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关键词： integrin activation   smooth muscle   force transmission  

摘要： Integrin activation resulting in enhanced adhesion to the extracellular matrix plays a key role in fundamental cellular processes. Although integrin activation has been extensively studied in circulating cells such as leukocytes and platelets, much less is known about the regulation and functional impact of integrin activation in adherent cells such as smooth muscle. Here, we show that two different asthmagenic cytokines, IL- 13 and IL- 17A, activate type I and IL- 17 cytokine receptor families, respectively, to enhance adhesion of airway smooth muscle. These cytokines also induce activation of beta 1 integrins detected by the conformation- specific antibody HUTS- 4. Moreover, HUTS- 4 binding is increased in the smooth muscle of patients with asthma compared to nonsmokers without lung disease, suggesting a disease- relevant role for integrin activation in smooth muscle. Indeed, integrin activation induced by the beta 1- activating antibody TS2/16, the divalent cation manganese, or the synthetic peptide beta 1- CHAMP that forces an extended- open integrin conformation dramatically enhances force transmission in smooth muscle cells and airway rings even in the absence of cytokines. We demonstrate that cytokine- induced activation of beta 1 integrins is regulated by a common pathway of NF-kappa B- mediated induction of RhoA and its effector Rho kinase, which in turn stimulates PIP5K1 gamma- mediated synthesis of PIP2 at focal adhesions, resulting in beta 1 integrin activation. Taken together, these data identify a pathway by which type I and IL- 17 cytokine receptor family stimulation induces functionally relevant beta 1 integrin activation in adherent smooth muscle and help to explain the exaggerated force transmission that characterizes chronic airway diseases such as asthma.

关键词： 5-Aza-2’-Deoxycytidine/Decitabine/Dacogen   CD11c   CD11c+ CD8+ T cell   DNA Therapeutic Cancer Vaccine   IFNα/Interferon alpha/Type I interferon   MIP3α/CCL20   Tumor microenvironment  

摘要： Previous studies in the B16F10 mouse melanoma model have demonstrated that combining a DNA vaccine comprised of regions of gp100 and tyrosinase-related protein 2 fused to Macrophage-inflammatory protein 3-alpha (MIP3α) with recombinant Interferon alpha (IFN) and 5-Aza-2'-Deoxycytidine (5Aza) treatments resulted in significantly greater anti-tumor activity and immunogenicity in the tumor microenvironment (TME). This brief report details that the combination of vaccine with treatments IFN and 5Aza results in both the upregulation of genes expressing CD11c-interacting proteins and an increase in the TME of a distinct CD11c+ CD8+ T cell population. This cell population correlates with tumor size, is primarily comprised of effector or effector memory T cells, and has a more robust response to ex vivo stimulation as compared to CD11c- CD8+ T cells as measured by surface activation markers 4-1BB (CD137) and KLRG1 (Killer cell lectin-like receptor G1) and intracellular IFNγ production. In conclusion, this combination therapy results in greater presence of highly active effector CD8+ T-cells expressing CD11c in the TME that correlate with and are likely primary contributors to treatment efficacy.

关键词： Acute myeloid leukaemia   Microtransplantation   Fine immune indices   Immunologic mechanism   Immunotherapy  

摘要： The aim of this study was to observe the effects of different conditioning regimens on fine immune indices after microtransplantation (MST) in patients with acute myeloid leukaemia (AML). This article discusses the possible immune mechanism of microtransplantation and describes a more optimized conditioning regimen. A total of 55 AML patients who received MST treatment at the Second Hospital of Lanzhou University from August 2015 to October 2023 were included in this study, and 13 AML patients who did not receive MST but directly received the maintenance therapy were included as the control group (C). The MST patients were divided into a conditioning regimen with venetoclax group (A) and a conditioning regimen without venetoclax group (B). The fine immune indices were detected by flow cytometry and cytometric bead array analysis. Changes in the immune indices before and after treatment were observed, and the progression-free survival (PFS) and overall survival (OS) of patients in the MST group were analysed. Compared with those in Group B, patients in Group A had better PFS and OS. The proportion of Treg cells and the expression level of IL-2 were increased, while TNF-alpha and IFN-alpha were decreased after MST (P < 0.05). In Group B, total T cells, CD4(+)T cells and CD4(+)/CD8(+)T cells decreased;NK cells and total B cells increased;and IL-17A first increased and then decreased during the MST (P < 0.05). There were significant differences in total B cells, IL-4 and IFN-gamma between Group A and Group B during MST. Moreover, there were significant differences in total T cells, CD4(+)T cells, Treg cells, IL-17A, IFN-gamma and IL-2 between the patients in the MST group and those in the control group (P < 0.05). The MST conditioning regimen containing venetoclax significantly changed the fine immune indices and showed improved efficacy, which is worthy of further study and clinical application.

