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Introduction: The term theragnostic refers to the combination of a predictive imaging biomarker with a therapeutic agent. The promising application of prostate-specific membrane antigen (PSMA)-based radiopharmaceuticals in the imaging and treatment of prostate cancer (PCa) patients opens the way to investigate a possible role of PSMA-based radiopharmaceuticals in cancers beyond the prostate. Therefore, the aim of this review was to evaluate the role of 177Lu-PSMA radioligand therapy (RLT) in malignancies other than prostate cancer by evaluating preclinical, clinical studies, and ongoing clinical trials. Methods: An extensive literature search was performed in three different databases using different combinations of the following terms: "Lu-PSMA", "177Lu-PSMA", "preclinical", "mouse", "salivary gland cancer", "breast cancer", "glioblastoma", "solid tumour", "renal cell carcinoma", "HCC", "thyroid", "salivary", "radioligand therapy", and "lutetium-177". The search had no beginning date limit and was updated to April 2024. Only articles written in English were included in this review. Results: A total of four preclinical studies were selected (breast cancer model n = 3/4). PSMA-RLT significantly reduced cell viability and had anti-angiogenic effects, especially under hypoxic conditions, which increase PSMA binding and uptake. Considering the clinical studies (n = 8), the complexity of evaluating PSMA-RLT in cancers other than prostate cancer was clearly revealed, since in most of the presented cases a sufficient tumour radiation dose was not achieved. However, encouraging results can be found in some types of diseases, such as thyroid cancer. Some clinical trials are still ongoing, and results from prospective larger cohorts of patients are awaited. Conclusions: The need for larger patient cohorts and more RLT cycles administered underscores the need for further comprehensive studies. Given the very preliminary results of both preclinical and clinical studies, ongoing clinical trials in the near future may provide stronger evidence of both the safety and therapeutic efficacy of PSMA-RLT in malignancies other than prostate cancer. [ABSTRACT FROM AUTHOR]

In the context of macroevolutionary transitions, environmental changes prompted vertebrates already bearing genetic variations to undergo gradual adaptations resulting in profound anatomical, physiological, and behavioral adaptations. The emergence of new genes led to the genetic variation essential in metazoan evolution, just as was gene loss, both sources of genetic variation resulting in adaptive phenotypic diversity. In this context, F12‐coding protein with defense and hemostatic roles emerged some 425 Mya, and it might have contributed in aquatic vertebrates to the transition from water‐to‐land. Conversely, the F12 loss in marine, air‐breathing mammals like cetaceans has been associated with phenotypic adaptations in some terrestrial mammals in their transition to aquatic lifestyle. More recently, the advent of technological innovations in western lifestyle with blood‐contacting devices and harmful environmental nanoparticles, has unfolded new roles of FXII. Environment operates as either a positive or a relaxed selective pressure on genes, and consequently genes are selected or lost. FXII, an old dog facing environmental novelties can learn new tricks and teach us new therapeutic avenues. [ABSTRACT FROM AUTHOR]

Mammalian plasma kallikrein (PK) and coagulation factor XI (fXI) are serine proteases that play in the kinin–kallikrein cascade and in the blood clotting pathway. These proteases share sequence homology and have four apple domains (APDs) and a serine protease domain (SPD) from their N-terminus to C-terminus. No homologs of these proteases are believed to be present in fish species, except for lobe-finned fish. Fish, however, have a unique lectin, named kalliklectin (KL), which is composed of APDs only. In the present study, we found genomic sequences encoding a protein with both APDs and SPD in a few cartilaginous and bony fishes, including the channel catfish Ictalurus punctatus, using bioinformatic analysis. Furthermore, we purified two ~ 70 kDa proteins from the blood plasma of the catfish using mannose-affinity and gel filtration chromatography sequentially. Using de novo sequencing with quadrupole time-of-flight tandem mass spectrometry, several internal amino acid sequences in these proteins were mapped onto possible PK/fXI-like sequences that are thought to be splicing variants. Exploration of APD-containing proteins in the hagfish genome database and phylogenetic analysis suggested that the PK/fXI-like gene originated from hepatocyte growth factor, and that the gene was acquired in a common ancestor of jawed fish. Synteny analysis provided evidence for chromosomal translocation around the PK/fXI-like locus that occurred in the common ancestor of holosteans and teleosts after separation from the lobe-finned fish lineage, or gene duplication into two chromosomes, followed by independent gene losses. This is the first identification of PK/fXI-like proteins in teleosts. [ABSTRACT FROM AUTHOR]

