Biology subjects

MacNeil, A. J.

Publications and source records attributed to MacNeil, A. J..

5 recordsLinked to original sources

bioRxiv2025

Antiviral activity of rosemary extract against Zika virus in human dermal fibroblasts

Flaviviruses have increasingly emerged and re-emerged in recent decades, infecting millions of people annually. Zika virus (ZIKV) is particularly concerning due to its associated pathological complications, including microcephaly in newborns and Guillain-Barre syndrome in adults, posing a significant threat to public health. Despite efforts made by the scientific community, no licensed drugs against flaviviruses have been developed. Medicinal plants show promise as a novel source of antiviral agents, as they possess a diverse array of biologically active secondary metabolites, making them potential candidates for therapeutic use. Here, we sought to investigate the antiviral potential of rosemary extract (RE) against ZIKV in human dermal fibroblasts (HFF-1), one of the earliest cellular targets of infection. ZIKV was treated with various concentrations of RE or its major polyphenols, including rosmarinic acid (RA), carnosic acid (CA), and carnosol (CO), and the infectivity of each sample was measured by plaque reduction assay. To evaluate the impact of RE on different stages of the ZIKV replication cycle, HFF-1 cells were treated before, during, and after infection, or the virus was treated before infection. RE exerted potent virucidal activity against ZIKV in both Vero and HFF-1 cells by directly acting on virus particles before infection. Importantly, RE significantly inhibited the later stages of the virus replication cycle by interfering with post-entry mechanisms within the host cell. Moreover, major RE-derived polyphenols CA and CO, but not RA, were shown to significantly reduce infectivity when ZIKV was pre-treated with each compound individually. Overall, RE significantly impairs ZIKV infection in vitro by directly interacting with virus particles prior to adsorption and interfering with post-entry processes of the viral replication cycle. This study highlights the antiviral potential of RE and its individual components, wFigurearranting further investigation into the mechanisms underlying their activity and their effects on other medically important flaviviruses.

microbiology↗

bioRxiv2024

Treatment with carnosic acid attenuates the secretion of pro-inflammatory mast cell mediators following IL-33 activation

IL-33 is an alarmin cytokine, released upon cellular damage, that has gained significant attention as a regulator of inflammation in several pathologies, including allergy. Once released, IL-33 binds to and activates its cognate receptor ST2, leading to the activation of the classical inflammatory Myddosome signalosome in an array of cells, including mast cells. Our group has recently identified the polyphenol carnosic acid (CA), as a potent regulator of mast cell activation in the context of allergic inflammation. Due to the key role IL-33 plays in the enhancement of allergies and other mast cell-associated diseases, we sought to determine the inhibitory potential of CA in a model of IL-33-mediated mast cell activation. Bone marrow-derived mast cells were stimulated with IL-33 under potentiation of SCF and treated with CA in the presence or absence of an allergen co-stimulation. Here, it was determined that treatment with CA led to a reduction in early ROS production, which translated into a significant impairment in the release of pro-inflammatory cytokines IL-6, IL-13, TNF and chemokines CCL1, CCL2 and CCL3. Surprisingly however, it was determined that CA treatment increased signaling through Akt and NF{kappa}B protein phosphorylation, leading to increased gene expression of IL6, IL13, and CCL3 as well as increased intracellular concentrations of IL-6 and CCL3. Taken together, our data suggests treatment with CA impairs the release mechanisms of pro-inflammatory mediators following IL-33 activation, warranting further investigation into the versatile biological activity of CA toward advance our understanding of CA as a potential anti-inflammatory therapeutic.

immunology↗

bioRxiv2023

Antibody targeting of aging damaged isoDGR-protein doubles lifespan in a mouse model of chronic inflammation