关键词： 4-Octyl itaconate   Methylation   Ferroptosis   Osteoarthritis   GPX4  

摘要： The role of oxidative stress and ferroptosis in osteoarthritis (OA) pathogenesis is increasingly recognized. Notably, 4-octyl Itaconate (OI) has been documented to counteract oxidative stress and inflammatory responses, highlighting its therapeutic potential in OA. This study explored the effects of OI on GPX4 methylation, oxidative stress, and ferroptosis in chondrocytes affected by OA. Our results demonstrated that OI mitigated IL-1n-induced chondrocyte degeneration in a dose-dependent manner. It also suppressed reactive oxygen species (ROS) production and sustained GPX4 expression, thereby attenuating the degenerative impact of IL-1n and Erastin on chondrocytes by curtailing ferroptosis. Moreover, we observed that blocking GPX4 methylation could alleviate IL-1n-induced degeneration, oxidative stress, and ferroptosis in chondrocytes. The regulatory mechanism of OI on GPX4 expression in chondrocytes involved the inhibition of GPX4 methylation. In a mouse model of OA, OI's protective effects against OA were comparable to those of Ferrostatin-1. Thus, OI reduced chondrocyte degeneration, oxidative stress, and ferroptosis by inhibiting GPX4 methylation, offering a novel mechanistic insight into its therapeutic application in OA.

关键词： Certolizumab pegol   TNF-alpha   Leukocyte infiltration   Microglial pyroptosis   Cerebral ischemia-reperfusion injury   Caspase 8  

摘要： The neuroinflammatory response triggered by cerebral ischemia-reperfusion injury (CIRI) is characterized by the upsurge of pro-inflammatory cytokines, including TNF-alpha, IL-1R, and IL-6, which promote leukocyte infiltration and subsequent accumulation in the ischemic zone. This accumulation further intensifies inflammation and aggravates ischemic damage. Certolizumab pegol (CZP), a monoclonal antibody targeting TNF-alpha, is widely used in treating various inflammatory diseases. This study explored the therapeutic potential of CZP in a mouse model of CIRI, induced by middle cerebral artery occlusion (MCAO), focusing on its influence on the microglial inflammatory response. In vitro analyses revealed that CZP markedly inhibits TNF-alpha-stimulated inflammation in primary microglia with an EC50 50 of 1.743 ng/mL. In vivo, , MCAO mice treated with CZP (10 mu g/mouse, i.p.) for 3 days showed reduced infarct volume, partially improved neurological function, and diminished blood-brain barrierdisruption. Additionally, CZP treatment curtailed microglial activation and the release of pro- inflammatory mediators in the early stages of stroke. It also favorably modulated microglial M1/M2 polarization, rebalanced Th17/Treg cells dynamics, and inhibited Caspase-8-mediated GSDMD cleavage, preventing microglial pyroptosis. Collectively, this study described that the treatment with CZP reversed damaging process caused by CIRI, offering a promising therapeutic strategy for the treatment of ischemic stroke.

关键词： diabetes mellitus   Bertholletia excelsa   MAPK-mTOR   metabolic complication   cardiovascular diseases   heart disease  

摘要： Background: The global prevalence of diabetic heart complication has been on the increase, and some of the drugs that are currently used to treat diabetes mellitus (DM) have not been able to mitigate this complication. Objective: This study determines the effect of Brazil nut (Bertholletia excelsa) and metformin on diabetic cardiomyopathy (DCM) in fructose/streptozotocin (STZ)-induced type 2 diabetic rats and also characterizes using Gas Chromatography Mass Spectrophotometry and Fourier Transform Infrared the bioactive compounds in 50% aqueous ethanol extract of Brazil nut. Design: After inducing type 2 DM, 30 male albino Wistar rats were separated into five groups that comprised of six rats per group, and they were treated as follows: groups 1 (Control) and 2 (Diabetic control) rats received rat pellets and distilled water;group 3 (Diabetic + Brazil nut) received rat pellets and Brazil nut extract (100 mg/kg, orally) dissolved in distilled water, group 4 (Diabetic + metformin) received metformin (100 mg/kg, orally) dissolved in distilled water, while group 5 (Diabetic + Brazil nut + metformin) received oral administrations of Brazil nut (100 mg/kg) and metformin (100 mg/kg) dissolved in distilled water. This study lasted for 6 weeks. The dose of Brazil nut used was selected from our pilot study on the minimum therapeutic dose of nase), and heart histology of the diabetic control, which was ameliorated after treatment with Brazil nut and metformin, but their combined treatment was better than the single treatments. cations arising from DM in rats.

