The Involvement of Phospholipases A<sub><b>2</b></sub>in Asthma and Chronic Obstructive Pulmonary Disease

Pniewska, Ewa; Pawliczak, Rafał

doi:10.1155/2013/793505

Cited by 42 publications

(30 citation statements)

References 105 publications

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“…Childhood asthma represents a significant burden, not only in terms of morbidity and reduced quality of life but also in terms of healthcare costs, as reflected by the high rates of unscheduled emergency department visits, hospitalization, and school absenteeism [5]. In developing countries, the terms “chest allergy” and “dyspnea” are commonly used instead of asthma to avoid the social stigma associated with the chronic nature of the disease [6].…”

Section: Introductionmentioning

confidence: 99%

Parental Perceptions and Practices toward Childhood Asthma

Abu-Shaheen

Nofal

Heena

2016

BioMed Research International

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Introduction. Parental perceptions and practices are important for improving the asthma outcomes in children; indeed, evidence shows that parents of asthmatic children harbor considerable misperceptions of the disease. Objective. To investigate the perceptions and practices of parents toward asthma and its management in Saudi children. Methods. Using a self-administered questionnaire, a two-stage cross-sectional survey of parents of children aged between 3 and 15 years, was conducted from schools located in Riyadh province in central Saudi Arabia. Results. During the study interval, 2000 parents were asked to participate in the study; 1450 parents responded, of whom 600 (41.4%) reported that their children had asthma, dyspnea, or chest allergy (recurrent wheezing or coughing), while 478 (32.9%) of the parents reported that their children were diagnosed earlier with asthma by a physician. Therefore, the final statistical analyses were performed with 600 participants. Furthermore, 321 (53.5%) respondents believed that asthma is solely a hereditary disease. Interestingly, 361 (60.3%) were concerned about side effects of inhaled corticosteroids and 192 (32%) about the development of dependency on asthma medications. Almost 76% of parents had previously visited a pediatric emergency department during an asthma attack. Conclusions. Parents had misperceptions regarding asthma and exhibited ineffective practices in its management. Therefore, improving asthma care and compliance requires added parental education.

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Section: Introductionmentioning

confidence: 99%

Parental Perceptions and Practices toward Childhood Asthma

Abu-Shaheen

Nofal

Heena

2016

BioMed Research International

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“…The PLA 2 family includes six main types: cytosolic (cPLA 2 ), secreted (sPLA 2 ), calcium-independent (iPLA 2 ), platelet-activating factor acetylhydrolase (PAF-AH) also referred to as lipoprotein-associated phospholipase A 2 (Lp-PLA2), lysosomal phospholipase A 2 (L-PLA2), and adipose-PLA 2 (AdPLA) [1]. During the last decade, it has been shown that PLA 2 s are associated with several inflammatory diseases including asthma, arthritis, and cancer, and thus constitute an attractive target for inhibitor development [6-8]. …”

Section: Introductionmentioning

confidence: 99%

Computer-aided drug design guided by hydrogen/deuterium exchange mass spectrometry: A powerful combination for the development of potent and selective inhibitors of Group VIA calcium-independent phospholipase A2

Mouchlis

Morisseau

Hammock

et al. 2016

Bioorganic & Medicinal Chemistry

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Potent and selective inhibitors for phospholipases A2 (PLA2) are useful for studying their intracellular functions. PLA2 enzymes liberate arachidonic acid from phospholipids activating eicosanoid pathways that involve cyclooxygenases (COX) and lipoxygenases (LOX) leading to inflammation. Anti-inflammatory drugs target COX and LOX; thus, PLA2 can also be targeted to diminish inflammation. This paper describes the employment of enzymatic assays, hydrogen/deuterium exchange mass spectrometry (DXMS) and computational chemistry to develop PLA2 inhibitors. Beta-thioether trifluoromethylketones (TFKs) were screened against human GVIA calcium-independent, GIVA cytosolic and GV secreted PLA2s. These compounds exhibited inhibition towards Group VIA calcium-independent PLA2 (GVIA iPLA2), with the most potent and selective inhibitor 3 (OTFP) obtaining an XI(50) of 0.0002 mole fraction (IC50 of 110 nM). DXMS binding experiments in the presence of OTFP revealed the peptide regions of GVIA iPLA2 that interact with the inhibitor. Molecular docking and dynamics simulations in the presence of a membrane were guided by the DXMS data in order to identify the binding mode of OTFP. Clustering analysis showed the binding mode of OTFP that occurred 70% during the simulation. The resulted 3D complex was used for docking studies and a structure-activity relationship (SAR) was established. This paper describes a novel multidisciplinary approach in which a 3D complex of GVIA iPLA2 with an inhibitor is reported and validated by experimental data. The SAR showed that the sulfur atom is vital for the potency of beta-thioether analogues, while the hydrophobic chain is important for selectivity. This work constitutes the foundation for further design, synthesis and inhibition studies in order to develop new beta-thioether analogues that are potent and selective for GVIA iPLA2 exclusively.