Objective. This study is aimed at exploring the ability to use heparin-binding protein (HBP) in bronchoalveolar lavage fluid (BALF) to differentially diagnose bacterial infection from viral infection for severe community-acquired pneumonia (CAP) in critically ill children. Methods. A total of 181 children with severe CAP admitted to the intensive care unit (ICU) were included in this study. BALF and blood samples were collected within the first 24 hours of admission. BALF HBP and interleukin-6 (IL-6) concentrations and neutrophil percentage (N%) as well as blood HBP, IL-6, procalcitonin (PCT), C-reactive protein, white blood cell concentrations and N% were measured. Results. Of the enrolled children, 126 were confirmed to have bacterial pneumonia, and 55 were confirmed to have viral pneumonia. Blood HBP and PCT concentrations and N% and BALF HBP and IL-6 concentrations and N% were significantly higher in bacterial pneumonia than in viral pneumonia (P < 0.05). In the bacterial pneumonia group, HBP and IL-6 concentrations and N% in BALF samples were all significantly higher than those in blood samples (P < 0.001), and BALF HBP and IL-6 concentrations and N% were correlated with blood HBP and IL-6 concentrations and N%, respectively (r = 0.439 , 0.250, and 0.235, P < 0.01). BALF N% and blood N% were both correlated with BALF HBP concentrations and blood HBP concentrations, respectively (r = 0.622 and 0.346, P < 0.001). ROC analysis revealed that BALF HBP showed the best ability to predict bacterial pneumonia, with an area under the curve of 0.994, a sensitivity of 95.24%, and a specificity of 100.00% at its optimal cutoff value of 74.05 ng/mL. Conclusion. BALF HBP might be a promising biomarker for the early discrimination of bacterial infection from viral infection in critically ill children with severe CAP. [ABSTRACT FROM AUTHOR]

The complex mechanisms, which are related to the pathophysiology and the development of autoimmune thyroid diseases, involve transforming growth factor beta (TGF-β) and its interplay with the immune system. The aim of this review is to examine the role of TGF-β regarding thyroid autoimmunity and explore the potent role of this molecule either as a diagnostic or prognostic marker or a therapeutic target regarding autoimmune thyroid diseases. TGF-β is clearly a master regulator of the immune response, exerting either inhibitory or facilitatory effects on cells of the immune system. Thus, this molecule is involved in the pathogenesis and development of autoimmune thyroid diseases. Recent research has revealed the involvement of TGF-β in the pathophysiology of autoimmune thyroid diseases. The role of TGF-β in the development of autoimmune thyroid diseases varies, depending on its concentrations, the type of the activated TGF-β signalling pathway, the genetic predisposition of the patient and the pathophysiologic stage of the disease. TGF-β could emerge as a useful diagnostic or prognostic marker for the evolution of thyroid autoimmunity. Promising perspectives for the effective therapeutic use of TGF-β regarding thyroid autoimmunity exist. The main treatment approaches incorporate either enhancement of the immunosuppressive role of TGF-β or inhibition of its facilitatory role in the autoimmune thyroid diseases. Further research towards deeper understanding of TGF-β physiology and clinical application of its possible therapeutic role regarding thyroid autoimmunity is needed. [ABSTRACT FROM AUTHOR]

: Transforming growth factor beta (TGF-β), as a master regulator of immune response, is deeply implicated in the complex pathophysiology and development of autoimmune thyroid diseases. Based on the close interplay between thyroid autoimmunity and TGF-β, scientific interest was shifted to the understanding of the possible role of this molecule regarding the diagnosis, prognosis, and therapy of these diseases. The main aim of this review is to present research data about possible treatment options based on the role of TGF-β in thyroid autoimmunity. Suggested TGF-β-mediated therapeutic strategies regarding autoimmune thyroid diseases include either the enhancement of its immunosuppressive role or inhibition of its facilitatory role in thyroid autoimmunity. For example, the application of hr-TGF-β can be used to bolster the inhibitory role of TGF-β regarding the development of thyroid diseases, whereas anti-TGF-β antibodies and similar molecules could impede its immune-promoting effects by blocking different levels of TGF-β biosynthesis and activation pathways. In conclusion, TGF-β could evolve to a promising, novel therapeutic tool for thyroid autoimmunity. [ABSTRACT FROM AUTHOR]

Beer is a hostile environment for microorganisms to survive. However, some strains of lactic acid bacteria (LAB) have chosen this harsh environment for their ecological niche and evolved by incrementally acquiring various genetic elements to overcome a range of growth hurdles posed by beer. In fact, over 100 genes appear to be involved for one beer spoilage LAB strain to grow in and spoil beer. Although many of them are chromosomally encoded genes, an increasing number of brewery-specific genetic clusters have been also identified on plasmids, which are often horizontally shared by a variety of beer spoilage LAB species/strains. These plasmid-localized genetic factors were once represented by hop tolerance genes, such as horA, horC, and hitA, that were uncovered in the early days of hop tolerance research. But the recent evidence increasingly indicates that beer spoilage potential of LAB is conferred by multifactorial and complex adaptive responses that are related to a large number of defense mechanisms, including divalent cation homeostasis, cell envelope modification, oxidative stress response, and pH homeostasis. Many of these defense systems have been shown to be encoded on plasmids that are carried by beer spoilage LAB. In the past decade, new plasmid-encoded diagnostic marker genes (DMGs), such as gtfD15 and fabZ, have been additionally reported for the discrimination of beer spoilage potential of LAB strains. This review summarizes the recent progress in this area of research and provides some insights into the microbiological quality control (QC) tests adopted in brewery laboratories. [ABSTRACT FROM AUTHOR]

