Recent Submissions

  • Concordance of objectively-detected retinal nerve fiber bundle defects in en face OCT images with conventional structural and functional changes in glaucoma.

    Cheloni, Riccardo; Denniss, Jonathan (2022)
    To assess how objectively-detected defects of retinal nerve fibre bundle (RNFB) reflectance in en face OCT images relate to circumpapillary retinal nerve fibre layer thickness (cpRNFLT) and visual field defects. Cross-sectional study. 16 participants with early-glaucoma and 29 age-similar healthy controls, among which 22 had usable en face images to establish normative levels of RNFB reflectance. All participants underwent cpRNFLT scans, visual field examination and wide-field OCT. En face reflectivity was assessed objectively using the Summary of Multiple Anatomically-Adjusted Slabs (SMAS) method. En face defects were deemed concordant with cpRNFLT when they had at least one cpRNFLT point with p
  • A Combined Rheological and Thermomechanical Analysis Approach for the Assessment of Pharmaceutical Polymer Blends

    Isreb, Mohammad; Chalkia, Marianiki; Gough, Timothy D.; Forbes, Robert T.; Timmins, P. (MDPI, 2022-08)
    The viscoelastic nature of polymeric formulations utilised in drug products imparts unique thermomechanical attributes during manufacturing and over the shelf life of the product. Nevertheless, it adds to the challenge of understanding the precise mechanistic behaviour of the product at the microscopic and macroscopic level during each step of the process. Current thermomechanical and rheological characterisation techniques are limited to assessing polymer performance to a single phase and are especially hindered when the polymers are undergoing thermomechanical transitions. Since pharmaceutical processing can occur at these transition conditions, this study successfully proposes a thermomechanical characterisation approach combining both mechanical and rheological data to construct a comprehensive profiling of polymeric materials spanning both glassy and rubbery phases. This approach has been used in this study to assess the mechanical and rheological behaviour of heterogenous polymer blends of hydroxypropyl cellulose (HPC) and hydroxypropyl methylcellulose (HPMC) over a shearing rate range of 0.1–100 s−1 and a temperature range of 30–200 °C. The results indicate that HPC and HPMC do not appear to interact when mixing and that their mixture exhibits the mechanistic properties of the two individual polymers in accordance with their ratio in the mixture. The ability to characterise the behaviour of the polymers and their mixtures before, throughout, and after the glassy to rubbery phase transition by application of the combined techniques provides a unique insight towards a quality-by-design approach to this and other polymer-based solid dosage forms, designed with the potential to accelerate their formulation process through obviating the need for multiple formulation trials.
  • Zirconium-based MOFs and their biodegradable polymer composites for controlled and sustainable delivery of herbicides

    Mahmoud, L.A.M.; Telford, Richard; Livesey, T.C.; Katsikogianni, Maria G.; Kelly, Adrian L.; Terry, L.R.; Ting, V.P.; Nayak, Sanjit (2022-07-29)
    Adsorption and controlled release of agrochemicals has been studied widely using different nanomaterials and a variety of formulations. However, the potential for application of high surface-area metal-organic frameworks (MOFs) for the controlled release of agrochemicals has not been thoroughly explored. Herein, we report controlled and sustainable release of a widely used herbicide (2-methyl-4-chlorophenoxyacetic acid, MCPA) via incorporation in a range of zirconium-based MOFs and their biodegradable polymer composites. Three Zr-based MOFs, viz., UiO-66, UiO-66-NH2, and UiO-67 were loaded with MCPA either postsynthetically or in situ during synthesis of the MOFs. The MCPA-loaded MOFs were then incorporated into a biodegradable polycaprolactone (PCL) composite membrane. All three MOFs and their PCL composites were thoroughly characterized using FT-IR, TGA, SEM, PXRD, BET, and mass spectrometry. Release of MCPA from each of these MOFs and their PCL composites was then studied in both distilled water and in ethanol for up to 72 h using HPLC. The best performance for MCPA release was observed for the postsynthetically loaded MOFs, with PS-MCPA@UiO-66-NH2 showing the highest MCPA concentrations in ethanol and water of 0.056 and 0.037 mg/mL, respectively. Enhanced release of MCPA was observed in distilled water when the MOFs were incorporated in PCL. The concentrations of herbicides in the release studies provide us with a range of inhibitory concentrations that can be utilized depending on the crop, making this class of composite materials a promising new route for future agricultural applications.
  • Generation and Use of Functional Hydrogels That Can Rapidly Sample Infected Surfaces