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“…AA and other PUFAs are metabolic precursors for the biosynthesis of eicosanoids, including prostaglandins and leukotrienes, which are implicated in many inflammatory conditions (2). Through the eicosanoid pathways, PLA 2 s have been implicated in many inflammatory diseases, including asthma, arthritis, atherosclerosis, pain, and cancer (3)(4)(5). There are 16 groups and many subgroups of PLA 2 , but they can be considered as six types: cytosolic (cPLA 2 ), secreted (sPLA 2 ), calcium-independent (iPLA 2 ), platelet-activating factor acetylhydrolase (PAF-AH), also known as lipoproteinassociated PLA 2 (Lp-PLA 2 ), lysosomal PLA 2 (LPLA 2 ), and adipose-PLA 2 (AdPLA 2 ) (1).…”

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confidence: 99%

Membranes serve as allosteric activators of phospholipase A ₂ , enabling it to extract, bind, and hydrolyze phospholipid substrates

Mouchlis¹,

Bucher²,

McCammon

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

159

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Defining the molecular details and consequences of the association of water-soluble proteins with membranes is fundamental to understanding protein-lipid interactions and membrane functioning. Phospholipase A 2 (PLA 2 ) enzymes, which catalyze the hydrolysis of phospholipid substrates that compose the membrane bilayers, provide the ideal system for studying protein-lipid interactions. Our study focuses on understanding the catalytic cycle of two different human PLA 2 s: the cytosolic Group IVA cPLA 2 and calcium-independent Group VIA iPLA 2 . Computer-aided techniques guided by deuterium exchange mass spectrometry data, were used to create structural complexes of each enzyme with a single phospholipid substrate molecule, whereas the substrate extraction process was studied using steered molecular dynamics simulations. Molecular dynamic simulations of the enzyme-substrate-membrane systems revealed important information about the mechanisms by which these enzymes associate with the membrane and then extract and bind their phospholipid substrate. Our data support the hypothesis that the membrane acts as an allosteric ligand that binds at the allosteric site of the enzyme's interfacial surface, shifting its conformation from a closed (inactive) state in water to an open (active) state at the membrane interface.GIVA cPLA 2 | GVIA iPLA 2 | PAPC | MD simulations | DXMS

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The Involvement of Phospholipases A₂in Asthma and Chronic Obstructive Pulmonary Disease

Cited by 42 publications

References 105 publications

Parental Perceptions and Practices toward Childhood Asthma

Parental Perceptions and Practices toward Childhood Asthma

Computer-aided drug design guided by hydrogen/deuterium exchange mass spectrometry: A powerful combination for the development of potent and selective inhibitors of Group VIA calcium-independent phospholipase A2

Membranes serve as allosteric activators of phospholipase A ₂ , enabling it to extract, bind, and hydrolyze phospholipid substrates

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The Involvement of Phospholipases A2in Asthma and Chronic Obstructive Pulmonary Disease

Cited by 42 publications

References 105 publications

Parental Perceptions and Practices toward Childhood Asthma

Parental Perceptions and Practices toward Childhood Asthma

Computer-aided drug design guided by hydrogen/deuterium exchange mass spectrometry: A powerful combination for the development of potent and selective inhibitors of Group VIA calcium-independent phospholipase A2

Membranes serve as allosteric activators of phospholipase A 2 , enabling it to extract, bind, and hydrolyze phospholipid substrates

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The Involvement of Phospholipases A₂in Asthma and Chronic Obstructive Pulmonary Disease

Membranes serve as allosteric activators of phospholipase A ₂ , enabling it to extract, bind, and hydrolyze phospholipid substrates