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关键词： Inflammatory cytokine   Angiogenesis   Systems biology   Intracellular signaling   Mathematical model   Computational model   PAD   Endothelial cells   In vitro assay  

摘要： Many diseases associated with angiogenesis involve inflammatory cytokine mediated responses. Targeting angiogenesis as a predominant strategy has shown limited effects in many contexts including peripheral arterial disease (PAD). One potential reason for the unsuccessful outcome is the interdependence between inflammation and angiogenesis. Inflammation-based therapies primarily target inflammatory cytokines such as interleukin-6 (IL-6) in T cells, macrophages, cancer cells, muscle cells. However, the mechanism of how these cytokines act on endothelial cells under PAD-specific hypoxia serum starvation (HSS) conditions are not well understood. Thus, we focus on one of the major inflammatory cytokines, IL-6, mediated intracellular signaling in endothelial cells under HSS conditions by conducting relevant in vitro experiments on human umbilical vein endothelial cells (HUVECs) and developing an experimentally validated computational model. Our model quantitatively characterized the effects of IL-6 classic and trans-signaling in activating the signal transducer and activator of transcription 3 (STAT3), phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt), and mitogen-activated protein kinase (MAPK) signaling to phosphorylate STAT3, extracellular regulated kinase (ERK) and Akt, respectively in endothelial cells under HSS condition. The trained and validated experiment-based computational model was used to characterize the dynamics of phosphorylated STAT3 (pSTAT3), Akt (pAkt), and ERK (pERK) in response to IL-6 classic and/or trans-signaling under HSS conditions. The model predicts that IL-6 classic and trans-signaling induced responses are dose dependent. In addition, IL-6 trans-signaling induces greater downstream signaling responses compared to classic signaling and plays a dominant role in the overall effects due to a tighter binding of the ligand and receptors and an abundant supply of soluble receptor sIL-6R because of the experimental setting. Moreover, our mode

关键词： Huaier   Colorectal cancer   TME   Immunotherapy   MHC I  

摘要： Background: Colorectal cancer (CRC) remains a leading cause of cancer-related mortality, primarily due to its immunosuppressive microenvironment that facilitates immune evasion and resistance to therapy. Although the traditional Chinese medicine Trametes robiniophila Murr (Huaier) has been shown to exert anti-tumor effects, its immunomodulatory potential in CRC and mechanistic interaction with immune checkpoints have not been investigated. Results: Treatment with Huaier significantly improved overall survival in CRC patients (HR=0.682, 95 % CI=0.576-0.809) and reduced tumor burden in both AOM/DSS-induced colitis-associated cancer and subcutaneous models. Notably, Huaier restored intestinal barrier integrity and reprogramed the tumor immune landscape by upregulating the expression of major histocompatibility complex class I (MHC I), which enhanced CD8+ T cell infiltration and cytolytic activity while depleting regulatory T cells. Mechanistically, Huaier activated the STAT1-MHC I pathway, leading to the upregulation of MHC I antigen presentation components, which facilitates the effective recognition of neoantigens by cytotoxic T cells. Crucially, in patient-derived organoids, Huaier synergized with anti-PD-1 therapy, enhancing T cell cytotoxicity. A subcutaneous tumor model was also developed to assess the synergistic effects of Huaier and anti-PD-1, demonstrating that combination therapy exhibited superior efficacy compared to monotherapy.

关键词： Cell death  

摘要： Gaining attention of immunomodulatory therapies has led to the investigation of natural protein Allium sativum lectin (ASL) for anti-cancer properties. Current investigation explores the immunomodulatory mediated anticancer effect of ASL against lung cancer. The ASL accelerates immune cell proliferation;in particular elicits "M1"-macrophage polarization of THP-1 cells, by elevating expression of CD86, interleckin-12 (IL-12) and interferon-γ (IFN-γ). Conditioned medium from ASL-treated"M1"-polarized THP-1 macrophages (ASL-CM) demonstrated significant cytotoxicity against lung cancer cells. Unraveling the mechanism, revealed that IFN-γ modulates tumor microenvironment (TME) by generating reactive oxygen species (ROS), intern leading to activation of Janus activates kinase/signal transducer and activator of transcription 1 (JAK1/STAT1) as well as ataxia-telangiectasia mutated kinase/checkpoint kinase 2 (ATM/CHK2) signalling pathway. Both the pathway converges at p53/PUMA (p53 upregulated modulator of apoptosis) to activate its downstream apoptotic protein BCL-2-associated X protein/Bcl-2 antagonist/killer (BAX, BAK), cytochrome-c and caspases to induce cell death. The in-vivo experimental results with Lewis lung carcinoma (LLC) mice model, further validated ASL mediated immunomodulatory role by regressing lung tumor with enhanced survival rate. Polarization of macrophage into "M1" phenotype were much more supportive. Reduction of tumor associated macrophages (TAM) was validated with reduced secretion of IL-1β & IL-10 and enhanced secretion IFN-γ & IL-12. The ASL activated JAK1/STAT1 and ATM/CHK2/p53 pathways, converge to induce cell death signalling was also evident. Overall ASL initiates dual signalling cascades by establishing the cross-talk between two death signalling pathways through immunomodulation. The findings suggest that ASL could be translated to possible option for combinatorial cancer immunotherapy, by reprogramming immune responses. © 2025

