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Radiotherapy (RT) stands as a frontline treatment modality in clinical breast oncology, yet challenges like ROS reduction, high toxicity, non-selectivity, and hypoxia hinder efficacy. Additionally, RT administered at different doses can induce varying degrees of radioimmunotherapy. High doses of radiation (>10 Gy) may result in immune suppression, while moderate doses (4–10 Gy), although capable of mitigating the immune suppression caused by high-dose radiation, are often insufficient in effectively killing tumor cells. Therefore, enhancing the generation of ROS and ameliorating the tumor hypoxic immune-suppressive microenvironment at moderate radiation doses could potentially drive radiation-induced immune responses, offering a fundamental solution to the limitations of RT. In this study, a novel multifunctional nanoplatform, RMLF, integrating a Ru (II) complex into folate-functionalized liposomes with BSA-MnO2 nanoparticles was proposed. Orthogonal experimental optimization enhances radiosensitization via increasing accumulation in cancer cells, elevating ROS, and contributing to a dual enhancement of the cGAS-STING-dependent type I IFN signaling pathway, aimed to overcome the insufficient DAMPs typically seen in the conventional RT at 4 Gy. Such a strategy effectively activated cytotoxic T lymphocytes for infiltration into tumor tissues and promoted the polarization of tumor-associated macrophages from the M2 to M1 phenotype, substantially bolstering immune memory responses. This pioneering approach represents the first use of a ruthenium complex in radioimmunotherapy, activating the cGAS-STING pathway to amplify immune responses, overcome RT resistance, and extend immunotherapeutic potential. [ABSTRACT FROM AUTHOR]

The role of mitochondria in immunity is increasingly recognized, but it is unclear how variation in mitochondrial DNA (mtDNA) contributes to variable infection outcomes. To quantify the effect of mtDNA variation on humoral and cell-mediated innate immune responses, we utilized a panel of fruit fly Drosophila melanogaster cytoplasmic hybrids (cybrids), where unique mtDNAs (mitotypes) were introgressed into a controlled isogenic nuclear background. We observed substantial heterogeneity in infection outcomes within the cybrid panel upon bacterial, viral and parasitoid infections, driven by the mitotype. One of the mitotypes, mtKSA2 protected against bacterial, parasitoid, and to a lesser extent, viral infections. Enhanced survival was not a result of improved bacterial clearance, suggesting mtKSA2 confers increased disease tolerance. Transcriptome sequencing showed that the mtKSA2 mitotype had an upregulation of genes related to mitochondrial respiration and phagocytosis in uninfected flies. Upon infection, mtKSA2 flies exhibited infection type and duration specific transcriptomic changes. Furthermore, uninfected mtKSA2 larvae showed immune activation of hemocytes (immune cells), increased hemocyte numbers and ROS production, and enhanced encapsulation response against parasitoid wasp eggs and larvae. Our results show that mtDNA variation acts as an immunomodulatory factor in both humoral and cell-mediated innate immunity and that specific mitotypes can provide broad protection against infections. Author summary: The strength of immune response and the disease symptoms vary among individuals even when exposed to the same pathogen. Much of this variation is due to the genes directly involved in adaptive and innate immune pathways. In addition, mitochondria are emerging as one of the factors modulating immune responses. Mitochondria are cellular organelles with their own genome (mtDNA) involved in many important processes, including producing ATP, the energy currency of the cells. mtDNA mutations leading to mitochondrial dysfunction are often considered harmful upon exposure to pathogens. Here, we used a fruit fly model where unique mtDNA variants are placed in a controlled nuclear genomic background to find out how mtDNA shapes infection outcomes upon bacterial, viral and parasitoid infections. We found that mtDNA variation alters the efficiency of immune response and describe a mtDNA variant that confers protection against variety of pathogens. This protection was at least partially caused by enhanced cell-mediated innate immunity, including higher numbers of immune cells prior to and during infection. [ABSTRACT FROM AUTHOR]

Natural killer (NK) cell therapy represents an attractive immunotherapy approach against recurrent epithelial ovarian cancer (EOC), as EOC is sensitive to NK cellmediated cytotoxicity. However, NK cell antitumor activity is dampened by suppressive factors in EOC patient ascites. Here, we integrated functional assays, soluble factor analysis, high-dimensional flow cytometry cellular component data and clinical parameters of advanced EOC patients to study the mechanisms of ascites-induced inhibition of NK cells. Using a suppression assay, we found that ascites from EOC patients strongly inhibits peripheral blood-derived NK cells and CD34+ progenitor-derived NK cells, albeit the latter were more resistant. Interestingly, we found that higher ascites-induced NK cell inhibition correlated with reduced progression-free and overall survival in EOC patients. Furthermore, we identified transforming growth factor (TGF)-b1 to correlate with ascites-induced NK cell dysfunction and reduced patient survival. In functional assays, we showed that proliferation and anti-tumor reactivity of CD34+ progenitor-derived NK cells are significantly affected by TGF-b1 exposure. Moreover, inhibition of TGF-b1 signaling with galunisertib partly restored NK cell functionality in some donors. For the cellular components, we showed that the secretome is associated with a different composition of CD45+ cells between ascites of EOC and benign reference samples with higher proportions of macrophages in the EOC patient samples. Furthermore, we revealed that higher TGF-b1 levels are associated with the presence of M2-like macrophages, B cell populations and T-regulatory cells in EOC patient ascites. These findings reveal that targeting TGF-b1 signaling could increase NK cell immune responses in high-grade EOC patients. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis is a chronic autoimmune disease of undetermined etiology characterized by symmetric synovitis with predominantly destructive and multiple joint inflammation. Cytoplasmic DNA sensors that recognize protein molecules that are not themselves or abnormal dsDNA fragments play an integral role in the generation and perpetuation of autoimmune diseases by activating different signaling pathways and triggering innate immune signaling pathways and host defenses. Among them, melanoma deficiency factor 2 (AIM2) recognizes damaged DNA and double-stranded DNA and binds to them to further assemble inflammasome, initiating the innate immune response and participating in the pathophysiological process of rheumatoid arthritis. In this article, we review the research progress on the source of cytoplasmic DNA, the mechanism of assembly and activation of AIM2 inflammasome, and the related roles of other cytoplasmic DNA sensors in rheumatoid arthritis. [ABSTRACT FROM AUTHOR]

Background: Granuloma is a delayed type hypersensitivity reaction in response to foreign material. It is manifested by the organized accumulation of mature mononuclear macrophages. Sometimes granuloma may be formed in the absence of external factors. In addition to infectious agents, autoimmune diseases and primary immune deficiencies can cause granuloma. A number of primary immune deficiencies can cause autoimmune disorders and granulomatous inflammation, so these people in addition to frequent infections suffer from non-infectious complications that can have an important effect on prognosis. In this review, we intended to have an overview of primary immunodeficiency diseases with granulomatous inflammation and evaluate the effects of these lesions on the prognosis and course of the disease. Article search was performed by Scopus, Web of Science, and Google Scholar databases. We tried to use the latest and most reliable articles in English and Persian language that are related to our topic. The best articles were selected as references after evaluation of the journal and methodology of the paper. Conclusion: Timely diagnosis and treatment of inflammatory conditions, which sometimes appear before infectious manifestations, will be effective in improving the prognosis of the disease. The treatment of these patients with immunosuppressive drugs and corticosteroids should be based on several factors such as: patient's condition, severity of granulomatous inflammation, and presence of active fungal or bacterial infection. [ABSTRACT FROM AUTHOR]

