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Frontiers in Cellular and Infection... 2021, also known as pneumococcus, is a Gram-positive diplococcus and a major human pathogen. This bacterium is a leading cause of bacterial pneumonia, otitis media,... (Review)
Review
, also known as pneumococcus, is a Gram-positive diplococcus and a major human pathogen. This bacterium is a leading cause of bacterial pneumonia, otitis media, meningitis, and septicemia, and is a major cause of morbidity and mortality worldwide. To date, studies on have mainly focused on the role of its virulence factors including toxins, cell surface proteins, and capsules. However, accumulating evidence indicates that in addition to these studies, knowledge of host factors and host-pathogen interactions is essential for understanding the pathogenesis of pneumococcal diseases. Recent studies have demonstrated that neutrophil accumulation, which is generally considered to play a critical role in host defense during bacterial infections, can significantly contribute to lung injury and immune subversion, leading to pneumococcal invasion of the bloodstream. Here, we review bacterial and host factors, focusing on the role of neutrophils and their elastase, which contribute to the progression of pneumococcal pneumonia.
Topics: Bacterial Proteins; Humans; Leukocyte Elastase; Neutrophils; Pneumococcal Infections; Pneumonia, Pneumococcal; Streptococcus pneumoniae
PubMed: 33796475
DOI: 10.3389/fcimb.2021.615959 -
Journal of Enzyme Inhibition and... Dec 2021Elastase is a proteolytic enzyme belonging to the family of hydrolases produced by human neutrophils, monocytes, macrophages, and endothelial cells. Human neutrophil... (Review)
Review
Elastase is a proteolytic enzyme belonging to the family of hydrolases produced by human neutrophils, monocytes, macrophages, and endothelial cells. Human neutrophil elastase is known to play multiple roles in the human body, but an increase in its activity may cause a variety of diseases. Elastase inhibitors may prevent the development of psoriasis, chronic kidney disease, respiratory disorders (including COVID-19), immune disorders, and even cancers. Among polyphenolic compounds, some flavonoids and their derivatives, which are mostly found in herbal plants, have been revealed to influence elastase release and its action on human cells. This review focuses on elastase inhibitors that have been discovered from natural sources and are biochemically characterised as flavonoids. The inhibitory activity on elastase is a characteristic of flavonoid aglycones and their glycoside and methylated, acetylated and hydroxylated derivatives. The presented analysis of structure-activity relationship (SAR) enables the determination of the chemical groups responsible for evoking an inhibitory effect on elastase. Further study especially of the efficacy and safety of the described natural compounds is of interest in order to gain better understanding of their health-promoting potential.
Topics: COVID-19; Enzyme Inhibitors; Flavonoids; Humans; Leukocyte Elastase; Neoplasms; Neutrophils; Structure-Activity Relationship; COVID-19 Drug Treatment
PubMed: 33980119
DOI: 10.1080/14756366.2021.1927006 -
Respiratory Research Dec 2017The role of neutrophil elastase (NE) is poorly understood in bronchiectasis because of the lack of preclinical data and so most of the assumptions made about NE... (Review)
Review
The role of neutrophil elastase (NE) is poorly understood in bronchiectasis because of the lack of preclinical data and so most of the assumptions made about NE inhibitor potential benefit is based on data from CF. In this context, NE seems to be a predictor of long-term clinical outcomes and a possible target of treatment. In order to better evaluate the role of NE in bronchiectasis, a systematic search of scientific evidence was performed.Two investigators independently performed the search on PubMed and included studies published up to May 15, 2017 according to predefined criteria. A final pool of 31 studies was included in the systematic review, with a total of 2679 patients. For each paper data of interest were extracted and reported in table.In this review sputum NE has proved useful as an inflammatory marker both in stable state bronchiectasis and during exacerbations and local or systemic antibiotic treatment. NE has also been associated with risk of exacerbation, time to next exacerbation and all-cause mortality. This study reviews also the role of NE as a specific target of treatment in bronchiectasis. Inhibition of NE is at a very early stage and future interventional studies should evaluate safety and efficacy for new molecules and formulations.
