CORA
Cork Open Research Archive (CORA) is UCC’s Open Access institutional repository which enables UCC researchers to make their research outputs freely available and accessible.
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The effects of a powdered meal replacement on inflammation, gut microbiota, and metabolism in people with excess body weight: A randomized controlled trial
(Elsevier B.V., 2026-06-04) Montenegro, Julia; Oliveira, Camila L.P.; Nguyen, Nguyen Khoi; Armet, Anissa M.; Berg, Aloys; Sharma, Arya M.; Mereu, Laurie; Cominetti, Cristiane; Ghosh, Sunita; Cani, Patrice D.; Richard, Caroline; Walter, Jens; Prado, Carla M.; Almased Wellness-GmbH; Canadian Foundation for Innovation, 34115; Canada Research Chairs; Campus Alberta Innovation Program; Mitacs Accelerate International; Fonds De La Recherche Scientifique - FNRS, FNRS, T.0032.25; Fonds De La Recherche Scientifique - FNRS, FNRS, J.0027.22; Walloon excellence in life sciences and biotechnology, WELBIO-CR-2022A-02P; Alberta Diabetes Institute; Fresenius Kabi; Abbott Nutrition; AMRA Medical Inc.; Almased Wellness GmbH; AbbVie; Amgen Incorporated; AstraZeneca; Currax; Eli Lilly; Novo Nordisk; Nutricia; a Nestlé Health Science Company; Boehringer Ingelheim GmbH
Background: Excess body weight is associated with chronic low-grade inflammation and metabolic abnormalities, such as insulin resistance, and dyslipidemia. Objectives: This study aimed to assess the impact of a soy protein-yogurt-honey powdered meal replacement (PMR) on inflammation, gut microbiota, and metabolism in individuals with excess body weight and in weight-stable conditions. Methods: The Powdered meal REplacement on MetabolIsm and gUt Microbiota (PREMIUM) Study was a 12-week, parallel-arm, randomized controlled trial. Participants (body mass index: 25–37 kg/m2) were randomized into either control (CON; usual diet, n = 34) or PMR (2 daily doses added to usual diet, n = 29) groups, maintaining a stable body weight. Assessments occurred at baseline, week 6, and week 12, and included inflammation markers (primary outcome: IL-6), gut microbiota diversity and composition (secondary outcome), metabolic blood markers (glucose and lipid profile), body composition (via dual-energy X-ray absorptiometry), and dietary intake. Data of completers were analyzed by 2-way repeated measures analysis of variance or generalized estimating equations with Bonferroni-corrected post hoc tests. Between-group differences in changes over time are expressed as mean and 95% confidence intervals. Results: Adherence to PMR was 98% of total doses, which increased protein intake [6.53% (5.04%, 8.02%), P < 0.001] and decreased fat intake [−5.23% (−7.10%, −3.35%), P < 0.001] compared with CON. By design, body weight remained stable. There were no changes in IL-6 [−0.01 (−0.47, 0.45) pg/mL, P = 0.412], with a low statistical power of 13.7%. Minor changes in gut microbiota composition included an increase in relative abundance of Subdoligranulum (0.72 Log2 fold-change, q = 0.002). In exploratory outcomes, PMR increased lean soft tissue [0.57 (0.12, 1.02) kg, P = 0.014] and reduced total cholesterol [−0.33 (−0.58, −0.08) mmol/L, P = 0.01] and low-density lipoprotein cholesterol [−0.28 (−0.46, −0.10) mmol/L, P = 0.003]. Conclusions: In this population, PMR intake did not improve chronic low-grade inflammation and had limited effects on gut microbiota, but was associated with improvements in lean soft tissue and lipid profile that warrant further exploration.This trial was registered at clinicaltrials.gov as NCT03235804 on August 1, 2017.
Predicting surfactant effects on drug permeation across hollow fiber membrane
(Elsevier B.V., 2026-05-15) Patel, Roshni P.; Murray, Jack D.; Griffin, Brendan T.; Polli, James E.; U.S. Food and Drug Administration, FDA, U01FD005946; U.S. Department of Health and Human Services, HHM, U01FD005946
The hollow fiber membrane (HFM) system is a potential combined dissolution/permeation in vitro tool to predict oral solid dosage form performance. However, drug permeability interpretation in the presence of surfactants remains mechanistically challenging, particularly when surfactants are present in both the donor and receiver compartments. A model denoted the reduced resistance model was recently employed to explain enhanced drug permeability when surfactant was present in the receiver. The objective was to re-examine previously published HFM flux of griseofulvin and meloxicam to consider the reduced resistance model as an additional contributing mechanism impacting drug flux. Published HFM data under all four surfactant experimental scenarios (i.e., no surfactant, surfactant in the receiver only, surfactant in the donor only, and surfactant in both donor and receiver) were re-analyzed. For the latter two most complex scenarios, there were six competing permeation models. For these two scenarios, the best predictive model for griseofulvin was the reduced resistance model for total donor drug concentration; meanwhile, for meloxicam, which was much less micelle incorporated, the best predictive model was the simple free drug permeation model. Overall, these findings demonstrate that drug permeation across HFM in surfactant-containing systems is governed by the interplay between donor-side micellar sequestration and receiver-side resistance reduction.