Multiple peptide resistance factor (MprF) confers resistance to cationic antimicrobial peptides (AMPs) in several pathogens, thereby enabling evasion of the host immune response. The role of MprF in commensals remains, however, uncharacterized. To close this knowledge gap, we used a common gut commensal of animals, Lactiplantibacillus plantarum, and its natural host, the fruit fly Drosophila melanogaster, as an experimental model to investigate the role of MprF in commensal-host interactions. The L. plantarum ΔmprF mutant that we generated exhibited deficiency in the synthesis of lysyl-phosphatidylglycerol (Lys-PG), resulting in increased negative cell surface charge and increased susceptibility to AMPs. Susceptibility to AMPs had no effect on ΔmprF mutant's ability to colonize guts of uninfected flies. However, we observed significantly reduced abundance of the ΔmprF mutant after infection-induced inflammation in the guts of wild-type flies but not flies lacking AMPs. Additionally, we found that the ΔmprF mutant compared to wild-type L. plantarum induces a stronger intestinal immune response in flies due to the increased release of immunostimulatory peptidoglycan fragments, indicating an important role of MprF in promoting host tolerance to commensals. Our further analysis suggests that MprF-mediated lipoteichoic acid modifications are involved in host immunomodulation. Overall, our results demonstrate that MprF, besides its well-characterized role in pathogen immune evasion and virulence, is also an important commensal resilience factor. Author summary: Commensal microbial communities residing in the host intestine often experience the exposure to host immune effectors triggered by the pathogens during infection. Despite these perturbations, intestinal commensals stably colonize the host, thus exhibiting resilience to inflammation. Here, we used the fruit fly Drosophila melanogaster and its gut commensal, Lactiplantibacillus plantarum, as a model to investigate the role of a specific bacterial gene, multiple peptide resistance factor (MprF), in commensal-host interactions during infection. We generated an L. plantarum ΔmprF mutant and demonstrated susceptibility of this mutant to AMPs and deficiency in the colonization of flies after infection. Importantly, ΔmprF mutant efficiently colonized flies that lack AMPs, demonstrating that MprF-mediated resistance to host AMPs is crucial for commensal persistence during infection. Additionally, we discovered that the ΔmprF mutant induced due to an increased release of cell-wall fragments enhanced immune response in flies as compared to wild-type bacteria. Hence, MprF confers two highly-relevant functions for commensal-host association: AMP resistance and immune evasion. Finally, we showed a role of MprF in regulating LTA size, implying a broader role of MprF in the bacterial physiology then previously appreciated. Collectively, our work shows that AMP resistance via MprF-mediated lipid and LTA modifications is essential for commensal resilience during inflammation. [ABSTRACT FROM AUTHOR]

Background: Although rheumatoid arthritis (RA) is a chronic systemic tissue disease often accompanied by osteoporosis (OP), the molecular mechanisms underlying this association remain unclear. This study aimed to elucidate the pathogenesis of RA and OP by identifying differentially expressed mRNAs (DEmRNAs) and long non-coding RNAs (lncRNAs) using a bioinformatics approach. Methods: Expression profiles of individuals diagnosed with OP and RA were retrieved from the Gene Expression Omnibus database. Differential expression analysis was conducted. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway (KEGG) pathway enrichment analyses were performed to gain insights into the functional categories and molecular/biochemical pathways associated with DEmRNAs. We identified the intersection of common DEmRNAs and lncRNAs and constructed a protein-protein interaction (PPI) network. Correlation analysis between the common DEmRNAs and lncRNAs facilitated the construction of a coding-non-coding network. Lastly, serum peripheral blood mononuclear cells (PBMCs) from patients with RA and OP, as well as healthy controls, were obtained for TRAP staining and qRT-PCR to validate the findings obtained from the online dataset assessments. Results: A total of 28 DEmRNAs and 2 DElncRNAs were identified in individuals with both RA and OP. Chromosomal distribution analysis of the consensus DEmRNAs revealed that chromosome 1 had the highest number of differential expression genes. GO and KEGG analyses indicated that these DEmRNAs were primarily associated with " platelets (PLTs) degranulation", "platelet alpha granules", "platelet activation", "tight junctions" and "leukocyte transendothelial migration", with many genes functionally related to PLTs. In the PPI network, MT-ATP6 and PTGS1 emerged as potential hub genes, with MT-ATP6 originating from mitochondrial DNA. Co-expression analysis identified two key lncRNA-mRNA pairs: RP11 − 815J21.2 with MT − ATP6 and RP11 − 815J21.2 with PTGS1. Experimental validation confirmed significant differential expression of RP11-815J21.2, MT-ATP6 and PTGS1 between the healthy controls and the RA + OP groups. Notably, knockdown of RP11-815J21.2 attenuated TNF + IL-6-induced osteoclastogenesis. Conclusions: This study successfully identified shared dysregulated genes and potential therapeutic targets in individuals with RA and OP, highlighting their molecular similarities. These findings provide new insights into the pathogenesis of RA and OP and suggest potential avenues for further research and targeted therapies. [ABSTRACT FROM AUTHOR]

Background: Lung adenocarcinoma (LUAD) is the most common type of lung cancer and closely associated with the immune system. Emerging evidence suggests that blood immune cell phenotypes in patients with LUAD may undergo alterations. Nevertheless, the limited amount of relevant research makes it difficult to understand the causal links between LUAD and changes in the immune cells. This study aimed to reveal the potential causal relationships between 731 immune cell phenotypes and LUAD. Methods: A bidirectional two‐sample Mendelian randomization (MR) analysis was used to clarify causal relationships. Four types of immune phenotypes, absolute cell counts, relative cell counts, median fluorescence intensities (MFIs) of surface antigens, and morphological parameters, were investigated in this study. Heterogeneity tests, horizontal pleiotropy tests, and leave‐one‐out analyses were performed to validate the reliability of our study. Results: A total of 26 immune cell characteristics were identified as contributing to the occurrence of LUAD. Memory B cells, IgD−CD38br cells, CD4+ regulatory T cells (Tregs), and plasmacytoid dendritic cells (DCs) may play a role in the development of LUAD. Through reverse MR, our study discovered that the presence of LUAD also induced changes in the expression levels of 16 immune cell traits involving specific surface markers and various types of immune cells, some of which pertain to antigen presentation and immune activation processes. Conclusion: Our study demonstrated causal links between several immune cell phenotypes and LUAD, thereby providing indications of the potentially oncogenic physiological state and early screening biomarkers for future research. [ABSTRACT FROM AUTHOR]

