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关键词： cytokines   inflammation   repair   wound healing  

摘要： Interferon-gamma (IFN gamma) is traditionally recognized for its pro-inflammatory role during intestinal inflammation. Here, we demonstrate that IFN gamma also functions as a pro-repair molecule by increasing TNF alpha receptor 2 (TNFR2 protein/TNFRSF1B gene) expression on intestinal epithelial cells (IEC) following injury in vitro and in vivo. In silico analyses identified binding sites for the IFN gamma signaling transcription factor STAT1 in the promoter region of TNFRSF1B. Scratch-wounded IEC exposed to IFN gamma exhibited a STAT1-dependent increase in TNFR2 expression. In situ hybridization revealed elevated Tnfrsf1b mRNA levels in biopsy-induced colonic mucosal wounds, while intraperitoneal administration of IFN gamma neutralizing antibodies following mucosal injury resulted in impaired IEC Tnfrsf1b mRNA and inhibited colonic mucosal repair. These findings challenge conventional notions that "pro-inflammatory" mediators solely exacerbate damage by highlighting latent pro-repair functions. Moreover, these results emphasize the critical importance of timing and amount in the synthesis and release of IFN gamma and TNF alpha during the inflammatory process, as they are pivotal in restoring tissue homeostasis.

关键词： CD44(high)CD8(+) T cells   G1/S phase   IL-18   Notch signaling   stem cell-like memory CD8(+) T cells  

摘要： Recent studies have revealed that a subset of CD8(+) T cells exhibit innate features and can be activated by cytokines. However, the precise mechanisms underlying the proliferation and differentiation of these cells remain unclear. Here, we demonstrated that CD44(high)CD8(+) T cells in the mouse spleen express functional interleukin-18 (IL-18) receptors, whereas CD44(low)CD8(+) T cells do not. In response to IL-18 stimulation, these cells activated various metabolic pathways, upregulated the expression of surface molecules, such as c-Kit (CD117), CD25, and PD-1, and induced progression through the G1/S phase in the cell cycle. IL-18-primed cells, expressing a high-affinity receptor for IL-2, exhibited robust proliferation in response to IL-2 and underwent differentiation into effector cells. The splenic CD44(high)CD8(+) T cells exhibited high expression levels of CD122, CD62L, CCR7, and CXCR3, along with CD5, indicating their potential for migration to the lymph nodes, where they could undergo expansion and terminal differentiation into effector cells. Additionally, in a tumor model, administration of IL-18 increased the accumulation of CD8(+) T cells in both the lymph nodes and tumors. It is noteworthy that stimulation of CD44(high)CD8(+) T cells with IL-18 upregulated the Notch-1 receptor and c-Myc. Moreover, inclusion of gamma-secretase inhibitors attenuated the effect of IL-18 on both proliferation and interferon-gamma production in the cells. These results demonstrate that IL-18 primes CD44(high)CD122(high)CXCR3(high)CD62L(high)CD8(+) T cells for expansion and differentiation into effector cells in a Notch signaling-dependent manner.

关键词： arthritis, psoriatic   T-lymphocytes   cytokines  

摘要： Background Immune checkpoint inhibitors (ICIs) have significantly improved outcomes for patients with cancer. However, these therapies are associated with adverse events including de novo immune-related adverse events or flare of pre-exiting autoimmune disorders. Up to 80% of patients with cancer and pre-existing psoriasis (PsO) or psoriatic arthritis (PsA) experience PsO/PsA flare after initiating ICIs. Targeting the interleukin (IL)-17/IL-23 axis is a mainstream of the PsO/PsA treatment. However, whether this treatment can effectively control PsO/PsA with ICI exposure while preserving anti-tumour efficacy remains *** reports We report three patients with PsA and cancer, who received ICIs for their cancer treatment. All patients were male. Two patients had clear cell renal cell carcinoma, and one had melanoma. Two patients received anti-PD-1 antibody monotherapy, while one patient received combined anti-CTLA-4 and PD-1 antibody therapy. One patient had been receiving anti-IL-17A antibody (secukinumab), while the other two patients started anti-IL-17A antibody (ixekizumab) and anti-IL-23 antibody (guselkumab) after their PsA flared up during ICI treatment. Of note, with the anti-IL-17A or anti-IL-23 antibody treatment, their PsA remained in remission, and they well tolerated the ICI therapy. Importantly, all three patients showed persistent tumour responses to ICI therapy, including two complete remissions and one stable disease, *** These three cases suggest that targeting the IL-17/23 axis may be an effective and safe approach for patients with cancer and pre-existing PsA being considered for ICI therapy.

