PMN surface expression of RPSA also alleviates local inflammation and tissue injuries by inhibiting secretion of the pro-inflammatory cytokines, TNF-α and IL-6. Moreover, the single-cell BBB model showed that RPSA disrupts BBB integrity by downregulating expression of tight junction-associated membrane proteins on PMNs. Taken together, our data suggest that PMN-surface expression of RPSA is a double-edged sword. RPSA+ PMN owns a stronger ability of bacterial cleaning and weakens inflammatory cytokines release which are useful to anti-infection, but does hurt BBB. Partly, RPSA+ PMN may be extremely useful to control the infection as a therapeutic cellular population, following novel insights into the special PMN population.Current strategies for improving protective response to influenza vaccines during immunosenescence do not adequately protect individuals over 65 years of age. Here, we used an aged mouse model to investigate the potential of co-delivery of influenza vaccine with the recently identified combination of a saponin adjuvant Quil-A and an activator of the STING pathway, 2'3 cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) via dissolving microneedle patches (MNPs) applied to skin. We demonstrate that synergy between the two adjuvant components is observed after their incorporation with H1N1 vaccine into MNPs as revealed by analysis of the immune responses in adult mice. Aged 21-month-old mice were found to be completely protected against live influenza challenge after vaccination with the MNPs adjuvanted with the Quil-A/cGAMP combination (5 µg each) and demonstrated significantly reduced morbidity compared to the observed responses in these mice vaccinated with unadjuvanted MNPs. Analysis of the lung lysates of the surviving aged mice post challenge revealed the lowest level of residual inflammation in the adjuvanted groups. We conclude that combining influenza vaccine with a STING pathway activator and saponin-based adjuvant in MNPs is a novel option for skin vaccination of the immunosenescent population, which is at high risk for influenza.We report here a patient with stage IV mucosal melanoma treated with dual immune checkpoint inhibitor (ICI) therapy (Nivolumab/Ipilimumab) who experienced rapid disease progression and metastatic spread within three weeks of first infusion. Surprisingly, this patient also developed fulminant myocarditis within the same time frame. Immunohistochemical staining of the primary tumor and a metastatic omental lesion revealed robust CD8+ PD-1+ T cell infiltration after ICI treatment, as would be expected following immune activation. However, the CD8+ T cell infiltrate was largely negative for both Granzyme B and TIA-1, suggesting these T cells were not capable of effective tumor lysis. We discuss the possibility that heightened pro-inflammatory T cell activity (rather than tumor-directed cytolytic activity) was induced by anti-PD-1 and anti-CTLA-4, which could have provoked both rapid tumor resistance mechanisms and myocarditis. This case highlights the fact that the mere presence of tumor infiltrating lymphocytes (TILs) does not necessarily correlate to ICI response and that additional functional markers are necessary to differentiate between inflammatory and cytolytic CD8+ TILs.Pathogenic intestinal bacteria lead to significant disease in humans. Here we investigated the role of the multifunctional protein, Apurinic/apyrimidinic endonuclease 1 (APE1), in regulating the internalization of bacteria into the intestinal epithelium. Intestinal tumor-cell lines and primary human epithelial cells were infected with Salmonella enterica serovar Typhimurium or adherent-invasive Escherichia coli. The effects of APE1 inhibition on bacterial internalization, the regulation of Rho GTPase Rac1 as well as the epithelial cell barrier function were assessed. Increased numbers of bacteria were present in APE1-deficient colonic tumor cell lines and primary epithelial cells. Activation of Rac1 was augmented following infection but negatively regulated by APE1. Pharmacological inhibition of Rac1 reversed the increase in intracellular bacteria in APE1-deficient cells whereas overexpression of constitutively active Rac1 augmented the numbers in APE1-competent cells. Enhanced numbers of intracellular bacteria resulted in the loss of barrier function and a delay in its recovery. Our data demonstrate that APE1 inhibits the internalization of invasive bacteria into human intestinal epithelial cells through its ability to negatively regulate Rac1. This activity also protects epithelial cell barrier function.Acute pancreatitis (AP) is characterized by disordered inflammation of the pancreas, and the underlying mechanisms remain unclear. Purinergic signaling plays crucial roles in initiating and amplifying inflammatory signals. Recent evidence reveals that targeting dysregulated purinergic signaling is promising for treating inflammation-associated diseases. To explore the potential involvement of purinergic signaling in AP, we investigated the expression profiles of purinergic signaling molecules in human and mouse pancreas tissues. Results showed that purinergic receptor P2RX1 was among the most highly expressed genes in both human and mouse pancreas tissues. Genetic ablation or specific antagonism of P2RX1 markedly alleviated inflammatory responses in caerulein-induced AP mice. Bone marrow chimeras and adoptive transfer studies revealed that neutrophil-derived P2RX1 contributed to the inflammatory responses in AP. Further studies demonstrated that P2RX1 promoted neutrophil activation by facilitating glycolytic metabolism. Therefore, our study indicates that purinergic receptor P2RX1 may be a potential therapeutic target to treat disordered inflammation in AP.Streptococcus mutans converts extracellular sucrose (Suc) into exopolysaccharides (EPS) by glucosyl-transferase and fructosyl-transferase enzymes and internalizes Suc for fermentation through the phosphotransferase system (PTS).  https://www.selleckchem.com/products/sumatriptan.html  Here, we examined how altering the routes for sucrose utilization impacts intracellular polysaccharide [IPS; glycogen, (glg)] metabolism during carbohydrate starvation. Strain UA159 (WT), a mutant lacking all exo-enzymes for sucrose utilization (MMZ952), and a CcpA-deficient mutant (∆ccpA) were cultured with sucrose or a combination of glucose and fructose, followed by carbohydrate starvation. At baseline (0h), and after 4 and 24h of starvation, cells were evaluated for mRNA levels of the glg operon, IPS storage, glucose-1-phosphate (G1P) concentrations, viability, and PTS activities. A pH drop assay was performed in the absence of carbohydrates at the baseline to measure acid production. We observed glg operon activation in response to starvation (p less then 0.05) in all strains, however, such activation was significantly delayed and reduced in magnitude when EPS synthesis was involved (p less then 0.