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关键词： Arginase 1   Epithelial–mesenchymal transition   miR-135a-5p   Non-small cell lung cancer   STAT6   Tumor-associated macrophage  

摘要： Arginase 1 (Arg1), a key indicator of M2 polarization in tumor-associated macrophages (TAMs), plays a crucial role in inhibiting T-cell activation and proliferation by depleting local arginine levels, thereby facilitating tumor immune escape. The epithelial–mesenchymal transition (EMT), a fundamental biological process in cancer proliferation and progression, is intricately linked to the interactions between TAMs and cancer cells. However, the underlying mechanisms of EMT and how EMT-programmed cancer cells specifically modulate Arg1 expression in M2-like TAMs remain incompletely understood. Our comprehensive analysis confirmed that Arg1 expression was significantly upregulated in non-small cell lung cancer (NSCLC) tissues, and patients with elevated Arg1 levels exhibited a notably shorter overall survival. Furthermore, alterations in miR-135a-5p expression were found to profoundly influence the proliferation, migration, invasion, EMT, and apoptotic processes of NSCLC cells. Mechanistically, miR-135a-5p post-transcriptionally inhibited STAT6 expression by regulating its 3′-untranslated region (3’-UTR). Subsequently, the miR-135a-5p/STAT6 axis inhibited GATA3-mediated interleukin-4 (IL-4) secretion from NSCLC cells, ultimately suppressing Arg1 expression in M2-like TAMs. MiR-135a-5p may exert pivotal roles in modulating STAT6-induced EMT in tumor cells, which subsequently impacts IL-4-related Arg1 expression and M2 polarization of TAMs in NSCLC. This, in turn, reduced the capacity of M2-like TAMs to secrete tumor-promoting cytokines. Therefore, Arg1 holds potential as a diagnostic biomarker for NSCLC, and miR-135a-5p may emerge as a promising target for inhibiting NSCLC progression. © 2025 The Authors

关键词： Diabetic wound healing   IL-27   M1-to-M2 polarization   Macrophage   STAT3  

摘要： Diabetic foot ulcer (DFU), a serious complication of diabetes, is a life-threatening disease that often leads to lower limb amputation and a shortened lifespan. Interleukin-27 (IL-27) is a member of the IL-12 family and has the potential to exert dual effects on the immune response. The role of IL-27 in diabetic skin wound healing is unknown. The aim of this study was to investigate whether there is abnormal expression of IL-27 in diabetic skin and whether supplementation with IL-27 can promote diabetic wound healing by modulating macrophage polarization. We established a streptozotocin (STZ)-induced diabetic mouse model and constructed diabetic wounds. We assessed protein expression by western blotting (WB) and immunohistochemical (IHC) staining. We also performed hematoxylin–eosin (H&E) staining and Masson's trichrome staining. In the presence of lipopolysaccharide (LPS) and high glucose (HG), we treated the mononuclear macrophage line RAW264.7 and bone marrow-derived macrophages (BMDMs) with IL-27. To assess macrophage polarization, we examined the expression of inducible nitric oxide synthase (iNOS), IL-1β and arginase-1 (Arg-1). To understand the underlying mechanisms, we used macrophage IL-27ra knockout mice to knockout macrophage IL-27 receptors. Our in vivo experiments revealed that the expression of IL-27 in the skin of diabetic mice was significantly decreased and that supplementation with IL-27 promoted diabetic wound healing. In vitro, compared with the LPS group, supplementation with IL-27 alleviated the suppression of multiple cellular functions, such as iNOS and IL-1β expression, cell migration, and phagocytosis, in macrophages after HG exposure. Mechanistically, we found that IL-27 expression was decreased and that the activation of signal transducer and activator of transcription 3 (STAT3) by phosphorylation was inhibited in diabetic skin, leading to an inability of wound macrophages to polarize to an M1 phenotype effectively, which in turn blocked

