Neutrophil Elastase Inhibitors and Chronic Kidney Disease

Bronze-da-Rocha, Elsa; Santos-Silva, Alice

doi:10.7150/ijbs.26111

Cited by 61 publications

(62 citation statements)

References 170 publications

(302 reference statements)

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“…On the one hand, neutrophils promote tissue repair through phagocytosis and activation of the immune response. Conversely, neutrophils may cause tissue damage through the release of proteolytic enzymes and reactive oxygen metabolites . Furthermore, activated neutrophils contribute to the development of interstitial edema through different mechanisms.…”

Section: Discussionmentioning

confidence: 99%

“…Conversely, neutrophils may cause tissue damage through the release of proteolytic enzymes and reactive oxygen metabolites. 71,[73][74][75] Furthermore, activated neutrophils contribute to the development of interstitial edema through different mechanisms. First, adhesion of neutrophils to the endothelial cell wall (leukocyte plugging) reduces the diameter of the postcapillary venules, which results in an increase in hydrostatic pressure.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Physiological processes of inflammation and edema initiated by sustained mechanical loading in subcutaneous tissues: A scoping review

Damme

Hecke

Remue

et al. 2019

Wound Repair Regeneration

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Deep tissue injuries are pressure ulcers which initiate in the subcutaneous tissues and extend through a bottom‐up pathway. Once deep tissue injuries are visual at skin level, serious irreversible tissue damage has already occurred. In pressure ulcer development, inflammation and edema are coupled physiological processes associated with tissue damage arising due to sustained mechanical loading. This study aimed to provide an in‐depth overview of the physiological processes of inflammation and edema initiated by sustained mechanical loading in subcutaneous tissues, in the context of pressure ulceration. A scoping review was performed according to the framework by Arksey and O'Malley. The databases MEDLINE, EMBASE, Web of Science, and Scopus, and the reference lists of included studies were searched for in vivo (animal, human), and in vitro studies matching the study objectives (from inception to 28 May 2018). No restrictions for inclusion were applied for study design, setting, participants, and year of publication. A total of 12 studies were included, varying in study design, sample characteristics, amount and duration of mechanical loads that were applied, follow‐up time, and assessment methods. Neutrophil infiltration and edema occur in the subcutaneous tissues nearly immediately after the application of load on soft tissues. The amount of neutrophils and edema increase in the first days after the mechanical insult and decrease once healing has been initiated and no supplementary mechanical load was applied. One study indicated that edema may extend up to the level of the dermo‐epidermal junction. Further research should focus on how deep tissue inflammation and edema are reflected into unique tissue changes at skin level, and how abnormal inflammatory responses manifest (e.g. when the nervous system is not functioning normally).

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Physiological processes of inflammation and edema initiated by sustained mechanical loading in subcutaneous tissues: A scoping review

Damme

Hecke

Remue

et al. 2019

Wound Repair Regeneration

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“…The similar inhibitory tendency was also observed from other alkylated flavones 3 and 4, which indicated that the prenyl group on C3 was a crucial functionality to HNE inhibition. Dihydrobenzoxanthones (5)(6)(7)(8) inhibited HNE significantly with IC 50 values of 9.8 ~ 28.7 μM, compared to the mother compound. The number of the hydroxyl group of B-ring affected inhibitory capacities as follow: compounds 5 (IC 50 = 9.8 μM) versus 8 (IC 50 = 28.7 μM).…”

Section: Hne Inhibitory Activity Of Isolated Compounds and Their Kinementioning

confidence: 96%

“…Augmentation therapy has been accepted as the best therapy for AAT deficiency, and less costly methods such as low molecular weight NE inhibitors have failed clinically, despite diligent efforts over the past three decades [6]. On the other hand, the release of granular contents leads to the recruitment of inflammatory cells through cytokines (TNF-α, IL-1β, IL-6, IL-18, IL-10), adipokines (adiponectin, resistin and leptin), and chemokines (IL-8), which are the main intermediaries and progressors of renal tissue damage [7]. Thus, the invention of novel protease inhibitors is an invaluable therapeutic tool.…”