Background: Staphylococcus shinii appears as an umbrella species encompassing several strains of Staphylococcus pseudoxylosus and Staphylococcus xylosus. Given its phylogenetic closeness to S. xylosus, S. shinii can be found in similar ecological niches, including the microbiota of fermented meats where the species may contribute to colour and flavour development. In addition to these conventional functionalities, a biopreservation potential based on the production of antagonistic compounds may be available. Such potential, however, remains largely unexplored in contrast to the large body of research that is available on the biopreservative properties of lactic acid bacteria. The present study outlines the exploration of the genetic basis of competitiveness and antimicrobial activity of a fermented meat isolate, S. shinii IMDO-S216. To this end, its genome was sequenced, de novo assembled, and annotated. Results: The genome contained a single circular chromosome and eight plasmid replicons. Focus of the genomic exploration was on secondary metabolite biosynthetic gene clusters coding for ribosomally synthesized and posttranslationally modified peptides. One complete cluster was coding for a bacteriocin, namely lactococcin 972; the genes coding for the pre-bacteriocin, the ATP-binding cassette transporter, and the immunity protein were also identified. Five other complete clusters were identified, possibly functioning as competitiveness factors. These clusters were found to be involved in various responses such as membrane fluidity, iron intake from the medium, a quorum sensing system, and decreased sensitivity to antimicrobial peptides and competing microorganisms. The presence of these clusters was equally studied among a selection of multiple Staphylococcus species to assess their prevalence in closely-related organisms. Conclusions: Such factors possibly translate in an improved adaptation and competitiveness of S. shinii IMDO-S216 which are, in turn, likely to improve its fitness in a fermented meat matrix. [ABSTRACT FROM AUTHOR]

DltB, a model member of the Membrane-Bound O-AcylTransferase (MBOAT) superfamily, plays a crucial role in D-alanylation of the lipoteichoic acid (LTA), a significant component of the cell wall of gram-positive bacteria. This process stabilizes the cell wall structure, influences bacterial virulence, and modulates the host immune response. Despite its significance, the role of DltB is not well understood. Through biochemical analysis and cryo-EM imaging, we discover that Streptococcus thermophilus DltB forms a homo-tetramer on the cell membrane. We further visualize DltB in an apo form, in complex with DltC, and in complex with its inhibitor amsacrine (m-AMSA). Each tetramer features a central hole. The C-tunnel of each protomer faces the intratetramer interface and provides access to the periphery membrane. Each protomer binds a DltC without changing the tetrameric organization. A phosphatidylglycerol (PG) molecule in the substrate-binding site may serve as an LTA carrier. The inhibitor m-AMSA bound to the L-tunnel of each protomer blocks the active site. The tetrameric organization of DltB provides a scaffold for catalyzing D-alanyl transfer and regulating the channel opening and closing. Our findings unveil DltB's dual function in the D-alanylation pathway, and provide insight for targeting DltB as a anti-virulence antibiotic. Here, the authors structurally and functionally characterise DltB, a member of the Membrane-Bound O-AcylTransferase (MBOAT) superfamily responsible for D-alanine incorporation in the cell wall of gram-positive bacteria. [ABSTRACT FROM AUTHOR]

The immune system of Asian elephants (Elephas maximus) is poorly studied, compared to that of livestock, rodents or humans. The innate immune response has become a focus of interest in relation to Elephant endotheliotropic herpesviruses (EEHVs). EEHVs cause a fatal hemorrhagic disease (EEHV-HD) and are a significant threat to captive Asian elephant populations worldwide. Similar to other herpesvirus infections, nearly all animals become infected, but only some develop disease. As progression to EEHV-HD is often acute, a robust innate immune response is crucial to control EEHV infections. This is invariably true of the host in the first instance, but it can also potentially be modulated by intervention strategies. Here, two immunostimulant veterinary medicinal products, authorized for use in domestic species, were tested for their ability to induce innate anti-viral immune responses in Asian elephant blood cells. Sequence data were obtained for a range of previously unidentified Asian elephant immune genes, including C-X-C motif chemokine ligand 10 (CXCL10), interferon stimulated gene 15 (ISG15) and myxovirus GTPase 1 (Mx1), and were employed in the design of species-specific qPCR assays. These assays were subsequently used in analyses to determine fold changes in gene expression over a period of 24 hours. This study demonstrates that both immunostimulant medications are capable of inducing significant innate antiviral immune responses which suggests that both could be beneficial in controlling EEHV infections in Asian elephants. [ABSTRACT FROM AUTHOR]

Background Periodontitis is a chronic infectious disease, characterized by an exacerbated inflammatory response and a progressive loss of the supporting tissues of the teeth. Porphyromonas gingivalis is a key etiologic agent in periodontitis. Cystatin C is an antimicrobial salivary peptide that inhibits the growth of P. gingivalis. This study aimed to evaluate the antimicrobial activity of this peptide and its effect on cytokine production, nitric oxide (NO) release, reactive oxygen species (ROS) production, and programmed cell death in human macrophages infected with P. gingivalis. Methods Monocyte-derived macrophages generated from peripheral blood were infected with P. gingivalis (MOI 1:10) and stimulated with cystatin C (2.75 µg/ml) for 24 h. The intracellular localization of P. gingivalis and cystatin C was determined by immunofluorescence and transmission electron microscopy (TEM). The intracellular antimicrobial activity of cystatin C in macrophages was assessed by counting Colony Forming Units (CFU). ELISA assay was performed to assess inflammatory (TNFα, IL-1β) and anti-inflammatory (IL-10) cytokines. The production of nitrites and ROS was analyzed by Griess reaction and incubation with 2',7'-dichlorodihydrofluorescein diacetate (H2DCFDA), respectively. Programmed cell death was assessed with the TUNEL assay, Annexin-V, and caspase activity was also determined. Results Our results showed that cystatin C inhibits the extracellular growth of P. gingivalis. In addition, this peptide is internalized in the infected macrophage, decreases the intracellular bacterial load, and reduces the production of inflammatory cytokines and NO. Interestingly, peptide treatment increased ROS production and substantially decreased bacterial-induced macrophage apoptosis. Conclusions Cystatin C has antimicrobial and immuno-regulatory activity in macrophages infected with P. gingivalis. These findings highlight the importance of understanding the properties of cystatin C for its possible therapeutic use against oral infections such as periodontitis. [ABSTRACT FROM AUTHOR]

The host defence responses play vital roles in viral infection and are regulated by complex interactive networks. The host immune system recognizes viral pathogens through the interaction of pattern-recognition receptors (PRRs) with pathogen-associated molecular patterns (PAMPs). As a PRR mainly in the cytoplasm, cyclic GMP-AMP synthase (cGAS) senses and binds virus DNA and subsequently activates stimulator of interferon genes (STING) to trigger a series of intracellular signalling cascades to defend against invading pathogenic microorganisms. Integrated omic and functional analyses identify the cGASSTING pathway regulating various host cellular responses and controlling viral infections. Aside from its most common function in regulating inflammation and type I interferon, a growing body of evidence suggests that the cGAS-STING signalling axis is closely associated with a series of cellular responses, such as oxidative stress, autophagy, and endoplasmic reticulum stress, which have major impacts on physiological homeostasis. Interestingly, these host cellular responses play dual roles in the regulation of the cGAS-STING signalling axis and the clearance of viruses. Here, we outline recent insights into cGAS-STING in regulating type I interferon, inflammation, oxidative stress, autophagy and endoplasmic reticulum stress and discuss their interactions with viral infections. A detailed understanding of the cGAS-STING-mediated potential antiviral effects contributes to revealing the pathogenesis of certain viruses and sheds light on effective solutions for antiviral therapy. [ABSTRACT FROM AUTHOR]

