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关键词： Inflammatory signaling   oxidative stress signaling   immune signaling   myocardial cell injury   elderly  

摘要： Introduction The mutual activations of multiple signaling pathways are the key factors in the development and progression of myocardial cell injuries. Objective This research aimed to compare the different degrees of myocardial injury after coronary stenting, permanent pacemaker implantations, or cardiac radiofrequency ablation and to investigate the effects of the mutual activation of TNF-alpha/NF-kappa B, TLR2/TLR4, and ROS/MDA signaling pathways on myocardial injury in elderly patients after coronary stents or permanent pacemakers or radiofrequency ablation. Methods We determined reactive oxygen species (ROS), malondialdehyde (MDA), toll-like receptor 2 (TLR2), toll-like receptor 4 (TLR4), nuclear factor kappa B (NF-kappa B), tumor necrosis factor-alpha (TNF-alpha) and high-sensitive cardiac troponin T (hs-cTnT) as a marker of myocardial injury in patients. Results The levels of ROS, MDA, TLR2, TLR4, NF-kappa B, TNF-alpha, and hs-cTnT were increased in patients with permanent pacemaker implantations when compared to patients with cardiac radiofrequency ablation (P < 0.01) at 6 months and were further increased in patients with coronary stenting compared to patients with cardiac radiofrequency ablation and permanent pacemaker implantations at 6 months, respectively (P < 0.01). This research confirmed that ROS, MDA, TLR2, TLR4, NF-kappa B, and TNF-alpha predicted myocardial injury severity. Conclusion Oxidative stress (ROS/MDA signaling pathway) may be linked to immune response (TLR2/TLR4 signaling pathway) and pro-inflammatory response (TNF-alpha/NF-kappa B signaling pathway) in myocardial injury, and ROS/MDA signaling may play a dominant role.

关键词： Baculoviruses   gene therapy   inflammation   proliferation   superoxide dismutase 3   tumor necrosis factor-alpha  

摘要： Background Superoxide dismutase 3 (SOD3), recognized as a potent free radical scavenger, exhibits antioxidant, anti-inflammatory, and anti-angiogenic properties. However, the molecular mechanisms underlying the protective effects of SOD3 on the vascular smooth muscle cell during atherosclerosis remain *** This study aimed to investigate the efficacy of the baculovirus expressing SOD3 gene delivery to vascular smooth muscle cells (VSMCs) and investigate whether the overexpression of SOD3 mitigates cell proliferation and migration induced by tumor necrosis factor-alpha (TNF-alpha).Methods A baculoviral vector containing SOD3 cDNA (vAcMBac-CMV-IE-SOD3) was constructed and utilized to deliver the SOD3 gene into primary rat VSMCs. Cells were stimulated with recombinant TNF-alpha, and then cell proliferation and migration were evaluated using the bromodeoxyuridine and wound healing assay. Western blot was used to verify the expression of cell cycle regulators, cellular mediators, and proliferative biomarkers. Zymography, immunofluorescence staining, and ELISA assay were conducted to assess the expression levels of matrix *** The results demonstrated efficient and non-cytotoxic transduction of vAcMBac-CMV-IE-SOD3 in VSMCs. SOD3 overexpression significantly suppressed cell proliferation and motility by inhibiting cell cycle regulators in TNF-alpha-induced cells. TNF-alpha elevated protein levels of phospho-ERK and phospho-Akt were reduced markedly by SOD3-overexpressing. Additionally, SOD3 overexpression attenuated the elevation of MMP-2 and MMP-9, the pro-inflammatory and proliferative biomarkers. Overall, the SOD3 gene delivery exhibited potent anti-proliferation and anti-inflammation effects on TNF-alpha-induced *** An effective SOD3 gene delivery using a recombinant baculoviral vector has been successfully established and is useful for overexpression of the SOD gene family. This approach provides new therapeutic strateg

