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关键词： Inflammation   Immune epilepsy   Cytokines   Ghrelin  

摘要： Purpose: This study aimed to investigate the relationship between ghrelin levels and severity of inflammation in children with epilepsy by evaluating the differences in total ghrelin, High Mobility Group Box 1 (HMGB1), Interleukin-1 Receptor Type 1 (IL1R1), and Interleukin-1 Beta (IL1-beta) levels in patients with drug-resistant and non-drug-resistant epilepsy and comparing these parameters with those of healthy controls. Methods: We measured total ghrelin, HMGB1, IL1R1, and IL1-beta levels-known to play roles in epileptogenesis-in patients with severe (n: 28), mild (n:29) epilepsy, and 31 healthy controls. The severe epilepsy group included patients with treatment-resistant epilepsy, while the mild epilepsy group consisted of patients whose seizures could be controlled with monotherapy. Results: Total ghrelin levels, along with HMGB1, IL1R1, and IL1-beta, were significantly elevated in children with epilepsy compared to healthy controls. This increase was more pronounced in the drug-resistant epilepsy group, suggesting a potential role for ghrelin in drug-resistant epilepsy. While no direct correlation was found between ghrelin and the inflammatory markers, we observed that ghrelin levels rose significantly when levels of IL1R1, IL1-beta, and HMGB1 surpassed their respective cut-off values in epilepsy patients. The biomarkers IL1R1 and IL1-beta had the strongest discriminative potential in distinguishing patients with severe epilepsy from healthy controls. Although ghrelin was not as powerful a diagnostic marker as IL1R1 or IL1-beta, it still showed moderate diagnostic value. Conclusion: Ghrelin could serve as a biomarker reflecting both inflammation and drug resistance in epilepsy. It may be associated with inflammatory responses in epilepsy and could play a potential role in the pathophysiology of the disease.

关键词： PARP inhibitors   NK cells   Tumor immune evasion   HLA-G   TFEB  

摘要： Resistance to poly(ADP-ribose) polymerase inhibitors (PARPi) poses a significant challenge to enhancing the efficacy of cancer treatments. Beyond the cellular mechanisms intrinsic to tumor cells, the modulation of the tumor immune microenvironment is crucial in dictating the responsiveness to pharmacological interventions. Thus, there is a pressing need to elucidate the intricate interplay between PARPi and antitumor immune responses and to develop an optimized combinatorial therapeutic approach. In this study, using matched tumor samples before and after neoadjuvant monotherapy with the PARPi niraparib in a prospective clinical trial (NCT04507841), we observed a significant increase in natural killer (NK) cell infiltration post-treatment. However, this was not accompanied by the expected enhancement in their cytotoxic functions. This observation underscores the necessity to optimize the antitumor potential of NK cells by enhancing their cytotoxic capabilities. Upon exposure to niraparib, tumor cells, particularly those with wild-type EGFR, exhibited a pronounced upregulation of human leukocyte antigen G (HLA-G), an immune checkpoint impeding NK cell functions. Niraparib promotes EGFR internalization, which in turn diminishes AKT/mTOR signaling, leading to the increased transcriptional activity of the transcription factor EB (TFEB) and subsequent enhancement of HLA-G expression. The combination of niraparib with HLA-G blockade not only augmented NK cell-mediated tumor lysis in vitro but also synergistically inhibited tumor growth in humanized patient-derived xenograft models. Collectively, our results shed light on a previously unrecognized immune evasion mechanism and offer a compelling argument for the integration of HLA-G blockade with PARPi in cancer therapy.