Introduction: Loss of NADPH oxidase activity results in proinflammatory macrophages that contribute to hyperinflammation in Chronic Granulomatous Disease (CGD). Previously, it was shown in a zymosan-induced peritonitis model that gp91phox-/- (CGD) monocyte-derived macrophages (MoMacs) fail to phenotypically mature into pro-resolving MoMacs characteristic of wild type (WT) but retain the ability to do so when placed in the WT milieu. Accordingly, it was hypothesized that soluble factor(s) in the CGD milieu thwart appropriate programming. Methods: We sought to identify key constituents using ex vivo culture of peritoneal inflammatory leukocytes and their conditioned media. MoMac phenotyping was performed via flow cytometry, measurement of efferocytic capacity and multiplex analysis of secreted cytokines. Addition of exogenous TNFa, TNFa neutralizing antibody and TNFR1-/- MoMacs were used to study the role of TNFa: TNFR1 signaling in MoMac maturation. Results: More extensive phenotyping defined normal MoMac maturation and demonstrated failure of maturation of CGD MoMacs both ex vivo and in vivo. Protein components, and specifically TNFa, produced and released by CGD neutrophils and MoMacs into conditioned media was identified as critical to preventing maturation. Exogenous addition of TNFa inhibited WT MoMac maturation, and its neutralization allowed maturation of cultured CGD MoMacs. TNFa neutralization also reduced production of IL-1b, IL-6 and CXCL1 by CGD cells though these cytokines played no role in MoMac programming. MoMacs lacking TNFR1 matured more normally in the CGD milieu both ex vivo and following adoptive transfer in vivo. Discussion: These data lend mechanistic insights into the utility of TNFa blockade in CGD and to other diseases where such therapy has been shown to be beneficial. [ABSTRACT FROM AUTHOR]

Diabetic cardiomyopathy (dCM) is a major complication of diabetes; however, specific treatments for dCM are currently lacking. RTA 408, a semisynthetic triterpenoid, has shown therapeutic potential against various diseases by activating the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway. We established in vitro and in vivo models using high glucose toxicity and db/db mice, respectively, to simulate dCM. Our results demonstrated that RTA 408 activated Nrf2 and alleviated various dCMrelated cardiac dysfunctions, both in vivo and in vitro. Additionally, it was found that silencing the Nrf2 gene eliminated the cardioprotective effect of RTA 408. RTA 408 ameliorated oxidative stress in dCM mice and high glucose-exposed H9C2 cells by activating Nrf2, inhibiting mitochondrial fission, exerting anti-inflammatory effects through the Nrf2/NF-κB axis, and ultimately suppressing apoptosis, thereby providing cardiac protection against dCM. These findings provide valuable insights for potential dCM treatments. NEW & NOTEWORTHY We demonstrated first that the nuclear factor erythroid 2-related factor 2 (Nrf2) activator RTA 408 has a protective effect against diabetic cardiomyopathy. We found that RTA 408 could stimulate the nuclear entry of Nrf2 protein, regulate the mitochondrial fission-fusion balance, and redistribute p65, which significantly alleviated the oxidative stress level in cardiomyocytes, thereby reducing apoptosis and inflammation, and protecting the systolic and diastolic functions of the heart. [ABSTRACT FROM AUTHOR]

Streptococcus uberis is frequently isolated from milk collected from dairy cows with mastitis. According to the host's immunity, bacterial virulence, and their interaction, infection with some strains can induce persistent subclinical inflammation, while infection with others induces severe inflammation and transient mastitis. This study compared the inflammatory response of milk-isolated white blood cells (mWBCs) to persistent and transient S. uberis strains. Quarter milk samples were collected aseptically for bacterial culture from all lactating cows once a week over a 10-week period. A transient and noncapsular strain with a 1-week intramammary infection duration was selected from this herd, while a persistent and capsular S. uberis strain with an intramammary infection longer than 2 months from our previous study was selected based on an identical pulse field gel electrophoresis pattern during the IMI episode. Cellular and molecular responses of mWBCs were tested, and the data were analyzed using repeated analysis of variance. The results showed a higher response in migration, reactive oxygen species generation, and bacterial killing when cells were stimulated with transient S. uberis. In contrast, the persistent strain led to increased neutrophil extracellular trap release. This study also highlighted several important molecular aspects of mWBCs. Gene expression analyses by real-time RT-PCR revealed a significant elevation in the expression of Toll-like receptors (TLR-1, TLR-2, TLR-6) and proinflammatory cytokines (tumor necrosis factor-alpha or TNF-α) with the transient strain. Additionally, Streptococcus uberis capsule formation might contribute to the capability of these strains to induce different immune responses. Altogether, these results focus on the immune function of activated mWBCs which demonstrate that a transient strain can elicit a stronger local immune response and, subsequently, lead to rapid recovery from mastitis. [ABSTRACT FROM AUTHOR]

Purpose: Prolonged exposure to plasma free fatty acids (FFAs) leads to impaired glucose tolerance (IGT) which can progress to type 2 diabetes (T2D) in the absence of timely and effective interventions. High-fat diet (HFD) leads to chronic inflammation and oxidative stress, impairing pancreatic beta cell (PBC) function. While Didymin, a flavonoid glycoside derived from citrus fruits, has beneficial effects on inflammation dysfunction, its specific role in HFD-induced IGT remains yet to be elucidated. Hence, this study aims to investigate the protective effects of Didymin on PBCs. Methods: HFD-induced IGT mice and INS-1 cells were used to explore the effect and mechanism of Didymin in alleviating IGT. Serum glucose and insulin levels were measured during the glucose tolerance and insulin tolerance tests to evaluate PBC function and insulin resistance. Next, RNA-seq analysis was performed to identify the pathways potentially influenced by Didymin in PBCs. Furthermore, we validated the effects of Didymin both in vitro and in vivo. Mitochondrial electron transport inhibitor (Rotenone) was used to further confirm that Didymin exerts its ameliorative effect by enhancing mitochondria function. Results: Didymin reduces postprandial glycemia and enhances 30-minute postprandial insulin levels in IGT mice. Moreover, Didymin was found to enhance mitochondria biogenesis and function, regulate insulin secretion, and alleviate inflammation and apoptosis. However, these effects were abrogated with the treatment of Rotenone, indicating that Didymin exerts its ameliorative effect by enhancing mitochondria function. Conclusions: Didymin exhibits therapeutic potential in the treatment of HFD-induced IGT. This beneficial effect is attributed to the amelioration of PBC dysfunction through improved mitochondrial function. [ABSTRACT FROM AUTHOR]

Inflammation is a tightly coordinated response of the host immune system to bacterial and viral infections, triggered by the production of inflammatory cytokines. Sepsis is defined as a systemic inflammatory response followed by immunosuppression of the host and organ dysfunction. This imbalance of the immune response increases the risk of mortality of patients with sepsis, making it a major problem for critical care units worldwide. The P2X7 receptor plays a crucial role in activating the immune system by inducing the activation of peripheral blood mononuclear cells. In this study, we analyzed a cohort of abdominal origin septic patients and found that the expression of the P2X7 receptor in the plasma membrane is elevated in the different subsets of lymphocytes. We observed a direct relationship between the percentage of P2X7-expressing lymphocytes and the early inflammatory response in sepsis. Additionally, in patients whose lymphocytes presented a higher percentage of P2X7 surface expression, the total lymphocytes populations proportionally decreased. Furthermore, we found a correlation between elevated soluble P2X7 receptors in plasma and inflammasome-dependent cytokine IL-18. In summary, our work demonstrates that P2X7 expression is highly induced in lymphocytes during sepsis, and this correlates with IL-18, along with other inflammatory mediators such as IL-6, IL-8, and procalcitonin. [ABSTRACT FROM AUTHOR]

