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关键词： Pcdh7   Pydc3   IFN-beta   osteoclast differentiation  

摘要： Protocadherin-7 (Pcdh7) is a member of the protocadherin family, a subgroup of the cadherin superfamily. We previously demonstrated that Pcdh7 functions as a signaling receptor in osteoclast differentiation. In this study, we investigated the potential gene regulatory role of Pcdh7 in this process and identified Pyrin domain-containing protein 3 (Pydc3) as a key mediator of Pcdh7-mediated regulation of osteoclast differentiation. Differential gene expression analysis comparing wild-type (Pcdh7+/+) and Pcdh7-deficient (Pcdh7-/-) cells revealed a significant upregulation of Pydc3 in Pcdh7-/- cells. RNAi-mediated knockdown of Pydc3 rescued the impaired osteoclast differentiation in Pcdh7-/- cells, whereas overexpression of Pydc3 suppressed osteoclast differentiation in Pcdh7+/+ cells, suggesting that Pydc3 negatively regulates osteoclast differentiation. Additionally, Pcdh7-/- cells showed elevated expression of interferon response genes and increased production of interferon-beta (IFN-beta). Neutralization of IFN-beta signaling using anti-IFN-beta and/or anti-interferon alpha and beta receptor 1 (IFNAR1) antibodies significantly restored osteoclast differentiation in Pcdh7-/- cells. Collectively, these findings uncover a novel role for Pcdh7 in osteoclast differentiation through regulation of Pydc3 expression and IFN-beta production.

关键词： iPS   melanocyte   keratinocyte   co-culture   ROCK inhibitor   IFN-gamma   Vitiligo   bFGF   ET-1   dendrites  

摘要： Vitiligo is a chronic autoimmune dermatosis defined by selective melanocyte depletion and patchy depigmentation. IFN-gamma-driven recruitment of autoreactive CD8+ T cells and induction of melanocyte apoptosis are central to its pathogenesis. Current therapies-including UVB phototherapy, tacrolimus, vitamin D3 analogs, and surgical methods-show limited and inconsistent efficacy. Emerging treatments like JAK inhibitors and WNT activators offer potential but require further validation. Translational progress is hindered by a lack of scalable human models. Here, we describe a tunable in vitro vitiligo platform in which human iPSC-derived melanocytes (iMc) are co-cultured with keratinocytes on Matrigel and exposed to precise graded IFN-gamma concentrations. Our data revealed dose-dependent decreases in iMc survival and dendritic structure, faithfully mirroring derived melanocyte pathology. Leveraging this platform, we first evaluated the short-term efficacy of the ROCK inhibitor Y27632 under early-stage patient IFN-gamma concentrations representative of patient lesional thresholds. At three days, Y27632 significantly upregulated adhesion molecules E-cadherin and DDR1, and two central factors-ET1 and bFGF. Importantly, ROCK inhibition reversed dendritic retraction and improved overall viability of iMc-keratinocytes. These findings position ROCK blockade as a promising adjunctive strategy and establish a pre-clinical platform for evaluating combination therapies for durable pigment restoration.

关键词： HLA   Immunogenetics   Islet autoimmunity   Killer-cell immunoglobulin-like receptors   KIR   Natural killer (NK) cells   Progression   Seroconversion   Type 1 diabetes  

摘要： Aims/hypothesis The aim of this work was to explore associations between type 1 diabetes progression from stages 1 or 2 to stage 3 and interacting ligand-receptor complexes of HLA class I (HLA-I) and KIR gene products. Methods Applying next-generation sequencing technology to genotype HLA-I genes (HLA-A, -B, -C) and KIR genes (KIR2DL1, KIR2DL2, KIR2DL3, KIR2DL4, KIR2DL5, KIR2DS1, KIR2DS2, KIR2DS3, KIR2DS4, KIR2DS5, KIR3DL1, KIR3DL3, KIR3DS1, KIR2DP1, KIR3DP1) from 1215 participants in the Diabetes Prevention Trial-Type 1 (DPT-1) and the Diabetes Prevention Trial (TN07), we systematically explored associations of HLA-I-KIR ligand-receptor interactions (LRIs) with disease progression via a Cox regression model. We investigated the structural properties of identified LRI complexes. Results KIR and HLA-I genes had no or sporadic associations with disease progression. Out of all possible LRIs, nine HLA-A ligands and 14 HLA-B ligands with corresponding receptors had modest associations with progression (p<0.05). As an example, carriers of A*03:01-KIR2DS4 had slower progression (HR 0.36, p=3.06 x 10(-2)), as did B*07:02-KIR2DL3 carriers (HR 0.26, p=7.76 x 10(-3)). Structural investigations of KIR-HLA-I complexes via homology modelling based on already-solved respective complex structures suggested that the respective electrostatic and van der Waals interactions encoded in the protein sequences result in strong biophysical LRIs, which could alter the progression of type 1 diabetes. Conclusions/interpretation These results reveal that LRIs of KIR-HLA-I gene products, rather than individual genes, contribute to type 1 diabetes progression, and such interactions are likely to be stabilised by electrostatic and van der Waals forces. As the KIR-HLA-I interactions involve part of the C-terminus of the antigen-binding groove of HLA-I, but may be affected by the respective bound peptide, this suggests a new mechanism for type 1 diabetes pathogenesis. Data availability Clinical data