Aging is the result of the accumulation of molecular damages that impair normal biochemical activities. We previously reported that aging-damaged amino acid sequence NGR (Asn-Gly-Arg) results in a gain-of-function conformational switching to isoDGR (isoAsp-Gly-Arg) motif. This integrin-binding motif activates leukocytes to induce chronic inflammation, which are characteristic features of age-linked cardiovascular disorders. We now report that anti-isoDGR immunotherapy doubles lifespan in mouse model of chronic inflammation. We observed extensive accumulation of isoDGR and inflammatory cytokine expression in multiple tissues from Pcmt1-KO and old WT animals, which could also be induced via injection of isoDGR-modified plasma proteins or synthetic peptides into young WT animals. However, weekly injection of anti-isoDGR mAb (1mg/kg) was sufficient to significantly reduce isoDGR-modified proteins and pro-inflammatory cytokine expression, improve behaviour and coordination, and double the average lifespan of Pcmt1-KO mice. Mechanistically, isoDGR-mAb mediated the immune clearance of damaged isoDGR-proteins by antibody-dependent cellular phagocytosis. These results indicate that immunotherapy targeting aging-damaged proteins may represent effective interventions for a range of age-linked degenerative disorders. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=105 SRC="FIGDIR/small/532237v1_ufig1.gif" ALT="Figure 1"> View larger version (12K): org.highwire.dtl.DTLVardef@81610borg.highwire.dtl.DTLVardef@a22aaorg.highwire.dtl.DTLVardef@169fe50org.highwire.dtl.DTLVardef@1b73d11_HPS_FORMAT_FIGEXP M_FIG Anti-isoDGR immunotherapy induces immune clearance of aging damaged isoDGR-proteins to reduce chronic inflammation, improve behaviour and coordination, and double lifespan in PCMT-/- mice. C_FIG

biochemistry↗

bioRxiv2022

Tideglusib mitigates dystrophic pathology in skeletal muscle and restores diastolic function in young D2 mdx mice

Introductory paragraphDuchenne muscular dystrophy (DMD) is a severe X-linked muscle wasting disorder that affects 1 in 5,000 males worldwide1. It is caused by the absence of functional dystrophin, which compromises muscle integrity, leading to progressive muscle wasting and weakness2. Glucocorticoids are the standard of care for patients with DMD as they delay the loss of ambulation by an average of 3 years3; however, they are also associated with adverse effects such as insulin resistance and increased risk of type 2 diabetes4. Thus, alternative therapeutic options should be explored. Here, we show that treating the DBA/2J mdx mouse with the glycogen synthase kinase 3 (GSK3) inhibitor, tideglusib, improved skeletal muscle function and insulin sensitivity, while also attenuating the hypermetabolic phenotype previously observed in these mice5. Furthermore, treating mdx mice with the GSK3 inhibitor, lithium, augmented the benefits of voluntary wheel running on insulin sensitivity and skeletal muscle function despite running half of the total distance compared to control-treated mdx mice. This is important given that some patients with DMD may not be able to engage in adequate amounts of physical activity. Thus, GSK3 inhibition alone or in combination with exercise can enhance skeletal muscle function and insulin sensitivity in mdx mice.

physiology↗

bioRxiv2022

Kynurenine metabolism is altered in mdx mice: a potential muscle to brain connection

Regular exercise can direct muscle kynurenine (KYN) metabolism toward the neuroprotective branch of the kynurenine pathway thereby limiting the accumulation of neurotoxic metabolites in the brain and contributing to mental resilience. While the effect of regular exercise has been studied, the effect of muscle disease on KYN metabolism has not yet been investigated. Previous work has highlighted anxiety-like behaviors in approximately 25% of patients with DMD, possibly due to altered KYN metabolism. Here, we characterized KYN metabolism in mdx mouse models of Duchenne muscular dystrophy (DMD). Young (8-10 week old) DBA/2J (D2) mdx mice, but not age-matched C57BL/10 (C57) mdx mice, had lower levels of circulating KYNA and KYNA:KYN ratio compared with their respective wild-type (WT) controls. Moreover, only D2 mdx mice displayed signs of anxiety-like behaviour, spending more time in the corners of their cages during a novel object recognition test when compared with WT. Along with this, we found that muscles from D2 mdx mice had less peroxisome proliferator-activated receptor-gamma coactivator 1-alpha and kynurenine amino transferase-1 enzyme content as well as elevated expression of inflammatory cytokines compared with WT muscles. Thus, our pilot work shows that KYN metabolism is altered in D2 mdx mice, with a potential contribution from altered muscle health.

physiology↗