Chronic obstructive pulmonary disease (COPD) is a complex disease caused by the disturbance of genetic and environmental factors. Single-nucleotide polymorphisms (SNPs) play a vital role in the genetic dissection of complex diseases. In-depth analysis of SNP-related information could recognize disease-associated biomarkers and further uncover the genetic mechanism of complex diseases. Risk-related variants might act on the disease by affecting gene expression and gene function. Through integrating SNP disease association study and expression quantitative trait loci (eQTL) analysis, as well as functional enrichment of containing known causal genes, four risk SNPs and four corresponding susceptibility genes were identified utilizing next-generation sequencing (NGS) data of COPD. Of the four risk SNPs, one could be found in the SNPedia database that stored disease-related SNPs and has been linked to a disease in the literature. Four genes showed significant differences from the perspective of normal/disease or variant/nonvariant samples, as well as the high performance of sample classification. It is speculated that the four susceptibility genes could be used as biomarkers of COPD. Furthermore, three of our susceptibility genes have been confirmed in the literature to be associated with COPD. Among them, two genes had an impact on the significance of expression correlation of known causal genes they interact with, respectively. Overall, this research may present novel insights into the diagnosis and pathogenesis of COPD and susceptibility gene identification of other complex diseases. [ABSTRACT FROM AUTHOR]

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is an unexplained chronic, debilitating illness characterized by fatigue, sleep disturbances, cognitive dysfunction, orthostatic intolerance and gastrointestinal problems. Using ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), we analyzed the plasma proteomes of 39 ME/CFS patients and 41 healthy controls. Logistic regression models, with both linear and quadratic terms of the protein levels as independent variables, revealed a significant association between ME/CFS and the immunoglobulin heavy variable (IGHV) region 3-23/30. Stratifying the ME/CFS group based on self-reported irritable bowel syndrome (sr-IBS) status revealed a significant quadratic effect of immunoglobulin lambda constant region 7 on its association with ME/CFS with sr-IBS whilst IGHV3-23/30 and immunoglobulin kappa variable region 3–11 were significantly associated with ME/CFS without sr-IBS. In addition, we were able to predict ME/CFS status with a high degree of accuracy (AUC = 0.774–0.838) using a panel of proteins selected by 3 different machine learning algorithms: Lasso, Random Forests, and XGBoost. These algorithms also identified proteomic profiles that predicted the status of ME/CFS patients with sr-IBS (AUC = 0.806–0.846) and ME/CFS without sr-IBS (AUC = 0.754–0.780). Our findings are consistent with a significant association of ME/CFS with immune dysregulation and highlight the potential use of the plasma proteome as a source of biomarkers for disease. [ABSTRACT FROM AUTHOR]

Objectives: We aimed to describe the variation of hemostasis proteins in children with bacterial infections due to different pathogens ( Neisseria meningitidis, Streptococcus pneumoniae, Staphylococcus aureus , and group A streptococcus [GAS]) and to study hemostasis proteins in relation to mortality., Design: Preplanned analysis in prospective cohort study., Setting: Hospitals in five European countries (Austria, The Netherlands, Spain, Switzerland, and the United Kingdom)., Patients: Admitted children (2012-2016) with community-acquired infections due to meningococci ( n = 83), pneumococci ( n = 64), S. aureus (n = 50), and GAS ( n = 44) with available serum samples collected less than 48 hours after admission., Interventions: None., Measurements and Main Results: Fibronectin, plasminogen activator inhibitor type 1 (PAI-1), thrombomodulin, and a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS-13) were measured in serum in 2019-2020. Additionally, von Willebrand factor, protein C, protein S, and factor IX were measured in citrate plasma available from a subset of patients. Outcome measures included in-hospital mortality and disease severity (need for ventilation/inotropes, Pediatric Index of Mortality score).Of 241 children, 21 (8.7%) died and 177 (73.5%) were admitted to PICU. Mortality rate was similar for the pathogen groups. Levels of fibronectin and thrombomodulin differed for the different pathogens ( p < 0.05). Fibronectin levels were lower in GAS infections than in S. pneumoniae and S. aureus infections but did not differ from meningococcal infections. Thrombomodulin levels in meningococcal infections were higher than in S. aureus and pneumococcal infections. Overall, the area under the curve for mortality was 0.81 (95% CI, 0.70-0.92) for thrombomodulin and 0.78 (95% CI, 0.69-0.88) for ADAMTS-13. The association of each hemostasis protein did not vary across pathogens for any of the outcome measures., Conclusions: Hemostatic disturbances in childhood bacterial infections are not limited to meningococcal sepsis but occur with a comparable severity across nonmeningococcal infections. High thrombomodulin and high ADAMTS-13 had good discriminative ability for mortality. Our results emphasize the importance of hemostatic disturbances in meningococcal and nonmeningococcal pediatric bacterial infections., Competing Interests: Drs. Hagedoorn’s and Zenz’s institutions received funding from the European Union (EU). Dr. Boeddha received funding from GlaxoSmithKline. Drs. Kohlfuerst’s, Hazelzet’s, and Emonts’ institutions received funding from EU Project European Union Childhood Life-threatening Infectious Disease study (EUCLIDS). Dr. Kohlfuerst received support for article research from EU Project EUCLIDS. Drs. Carrol, van der Flier, and Herberg received support for article research from EU Horizon 2020. Dr. Hazelzet’s institution received funding from Erasmus Medical Centre. Dr. Zenz received support for article research from the EU. Dr. Driessen’s institution received funding from Merck and the Elizabeth von Freyburg Foundation. Dr. Emonts’ institution received funding from the EU, FP7, EU H2020 Personalized Risk assessment in Febrile illness to Optimize Real-life Management across the European Union (PERFORM), and EU H2020 Diagnosis and Management of Febrile Illness using RNA Personalised Molecular Signature Diagnosis (DIAMONDS). The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