Topics: Biomarkers; Bronchiectasis; Cross-Sectional Studies; Humans; Leukocyte Elastase; Sputum
PubMed: 29258516
DOI: 10.1186/s12931-017-0691-x -
International Journal of Molecular... Mar 2022Elastases are a broad group of enzymes involved in the lysis of elastin, the main component of elastic fibres. They are produced and released in the human body, mainly... (Review)
Review
Elastases are a broad group of enzymes involved in the lysis of elastin, the main component of elastic fibres. They are produced and released in the human body, mainly by neutrophils and the pancreas. The imbalance between elastase activity and its endogenous inhibitors can cause different illnesses due to their excessive activity. The main aim of this review is to provide an overview of the latest advancements on the identification, structures and mechanisms of action of peptide human neutrophil elastase inhibitors isolated from natural sources, such as plants, animals, fungi, bacteria and sponges. The discovery of new elastase inhibitors could have a great impact on the pharmaceutical development of novel drugs through the optimization of the natural . Bacteria produce mainly cyclic peptides, while animals provide for long and linear amino acid sequences. Despite their diverse natural sources, these elastase inhibitors show remarkable IC values in a range from nM to μM values, thus representing an interesting starting point for the further development of potent bioactive compounds on human elastase enzymes.
Topics: Animals; Humans; Leukocyte Elastase; Neutrophils; Peptides; Proteinase Inhibitory Proteins, Secretory; Serine Proteinase Inhibitors
PubMed: 35328340
DOI: 10.3390/ijms23062924 -
Frontiers in Immunology 2021Severe congenital neutropenia (SCN) is a rare hematological condition with heterogenous genetic background. Neutrophil elastase (NE) encoded by gene is mutated in over... (Review)
Review
Severe congenital neutropenia (SCN) is a rare hematological condition with heterogenous genetic background. Neutrophil elastase (NE) encoded by gene is mutated in over half of the SCN cases. The role of NE defects in myelocytes maturation arrest in bone marrow is widely investigated; however, the mechanism underlying this phenomenon has still remained unclear. In this review, we sum up the studies exploring mechanisms of neutrophil deficiency, biological role of NE in neutrophil and the effects of mutation and neutropenia pathogenesis. We also explain the hypotheses presented so far and summarize options of neutropenia therapy.
Topics: Congenital Bone Marrow Failure Syndromes; Gene Expression Regulation; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Leukocyte Elastase; Mutation; Neutropenia; Neutrophils; Protein Processing, Post-Translational; Protein Transport; Signal Transduction; Structure-Activity Relationship
PubMed: 33968054
DOI: 10.3389/fimmu.2021.653932 -
The FEBS Journal Jan 2022Cartilage homeostasis is maintained by a delicate balance between anabolism and catabolism. In osteoarthritis, pathological biomechanics or injury triggers cartilage...
Cartilage homeostasis is maintained by a delicate balance between anabolism and catabolism. In osteoarthritis, pathological biomechanics or injury triggers cartilage breakdown, nonresolving synovial inflammation, and bone changes, causing reduced joint mobility and incapacitating pain. Undoubtedly, the most important cartilage degrading collagenase during osteoarthritis, matrix metalloproteinase (MMP)-13, is activated by an unlikely player: neutrophil elastase. Although primarily associated with inflammatory arthritis, neutrophil elastase is present in the osteoarthritic joint, and through activating MMP-13, spurs a cascade of events leading not just to the aberrant destruction of the cartilage itself, but to the proteolysis of its own inhibitor, alpha-1-antitrypsin, as described in the new study by Wilkinson et al. Endowed with potent chondrogenic and cartilage-protective properties, the loss of alpha-1-antitrypsin from cartilage will have major consequences for osteoarthritis progression, and strategies to prevent its loss, or replace it, might provide an innovative treatment opportunity that should not be ignored. Comment on: https://doi.org/10.1111/febs.16127.
