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关键词： Pancreatic cancer   carbon-ion radiation therapy   soluble IL-6 receptor  

摘要： BACKGROUND/AIM:For patients with unresectable locally advanced pancreatic cancer (LAPC), carbon-ion radiotherapy (C-ion RT) can safely deliver higher doses than conventional photon therapy, increasing the potential for long-term survival. However, achieving meaningful improvements in survival rates requires reliable prognostic biomarkers to identify patients likely to benefit from treatment. PATIENTS AND METHODS:In this study, we measured plasma levels of soluble interleukin-6 receptor (sIL-6R) before C-ion RT and examined their association with the risk of distant metastasis (DM), local recurrence (LR), and overall survival (OS). RESULTS:Results showed that patients with higher plasma sIL-6R levels had a lower risk of DM [hazard ratio (HR)=0.53; p=0.033] and improved OS (HR=0.55; p=0.037). No significant association was observed between LR and plasma sIL-6R levels (HR=1.47; p=0.273). CONCLUSION:These findings suggest that pretreatment plasma sIL-6R levels may serve as a prognostic marker for C-ion RT in LAPC.

关键词： Perioperative cognitive disorders   Double negative T cells   Interleukin 17   Neuroinflammation   Microglia   Astrocyte  

摘要： CD3(+) CD4(-) CD8(-) double negative T cells (DNTs) manifest themselves in autoimmune diseases and associated inflammation. In the central nervous system, the increased presence of DNTs is associated with the progression of neurological conditions and brain injury. Active DNTs that produce IL-17 have been regarded as a pro-inflammatory phenotype. The IL-17 signaling pathway mediates neuroinflammatory responses by inducing glial activation and producing inflammatory factors. Neuroinflammation is considered integral to the pathogenesis of perioperative neurocognitive disorders (PNDs), commonly developed after surgery in susceptible patients. We and others have demonstrated a significant role for complement C3 in surgery-induced neuroinflammation and cognitive impairment but the regulatory mechanisms for this remain unexplored. We hypothesized that surgery induces DNT infiltration into the CNS that in turn upregulates complement C3 expression and this causes changes that contribute to cognitive impairment. Using an adult murine abdominal surgery model, we investigated perioperative changes in cognitive performance, quantifying the presence of T cell subsets and phenotype, IL-17 signaling pathway activation, glial cell activation and C3 expression in the brain. Postoperative IL-17 specific inhibitor GSK2981278 administration or preoperatively conditional CEBP(3 knockdown by AAV9 viral vector were then applied to evaluate the effect of inhibiting IL-17 signaling pathway on postoperative C3 expression and cognitive performance. The results showed an increased hippocampus infiltration of DNTs with augmented IL-17 production, along with C3 upregulation and cognitive impairment. Both inhibition of IL-17 or knock-down of CEBP(3 significantly suppressed C3 expression, synaptic engulfment by microglia and attenuated cognitive impairment. These findings indicate that DNTs promote postoperative neuroinflammation and cognitive impairment via the IL-17/CEBP(3/C3 pathway and targeti