关键词： IL2RA   Iranian population   Meta-analysis   Multiple sclerosis   rs2104286  

摘要： The interleukin-2 receptor alpha chain (IL2RA) gene has been implicated in multiple sclerosis (MS) susceptibility, particularly through the rs2104286 and rs12722489 SNPs. However, previous studies have yielded inconsistent results across different populations, likely due to small sample sizes and ethnic variations. This study aimed to investigate the association of IL2RA SNPs with MS risk in eastern Iranian population and through a comprehensive meta-analysis. Our case-control study included 400 Iranian individuals from North Khorasan and Sistan & Baluchistan provinces, comprising 200 MS patients across all subtypes and genders and 200 controls. The meta-analysis incorporated pooled odds ratios (ORs) with 95 % confidence intervals (CIs) to assess the strength of these associations. Our case-control findings demonstrated a significant association between rs2104286 and MS risk, which was further supported by the meta-analysis in Iranian populations. Specifically, the association was observed at both the genotype (P = 0.001) and allelic (P = 0.003) levels in North Khorasan and at the genotype level in Sistan & Baluchistan (P = 0.001). A global meta-analysis of rs2104286, encompassing 24,931 MS patients and 36,036 controls, revealed a significant association between the A allele and all genotype models with increased MS risk (P < 0.05). Similarly, a meta-analysis of rs12722489, including 19,797 MS patients and 32,085 controls, identified the CC + CT genotype as a risk factor for MS (P = 0.04). In conclusion, our findings suggest that the rs2104286 A allele and rs12722489 CC + CT genotype are associated with an increased risk of MS in both Caucasian and Asian populations, including Iranians. © 2025 The Author(s)

摘要： Highlights•We experienced Surfer's myelopathy (SM) occurred during exercise unrelated to surfing. •Spine MRI showed T2 hyperintensity with “pencil-like” long-axis lesion, typical for SM. •Significant elevation of IL-6 levels were seen in the CSF. •The nerve conduction tests indicated motor dominant neuropathy in the lower limbs. •The flaccid paralysis and sensory loss only slightly improved after steroid pulse therapies.

关键词： IL-1 beta   Rheumatoid arthritis   Epilepsy  

摘要： Aims: Numerous clinical studies have revealed a positive correlation between rheumatoid arthritis (RA) and an elevated risk of epilepsy. This study aimed to investigate the seizure susceptibility in the collagen-induced arthritis (CIA) mice model. Main methods: The classic CIA model was used to mimic RA pathogenesis in mice. The pentylenetetrazole (PTZ)induced seizure model and audiogenic seizure model were used to evaluate seizure susceptibility. Neuroinflammation was assessed through ELISA, Western blot, and immunofluorescence staining. Additionally, electrophysiological techniques were applied to investigate the excitation/inhibition (E/I) balance. Key findings: CIA modeling raised the level of IL-1(3, induced E/I imbalance in the dentate gyrus (DG) region, and enhanced seizure susceptibility to PTZ in C57BL/6 mice. However, knockout (KO) of IL-1(3 attenuated peripheral inflammatory symptoms and blocked the increase in seizure susceptibility in CIA-modeled mice. Additionally, conditional IL-1R1 KO in CaMKII alpha-positive neurons did not affect the peripheral inflammatory symptoms but rescued both the increased seizure susceptibility and E/I imbalance in CIA-modeled mice. Furthermore, increased susceptibility to audiogenic seizure susceptibility was also observed in CIA-modeled BDA/1 mice, accompanied by the elevated IL-1(3 levels and neuronal IL-1R1-related Akt phosphorylation in the hippocampus. Significance: Increased seizure susceptibility in the CIA mouse model depends on IL-1(3 and neuronal IL-1R1. These data indicated that IL-1(3 and neuronal IL-1R1 may be the key targets for its intervention.

关键词： Subarachnoid hemorrhage   IL-33   ST2   AKT   Microglia  

摘要： Background and purpose: ST2, a member of the interleukin-1 (IL-1) receptor family, along with its ligand IL-33, plays critical roles in immune regulation and inflammatory responses. This study investigates the roles of endogenous IL-33/ST2 signaling in subarachnoid hemorrhage (SAH) and elucidates the underlying mechanisms. Methods: Dynamic changes in endogenous IL-33 levels were examined following SAH induction in vivo. Rats underwent the endovascular perforation model of SAH and were randomly assigned to receive either recombinant IL-33 (rIL-33) or a vehicle, administered intranasally 1 h post-SAH. ST2 siRNA or an AKT selective inhibitor was administered intraperitoneally (i.p.) 48 h prior to SAH induction to explore the potential mechanisms of IL33-mediated neuroprotection. Results: Endogenous IL-33 and ST2 levels were elevated in in vitro models of SAH. Exogenous IL-33 significantly alleviated neuronal apoptosis, reduced brain edema, and enhanced short-term neurofunction in a dosedependent manner following SAH in rats. Conclusion: Exogenous rIL-33 alleviates SAH-induced neurological deficits by promoting M2-like polarization of microglia post-SAH. These findings suggest a potential role of the microglial ST2/AKT axis in IL-33-related neuroprotection, which warrants further investigation.

