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关键词： Angiogenesis   CD8(+) T cells   Diabetic retinopathy   IL-2   Oxygen-induced retinopathy   Regulatory T cells   Tregs  

摘要： Aims/hypothesis Diabetic retinopathy features damage to the retinal microvasculature that causes vessels to leak and proliferate and can lead to vision loss and blindness. Inflammation contributes to the development of diabetic retinopathy, but little is known about the role of the adaptive immune system, including the benefits of augmenting the Forkhead box protein P3 (Foxp3) regulatory T cell (Treg) compartment. We aimed to determine whether treatment with low-dose IL-2 expands and activates Tregs and reduces CD8(+) T cells in the retina, and attenuates retinal inflammation and vasculopathy in murine models of diabetic retinopathy and neovascular retinopathy. Methods Mouse models of streptozocin-induced diabetes and oxygen-induced retinopathy (OIR) were administered low-dose IL-2 (25,000 U) or vehicle (sterile water) by i.p. injection. Reporter mice expressing Foxp3 as a red fluorescent protein (RFP) conjugate or CD8 as a green fluorescent protein (GFP) conjugate were used to evaluate Foxp3(+) Tregs and CD8(+) T cells, respectively, in blood, lymphoid organs and retina using flow cytometry or confocal microscopy. Vasculopathy and the expression of angiogenic and inflammatory factors were assessed in the retina. Results Low-dose IL-2 significantly expanded CD4(+)CD25(+)Foxp3(+) Tregs in the blood and spleen of mouse models of OIR and diabetes (1.4- to 1.9-fold increase, p<0.01). This expansion enhanced Treg functionality, increasing the expression of cytotoxic T-lymphocyte-associated protein4 (CTLA4), programmed cell death protein1 (PD1) and T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT), and increased the ratio of Tregs to CD8(+) T cells. This was accompanied in the retina by a twofold increase in Foxp3(+) Tregs (diabetes: 3.01 +/- 0.41 vs 5.90 +/- 1.25 cells per field, p<0.001;OIR: 4.41 +/- 1.48 vs 10.05 +/- 2.91 cells per field, p<0.001) and a reduction in CD8(+) T cells (diabetes: 4.65 +/- 0.58

关键词： HLA-C   nanotype sequencing   NGS   sequencing-based typing  

摘要： The novel HLA-C*14:168 allele differs from HLA-C*14:02:01:02 by three nucleotides in exon 7.

关键词： Clinical efficacy   Cold-dampness arthralgia type knee osteoarthritis   Fire-needle warming method   IL-1 beta   MMP-3  

摘要： ObjectiveThis study aims to explore the clinical efficacy of fire-needle warming therapy in managing knee osteoarthritis attributed to cold-dampness patterns. Specifically, it evaluates the therapy's influence on interleukin-1 beta (IL-1 beta) serum concentrations and matrix metalloproteinase-3 (MMP-3). MethodsA retrospective analysis was conducted on 80 patients treated for knee osteoarthritis from September 2023 to February 2024. Patients were divided into two groups: 40 received electroacupuncture, and 40 received fire acupuncture combined with warming techniques. The primary outcome measures included treatment efficacy, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores, compare the changes in IL-1 beta and MMP-3 levels in serum and synovial fluid between two groups, and compare the total knee joint X-ray scores between the two groups: pain levels and knee joint function. Adverse reactions were also recorded. ResultsThe fire acupuncture group had a significantly higher treatment efficacy rate (92.5%) compared to the electroacupuncture group (75%, P < 0.05). Both groups showed significant reductions in WOMAC scores post-treatment, with a greater reduction in the fire acupuncture group (P < 0.05). Serum levels of IL-1 beta and MMP-3 decreased significantly in both groups, with a more pronounced decrease in the fire acupuncture group (P < 0.05). After 4 weeks of intervention and 8 weeks of follow-up, the levels of IL-1 beta and MMP-3 in the synovial fluid of the fire needle group and the electroacupuncture group were significantly reduced (P < 0.05), and the fire needle group was significantly lower than the electroacupuncture group (P < 0.05). Pain and knee function scores improved significantly in both groups, with the fire acupuncture group showing greater improvements (P < 0.05). After 4 weeks of intervention and 8 weeks of follow-up, the total joint X-ray scores of the fire needle group and the electroacupuncture group were significa