摘要： Background: Kawasaki disease (KD) is a pediatric vasculitis that has a predilection for coronary artery involvement. Activated macrophages play an important role in the destruction of the coronary arteries in KD. Although intravenous immunoglobulin (IVIG) is standard therapy, corticosteroids are sometimes given to patients at a higher risk of IVIG non-responsiveness. In this study, we examined the effect of IVIG and corticosteroids in U937 derived M1 and M2 a macrophages. Methods: A total of 40 children with KD and 30 healthy controls were enrolled. U937-derived macrophages were stimulated with patient plasma to examine its effect on macrophage polarization. U937 derived M1 and M2 macrophages were then stimulated with IVIG and methylprednisolone. RNA was extracted from cell cultures and the expression levels of STAT1, interleukin (IL)-1 beta, PPAR gamma and IL-10 were determined by RT-PCR. Results: IVIG was effective at suppressing IL-10 expression in M2 macrophages (relative mRNA expression mean +/- SE, high dose IVIG Vs. untreated 0.304 +/- 0.095 Vs. 2.541 +/- 0.157, p = 0.002), but did not suppress the production of IL-1 beta in M1 macrophages. In contrast, methylprednisolone both suppressed the IL-1 beta in M1 macrophages and also enhanced IL-10 in M2 macrophages even at low doses (relative mRNA expression mean +/- SE, low dose methylprednisolone Vs. untreated IL-1 beta 6.353 +/- 0.414 Vs. 93.838 +/- 1.321, p < 0.001, IL-10 61.117 +/- 2.319 Vs. 46.867 +/- 2.893, p = 0.005). Discussion: In this study we found that methylprednisolone was effective at suppressing the inflammatory cytokine IL-1 beta in M1 macrophages, and enhanced the production of anti-inflammatory IL-10 in M2 macrophages, an effect that could not be produced by IVIG. Our findings provide further mechanistic evidence that corticosteroid therapy, even at low doses may be a cost-effective adjuvant to IVIG therapy in patients with high-risk KD.

关键词： CD8 T cells   HLA‐E   MHC class I   MHC‐E   NKG2A   T‐cell receptors  

摘要： HLA-E is a nonclassical, nonpolymorphic, class Ib HLA molecule. Its primary function is to present a conserved nonamer peptide, termed VL9, derived from the signal sequence of classical MHC molecules to the NKG2x-CD94 receptors on NK cells and a subset of T lymphocytes. These receptors regulate the function of NK cells, and the importance of this role, which is conserved across mammalian species, probably accounts for the lack of genetic polymorphism. A second minor function is to present other, weaker binding, pathogen-derived peptides to T lymphocytes. Most of these peptides bind suboptimally to HLA-E, but this binding appears to be enabled by the relative stability of peptide-free, but receptive, HLA-E-β2m complexes. This, in turn, may favor nonclassical antigen processing that may be associated with bacteria infected cells. This review explores how the structure of HLA-E, bound to different peptides and then to NKG2-CD94 or T-cell receptors, relates to HLA-E cell biology and immunology. A detailed understanding of this molecule could open up opportunities for development of universal T-cell and NK-cell-based immunotherapies.

关键词： Caspase 3   FSP1   Intervertebraldisc degeneration   NF-κB   TNFα   iFSP1  

摘要： Intervertebral disc degeneration (IDD) is a common chronic inflammatory degenerative disease that causes lower back pain. However, the underlying mechanisms of IDD remain unclear. Ferroptosis suppressor protein 1 (FSP1) is a newly identified suppressor for ferroptosis. This study aims to investigate the role of FSP1 in IDD. Nucleus pulposus (NP) tissues in humans were collected and NP cells from rats were isolated to detect FSP1 expression pattern. The relationship between FSP1-mediated ferroptosis and apoptosis was identified using FSP1 inhibitor iFSP1. RNA sequencing was utilized to seek downstream molecules and related signaling pathways. Moreover, both exogenous recombinant FSP1 protein and endogenous small interfering RNA were implemented in this study to clarify the role of FSP1 in tumor necrosis factor-alpha (TNFα)-mediated NP cell apoptosis. Ultimately, the underlying mechanisms of FSP1-related signaling pathway in IDD were uncovered both and . As a result, FSP1 was up-regulated in human degenerative NP tissues and after TNFα stimulation. FSP1 inhibition by iFSP1 fails to trigger ferroptosis in NP cells while inhibiting TNFα-mediated apoptosis. Further experiments demonstrated that FSP1 was closely related to TNFα-reliant caspase 3 activation and mitochondrial damage. However, the exogenous addition of recombinant protein FSP1 does not induce cell death or intensify the efficacy of TNFα. Mechanically, FSP1 is involved in TNFα-mediated NF-κB signaling activation to accelerate the development of IDD. This study demonstrated that FSP1 promotes IDD through TNFα-reliant NF-κB signaling activation and caspase 3-dependent apoptosis. These findings suggested a novel therapeutic target for the treatment of IDD.