    Swift, Thomas; Pinnock, A.; Shivshetty, N.; Pownall, David; MacNeil, S.; Douglas, I.; Garg, P.; Rimmer, Stephen (2022-04)
    This paper outlined our method for developing polymer-linked contact lens type materials for rapid detection and differentiation of Gram-positive, Gram-negative bacteria and fungi in infected corneas. It can be applied to both model synthetic or ex-vivo corneal models and has been successfully trialed in an initial efficacy tested animal study. First a hydrogel substrate for the swab material is selected, we have demonstrated selective swabs using a glycerol monomethacrylate hydrogel. Alternatively any commercial material with carboxylic acid functional groups is suitable but risks nonspecific adhesion. This is then functionalised via use of N-hydroxysuccinimide reaction with amine groups on the specified highly branched polymer ligand (either individually gram negative, gram positive or fungal binding polymers or a combination of all three can be employed for desired sensing application). The hydrogel is then cut into swabs suitable for sampling, used, and then the presence of gram positive, game negative and fungi are disclosed by the sequential addition of dyes (fluorescent vancomycin, fluorescein isothiocyanate and calcofluor white). In summary this method presents: Method to produce glycerol monomethacrylate hydrogels to minimize nonspecific binding Methods of attaching pathogen binding highly branched polymers to produce selective hydrogel swabs Method for disclosing bound pathogens to this swab using sequential dye addition
  • Fluorescence spectroscopy analysis of fly ash removal from aqueous systems: adsorption of alginate to silica and alumina

    Eltaboni, F.; Singh, Sehaj; Swanson, L.; Swift, Thomas; Almalki, A.S.A. (2022-07)
    Fly ash is a toxic industrial waste, mainly consisting of silica and alumina particles, that has been found discharged into the environment. It is proposed that alginate, a naturally occurring biopolymer, can bind to these minerals and thus play a role in water purification. The binding forces involved in this process consist of weak interactions, such as van der Waals forces and electrostatic interactions. Although the attachment of alginate to mineral surfaces is mainly governed by its carboxylate groups, hydroxyl moieties could play a role in the interaction between the polymer and minerals. This work aims to use the SiO2 and Al2O3 particles as models for fly ash and to show the use of alginate biopolymers (fluorescently labelled with an aminonaphthaline sulfonate fluorophore (AmNS)) to coagulate them. The addition of simple electrolytes like NaCl and CaCl2 encourages the coiling of the polymer chain at high pH values which has an effect on its capability to bind to the inorganic particles. A combination of fluorescence and ICP-MS demonstrated that alginate has a considerable adsorption affinity for Al2O3, whereas it attracts SiO2 weakly. The adsorption process is pH dependent: strong adsorption was observed at low pH values. The dependence of adsorption on the mineral (Al2O3 and SiO2) concentration was also examined under different pH conditions: the adsorption amount was observed to increase by increasing the solid concentration. Adsorption isotherms obtained at low and high mineral concentrations were found to be Henry in type.
  • USP5 enhances SGTA mediated protein quality control.

    Hill, J.; Nyathi, Yvonne (2022-07)
    Mislocalised membrane proteins (MLPs) present a risk to the cell due to exposed hydrophobic amino acids which cause MLPs to aggregate. Previous studies identified SGTA as a key component of the machinery that regulates the quality control of MLPs. Overexpression of SGTA promotes deubiqutination of MLPs resulting in their accumulation in cytosolic inclusions, suggesting SGTA acts in collaboration with deubiquitinating enzymes (DUBs) to exert these effects. However, the DUBs that play a role in this process have not been identified. In this study we have identified the ubiquitin specific peptidase 5 (USP5) as a DUB important in regulating the quality control of MLPs. We show that USP5 is in complex with SGTA, and this association is increased in the presence of an MLP. Overexpression of SGTA results in an increase in steady-state levels of MLPs suggesting a delay in proteasomal degradation of substrates. However, our results show that this effect is strongly dependent on the presence of USP5. We find that in the absence of USP5, the ability of SGTA to increase the steady state levels of MLPs is compromised. Moreover, knockdown of USP5 results in a reduction in the steady state levels of MLPs, while overexpression of USP5 increases the steady state levels. Our findings suggest that the interaction of SGTA with USP5 enables specific MLPs to escape proteasomal degradation allowing selective modulation of MLP quality control. These findings progress our understanding of aggregate formation, a hallmark in a range of neurodegenerative diseases and type II diabetes, as well as physiological processes of aggregate clearance.
  • Kinship practices in Early Iron Age southeast Europe: genetic and isotopic analysis of burials from the Dolge njive barrow cemetery, Dolenjska, Slovenia