This longitudinal study identifies espoused change orientations and actual youth violence prevention (YVP) practices over five years by 99 public and nonprofit organizations in one city. Annual key informant interviews provided both qualitative and quantitative data, including organizational collaborative network data. Data were also obtained on participation in a citywide YVP coalition, juvenile arrests and court referrals. On average, organizations both in and outside the coalition adopted a problem-focused as often as a strengths-based change orientation, and were only marginally more oriented toward empowering community members than professionals and changing communities than individual youth. Most surprisingly, YVP coalition members adopted more of a tertiary (reactive/rehabilitative) than primary prevention orientation compared to nonmembers. The number of different YVP strategies implemented increased over five years from mainly positive youth development and education interventions to those strategies plus mentoring, youth activities, events and programs, and counseling youth. Network analysis reveals dense initial collaboration with no critical gatekeepers and coalition participants more central to the city-wide organizational network. Coalition participation and total network collaboration declined in Years 3–5. Youth violence arrests and court referrals also declined. The coalition was marginally involved in successful community-collaborative, school-based interventions and other strategies adopted, and it disbanded a year after federal funding ended. Despite, or possibly due to, both national and local government participation, the coalition missed opportunities to engage in collective advocacy for local YVP policy changes. Coalitions should help nonprofit and public organizations develop more effective change orientations and implement commensurate strategies at the community level. [ABSTRACT FROM AUTHOR]

In accordance with the endosymbiotic theory, mitochondrial components bear characteristic prokaryotic signatures, which act as immunomodulatory molecules when released into the extramitochondrial compartment. These endogenous immune triggers, called mitochondrial damage‐associated molecular patterns (mtDAMPs), have been implicated in the pathogenesis of various diseases, yet their role remains largely unexplored. In this review, we summarise the available literature on mtDAMPs in diseases, with a special focus on respiratory diseases. We highlight the need to bolster mtDAMP research using a multipronged approach, to study their effect on specific cell types, receptors and machinery in pathologies. We emphasise the lacunae in the current understanding of mtDAMPs, particularly in their cellular release and the chemical modifications they undergo. Finally, we conclude by proposing additional effects of mtDAMPs in diseases, specifically their role in modulating the immune system. [ABSTRACT FROM AUTHOR]

Malnourished children are susceptible to an increased risk of mortality owing to impaired immune functions. However, the underlying mechanism of altered immune functions and its interaction with malnutrition is poorly understood. This study investigates the immune function and evaluates the effect of a particular nutritional intervention on the immune cells of undernourished children. Stunted (LAZ <−2) and at‐risk of being stunted (length‐for‐age Z‐scores, LAZ <−1 to −2) children aged between 12 and 18 months were enrolled and were provided with the daily nutritional intervention of one egg and 150 mL cow's milk for 90 days. Peripheral blood mononuclear cells (PBMCs) were isolated at enrolment and upon completion of the intervention. Phenotypic profiles for CD3+ cells, CD4+ cells, CD8+ cells, NKT cells, and B cells were similar in both cohorts, both before and after the intervention. However, activated B cells (CD25+) were increased after nutritional intervention in the at‐risk of being stunted cohort. Several pro‐inflammatory cytokines, IL‐6, IFN‐γ, and TNF‐α, were elevated in the stunted children following the nutritional intervention. The results of the study indicate that nutritional intervention may have a role on activated B cells (CD25+) s in children who are at‐risk of being stunted and may alter the capacity of PBMC to produce inflammatory cytokines in stunted children. [ABSTRACT FROM AUTHOR]

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous myeloid cell population and serve as a vital contributor to the tumor microenvironment. Reactive oxygen species (ROS) are byproducts of aerobic respiration and are involved in regulating normal biological activities and disease progression. MDSCs can produce ROS to fulfill their immunosuppressive activity and eliminate excessive ROS to survive comfily through the redox system. This review focuses on how MDSCs survive and function in high levels of ROS and summarizes immunotherapy targeting ROS in MDSCs. The distinctive role of ROS in MDSCs will inspire us to widely apply the blocked oxidative stress strategy in targeting MDSC therapy to future clinical therapeutics. [ABSTRACT FROM AUTHOR]

Introduction: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is highly pathogenic to humans and has caused the ongoing coronavirus disease 2019 (COVID-19) pandemic. Vaccines are one of the efficient ways to prevent the viral infection. After COVID-19 vaccination, the monitoring of the dynamic change in neutralizing antibodies is necessary to determine booster requirements. Methods: We estimated the effectiveness of the inactivated vaccines by monitoring dynamic SARS-CoV-2 neutralizing antibodies for over 2 years. Additionally, we also investigated the activation of T lymphocytes (CD3+ T cells) after three doses of the inactivated vaccine. Result: The results showed that the rate of reduction of SARS-CoV-2 neutralizing antibody levels gradually showed after each booster dose. The IgG/IgM level at 9 months after the third vaccination were significantly higher than those at 6 months after the second dose (p<0.0001). The expression of CD25+T cell in 18-35 age group was significantly higher than that in the other groups. Nine months after the third dose (the time of last blood sample collection), the expression of CD25+T cell in the 18-35 age group was significantly higher than that at 6 months after the second dose. CD25+T cell in the 18-35 years old group was significantly higher than 6 months after the second vaccination. Conclusion: CD25, a late activation marker of lymphocytes and high-activity memory T cell subgroup, exhibited higher levels at the later stages after vaccination. COVID-19 booster vaccination in older adults and regular testing of SARS-CoV-2 neutralizing antibodies are recommended. Booster doses should be administered if the antibody level falls below the 30% inhibition rate. [ABSTRACT FROM AUTHOR]

Endogenous DNA is released into the bloodstream as cell-free DNA (cfDNA) following cell death and is associated with various pathological conditions. However, their association with therapeutic drugs against rheumatoid arthritis (RA) remains unknown. Therefore, we investigated the significance of cfDNA in RA treated with tocilizumab and tumour necrosis factor inhibitor (TNF-I). Biological DMARDs (bDMARDs), including tocilizumab and TNF-I, were administered to 77 and 59 RA patients, respectively. Plasma cfDNA levels were measured at weeks 0, 4, and 12 by quantitative polymerase chain reaction. Disease activity was evaluated at the same time point using DAS28ESR. cfDNA levels from RA synovial cells treated with tocilizumab or etanercept for 24 h were measured. Human toll-like receptor 9 (hTLR9)-expressing HEK293 cells, which release secreted embryonic alkaline phosphatase (SEAP) upon NF-κB activation, were stimulated by cfDNA from RA patients, and subsequently, SEAP levels were determined. NF-κB translocation was evaluated by immunofluorescence staining with or without tocilizumab. The DAS28ESR significantly improved in both bDMARD groups at week 12. However, plasma cfDNA levels significantly decreased in the tocilizumab group at week 12 compared to that in week 0. cfDNA levels correlated with DAS28ESR in biological treatment-naïve patients administered tocilizumab. cfDNA levels in synovial cells were significantly suppressed by tocilizumab treatment and unaltered with etanercept. HEK293 cells released SEAP upon cfDNA stimulation, and the observed NF-κB nuclear translocation was suppressed by tocilizumab. Tocilizumab suppressed inflammation via the TLR9 pathway by decreasing cfDNA levels. Regulation of cfDNA may be a therapeutic target for RA. Cell-free DNA (cfDNA) from patients with rheumatoid arthritis (RA) activates NF-κB via the toll-like receptor 9 (TLR-9) signalling pathway in vitro. Tocilizumab, but not tumour necrosis factor inhibitors, decreases cfDNA levels in RA patients and RA-associated fibroblast-like synoviocytes. Tocilizumab degrades cfDNA at clinically relevant concentrations, suggesting tocilizumab likely controls inflammation in RA by suppressing TLR-9-dependent NF-κB signalling. [ABSTRACT FROM AUTHOR]