Characterisation of fetal fluids in healthy and disease states of pregnant mares can help to unravel the pathophysiology and to identify putative markers of disease. Thus, this study aimed to compare the protein composition of: (1) amniotic and allantoic fluids of healthy mares obtained immediately after euthanasia and (2) allantoic fluid harvested via centesis before and after experimental induction of placentitis via transcervical inoculation of Streptococcus equi ssp zooepidemicus in healthy mares. Fetal fluids were analysed with a high-throughput proteomic technique after in-gel digestion. Statistical comparisons were performed following normalisation of peptide spectral match. Global normalisation was performed to calculate relative expression. There were 112 unique proteins present in both allantoic and amniotic fluids. There were 13 and 29 proteins defined as amniotic- or allantoic-specific respectively that were present in at least two fluid samples. Another 26 proteins were present in both amniotic and allantoic fluids. Panther DB functional classification grouped fetal-fluid proteins as transfer carriers, signalling molecules, receptors, immunity, hydrolase, enzymes, membrane traffic, cytoskeleton, cell adhesion, calcium binding and extracellular matrix. Experimentally induced placentitis resulted in 10 proteins being upregulated and 10 downregulated in allantoic fluid. Newly identified proteins and changes in the fetal-fluid proteome provide clues about the physiology of pregnancy and pathogenesis of placentitis. Characterisation of fetal fluids can help to unravel the pathophysiology of placentitis. Protein composition of amniotic and allantoic fluids of healthy mares and mares with placentitis were assessed. One-hundred and twelve proteins were present in allantoic and amniotic fluids. Placentitis resulted in 10 proteins being upregulated and 10 downregulated in allantoic fluid. The findings in this paper suggest that fetal-fluid proteomics has the potential to be a useful technique to better understand the pathophysiology of disease. [ABSTRACT FROM AUTHOR]

Activation of the contact system generates bradykinin from high‐molecular‐weight kininogen and has been suggested to participate in the pathophysiology of sepsis. To test this, we prospectively measured bradykinin and high‐molecular‐weight kininogen levels in a cohort of sepsis patients requiring intensive care. From 29 patients meeting criteria for sepsis or septic shock according to Sepsis‐3, blood was sampled within 24 h and on the fourth day following admittance to intensive care. Patients planned for neurosurgery served as matched controls. Sequential organ failure assessment score and 90‐day mortality was registered. Bradykinin levels (median [interquartile range]) were lower in sepsis patients (79 [62–172] pg/ml) compared to controls (130 [86–255] pg/ml, p < 0.025) and did not correlate with mortality or severity of circulatory derangement. High‐molecular‐weight kininogen levels were lower in sepsis patients (1.6 [0.8–4.8] densitometry units) compared to controls (4.4 [2.9–7.7] densitometry units, p < 0.001), suggesting previous contact system activation. High‐molecular‐weight kininogen levels were lower in non‐survivors than survivors (p = 0.003) and negatively correlated to severity of circulatory derangement. We conclude that a role for bradykinin in later stages of severe sepsis must be challenged. Low high‐molecular‐weight kininogen concentrations suggest that the decrease in bradykinin is due to substrate depletion. [ABSTRACT FROM AUTHOR]

Plasma contact system is the initial part of both the intrinsic coagulation pathway and kallikrein–kinin pathway, which mainly involves three proteins: coagulation factor XII (FXII), prekallikrein (PK) and high-molecular weight kininogen. Fucosylated chondroitin sulfate (FCS) is a unique sulfated glycosaminoglycan (GAG) composed of a chondroitin sulfate-like backbone and sulfated fucose branches. The native FCS was preliminary found to cause undesired activation of the plasma contact system. How this unusual GAG functions in this process remains to be clarified. Herein, the relationship between its structure, plasma contact activation and its effects on the PK–FXII reciprocal activation loop were studied. The recalcification time assay indicated that the FCS at high concentration could be procoagulant which may be attributed to its contact activation activity. The structure–activity relationship study indicated that its high molecular weight and distinct fucose side chains are required for contact activation by FCS, although the sulfate substitution types of its side chains have less impact. In human plasma, the native FCSs potently induced FXII-dependent contact activation. However, in purified systems FCS did not significantly activate FXII per se or induce its autoactivation, whereas FCS significantly promoted the activation of PK by factor XIIa. Polysaccharide–protein interaction assays showed that FCS bound to PK with higher affinity than other contact system proteins. These data suggested that potent contact activation by FCS requires the positive feedback loop between PK and FXII. These findings contribute to better understanding of contact activation by complex GAG. [ABSTRACT FROM AUTHOR]