Section: Introductionmentioning

confidence: 99%

Human neutrophil elastase inhibitory dihydrobenzoxanthones and alkylated flavones from the Artocarpus elasticus root barks

et al. 2020

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Neutrophil elastases are deposited in azurophilic granules interspace of neutrophils and tightly associated with inflammatory ailments. The root barks of Artocarpus elasticus had a strong inhibitory potential against human neutrophil elastase (HNE). The responsible components for HNE inhibition were confirmed as alkylated flavones (2–4, IC50 = 14.8 ~ 18.1 μM) and dihydrobenzoxanthones (5–8, IC50 = 9.8 ~ 28.7 μM). Alkyl groups on flavone were found to be crucial functionalities for HNE inhibition. For instance, alkylated flavone 2 (IC50 = 14.8 μM) was 20-fold potent than mother compound norartocarpetin (1, IC50 > 300 μM). The kinetic analysis showed that alkylated flavones (2–4) were noncompetitive inhibition, while dihydrobenzoxanthones (5–8) were a mixed type I (KI < KIS) inhibitors, which usually binds with free enzyme better than to complex of enzyme–substrate. Inhibitors and HNE enzyme binding affinities were examined by fluorescence quenching effect. In the result, the binding affinity constants (KSV) had a significant correlation with inhibitory potencies (IC50).

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“…HNE and other serine proteases are key enzymes involved in inflammation, coagulation, and host defense (Massberg et al, ; Pham, ). On the other hand, HNE also plays a central role in several inflammatory diseases, such as chronic obstructive pulmonary disease (Lucas, Costa, Guedes, & Moreira, ; Pandey, De, & Mishra, ), cystic fibrosis (Twigg et al, ), rheumatoid arthritis (Hilbert, Schiller, Arnhold, & Arnold, ), cancer (Akizuki et al, ; Lerman et al, ; Lerman & Hammes, ; Vaguliene, Zemaitis, Lavinskiene, Miliauskas, & Sakalauskas, ), and other disorders with an inflammatory component (Bronze‐da‐Rocha & Santos‐Silva, ; Marto et al, ). Because of their potential for proteolytic tissue damage, neutrophil protease activity is regulated by specific endogenous (α‐1 antitrypsin, secretory leucocyte protease inhibitor and elafin) and exogenous inhibitors, thereby preventing several inflammatory diseases with severe impact on organ tissue integrity (von Nussbaum et al, ; von Nussbaum & Li, ).…”

Section: Introductionmentioning

confidence: 99%

New 3‐unsubstituted isoxazolones as potent human neutrophil elastase inhibitors: Synthesis and molecular dynamic simulation

Giovannoni

Crocetti

Cantini

et al. 2019

Drug Development Research

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Human neutrophil elastase (HNE) is a proteolytic enzyme belonging to the serine protease family and is involved in a variety of pathologies. Thus, compounds able to inhibit HNE represent promising therapeutics for the treatment of inflammatory diseases. Here, we report the further elaboration of our previously reported 3-methylisoxazolone derivatives, synthesizing a new series of 3-nor-derivatives bearing different substituents at the 4-phenyl ring. The most potent compounds 3a, 3g, and 3h, had IC 50 values of 16, 11, and 18 nM, respectively. Molecular modeling studies and molecular dynamic (MD) simulations demonstrated no substantial differences between the 3-methylisoxazole derivatives previously tested and the corresponding 3-unsubstituted derivatives in the snapshot conformations sampled during the MD simulations, which is consistent with their similar levels of HNE inhibitory activity.Thus, we conclude that the isoxazolone scaffold is a good scaffold for developing HNE inhibitors, as it tolerates several modifications when adhering to basic scaffold requirements, and the resulting derivatives are quite potent HNE inhibitors. K E Y W O R D Shuman neutrophil elastase inhibitors, molecular and crystal structures, molecular modeling

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Neutrophil Elastase Inhibitors and Chronic Kidney Disease

Cited by 61 publications

References 170 publications

Physiological processes of inflammation and edema initiated by sustained mechanical loading in subcutaneous tissues: A scoping review

Physiological processes of inflammation and edema initiated by sustained mechanical loading in subcutaneous tissues: A scoping review

Human neutrophil elastase inhibitory dihydrobenzoxanthones and alkylated flavones from the Artocarpus elasticus root barks

New 3‐unsubstituted isoxazolones as potent human neutrophil elastase inhibitors: Synthesis and molecular dynamic simulation

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