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摘要： Dysregulations in protein kinases significantly contribute to the initiation, progression, and drug resistance in non-small cell lung cancer (NSCLC). Identification of novel oncogenic drivers within the human kinome is crucial for targeted therapy. In this study, we conducted a comprehensive analysis of the TCGA database and literature, pinpointing 16 candidate genes in lung cancer exhibiting frequent dysregulation and limited research. Our functional analysis revealed Serine/threonine kinase 31 (STK31) as a key player in driving tumor growth, in immune-competent mice, with minimal impact in nude mice. Further investigations unveiled upregulation of STK31 led to CD8+ T cell exhaustion. Mechanistically, STK31 induced CD8+ T cell exhaustion through the signal transducer and activator of transcription 3 (STAT3) - interleukin 6 (IL-6) signaling pathway. Direct interaction between STK31 and STAT3 activated the transcription of downstream oncogenic targets, such as IL-6, facilitating immune escape. Moreover, STK31 exhibited elevated expression levels in lung cancer tissues compared to adjacent tissues and displayed a significant correlation with poor prognosis in lung cancer patients. This study defines a critical role of STK31 in promoting immune escape through STAT3 activation, positioning it as a promising therapeutic target for lung cancer.

关键词： Glycosylation   Autoimmune disorder   Homology modeling   Molecular docking   Molecular dynamics simulation  

摘要： Interleukin-1 receptor antagonist (IL-1ra) is a vital anti-inflammatory molecule, acting as a decoy protein that competitively binds to Interleukin-1 receptors (IL-1RI and IL-1RII). The deregulation of IL-1 activity has been linked to autoimmune disorders, impaired wound healing, and the occurrence of cytokine storms in the context of infections. At present, *** expressed IL-1ra isoform was used as a therapeutic drug for the treatment of IL-1 mediated inflammatory diseases;however, daily dosing raises concerns about allergens and infection. Notably, the drug lacks glycosylation, an important post-translational modification for protein stability and pharmacodynamics. The present study utilizes computational molecular dynamics simulations to investigate the influence of glycosylation on the stability and binding efficacy of IL-1ra. To study the impact, we introduced mammalian bi-antennary hybrid glycan with terminal sialic acid/ N-Acetylneuraminic acid (Neu5Ac) added to the respective Asparagine (Asn) residue of 3D modeled IL-1ra structure. The molecular dynamics simulations demonstrated that glycosylated IL-1ra increased the structural stability and exhibited a sustained level of binding stability with 24 hydrogen bonds and 8 salt bridges in comparison to non-glycosylated IL-1ra protein with 20 hydrogen bonds and 6 salt bridges as the result of post simulation. This finding underscores the possibility of glycosylation as it means to augment the effectiveness of therapeutic medications that specifically target immune regulation. These understandings help to translate the concept to the complete expression of proteins. Our study addressed the mechanism of how the N-glycan regulates cytokine, which will provide insight into the design of novel anti-inflammatory drugs and specifically glycan play a role in RA.

关键词： Brain death   TNF-alpha   kidney donor  

摘要： Kidney transplant outcomes depend on various factors, including donor type. Brain death (BD) has been associated with significant kidney injury, with long-term sequelae. Deciphering the impact of BD circulatory death on kidney pathophysiology may help to prevent kidney transplant injury. We developed 3 rat models: 6h of BD (DBD, n=10); circulatory death (DCD, n=10) with 20min of warm ischemia; and 6-hour BD with renal denervation prior to BD (DNRV, n=6). RNA-seq was performed on kidney tissue, followed by differential gene expression and pathway enrichment analyses. Circulating cytokines were measured by Luminex/ELISA. Our findings were validated in 10 human pre-implantation biopsies matching our rat models (n=5 DBD; n=5 DCD). After BD, serum creatinine levels increased from 0.33 [0.31-0.38] to 0.61 [0.59-0.67]mg/dL (p<0.0001). Compared to DCD, DBD rats exhibited significantly higher levels of IL-6 (26.67 [19.10-32.35] 10.32 [9.76-13.28]ng/mL, p=0.006) and TNFᵬ (21.98 [16.48-32.60] 9.64pg/mL [7.96-11.13], p=0.0012), and lower levels of IL-10 (1.28 [1.11-1.65] 1.79 [1.46-2.18]ng/mL, p=0.049). Differential expression analysis revealed that DBD kidneys exhibited CD11b-associated inflammation, caspase-3-mediated apoptosis, and TNFᵬ-driven injury (p=7.34×10; z-score=2.475), while DCD kidneys activated EIF2/NRF2 stress-response pathways. Notably, denervation did not mitigate BD-induced injury. Human biopsies confirmed the positive enrichment of inflammatory pathways (p=0.01 to 1.18×10) in DBD compared to DCD, with 6 out of the top 15 pathways shared across species. Our findings highlight specific mechanisms affecting differently kidneys derived from DBD DCD donors, with a potential role of TNFᵬ in BD-associated kidney injury. Kidney denervation prior to BD does not prevent kidney injury.

