLA-B*44:03 (Pc<0.001, OR: 4.08), HLA-B*38:01 (Pc<0.001, OR: 5.66), and HLA-C*04:01 (Pc=0.003, OR: 2.50) were independently associated with co-trimoxazole-induced SJS/TEN in the US. HLA-B*44:03 was also associated with co-trimoxazole-induced DRESS in SA (Pc=0.019, OR: 10.69). Distinct HLA-B variants with shared peptide binding specificities (SPBS) and HLA-C*04:01 identified 94% and 78% of co-trimoxazole-induced SJS/TEN and DRESS in the US, respectively. The SEA risk allele HLA-B*13:01, with SPBS to HLA-B*44:03, was identified in just 1/63 US SCAR patients. Conclusion:HLA alleles with SPBS to SEA-related risk alleles including HLA-B*44:03 (SPBS with HLA-B*13:01) and HLA-B*38:01 (SPBS with HLA-B*38:02) but also HLA-C*04:01 predisposed to co-trimoxazole-induced SCAR in the US and SA. These findings provide biological plausibility and strategies for global risk prediction and diagnosis of co-trimoxazole-induced SCAR. HIGHLIGHTS BOX:HLA alleles including HLA-B*13:01 and HLA-B*38:02 ar

关键词： Obese asthma   Huatanhuoxue decoction   Network pharmacology   Neutrophils   IL-17A signaling pathway  

摘要： Ethnopharmacological relevance: Huatanhuoxue Decoction (HTHX) is a traditional Chinese formula consisting of nine herbs. It is used to improve obesity-related asthma symptoms and reduce airway inflammation. Aim of the study: To study HTHX effects on airway inflammation in obese asthmatic mice via the IL-17 A signaling pathway. Materials and methods: Network pharmacology was used to predict the bioactive ingredients in HTHX. Subsequently, an obese asthma model was established by high-fat diet feeding and exposure to house dust mite. The effects of HTHX on obesity-related asthma progression were investigated using histopathological examinations, airway hyperresponsiveness determinations, and enzyme-linked immunosorbent assays. The mechanism of action of HTHX was confirmed by Western blots, flow cytometry, immunohistochemistry, and immunofluorescence analyses. Results: HTHX alleviated the development in obese asthma mice by improving the pathological condition of lung tissue, airway hyperresponsiveness, and inflammatory factors. Network pharmacology identified the involvement of the IL-17 signaling pathway. HTHX decreased the production of neutrophils and the expression of NETs in lung tissue. HTHX also reduced group 3 innate lymphoid cells and Th17 cells, which are responsible for producing IL-17 A. The production of IL-17 A-related protein was also suppressed. The results indicate that HTHX inhibited the excessive activation of the IL-17 A signaling pathway. Conclusions: HTHX alleviated airway inflammation by regulating the IL-17 A signaling pathway in obese asthmatic mice.

关键词： IL-4 signaling   dendritic cells   skin allergy  

摘要： IL-13 produced by innate lymphoid cells (ILC2s) is crucial for the steady-state differentiation of dermal CD11b-low type-2 dendritic cells (DC2s), a murine KLF4-dependent DC2 population that is found only in skin and drives enhanced Th2 differentiation. In this study, we examined how CD11b-low DC2s respond to skin inflammation, particularly in the absence of IL-13. We employed a model of MC903-induced atopic dermatitis in which CD11b-low DC2s migrate from skin to the draining lymph node (dLN) in a thymic stromal lymphopoietin receptor (TSLPR)-dependent manner, temporarily depleting the skin CD11b-low population. In C57BL/6J mice, DC2s replenished the empty niche gradually over several days and required IL-4RA-dependent signaling for their differentiation into CD11b-low DC2s. In IL-13 KO mice treated with MC903, IL-4 produced by basophils and CD4+ T cells could compensate for the absence of IL-13 to drive differentiation of skin CD11b-low DC2s. We confirmed this latter finding by showing that IL-4 treatment was sufficient to induce CD11b-low differentiation both in DC cultures and in IL-13 KO mice. Our findings suggest that, in the absence of IL-13, IL-4 produced during type-2 skin inflammation can induce CD11b-low DC2 differentiation, providing insight into how inflammation can drive an environment that supports further allergic sensitization.