Objectives ANCA-associated vasculitis (AAV) includes granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). ANCA triggers neutrophil extracellular trap formation, which releases either mitochondrial (mt) DNA or nuclear DNA (n) DNA, contributing to inflammation. Our aim was to prospectively examine the extent and nature of circulating DNA in AAV and the clinical utility of DNA quantification. Methods DNA was isolated from platelet-free plasma of consecutive GPA and MPA patients and healthy controls (HCs). mtDNA and nDNA copy numbers were quantified by PCR. Clinical data, including the BVAS, were collected. Results Ninety-two HCs (median age 51 years, 58.7% female) and 101 AAV patients (80 GPA, 21 MPA, median age 64 years, 50.5% female, BVAS range: 0–30) were included. Median mtDNA copies were 13-fold higher in patients with AAV than in HCs; nDNA concentrations did not differ. Patients with active AAV (BVAS > 0) had 4-fold higher median mtDNA copies than patients in remission (P  = 0.03). mtDNA, unlike nDNA, correlated with BVAS (r  = 0.30, P  = 0.002) and was associated with AAV activity at multivariable analysis. Receiver operating characteristic curve analysis indicated that mtDNA quantification differentiates patients with active AAV (BVAS > 0) from HCs with 96.1% sensitivity and 98.9% specificity (area under the curve 0.99). In 27 AAV patients with follow-up, mtDNA changes but not CRP or ANCA-titres correlated with BVAS changes (r  = 0.56, P  = 0.002). Conclusions mtDNA, unlike nDNA, is elevated in the plasma of AAV patients and may contribute to systemic inflammation. mtDNA could be superior to established biomarkers in the laboratory monitoring of AAV activity. [ABSTRACT FROM AUTHOR]

Background: We sought to determine whether two soluble forms with different size of mtDNA are linked to prostatic inflammation, and whether they discriminate prostate cancer (PCa) from inflammatory prostatic conditions. Methods: Histopathologically diagnosed prostatitis, PCa and benign prostatic hyperplasia patients (n = 93) were enrolled in this study and they were categorized as with and without prostate inflammation. Quantitative RT-PCR was used to analyze the levels of 79-bp and 230-bp fragments in urine and blood samples collected following prostate massage. Results: The urine mtDNA-79 and mtDNA-230 were significantly increased in patients with prostate inflammation compared with those in without inflammation. Here, 79-bp fragment of apoptotic origin was significantly higher level than 230-bp fragment of necrotic origin. Although mtDNA-79 copy number in serum samples was also increased in patients with prostate inflammation, mtDNA-230 was similar in the two groups. Furthermore, mtDNA-79 and mtDNA-230 copy numbers in post-prostate massage urine were higher (about 16-fold and 22-fold, respectively) than those from serum samples. ROC analysis showed that, although post-prostate massage urine have relatively higher performance than blood, ability to discriminate cases of both fragments was not better than that of serum total PSA. Conclusions: Our results demonstrate that shorter cf-mtDNA fragment size in particular, increase in the presence of prostate inflammation in post-prostatic massage urine but both fragments could never improve serum total PSA performance. [ABSTRACT FROM AUTHOR]

Background: Patients with Sjögren's syndrome, like other patients with autoimmune disorders, display dysregulation in the function of their immune system. Fas and Fas Ligand (FasL) are among the dysregulated proteins. Methods: We studied Fas and FasL on IL-2Rα+ cells and in serum of patients with Sjögren's syndrome (n = 16) and healthy individuals (n = 16); both from same ethnic and geographical background. We used flow cytometry and enzyme-linked immunosorbent for this purpose. We also measured the expression of Bcl-2 and Bax by reverse transcription quantitative real-time PCR (RT-qPCR) and percentage of apoptotic and dead cells using Annexin V and 7-AAD staining in lymphocytes. Results: FasL was increased in patients' T and B cells while Fas was increased in patients' monocytes, T and B cells. No signs of increased apoptosis were found. sFas and sFasL in patients' serum were increased, although the increase in sFasL was not significant. We suspect an effect of non-steroidal anti-inflammatory therapy on B cells, explaining the decrease of the percentage Fas+ B cells found within our samples. In healthy individuals, there was a noticeable pattern in the expression of FasL which mutually correlated to populations of mononuclear cells; this correlation was absent in the patients with Sjögren's syndrome. Conclusions: Mononuclear cells expressing IL-2Rα+ had upregulated Fas in Sjögren's syndrome. However, the rate of apoptosis based on Annexin V staining and the Bcl-2/Bax expression was not observed in mononuclear cells. We suspect a functional role of abnormal levels of Fas and FasL which has not been cleared yet. [ABSTRACT FROM AUTHOR]

According to the endosymbiotic theory, most of the DNA of the original bacterial endosymbiont has been lost or transferred to the nucleus, leaving a much smaller (∼16 kb in mammals), circular molecule that is the present-day mitochondrial DNA (mtDNA). The ability of mtDNA to escape mitochondria and integrate into the nuclear genome was discovered in budding yeast, along with genes that regulate this process. Mitochondria have emerged as key regulators of innate immunity, and it is now recognized that mtDNA released into the cytoplasm, outside of the cell, or into circulation activates multiple innate immune signaling pathways. Here, we first review the mechanisms through which mtDNA is released into the cytoplasm, including several inducible mitochondrial pores and defective mitophagy or autophagy. Next, we cover how the different forms of released mtDNA activate specific innate immune nucleic acid sensors and inflammasomes. Finally, we discuss how intracellular and extracellular mtDNA release, including circulating cell-free mtDNA that promotes systemic inflammation, are implicated in human diseases, bacterial and viral infections, senescence and aging. [ABSTRACT FROM AUTHOR]

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, has infected >600 million people in the ongoing global pandemic. Several variants of the SARS-CoV-2 have emerged in the last >2 years, challenging the continued efficacy of current COVID vaccines. Therefore, there is a crucial need to investigate a highly cross-protective vaccine effective against variants of SARS-CoV-2. In this study, we examined seven lipopeptides derived from highly conserved, immunodominant epitopes from the S, N, and M proteins of SARS-CoV-2, that are predicted to contain epitopes for clinically protective B cells, helper T cells (TH) and cytotoxic T cells (CTL). Intranasal immunization of mice with most of the lipopeptides led to significantly higher splenocyte proliferation and cytokine production, mucosal and systemic antibody responses, and induction of effector B and T lymphocytes in both lungs and spleen, compared to immunizations with the corresponding peptides without lipid. Immunizations with Spike-derived lipopeptides led to cross-reactive IgG, IgM and IgA responses against Alpha, Beta, Delta, and Omicron Spike proteins as well as neutralizing antibodies. These studies support their potential for development as components of a cross-protective SARS-CoV-2 vaccine. [ABSTRACT FROM AUTHOR]