关键词： Sepsis   Mesenchymal stem cells   Exosomes   HMGB1   M2 macrophage polarization  

摘要： Background Sepsis is a life-threatening disease caused by infection, and developing novel strategies against sepsis is still required. Exosomes derived from mesenchymal stem cells (MSCs) have shown promising therapeutic potential for various diseases. In this study, we aimed to investigate the action and mechanism of exosomes derived from IL-1 beta-pre-conditioned bone marrow-derived mesenchymal stromal cells (BMSCs) in *** Exosomes were isolated from BMSCs that were pretreated with (IL-1 beta-BMSC/exos) or without IL-1 beta (BMSC/exos). In vitro, a cell model of sepsis was induced by treating human umbilical vein endothelial cells (HUVECs) with lipopolysaccharide (LPS), while in vivo, a sepsis model was established through cecal ligation and puncture (CLP) operation. Immunofluorescence staining was used to detect the uptake of exosomes by HUVECs. The effects of exosomes on the cellular function of HUVECs were determined through EDU proliferation assay, migration assay, and tube formation assay. Gene and protein expression were analyzed using qRT-PCR, Western blot, ELISA, immunofluorescence staining, and immuno-histochemistry *** IL-1 beta-BMSC/exos significantly enhanced the proliferation, migration, and tube formation of HUVECs. Treatment with LPS induced the expression of high mobility group box 1 (HMGB1) and the phosphorylation of AKT in HUVECs, but these effects were counteracted by the treatment of IL-1 beta-BMSC/exos. The protective effect of IL-1 beta-BMSC/exos on the viability and tube formation ability of HUVECs was reversed by overexpression of HMGB1. Moreover, IL-1 beta-BMSC/exos promoted the polarization of M2 macrophages and reduced the secretion of inflammatory chemokines. Additionally, IL-1 beta-BMSC/exos alleviated cecal ligation and puncture (CLP)-induced sepsis in *** IL-1 beta-BMSC/exos alleviates sepsis by modulating the HMGB1/AKT pathway and triggering M2 macrophage polarization.

关键词： Chemotaxis   Galleria mellonella   IFN-gamma   Impedance   Oxidative stress   Wound healing  

摘要： Cytokines are highly conserved between mammals and insects. The present study examines the multiple effects of interferon-gamma (IFN-gamma) application on the immunological defence mechanisms of Galleria mellonella larvae, invertebrates which are gaining popularity as a replacement for mammalian research models in immunological studies. G. mellonella hemolymph is known to contain an IFN-gamma homolog that shares 33 % similarity with its mammalian analogue, and its level in insect hemocytes increases during exposition to entomopathogenic fungus Conidiobolus coronatus. The present research examines the impact of IFN-gamma on larval development, the effectiveness of fungal infection, and the morphology and physiology of wax moth immunocompetent cells. Treatment with IFN-gamma enhanced wound healing, chemotaxis activity and hemocyte impedance, while reducing hemocyte phagocytosis and oxidative stress in cultured immunocompetent cells;it also appears to increase the levels of Jak-2- and NF-kappa B-like molecules in hemocytes. Our findings suggest that IFN-gamma demonstrated considerable similarity between mammals and humans, thus further demonstrating the evolutionary conservatism of cytokines.