关键词： IL-24   Penta-O-galloyl-β-D-glucose   STAT3   in silico   skin barrier  

关键词： Ichthyophthirius multifiliis   Pelteobagrus vachelli   interleukin-1 beta   interleukin-6   serum amyloid A  

摘要： Interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6), and serum amyloid A (SAA) are key pro-inflammatory mediators in the regulation of immune responses. The hypothesis posits that their expression varies with the progression of Ichthyophthirius multifiliis (Ich) infection and may serve as predictors of disease outcome. To elucidate their spatiotemporal dynamics, the full-length CDS of IL-1 beta, IL-6, and SAA in Pelteobagrus vachelli were cloned, and then their mRNA levels were tracked from infection onset (day 0) to resolution (day 40) or mortality in seven tissues. Key findings revealed a surge in IL-1 beta expression in the kidney and SAA expression in the spleen at 5 days post-infection (dpi), coinciding with no visible symptoms. Significant SAA elevation in the head kidney was observed at 10 dpi, preceding the emergence of white spots on the skin. This was followed by gill-specific SAA downregulation at 20 dpi, when 40% of fish presented with white spots. Complete clinical resolution by 40 dpi correlated with reduced hepatic SAA and branchial IL-1 beta levels. Notably, the concurrent upregulation of all three mediators occurred exclusively in the skin of moribund individuals. These findings identify potential biomarkers for tracking host inflammatory responses in ichthyophthiriasis.

关键词： 急性胰腺炎   生长抑素   乌司他丁   肿瘤坏死因子   白介素-6  

摘要： 文章旨在对重症急性胰腺炎(SAP)患者实施乌司他丁+生长抑素治疗下改善血清[C反应蛋白(CRP)、白介素-6(IL-6)、血清肿瘤坏死因子-α(TNF-α)]水平的效果。方法 于2021年1月至2023年12月,选取SAP患者为研究对象,通过电脑随机分组,将患者分为接受生长抑素治疗的对照组(共54例)以及额外加入乌司他丁治疗的实验组(亦为54例),进而对比两组在用药方案上的病情改善成效。结果 研究发现,干预组的总体疗效显著优于参照组(96.30%对比85.19%),差异具有统计学意义,P值<0.05。参照组与干预组CRP、IL-6、TNF-α与血清淀粉酶(AMS)、内毒素(ET)水平治疗相比未见差异,P>0.05;干预组治疗后较参照组更低,P<0.05;两组急性生理及慢性健康状况评分系统(APACHEⅡ)评分在治疗相比未见差异,P>0.05;于治疗后对比参照组,干预组更低,P<0.05。结论 SAP患者经生长抑素+乌司他丁治疗,在改善血清指标的同时,缓解病情严重程度,值得被临床推广与应用。

关键词： 3'UTR   HLA-G   immunogenetics   polymorphisms   uveitis  

摘要： PurposeHLA-G is a non-classical HLA class I gene encoding a molecule endowed with immunomodulatory properties, playing important immunosuppressive and tolerogenic roles in immuno-privileged organs. Fluctuations in its expression levels have been correlated with the predisposition to autoinflammatory disorders, notably uveitis, characterized by inflammation of the uvea. In the present work, DNA was obtained from saliva samples of 147 Spanish patients with uveitis, with subsequent analysis focusing on the distribution of polymorphisms within the 3'UTR region of the HLA-G gene (a region known to modulate the expression of the HLA-G molecule).MethodsAnalysis techniques employed included PCR-RFLP or DNA sequencing. Comparative analysis was conducted against a control cohort comprising 117 healthy *** frequency of the UTR-2 haplotype is increased in patients affected with anterior uveitis (OR (95% CI) 2.35 (1.06-5.21);p = 0.036). Additionally, a higher number of patients with posterior uveitis bearing in homozygosis the G allele of the 3142 C/G SNP (OR (95% CI) 2.67 (1.15-6.20);p = 0.023), was observed. Both markers are associated with diminished HLA-G *** findings present the first evidence of the involvement of polymorphisms within the 3'UTR region of the HLA-G gene in susceptibility to uveitis.