关键词： 滋养细胞   TNF-α   BeWo   细胞融合率  

摘要： 目的 探究不同糖分条件下TNF-α对胎盘滋养细胞融合的影响。方法 在BeWo细胞中添加Forskolin构建滋养细胞融合模型，用激光共聚焦显微镜观察细胞融合状况，用CCK-8法检测细胞增殖活力、ELISA法检测细胞hCG浓度，用实时荧光定量PCR和WB法检测融合相关基因和蛋白的表达水平。结果 Forskolin会促进细胞融合并释放大量hCG。在正常培养条件下，随着TNF-α浓度的升高，滋养细胞融合效率以及hCG的释放量均呈显著下降趋势；而在高糖培养中，TNF-α对细胞的融合与hCG的释放均无上述影响。在正常与高糖条件下，TNF-α都会促进细胞融合相关基因的表达，但会抑制其在蛋白水平上的表达；TNF-α对hCG合成基因的影响呈相反趋势。结论 TNF-α会抑制滋养细胞的融合与hCG的释放，但这种作用在高糖培养下不显著。

关键词： Diabetes   Endothelial cells   High glucose   Epidermal growth factor   Mathurameha  

摘要： Mathurameha is a traditional Thai herbal formula with a clinically proven effect of blood sugar reduction in patients with diabetes mellitus, but its anti-diabetic complication potential is largely unknown. This study aimed to elucidate the effects of Mathurameha and its underlying mechanisms against high glucose-induced endothelial dysfunction in human endothelial ***926 cells. After confirming no cytotoxic effects, the cells were treated with normal glucose (NG), high glucose (HG), or high glucose plus Mathurameha (HG + M) for 24 h. A quantitative label-free proteomic analysis using the sequential window acquisition of all theoretical mass spectra (SWATH-MS) approach identified 24 differentially altered proteins among the three groups: 7 between HG and NG, 9 between HG + M and NG, and 13 between HG + M and HG. Bioinformatic analyses suggested a potential anti-diabetic action through the epidermal growth factor (EGF) pathway. Subsequent functional validations demonstrated that Mathurameha reduced the EGF secretion and the intracellular reactive oxygen species (ROS) level in high glucose-treated cells. Mathurameha also exhibited a stimulatory effect on nitric oxide (NO) production while significantly reducing the secretion of endothelin-1 (ET-1) and interleukin-1 beta (IL-1 beta) in high glucose-treated cells. In conclusion, our findings demonstrated that Mathurameha attenuated high glucoseinduced endothelial dysfunction through the EGF/NO/IL-1 beta regulatory axis. Significance: This study reveals the potential of Mathurameha, a traditional Thai herbal formula, in mitigating high glucose-induced endothelial dysfunction, a common complication in diabetes mellitus. Using proteomics and bioinformatic analyses followed by functional validations, the present study highlights the protective effects of Mathurameha through the EGF/NO/IL-1 beta regulatory axis. These findings support its potential use as a therapeutic intervention for diabetic vascular complications and p

关键词： Brain   Metastasis   Breast cancer   Interferon-gamma   Blood-brain barrier   Immune response   T lymphocytes  

摘要： The appearance of brain metastasis is the most serious complication of breast cancer with mostly fatal outcomes. To reach the brain, tumor cells need to pass the blood-brain barrier (BBB). The molecular mechanisms underlying penetration of the BBB are largely unknown. Previously we found that tumor-infiltrating T lymphocytes enhance the development of brain metastasis of estrogen receptor-negative (ER-) breast cancer. In the current study, we investigate the contribution of T lymphocytes and the IFN-gamma pathway in enabling breast cancer cells to pass the in vitro BBB. CD8+ cells display the strongest stimulatory effect on breast cancer cell passage. We show that inhibition of the IFN-gamma receptor in MDA-MB-231 breast cancer cells, or neutralization of soluble IFN-gamma, impairs the in vitro trespassing of breast cancer cells. Importantly, we validated our findings using gene expression data of breast cancer patients. The CXCL-9,-10,-11/CXCR3 axis, dependent on IFN-gamma signaling activity, was overexpressed in primary breast cancer samples of patients who developed brain metastasis. The data support a role for T-lymphocytes and the IFN-gamma pathway in the formation of brain metastasis of ER-breast cancer, and offer targets to design future therapies for preventing breast cancer cells to cross the BBB.

关键词： Enthesitis-related arthritis   HLA-B27   Clinical characteristics   JSpADA score   Treatment outcomes  

摘要： BackgroundEnthesitis-related arthritis (ERA) is a subtype of juvenile idiopathic arthritis with high disease burden. The objectives of this study were to explore the prevalence of HLA-B27, clinical characteristics, and treatment outcomes in children with ERA and compare the differences between HLA-B27 positive and negative *** retrospective cohort study at a pediatric rheumatology clinic in a tertiary referral hospital in Bangkok, Thailand, including ERA patients with at least 6 months of follow-up (July 2011-April 2022) was performed. Data were collected from medical records from diagnosis to recent follow-up, assessing disease activity and treatment outcomes, with an analysis comparing HLA-B27 positive and negative patients. Descriptive statistics were used for data *** were 59 ERA patients with mean age +/- SD at diagnosis 11.2 +/- 2.5 years, 53 males (89.8%), and positive HLA-B27 in 38 patients (64.4%). The HLA-B27 positive group had significantly higher levels of inflammatory markers at initial diagnosis (p = 0.001), lower baseline hemoglobin (p = 0.001) and hematocrit (p = 0.002), higher disease activity assessed by the Juvenile Spondyloarthritis Disease Activity score at 6 and 12 months of follow-up (p = 0.028 and 0.040, respectively), increased utilization of bridging systemic corticosteroids (60.5% vs. 14.3%, p = 0.001) and anti-TNF (39.5% vs. 9.5%, p = 0.018), and longer duration of methotrexate (median[IQR] 1.7[1.1-3.1] vs. 1.3[0.6-1.9] years, p = 0.040). The HLA-B27 negative group had more prevalent hip arthritis than the positive group at initial diagnosis (66.7% vs. 28.9%, p = 0.005) and during the course of the disease (71.4% vs. 36.8%, p = 0.011).ConclusionMost of the ERA patients tested positive for HLA-B27. Throughout the follow-up period, these patients demonstrated greater disease activity, greater use of corticosteroids and anti-TNF, and longer duration of methotrexate to control the disease. center dot HLA-B27 wa