Exposure of blood to a variety of artificial surface induces contact activation, a process that contributes to the host innate response to foreign substances. On the foreign surface, the contact factors, factor XII (FXII), and plasma prekallikrein undergo reciprocal conversion to their fully active protease forms (FXIIa and a-kallikrein, respectively) by a process supported by the cofactor high-molecular-weight kininogen. Contact activation can trigger blood coagulation by conversion of factor XI (FXI) to the protease FXIa. There is interest in developing therapeutic inhibitors to FXIa and FXIIa because these activated factors can contribute to thrombosis in certain situations. Drugs targeting these proteases may be particularly effective in thrombosis triggered by exposure of blood to the surfaces of implantable medical devices. Here, we review clinical data supporting roles for FXII and FXI in thrombosis induced by medical devices, and preclinical data suggesting that therapeutic targeting of these proteins may limit surface-induced thrombosis. [ABSTRACT FROM AUTHOR]

Streptococcus gallolyticus subsp. gallolyticus, formerly classified as S. bovis biotype I, is an increasing cause of bacteremia and infective endocarditis in the elderly. The physiopathology of infective endocarditis is poorly understood and involves immune and coagulation systems. In this study, we found that S. gallolyticus subsp. gallolyticus activates the human contact system, which in turn has two consequences: cleavage of high-molecular-weight kininogen (HK) resulting in release of the potent pro-inflammatory peptide bradykinin, and initiation of the intrinsic pathway of coagulation. S. gallolyticus subsp. gallolyticus was found to bind and activate factors of the human contact system at its surface, leading to a significant prolongation of the intrinsic coagulation time and to the release of bradykinin. High-affinity binding of factor XII to the bacterial Pil1 collagen binding protein was demonstrated with a KD of 13 nM. Of note, Pil1 expression was exclusively found in S. gallolyticus subsp. gallolyticus, further supporting an essential contribution of this pilus in virulence. [ABSTRACT FROM AUTHOR]

Kallistatin, an endogenous serine proteinase inhibitor, is protective against sepsis in animal models. The aim of this study was to determine the plasma concentration of kallistatin in intensive care unit (ICU) patients with severe sepsis and septic shock and to determine their potential correlation with disease severity and outcomes. We enrolled 86 ICU patients with severe sepsis and septic shock. Their plasma concentrations of kallistatin, kallikrein, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and IL-8 were measured by enzyme-linked immunosorbent assay. The association of kallistatin levels with disease severity and patient outcomes was evaluated. The relationship between kallistatin and other biomarkers was also analyzed. Plasma kallistatin levels on day 1 of ICU admission were lower in patients with septic shock compared with patients with severe sepsis (p = 0.004). Twenty-nine patients who died in the hospital had significantly lower day 1 kallistatin levels than patients who survived (p = 0.031). Using the optimal cutoff value (4 μg/ml) of day 1 plasma kallistatin determined by receiver operating characteristic curves for 60-day mortality, we found that high kallistatin levels were associated with a preferable 60-day survival (p = 0.012) by Kaplan-Meier analysis and lower Sequential Organ Failure Assessment (SOFA) scores over the first 5 days in the ICU (p = 0.001). High kallistatin levels were also independently associated with a decreased risk of septic shock, the development of acute respiratory distress syndrome, and positive blood cultures. In addition, there were inverse correlations between day 1 kallistatin levels and the levels of TNF-α, IL-1β, IL-6, and C-reactive protein, and SOFA scores on day 1. Our results indicate that during severe sepsis and septic shock, a decrease in plasma concentrations of kallistatin reflects increased severity and poorer outcome of disease. [ABSTRACT FROM AUTHOR]

Mannose-binding lectin ( MBL)-associated serine proteases ( MASPs) are the enzymatic constituents of the lectin pathway of the complement system. They are complexed with large pattern recognition molecules ( PRMs) such as MBL, other collectins, and ficolins. The main function of two of the three MASPs has crystallized lately: MASP-1 autoactivates first, then it activates MASP-2, and finally both participate in the formation of the C4b2a convertase. In addition to this, both enzymes are involved in several other processes which are subject to intense research nowadays. Notably, MASP-1, as a promiscuous enzyme, has been implicated in the coagulation cascade, in the kinin generating contact system, and in cellular activation through protease-activated receptor ( PAR) cleavage on endothelial cells. The third protease MASP-3 has emerged recently as the protease responsible for pro-factor D activation in resting blood, providing a fundamental link between two complement pathways. At present all three MASPs have at least one well-defined role and several other possible functions were implicated. Defect or more likely over-activation of MASPs may culminate into diseases such as ischemia-reperfusion injury ( IRI); hence, MASPs are all potential targets of drug development. [ABSTRACT FROM AUTHOR]