Topics: Cartilage; Chondrogenesis; Collagenases; Humans; Leukocyte Elastase; Osteoarthritis
PubMed: 34580987
DOI: 10.1111/febs.16194 -
Medicine Oct 2022The study analyzed the effect of leukocyte elastase (LE) in 460 semen on sperm quality, and explore the reference interval of normal level of LE in semen. The...
The study analyzed the effect of leukocyte elastase (LE) in 460 semen on sperm quality, and explore the reference interval of normal level of LE in semen. The differences of LE levels between normal semen and few, weak and abnormal semen were analyzed. Referring to domestic standards, the samples were divided into normal group (LE ≤ 250 ng/mL), occult infection (250 < LE ≤ 1000 ng/mL), and infection group (LE > 1000 ng/mL), and the differences in semen quality among the groups were compared. According to European standards, the samples were divided into normal group (≤600 ng/mL) and abnormal group (>600 ng/mL), and the differences in semen quality between the 2 groups were compared. The correlation between LE levels in semen and semen quality were analyzed. The positive rates of LE in the normal semen group and abnormal semen groups were 30.7% versus 34.7%, and there was no significant difference between the two groups (P > .05). When the semen divided into 3 groups, there was no significant difference between the physicochemical parameters, kinetic parameters, movement trajectory parameters, morphological parameters, and sperm DNA fragmentation index (DFI) (P > .05). There were significant differences in sperm morphology and sperm DFI between the two groups at 600 ng/mL (P < .05). Spearman correlation analysis showed that there was no significant difference between the level of LE in semen and physicochemical parameters, sperm kinetic parameters, sperm movement trajectory parameters, sperm morphological parameters, and sperm DFI (P > .05). It is appropriate to use 600 ng/mL as the threshold for the concentration of LE in semen; the correlation between the level of LE and sperm quality is not significant.
Topics: DNA Fragmentation; Humans; Infertility, Male; Leukocyte Elastase; Male; Semen; Semen Analysis; Sperm Count; Sperm Motility; Spermatozoa
PubMed: 36253993
DOI: 10.1097/MD.0000000000031111 -
Expert Opinion on Therapeutic Patents Mar 2011Chronic obstructive pulmonary disease (COPD) constitutes a worldwide health problem. There is currently an urgent and unmet need for the development of small molecule... (Review)
Review
INTRODUCTION
Chronic obstructive pulmonary disease (COPD) constitutes a worldwide health problem. There is currently an urgent and unmet need for the development of small molecule therapeutics capable of blocking and/or reversing the progression of the disorder. Recent studies have greatly illuminated our understanding of the multiple pathogenic processes associated with COPD. Of paramount importance is the key role played by proteases, oxidative stress, apoptosis and inflammation. Insights gained from these studies have made possible the exploration of new therapeutic approaches.
AREAS COVERED
An overview of major developments in COPD research with emphasis on low-molecular mass neutrophil elastase inhibitors is described in this review.
EXPERT OPINION
Great strides have been made toward our understanding of the biochemical and cellular events associated with COPD. However, our knowledge regarding the inter-relationships among the multiple pathogenic mechanisms and their mediators involved is still limited. The problem is further compounded by the unavailability of suitable validated biomarkers for assessing the efficacy of potential therapeutic interventions. The complexity of COPD suggests that effective therapeutic interventions may require the administration of more than one agent such as a human neutrophil elastase or MMP-12 inhibitor with an anti-inflammatory agent such as a PDE4 inhibitor or a dual function agent capable of disrupting the cycle of proteolysis, apoptosis, inflammation and oxidative stress.