关键词： Cryptosporidium parvum   Ileocecal adenocarcinoma   Niclosamide   Wnt/beta-catenin signaling   STAT3 signaling   Intrinsic apoptosis  

摘要： Cryptosporidiosis, a protozoal disease caused by Cryptosporidium parvum (C. parvum), is a globally emerging waterborne infection leading to moderate to severe diarrhea, particularly in immunocompromised individuals. Emerging evidence proposes a potential correlation between chronic infection and digestive cancers, though the underlying mechanisms remain unclear. Therapeutic options are minimal, with nitazoxanide (NTZ) being the only drug available, despite its constrained effectiveness. Niclosamide (NICLO), an anthelmintic drug, exhibits antiparasitic properties and modulates oncogenic signaling pathways, making it a promising candidate for dual therapeutic effects. This study investigated NICLO's efficacy against chronic C. parvum infection and its potential to prevent ileocecal adenocarcinoma development in immunocompromised mice. Mice were immunosuppressed using dexamethasone, infected with C. parvum oocysts, and administered NTZ or NICLO. NICLO administration significantly reduced parasite burden by 90 %, restored histopathological alterations, and suppressed C. parvuminduced inflammation, as evidenced by suppressed IL-6 and IL-22 levels and STAT3 activation. NICLO also counteracted the antiapoptotic effects of infection by downregulating Bcl-2 and upregulating Bax and cleaved caspase-3 levels. Moreover, NICLO deactivated the Wnt/beta-catenin pathway and its target genes (survivin, c-myc, and cyclin D) while elevating p53 levels. These findings highlight NICLO's dual therapeutic potential, which effectively targets C. parvum infection and mitigates its tumorigenic effects by disrupting key signaling pathways involved in ileocecal cancer progression. This study provides novel insights into NICLO's chemotherapeutic efficacy in managing cryptosporidiosis and its associated oncogenic potential.

关键词： Ferulic acid ethyl ester   Inflammatory adipocytes   Atrial arrhythmias   Secretome   Electrical remodeling  

摘要： Inflammatory epicardial adipose tissue impacts cardiomyocytes, creating an arrhythmogenic substrate. This study examines the effects of tumor necrosis factor-alpha (TNF-alpha)-stimulated adipocytes on atrial cardiomyocytes and the protective role of ferulic acid ethyl ester (FAEE). TNF-alpha-stimulated 3T3-L1-derived adipocytes were utilized and analyzed. Conditioned media from TNF-alpha-stimulated and TNF alpha/FAEE-cotreated adipocytes were examined. Biochemical and electrophysiological studies were performed on HL-1 myocytes exposed to these media. TNF-alpha stimulation increased the levels of the proinflammatory proteins monocyte chemoattractant protein-1 (MCP-1) and interleukin-6 (IL-6) in the adipocytes and conditioned media. The ratio of phosphorylated-NF-kappa B (pNF-kappa B) to NF-kappa B was higher in TNF-alpha-stimulated adipocytes than in the control group. While the levels of IL-6, MCP-1, and pNF-kappa B induced by TNF alpha stimulation in the adipocytes remained unchanged with FAEE cotreatment, FAEE increased the protein levels of adiponectin in the adipocytes and the conditioned medium. FAEE also upregulated the protein levels of heme-oxygenase 1 (HO-1) and nuclear translocation of nuclear factor-erythroid 2-related factor-2 (Nrf2). The elevated adiponectin levels observed in FAEE-cotreated adipocytes were abolished following treatment with SnPP, a HO-1 inhibitor. The elevated levels of Ca2 + /calmodulin-dependent protein kinase II and connexin 43, and the enhanced reverse mode Na+ -Ca2+ exchanger current observed in HL-1 myocytes cultured in TNF-alpha-conditioned medium were abolished when these cardiomyocytes were cultured in TNF alpha/FAEE-conditioned medium. FAEE modulates the electrical remodeling of HL-1 cardiomyocytes induced by the secretome of TNF-alpha-stimulated adipocytes, possibly through Nrf2/HO-1 signaling and adiponectin expression. These findings demonstrate FAEE's cardioprotective mechanisms and therapeutic potential. (c) 2025 The Au

