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Seminars in Cell & Developmental Biology Feb 2017SERPINB1, also called Leukocyte Elastase Inhibitor (LEI) is a member of the clade B of SERPINS. It is an intracellular protein and acts primarily to protect the cell... (Review)
Review
SERPINB1, also called Leukocyte Elastase Inhibitor (LEI) is a member of the clade B of SERPINS. It is an intracellular protein and acts primarily to protect the cell from proteases released into the cytoplasm during stress. Its role in inflammation is clear due to its involvement in the resolution of chronic inflammatory lung and bowel diseases. LEI/SERPINB1 intrinsically possesses two enzymatic activities: an antiprotease activity dependent on its reactive site loop, which is analogous to the other proteins of the family and an endonuclease activity which is unveiled by the cleavage of the reactive site loop. The conformational change induced by this cleavage also unveils a bipartite nuclear localization signal allowing the protein to translocate to the nucleus. Recent data indicate that it has also a role in cell migration suggesting that it could be involved in diverse processes like wound healing and malignant metastases.
Topics: Animals; Apoptosis; Evolution, Molecular; Humans; Leukocyte Elastase; Phylogeny; Protease Inhibitors; Serpins
PubMed: 27422329
DOI: 10.1016/j.semcdb.2016.07.010 -
American Journal of Respiratory and... Sep 2001
Review
Topics: Animals; Disease Models, Animal; Humans; Leukocyte Elastase; Neutrophils; Respiratory Distress Syndrome; Wound Healing
PubMed: 11549552
DOI: 10.1164/ajrccm.164.5.2103040 -
Arteriosclerosis, Thrombosis, and... Oct 2023Thoracic aortic dissection (TAD) is a life-threatening aortic disease without effective medical treatment. Increasing evidence has suggested a role for NE (neutrophil...
BACKGROUND
Thoracic aortic dissection (TAD) is a life-threatening aortic disease without effective medical treatment. Increasing evidence has suggested a role for NE (neutrophil elastase) in vascular diseases. In this study, we aimed at investigating a causal role for NE in TAD and exploring the molecular mechanisms involved.
METHODS
β-aminopropionitrile monofumarate was administrated in mice to induce TAD. NE deficiency mice, pharmacological inhibitor GW311616A, and adeno-associated virus-2-mediated in vivo gene transfer were applied to explore a causal role for NE and associated target gene in TAD formation. Multiple functional assays and biochemical analyses were conducted to unravel the underlying cellular and molecular mechanisms of NE in TAD.
RESULTS
NE aortic gene expression and plasma activity was significantly increased during β-aminopropionitrile monofumarate-induced TAD and in patients with acute TAD. NE deficiency prevents β-aminopropionitrile monofumarate-induced TAD onset/development, and GW311616A administration ameliorated TAD formation/progression. Decreased levels of neutrophil extracellular traps, inflammatory cells, and MMP (matrix metalloproteinase)-2/9 were observed in NE-deficient mice. TBL1x (F-box-like/WD repeat-containing protein TBL1x) has been identified as a novel substrate and functional downstream target of NE in TAD. Loss-of-function studies revealed that NE mediated inflammatory cell transendothelial migration by modulating TBL1x-LTA4H (leukotriene A4 hydrolase) signaling and that NE regulated smooth muscle cell phenotype modulation under TAD pathological condition by regulating TBL1x-MECP2 (methyl CpG-binding protein 2) signal axis. Further mechanistic studies showed that TBL1x inhibition decreased the binding of TBL1x and HDAC3 (histone deacetylase 3) to and gene promoters, respectively. Finally, adeno-associated virus-2-mediated gene knockdown in aortic smooth muscle cells confirmed a regulatory role for TBL1x in NE-mediated TAD formation.
CONCLUSIONS
We unravel a critical role of NE and its target TBL1x in regulating inflammatory cell migration and smooth muscle cell phenotype modulation in the context of TAD. Our findings suggest that the NE-TBL1x signal axis represents a valuable therapeutic for treating high-risk TAD patients.