Mitochondria are versatile organelles and essential components of numerous biological processes such as energy metabolism, signal transduction, and cell fate determination. In recent years, their critical roles in innate immunity have come to the forefront, highlighting impacts on pathogenic defense, tissue homeostasis, and degenerative diseases. This review offers an in-depth and comprehensive examination of the multifaceted mechanisms underlying the interactions between mitochondria and innate immune responses. We will delve into the roles of healthy mitochondria as platforms for signalosome assembly, the release of mitochondrial components as signaling messengers, and the regulation of signaling via mitophagy, particularly to cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling and inflammasomes. Furthermore, the review will explore the impacts of mitochondrial proteins and metabolites on modulating innate immune responses, the polarization of innate immune cells, and their implications on infectious and inflammatory diseases. [ABSTRACT FROM AUTHOR]

Background: Epidemiological findings on the association between soybean product consumption and gastric cancer risk remain inconsistent. We evaluated the relationship between soybean product consumption and the risk of gastric cancer in a prospective cohort study in Korea. Methods: This prospective cohort study included a total of 139,267 participants aged 40–69 years from the Health Examinees-Gem (HEXA-G) study between 2004 and 2013. Information on cancer diagnosis was retrieved from the Korea Central Cancer Registry until 31 December 2018. Multivariate hazard ratios (HRs) and 95% of confidence intervals (CIs) for the risk of gastric cancer according to the consumption of soybean products were estimated using Cox proportional hazards models. Results: A total of 767 incident cases of gastric cancer occurred over an average follow-up period of 9.21 years. We found that men who consumed two servings per week had 37% lower risk of gastric cancer compared with who consume those who almost never consumed (HR for tofu consumption of more than two servings/week vs. almost never consumed was 0.63 (95% CI 0.45, 0.89); p for trend = 0.04). Among men with a BMI of less than 25 kg/m2, increased consumption of soybean paste (p for trend = 0.02) and tofu (HR 0.51 (95% CI 0.32, 0.82 for more than two servings/week vs. almost never consumed); p for trend = 0.01) was associated with decreased risk of gastric cancer. Conclusion: Our results suggest that a high consumption of soybean products has a protective effect against gastric cancer. [ABSTRACT FROM AUTHOR]

NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is a cytoplasmic multiprotein complex composed of the innate immune receptor protein NLRP3, the adapter protein apoptosis-associate speck-like protein containing a caspase recruitment domain (ASC), and the inflammatory protease cysteine-1. Pathogen-associated molecular patterns (PAMPs) or other endogenous danger-associated molecular patterns (DAMPs) activate the NLRP3 inflammasome. As part of the innate immune response, activated NLRP3 promotes GSDMD-dependent pyroptosis, and IL-1β and IL-18 are released during inflammation. Aberrantly activated NLRP3 is deeply involved in various inflammatory diseases. Due to its interaction with adaptive immunity. NLRP3 inflammation has increasingly received attention in autoimmune diseases. Rheumatoid arthritis (RA) is a classic autoimmune disease, which mainly causes bone and cartilage damage. Elevated levels of NLRP3 can be detected in the synovium of RA patients. NLRP3 overactivation is strongly associated with RA activity. Mouse models of spontaneous arthritis has shown that NLRP3/IL-1β axis is implicated in periarticular inflammation in RA. In this review, we describe the current understanding of NLRP3 activation in RA pathogenesis and dissect its impact on innate and adaptive immunity. We also discuss the potential application of specific inhibitors of NLRP3 to provide new therapeutic strategies for treating RA. [ABSTRACT FROM AUTHOR]

Objective: Mitochondria are found in the extracellular space in rheumatoid arthritis (RA). However, whether mitochondria are a source of autoantigens in RA has not been carefully addressed. Thus, we undertook this study to investigate the presence and significance of antimitochondrial antibodies (AMAs) in patients with RA. Methods: AMAs were measured in serum samples from 3 cross‐sectional cohorts of RA patients (n = 95, n = 192, and n = 117) and healthy individuals (n = 38, n = 72, and n = 50) using a flow cytometry–based assay. Further, AMAs were detected using an anti–mitofusin‐1 (anti–MFN‐1) IgG enzyme‐linked immunosorbent assay and Western blot analysis. A longitudinal inception cohort, followed up for a median of 8 years, was used to study disease progression. Results: AMA levels were elevated in RA patients from all 3 cohorts as compared to healthy individuals (P < 0.001, P < 0.05, and P < 0.01), with a range of 14–26% positivity. Levels of anti–MFN‐1 antibodies correlated with AMA levels (r = 0.31, P = 0.006) and were elevated in RA patients as compared to healthy individuals (P < 0.001). The presence of AMAs was associated with erosive disease (P < 0.05) and interstitial lung disease (P < 0.01). Further, AMA levels were found to predict erosive disease (odds ratio [OR] 4.59, P = 0.006) and joint space narrowing (OR 3.08, P = 0.02) independent of anti–citrullinated protein antibodies. Finally, anti–MFN‐1 antibodies identified seronegative patients developing erosive disease (OR 9.33; P = 0.02). Conclusion: Our findings demonstrate the presence of novel autoantibodies targeting mitochondria in the setting of RA. AMAs were used to stratify patients based on disease phenotype and to predict development of erosive disease, including in patients with seronegative disease. Our results highlight the essential role of mitochondria in the pathogenesis of RA and suggest a possible benefit of therapies targeting mitochondrial‐mediated inflammation and clearance in these patients. [ABSTRACT FROM AUTHOR]

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Summary: Neutrophils are the most abundant innate immune cells in human blood, emerging as important players in a variety of diseases. Mitochondria are bioenergetic, biosynthetic, and signaling organelles critical for cell fate and function. Mitochondria have been overlooked in neutrophil research owing to the conventional view that neutrophils contain few, if any, competent mitochondria and do not rely on these organelles for adenosine triphosphate production. A growing body of evidence suggests that mitochondria participate in neutrophil biology at many levels, ranging from neutrophil development to chemotaxis, effector function, and cell death. Moreover, mitochondria and mitochondrial components, such as mitochondrial deoxyribonucleic acid, can be released by neutrophils to eliminate infection and/or shape immune response, depending on the specific context. In this review, we provide an update on the functional role of mitochondria in neutrophils, highlight mitochondria as key players in modulating the neutrophil phenotype and function during infection and inflammation, and discuss the possibilities and challenges to exploit the unique aspects of mitochondria in neutrophils for disease treatment. [ABSTRACT FROM AUTHOR]

Summary: Human and murine neutrophils differ with respect to representation in blood, receptors, nuclear morphology, signaling pathways, granule proteins, NADPH oxidase regulation, magnitude of oxidant and hypochlorous acid production, and their repertoire of secreted molecules. These differences often matter and can undermine extrapolations from murine studies to clinical care, as illustrated by several failed therapeutic interventions based on mouse models. Likewise, coevolution of host and pathogen undercuts fidelity of murine models of neutrophil‐predominant human infections. However, murine systems that accurately model the human condition can yield insights into human biology difficult to obtain otherwise. The challenge for investigators who employ murine systems is to distinguish models from pretenders and to know when the mouse provides biologically accurate insights. Testing with human neutrophils observations made in murine systems would provide a safeguard but is not always possible. At a minimum, studies that use exclusively murine neutrophils should have accurate titles supported by data and restrict conclusions to murine neutrophils and not encompass all neutrophils. For now, the integration of evidence from studies of neutrophil biology performed using valid murine models coupled with testing in vitro of human neutrophils combines the best of both approaches to elucidate the mysteries of human neutrophil biology. [ABSTRACT FROM AUTHOR]