关键词： adoptive transfer   iNKT cells   Kupffer cells   liver injury   neutrophils  

摘要： To explore the innate immune response in the occurrence and development of APAP-induced drug-induced liver injury and the biological effect caused by the interaction between immune cells through real-time, in vivo analysis. We used conventional molecular biology technology and multi-photon confocal live imaging to explore the effect of the interactive dialogue between iNKT and Kupffer cells on neutrophil recruitment in the occurrence and development of APAP-induced liver injury. iNKT cell deficient mice were more prone to liver injury induced by excessive APAP, and the degree of liver injury was more severe. After injury, iNKT cells were recruited into the liver and showed IL-4 high expression activation mode. Furthermore, we also found that Kupffer cells in APAP induced liver injury produce M1 polarisation and highly expressed IL-12, that Kupffer cells regulate the activation of iNKT cells through IL-12;and that IL-4 produced by iNKT cells in the liver can also inhibit inflammatory damage caused by neutrophil recruitment. Our study shows that Kupffer cells produce IL-12 and promote activated iNKT cells to produce more IL-4, and inhibit the recruitment of neutrophils, thereby reducing the degree of liver inflammatory injury induced by APAP.

关键词： HLA   HLA-DPB1   next-generation sequencing   novel allele  

摘要： HLA-DPB1*1748:01 differs from HLA-DPB1*04:01:01:01 by one nucleotide substitution in codon-1 in exon 1.

关键词： diet   inflammation   inflammatory markers   multimorbidity   obesity   weight loss  

摘要： BackgroundA chronic inflammatory state characterizes a wide range of diseases for which obesity is a risk factor. Weight loss could reduce levels of circulating inflammatory markers potentially reducing the incidence of associated diseases and improving response to treatment. However, dietary weight loss studies have reported inconsistent effects on serum inflammatory makers and the long-term effects are *** systematically review randomized controlled trials and analyze any differences in serum interleukin-6 and tumor necrosis factor-alpha between adults with obesity achieving weight loss through dietary intervention compared to those receiving none or standard *** were identified by searching databases from 1966 to November 2024. Randomized controlled trials with at least 12 months' follow-up were included in this systematic review and meta-analysis with an assessment of Cochrane risk of bias version *** eligible studies were included. No trials reported a significant effect of weight loss on circulating tumor necrosis factor-alpha, whilst studies achieving greater than 5% weight loss significantly reduced circulating interleukin-6 in adults with *** loss interventions achieving and maintaining greater than 5% weight loss appear to be required to reduce circulating interleukin-6 levels in adults with obesity.

摘要： (no summary available)

关键词： ferroptosis   IL-9   intestinal mucosal barrier   sepsis  

摘要： Background:Interleukin-9 (IL-9) is an emerging pro-inflammatory cytokine that promotes intestinal barrier injury (IBI) in sepsis. The specific mechanisms of IL-9-induced IBI still need to be clarified. As a newly discovered form of programmed cell death, ferroptosis was demonstrated to be involved in sepsis-related organ dysfunction, yet its role in IL-9-induced IBI in sepsis remains ***:Serum levels of IL-9, D-lactate, intestinal fatty acid binding protein (iFABP), glutathione (GSH), and glutathione peroxidase 4 (GPX4) were tested in septic patients and control subjects. Biomarkers reflecting barrier function in serum and intestinal tissue were tested in treated rats. Rats underwent sepsis induction, IL-9, IL-9 inhibition (IL-9i), and ferroptosis inhibition (Fei) treatment were selected to examine the severity of IBI and survival ***:Significantly elevated levels of IL-9, D-lactate, iFABP, GSH, and GPX4 were observed in septic patients and rats. IL-9 levels showed a negative correlation with GSH and GPX4 levels, while GSH or GPX4 levels showed an inverse correlation with D-lactate and iFABP levels. Serum GSH and GPX4 levels demonstrated strong predictive value for acute gastrointestinal injury of grade II and above in septic patients. IL-9 administration increased levels of transferrin receptor, Fe2+, and iFABP in serum and intestinal tissue of septic rats, while decreasing GSH, GPX4, and zonula occludens 1 levels. Inhibition of ferroptosis reversed these biomarkers alterations. Intestinal permeability, transmission electron microscopy, histopathology, and apoptosis assays confirmed exacerbated IBI following IL-9 upregulation and its attenuation upon ferroptosis ***:Ferroptosis was implicated in the IL-9-induced intestinal barrier injury in sepsis.

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.