Topics: Animals; Humans; Mice; Aminopropionitrile; Aortic Aneurysm, Thoracic; Aortic Dissection; Dissection, Thoracic Aorta; Leukocyte Elastase
PubMed: 37589142
DOI: 10.1161/ATVBAHA.123.319281 -
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 -
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 -
Nihon Rinsho. Japanese Journal of... May 1995Elastases are unique among the proteases in that they are capable of hydrolyzing the scleroprotein elastin. The enzymes include pancreatic elastases 1 (Protease E) and... (Review)
Review
Elastases are unique among the proteases in that they are capable of hydrolyzing the scleroprotein elastin. The enzymes include pancreatic elastases 1 (Protease E) and 2, and neutrophil elastase. These three elastases also have esterase and amidase activity toward synthetic substrates such as succinyl-trialanine-p-nitroanilide. Although the three enzymes are similar to each other in enzyme activity, they are quite different in immunoactivity. Therefore, each elastase has its own specific immunoassay either by RIA or EIA. Serum immunoreactive pancreatic elastases reflect disease conditions of pancreatic diseases, especially acute pancreatitis and pancreatic cancer. On the other hand, serum neutrophil elastase increases in various inflammatory diseases or conditions.
Topics: Humans; Inflammation; Isoenzymes; Leukocyte Elastase; Neutrophils; Pancreas; Pancreatic Diseases; Pancreatic Elastase
PubMed: 7602777
DOI: No ID Found -
Steroids May 2018Myeloid cell production within the bone marrow is accelerated in the setting of cancer, and the numbers of circulating and infiltrating neutrophils and granulocytic... (Review)
Review
Myeloid cell production within the bone marrow is accelerated in the setting of cancer, and the numbers of circulating and infiltrating neutrophils and granulocytic myeloid derived suppressor cells (MDSCs) correlate with tumor progression and patient survival. Cancer is therefore able to hijack the normally host-protective immune system and use it to further fuel growth and metastasis. Myeloid cells secrete neutrophil elastase and neutrophil extracellular traps (NETs) in response to cues within the tumor microenvironment, thereby leading to enhanced activity in a variety of cancer types. Neutrophil elastase may indeed be a driver of tumorigenesis, since genetic deletion and pharmacological inhibition markedly reduces tumor burden and metastatic potential in numerous preclinical studies. In this review, we examine the current evidence for neutrophil elastase as a stimulatory factor in cancer, focusing on precise mechanisms by which it facilitates primary tumor growth and secondary organ metastasis. We conclude with a brief overview of neutrophil elastase inhibitors and discuss their potential use in cancer therapy.
Topics: Animals; Cell Proliferation; Humans; Leukocyte Elastase; Molecular Targeted Therapy; Neoplasm Metastasis; Neoplasms; Tumor Microenvironment
PubMed: 29155217
DOI: 10.1016/j.steroids.2017.11.006 -
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 -
The Journal of Investigative Dermatology Jan 2002Neutrophil infiltration and epidermal hyperproliferation are major histopathologic changes observed in psoriasis. Neutrophils contain human leukocyte elastase, which is...
Neutrophil infiltration and epidermal hyperproliferation are major histopathologic changes observed in psoriasis. Neutrophils contain human leukocyte elastase, which is thought to be released during neutrophil infiltration of the epidermis. As active human leukocyte elastase is known to be present in psoriatic lesions we were interested whether human leukocyte elastase induces hyperproliferation in keratinocytes in vitro and in vivo. In the cultured murine keratinocyte cell line PAM-212 concentrations of human leukocyte elastase from 1 to 30 nM induced significant proliferation as determined by 5-bromo-2'-deoxy-uridine-incorporation. Daily topical application of 0.043-434.8 pmol human leukocyte elastase per cm2 skin on hairless mice induced a concentration-dependent epidermal hyperproliferation and an increase in 5-bromo-2'-deoxy-uridine incorporation of up to 5-fold in basal keratinocytes within 3 d. Hyperproliferation resulted in a up to 2-fold increase of keratinocyte layers. Histologic analysis revealed marked vasodilatation but no inflammatory infiltrate. Application of porcine pancreatic elastase (3-300 pmol per cm2 skin) resulted in similar epidermal changes as observed for human leukocyte elastase. Hyperproliferative effects of human leukocyte elastase in vitro and in vivo were abolished by the addition of elastase inhibitors, such as elafin, anti-leukoprotease, and alpha1-protease inhibitor. In summary, human leukocyte elastase induces proliferation in murine keratinocytes in concentrations, which can be found on the skin surface of psoriatic lesions. These results may provide an explanation for the epidermal hyperproliferation observed in psoriasis.
Topics: Animals; Cell Division; Cells, Cultured; Humans; Keratinocytes; Leukocyte Elastase; Mice; Protease Inhibitors
PubMed: 11851875
DOI: 10.1046/j.0022-202x.2001.01650.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