Summary: Neutrophils are a critical element of host defense and are rapidly recruited to inflammatory sites. Such sites are frequently limited in oxygen and/or nutrient availability, presenting a metabolic challenge for infiltrating cells. Long believed to be uniquely dependent on glycolysis, it is now clear that neutrophils possess far greater metabolic plasticity than previously thought, with the capacity to generate energy stores and utilize extracellular proteins to fuel central carbon metabolism and biosynthetic activity. Out‐with cellular energetics, metabolic programs have also been implicated in the production of neutrophils and their progenitors in the bone marrow compartment, activation of neutrophil antimicrobial responses, inflammatory and cell survival signaling cascades, and training of the innate immune response. Thus, understanding the mechanisms by which metabolic processes sustain changes in neutrophil effector functions and how these are subverted in disease states provides exciting new avenues for the treatment of dysfunctional neutrophilic inflammation which are lacking in clinical practice to date. [ABSTRACT FROM AUTHOR]

Summary: Neutrophils, the most abundant white blood cell in human blood, express receptors that recognize damage/microbial associated pattern molecules of importance for cell recruitment to sites of inflammation. Many of these receptors belong to the family of G protein coupled receptors (GPCRs). These receptor‐proteins span the plasma membrane in expressing cells seven times and the down‐stream signaling rely in most cases on an activation of heterotrimeric G proteins. The GPCRs expressed in neutrophils recognize a number of structurally diverse ligands (activating agonists, allosteric modulators, and inhibiting antagonists) and share significant sequence homologies. Studies of receptor structure and function have during the last 40 years generated important information on GPCR biology in general; this knowledge aids in the overall understanding of general pharmacological principles, governing regulation of neutrophil function and inflammatory processes, including novel leukocyte receptor activities related to ligand recognition, biased/functional selective signaling, allosteric modulation, desensitization, and reactivation mechanisms as well as communication (receptor transactivation/cross‐talk) between GPCRs. This review summarizes the recent discoveries and pharmacological hallmarks with focus on some of the neutrophil expressed pattern recognition GPCRs. In addition, unmet challenges, including recognition by the receptors of diverse ligands and how biased signaling mediate different biological effects are described/discussed. [ABSTRACT FROM AUTHOR]

Cardiac cell death after myocardial infarction release endogenous structures termed damage‐associated molecular patterns (DAMPs) that trigger the innate immune system and initiate a sterile inflammation in the myocardium. Cardiomyocytes are energy demanding cells and 30% of their volume are mitochondria. Mitochondria are evolutionary endosymbionts originating from bacteria containing molecular patterns similar to bacteria, termed mitochondrial DAMPs (mDAMPs). Consequently, mitochondrial debris may be particularly immunogenic and damaging. However, the role of mDAMPs in myocardial infarction is not clarified. Identifying the most harmful mDAMPs and inhibiting their early inflammatory signaling may reduce infarct size and the risk of developing post‐infarct heart failure. The focus of this review is the role of mDAMPs in the immediate pro‐inflammatory phase after myocardial infarction before arrival of immune cells in the myocardium. We discuss different mDAMPs, their role in physiology and present knowledge regarding their role in the inflammatory response of acute myocardial infarction. [ABSTRACT FROM AUTHOR]

Loss of Krev interaction‐trapped‐1 (KRIT1) expression leads to the development of cerebral cavernous malformations (CCM), a disease in which abnormal blood vessel formation compromises the structure and function of the blood–brain barrier. The role of KRIT1 in regulating endothelial function is well‐established. However, several studies have suggested that KRIT1 could also play a role in regulating nonendothelial cell types and, in particular, immune cells. In this study, we generated a mouse model with neutrophil‐specific deletion of KRIT1 in order to investigate the effect of KRIT1 deficiency on neutrophil function. Neutrophils isolated from adult Ly6Gtm2621(cre)Arte Krit1flox/flox mice had a reduced ability to attach and spread on the extracellular matrix protein fibronectin and exhibited a subsequent increase in migration. However, adhesion to and migration on ICAM‐1 was unchanged. In addition, we used a monomeric, fluorescently‐labelled fragment of fibronectin to show that integrin activation is reduced in the absence of KRIT1 expression, though β1 integrin expression appears unchanged. Finally, neutrophil migration in response to lipopolysaccharide‐induced inflammation in the lung was decreased, as shown by reduced cell number and myeloperoxidase activity in lavage samples from Krit1PMNKO mice. Altogether, we show that KRIT1 regulates neutrophil adhesion and migration, likely through regulation of integrin activation, which can lead to altered inflammatory responses in vivo. [ABSTRACT FROM AUTHOR]

Antimicrobial peptides (AMPs) are a potential alternative to antimicrobial agents that have got considerable research interest owing to their significant role in the inhibition of bacterial pathogens. These AMPs can essentially inhibit the growth and multiplication of microbes through multiple mechanisms including disruption of cellular membranes, inhibition of cell wall biosynthesis, or affecting intracellular components and cell division. Moreover, AMPs are biocompatible and biodegradable therefore, they can be a good alternative to antimicrobial agents and chemical preservatives. A few of their features for example thermostability and high selectivity are quite appealing for their potential use in the food industry for food preservation to prevent the spoilage caused by microorganisms and foodborne pathogens. Despite these advantages, very few AMPs are being used at an industrial scale for food preservation as these peptides are quite vulnerable to external environmental factors which deter their practical applications and commercialization. The review aims to provide an outline of the mechanism of action of AMPs and their prospects as an alternative to chemical preservatives in the food industry. Further studies related to the structure–activity relationship of AMPs will help to expand the understanding of their mechanism of action and to determine specific conditions to increase their stability and applicability in food preservation. [ABSTRACT FROM AUTHOR]

Diabetic cardiomyopathy (DCM) is characterized by lipid accumulation, mitochondrial dysfunction, and aseptic inflammatory activation. Mitochondria-derived cytosolic DNA has been reported to induce inflammation by activating cyclic GMP-AMP synthase (cGAS)/the stimulator of interferon genes (STING) pathway in the adipose, liver, and kidney tissues. However, the role of cytosolic mtDNA in the progression of DCM is unclear. In this study, with an obesity-related DCM mouse model established by feeding db/db mice with a high-fat diet (HFD), we observed increased mtDNA in the cytosol and activated cGAS-STING signaling pathway during DCM, as well as the downstream targets, IRF3, NF-κB, IL-18, and IL-1β. In a further study with a palmitic acid (PA)-induced lipotoxic cell model established in H9C2 cells, we revealed that the cytosolic mtDNA was the result of PA-induced overproduction of mitochondrial ROS, which also led to the activation of the cGAS/STING system and its downstream targets. Notably, treatment of extracted mtDNA alone was sufficient to activate the cGAS-STING signaling pathway in cultured H9C2 cells. Besides, both knockdown of STING in PA-induced H9C2 cells and inhibition of STING by C-176 injection in the DCM mouse model could remarkably block the inflammation and apoptosis of cardiomyocytes. In conclusion, our study elucidated the critical role of cytosolic mtDNA-induced cGAS-STING activation in the pathogenesis of obesity-related DCM and provided preclinical validation for using a STING inhibitor as a new potential therapeutic strategy for the treatment of DCM. Highlights: Mitochondria-derived cytosolic DNA acts as a critical linker between hyperlipidemia-induced mitochondrial dysfunction and pathogenesis of DCM. cGAS-STING pathway mediates the lipotoxicity-induced myocardial dysfunction through sensing released cytosolic mtDNA. STING was identified as a new potential therapeutic target for the treatment of DCM. [ABSTRACT FROM AUTHOR]