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关键词： Dang-Gui-Bu-Xue-Tang   Traditional chinese medicine   Granulocyte macrophage-colony stimulating factor   Interleukin-4   Immunoglobulin-G   Immunoglobulin-A  

摘要： Dang-Gui-Bu-Xue-Tang (DGBXT, (sic)(sic)(sic)(sic)(sic)) is a two-herb decoction that is used in traditional Chinese medicine (TCM) to invigorate the blood. DGBXT reportedly enhances red and white blood cell counts and increases bone regeneration in models. However, the effects of DGBXT on immune responses in humans are unknown. All study participants completed questionnaires measuring quality of life, emotional and cognitive functioning: the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT Fatigue) Scale;the Pittsburgh Sleep Quality Index (PSQI);and the 36-Item Short Form Health Survey (SF-36). The Milliplex assay evaluated cytokine, chemokine and immunoglobulin expression. DNA microarray hybridization examined gene expression. DGBXT improved levels of physical functioning and pain sensations, according to self-reported health-related quality of life data. Feelings of fatigue and sleep quality were also improved by DGBXT. Moreover, DGBXT enhanced the production of granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin 4 (IL-4), interleukin 5 (IL-5) and macrophage inflammatory protein-1 beta (MIP-1 beta), and upregulated protein levels of immunoglobulins IgG, IgA and IgM, as well as messenger RNA expression of GM-CSF, IL-5 and IgM. We observed a time-dependent, positive correlation between levels of GM-CSF, IL-4 and MIP-1 beta and a decline in fatigue among these healthy volunteers. DGBXT supplementation appears to enhance the immune response and improve quality of life.

摘要： The immunotherapy has achieved some efficacy in triple-negative breast cancer (TNBC), but the benefit population is limited, primarily due to an abnormal immune microenvironment. Thus, it is necessary to explore new molecular targets to enhance the immunogenicity of TNBC cells and improve their responsiveness to immunotherapy. We found that a key component of the DNA repair system, Ataxia telangiectasia mutated (ATM), may function as an immune response inhibitor. In this study, the inverse correlation between ATM and CD8 T cells and tumor-infiltrating lymphocytes (TILs) was confirmed by immunochemical staining of 191 TNBC specimens. Subsequently, inhibition of ATM increased the expression of major histocompatibility complex I (MHC-I) and enhanced the infiltration and cytotoxic activity of CD8 T cells by Western blot and flow cytometry analysis. In addition, we further confirmed that the MHC-I upregulation induced by ATM inhibition depends on the activation of the c-Jun/TNF-α/p-STAT1 pathway. Animal studies have shown that ATM deficiency delays tumor growth and sensitizes tumors to PD-1 blockade and radiotherapy. This study reveals a new mechanism by which ATM negatively regulates MHC-I by inhibiting the c-Jun/TNF-α/p-STAT1 pathway in TNBC, and shows an important role in mediating CD8 T cells infiltration and regulating the "heat" of the immune microenvironment. The combination of ATM inhibitors with radiotherapy and Immune-checkpoint blockade (ICB) therapies may be a new strategy for TNBC treatment.

关键词： 慢性再生障碍性贫血   补肾生血方   肾虚血瘀型   T淋巴细胞   骨髓造血微环境  

摘要： 目的：观察补肾生血方联合司坦唑醇治疗肾虚血瘀型慢性再生障碍性贫血患者的临床疗效，并分析其对免疫功能和骨髓造血微环境的影响。方法：选择北京中医药大学东直门医院洛阳医院符合纳入标准的肾虚血瘀型慢性再生障碍性贫血患者120例，依据随机数字表随机分为治疗组和对照组，每组各60例。对照组给予常规保肝、止血、抗感染治疗基础上口服司坦唑醇，治疗组在对照组治疗基础上给予补肾生血方，两组均治疗6个月。比较两组患者治疗前后中医主症、次症积分和总积分、外周血象指标（PLT、WBC、Hb）、T淋巴细胞（CD3+、CD4+、CD8+、CD4+/CD8+）、骨髓造血微环境相关指标（bFGF、MVD、VEGF）和miRNA-155-5p、miRNA-1260b的表达情况，并比较临床疗效。结果：与治疗前比较，两组中医主症、次症和总积分、CD8+、miRNA-155-5p、miRNA-1260b表达均明显降低（P <0.05）,PLT、WBC、Hb、b FGF、MVD、VEGF、CD3+、CD4+含量和CD4+/CD8+比值均明显升高（P <0.05）。与对照组治疗后比较，治疗组中医主症、次症和总积分、CD8+、miRNA-155-5p、miRNA-1260b表达明显降低（P <0.05）,PLT、WBC、Hb、b FGF、MVD、VEGF、CD3+、CD4+含量和CD4+/CD8+比值明显升高（P <0.05）。治疗组临床总有效率90%（54/60），明显高于对照组临床总有效率73.3%（44/60）(P <0.05)。结论：补肾生血方联合司坦唑醇治疗肾虚血瘀型慢性再生障碍性贫血，可调控免疫细胞、下调miRNA的表达，利于改善骨髓造血微环境。