关键词： Zebrafish   ARRDC3a   SVCV   RLR signaling pathway   Type I IFN  

摘要： Arrestin domain-containing 3 (ARRDC3), a member of the alpha-arrestins family, plays an important regulatory role in host anti-tumor and cellular metabolism by modulating the degradation and transportation of G proteincoupled receptors (GPCRs). However, the function of ARRDC3 in fish remains largely unexplored, particularly in host antiviral response. Here, we identified a paralog of ARRDC3 in teleost, zebrafish ARRDC3a, which was found to be induced by spring viremia of carp virus (SVCV) in vivo and in vitro. Overexpression of ARRDC3a significantly attenuated IFN expression and facilitated SVCV replication, whereas its knockdown inhibited viral proliferation. Furthermore, ARRDC3a overexpression markedly suppressed the IFN response triggered by retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) signaling pathway, and reduced the protein stability of TBK1, MITA, and IRF3. In summary, our findings suggest that zebrafish ARRDC3a acts as a negative regulator of type I IFN production by targeting RLR-associated signaling molecules, thereby promoting SVCV replication in the host. Our study provides novel insights into the biological function of ARRDC3a in fish.

关键词： immune-related adverse events   IL-6   therapeutic potential   immune checkpoint inhibitor-induced inflammatory arthritis  

摘要： The incorporation of immune checkpoint inhibitors (ICIs) into cancer treatment has revolutionized oncology, providing marked advantages in managing various types of cancer. Nevertheless, the increasing use of ICIs has led to the emergence of immune-related side effects, including autoimmune diseases such as inflammatory arthritis. IL-6 signaling is crucial in the development of inflammatory arthritis and is linked to both the benefits and adverse effects of ICIs. The present review summarizes the latest progress in the IL-6 pathway in inflammatory arthritis and discusses the therapeutic potential of IL-6 pathway inhibitors for ICI-induced inflammatory arthritis.

关键词： A2BR   adenosine A2B receptor   ABCA1   ATP-binding cassette subfamily A member 1   ADME   absorption, distribution, metabolism, and excretion   AKAP9   A-kinase anchoring protein 9   AGEs   advanced glycation end-products   AMD   age-related macular disease   AM-ester   acetoxymethyl ester   ANF   anfibatide   Ang II   angiotensin II   ANP   atrial natriuretic peptide   AT-1R   Ang II type 1 receptor   BBB   blood-brain barrier   bFGF   basic fibroblast growth factor   BKCa   Ca2+-activated large conductance K+ channel   BRB   blood-retinal barrier   CaMKII   Ca2+/calmodulin-dependent protein kinase II   cAMP   cyclic adenosine monophosphate   CBD   cAMP-binding domain   CDC25-HD   CDC25 homology domain   CD36   cluster of differentiation 36   CICR   Ca2+-induced Ca2+ release   CI/R   cerebral ischemia/reperfusion   CNG   the cyclic nucleotide-gated channels   CNS   central nervous system   CRIS   cyclic nucleotide receptor involved in sperm function   DEP   Dishevelled/EGL-10/Pleckstrin domain   DP1   prostaglandin D2 receptor 1   DPP   dipeptidyl peptidase   DR   diabetic retinopathy   ECM   extracellular matrix   ECs   endothelial cells   eNOS   endothelial nitric oxide synthase   EP2   E prostanoid receptor 2   EPACs   exchange proteins directly activated by cAMP   ESIs   EPAC-specific inhibitors   FGF2   fibroblast growth factor 2   GEPs   guanine nucleotide exchange factors   GGTase I   geranylgeranyltransferase I   GIP   gastric inhibitory polypeptide   GLP-1   glucagon-like peptide-1   GP   glyco-protein   GPCRs   G-protein coupled receptors   HA   hyaluronan   HCN   the hyperpolarization-activated cyclic nucleotide-gated channels   HDX-MS   hydrogen-deuterium exchange mass spectrometry   HFD   high-fat diet   HIF-1α   hypoxia-inducible factor 1α   HIV   human immunodeficiency virus   HMGB1   high-mobility group box 1   HMPV   human metapneumovirus   HSCs   hematopoietic stem cells   HS   heparan sulfate   HSQC   15N, 1H Heteronuclear Single Quantum Coherence   HTS   high-throughput screening   HUVECs   human umbilical vein endothelial cells   Id1   inhibitor of differentiation 1   iECs   induced endothelial cells   IGFBP-3   insulin-like growth factor binding protein 3   IL   interleukin   iPSC   induced pluripotent stem cell   ISO   isopre  