关键词： Tripterygium wilfordii polyglycoside tablets   Hepatocellular carcinoma   therapeutic drug   IL-6   PI3K/MAPK/STAT3 signaling pathway  

摘要： Tripterygium wilfordii polyglycoside tablets (TWPT) have traditionally been used to treat certain inflammatory diseases. This study validated TWPT as a novel application in hepatocellular carcinoma treatment through multiple targets, thereby expanding its clinical medication scope. TWPT exhibited a low toxicity and a significantly antihepatoma effects in vitro and in vivo. Through network pharmacology analysis, we found TWPT attenuated the progression of hepatocellular carcinoma by multi-targeting, including IL-6, MMP9, TNF-alpha and VEGFA. Additionally, TWPT targeted IL-6 to regulate downstream pathways, including the PI3K/Akt, JAK2/STAT3, and MAPK signaling pathways. Thus, TWPT could be developed as a potential therapeutic drug for hepatocellular carcinoma.

关键词： Porcine pancreatic elastase (PPE)   Emphysema   Siglec-F+ neutrophils   IL-17A   G-CSF   gamma delta(+) T cells   Epithelial/stromal cells   G-CSF receptor signaling  

摘要： Neutrophils play a pivotal role in the progression of IL-17-mediated airway inflammation, but the mechanisms underlying their pathological differentiation remain poorly understood. In this study, we identified a distinct population of lung-specific pathogenic Siglec-F+ neutrophils in a porcine pancreatic elastase (PPE)-induced mouse model of emphysema. Compared with conventional neutrophils, these Siglec-F+ neutrophils exhibited increased phagocytic activity, increased extracellular trap formation, increased production of proinflammatory cytokines, and reduced IL-10 levels. During the early phase of acute inflammation following PPE instillation, IL-17A levels in the lungs increase, which is driven primarily by gamma delta(+) T cells. IL-17A stimulated lung epithelial/stromal cells to secrete granulocyte colony-stimulating factor (G-CSF), which promoted the differentiation of Siglec-F+ neutrophils via the JAK2/STAT3 pathway and the PI3K-independent mTOR and p38 MAPK signaling pathways. Neutralizing G-CSF or inhibiting JAK2/STAT3, mTOR or p38 MAPK signaling significantly suppressed Siglec-F+ neutrophil development, resulting in the alleviation of emphysematous symptoms. Our findings underscore the crucial role of Siglec-F+ neutrophils in the pathogenesis of PPE-induced emphysema and suggest that targeting the IL-17A/G-CSF axis or G-CSF receptor downstream signaling pathways may represent a promising therapeutic strategy for treating emphysema.

关键词： AIDS/HIV   Immunotherapy   Infectious disease   NK cells  

摘要： BACKGROUND:NK cell function is impaired in people with HIV (PWH), hindering their potential to reduce the lymphoid tissue (LT) reservoir. The IL-15 superagonist N-803 has been shown to enhance NK and T cell function, and thus may reduce viral reservoirs. METHODS:To determine the impact of N-803 on LTs, we conducted a clinical trial where 10 PWH on effective antiretroviral therapy (ART) were given three 6 mcg/kg doses of N-803 subcutaneously. We obtained PBMCs and lymph node (LN) and gut biopsies at baseline and after the last N-803 dose. RESULTS:We found a non-statistically significant ~0.50 median log reduction in the frequency of viral(v)RNA+ and vDNA+ cells/g in the 6 participants with baseline and post-treatment LNs. In the ileum, we observed reductions of vRNA+ cells in 8/10 participants and vDNA+ cells in all participants. We also found significant inverse correlations between NK cell proliferation and the frequency of vRNA+ cells, and between NKG2A expression on NK cells and the frequency of vRNA+ cells. CONCLUSIONS:Our findings suggest N-803 may reduce the HIV reservoir in LTs of PWH on ART, an effect likely mediated by enhanced NK cell function. Controlled studies assessing the impact of NK cell therapy on HIV LTs are needed.

关键词： human leukocyte antigen   tuberculosis   local ancestry   admixture   KhoeSan  

摘要： Previously, the International Tuberculosis Host Genetics Consortium (ITHGC) demonstrated the power of large-scale GWAS analysis across diverse ancestries in identifying tuberculosis (TB) susceptibility loci (Schurz et al., 2024). Despite identifying a significant genetic correlate in the human leukocyte antigen (HLA)-II region, this association did not replicate in the African ancestry-specific analysis, due to small sample size and the inclusion of admixed samples. Our study aimed to build upon the findings from the ITHGC and identify TB susceptibility loci in an admixed South African cohort using the local ancestry allelic adjusted association (LAAA) model. We identified a suggestive association peak (rs3117230, p-value = 5.292 x 10(-6), OR = 0.437, SE = 0.182) in the HLA-DPB1 gene originating from KhoeSan ancestry. These findings extend the work of the ITHGC, underscore the need for innovative strategies in studying complex admixed populations, and confirm the role of the HLA-II region in TB susceptibility in admixed South African samples.