关键词： immunology   infectious disease   inflammation   microbiology  

关键词： 清宣导滞方   儿童   流感   随机对照研究   治疗  

摘要： 目的：观察清宣导滞方治疗儿童流行性感冒（肺胃积热证）的症状改善及抗原转阴率效果。设计：采用多中心随机对照的方法学设计，于2022年10月至2023年4月在北京中医药大学东方医院等8家医院儿科收集流感确诊病例。通过诊间招募180例符合标准的流感肺胃积热证患儿。将符合纳入标准的患儿采用区组随机的方法进行随机分组，试验组予清宣导滞方治疗5天，对照组予磷酸奥司他韦颗粒治疗5天。主要疗效指标：流感抗原检测转阴率；次要疗效指标：加拿大呼吸道疾病和流感量表（CARIFS）评分；并发症、重症及危重症发生率。入组当天、用药后48小时、用药后72小时、用药后6 ± 1天进行随访观察。结果：180例参与者随机分配到试验组（n=90）或对照组（n=90）。主要疗效指标：流感抗原检测结果比较：试验组流感抗原平均转阴时间为5.29 ± 1.245天，对照组流感抗原平均转阴时间为5.40 ± 1.681天，差异无统计学意义（P＞0.05）。干预5天后，试验组52例转阴，对照组51例转阴，差异无统计学意义（P＞0.05）。次要疗效指标：CARIFS评分：干预后72h，试验组与对照组在头痛、肌肉酸痛、需要额外照顾3项，差异有统计学意义（P＜0.05）。干预后6天±1天试验组与对照组在咽痛、睡眠不好、感觉不舒服、精神差易疲劳、比平时爱哭、要额外照顾、症状维度、功能维度、影响父母维度、总分计10项，差异有统计学意义（P＜0.05）。症状维度积分、功能维度积分、影响父母维度积分、CARIFS总分组内比较：随着随访时间后延，两组积分都出现明显下降，差异有统计学意义（P＜0.001）。组间比较，入组时试验组积分均值高于对照组，随着干预的进行，试验组积分下降较对照组明显，随访结束时，积分均值低于对照组，差异无统计学意义（P＞0.05）。并发症、重症及危重症发生率：两组均无并发症、重症及危重症，差异无统计学意义（P＞0.05）。结论：清宣导滞方治疗儿童流感（肺胃积热证）症状改善效果及抗原转阴率不劣于磷酸奥司他韦颗粒，患儿接受度较好，可以尝试更广泛的应用于临床治疗儿童流感（肺胃积热证）。

关键词： Rux   cancer cachexia   IL-6/JAK/STAT3   macrophages   systemic inflammatory response   muscle atrophy  

摘要： Objectives Ruxolitinib (Rux), an oral Janus tyrosine Kinase (JAK) tyrosine kinase inhibitor, has demonstrated anti-inflammatory properties and the ability to mitigate denervation-induced skeletal muscle atrophy. Here, we checked the potential efficacy of Rux on cancer cachexia and tried to clarified its *** The in vitro cell models of C26 or LLC CM-induced C2C12 myotubes were used to check the influence of Rux on myotube atrophy. C26 tumour-bearing mice (male BALB/c mice) were applied as the animal model to examine the effects of Rux in attenuating cachexia symptoms. Western blot analysis was utilized to investigate the potential mechanisms of *** findings Rux significantly attenuated C2C12 myotube atrophy in vitro. Rux suppressed the interleukin-6 secretion by inhibiting STAT3 activation in tumour cells and macrophages. The administration of Rux prevented body weight loss and muscle wasting in C26 tumour-bearing mice without affecting tumour growth. At the end of the experiment, mice in the Rux treatment group exhibited a 6.7% increase in body weight compared to the C26 model group. Furthermore, Rux enhanced in gastrocnemius myofibres cross-sectional area and grip *** Rux ameliorates cancer cachexia muscle atrophy by inhibiting STAT3/Atrogin-1 signaling. Rux may represent a promising therapeutic candidate for the treatment of cancer cachexia.