Imagining justice: approaching justice as a process of imaginative hybridity in times of polycrisis
(Frontiers Media SA, 2026-07-07) Mullally, Gerard; Boyle, Evan; Gaston, Sadhbh; Wood, Nathan; McElherron, Catherine; Revez, Alexandra; Creed, Elizabeth; Dunphy, Niall; Environmental Protection Agency; Taighde Éireann - Research Ireland
In times of polycrisis, the range of interconnected risks – environmental, societal, economical, geopolitical, technological – create the milieu in which we must face these challenges as nodes within a network. No individual one can be addressed in isolation but instead must be understood as relational and operating within a unified system. Within this context, considerations of justice are increasingly referred to in relation to climate change. The system-wide changes needed in responding to the polycrisis ensures that social inequality must be understood as a central tenet across any potential or aspirational transformative change. As such, it is important to consider what justice might look like with regards to how we get there, who leads the narrative of the future, and in what fundamental ways is it different from where we currently are. We aim not to separate specific justice narratives (e.g., climate justice, energy justice) from societal justice on a broader level. Instead, within this paper, the importance of imagination in questions of justice is outlined as it is concerned with responding to climate change, and the polycrisis with which it is entangled. Climate (in)justice acts as a useful heuristic for understanding normative issues that may culminate in relation to climate change but is not operative as a specific isolated outcome or orientation. Climate justice is not a possible outcome outside of wider societal justice. Climate change represents an unprecedented challenge to the human imagination in terms of the scope and scale of the impact on the natural world; the ability to visualise the social, political and economic consequences of these changes and how changing course is envisaged. Yet, since their foundations, questions of social justice have been related to processes of imagination. Within this paper, we explore the role of imagination in shaping attitudes and responses to the climate crisis, specifically examining how imaginative processes influence perceptions of justice and ethical considerations. The primary research question guiding this study is: How do imaginative processes contribute to shaping notions of justice in relation to the climate crisis?
Fermentation in breadmaking: enhancing digestibility and nutritional value for gastrointestinal health
(Frontiers Media SA, 2026-05-21) Ribet, Léa; Desalles, Robin; Clement, Héliciane; Nyhan, Laura; Baptista, Nathália Trunckle; wang, Yaqin; Arendt, Elke; Durand-Dubief, Mickael; Lesaffre Institute of Research and Technology at Lesaffre International (Marcq-en-Baroeul, France)
Fermentation is a traditional food process that has been used for ages, notably contributing to the production of bread, one of the main staple foods. The aim of this review is to explore how fermentation may be leveraged to enhance the digestibility and nutritional value of bread, addressing potential gastrointestinal disorders related to its consumption. Emerging gastrointestinal disorders such as non-celiac gluten or wheat sensitivity and irritable bowel syndrome (IBS) are discussed, highlighting the complex and often poorly understood, nature of these conditions involving both physiological and psychological aspects. Yeasts and lactic acid bacteria used in the bread making process can positively influence bread characteristics through the enhancement of mineral bioaccessibility or the reduction of triggering components like gluten and FODMAPs, especially when selecting microorganisms with targeted properties. However, the characterization and selection of these microorganisms require further standardization, and the clinical implications need to be firmly established as the strength of the evidence remains insufficient. The review also discusses the potential for fermentation to generate beneficial metabolites, such as exopolysaccharides (EPS) and short-chain fatty acids (SCFA). While these compounds show promise, their actual content, stability, and bioavailability in baked bread require further investigation. Overall, fermentation appears as a versatile transformative tool for the creation of digestible and nutritionally enhanced bread. Yet well-designed human studies are needed to substantiate the clinical benefits and better define the conditions where modification through fermentation may provide gastrointestinal health advantages.
Investigation into the role of Ubiquitin Specific Peptidase 18 in oesophageal cancer
(University College Cork, 2025-09-30) Carey, Maria; McKenna, Sharon L.; O'Donovan, Tracey; Research Ireland; Breakthrough Cancer Research
Oesophageal cancer is the seventh most common cancer and the sixth leading cause of cancer-related deaths worldwide, with a five-year survival rate of 20%. There are two main histological subtypes: squamous cell carcinoma and adenocarcinoma. Treatment of both involves chemotherapy, chemo-radiotherapy, and/or surgery, depending on tumour stage and patient status. Unfortunately, resistance to chemotherapy is common and often contributes to this poor prognosis. Novel therapeutic targets are therefore urgently required to improve treatment regimens for people with oesophageal cancer.
Earlier research by this group found that a network of interferon-stimulated genes (ISGs), known as the ISGylation network, is differentially expressed in drug-sensitive and resistant oesophageal cancer cells. The ISGylation network is similar to the ubiquitin network, involving the conjugation of Interferon-Stimulated Gene 15 (ISG15), a ubiquitin-like protein (Ubl), to target proteins in a sequential manner, mediated by E1, E2, and E3 enzymes. Ubiquitin Specific Peptidase 18 (USP18) selectively removes ISG15 in a process referred to as deISGylation. USP18 also negatively regulates the type I interferon (IFN) response, independent of its enzymatic activity. USP18 is expressed at high levels in a panel of chemo-sensitive and apoptosis-competent oesophageal cancer cells, and expressed at low levels in chemo- and apoptosis-resistant oesophageal cancer cells.