关键词： Pt(IV) prodrug   Gramine   TGF-beta targeting   Immune regulation  

摘要： Platinum(II) (Pt(II)) drugs, such as cisplatin and oxaliplatin, played critical roles in cancer therapy;however, their efficacy is often limited by significant toxicity and the development of drug resistance. Recently, multi-target platinum(IV) (Pt(IV)) complexes, particularly those optimized with axial ligands, have emerged as promising alternatives enhancing tumor selectivity and drug stability. In this study, we synthesized a series of novel platinum(IV) prodrugs, gramine-platinum(IV), by incorporating gramine-a natural indole alkaloid that antagonizes TGF-beta receptors I and II to inhibit the TGF-beta signaling pathway-as an axial ligand. Among them, compound 8 (referred to as GP) was screened out to have the best antitumor activity. GP not only enhances the therapeutic efficacy of platinum(II) drugs but also targets TGF-beta signaling. Our findings demonstrate that GP rapidly enters cells and preferentially accumulates in critical subcellular compartments, such as the nucleus and mitochondria, significantly amplifying its therapeutic impact. Notably, GP exhibits great tumor accumulation compared to cisplatin and oxaliplatin, with minimal uptake in normal tissues, highlighting its superior tumor specificity with reduced systemic toxicity. This unique characteristic enables GP to enhance therapeutic efficiency through multiple modalities, including strengthening DNA damage, reducing mitochondrial membrane potential, promoting apoptosis, and arresting cell cycle in the S phase. Moreover, GP activates the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling (cGAS-STING) pathway, enhancing antigen presentation and fostering robust anti-tumor immune responses. In mouse models of pancreatic and breast cancer, GP significantly inhibits tumor growth and triggers strong innate immune activation. By combining GP with anti-PD-1 therapy, immunotherapy-resistant tumors are rendered responsive, leading to a pronounced suppression of tumor growth. O

关键词： allergic rhinitis   indolepropionic acid   immune modulation   AKT/CCAAT enhancer binding protein beta/IL-10 pathway   inflammatory response  

摘要： Allergic rhinitis (AR) is a common inflammatory disorder of the nasal mucosa, usually triggered by environmental allergens. Indolepropionic acid (IPA) can influence immune responses;however, the specific mechanisms underlying the effects of IPA on immune regulation in AR remain largely unexplored. In the present study, an experimental mouse model of AR was established by sensitizing and exposing the mice to allergens, followed by the administration of IPA via gavage. Nasal symptoms were assessed through behavioral scoring, histological examinations were conducted to evaluate changes in nasal mucosa, and cytokine levels were quantified using ELISA. The expression of key signaling molecules was analyzed by immunohistochemistry, reverse transcription-quantitative PCR and western blotting. Additionally, the effects of IPA combined with an AKT inhibitor (HY-10355) on signaling pathway-related proteins in human nasal epithelial cells were evaluated using cellular immunofluorescence and western blotting. The results revealed that IPA treatment significantly reduced nasal inflammation, as indicated by decreased sneezing and mucus secretion. Histological analysis showed reduced inflammatory cell infiltration and epithelial damage in IPA-treated mice compared to controls. Furthermore, cytokine analysis revealed reduced levels of the pro-inflammatory cytokines IL-4, IL-5, IL-13 and immunoglobulin E, along with increased levels of the anti-inflammatory cytokine IL-10. Molecular investigations demonstrated that IPA can activate the AKT/CCAAT enhancer binding protein beta pathway, leading to increased IL-10 expression and reduced inflammation. In conclusion, these findings suggested that IPA may serve as a promising therapeutic strategy for managing AR, pending further clinical validation.

关键词： Interleukin-27   BCG   Tuberculosis   Vaccine   Neonatal  

摘要： Tuberculosis (TB) is the leading cause of death due to a pathogen. The live-attenuated BCG vaccine is the only approved vaccine to prevent TB, but it fails to confer long-term protection. We hypothesize that the immunosuppressive cytokine IL-27 may contribute to the inefficacies of the BCG vaccine. IL-27 is elevated in neonates, the population most commonly administered BCG, and levels increase further upon vaccination. IL-27 interferes with the phagolysosomal pathway, suggesting it may limit the diversity of antigens processed and presented to T cells. We hypothesized that in the absence of IL-27 signaling, BCG vaccination induces antigen-specific T cells that recognize a greater number of antigens and provide enhanced protection during M. tuberculosis (Mtb) challenge. CD3+ T cells isolated from IL-27R alpha KO mice vaccinated with BCG as neonates were more responsive to BCG and a Mtb peptide pool than T cells from vaccinated WT mice. Adoptive transfer of IL-27R alpha KO T cells provided more consistent protection against Mtb than WT, but this was not observed in TCR alpha- /- mice. A principal component analysis suggested a more consistent multifunctional cytokine response was associated IL27R alpha KO T cells. These findings enhance our understanding of IL-27 during neonatal vaccination and development of protective immunity.