Topics: Animals; Humans; Leukocyte Elastase; Proteinase Inhibitory Proteins, Secretory; Pulmonary Disease, Chronic Obstructive
PubMed: 21235378
DOI: 10.1517/13543776.2011.551115 -
Journal of Translational Medicine Dec 2019Polymorphonuclear (PMN) elastase plays an important role in a variety of inflammatory disorders. Our aim was to analyse PMN elastase in idiopathic inflammatory...
BACKGROUND
Polymorphonuclear (PMN) elastase plays an important role in a variety of inflammatory disorders. Our aim was to analyse PMN elastase in idiopathic inflammatory myopathies (IIMs) and its association with disease activity.
METHODS
PMN elastase levels were measured using enzyme-linked immunosorbent assay in serum samples obtained from 74 patients with myositis (58 with dermatomyositis [DM] and 16 with polymyositis [PM]) and 22 healthy controls. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the discriminant capacity of PMN elastase level and PMN elastase-to-neutrophil ratio (ENR) in patients with active and remission myositis. The association of serum PMN elastase level and ENR with disease variables was evaluated in patients with IIMs. The disease specificity of PMN elastase level and ENR was further examined in 60 patients with other systemic autoimmune diseases.
RESULTS
PMN elastase level and ENR were significantly higher in patients with active IIMs, DM, and PM than in patients with remission. ROC curve analysis revealed that PMN elastase level and ENR both outperformed creatine kinase (CK), the currently used laboratory marker, and strongly discriminated patients with active disease and those with remission of IIMs, DM, and PM (area under the ROC curve [AUC] 0.9, 0.9, and 0.88 for PMN elastase; AUC 0.96, 0.96, and 1.0 for ENR; AUC 0.72, 0.70, and 0.80 for CK, respectively). PMN elastase level and ENR were positively correlated with myositis disease activity assessment, CK, lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase, C-reactive protein, and erythrocyte sedimentation rate. PMN elastase level and ENR were higher in the anti-PM-Scl positive myositis group than those in the anti-PM-Scl negative myositis group. Nevertheless, PMN elastase was not a specific disease marker for IIMs when compared with other autoimmune diseases.
CONCLUSIONS
PMN elastase, particularly ENR, were significantly correlated with disease activity and could serve as useful biochemical markers for evaluating the disease activity of patients with IIMs. Thus, they are potentially helpful in monitoring disease progression and guiding treatment.
Topics: Adult; Aged; Area Under Curve; Autoantibodies; Biomarkers; Case-Control Studies; Female; Humans; Inflammation Mediators; Leukocyte Elastase; Male; Middle Aged; Muscles; Myositis; Neutrophils; Predictive Value of Tests; ROC Curve; Sensitivity and Specificity; Young Adult
PubMed: 31842908
DOI: 10.1186/s12967-019-02176-z -
Nature Nanotechnology Sep 2022Targeted drug delivery to disease-associated activated neutrophils can provide novel therapeutic opportunities while avoiding systemic effects on immune functions. We...
Targeted drug delivery to disease-associated activated neutrophils can provide novel therapeutic opportunities while avoiding systemic effects on immune functions. We created a nanomedicine platform that uniquely utilizes an α-antitrypsin-derived peptide to confer binding specificity to neutrophil elastase on activated neutrophils. Surface decoration with this peptide enabled specific anchorage of nanoparticles to activated neutrophils and platelet-neutrophil aggregates, in vitro and in vivo. Nanoparticle delivery of a model drug, hydroxychloroquine, demonstrated significant reduction of neutrophil activities in vitro and a therapeutic effect on murine venous thrombosis in vivo. This innovative approach of cell-specific and activation-state-specific targeting can be applied to several neutrophil-driven pathologies.
Topics: Animals; Humans; Hydroxychloroquine; Leukocyte Elastase; Mice; Nanomedicine; Neutrophils; alpha 1-Antitrypsin Deficiency
PubMed: 35851383
DOI: 10.1038/s41565-022-01161-w