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yd88/nf-κb pathways. Taken together, these findings indicated that FoxO3 may play important roles in liver immune responses to LPS in turbot and the research of FoxO3 in liver immunity enriches the studies on immune regulation, and provides theoretical basis and molecular targets for solving liver inflammation and liver injury in fish.Macrophages play an important role in the host defense mechanism. In response to infection, macrophages activate a genetic program of pro-inflammatory response to kill any invading pathogen, and initiate an adaptive immune response. We have identified RUVBL2 - an ATP-binding protein belonging to the AAA+ (ATPase associated with diverse cellular activities) superfamily of ATPases - as a novel regulator in pro-inflammatory response of macrophages. Gene knockdown of Ruvbl2, or pharmacological inhibition of RUVBL1/2 activity, compromises type-2 nitric oxide synthase (Nos2) gene expression, nitric oxide production and anti-bacterial activity of mouse macrophages in response to lipopolysaccharides (LPS). RUVBL1/2 inhibitor similarly inhibits pro-inflammatory response in human monocytes, suggesting functional conservation of RUVBL1/2 in humans. Transcriptome analysis further revealed that major LPS-induced pro-inflammatory pathways in macrophages are regulated in a RUVBL1/2-dependent manner. Furthermore, RUVBL1/2 inhibition significantly reduced the level of histone H3K4me3 at the promoter region of Nos2 and Il6, two prototypical pro-inflammatory genes, and diminished the recruitment of NF-kappaB to the corresponding enhancers. Our study reveals RUVBL1/2 as an integral component of macrophage pro-inflammatory responses through epigenetic regulations, and the therapeutic potentials of RUVBL1/2 inhibitors in the treatment of diseases caused by aberrant activation of pro-inflammatory pathways.The ability to use large doses of vitamin D3 (D3) to chronically treat autoimmune diseases such as rheumatoid arthritis (RA) is prohibitive due to its calcemic effect which can damage vital organs. Cytochrome P450scc (CYP11A1) is able to convert D3 into the noncalcemic analog 20S-hydroxyvitamin D3 [20S(OH)D3]. We demonstrate that 20S(OH)D3 markedly suppresses clinical signs of arthritis and joint damage in a mouse model of RA. Furthermore, treatment with 20S(OH)D3 reduces lymphocyte subsets such as CD4+ T cells and CD19+ B cells leading to a significant reduction in inflammatory cytokines. The ratio of T reg cells (CD4+CD25+Foxp3+ T cells) to CD3+CD4+ T cells is increased while there is a decrease in critical complement-fixing anti-CII antibodies. Since pro-inflammatory cytokines and antibodies against type II collagen ordinarily lead to destruction of cartilage and bone, their decline explains why arthritis is attenuated by 20(OH) D3. These results provide a basis for further consideration of 20S(OH)D3 as a potential treatment for RA and other autoimmune disorders.PTX3 is a soluble pattern recognition molecule (PRM) belonging to the humoral innate immune system, rapidly produced at inflammatory sites by phagocytes and stromal cells in response to infection or tissue injury. PTX3 interacts with microbial moieties and selected pathogens, with molecules of the complement and hemostatic systems, and with extracellular matrix (ECM) components. In wound sites, PTX3 interacts with fibrin and plasminogen and favors a timely removal of fibrin-rich ECM for an efficient tissue repair. Idiopathic Pulmonary Fibrosis (IPF) is a chronic and progressive interstitial lung disease of unknown origin, associated with excessive ECM deposition affecting tissue architecture, with irreversible loss of lung function and impact on the patient's life quality. Maccarinelli et al. recently demonstrated a protective role of PTX3 using the bleomycin (BLM)-induced experimental model of lung fibrosis, in line with the reported role of PTX3 in tissue repair. However, the mechanisms and therapeutic potential of PTX3 in IPF remained to be investigated. Herein, we provide new insights on the possible role of PTX3 in the development of IPF and BLM-induced lung fibrosis. In mice, PTX3-deficiency was associated with worsening of the disease and with impaired fibrin removal and subsequently increased collagen deposition. In IPF patients, microarray data indicated a down-regulation of PTX3 expression, thus suggesting a potential rational underlying the development of disease. Therefore, we provide new insights for considering PTX3 as a possible target molecule underlying therapeutic intervention in IPF.Antibiotic-resistant bacterial pathogens have become a serious threat worldwide. One of these pathogens is methicillin-resistant Staphylococcus aureus (MRSA), a major cause of skin and soft tissue infections. In this study we identified a strain of Staphylococcus equorum producing a substance with high antimicrobial activity against many Gram-positive bacteria, including MRSA. By mass spectrometry and whole genome sequencing the antimicrobial substance was identified as the thiopeptide bacteriocin micrococcin P1 (MP1). Based on its properties we developed a one-step purification protocol resulting in high yield (15 mg/L) and high purity (98%) of MP1. For shorter incubation times (5-7 h) MP1 was very potent against MRSA but the inhibitory effect was overshadowed by resistance development during longer incubation time (24h or more). To overcome this problem a synergy study was performed with a number of commercially available antibiotics. Among the antibiotics tested, the combination of MP1 and rifampicin gave the best synergistic effect, with MIC values 25 and 60 times lower than for the individual drugs, respectively. To assess the therapeutic potential of the MP1-rifampicin combination, we used a murine skin infection model based on the use of the multidrug-resistant luciferase-tagged MRSA strain Xen31. As expected, neither of the single antimicrobials (MP1 or rifampicin) could eradicate Xen31 from the wounds. By contrary, the MP1-rifampicin combination was efficient not only to eradicate but also to prevent the recurrence