关键词： RNA editing   TNF signaling pathway   ileum   pig   villus height  

摘要： The ileum serves as the primary site for nutrient digestion and absorption in the intestine, with villus height representing a critical indicator of intestinal absorptive capacity. To investigate the regulatory mechanisms underlying ileal villus development, we conducted a feeding trial using crossbred pigs (Duroc × Landrace × Yorkshire) with an initial body weight of 27.74 ± 0.28 kg, stratifying them into high-villus and low-villus groups based on ileal villus height (n = 4). The results revealed 849 differentially RNA-edited genes (REGs) between the two groups, including 472 hyper-edited genes in the low-villus group and 377 in the high-villus group. Functional enrichment analysis showed that these REGs were significantly enriched in inflammation-related pathways, particularly the TNF signaling pathway and IL-17 signaling pathway, with TNF pathway genes exhibiting notably higher editing levels in the high-villus group. Additionally, 46 differentially expressed genes (DEGs) were identified, comprising 22 upregulated in the low-villus group and 24 in the high-villus group, which were similarly enriched in TNF and IL-17 signaling pathways. Integrated quadrant analysis of the RNA editing and transcriptomic profiles demonstrated that pro-inflammatory genes CXCL10 (C-X-C motif chemokine 10), CCL2 (C-C motif chemokine ligand 2), CREB3L2 (CAMP-responsive element-binding protein 3-like 2), and PIK3R1 (Phosphoinositide-3-kinase regulatory subunit 1) were highly expressed in the low-villus group but exhibited significantly lower RNA editing levels compared to the high-villus group. Furthermore, the expression of the inflammation-suppressive RNA editing enzyme APOBEC1 (apolipoprotein B mRNA editing enzyme catalytic subunit 1) showed correlation with villus height (R = 0.81, < 0.05). Collectively, our findings indicate that RNA editing dynamics influence the variation in ileal villus height within inflammation-associated pathways, particularly the TNF signaling pathway. Enhan

关键词： Interleukin-6   Ischemia-reperfusion   Meprin metalloprotease β   Proliferation  

摘要： BACKGROUND:Inflammation plays a central role in the progression of kidney injury induced by ischemia/reperfusion (IR). Meprin metalloproteinases have been implicated in the pathophysiology of IR-induced kidney injury. Existing data from in vitro and in vivo studies show that meprins modulate interleukin-6 (IL-6)-mediated inflammation via proteolytic processing of IL-6 and its receptor. IL-6 trans-signaling induces proliferation through either Mitogen-activated protein kinase /extracellular signal-regulated kinase (MAPK/ERK) or Phosphatidylinositol 3-Kinase/ protein kinase B (PI3K/AKT) pathway or in crosstalk with AKT/ERK. We previously showed that meprin β modulates cellular survival B-Cell Lymphoma/Leukemia 2 (BCL-2) through IL-6/Janus kinase/ Signal Transducer and Activator of Transcription (IL-6/JAK/STAT) signaling pathway in IR-induced kidney injury. However, it's not known how meprin β modulation of the IL-6 signaling pathway impacts the cellular proliferation in IR-induced acute kidney injury. The goal of the current study was to determine how meprin β modulation of the IL-6 signaling pathway impacts downstream cellular proliferation in IR-induced kidney injury. METHODS:We induced Ischemia/Reperfusion injury with unilateral IR as a model of renal inflammation in wild-type (WT) and meprin β knockout (βKO) mice, with the contralateral kidneys serving as controls. The mice were sacrificed at 96 h post-IR, and kidney tissue processed for evaluation by RT-PCR and immunohistochemistry. Statistical analysis utilized two-way ANOVA. RESULTS:RT-PCR data showed a significant increase in mRNA levels for IL-6 and proliferating cell nuclear antigen (PCNA) in WT and βKO mice at 96 h-post IR when compared to WT control kidneys. However, the baseline mRNA levels for PCNA were significantly higher in βKO when compared to WT kidneys. Immunohistochemical data showed significant increases in IL-6, PCNA, p-AKT and p-ERK in select tubules in both genotypes at 96 h post-IR when compa