关键词： Interleukin-2   Cytokine family   Parkinson's disease   Neurodegeneration  

摘要： Parkinson's disease (PD) is a neurodegenerative disorder, which primarily impacts the nervous system, marked by its immune and inflammatory characteristics. The interleukin-2 (IL-2) cytokine family has a crucial role in regulating both neuroinflammation and immune activity, positioning it as one of the critical immune pathways in PD. Balancing pro-inflammatory and anti-inflammatory signals in PD heavily depends on the IL-2 cytokine family, that includes IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21. This balance is vital for neuron survival and resistance to degeneration. Disruptions in IL-2 signaling can upset the equilibrium among regulatory T cells (Tregs) and proinflammatory T cells, such as Th1 and Th17, further aggravating the chronic neuroinflammation typical of PD. In PD, a decline in IL-2 or receptor dysfunction can hinder Treg activity, leading to increased inflammation and neurodegeneration. Similarly, IL-15 and IL-21 supports cytotoxic immune cell function, including natural killer (NK) cells and CD8+ T cells, which may exacerbate neuronal damage by sustaining pro-inflammatory processes. Moreover, IL-4 and IL-7 have anti-inflammatory roles in maintaining T cell homeostasis, and their dysregulation can contribute to interruption of the blood-brain barrier and increased infiltration of immune cells into the central nervous system. Targeting the IL-2 cytokine family in Parkinson's disease has shown therapeutic potential by expanding Tregs, which reduce neuroinflammation and promote dopaminergic neuron survival. Recombinant IL-2 and IL-2/anti-IL-2 complexes have demonstrated efficacy in animal models, enhancing Treg function and leading to improved neuroprotection. Additionally, IL-4-based therapies have been explored for their ability to shift microglia toward a neuroprotective phenotype, further enhancing neuronal survival by modulating inflammatory responses and cellular metabolism. Current research is exploring how to optimize cytokine delivery while minimizin

关键词： IL-10   hydrogel   macrophage polarization   inflammatory response   spinal cord injury  

摘要： (1)Background: Inflammation plays a key role in spinal cord injury (SCI), where excessive inflammatory responses exacerbate neural damage and hinder regeneration. Modulating macrophage polarization, particularly through the sustained release of IL-10 to promote the anti-inflammatory M2 phenotype, represents a promising strategy to mitigate inflammation. In this study we developed a Hyaluronic Acid Methacryloyl (HAMA) hydrogel capable of sustained IL-10 release to regulate macrophage polarization and explore its therapeutic potential. (2)Methods: A photo-curable HAMA hydrogel was synthesized via methacrylation and designed for the sustained release of IL-10. The structural and functional properties were characterized using NMR and FT-IR. In vitro assays, including immunofluorescence, flow cytometry, and Western blotting, were performed to evaluate IL-10's effect on macrophage polarization. The anti-inflammatory and reparative effects of the hydrogel were further validated in a rat SCI. (3)Results: The HAMA hydrogel with sustained IL-10 release demonstrated excellent biocompatibility. It significantly promoted macrophage polarization to the anti-inflammatory M2 phenotype by increasing the expression of CD206. In vivo studies demonstrated that the group treated by HAMA with IL-10 exhibited recovery of sensory and motor functions, along with improvement of the inflammatory microenvironment at the site of injury. (4)Conclusion: The HAMA hydrogel with sustained IL-10 release effectively alleviates inflammation, enhances motor function after SCI, and serves as a promising immunomodulatory platform. This novel approach presents considerable potential for improving neural regeneration.

关键词： Systemic lupus erythematosus   Double-negative T cells   Interleukin-10 signaling pathway   SLE disease activity index   RNA sequencing   Autoantibodies  

摘要： Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that causes immune system overactivity and organ damage. Among T-cell subsets involved in SLE, CD4 and CD8 double-negative alpha beta T (DNT) cells have attracted attention in recent years, although their role in SLE remains poorly understood. Examining the minute intricacies, particularly signaling pathway modifications is crucial, as it may unveil potential therapeutic targets and lead to the development of more effective treatments. Our study found increased DNT cells in pediatric SLE patients, with elevated IL-10 signaling. These IL-10-producing DNT cells were positively related to disease activity defined by SLE Disease Activity Index (SLEDAI), and were further elevated in patients with lupus nephritis. Additionally, our results indicated that IL-10-producing DNT cells correlated positively with anti-Sm autoantibodies. Collectively, our study revealed that modulation of IL-10 production within DNT-cell subset could affect both immune regulation and autoantibody production, contributing to the immunological dysregulation in SLE.

摘要： [This corrects the article DOI: 10.1016/***.2022.100460.].