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关键词： Colorectal cancer (CRC)   IL-13   tyrosine kinase 2  

摘要： IntroductionColorectal cancer (CRC) is a third cause of death worldwide. The immune system plays a significant role in the tumor microenvironment and identifying its components involved in cancer development can aid in finding new biomarkers for prognosis, treatment monitoring, and immune-based therapies. Interleukin 13 (IL-13) is a cytokine produced by immune cells that has been implicated in tumor invasion, proliferation, and metastasis. Previous studies have shown that IL-13 causes the phosphorylation of Tyrosine kinase 2 (TYK2), which may contribute to the development and progression of cancer. This study investigated the levels expression of IL-13 and TYK2 in the tissue and serum of CRC patients and explored their possible association with pathological and clinical ***105 patients with CRC and 105 healthy individuals were involved in the study. Tissue and blood samples were collected. The quantitative Real-Time PCR (qRT-PCR) technique was used to assess the expression levels of the IL-13 and TYK2 CRC tissue samples in comparison with the adjacent control *** expression levels of IL-13 were lower and TYK2 were found to be higher in CRC tissue compared to normal tissue. Additionally, serum levels of IL-13 were decreased in CRC patients while TYK2 levels were elevated. A significant negative correlation was found between the expression levels of IL-13 in both serum and tissue and the cancer *** results suggest that IL-13 and TYKMay 2 play essential roles in CRC development and progression and may serve as potential biomarkers for early detection and treatment.

关键词： 空肠弯曲菌   Cia效应蛋白   黏附   侵袭   炎性细胞因子  

摘要： 【背景】空肠弯曲菌是(Campylobacter jejuni)世界范围内最重要食源性病原菌之一，在家禽盲肠内通常共生定殖，成为感染人的主要来源，目前该菌在家禽肠道内定殖机制尚未阐明。【目的】探究空肠弯曲菌不同效应蛋白参与黏附侵袭肠上皮细胞和免疫细胞以及激活炎性细胞因子中的作用，解析该菌在鸡肠道内定殖的机制，为其防控提供潜在的作用靶标。【方法】首先利用同源重组技术构建空肠弯曲菌NCTC 11168菌株不同效应蛋白CiaB、CiaC、CiaD和CiaI基因缺失突变株，测定突变株对细菌生物膜形成和自身凝集能力的影响，进而测定突变株对肠上皮细胞Caco-2的黏附和侵袭能力，以及对鸡巨噬细胞系HD11的侵袭能力，最后利用qRT-PCR鉴定突变株感染HD11细胞对炎性细胞因子表达的影响。【结果】构建成功空肠弯曲菌不同效应蛋白CiaB、CiaC、CiaD和CiaI基因缺失突变株；△ciaD突变株生物膜形成能力降低，△ciaC、△ciaD和△ciaI突变株自身凝集能力增强；△ciaB突变株黏附侵袭Caco-2细胞能力增强，而△ciaC、△ciaD和△ciaI突变株黏附侵袭Caco-2以及侵袭HD11细胞能力均显著降低；空肠弯曲菌感染HD11显著提高不同炎性细胞因子表达水平，△ciaB、△ciaC和△ciaD突变株显著降低不同炎性因子表达水平，而△ciaI突变株显著增强不同炎性因子表达水平。【结论】结果显示空肠弯曲菌不同Cia效应蛋白在黏附侵袭肠上皮细胞和免疫细胞以及激活炎性细胞因子表达中发挥不同的作用，为解析空肠弯曲菌与宿主肠道上皮相互作用机制提供理论依据，为该菌的防控提供潜在靶标。

关键词： Periodontitis   Vitamin D   Interleukin-8   Stages  

摘要： ObjectivesThe current literature lacks the correlation between serum levels of vitamin D and interleukin-8 (IL-8) to the stages of periodontitis. The present research objectives are to evaluate the serum levels of vitamin D and IL-8 in periodontitis participants and healthy controls and to measure their correlation with the stages of *** current case-control study was conducted on patients with periodontitis and healthy controls. After obtaining a questionnaire from the participants, the following clinical parameters were measured;periodontal probing depth (PPD), clinical attachment loss (CAL), plaque index (PI), gingival index (GI), bleeding on probing (BOP), and tooth count. The serum levels of vitamin D and IL-8 were measured using ELISA kits. Then, we measured the correlation of the stages of periodontitis with the serum levels of vitamin D and ***-eight participants;52 with periodontitis and 46 healthy controls were included. The patients with periodontitis showed a significantly lower level of vitamin D, higher PPD, CAL, BOP, and lower number of teeth than the controls. In addition, serum vitamin D significantly correlated with the stages of periodontitis. Serum IL-8 showed no significant difference between the study and control groups while it does not significantly correlate with the stages of *** current study's findings suggest a potential association between serum level of vitamin D with severity of periodontitis which necessitates screening vitamin D status in patients with periodontitis and investigating the possibility of vitamin D supplementation in decreasing the progression of periodontitis.