The complement system is a major constituent of the innate immune system. It not only bridges innate, adaptive arms of the immune system but also links the immune system with the coagulation system. Current understanding of the role of complement has extended far beyond fighting of infections,, now encompasses maintenance of homeostasis, tissue regeneration,, pathophysiology of multiple diseases. It has been known for many years that complement activation is strongly pH sensitive, but only relatively recently has the physiological significance of this been appreciated. Most complement assays are carried out at the physiological pH 7.4. However, pH in some extracellular compartments, for example, renal tubular fluid in parts of the tubule,, extracellular fluid at inflammation loci, is sufficiently acidic to activate complement. The exact molecular mechanism of this activation is still unclear, but possible cross-talk between the contact system (intrinsic pathway), complement may exist at low pH with subsequent complement activation. The current article reviews the published data on the effect of pH on the contact system, complement activity, the nature of the pH sensor molecules,, the clinical implications of these effects. Of particular interest is chronic kidney disease (CKD) accompanied by metabolic acidosis, in which therapeutic alkalinization of urine has been shown significantly to reduce tubular complement activation products, an effect, which may have important implications for slowing progression of CKD. [ABSTRACT FROM AUTHOR]

Background: Candida albicans yeast produces 10 distinct secreted aspartic proteases (Saps), which are some of the most important virulence factors of this pathogenic fungus. One of the suggested roles of Saps is their deregulating effect on various proteolytic cascades that constitute the major homeostatic systems in human hosts, including blood coagulation, fibrinolysis, and kallikrein-kinin systems. This study compared the characteristics of the action of all 10 Saps on human kininogens, which results in generating proinflammatory bradykinin-related peptides (kinins). Results: Recombinant forms of Saps, heterologously overexpressed in Pichia pastoris were applied. Except for Sap7 and Sap10, all Saps effectively cleaved the kininogens, with the highest hydrolytic activity toward the low-molecular-mass form (LK). Sap1-6 and 8 produced a biologically active kinin-Met-Lys-bradykinin-and Sap3 was exceptional in terms of the kinin-releasing yield (>60% LK at pH 5.0 after 24 hours). Des-Arg1-bradykinin was released from LK by Sap9 at a comparably high yield, but this peptide was assumed to be biologically inactive because it was unable to interact with cellular B2-type kinin receptors. However, the collaborative actions of Sap9 and Sap1, -2, -4-6, and -8 on LK rerouted kininogen cleavage toward the high-yield release of the biologically active Met-Lys-bradykinin. Conclusions: Our present results, together with the available data on the expression of individual SAP genes in candidal infection models, suggest a biological potential of Saps to produce kinins at the infection foci. The kinin release during candidiasis can involve predominant and complementary contributions of two different Sap3- and Sap9-dependent mechanisms. [ABSTRACT FROM AUTHOR]

Two distinct defense strategies can protect the host from infection: resistance is the ability to destroy the infectious agent, and tolerance is the ability to withstand infection by minimizing the negative impact it has on the host's health without directly affecting pathogen burden. Burkholderia pseudomallei is a Gram-negative bacterium that infects macrophages and causes melioidosis. We have recently shown that inflammasome-triggered pyroptosis and IL-18 are equally important for resistance to B. pseudomallei, whereas IL-1β is deleterious. Here we show that the detrimental role of IL-1β during infection with B. pseudomallei (and closely related B. thailandensis) is due to excessive recruitment of neutrophils to the lung and consequent tissue damage. Mice deficient in the potentially damaging enzyme neutrophil elastase were less susceptible than the wild type C57BL/6J mice to infection, although the bacterial burdens in organs and the extent of inflammation were comparable between C57BL/6J and elastase-deficient mice. In contrast, lung tissue damage and vascular leakage were drastically reduced in elastase-deficient mice compared to controls. Bradykinin levels were higher in C57BL/6 than in elastase-deficient mice; administration of a bradykinin antagonist protected mice from infection, suggesting that increased vascular permeability mediated by bradykinin is one of the mechanisms through which elastase decreases host tolerance to melioidosis. Collectively, these results demonstrate that absence of neutrophil elastase increases host tolerance, rather than resistance, to infection by minimizing host tissue damage. [ABSTRACT FROM AUTHOR]