关键词： TNF-alpha   Anti-TNF-alpha therapy   Sepsis   Treatment failure  

摘要： Sepsis, a condition of significant clinical concern, is characterized by life-threatening organ dysfunction that arises from an infection and is exacerbated by a dysregulated host response. Targeting immune modulation, particularly against tumor necrosis factor-alpha (TNF-alpha), has emerged as a promising anti-inflammatory therapeutic strategy. However, approaches such as blood purification to eliminate inflammatory mediators or the use of anti-TNF-alpha therapies have shown limited efficacy in clinical practice. This literature review aims to elucidate the pathogenesis of sepsis and dissect the factors contributing to unfavorable outcomes in TNF-alpha-targeted treatments. Our analysis highlights several potential reasons for therapeutic failure. Complete blockade of TNF-alpha may adversely affect both TNFR1 and TNFR2 signaling, thereby reducing the efficacy of TNF-alpha inhibitors. Additionally, the complex heterogeneity of sepsis, including the etiology of infection, patient-specific factors (e. g., immune responsiveness, body mass index, and obesity), the development of anti-drug antibodies, and treatment duration, significantly influences therapeutic outcomes. Based on these insights, we emphasize the need for precision medicine in sepsis management. This includes stratifying patients into subgroups, using TNFR2 agonists or TNFR1-specific antagonists, refining drug design, implementing multi-target combination therapies, and considering the patient's physiological state at the time of treatment. Collectively, these strategies could enhance the efficacy of sepsis management. This review underscores the multifaceted nature of sepsis treatment and highlights the imperative for personalized, multimodal therapeutic approaches to improve clinical outcomes.

关键词： Anti-tumor   IL-21   Melanoma   Radiotherapy  

摘要： Melanoma, known for its aggressive behavior and tendency to metastasize to the brain and lungs, is a formidable challenge in oncology. Radiotherapy is a potent treatment for localized solid tumors, effective against both intracranial and extracranial metastases. Yet, some melanoma patients exhibit substantial resistance to radiotherapy, with the underlying mechanisms of this resistance remaining elusive. While radiotherapy can stimulate the infiltration of immune cells, thereby triggering a range of immunostimulatory effects, it can also suppress the tumor microenvironment (TME), limiting its effectiveness. In physiological conditions, cytokines inhibit the activity of immunosuppressive cells through paracrine and autocrine signaling, while also activating immune cells to boost antitumor responses. Here, we found that Interleukin (IL)-21 expression was higher in the mice with good radiotherapy response to melanoma than in the mice with poor radiotherapy response. Interestingly, we also observed the higher infiltration of M2 TAMs and lower CD8⁺ T cells in the group with poor radiotherapy response. To tackle this issue, we explored the therapeutic potential of a plasmid encoding IL-21, delivered via attenuated Salmonella, in mice bearing melanomas. Our findings revealed that IL-21 administration significantly reduced M2 TAMs infiltration and enhanced CD8⁺ T cells infiltration and granzyme B (GZMB) expression within melanoma tumors. Most importantly, the combination of IL-21 with radiotherapy led to markedly tumor reduction compared to either treatment alone. This research highlights the potential of IL-21 as a valuable adjunct to radiotherapy in the treatment of melanoma, presenting a promising strategy for enhancing antitumor immune responses and optimizing patient outcomes. © 2025 Elsevier B.V.

关键词： Pancreatic Cancer   Irreversible Electroporation   Immune Therapy   Type-2 Conventional Dendritic Cells   CD4+T Cells  