关键词： IL-7   mRNA vaccine   Adjuvant   Lipid nanoparticles   Long-term protection  

摘要： Messenger RNA (mRNA) vaccines are a key technology in combating existing and emerging infectious diseases. However, improving the immunogenicity and durability of mRNA vaccines remains a challenge. To elicit optimal immune responses, integrating antigen-encoded mRNA and immunostimulatory adjuvants into a single formulation is a promising approach to enhancing the efficacy of mRNA vaccines. Here, we report an adjuvant strategy to enhance the efficacy of mRNA vaccines by co-loading mRNA encoding the antigen (rabies virus glycoprotein, RABV-G) and mRNA encoding IL-7 into lipid nanoparticles, achieving co-delivery to the same antigen-presenting cells. A single immunization with G&IL-7 mRNA vaccine elicited robust humoral immune responses in mice and conferred complete protection against RABV challenge. Notably, the high levels of neutralizing antibody induced by the G&IL-7 mRNA vaccine were maintained for at least 6 months, providing mice with long-term significant and complete protection against RABV. Additionally, IL-7 also enhanced antibody responses against the SARS-CoV-2. These data demonstrate that IL-7 is a potent mRNA vaccine adjuvant that can provide the required immune stimulation in various mRNA vaccine formulations.

关键词： Solid tumors   Tumor immunology  

摘要： Dampened antigen presentation underscores the resistance of pancreatic cancer to T cell-mediated anti-tumor immunity, rendering immunotherapy largely ineffective. By high-throughput CRISPR activation perturbation, we discovered that the transcriptional regulator MCRS1 significantly augmented the sensitivity of mouse pancreatic cancer cells to T cell immunity in vitro and in vivo. Mechanistically, MCRS1 interacted with the transcription factor and genome organizer YY1 to coordinately increase the chromatin accessibility and expression of MHC-I genes. Elevated MCRS1 subverted MHC-I suppression and activated anti-tumor T cells, which sensitized mouse pancreatic cancer to alpha-PD-1 therapy. Remarkably, high MCRS1 expression was associated with increased T cell infiltration and extended survival of patients with pancreatic cancer and was predictive of favorable responses to alpha-PD-1 therapy in patients with lung cancer. Together, our study uncovers that MCRS1 sensitizes cancer cells to T cell immunity by transcriptionally subverting MHC-I suppression, which enhances the effectiveness of alpha-PD-1 therapy in mice and humans, paving the way to further improve immunotherapy against solid tumors.

摘要： IL-7 is a cytokine produced by stromal cells, which binds to IL-7Ra and plays an important role for homeostasis of T lymphocytes. Excessive activities of IL-7-triggered signaling pathways causes autoimmune diseases. How IL-7-triggered signaling and immune effects are regulated is not fully understood. In this study, we show that the membrane-associated RING-CH (MARCH) E3 ligase family member MARCH8 mediates K27-linked polyubiquitination of IL-7Ra, leading to its lysosomal degradation. Site-directed mutagenesis suggests that MARCH8 meditates polyubiquitination of IL-7Ra at K265/K266, and mutation of these residues renders IL-7Ra resistance to MARCH8-mediated polyubiquitination and degradation. MARCH8 deficiency increases IL-7-triggered activation of the downstream transcription factor STAT5 and transcriptional induction of the effector genes in human T lymphoma cells. MARCH8 deficiency also promotes IL-7-triggered T cell proliferation and splenic memory CD8+ T cell differentiation in mice. Our findings suggest that MARCH8 negatively regulates IL-7-triggered signaling by mediating K27-linked polyubiquitination and lysosomal degradation of IL-7Ra, which reveals a negative regulatory mechanism of IL-7-triggered T cell homeostasis. The Journal of Immunology, 2024, 213: 1467-1478.

关键词： Gingerdiol   Intervertebral disc degeneration   NLRP3   Nucleus pulposus cells  

摘要： Intervertebral disc degeneration (IDD) is a common cause of low back pain, causing a huge emotional and economic burden on patients and society. Reduction of nucleus pulposus cells (NPC) and extracellular matrix (ECM) is the main feature of IDD, and NPC is the main source of ECM. Thermal apoptosis is a newly discovered form of cell death in recent years that differs significantly from apoptosis in terms of molecular mechanisms and cellular morphological changes. Diacetoxy-6-gingerdiol(D-6-G), a type of gingerol, has anti-inflammatory and antioxidant effects, but whether it has an inhibitory effect on cellular pyroptosis is not clear. Therefore, in the present study, we investigated the effect of D-6-G on the ECM of the nucleus pulposus oblongata under IL-1β treatment, as well as the mechanism of its effect on NLRP3 inflammasome and cellular focal death. In vitro cellular experiments demonstrated that D-6-G could bind to and inhibit the activity of NLRP3 inflammasome, and interestingly, D-6-G could also inhibit cellular pyroptosis and protect the nucleus pulposusry cellular microenvironment by activating the Nrf2/HO-1 axis. In conclusion, we found that D-6-G could inhibit NLRP3 inflammatory vesicle activity as well as cellular pyroptosis in NPCs and protect the ECM, suggesting the potential of D-6-G to delay IDD. © 2024 The Authors

