Attenuation of experimental TPA-induced dermatitis by acetylenic acetogenins is associated with inhibition of PLA2 activity

Otuki, Michel Fleith; Schwob, Ouri; Prudente, Arthur Silveira; Zaltsman, Igor; Meretski, Shai; Segal, Jacob; Yedgar, Saul; Rosenblat, Gennady

doi:10.1016/j.ejphar.2011.09.184

Cited by 7 publications

(5 citation statements)

References 32 publications

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“…Skin myeloperoxidase (MPO) activity, an indicator of polymorphonuclear leukocyte infiltration, was assessed using a mouse MPO ELISA kit (HK210; Hycult Biotech Inc., Suite, PA) as previously described (Otuki et al, 2011). …”

Section: Methodsmentioning

confidence: 99%

Repositioning drugs for inflammatory disease-fishing for new anti-inflammatory agents

Hall

Wicker

Chien

et al. 2014

Disease Models &Amp; Mechanisms

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Inflammation is an important and appropriate host response to infection or injury. However, dysregulation of this response, with resulting persistent or inappropriate inflammation, underlies a broad range of pathological processes, from inflammatory dermatoses to type 2 diabetes and cancer. As such, identifying new drugs to suppress inflammation is an area of intense interest. Despite notable successes, there still exists an unmet need for new effective therapeutic approaches to treat inflammation. Traditional drug discovery, including structure-based drug design, have largely fallen short of satisfying this unmet need. With faster development times and reduced safety and pharmacokinetic uncertainty, drug repositioning – the process of finding new uses for existing drugs – is emerging as an alternative strategy to traditional drug design that promises an improved risk-reward trade-off. Using a zebrafish in vivo neutrophil migration assay, we undertook a drug repositioning screen to identify unknown anti-inflammatory activities for known drugs. By interrogating a library of 1280 approved drugs for their ability to suppress the recruitment of neutrophils to tail fin injury, we identified a number of drugs with significant anti-inflammatory activity that have not previously been characterized as general anti-inflammatories. Importantly, we reveal that the ten most potent repositioned drugs from our zebrafish screen displayed conserved anti-inflammatory activity in a mouse model of skin inflammation (atopic dermatitis). This study provides compelling evidence that exploiting the zebrafish as an in vivo drug repositioning platform holds promise as a strategy to reveal new anti-inflammatory activities for existing drugs.

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Section: Methodsmentioning

confidence: 99%

Repositioning drugs for inflammatory disease-fishing for new anti-inflammatory agents

Hall

Wicker

Chien

et al. 2014

Disease Models &Amp; Mechanisms

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“…47 Furthermore, it was suggested that reduced secretion of PGE 2 in keratinocytes was associated with inhibition of phospholipase A 2 activity in skin cells. 48 This may suggest that the mechanism through which compound 1 attenuates platelet aggregation can be related to lower hydrolysis of arachidonic acid from the inner membrane by inhibiting phospholipase A 2 action. However the proposed mechanisms need to be proved.…”

Section: Characterization Of Platelet Aggregation Inhibitory Properti...mentioning

confidence: 99%

Isolation and chemical identification of lipid derivatives from avocado (Persea americana) pulp with antiplatelet and antithrombotic activities

et al. 2015

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Platelets play a pivotal role in physiological hemostasis. However, in coronary arteries damaged by atherosclerosis, enhanced platelet aggregation, with subsequent thrombus formation, is a precipitating factor in acute ischemic events. Avocado pulp (Persea americana) is a good source of bioactive compounds, and its inclusion in the diet as a source of fatty acid has been related to reduced platelet aggregability. Nevertheless, constituents of avocado pulp with antiplatelet activity remain unknown. The present study aims to characterize the chemical nature of avocado constituents with inhibitory effects on platelet aggregation. Centrifugal partition chromatography (CPC) was used as a fractionation and purification tool, guided by an in vitro adenosine diphosphate (ADP), arachidonic acid or collagen-platelet aggregation assay. Antiplatelet activity was initially linked to seven acetogenins that were further purified, and their dose-dependent effects in the presence of various agonists were contrasted. This process led to the identification of Persenone-C (3) as the most potent antiplatelet acetogenin (IC₅₀=3.4 mM) among the evaluated compounds. In vivo evaluations with Persenone A (4) demonstrated potential protective effects against arterial thrombosis (25 mg kg⁻¹ of body weight), as coagulation times increased (2-fold with respect to the vehicle) and thrombus formation was attenuated (71% versus vehicle). From these results, avocado may be referred to as a functional food containing acetogenin compounds that inhibit platelet aggregation with a potential preventive effect on thrombus formation, such as those that occur in ischaemic diseases.

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“…In a clinical study by Ingber et al, topical application of a cream containing a cell-impermeable sPLA 2 inhibitor, designed and synthesized in our lab, was shown to be effective in treating those suffering from allergic contact dermatitis [17]. In a study by Otuki et al, another sPLA 2 inhibitor suppressed sPLA 2 activity in HaCat and primary human keratinocytes stimulated with 12-O-tetra decanoylphorbol-3-acetate (TPA) concomitantly with PGE 2 production [18]. In this study, a topical application of this inhibitor attenuated experimental TPA-induced dermatitis in mice [18].…”

Section: "The Quest For Novel Anti-inflammatory Drugs (Particularly T...mentioning

confidence: 99%

“…In a study by Otuki et al, another sPLA 2 inhibitor suppressed sPLA 2 activity in HaCat and primary human keratinocytes stimulated with 12-O-tetra decanoylphorbol-3-acetate (TPA) concomitantly with PGE 2 production [18]. In this study, a topical application of this inhibitor attenuated experimental TPA-induced dermatitis in mice [18]. These studies provide experimental evidence to support the potential of inhibiting the activity of PLA 2 s, especially secretory PLA 2 , as a therapeutic approach in the treatment of inflammatory dermatological conditions.…”

Section: "The Quest For Novel Anti-inflammatory Drugs (Particularly T...mentioning

confidence: 99%

Phospholipase A ₂ Inhibition as Potential Therapy for Inflammatory Skin Diseases

Mruwat¹,

Cohen

Yedgar³

2013

Immunotherapy

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Attenuation of experimental TPA-induced dermatitis by acetylenic acetogenins is associated with inhibition of PLA2 activity

Cited by 7 publications

References 32 publications

Repositioning drugs for inflammatory disease-fishing for new anti-inflammatory agents

Repositioning drugs for inflammatory disease-fishing for new anti-inflammatory agents

Isolation and chemical identification of lipid derivatives from avocado (Persea americana) pulp with antiplatelet and antithrombotic activities

Phospholipase A ₂ Inhibition as Potential Therapy for Inflammatory Skin Diseases

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Attenuation of experimental TPA-induced dermatitis by acetylenic acetogenins is associated with inhibition of PLA2 activity

Cited by 7 publications

References 32 publications

Repositioning drugs for inflammatory disease-fishing for new anti-inflammatory agents

Repositioning drugs for inflammatory disease-fishing for new anti-inflammatory agents

Isolation and chemical identification of lipid derivatives from avocado (Persea americana) pulp with antiplatelet and antithrombotic activities

Phospholipase A 2 Inhibition as Potential Therapy for Inflammatory Skin Diseases

Contact Info

Product

Resources

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Phospholipase A ₂ Inhibition as Potential Therapy for Inflammatory Skin Diseases