摘要： Pancreatic ductal adenocarcinoma (PDAC) is a "cold" solid tumor with frequent Major Histocompatibility Complex I (MHC-I) deficiency, thereby making it resistant to type-1-conventional dendritic cell (cDC1)-CD8+T cell mediated anti-tumor immunity. Current studies have demonstrated the emerging compensatory role of MHCII-mediated antigen presentation and CD4+T cell activation in anti-tumor immunity against MHC-I-deficient tumors. However, the underlying mechanism of the compensatory immune response by CD4+T cells in cancer ablation therapy remains to be elucidate. In clinical samples and murine models, we observed that irreversible electroporation (IRE) ablation therapy promoted immune infiltration and the conversion of CD4+T cells into anti-tumor IFN-gamma+Th1 cells and Th17 cells in MHC-I low-expressed PDAC using scRNA-seq and flow-cytometry analyses. Furthermore, we found that PD-L1 blockade predominantly enhanced the activation of CD11b+CD103-type-2 conventional dendritic cells (cDC2s) and their antigen presentation to CD4+T cells after ablation, stimulating the anti-tumor immune response through the tumor antigen-specific IFN-gamma+Th1-NK cell axis. Elevated plasma levels of IL-6 in pancreatic cancer patients receiving ablation therapy are significant indicators for impaired prognosis. IL-6 and PD-L1 dual blockade could significantly augment the ratio of IFN-gamma+Th1 in CD4+T cells to boost the anti-tumor immunity of NK cells, leading to prolonged survival of mouse bearing pancreatic cancer. Collectively, we have elucidated that PD-L1 blockade activates the cDC2-CD4+T cell axis after IRE therapy, thereby playing a pivotal compensatory anti-tumor role in MHC-I low-expressed pancreatic cancer. Moreover, a combination strategy involving dual-target blockade of PD-L1/IL-6 along with ablation therapy could emerge as a novel therapeutic approach for MHC-I deficient tumors.

关键词： 肺疾病,慢性阻塞性   频繁加重   T淋巴细胞亚群   预测  

摘要： 目的分析不同分组稳定期慢性阻塞性肺疾病(COPD)患者T淋巴细胞亚群变化,并探讨其对患者频繁加重的预测价值。方法前瞻性选取2023年1—10月在安徽医科大学附属安庆第一人民医院门诊就诊的稳定期COPD患者221例,根据《2023年GOLD慢性阻塞性肺疾病诊断、管理及预防全球策略》中COPD分组标准,COPD患者可分为A组、B组、E组。收集患者的临床资料。所有患者通过门诊、电话随访1年,记录其急性加重次数,其中急性加重次数≥2次定义为频繁加重。不同分组患者频繁加重的影响因素分析采用多因素Logistic回归分析。绘制ROC曲线以评估T淋巴细胞亚群对不同分组患者频繁加重的预测价值。结果A、B、E组患者分别为40、73、108例。B、E组患者CD_(3)^(+)T淋巴细胞百分比低于A组患者,CD_(8)^(+)T淋巴细胞百分比高于A组患者(P<0.05);E组患者CD_(3)^(+)T淋巴细胞百分比低于B组患者,CD_(8)^(+)T淋巴细胞百分比高于B组患者(P<0.05);E组患者CD_(4)^(+)T淋巴细胞百分比低于A、B组患者,频繁加重发生率高于A、B组患者(P<0.05)。A+B组患者中频繁加重者CD_(4)^(+)T淋巴细胞百分比低于非频繁加重者(P<0.05)。E组患者中频繁加重者CD_(3)^(+)、CD_(4)^(+)T淋巴细胞百分比低于非频繁加重者,CD_(8)^(+)T淋巴细胞百分比高于非频繁加重者(P<0.05)。多因素Logistic回归分析结果显示,CD_(4)^(+)T淋巴细胞百分比是A+B组患者频繁加重的独立影响因素(P<0.05);CD_(3)^(+)、CD_(4)^(+)、CD_(8)^(+)T淋巴细胞百分比是E组患者频繁加重的独立影响因素(P<0.05)。ROC曲线分析结果显示:CD_(4)^(+)T淋巴细胞百分比预测A+B组患者频繁加重的AUC为0.731〔95%CI(0.614~0.848)〕,CD_(3)^(+)、CD_(4)^(+)、CD_(8)^(+)T淋巴细胞百分比预测E组患者频繁加重的AUC分别为0.630〔95%CI(0.518~0.743)〕、0.777〔95%CI(0.692~0.863)〕、0.772〔95%CI(0.683~0.861)〕。结论不同分组稳定期COPD患者间T淋巴细胞亚群有所不同,CD_(4)^(+)T淋巴细胞百分比是A+B组患者频繁加重的影响因素,其对A+B组患者频繁加重具有中等预测价值。CD_(3)^(+)、CD_(4)^(+)、CD_(8)^(+)T淋巴细胞百分比是E组患者频繁加重的影响因素,其中CD_(4)^(+)、CD_(8)^(+)T淋巴细胞百分比对E组患者频繁加重具有中等预测价值,而CD_(3)^(+)T淋巴细胞百分比对其具有较低预测价值。