摘要： Tumor necrosis factor-α (TNF-α) is an immune regulator, involved in the pathogenesis of numerous diseases, such as systemic lupus erythematosus (SLE). Primary hyperparathyroidism (PHPT) is an endocrinopathy recognized by the hypersecretion of parathormone. Despite the increasing evidence of immune derangement in parathyroid disorders, results are still inconsistent. We aimed to examine TNF-α mRNA and serum levels in SLE with and without PHPT to elucidate the immunomodulatory and pathogenic roles of TNF-α mRNA and serum in both diseases. We recruited 70 patients and 70 age-and sex-matched controls. Diagnosis of PHPT and SLE was based on a combination of immunological markers, clinical symptoms, biochemical tests, imaging, and parathyroid scintigraphy. We evaluated serum levels of TNF-α using ELISA and the expression of TNF-α mRNA in peripheral blood using real-time PCR. TNF-α serum and mRNA relative expression values were overexpressed in SLE group with PHPT (28.25 ± 10.9, 6.31 ± 3.1, respectively) in comparison to SLE group without PHPT (19.09 ± 7.21,4.02 ± 1.9, respectively) and control group (3.6 ± 1.668, 0.91 ± 0.16, respectively), (P < 0.001*). TNF-α mRNA and serum levels were significantly positively correlated with SLEDAI, ESR, alkaline phosphatase, iPTH, adjusted calcium, ionized calcium, and 24-h urine for calcium. Linear regression tests revealed that serum TNF-α, ESR, and iPTH were the only predictors among other parameters studied, (P < 0.001*). Concerning TNF-α mRNA, adjusted calcium was the only predictor among other parameters studied, (P < 0.001*). TNF-α mRNA and serum levels are elevated in SLE, particularly in patients with PHPT. Intriguingly, they were significantly correlated to markers of lupus activity and bone resorption.

关键词： Bipolar disorder   immune biomarkers   NACHT   IL-6   neuroinflammation   mood disorders   diagnostic markers  

摘要： This study examines immune markers-P2X7, NACHT, and IL-6-as potential diagnostic and therapeutic biomarkers in Bipolar Disorder (BD). Among 120 participants (76 BD patients and 20 healthy controls), P2X7 levels were significantly elevated in BD patients both before (p = 0.001) and after treatment (p < 0.001), indicating strong diagnostic potential. NACHT levels also increased significantly after treatment (p = 0.007). Subgroup analysis revealed significantly higher P2X7 and NACHT levels in female BD patients compared to female controls (p < 0.001 for both). ROC curve analysis confirmed P2X7 as the most sensitive and specific marker for distinguishing BD from controls (p < 0.001), while NACHT showed predictive value after treatment (p < 0.05). Correlation analysis found significant associations between changes in P2X7 and NACHT levels and clinical improvement (p < 0.05). Despite limitations such as small sample size and potential medication effects, the findings support P2X7 and NACHT as promising biomarkers for BD diagnosis and treatment monitoring. The study contributes to the understanding of immune dysregulation in BD and suggests potential for immune-targeted therapies.