关键词： Forskolin   Multiple sclerosis   STEAP4   Interleukin 17   The calcium signaling pathway  

摘要： Multiple sclerosis (MS) is a chronic autoimmune disease in the central nervous system. Forskolin (FSK) is a plant-derived diterpene with excellent immunomodulatory properties and has not been systematically reported for treating MS. This study investigated the therapeutic effects of FSK on cellular and animal MS models and preliminarily explored related mechanisms. The results showed that FSK suppressed the inflammatory response, reduced the expression of STEAP4, and relieved iron deposition in BV-2 cells pretreated by LPS at the cellular level. Meanwhile, at the animal level, FSK treatment halted the progression of experimental autoimmune encephalomyelitis (EAE), alleviated the damage at the lesion sites, reduced the concentration of proinflammatory factors in peripheral blood, and inhibited the immune response of peripheral immune organs in EAE mice. Besides, FSK treatment decreased the expression of STEAP4 in the spinal cord and effectively restored the iron balance in the brain, spinal cord, and serum of EAE mice. Further investigation showed that FSK can reduce IL-17 expression, prevent the differentiation of TH17 cells, and inhibit the calcium signaling pathway. Thus, these results demonstrate that FSK may have the potential to treat MS clinically.

关键词： IFN-gamma   Anti-SARS-CoV-2 IgG   COVID-19 vaccination   IFN-gamma proximal promoter   Genetic polymorphism   Epigenetics  

摘要： IFN-gamma gamma is an immunological modulator influencing IgG isotype and concentration, which present a correlate of protection to evaluate vaccine efficacy. As transiently expressed, stable genetic and epigenetic signatures of the cytokine's expression may exist. This study investigates correlation between plasma IFN-gamma gamma and anti-SARS-CoV-2 IgG levels, seeking genetic polymorphisms and epigenetic variations within the IFN-gamma gamma gene proximal promoter. 200 COVID-19-vaccinated adults were classified into seropositive and seronegative groups based on plasma antiSARS-CoV-2 IgG. Upon correlation analysis between anti-SARS-CoV-2 IgG and IFN-gamma gamma levels, IFN-gamma gamma gene proximal promoter region was subjected to nucleotide sequencing for two subsets: seronegative (21 < Days post- vaccination <= 180, n = 11) and seropositive (IgG > Q(3) and Days post-vaccination >180, n = 24). Relative unmethylation of IFN-gamma gamma proximal promoter was assessed for the latter subset and its correlation with plasma IFN gamma and IgG levels was evaluated. A statistically significant positive correlation (r = 0.492, p = 0.018) was observed between IFN-gamma gamma and anti-SARS-CoV-2 IgG in the seropositive group with persistently high IgG titre (IgG > Q(3), Days elapsed post-vaccination >180). A heterozygous 5'-UTR variant (rs776667149:C>T) identified in one seronegative individual revealed a potential impact on PKR-mediated translational attenuation of IFN-gamma gamma mRNA. No significant correlation was found between IFN-gamma gamma proximal promoter unmethylation and its plasma levels among HAR individuals with Days post-vaccination of either >180 (r = 0.14, p = 0.679) or < 180 (r =-0.062, p = 0.693). This study demonstrates an extent of humoral immunity against SARS-CoV-2 among COVID-19 vaccinated Bangladeshi population. This study suggests plasma IFN-gamma gamma may play a role in maintaining persistent antiSARS-CoV-2 IgG levels, which warrants further inves

关键词： 猪流行性腹泻病毒   S蛋白   单克隆抗体   竞争ELISA  

摘要： 为建立基于猪流行性腹泻病毒（PEDV）S蛋白单克隆抗体竞争ELISA方法，利用真核表达系统表达PEDV S蛋白主要抗原区，将纯化的S蛋白免疫小鼠后制备抗PEDV S蛋白的单克隆抗体，经各组分和反应条件优化，建立了检测PEDV S蛋白抗体的竞争ELISA方法。结果表明，表达的S蛋白大小为92 ku，制备出IgG1亚类的抗S蛋白单克隆抗体5B3D6，建立的竞争ELISA方法S/N临界值为0.400，样品检测时间短（55 min），重复性稳定（变异系数小于10%），特异性强（无交叉反应），与血清中和试验的总符合率高（97.08%）。该方法为PEDV抗体评估和猪流行性腹泻防控提供了有力支撑。