关键词： Arthritis, Rheumatoid   Cytokines   T-Lymphocytes  

摘要： Objectives T helper 9 (Th9) cells are recognised for their characteristic expression of the transcription factor PU.1 and production of interleukin-9 (IL-9), which has been implicated in various autoimmune diseases. However, its precise relationship with rheumatoid arthritis (RA) pathogenesis needs to be further *** The expression levels of PU.1 and IL-9 in patients with RA were determined by ELISA, western blotting (WB) and immunohistochemical staining. PU.1-T cell-conditional knockout (KO) mice, IL-9 KO and IL-9R KO mice were used to establish collagen antibody-induced arthritis (CAIA), respectively. The inhibitor of PU.1 and IL-9 blocking antibody was used in collagen-induced arthritis (CIA). In an in vitro study, the effects of IL-9 were investigated using siRNAs and IL-9 recombinant proteins. Finally, the underlying mechanisms were further investigated by luciferase reporter analysis, WB and *** The upregulation of IL-9 expression in patients with RA exhibited a positive correlation with clinical markers. Using CAIA and CIA model, we demonstrated that interventions targeting PU.1 and IL-9 substantially mitigated the inflammatory phenotype. Furthermore, in vitro assays provided the proinflammatory role of IL-9, particularly in the hyperactivation of macrophages and fibroblast-like synoviocytes. Mechanistically, we uncovered that PU.1 and IL-9 form a positive feedback loop in RA: (1) PU.1 directly binds to the IL-9 promoter, activating its transcription and (2) Th9-derived IL-9 induces PU.1 via the IL-9R-JAK1/STAT3 *** These results support that the PU.1-IL-9 axis forms a positive loop in Th9 dysregulation of RA. Targeting this signalling axis presents a potential target approach for treating RA.

关键词： gut microbiota   NKG2A   HLA-E   tumor   immune cells  

摘要： One of major breakthroughs in immunotherapy against tumor is from blocking immune checkpoint molecules on tumor and reactive T cells. The development of CTLA-4 and PD-1 blockage antibodies has triggered to search for additional effective therapeutic strategies. This causes recent findings that blocking the interaction of checkpoint molecule NKG2A in NK and CD8 T cells with HLA-E in tumors is effective in defensing tumors. Interestingly, gut microbiota also affects this immune checkpoint immunotherapy against tumor. Gut microbiota such as bacteria can contribute to the regulation of host immune response and homeostasis. They not only promote the differentiation and function of immunosuppressive cells but also the inflammatory cells through the metabolites such as tryptophan (Trp) and bile acid (BA) metabolites as well as short chain fatty acids (SCFAs). These gut microbiota metabolites (GMMs) educated immune cells can affect the differentiation and function of effective CD8 and NK cells. Notably, these metabolites also directly affect the activity of CD8 and NK cells. Furthermore, the expression of CD94/NKG2A in the immune cells and/or their ligand HLA-E in the tumor cells is also regulated by gut microbiota associated immune factors. These findings offer new insights for the clinical application of gut microbiota in precise and/or personalized treatments of tumors. In this review, we will discuss the impacts of GMMs and GMM educated immune cells on the activity of effective CD8 and NK cells and the expression of CD94/NKG2A in immune cells and/or their ligand HLA-E in tumor cells.

关键词： IL-6 receptor   Mendelian randomization   idiopathic pulmonary fibrosis   Parkinson's disease   type 2 diabetes  

摘要： Background: High interleukin-6 levels correlate with diseases like cancer, autoimmune disorders, and infections. IL-6 receptor inhibitors (IL-6Ri), used for rheumatoid arthritis and COVID-19, may have wider uses. We apply drug-target Mendelian Randomization (MR) to study IL-6Ri's effects. Method: To simulate the effects of genetically blocking the IL-6R, we selected single nucleotide polymorphisms (SNPs) within or near the IL6R gene that show significant genome-wide associations with C-reactive protein. Using rheumatoid arthritis and COVID-19 as positive controls, our primary research outcomes included the risk of asthma, asthmatic pneumonia, cor pulmonale, non-small cell lung cancer, small cell lung cancer, Parkinson's disease, Alzheimer's disease, ulcerative colitis, Crohn's disease, systemic lupus erythematosus, type 1 diabetes, and type 2 diabetes. The Inverse Variance Weighted (IVW) method served as our principal analytical approach, with the hypotheses of MR being evaluated through sensitivity and colocalization analyses. Additionally, we conducted Bayesian Mendelian Randomization analyses to minimize confounding and reverse causation biases to the greatest extent possible. Results: IL-6 inhibitors significantly reduced the risk of idiopathic pulmonary fibrosis (OR= 0.278, 95% [CI], 0.138-0.558;P <0.001), Parkinson's disease (OR = 0.354, 95% CI, 0.215-0.582;P <0.001), and positively influenced the causal relationship with Type 2 diabetes (OR = 0.759, 95% CI, 0.637-0.905;P = 0.002). However, these inhibitors increased the risk for asthma (OR = 1.327, 95% CI, 1.118-1.576;P = 0.001) and asthmatic pneumonia (OR = 1.823, 95% CI, 1.246-2.666;P = 0.002). The causal effect estimates obtained via the BWMR method are consistent with those based on the IVW approach. Similarly, sIL-6R also exerts a significant influence on these *** such as Alzheimer's disease, Crohn's disease, pulmonary heart disease, systemic lupus erythematosus, Type 1 diabetes, Non-small