Sepsis and septic shock remain important medical problems with high mortality rates. Today's treatment is based mainly on using antibiotics to target the bacteria, without addressing the systemic inflammatory response, which is a major contributor to mortality in sepsis. Therefore, novel treatment options are urgently needed to counteract these complex sepsis pathologies. Heparin cofactor II (HCII) has recently been shown to be protective against Gram-negative infections. The antimicrobial effects were mapped to helices A and D of the molecule. Here we show that KYE28, a 28 amino acid long peptide representing helix D of HCII, is antimicrobial against the Gram-negative bacteria Escherichia coli and Pseudomonas aeruginosa, the Gram-positive Bacillus subtilis and Staphylococcus aureus, as well as the fungus Candida albicans. Moreover, KYE28 binds to LPS and thereby reduces LPS-induced pro-inflammatory responses by decreasing NF-κB/AP-1 activation in vitro. In mouse models of LPS-induced shock, KYE28 significantly enhanced survival by dampening the pro-inflammatory cytokine response. Finally, in an invasive Pseudomonas infection model, the peptide inhibited bacterial growth and reduced the pro-inflammatory response, which lead to a significant reduction of mortality. In summary, the peptide KYE28, by simultaneously targeting bacteria and LPS-induced pro-inflammatory responses represents a novel therapeutic candidate for invasive infections. [ABSTRACT FROM AUTHOR]

Sepsis is characterized by a dysregulated host-pathogen response, leading to high cytokine levels, excessive coagulation and failure to eradicate invasive bacteria. Novel therapeutic strategies that address crucial pathogenetic steps during infection are urgently needed. Here, we describe novel bioactive roles and therapeutic anti-infective potential of the peptide EDC34, derived from the C-terminus of tissue factor pathway inhibitor-2 (TFPI-2). This peptide exerted direct bactericidal effects and boosted activation of the classical complement pathway including formation of antimicrobial C3a, but inhibited bacteria-induced activation of the contact system. Correspondingly, in mouse models of severe Escherichia coli and Pseudomonas aeruginosa infection, treatment with EDC34 reduced bacterial levels and lung damage. In combination with the antibiotic ceftazidime, the peptide significantly prolonged survival and reduced mortality in mice. The peptide's boosting effect on bacterial clearance paired with its inhibiting effect on excessive coagulation makes it a promising therapeutic candidate for invasive Gram-negative infections. [ABSTRACT FROM AUTHOR]

Both the complement system and tissue factor ( TF), a key initiating component of coagulation, are activated in sepsis, and cross-talk occurs between the complement and coagulation systems. C1-inhibitor ( C1- INH) can act as a regulator in both systems. Our aim in this study was to examine this cross-talk by investigating the effects of C1- INH on Escherichia coli-induced haemostasis and inflammation. Fresh human whole blood collected in lepirudin was incubated with E. coli or ultrapurified E. coli lipopolysaccharide ( LPS) in the absence or presence of C1- INH or protease-inactivated C1- INH. C3 activation was blocked by compstatin, a specific C3 convertase inhibitor. TF mRNA was measured using reverse transcription-quantitative polymerase chain reaction ( RT- qPCR), and TF surface expression was measured by flow cytometry. In plasma, the terminal complement complex, prothrombin F1·2 ( PTF1·2) and long pentraxin 3 ( PTX3) were measured by enzyme-linked immunosorbent assay ( ELISA). Cytokines were analysed using a multiplex kit. C1- INH (1·25-5 mg/ml) reduced both LPS- and E. coli-induced coagulation, measured as a reduction of PTF1·2 in plasma, efficiently and dose-dependently ( P < 0·05). Both LPS and E. coli induced marked up-regulation of TF mRNA levels and surface expression on whole blood monocytes. This up-regulation was reduced efficiently by treatment with C1- INH ( P < 0·05). C1- INH reduced the release of PTX3 ( P < 0·05) and virtually all cytokines measured ( P < 0·05). Complement activation was inhibited more efficiently with compstatin than with C1- INH. C1- INH inhibited most of the other readouts more efficiently, consistent with additional non-complement-dependent effects. These results indicate that complement plays a role in activating coagulation during sepsis and that C1- INH is a broad-spectrum attenuator of the inflammatory and haemostatic responses. [ABSTRACT FROM AUTHOR]

Introduction: Community-acquired pneumonia (CAP) requiring intensive care unit (ICU) treatment commonly causes acute respiratory failure with high mortality. Kallistatin, an endogenous tissue kallikrein inhibitor, has been reported to be protective in various human diseases. The aim of this study was to assess the correlations of kallistatin with other biomarkers and to determine whether kallistatin levels have a prognostic value in severe CAP. Methods: Plasma samples and clinical data were prospectively collected from 54 patients with severe CAP requiring ICU admission. Seventeen healthy control subjects were included for comparison. Plasma kallistatin, kallikrein, and other biomarkers of inflammation (tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, IL-8, C-reactive protein (CRP)), and anti-coagulation (protein C, anti-thrombin III) were measured on days 1 and 4 of ICU admission. Comparison between survivors (n = 41) and nonsurvivors (n = 13) was performed. Results: Plasma kallistatin was significantly consumed in severe CAP patients compared with healthy individuals. Lower day 1 kallistatin levels showed a strong trend toward increased mortality (P = 0.018) and higher day 1 CURB-65 scores (P = 0.004). Plasma kallistatin levels on day 1 of ICU admission were significantly decreased in patients who developed septic shock (P = 0.017) and who had acute respiratory distress syndrome (P = 0.044). In addition, kallistatin levels were positively correlated with anti-thrombin III and protein C and inversely correlated with IL-1β, IL-6, and CRP levels. In a multivariate logistic regression analysis, higher day 1 CURB-65 scores were independent predictors of mortality (odds ratio = 29.9; P = 0.009). Also, higher day 1 kallistatin levels were independently associated with a decreased risk of death (odds ratio, 0.1) with a nearly significant statistical difference (P = 0.056). Furthermore, we found that a cutoff level of 6.5 µg/ml of day 1 kallistatin determined by receiver operating characteristic curves could be used to distinguish between patients who survived in 60 days and those who did not. Conclusions: These results suggest that kallistatin may serve as a novel marker for severe CAP prognosis and may be involved in the pathogenesis of CAP through antiinflammatory and anticoagulation effects. [ABSTRACT FROM AUTHOR]