of Xen31 infection. Furthermore, compared to fucidin cream, which is commonly used in skin infection treatments, MP1-rifampicin combination was superior in terms of preventing resistance development. Our results show that combining MP1, and probably other thiopeptides, with antibiotics can be a promising strategy to treat SSTIs caused by MRSA and likely many other Gram-positive bacteria.Graft-versus-host disease (GVHD), especially steroid-refractory GVHD, remains a life-threatening complication after hematopoietic stem cell transplantation (HSCT). The effect of the JAK1/2 kinase inhibitor ruxolitinib on treating steroid-refractory acute GVHD has been verified by the REACH1/2 study; however, its safety and efficacy in patients with steroid-refractory chronic GVHD (SR-cGVHD) remain unclear. In this retrospective study, 70 patients received ruxolitinib as a salvage therapy for SR-cGVHD. Twenty-four weeks after ruxolitinib treatment, the overall response rate (ORR) was 74.3% (52/70), including 34 patients who achieved complete remission (CR) and 18 who achieved partial remission (PR). The main adverse event was cytopenia, which occurred in 51.4% (36/70) of patients. After ruxolitinib treatment, the percentage of CD4 cells increased from 18.20% to 23.22% (P less then 0.001), while the percentages of NK (CD16+CD56+) cells and regulatory T cells (CD4+CD127 ± CD25+) decreased (P less then 0.001, P linued their ruxolitinib doses. Collectively, our results suggest that ruxolitinib is potentially a safe and effective treatment for SR-cGVHD.Neutrophils are the most abundant leukocytes in human peripheral blood, comprising about 70% of all leukocytes. They are regarded as the first line of defense of the innate immune system, but neutrophils have also the ability of regulating the adaptive immune response. Recently, However, multiple phenotypes and functional states of neutrophils have been reported, particularly in inflammation, autoimmunity, and cancer. One possible subtype of neutrophils, the so-called low-density neutrophils (LDN) is found among mononuclear cells (MNC), monocytes and lymphocytes, after separating the leukocytes from blood by density gradient centrifugation. LDN increase in numbers during several pathological conditions. However, LDN present in healthy conditions have not been investigated further. Therefore, in order to confirm the presence of LDN in blood of healthy individuals and to explore some of their cellular functions, neutrophils and MNC were isolated by density gradient centrifugation. Purified neutrophils were further characterized by multicolor flow cytometry (FACS) and then, using the same FACS parameters cells in the MNC fraction were analyzed. Within the MNC, LDN were consistently found. These LDN had a normal mature neutrophil morphology and displayed a CD10+, CD11b+, CD14low, CD15high, CD16bhigh, CD62L+, CD66b+, and CXCR4+ phenotype. MF-438 in vivo These LDN had an enhanced reactive oxygen species (ROS) production and increased phagocytic capacity and were able to produce neutrophil extracellular traps (NET) similarly to neutrophils. These data confirm the presence of a small number of LDN is blood of healthy individuals and suggest that these LDN represent mature cells with a primed phenotype.Plant polyphenols are rich sources of natural anti-oxidants and prebiotics. After ingestion, most polyphenols are absorbed in the intestine and interact with the gut microbiota and modulated metabolites produced by bacterial fermentation, such as short-chain fatty acids (SCFAs). Dietary polyphenols immunomodulatory role by regulating intestinal microorganisms, inhibiting the etiology and pathogenesis of various diseases including colon cancer, colorectal cancer, inflammatory bowel disease (IBD) and colitis. Foodomics is a novel high-throughput analysis approach widely applied in food and nutrition studies, incorporating genomics, transcriptomics, proteomics, metabolomics, and integrating multi-omics technologies. In this review, we present an overview of foodomics technologies for identifying active polyphenol components from natural foods, as well as a summary of the gastrointestinal protective effects of polyphenols based on foodomics approaches. Furthermore, we critically assess the limitations in applying foodomics technologies to investigate the protective effect of polyphenols on the gastrointestinal (GI) system. Finally, we outline future directions of foodomics techniques to investigate GI protective effects of polyphenols. Foodomics based on the combination of several analytical platforms and data processing for genomics, transcriptomics, proteomics and metabolomics studies, provides abundant data and a more comprehensive understanding of the interactions between polyphenols and the GI tract at the molecular level. This contribution provides a basis for further exploring the protective mechanisms of polyphenols on the GI system.COVID-19 severity due to innate immunity dysregulation accounts for prolonged hospitalization, critical complications, and mortality. Severe SARS-CoV-2 infections involve the complement pathway activation for cytokine storm development. Nevertheless, the role of complement in COVID-19 immunopathology, complement-modulating treatment strategies against COVID-19, and the complement and SARS-CoV-2 interaction with clinical disease outcomes remain elusive. This study investigated the potential changes in complement signaling, and the associated inflammatory mediators, in mild-to-critical COVID-19 patients and their clinical outcomes. A total of 53 patients infected with SARS-CoV-2 were enrolled in the study (26 critical and 27 mild cases), and additional 18 healthy control patients were also included. Complement proteins and inflammatory cytokines and chemokines were measured in the sera of patients with COVID-19 as well as healthy controls by specific enzyme-linked immunosorbent assay. C3a, C5a, and factor P (properdin), as well as interleukin (IL)-1β, IL-6, IL-8, tumor necrosis factor (TNF)-α, and IgM antibody levels, were higher in critical COVID-19 patients compared to mild COVID-19 patients.