关键词： Pseudellone C   Anti-glioma   Structure-activity relationship   TNF/TNFR pathway  

摘要： Glioma, a common primary brain tumor, is highly infiltrative and invasive, often leading to drug resistance and recurrence. Therefore, the development of novel therapeutic agents is urgently needed. Pseudellone C is a novel marine triindole alkaloid. Screening of its antiproliferative activity against 55 cell lines revealed its anti-CNS cancer potential. A total of 42 derivatives of Pseudellone C were designed and synthesized, and their inhibitory activities against two human glioma cell lines (U-87MG and LN-229) were evaluated using the CCK-8 assay. Ten derivatives exhibited potent antiproliferative activity with IC50 values below 10 mu mol, which are 18- to 39fold more potent than Pseudellone C. Among these, derivative 4o demonstrated favorable blood-brain barrier permeability. Mechanistic studies revealed that 4o induces apoptosis primarily by activating the downstream caspase 3 cascade via the TNF/TNFR pathway. Structure-activity relationship correlations were systematically analyzed, and a pharmacophore model for further rational design was constructed.

关键词： Anakinra   Biologics   IL-1   IL-1 inhibitors   Pediatric rheumatology   Pericarditis  

摘要： Recurrent pericarditis (RP) is defined by the European Society of Cardiology (ESC) as an instance of acute pericarditis (AP) that occurs at least 4-6 weeks after the resolution of a previous episode of the same ailment. To mitigate the risk of RP, it is advised to administer accurate and prolonged pharmacological treatment for both the initial AP and subsequent RP. ESC guidelines recommend commencing treatment for any single episode of AP, including those that contribute to RP, with non-steroidal anti-inflammatory drugs (NSAIDs) in conjunction with colchicine for several months, often followed by gradual tapering. If there is an inadequate response, corticosteroids (CS) may be introduced cautiously. However, in a minority of cases, even when NSAIDs, colchicine, and CS are administered together at the highest recommended dosages, they may prove ineffective. In such instances, treatment with immunosuppressive drugs or biologics is advised. Among biologics, interleukin (IL)-1 inhibitors have been extensively studied, although certain gaps remain. This narrative review delves into the rationale for employing IL-1 inhibitors and presents findings from existing studies regarding their efficacy, tolerability, and safety. Analysis of the literature indicates that there is currently insufficient data to ascertain the true therapeutic role of IL-1 inhibitors in managing and preventing RP. However, theoretically, drugs targeting both IL-1 alpha and IL1(3 may offer superior efficacy compared to those solely targeting IL-1(3 due to the significant involvement of both cytokines in inflammation. Further research is warranted to determine the comparative effectiveness of IL-1 alpha and IL-1(3 inhibitors.

关键词： Supplemented Gegen Qinlian Decoction   formula   Diabetic kidney disease   Renal fibrosis   Podocyte mitochondrial fission   Necroptosis  

摘要： Ethnopharmacological relevance: Recently, podocyte mitochondrial dysfunction and necroptosis have been shown to play critical roles in renal fibrosis (RF) in diabetic kidney disease (DKD);however, these conditions lack effective treatment. In China, the supplemented Gegen Qinlian Decoction Formula (SGQDF), which originates from the classical prescription Gegen Qinlian Decoction, has been widely used to treat patients with DKD. However, it remains unclear whether SGQDF alleviates podocyte injury-associated RF in patients with DKD. Aim of study: This study aimed to clarify the therapeutic effects of SGQDF compared with those of empagliflozin (EMPA) on podocyte mitochondrial fission and RF in DKD and its necroptosis-related mechanisms. Materials and methods: Modified DKD rat models were developed through a combination of uninephrectomy, streptozotocin administration through intraperitoneal injection, and exposure to a high-fat diet. Following RF formation, the DKD rat models received either a high dose of SGQDF (H-SGQDF), a low dose of SGQDF (LSGQDF), EMPA, or vehicle for 4 weeks. In our in vitro study, we subjected cultured murine podocytes to a highglucose environment and various treatments including Mdivi-1, adalimumab, and necrostatin-1, with or without H-SGQDF or EMPA. SGQDF target prediction and molecular docking verification were performed. For the in vivo study, we focused on examining changes in the parameters associated with renal injury, RF, and oxidative stress (OS)-induced injuries in podocytes. Both in vivo and in vitro studies included an analysis of changes in podocyte mitochondrial fission, TNF-alpha-induced podocyte necroptosis, and the RIPK1/RIPK3/MLKL signaling pathway activation. Results: SGQDF improved renal injury markers, including body weight, blood glucose, serum creatinine, blood urea nitrogen, and urinary albumin, in a dose-dependent manner. The beneficial effects of H-SGQDF in vivo were greater than those of L-SGQDF alone in vivo. Interesti