摘要： Vascular remodeling is a complex process involving the coordinated actions of multiple cellular signaling pathways in various cell types, leading to structural and functional changes in blood vessels. These changes can be adaptive, as in wound healing, or maladaptive, as seen in chronic vascular diseases such as atherosclerosis, hypertension, and retinopathy. Exchange proteins directly activated by cAMP (EPACs) are key players in cAMP-mediated cell signaling, distinct from the more traditionally studied protein kinase A pathway. EPAC proteins are guanine nucleotide exchange factors for the small G pro-teins Rap1 and Rap2. Recent studies have also revealed noncanonical functions of EPAC1 involving the formation of biomolecular condensates. EPAC proteins regulate various cellular processes, including cell adhesion, migration, proliferation, and differentiation. In this review, we discuss the roles of EPACs in vascular remodeling and diseases associated with the process, as well as the potential of EPACs as therapeutic targets for proliferative vascular diseases. Significance Statement: Vascular remodeling is associated with various human diseases, such as atherosclerosis, stroke, and retinopathy. Understanding the roles of exchange proteins directly activated by cAMP signaling in vascular remodeling provides insights into the mechanisms underlying vascular diseases and facilitates the development of targeted therapies. (c) 2025 American Society for Pharmacology and Experimental Therapeutics. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

关键词： C-reactive protein   gastrointestinal cancer   interleukin 10   interleukin 6  

摘要： Gastrointestinal (GI) cancers represent a major global health burden, significantly impacts the digestive system. Recent research has focused on the relationship between interleukin-6 (IL-6), interleukin-10 (IL-10), and C-reactive protein (CRP) to deepen understanding of GI cancer-including esophageal, gastric, pancreatic, hepatobiliary, and colorectal cancers-pathogenesis and to enhance diagnostic and therapeutic strategies. Elevated levels of IL-6, IL-10, and CRP have been associated with advanced disease stages and poor prognosis, underscoring their potential utility as biomarkers for disease progression and outcome prediction. Moreover, these markers appear to modulate the sensitivity of GI cancer cells to chemotherapy, suggesting that their assessment in serum and tissue samples could aid therapeutic decision-making and predict treatment responses. In addition to their diagnostic and prognostic value, IL-6, IL-10, and CRP are being investigated as targets for preventive strategies. These findings highlight the potential role of anti-inflammatory interventions in chemoprevention. Overall, studying the interplay among IL-6, IL-10, and CRP has yielded valuable insights into the molecular mechanisms driving GI cancer development and progression. Continued research is essential to fully elucidate these complex interactions and to translate these findings into effective clinical applications for the management of GI malignancies.

关键词： Methicillin-resistant Staphylococcus aureus   Community-associated methicillin-resistant   Staphylococcus aureus   Social determinants of infectious disease   Bayesian hierarchical modeling   Counterfactual simulation   Mediation analysis   Incarceration   Health disparities   Racial disparities  

摘要： Purpose: Describe inequities in community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) infections and identify social factors contributing to these disparities. Methods: We characterized census tract-level risk factors for CA-MRSA infections in the Cook County Health (CCH) catchment population in Cook County, IL from 2009 to 2022 using hierarchical Poisson regression models. We conducted mediation analyses to estimate a) the total risk attributable to and b) proportion of between-tract disparities in CA-MRSA accounted for by census tract-level inequities in risk factors. Results: CCH patients living in majority Black census tracts in Cook County had double the rate of CA-MRSA infections as compared to CCH patients living in majority white census tracts. Socio-economic indicators such as public transportation use and the presence of homeless shelters in a census tract were associated with CA-MRSA rates in multivariate analyses. However, jail admission rates explained the largest proportion of CA-MRSA burden (30 %) and racial inequities in CA-MRSA incidence (69 %). Discussion: High risks of MRSA infection and colonization have consistently been documented among incarcerated and recently incarcerated individuals. Our results suggest that incarceration may also drive infections among non-incarcerated individuals living in communities with high levels of indirect exposure to jails, especially in majority Black census tracts.

