Natural Phenolics as Inhibitors of the Human Neutrophil Elastase (HNE) Release: An Overview of Natural Anti-inflammatory Discoveries during Recent Years

Saleem, Muhammad; Nazir, Mamona; Hussain, Hidayat; Tousif, Muhammad Imran; Elsebai, Mahmoud Fahmi; Riaz, Naheed; Akhtar, Naseem

doi:10.2174/1871523017666180910104946

Cited by 10 publications

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“…Since most of these polypeptides are complex structures, which are difficult to synthesize chemically, to study their biological properties also requires screening of natural molecules. However, this is not the case for small molecules acting as elastase inhibitors (Saleem et al, 2018). Therefore, the in vitro elastase inhibitory studies of the natural polypeptides embodied in this document may provide a milestone for drug development and design.…”

Section: Discussionmentioning

confidence: 99%

The Natural Polypeptides as Significant Elastase Inhibitors

et al. 2020

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Human neutrophil elastase (HNE) is a major cause of the destruction of tissues in cases of several different chronic andinflammatory diseases. Overexpression of the elastase enzyme plays a significant role in the pathogenesis of various diseases including chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome, rheumatoid arthritis, the rare disease cyclic hematopoiesis (or cyclic neutropenia), infections, sepsis, cystic fibrosis, myocardial ischemia/reperfusion injury and asthma, inflammation, and atherosclerosis. Human neutrophil elastase is secreted by human neutrophils due to different stimuli. Medicine-based inhibition of the over-activation of neutrophils or production and activity of elastase have been suggested to mend inflammatory diseases. Although the development of new elastase inhibitors is an essential strategy for treating the different inflammatory diseases, it has been a challenge to specifically target the activity of elastase because of its overlapping functions with those of other serine proteases. This review article highlights the reported natural polypeptides as potential inhibitors of elastase enzyme. The mechanism of action, structural features, and activity of the polypeptides have also been correlated wherever they were available.

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Section: Discussionmentioning

confidence: 99%

The Natural Polypeptides as Significant Elastase Inhibitors

et al. 2020

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“…SLPI (PDB entry 2Z7F) has an IC 50 of 1.3 × 10 –8 , and EapH1 (PDB entry 4NZL) shows a 21 pM affinity for hNE . Thus, the mechanism of inhibition of hNE by protein inhibitors remains to be explored, because a wide range of highly potent, naturally present serine protease protein inhibitors with high affinity for hNE are available …”

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“…14 Thus, the mechanism of inhibition of hNE by protein inhibitors remains to be explored, because a wide range of highly potent, naturally present serine protease protein inhibitors with high affinity for hNE are available. 15 Ecotin, a 16 kDa periplasmic serine protease inhibitor from Escherichia coli, strongly inhibits many of the S1A family serine proteases bearing a chymotrypsin fold. Ecotin also exists in other Gram-negative bacteria, such as Yersinia pestis, Pseudomonas aeruginosa, and Pantoea citrea, and similarly inhibits the chymotrypsin family of proteases.…”

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Structural Basis for the Inhibition Mechanism of Ecotin against Neutrophil Elastase by Targeting the Active Site and Secondary Binding Site

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Human neutrophil elastase (hNE) is a serine protease that plays a major role in defending the bacterial infection. However, elevated expression of hNE is reported in lung and breast cancer, among others. Moreover, hNE is a target for the treatment of cardiopulmonary diseases. Ecotin (ET) is a serine protease inhibitor present in many Gram-negative bacteria, and it plays a physiological role in inhibiting host proteases, including hNE. Despite this known interaction, the structure of the hNE−ET complex has not been reported, and the mechanism of ecotin inhibition is not available. We determined the structure of the hNE−ET complex by molecular replacement method. The structure of the hNE−ET complex revealed the presence of six interface regions comprising 50s, 60s, and 80s loops, between the ET dimer and two independent hNE monomers, which explains the high affinity of ecotin for hNE (12 pM). Notably, we observed a secondary binding site of hNE located 24 Å from the primary binding site. Comparison of the closely related trypsin−ecotin complex with our hNE−ET complex shows movement of the backbone atoms of the 80s and 50s loops by 4.6 Å, suggesting the flexibility of these loops in inhibiting a range of proteases. Through a detailed structural analysis, we demonstrate the flexibility of the hNE subsites to dock various side chains concomitant with inhibition, indicating the broad specificity of hNE against various inhibitors. These findings will aid in the design of chimeric inhibitors that target both sites of hNE and in the development of therapeutics for controlling hNE-mediated pathogenesis.

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“…The decrease in the neutrophil count in the DAM group occurred due to the presence of phenolic compounds from the mangosteen rind extract that acted as antioxidants. Phenolic compounds are able to reduce the secretion of human neutrophil elastase (HNE), which is an enzyme that can break down the components of the extracellular matrix by reducing the number of neutrophils [45].…”

Section: Discussionmentioning

confidence: 99%

Wound Healing and Antioxidant Evaluations of Alginate from Sargassum ilicifolium and Mangosteen Rind Combination Extracts on Diabetic Mice Model

et al. 2021

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A diabetic foot ulcer is an open wound that can become sore and frequently occurs in diabetic patients. Alginate has the ability to form a hydrophilic gel when in contact with a wound surface in diabetic patients. Xanthones are the main compounds of mangosteen rind and have antibacterial and anti-inflammatory properties. The purpose of this research was to evaluate the wound healing and antioxidants assay with a combination of alginate from S. ilicifolium and mangosteen rind combination extracts on a diabetic mice model. The characterization of alginate was carried out by size exclusion chromatography with multiple angle laser light scattering (SEC-MALLS) and thermogravimetric analysis (TGA). The M/G ratio of alginate was calculated by using proton nuclear magnetic resonance (1H NMR). The antioxidant activity of mangosteen rind and the combination extracts was determined using the DPPH method. The observed parameters were wound width, number of neutrophils, macrophages, fibrocytes, fibroblasts, and collagen densities. The 36 male mice were divided into 12 groups including non-diabetic control (NC), diabetes alginate (DA), alginate–mangosteen (DAM), and diabetes control (DC) groups in three different groups by a histopathology test on skin tissue. The treatment was carried out for 14 days and mice were evaluated on Days 3, 7, and 14. The SEC-MALLS results showed that the molecular weight and dispersity index (Ð) of alginate were 2.77 × 104 Dalton and 1.73, respectively. The M/G ratio of alginate was 0.77 and described as single-stage decomposition based on TGA. Alginate, mangosteen rind extract, and their combination were divided into weak, medium, and strong antioxidant, respectively. The treatment of the DA and DAM groups showed a decrease in wound width and an increase in the number of fibrocytes, fibroblasts, and macrophages. The number of neutrophils decreased while the percentage of collagen densities increased for all the considered groups.

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Natural Phenolics as Inhibitors of the Human Neutrophil Elastase (HNE) Release: An Overview of Natural Anti-inflammatory Discoveries during Recent Years

Cited by 10 publications

References 0 publications

The Natural Polypeptides as Significant Elastase Inhibitors

The Natural Polypeptides as Significant Elastase Inhibitors

Structural Basis for the Inhibition Mechanism of Ecotin against Neutrophil Elastase by Targeting the Active Site and Secondary Binding Site

Wound Healing and Antioxidant Evaluations of Alginate from Sargassum ilicifolium and Mangosteen Rind Combination Extracts on Diabetic Mice Model

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