    Armit, I.; Fischer, C-E.; Koon, Hannah E.C.; Nicholls, Rebecca A.; Olalde, I.; Rohland, N.; Buckberry, Jo; Montgomery, J.; Mason, P.; Cresnar, M.; et al. (2022)
    DNA analysis demonstrates that all seven individuals buried in an Early Iron Age barrow at Dolge njive, southeast Slovenia, are close biological relatives. Although group composition does not suggest strict adherence to a patrilineal or matrilineal kinship system, the funerary tradition appears highly gendered, with family links through both the male and female line being important in structuring communities. We explore the implications for our understandings of kinship and funerary practices in Early Iron Age southeast Europe.
  • Experiences of patients with heart failure with medicines at transition intervention: Findings from the process evaluation of the Improving the Safety and Continuity of Medicines management at Transitions of care (ISCOMAT) programme

    Powell, Catherine; Ismail, Hanif; Davis, M.; Taylor, A.; Breen, Liz; Fylan, Beth; Alderson, S.L.; Gale, C.P.; Kellar, Ian; Silcock, Jonathan; et al. (Wiley International, 2022)
    Abstract: Background: Medicines are often suboptimally managed for heart failure patients across the transition from hospital to home, potentially leading to poor patient outcomes. The Improving the Safety and Continuity Of Medicines management at Transitions of care programme included: understanding the problems faced by patients and healthcare professionals; developing and co-designing the Medicines at Transitions of care Intervention (MaTI); a cluster randomized controlled trial testing the effectiveness of a complex behavioural MaTI aimed at improving medicines management at the interface between hospitals discharge and community care for patients with heart failure; and a process evaluation. The MaTI included a patient-held My Medicines Toolkit; enhanced communication between the hospital and the patient's community pharmacist and increased engagement of the community pharmacist postdischarge. This paper reports on the patients' experiences of the MaTI and its implementation from the process evaluation. Design: Twenty one-to-one semi-structured patient interviews from six intervention sites were conducted between November 2018 and January 2020. Data were analysed using the Framework method, involving patients as co-analysts. Interview data were triangulated with routine trial data, the Consolidated Framework for Implementation Research and a logic model. Results: Within the hospital setting patients engaged with the toolkit according to whether staff raised awareness of the My Medicines Toolkit's importance and the time and place of its introduction. Patients' engagement with community pharmacy depended on their awareness of the community pharmacist's role, support sources and perceptions of involvement in medicines management. The toolkit's impact on patients' medicines management at home included reassurance during gaps in care, increased knowledge of medicines, enhanced ability to monitor health and seek support and supporting sharing medicines management between formal and informal care networks. Conclusion: Many patients perceived that the MaTI offered them support in their medicines management when transitioning from hospital into the community. Importantly, it can be incorporated into and built upon patients' lived experiences of heart failure. Key to its successful implementation is the quality of engagement of healthcare professionals in introducing the intervention. Patient or Public Contribution: Patients were involved in the study design, as qualitative data co-analysts and as co-authors.
  • Synthesis of orthogonal push-pull chromophores via click reaction of arylynamines