关键词： berberine   pancreatic beta-cells   hormesis   p53 mediated apoptosis pathways   mitochondrial membrane potential  

摘要： Damage to pancreatic beta-cells serves as a critical pathological basis in the progression of diabetes. Berberine (BBR), an isoquinoline alkaloid, potentially protects pancreatic beta-cells, exerting hypoglycemic effects. However, the dose-response relationship and the specific protective mechanism are still unclear. Hormesis is a self-protective response triggered by mild stimuli and has been reported to determine the extent to which phytochemicals can combat diabetes. In this study, we found that BBR exhibited a typical hormetic effect in IL-1 beta-induced damage to pancreatic beta-cells, where low doses of BBR protect cells while high doses aggravate the damage. A model-based approach was used to describe dose-response relationships, as well as to detect and estimate hormetic effects. In addition, the regulatory effect of BBR in preventing apoptosis in pancreatic beta-cells was confirmed, and an appropriate dose of BBR stabilized the mitochondrial membrane potential and prevented DNA damage. Moreover, the results showed that the hormetic effect of BBR was closely related to p53 and apoptosis pathways. To further investigate the role of the p53-mediated apoptosis pathways, our study interfered with the p53 pathway, resulting in the attenuation of the hormetic effect of BBR. These results introduce the concept of hormesis to study the biphasic effects of berberine on damaged pancreatic beta-cells, while also exploring the relationship between the hormetic mechanism of BBR and the p53-mediated apoptosis pathway. These findings provide clues to explore the potential application of BBR in treating diabetes.

关键词： Non-HLA antibodies   Threshold cut off   Sensitization  

摘要： Background: Measuring non-HLA antibodies is a potentially important tool in assessing allograft dysfunction and needs to be correlated with clinical outcomes. Thus, determining the antibody distribution in healthy populations is important before correlating with clinical events. Using male blood donors, we selected a low immunological risk control cohort. Methods: We analyzed samples from 92 male, non-transfused blood donors (donors) to assess the detection of antibodies in a normal population cohort using a non-HLA 33 antigen multiplex commercial assay. Results: At manufacturer's suggested cutoff threshold (COT) of 75 % percentile, no donors had negative results and at 95 % percentile only three donors were negative across all 33 antigens. At each of the manufacturer's COT, the median (IQR) number positive antibody bead tests per donor was 13 (10-17), 11 (8-13) and 7 (5-10) at 75th, 85th and 95th percentile COT, respectively. There was poor correlation between manufacturer's COT and locally generated COT (range r = 0.520 to 0.595). The percentage of donors who had three or more positive antibody bead tests was: 98.9 % at 75th COT;95.7 % at 85th COT and 93.5 % at 95th COT. Conclusions: Considering the high proportion of positive results in a low immunological risk cohort, application of non-HLA antibody measurement in a diseased cohort is not optimal, and difficult to correlate with clinical events. Further studies to determine normal detection rates are needed for assay COT and clinical application in diseases.

关键词： autoimmunity   LADA   latent autoimmune diabetes in adults   T1D   type 1 diabetes   IFN-alpha   neutralizing antibody  

摘要： Context Autoantibodies against interferon-alpha (AAb-IFN-alpha) might be associated with the less aggressive autoimmunity in latent autoimmune diabetes in adults (LADA) compared to early-onset type 1 diabetes (T1D).Objective To investigate the presence and clinical relevance of the positivity to AAb-IFN-alpha in people with LADA compared to *** Design and Methods Serum levels of AAb-IFN-alpha isoforms were measured using a cell-based approach in 41 subjects with LADA and 90 subjects with *** The primary and secondary outcomes were the difference between LADA and T1D in the proportion of participants testing positive for autoantibodies (AAb) against >= 2 and against 3 interferon-alpha (IFN-alpha) isoforms, respectively. The presence and levels of AAb-IFN-alpha were related to clinical and biochemical features of participants with *** Seven (17.1%) and 5 (12.2%) participants with LADA and 3 (3.3%) and 0 participants with T1D showed positivity for AAb against >= 2 and 3 IFN-alpha isoforms (P = .011 and P = .0025, respectively). Fasting blood glucose and hemoglobin A1c levels were numerically lower among people with LADA testing positive for AAb against >= 2 IFN-alpha isoforms than among those who were either negative or positive for AAb against 1 IFN-alpha isoform. Among LADA-positive individuals, levels of AAb-IFN-alpha 2 isoform were inversely correlated with glutamic acid decarboxylase antibodies levels (rho = -0.513;P = .025).Conclusion Autoimmunity against IFN-alpha is peculiar to autoimmune diabetes and appears to be distinctive to its slowly progressive forms. Understanding the underlying molecular mechanisms and clinical significance of this novel autoimmunity could lead to the development of new therapeutic strategies in autoimmune diseases, advancing personalized medicine.