Phosphodiesterase inhibition in the treatment of autoimmune and inflammatory diseases: current status and potential

Miller, Mindi S.

doi:10.2147/jrlcr.s50401

Cited by 15 publications

(7 citation statements)

References 63 publications

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“…In several pre-clinical studies, PDE4 inhibitors have been shown to suppress bronchial hyperresponsiveness, eosinophil infiltration and production of histamine, leukotrienes and cytokines; however, they have significant side-effects when administered orally. PDE3 inhibitors act as bronchodilators, while PDE4 inhibitors have an anti-inflammatory effect [ 106 ]. PRL-554, an inhaled PDE3/4 inhibitor is now in a phase 1 trial for severe asthma.…”

Section: Future Therapeutic Targetsmentioning

confidence: 99%

Identification and treatment of T2-low asthma in the era of biologics

et al. 2020

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Currently, and based on the development of relevant biologic therapies, T2-high is the most well-defined endotype of asthma. Although much progress has been made in elucidating T2-high inflammation pathways, no specific clinically applicable biomarkers for T2-low asthma have been identified. The therapeutic approach of T2-low asthma is a problem urgently needing solution, firstly because these patients have poor response to steroids, and secondly because they are not candidates for the newer targeted biologic agents. There is, thus, an unmet need for the identification of biomarkers that can help the diagnosis and endotyping of T2-low asthmaOngoing investigation is focusing on neutrophilic airway inflammation mediators as therapeutic targets, including IL-8, IL-17, IL-1, IL-6, IL-23, TNF-a; molecules that target to restore corticosteroid sensitivity, mainly mitogen-activated protein kinase inhibitors, tyrosine kinase inhibitors and phosphatidylinositol 3-kinase inhibitors; PDE3 inhibitors that act as bronchodilators and PDE4 inhibitors that have an anti-inflammatory effect; and airway smooth muscle mass attenuation therapies, mainly for patients with paucigranulocytic inflammationThis manuscript aims to review the evidence for non-eosinophilic inflammation being a target for therapy in asthma, discuss current and potential future therapeutic approaches, such as novel molecules and biologic agents, and assess clinical trials of licensed drugs in the treatment of T2-low asthma.

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Section: Future Therapeutic Targetsmentioning

confidence: 99%

Identification and treatment of T2-low asthma in the era of biologics

et al. 2020

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“…The fact that increasing neutrophil cAMP and activating PKA would be beneficial for disease activity in mice aligns well with our previous work demonstrating the potential therapeutic target of this pathway in APS and lupus models with synthetic PDE4 inhibitors ( 22 ). Indeed, PDE inhibitors are attractive therapeutic targets for chronic inflammatory diseases ( 30 , 31 ). Specifically, there has been targeted drug development against PDE4, the predominant isotype expressed by leukocytes ( 32 , 33 ).…”

Section: Discussionmentioning

confidence: 99%

Ginger intake suppresses neutrophil extracellular trap formation in autoimmune mice and healthy humans

Ali,

Minarchick,

Zahavi

et al. 2023

JCI Insight

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We previously reported that treatment of mice with 6-gingerol, the most abundant phytochemical in ginger root, leads to phosphodiesterase inhibition that counteracts neutrophil hyperactivity in models of antiphospholipid syndrome (APS) and lupus. Here, we explored the extent to which oral intake of a whole-ginger extract would similarly impact neutrophils in both autoimmune mice and healthy humans. In vitro, a solubilized ginger extract was able to attenuate neutrophil extracellular trap formation (NETosis) by human neutrophils through a mechanism that was dependent upon the cyclic AMP–dependent kinase, protein kinase A. When mice with features of either APS or lupus were administered a ginger extract orally, they demonstrated reduced circulating NETs, as well as the tempering of other disease outcomes, such as large-vein thrombosis (APS) and autoantibody production (lupus). In a pilot clinical trial, which was validated in a second cohort, daily intake of a ginger supplement for 7 days by healthy volunteers boosted neutrophil cAMP, inhibited NETosis in response to disease-relevant stimuli, and reduced circulating plasma NET levels. In summary, this work demonstrates that ginger intake restrains neutrophil hyperactivity in autoimmune mouse models and that ginger consumption by healthy individuals makes their neutrophils more resistant to NETosis.

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“…The enzyme is involved in the metabolism of cyclic adenosine 3,5-monophosphate (cAMP) and regulation of cellular processes mediated by this compound. Inhibitors of 3′,5′-cyclic-nucleotide phosphodiesterase constitute potential treatment for cancer [ 50 ], inflammatory [ 51 , 52 ], autoimmune [ 51 ], and neurological diseases [ 52 ]. Antioxidant peptides from food, in particular short-chain peptides, are considered helpful in the prevention of oxidative damage [ 53 ].…”

Section: Biologically Active Peptidesmentioning

confidence: 99%

Common Amino Acid Subsequences in a Universal Proteome—Relevance for Food Science

Minkiewicz

Darewicz

Iwaniak

et al. 2015

IJMS

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A common subsequence is a fragment of the amino acid chain that occurs in more than one protein. Common subsequences may be an object of interest for food scientists as biologically active peptides, epitopes, and/or protein markers that are used in comparative proteomics. An individual bioactive fragment, in particular the shortest fragment containing two or three amino acid residues, may occur in many protein sequences. An individual linear epitope may also be present in multiple sequences of precursor proteins. Although recent recommendations for prediction of allergenicity and cross-reactivity include not only sequence identity, but also similarities in secondary and tertiary structures surrounding the common fragment, local sequence identity may be used to screen protein sequence databases for potential allergens in silico. The main weakness of the screening process is that it overlooks allergens and cross-reactivity cases without identical fragments corresponding to linear epitopes. A single peptide may also serve as a marker of a group of allergens that belong to the same family and, possibly, reveal cross-reactivity. This review article discusses the benefits for food scientists that follow from the common subsequences concept.

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Phosphodiesterase inhibition in the treatment of autoimmune and inflammatory diseases: current status and potential

Cited by 15 publications

References 63 publications

Identification and treatment of T2-low asthma in the era of biologics

Identification and treatment of T2-low asthma in the era of biologics

Ginger intake suppresses neutrophil extracellular trap formation in autoimmune mice and healthy humans

Common Amino Acid Subsequences in a Universal Proteome—Relevance for Food Science

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