Gram-negative sepsis is accompanied by a disproportionate innate immune response and excessive coagulation mainly induced by endotoxins released from bacteria. Due to rising antibiotic resistance and current lack of other effective treatments there is an urgent need for new therapies. We here present a new treatment concept for sepsis and endotoxin-mediated shock, based on host defense peptides from the C-terminal part of human thrombin, found to have a broad and inhibitory effect on multiple sepsis pathologies. Thus, the peptides abrogate pro-inflammatory cytokine responses to endotoxin in vitro and in vivo. Furthermore, they interfere with coagulation by modulating contact activation and tissue factor-mediated clotting in vitro, leading to normalization of coagulation responses in vivo, a previously unknown function of host defense peptides. In a mouse model of Pseudomonas aeruginosa sepsis, the peptide GKY25, while mediating a modest antimicrobial effect, significantly inhibited the pro-inflammatory response, decreased fibrin deposition and leakage in the lungs, as well as reduced mortality. Taken together, the capacity of such thrombin-derived peptides to simultaneously modulate bacterial levels, pro-inflammatory responses, and coagulation, renders them attractive therapeutic candidates for the treatment of invasive infections and sepsis. [ABSTRACT FROM AUTHOR]

Sepsis, the systemic inflammatory response to infection, represents the major cause of death in critically ill veterinary patients. Whereas important advances in our understanding of the pathophysiology of this syndrome have been made, much remains to be elucidated. There is general agreement on the key interaction between pathogen-associated molecular patterns and cells of the innate immune system, and the amplification of the host response generated by pro-inflammatory cytokines. More recently, the concept of immunoparalysis in sepsis has also been advanced, together with an increasing recognition of the interplay between regulatory T cells and the innate immune response. However, the heterogeneous nature of this syndrome and the difficulty of modeling it in vitro or in vivo has both frustrated the advancement of new therapies and emphasized the continuing importance of patient-based clinical research in this area of human and veterinary medicine. [ABSTRACT FROM AUTHOR]

Vasculitis is a systemic autoimmune inflammatory disease, characterized by inflammation in and around vessel walls leading to perturbed vessel patency and tissue damage. Many different organs may be involved. In this review, pathogenetic mechanisms of vasculitis are discussed, with special reference to activation of the kinin system. Mechanisms of kinin system activation are described, ultimately leading to release of kinins from high molecular weight kininogen. These vasoactive peptides promote inflammation. Kinin system activation during vasculitis promotes inflammation. [ABSTRACT FROM AUTHOR]

Bradykinin (BK), generated from high-molecular-weight kininogen (HK) is the major mediator of swelling attacks in hereditary angioedema (HAE), a disease associated with C1-inhibitor deficiency. Plasma kallikrein, activated by factor XIIa, is responsible for most of HK cleavage. However other proteases, which activate during episodes of angioedema, might also contribute to BK production. The lectin pathway of the complement system activates after infection and oxidative stress on endothelial cells generating active serine proteases: MASP-1 and MASP-2. Our aim was to study whether activated MASPs are able to digest HK to release BK. Initially we were trying to find potential new substrates of MASP-1 in human plasma by differential gel electrophoresis, and we identified kininogen cleavage products by this proteomic approach. As a control, MASP-2 was included in the study in addition to MASP-1 and kallikrein. The proteolytic cleavage of HK by MASPs was followed by SDS-PAGE, and BK release was detected by HPLC. We showed that MASP-1 was able to cleave HK resulting in BK production. MASP-2 could also cleave HK but could not release BK. The cleavage pattern of MASPs is similar but not strictly identical to that of kallikrein. The catalytic efficiency of HK cleavage by a recombinant version of MASP-1 and MASP-2 was about 4.0x102 and 2.7x102 M-1s21, respectively. C1-inhibitor, the major inhibitor of factor XIIa and kallikrein, also prevented the cleavage of HK by MASPs. In all, a new factor XII- and kallikrein-independent mechanism of bradykinin production by MASP-1 was demonstrated, which may contribute to the pro-inflammatory effect of the lectin pathway of complement and to the elevated bradykinin levels in HAE patients. [ABSTRACT FROM AUTHOR]