关键词： Cyprinus carpio   Un-ionized ammonia   RT-qPCR   Pro-inflammatory cytokines   Stress response   Leptin  

摘要： BackgroundCommon carp is one of the most economically important freshwater fish species globally. Ammonia exposure, a frequent challenge in aquaculture, can lead to significant economic losses. This study investigated the impact of un-ionized ammonia (UIA) exposure on the expression profiles of three key genes in common carp fry: interleukin-1 beta (IL-1 beta), corticotropin-releasing hormone (CRH), and leptin a1 (Lep-a1). These genes are crucial indicators of immune response, stress regulation, and appetite control, respectively. Fish were exposed to 0.7 mg/L of UIA, and gene expression was analysed in liver and gill tissues at five time points (12 h, 2-, 4-, 7-, and 14-days of exposure) using quantitative real-time PCR (RT-qPCR).ResultsResults demonstrated that expression levels of all three genes were significantly affected by exposure time and tissue type. IL-1 beta, CRH, and Lep-a1 were upregulated in both liver and gill tissues, with the liver consistently showing higher expression levels. Notably, significant positive correlations were observed between each pair of the three genes studied, suggesting a coordinated physiological response to ammonia stress. The liver emerged as a key organ in orchestrating the long-term adaptive response, while the gills exhibited a more acute, transient *** study provides valuable insights into the molecular mechanisms underlying the physiological response of common carp to ammonia toxicity. The findings highlight the complex interplay between immune, stress, and metabolic pathways in coping with ammonia exposure. A deep understanding of these mechanisms could lead to improved management strategies in aquaculture and the development of potential biomarkers for assessing stress responses in fish populations.

关键词： bile salt   demicellization   enthalpy   entropy   Gibbs free energy   IL   thermodynamics  

摘要： Isothermal titration calorimetric (ITC) study can probe critical micelle concentration (CMC) as well as the associated thermodynamics of surfactant aggregation. Micellization behavior of two bile salts, sodium cholate (NaC) and sodium deoxycholate (NaDC) were evaluated through ITC studies;subsequently the enthalpy change (Delta Hdemic0$$ {\Delta H}_{\mathrm{demic}}<^>0 $$), Gibbs free energy change (Delta Gdemic0$$ {\Delta G}_{\mathrm{demic}}<^>0 $$) and entropy change (Delta Sdemic0$$ {\Delta S}_{\mathrm{demic}}<^>0 $$) of demicellization processes were also evaluated in the presence of varied concentration of an ionic liquid (IL) 1-butyl-3-methylimidazolium tetrafluoroborate ([bmim]BF4) and at different temperatures at ascertain concentration of IL (1.0 mM). In order to distinguish the effect of IL from the corresponding common salt, studies were also carried out in aqueous sodium tetrafluoroborate (NaBF4) medium. CMC values decrease with increasing IL/NaBF4 concentration and increase with increasing temperature. CMC reduction in case of NaDC-NaBF4 system is more prominent, while considering temperature variation, the CMC rise in NaC-[bmim]BF4 system is more significant. Delta Hdemic0$$ {\Delta H}_{\mathrm{demic}}<^>0 $$ values considerably depend on temperature. Temperature rise causes an increase in Delta Gdemic0$$ {\Delta G}_{\mathrm{demic}}<^>0 $$ values. However, it decreases with increasing IL/NaBF4 concentration for both NaC and NaDC. Effect of temperature is less prominent on the Delta Gdemic0$$ {\Delta G}_{\mathrm{demic}}<^>0 $$ variation whereby the demicellization processes are found to be entropy driven processes. Temperature variation exhibits greater effect on Delta Hdemic0$$ {\Delta H}_{\mathrm{demic}}<^>0 $$ than the additive concentration. Such comprehensive studies hold promise for diverse scientific and industrial applications besides the fundamental understanding on IL induced micellization.