We investigated whether the expression levels of USP18 can affect the response of two chemo-resistant oesophageal cancer cell lines, KYSE450 and KYSE140, to chemotherapy. Treatment with IFN-α alone enhanced the sensitivity of KYSE450 cells to 5-fluorouracil (5-FU), but had no effect in KYSE140 cells and did not alter oxaliplatin sensitivity in either cell line. In contrast, silencing USP18 in the presence of IFN-α significantly increased the sensitivity of both cell lines to 5-FU and oxaliplatin and induced extensive apoptosis in these cell lines, which were previously considered to be apoptosis-resistant.
USP18 and its substrate ISG15 were induced by IFN-α treatment alone. However, ISG15 was predominantly present in the unconjugated form due to the co-upregulation of USP18. Knockdown of USP18 led to significant accumulation of ISG15-conjugated proteins, demonstrating the efficiency of USP18 in removing this modification. This accumulation of conjugates, together with the occurrence of cell death, raises the possibility that ISG15-modified proteins play an important role in the activation of cell death signalling. In addition, USP18 depletion in the presence of IFN-α increased LC3 II expression and autophagosome formation, both alone and in combination with chemotherapeutic agents, demonstrating negative regulation of autophagy. Together, these findings indicate that targeting USP18 could reactivate cell death signalling and restore sensitivity to chemo-resistant oesophageal cancer.
We then investigated whether Poly(I:C), a synthetic double-stranded RNA analogue that mimics viral infection, could provide an alternative to IFN-α. We demonstrated that Poly(I:C) induced ISGs, including USP18 and its substrate ISG15, in KYSE450 and KYSE140 cells. After depleting USP18 with siRNA, Poly(I:C) induced apoptosis to a level similar to IFN-α in KYSE450 cells. In contrast, KYSE140 cells were unresponsive, showing no significant decrease in viability. Notably, there was no induction of ISG15 conjugates in KYSE140 cells, suggesting that this modification may be important for cell death competency.
These findings demonstrate that combining USP18 depletion with an IFN-like stimulus to promote ISG15 conjugation represents a promising strategy to overcome resistance to cell death, and indeed also induces significant cell death without chemotherapy. While IFN-α remains the most reliable partner in this therapeutic strategy, Poly(I:C) or similar agents could expand therapeutic options if predictive biomarkers are established.
As USP18 depletion had such a profound effect on chemosensitivity, we wanted to create USP18 gene-knockout cell lines to validate the siRNA data and further explore the downstream signalling linked to ISGylation. We employed a CRISPR/Cas9 knock-out protocol that had been successful in other cell lines. Despite optimisation of CRISPR/Cas9 protocols, no knockout was generated in either the KYSE450 or KYSE140 cell lines. It is unclear why the CRISPR protocols did not achieve a knockout in these cell lines. Possible explanations include limited chromatin accessibility to the Cas9 nuclease or deficiencies in DNA repair pathways. By contrast, a knockout of USP18 was successfully generated in the OE21 cell line, providing a drug-sensitive USP18 knockout model to further expand this body of work.
The increased chemosensitivity and apoptosis in the oesophageal cancer cell lines was associated with elevated levels of ISGylation. However, the identity of the ISGylated proteins, which may mediate chemosensitivity, remains unknown. We sought to identify these ISG15-modified proteins. Following USP18 depletion with siRNA and treatment with IFN-α, ISG15 conjugates were purified by immunoprecipitation from the KYSE450 cell line. Three independent test samples were then analysed by mass spectrometry and filtered against a control IP using a non-specific antibody and the CRAPome database. We identified 117 ISG15-conjugated proteins in three independent test samples. Of these, 36 were common to databases or published IP studies, underscoring the novelty of our dataset. Gene ontology and network analyses of the ISG15 interactome revealed functional clusters enriched in protein synthesis and targeting, a role not previously associated with ISGylation. In addition, we identified components of the proteasome, consistent with prior reports and further supporting ISGylation's role in protein degradation. Importantly, three candidate targets were independently validated by co-immunoprecipitation, supporting the mass spectrometry findings.
Collectively, this thesis provides new insights into the role of USP18 in signalling pathways that influence cell viability. We have demonstrated a novel strategy to re-engage apoptosis in resistant oesophageal cancer cells by impeding USP18 in the presence of type I IFN signalling. Additionally, we have identified specific ISG15 targets that may mediate these effects. This research highlights a new approach to significantly improve therapeutic regimens by targeting USP18 or a downstream mediator of its effects. Expanding this research could lead to new treatment options for oesophageal cancer, especially for patients with limited response to current therapies. Further research of this pathway may enable ‘precision oncology’ to be available in oesophageal cancer, bringing more effective, tailored therapies within reach.