关键词： caspase substrates   caspase inhibitors   inflammasomes   pyroptosis   apoptosis   in vitro kinetics   Yersinia pseudotuberculosis  

摘要： Caspases are a family of cysteine proteases that act as molecular scissors to cleave substrates and regulate biological processes, such as programmed cell death and inflammation. Extensive efforts have been made to identify caspase substrates and to determine the factors that dictate specificity. We recently discovered that human inflammatory caspases (caspases-1, -4, and -5) cleave the cytokines IL-1 beta and IL-18 in a sequence-dependent manner. Here, we report the development of a new peptide-based probe and inhibitor derived from the tetrapeptide sequence of IL-18 (LESD). The LESD-based inhibitor showed a strong preference for caspase-8 with an IC50 of 50 nM, and was more potent in vitro than the commonly used zIETD-FMK inhibitor, which is considered the most selective and potent caspase-8 inhibitor. We further demonstrated that the LESD-based inhibitor prevents caspase-8 activation during Yersinia pseudotuberculosis infection in primary bone marrow-derived macrophages. In addition, we systematically characterized the selectivity and potency of known substrates and inhibitors of the apoptotic and inflammatory caspases using standardized activity units of each caspase. Our findings reveal that VX-765, a known inhibitor of caspases-1 and -4, also inhibits caspase-8 (IC50 = 1 mu M). Even when specificities are shared, the caspases exhibit different efficiencies and potencies for shared substrates and inhibitors. Altogether, we report the development of new tools that will facilitate the study of caspases and their roles in biology.

关键词： Bifidobacterium adolescentis   cell surface polysaccharide   tumor necrosis factor-alpha   LPS   TLR4  

摘要： Bifidobacterium adolescentis, a commensal probiotic, modulates immune responses and inversely correlates with TNF-alpha production. This study investigates the immunomodulatory effects of the probiotic B. adolescentis FXJWS49M31 and its cell surface polysaccharide (CSP) on lipopolysaccharide (LPS)-induced inflammation. In vitro coculture and in vivo LPS-induced mouse models demonstrated that FXJWS49M31 and its CSP significantly suppressed the secretion of TNF-alpha and other pro-inflammatory cytokines, alleviating inflammation in the colon and liver. Mechanistic analysis revealed that CSP competitively binds to CD14, blocking the LPS-CD14 interaction and inhibiting activation of the TLR4-NF-kappa B signaling pathway. Structural modeling identified specific binding sites between CSP1 and CD14, elucidating the molecular basis of its immunoregulatory function. These findings provide a theoretical foundation for the anti-inflammatory properties of probiotic polysaccharides and their potential therapeutic applications.

关键词： 类风湿性关节炎   托法替布   传统DMARDs   白细胞介素-22   白细胞介素-23   Th22细胞亚群  

摘要： 目的：探讨托法替布联合传统疾病修饰抗风湿药（DMARDs）治疗对类风湿性关节炎（RA）患者外周血白细胞介素-22（IL-22）、白细胞介素-23（IL-23）及Th22细胞亚群的影响。方法：回顾性分析2022年12月至2024年12月本院收治的100例RA患者临床资料。使用随机数字表法分为常规组（n=33，给予传统DMARDs治疗）、单一组（n=34，给予托法替布）及联合组（n=33，给予托法替布联合传统DMARDs治疗）。比较三组血清IL-22、IL-23水平、Th22细胞亚群比例、关节功能恢复情况、疾病改善情况及不良反应等。结果：治疗3个月后三组的IL-22、IL-23及Th22细胞亚群比例均较治疗前降低，且联合组显著低于常规组与单一组（P<0.05）；治疗3个月后三组的抗-CCP、RF水平也均较治疗前下降，且联合组显著低于常规组与单一组（P<0.05）；治疗3个月后三组的关节肿胀频次、压痛关节数目、晨僵时间及VAS评分均较治疗前降低，且联合组显著低于常规组与单一组（P<0.05）；治疗3个月后三组的DAS28评分及HAQ评分均较治疗前降低，且联合组显著低于常规组与单一组（P<0.05）；在治疗期间，三组不良反应发生率比较，差异无统计学意义（Z =0.290，P=0.865）。结论：托法替布联合传统DMARDs治疗RA的临床效果显著，能有效降低血清IL-22、IL-23水平及自身抗体水平，调节Th22细胞亚群比例，减轻炎症反应，改善关节功能。

关键词： CD317/tetherin   extracellular vesicles   immune modulation   mesenchymal stromal cells  

摘要： In spite of the numerous clinical trials conducted on mesenchymal stromal cells and their extracellular vesicles (MSC-EVs) across a wide range of diseases, the field faces challenges in reaching a consensus on crucial parameters such as source, marker definition, and culture conditions, adding to heterogeneous efficiencies. Nevertheless, there is widespread acceptance of the pro-inflammatory activation of MSCs with IFN-gamma and TNF-alpha to enhance immune modulation. Our study highlights the impact of activation duration on MSC-EV-mediated immune modulation of macrophages. Extended activation periods (24 h) revealed elevated levels of IFN-gamma-induced CD317 on the MSC surface. CD317 is known to tether enveloped viral particles to the cell membrane, impeding viral diffusion and spread. We demonstrated the accumulation of EVs on the MSC cell surface following activation or lentiviral CD317 overexpression. In contrast, CD317 knockdown eliminated the enrichment of EVs on the cell surface, significantly enhancing the MSC-EV-mediated immune modulation of macrophages. Considering the pivotal role of IFN-gamma in MSC immune modulation and its inevitable contact in patients, our findings propose CD317 as a potential modulator of MSC-based therapy efficacy in clinical applications.