关键词： ME/CFS   KIR   HLA   Association  

摘要： Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic and debilitating disease with unknown cause. Involvement of infection and immune dysregulation has been suggested, including changes in immune cell subsets and abnormal functions of natural killer (NK) cells. The regulatory NK cell receptors, killer cell immunoglobulin-like receptors (KIR) have previously been investigated in small cohorts of ME/CFS patients with conflicting results regarding gene content. Here, we studied KIR genes also at the allelic level using high-resolution sequencing, in 418 ME/CFS patients and 473 healthy controls. Human leukocyte antigen (HLA) class I genotype data were included for KIR ligand annotation. Our healthy control data represent KIR frequencies for a Norwegian population, which have not previously been reported. We found no association between ME/CFS and KIR gene content or copy number variations. However, our data suggested that specific KIR alleles at loci encoding inhibitory receptors were associated with ME/CFS, which was further supported by allelic haplotype analyses. Three alleles were more frequent in patients, i.e. KIR3DL3*002 (OR = 1.43, 95 % CI (1.09-1.86), p = 0.009), KIR3DL1*020 (OR = 2.20, 95 % CI (1.19-4.06), p = 0.01) and KIR3DL2*009 (OR = 1.56, 95 % CI (1.09-2.23), p = 0.01), while two alleles had a reduced patient frequency, i.e. KIR3DL3*013 (OR = 0.60, 95 % CI (0.42-0.86), p = 0.005) and KIR3DL2*010 (OR = 0.46, 95 % CI (0.30-0.71), p = 0.0005). Our data support an involvement of NK cells in ME/CFS.

关键词： Bovine mastitis   Ferroptosis   LPS   circ_HOMER3   TNF/MAPK9  

摘要： Bovine mastitis is a prevalent inflammatory disease in dairy cattle, involving dysregulated inflammatory responses and cell death in bovine mammary epithelial cells (bMECs), including ferroptosis. The regulatory roles of circular RNAs (circRNAs) in this process remain largely unexplored. This study investigated the function of circ_HOMER3 in lipopolysaccharide (LPS)-induced inflammatory injury in bMECs. Using siRNA-mediated knockdown and circ_HOMER3 overexpression models, combined with qPCR, Western blot, ELISA, and TMT proteomics, we demonstrated that circ_HOMER3 exacerbates inflammation by promoting I kappa B alpha degradation and p65 nuclear translocation, indicating activation of the TLR4/MyD88/NF-kappa B pathway, leading to significant upregulation of pro-inflammatory cytokines (IL-6, IL-8, IL-1 beta). Concurrently, circ_HOMER3 impacted the JAK1/ STAT1 pathway, correlating with suppressed cell proliferation and induced apoptosis. Proteomic analysis revealed that circ_HOMER3 modulates the TNF/MAPK signaling axis and ferroptosis pathway, associated with reduced MAPK9 (JNK2) expression and downregulation of the key ferroptosis factor NCOA4. Silencing circ_HOMER3 mitigated LPS-induced effects, reducing Fe2+/Fe3+ accumulation and lipid peroxidation markers (MDA, LPO), while enhancing antioxidant indicators (GSH, SOD). Collectively, these results indicate that circ_HOMER3 acts as a key regulator influencing multiple critical pathways (TLR4/NF-kappa B, JAK/STAT, TNF/ MAPK) to coordinate inflammatory injury and cell death processes, including ferroptosis, in bMECs. These findings identify circ_HOMER3 as a potential molecular target and provide new insights for developing therapeutic strategies against bovine mastitis.