关键词： IL-37   inflammation   oxidative stress   sepsis-induced lung injury   TGF-beta/Smad3  

摘要： Introduction: Sepsis is caused by an uncontrolled inflammatory response and immune dysfunction, with lung injury being the most common complication and one of the leading causes of death in clinically ill patients. Interleukin 37 (IL-37) is a multifunctional cytokine that plays a vital role in various pathophysiological processes, including inflammation, infection, and ***: The study involved both clinical and animal experiments (establishing an animal model of sepsis-induced lung injury). Firstly, 50 patients with sepsis-induced lung injury and 50 healthy controls were included. In addition, a more in-depth study was conducted using animal ***: IL-37, IL-6, PCT, and CRP levels were significantly higher in the sepsis-induced lung injury group. Correlation analysis revealed that IL-37 significantly correlated with IL-6, PCT, and CRP levels. In animal experiments, IL-37 significantly attenuated CLP-induced pulmonary edema and cellular injury while reducing the levels of inflammatory factors IL-6 and TNF-alpha, as well as sepsis-related inflammatory markers PCT and CRP. Moreover, IL-37 significantly downregulated the expression levels of genes and proteins of apoptosis-related molecules Caspase-3 and Bax and pathway molecules TGF-beta and Smad3. Discussion: The TGF-beta/Smad3 pathway is involved in the process of IL-37 inhibiting inflammatory response and ameliorating sepsis-induced lung injury.

关键词： post-translational modification (PTM)   histone deacetylase (HDAC)   lactic acid   lactate   lysine lactylation   glycolysis   macrophage   protein acylation   BMDM   bone marrow-derived macrophages   BSA   bovine serum albumin   CoA   co-enzyme A   DCA   dichloroacetate   HDAC   histone deacetylases   IFN   interferon   Kbhb   lysine β-hydroxybutyrylation   Kce   carboxyethyl-lysine   Kla   lysine ʟ-lactylation   LDH   lactate dehydrogenase   LGSH   S-ᴅ-lactoylglutathione   LPS   lipopolysaccharide   MGO   methylglyoxal   OXA   oxamate   PTM   post-translational modification   TLR4   toll-like receptor 4   TSA   trichostatin A  

摘要： Metabolism and post-translational modifications (PTMs) are intrinsically linked and the number of identified metabolites that can covalently modify proteins continues to increase. This metabolism/PTM crosstalk is especially true for lactate, the product of anaerobic metabolism following glycolysis. Lactate forms an amide bond with the ε-amino group of lysine, a modification known as lysine lactylation, or Kla. Multiple independent mechanisms have been proposed in the formation of Kla, including p300/CBP-dependent transfer from lactyl-CoA, a reactive intermediate lactoylglutathione species that non-enzymatically lactylates proteins, and several enzymes are reported to have lactyl transferase capability. We recently discovered that class I histone deacetylases (HDACs) 1, 2, and 3 can all reverse their canonical chemical reaction to catalyze lysine β-hydroxybutyrylation. Here we tested the hypothesis that HDACs can also catalyze Kla formation. Using biochemical, pharmacological, and genetic approaches, we found that HDACs are sufficient to catalyze Kla formation and that HDACs are a major driver of lysine lactylation. Dialysis experiments confirm this is a reversible reaction that depends on lactate concentration. We also directly quantified intracellular lactyl-CoA and found that Kla abundance can be uncoupled from lactyl-CoA levels. Therefore, we propose a model in which the majority of Kla is formed through enzymatic addition of lactate by HDACs 1, 2, and 3.

摘要： The ability of NK cells to establish antigen-specific responses has been demonstrated in various infections. NK cell receptors of the diverse family of Killer-cell Immunoglobulin-like Receptors (KIR) interact with HLA class I molecules, and this interaction is peptide-dependent. The activating receptor KIR2DS4 enables NK cell degranulation following interaction with specific peptides presented within HLA-C*05. However, the mechanism underlying the differential NK cell response depending on a peptide remains poorly understood and lacks explanation based on the structure of ligand-receptor interaction. Using AlphaFold 3, we generated models of KIR2DS4-peptide-HLA-C*05 complexes to analyze the contact interfaces. We confirmed the substantial role of the aromatic ring in the 8th amino acid residue of peptide sequences in mediating interactions with KIR2DS4. Even with the same amino acid residue at position 8, different peptides exhibited variability in polar contacts with KIR2DS4. Our results may contribute to the prediction of KIR-HLA interactions and facilitate the identification of specific peptides capable of activating NK cells.