关键词： Adipose tissue   Cell biology   Glucose metabolism   Metabolism   Obesity  

摘要： Type 2 innate lymphoid cells (ILC2s) regulate the proliferation of preadipocytes that give rise to beige adipocytes. Whether and how ILC2 downstream Th2 cytokines control beige adipogenesis remain unclear. We used cell systems and genetic models to examine the mechanism through which IL-13, an ILC2-derived Th2 cytokine, controls beige adipocyte differentiation. IL-13 priming in preadipocytes drove beige adipogenesis by upregulating beige-promoting metabolic programs, including mitochondrial oxidative metabolism and PPARγ-related pathways. The latter was mediated by increased expression and activity of PPARγ through the IL-13 receptor 1 (IL-13R1) downstream effectors STAT6 and p38 MAPK, respectively. Il13-KO or preadipocyte Il13ra1-KO mice were refractory to cold- or β3-adrenergic agonist–induced beiging in inguinal white adipose tissue, whereas Il4-KO mice showed no defects in beige adipogenesis. Il13-KO and Il13ra1-KO mouse models exhibited increased body weight and fat mass and dysregulated glucose metabolism but had a mild cold-intolerant phenotype, likely due to their intact brown adipocyte recruitment. We also found that genetic variants of human IL13RA1 were associated with BMI and type 2 diabetes. These results suggest that IL-13 signaling–regulated beige adipocyte function may play a predominant role in modulating metabolic homeostasis rather than in thermoregulation. © 2025, Yesian et al.

关键词： iPS cell   MHC class   rejection   retinal pigment epithelium   transplantation  

摘要： Purpose:We previously reported that suspensions of CIITA-/- monkey induced pluripotent stem cell-derived retinal pigment epithelium (moiPSC-RPE) that lacks expression of major histocompatibility complex (MHC) class Ⅱ avoided rejection without systemic immunosuppression. RPE strips represent a novel graft formulation for RPE impairment diseases that may enable mass engraftment but potentially increase rejection risk. This study evaluated host immune responses to allogeneic CIITA+/+ and CIITA-/- moiPSC-RPE strips in MHC-mismatched transplantation in monkey eyes with RPE damage, without systemic immunosuppression. Methods:RPE strips were generated from CIITA+/+ and CIITA-/- moiPSC-RPE. Following RPE ablation using a microsecond pulse laser, two RPE strips were transplanted into each eye at 1- to 3-week intervals. One monkey received CIITA+/+ moiPSC-RPE strips, while another received CIITA-/- moiPSC-RPE strips. Graft status was monitored through routine ophthalmic examinations, and immunohistologic evaluation was conducted after 5 months. Results:Fluorescein angiography revealed evident leakage in eyes with CIITA+/+ RPE strips beginning 1 to 2 months posttransplantation, with optical coherence tomography showing bulging at the graft site, indicating immune cell accumulation. Immunostaining confirmed the presence of immune cells (CD4, CD8, Iba1, IFN-γ, MHC class II, and CD20) at CIITA+/+ RPE strip grafts. In contrast, CIITA-/- RPE strip transplants showed no signs of rejection in either eye over 5 months and minimal immune cell presence at the graft site. Conclusions:Allogeneic transplantation of CIITA-/- RPE strips may reduce rejection risk in RPE-ablated disease model eyes, suggesting potential clinical benefits of MHC class II-deficient RPE grafts, particularly for diseases with inflammatory pathology.

关键词： Disease severity system   Hierarchical intervention   IgA vasculitis nephritis   Immune function   Inflammatory factors  

摘要： The objective of this study is to study the effects of a disease severity-based nursing intervention in children with immunoglobulin A (IgA) vasculitis nephritis, including recombinant human interferon-gamma (IFN-gamma), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha). A sample of 104 children treated at the Nephrology Department from May 2021 to May 2023 was selected for this study. The division into groups depended on distinct nursing approaches: the control group (n = 52) received conventional intervention, including basic skin care, dietary advice, and parental communication, without disease severity stratification. The research group (n = 52) received a three-level intervention (grade I, nurse-patient ratio 1:6, 12-hourly rounds, UV irradiation once daily;grade II, nurse-patient ratio 1:3, 9-hourly rounds, protein-restricted diet;grade III, nurse-patient ratio 1:1, 6-hourly rounds, liquid diet and continuous UV) based on severity. Both groups received standardized medications. Comparative analysis was conducted before intervention, 2 weeks, and 4 weeks to evaluate immune function, inflammatory factors, and renal function indicators. Initially, no statistically significant differences in immune indicators, inflammatory factors, or renal function indicators were observed in both groups (p > 0.05). After receiving care for 2 and 4 weeks, the research group displayed notably higher levels of CD3(+) and CD4(+) T cells in differentiated clusters (p < 0.05). Additionally, the research group demonstrated lower levels of natural killer cells, IgA, immunoglobulin G (IgG), and immunoglobulin M (IgM) (p < 0.05). Furthermore, IFN-gamma, IL-6, and TNF-alpha levels were notably lower in the research group (p < 0.05). Key renal function indicators, including erythrocyte count, microalbuminuria (mALB), 24-h urine protein quantity, and serum beta(2)-microglobulin (beta(2)-MG), were significantly reduced in the research group (p < 0.05). Systematic hierarchical