关键词： Autoinflammatory disorders   Immunology   Medical dermatology   Schnitzler syndrome   Urticaria  

摘要： Schnitzler syndrome (SchS) is a rare autoinflammatory condition characterized by chronic urticaria and systemic inflammation. Obligate diagnostic criteria include the presence of a monoclonal IgM or IgG band, with nearly all cases demonstrating a prompt response to IL-1 blockade. Recently, "Schnitzler-like" cases without a paraprotein have been reported. Although the exact nature of their relation to the original eponymous syndrome remains unclear, these cases share similar clinical features and response to IL-1 inhibition. Diagnostic delay is common in autoinflammatory syndromes, and the need to recognize potentially emerging cases is important. We present the case of a male aged 47 years with refractory urticaria, joint pain, and systemic inflammation resembling SchS but without detectable paraprotein, consistent with recently proposed paraprotein-negative IL-1-mediated inflammatory dermatosis (PANID). After failing conventional therapies, the patient achieved rapid and sustained remission with IL-1 blockade. This case underscores the importance of recognizing autoinflammatory syndromes, including PANID, in patients with refractory urticaria with associated inflammatory features. It also highlights the importance of a therapeutic trial of IL-1 inhibition.

关键词： Baicalein   EAM   Macrophages   Chemotactic   Th1 cells   TNF-alpha   CCR2  

摘要： Myocarditis refers to localized or diffuse inflammatory lesions of the myocardium. Experimental autoimmune myocarditis (EAM) in mice is commonly utilized as an animal model for studying the pathogenesis of myocarditis. Baicalein (BAI), the main active component extracted from Scutellaria baicalensis root, has been proven to possess diverse effects such as anti-inflammatory, anti-tumor, and antioxidant activities. However, further investigation is warranted to elucidate the mechanism of action underlying BAI's efficacy in EAM. The aim of this study is to the potential of BAI in combination with TNF-alpha to downregulate the TNF-alpha/TNFR1-AP-1 signaling pathway. Furthermore, we will explore whether BAI exhibits an inhibitory effect on the CCL2/CCR2-ROCK1 signaling pathway. In this study, we employed the EAM animal model to investigate the inhibitory effect of BAI on macrophage and Th1 cell chemotaxis towards cardiac tissue in EAM mice. Techniques such as HE staining, immunofluorescence, and other methods were utilized for assessment. Additionally, computer-simulated molecular docking, Streptavidin pull-down, and co-immunoprecipitation experiments were conducted to explore the potential binding of BAI with TNF-alpha and CCR2. Furthermore, real-time quantitative polymerase chain reaction (qPCR), western blotting, and flow cytometry were employed to elucidate the impact of BAI on the TNF-alpha/TNFR1-CCL2/CCR2 signaling pathway. BAI suppressed the expression of chemokine CCL2 in EAM mouse myocardial tissue and attenuated the infiltration of macrophages and Th1 cells. In vitro, BAI exhibited binding affinity to TNF-alpha, leading to downregulation of the TNF-alpha/TNFR1-AP-1 signaling pathway and subsequent inhibition of CCL2 secretion by macrophages and vascular endothelial cells. Additionally, BAI demonstrated binding capability to CCR2, resulting in downregulation of the CCL2/CCR2-ROCK1 pathway and consequent inhibition of chemotactic migration of macrophages and Th1

关键词： Aspergillus fumigatus   Mycobacterium tuberculosis   TNF   IL-1 beta   NOD2   NADPH oxidase complex  

摘要： Aspergillus fumigatus may cause infections in individuals with underlying lung damage, such as those with pulmonary tuberculosis (TB). Simultaneous exposure to A. fumigatus and Mycobacterium tuberculosis may worsen lung tissue damage, but the combined immune response to these pathogens has not yet been fully characterized. Peripheral blood mononuclear cells (PBMCs) from healthy volunteers were stimulated with A. fumigatus conidia, M. tuberculosis H37Rv lysate, or both combined. TNF and IL-1 beta were measured from culture supernatants. The role of different pattern recognition receptors (PRRs) important for the recognition of both pathogens were explored by using PRR inhibitors and PBMCs from donors deficient in certain pathways. A. fumigatus and M. tuberculosis synergistically induced TNF and IL-1 beta release by PBMCs, and this response was independent of TLR2 and dectin-1. We found that the synergy is regulated through distinct intracellular pathways. The activation of the intracellular receptor NOD2 by M. tuberculosis and NADPH oxidase complex-dependent ROS production triggered by A. fumigatus mediate TNF but not IL-1 beta synergy. Together, these findings indicate that A. fumigatus and M. tuberculosis jointly exacerbate proinflammatory responses. This may help to explain the persistent inflammation and immunopathology observed in patients with concurrent TB and aspergillosis.