关键词： Interleukin-4   Tissue regeneration   Cytokines   Macrophage   Immunomodulation  

摘要： Interleukin-4 (IL-4), which is traditionally associated with inflammation, has emerged as a key player in tissue regeneration. Produced primarily by T-helper 2 (Th2) and other immune cells, IL-4 activates endogenous lymphocytes and promotes M2 macrophage polarization, both of which are crucial for tissue repair. Moreover, IL-4 stimulates the proliferation and differentiation of various cell types, contributing to efficient tissue regeneration, and shows promise for promoting tissue regeneration after injury. This review explores the multifaceted roles of IL-4 in tissue repair, summarizing its mechanisms and potential for clinical application. This review delves into the multifaceted functions of IL-4, including its immunomodulatory effects, its involvement in tissue regeneration, and its potential therapeutic applications. We discuss the mechanisms underlying IL-4-induced M2 macrophage polarization, a crucial process for tissue repair. Additionally, we explore innovative strategies for delivering IL-4, including gene therapy, protein-based therapies, and cell-based therapies. By leveraging the regenerative properties of IL-4, we can potentially develop novel therapies for various diseases, including chronic inflammatory disorders, autoimmune diseases, and organ injuries. While early research has shown promise for the application of IL-4 in regenerative medicine, further studies are needed to fully elucidate its therapeutic potential and optimize its use. (c) 2024 Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

关键词： Urolithin B   5-Fluorouracil-induced nephrotoxicity   Nrf2/Keap1/HO-1   SIRT1/FOXO3   Drug discovery   Health care  

摘要： The clinical use of 5-fluorouracil (5-FU) in cancer patients has been associated with nephrotoxicity, which is greatly curbing its therapeutic application. The pathogenesis of 5-FU-induced nephrotoxicity is complex;however, oxidative stress-mediated inflammation is considered a central pathogenic factor. Urolithin B (UB), a product of ellagitannins, has recently been assigned diverse pharmacological activities due to its potent antioxidant and anti-inflammatory properties. Therefore, the current study explored the potential renoprotective effect of UB on 5-FU-induced nephrotoxicity in mice and illuminated its potential mechanistic pathways. In this study, administration of UB (50 and 100 mg/kg) mitigated 5-FU-induced elevated levels of kidney injury indices, including renal somatic index, serum creatinine, blood urea nitrogen, and serum cystatin C, that were concurrent with histopathological improvement. UB maintained renal oxidant/antioxidant balance and enhanced the nuclear factor-erythroid-2-related factor-2 (Nrf2)/heme oxygenase 1 (HO-1) as well as the silent information regulator factor 2-related enzyme 1 (SIRT1)/forkhead box O 3 (FOXO3) antioxidant protective responses. On the other hand, 5-FU-driven activation of the NF-& kcy;B/TNF-alpha inflammatory signaling was opposed by UB administration. Conclusively, UB protected against 5-FU-induced nephrotoxicity through dose-dependent antioxidant and anti-inflammatory effects. These effects are mediated mainly through upregulating Nrf2/HO-1 and SIRT-1/ FOXO3 antioxidant responses with subsequent suppression of NF-kappa B inflammatory signaling.

关键词： KIR   Ly49   MHC   NK receptor   structure   virus  

摘要： Natural killer (NK) cells are essential elements of the innate immune response against tumors and viral infections. NK cell activation is governed by NK cell receptors that recognize both cellular (self) and viral (non-self) ligands, including MHC, MHC-related, and non-MHC molecules. These diverse receptors belong to two distinct structural families, the C-type lectin superfamily and the immunoglobulin superfamily. NK receptors include Ly49s, KIRs, LILRs, and NKG2A/CD94, which bind MHC class I (MHC-I) molecules, and NKG2D, which binds MHC-I paralogs such MICA and ULBP. Other NK receptors recognize tumor-associated antigens (NKp30, NKp44, NKp46), cell-cell adhesion proteins (KLRG1, CD96), or genetically coupled C-type lectin-like ligands (NKp65, NKR-P1). Additionally, cytomegaloviruses have evolved various immunoevasins, such as m157, m12, and UL18, which bind NK receptors and act as decoys to enable virus-infected cells to escape NK cell-mediated lysis. We review the remarkable progress made in the past 25 years in determining structures of representatives of most known NK receptors bound to MHC, MHC-like, and non-MHC ligands. Together, these structures reveal the multiplicity of solutions NK receptors have developed to recognize these molecules, and thereby mediate crucial interactions for regulating NK cytolytic activity by self and viral ligands.