Biology subjects

Shields, D.

Publications and source records attributed to Shields, D..

3 recordsLinked to original sources

bioRxiv2026

Microplastics inhibit macrophage bioenergetics impairing homeostatic function and immune responsiveness

Since the 1950s, micro- and nanoplastics (MNPs) have become omnipresent, representing a novel environmental hazard which continually deposits in our airways. Pulmonary macrophages (pMacs) orchestrate the balance between inflammation and tolerance required for homeostasis of the lung and are among the first immune cells to encounter inhaled MNPs. Yet, how pMacs react to plastic deposition in the lung and implications for disease remain unknown. Here, we exposed mice in vivo, human precision-cut lung slices (hPCLS) ex vivo, and monocyte-derived macrophages and cell lines to polystyrene MNPs in vitro. MNP deposition in the lung and extrapulmonary tissues was determined over a 1-week period and pMacs from MNP-laden lungs isolated for RNA-sequencing. We compared the effects of MNPs or diesel exhaust particulate exposures on hPCLS viability and metabolism, monocyte-derived macrophage transcription, and macrophage mitochondrial function, inflammation, and antigen presentation. MNPs readily translocated the lung and were observed in all organs examined within 1-day. pMacs from MNP-exposed mice expressed transcriptional pathways associated with endocrine system disorders, tissue remodeling, and malignant disease. Macrophage phagocytosis was impaired through decreased mitochondrial function which could be rescued pharmacologically. MNPs inhibited the ability of macrophages to effectively present OVA-antigen preventing TCR-specific activation, an effect that could be restored by blocking PD-1/PD-L1. These findings indicate that MNPs impair macrophages via unique mechanisms linking phagocytic and bioenergetic dysfunction. Loss of antigen-presenting capabilities in MNP-laden macrophages may compromise immunosurveillance. As such, MNPs have the potential to increase susceptibility to lung disease independent of the conventional mechanisms of inflammation and oxidative stress. Clinical relevanceO_LIBioaccumulation of micro- and nanoplastics in macrophages impairs their ability to function as antigen-presenting cells increasing susceptibility to pathogenic and malignant disease. C_LIO_LIPulmonary macrophages residing in micro- and nanoplastic laden lungs possess transcriptional profiles associated with endocrine system disorders, gastrointestinal disease, and cancers. C_LI

immunology↗

bioRxiv2026

Peptidomics Mapping of Proteolysis Highlights Triple Activation of Sprouted Seeds by Germination, Homogenisation and Species Mixture.

We investigated how seed proteolysis was enhanced by germination, by subsequent homogenisation (disrupting sprout compartments), and by co-incubation of homogenates from different species. Mass spectrometry of released peptides tracked proteolytic signatures from chickpea, lentil, mung and broccoli proteins, in soaked seeds, in sprouted seeds, and after sprout homogenisation followed by incubation alone or in mixture with other sprouts. The proteolytic signatures differed markedly among the four species, and in the different treatment conditions. After homogenisation, legumain-like cleavage (after asparagine) increased in lentil, and proline-rich peptides increased in broccoli. For co-incubated homogenised sprouts, each species homogenate significantly contributed 6 to 57% of proteolytic patterns in peptides of other species, with chickpea and broccoli homogenates notably releasing metabolic protein peptides from mung and lentil. Thus, germination, homogenisation and homogenate species mixtures can each contribute to proteolysis of seed peptides, potentially increasing digestibility and reducing allergenicity. HIGHLIGHTSO_LIProteolysis motifs in soaked seeds and sprouts very diverse among species C_LIO_LISeed germination proteolysis altered by homogenisation C_LIO_LISeed germination proteolysis altered by co-incubation of different species C_LIO_LIFoods based on homogenised sprout mixtures may release more digestible peptides C_LI

bioinformatics↗

bioRxiv2018

Palbociclib and fulvestrant act in synergy to modulate central carbon metabolism in breast cancer cells

Palbociclib, is a selective inhibitor of cyclin-dependent kinases 4 and 6 and used as a first-line treatment for patients with estrogen receptor positive breast cancer. It has been shown that patients have improved progression-free survival when treated in combination with fulvestrant, an estrogen receptor antagonist. However, the mechanisms for this survival advantage are not known. We sought to analyze metabolic and transcriptomic changes in MCF-7 adenocarcinoma breast cancer cells following single and combined treatments to determine if selective metabolic pathways are targeted during combination therapy. Our results showed that individually, the drugs caused metabolic disruption to the same metabolic pathways, however fulvestrant additionally attenuated the pentose phosphate pathway and the production of important coenzymes. A comprehensive effect was observed when the drugs were applied together, confirming the combinatory therapy's synergism in the cell model. This study highlights the power of merging high-dimensional datasets to unravel mechanisms involved in cancer metabolism and therapy.\n\nHighlights{circ} First study employing multi-omics to investigate combined therapy on breast cancer cells\n{circ}Fulvestrant attenuates the pentose phosphate pathway and coenzyme production\n{circ}Synergism of palbociclib and fulvestrant was confirmed in vitro\n{circ}Altered key pathways have been identified\n\n\neTOC BlurbJohnson et al. applied an innovative multi-omics approach to decipher metabolic pathways affected by single versus combination dosing of palbociclib and fulvestrant in estrogen receptor positive breast cancer. Key metabolites and genes were correlated within metabolic pathways and shown to be involved in the drugs' synergism.

biochemistry↗