    Huang, S.; Ma, J.; Yi, Y.; Li, M.; Cai, P.; Wu, Na (Anna) (2022-04)
    Herein, we report a catalyst-free ‘click’ reaction: metal-free [2 + 2] cycloaddition–retro-electrocyclisation (CA–RE) of arylynamines with the sluggish acceptor tetracyanoquinodimethane (TCNQ) to provide orthogonal electron-push–pull light-harvesting small molecules: N-heterocyclic dicyanoquinodimethane-substituted methylene malononitriles. Ynamines are reactive alkynes and tend to induce over-reactions with the CA–RE adducts. The reactivity of arylynamines was balanced properly by ensuring the electrondensity of the nitrogen atom was delocalised more over the aromatic rings than the triple bond.
  • New aldo-keto reductase 1C3 (AKR1C3) inhibitors based on the hydroxytriazole scaffold

    Pippione, A.C.; Kilic-Kurt, Z.; Kovachka, S.; Sainas, S.; Rolando, B.; Denasio, E.; Pors, Klaus; Adinolfi, S.; Zonari, D.; Bagnati, R.; et al. (2022-07-05)
    The aldo-keto reductase 1C3 (AKR1C3) enzyme is considered an attractive target in Castration Resistant Prostate Cancer (CRPC) because of its role in the biosynthesis of androgens. Flufenamic acid, a non-selective AKR1C3 inhibitor, has previously been subjected to bioisosteric modulation to give rise to a series of compounds with the hydroxytriazole core. In this work, the hit compound of the previous series has been modulated further, and new, more potent, and selective derivatives have been obtained. The poor solubility of the most active compound (cpd 5) has been improved by substituting the triazole core with an isoxazole heteronucleous, with similar enzymatic activity being retained. Potent AKR1C3 inhibition is translated into antiproliferative effects against the 22RV1 CRPC cellular model, and the in-silico design, synthesis and biological activity of new compounds is described herein. Compounds have also been assayed in combination with two approved antitumor drugs, abiraterone and enzalutamide.
  • Anticancer water-soluble organoruthenium complexes: synthesis and preclinical evaluation

    Pitto-Barry, Anaïs; Azmanova, Maria; Rafols, Laia; Cooper, Patricia A.; Seaton, Colin C.; Shnyder, Steven D. (2022)
    The synthesis, characterisation, and evaluation of the in vitro cytotoxicity of five maleonitriledithiolate-based ruthenium metal complexes bearing various phosphine ligands towards two ovarian cancer cell lines (A2780 and A2780cisR), one non-small-cell lung cancer cell line (H460) and one normal prostate cell line (PNT2) are presented herein. These 18-electron complexes were designed with four water-soluble phosphine ligands to increase the water-solubility character of the corresponding electron-deficient ruthenium complex which showed great in vitro promises, and triphenylphosphine for comparison. The complexes with triphenylphosphine-3,3',3''trisulfonic acid and triphenylphosphine present similar cytotoxicity compared to the 16-electron precursor, with equal cytotoxicity to both A2780 and A2780cisR. Hints at the mechanism of action suggest an apoptotic pathway based on ROS production. No toxicity was observed in preliminary in vivo pilot studies for these two complexes in subcutaneous A2780 and A2780cisR xenograft models, with some evidence of tumour growth delay.
  • Controlled bioactive delivery using degradable electroactive polymers

    Ashton, M.D.; Cooper, Patricia A.; Municoy, S.; Desimone, M.F.; Cheneler, D.; Shnyder, Steven D.; Hardy, J.G. (2022-07)
    Biomaterials capable of precisely controlling the delivery of agrochemicals/biologics/drugs/fragrances have significant markets in the agriscience/healthcare industries. Here, we report the development of degradable electroactive polymers and their application for the controlled delivery of a clinically relevant drug (the anti-inflammatory dexamethasone phosphate, DMP). Electroactive copolymers composed of blocks of polycaprolactone (PCL) and naturally occurring electroactive pyrrole oligomers (e.g., bilirubin, biliverdin, and hemin) were prepared and solution-processed to produce films (optionally doped with DMP). A combination of in silico/in vitro/in vivo studies demonstrated the cytocompatibility of the polymers. The release of DMP in response to the application of an electrical stimulus was observed to be enhanced by ca. 10-30% relative to the passive release from nonstimulated samples in vitro. Such stimuli-responsive biomaterials have the potential for integration devices capable of delivering a variety of molecules for technical/medical applications.
  • The impact of industrialization on malignant neoplastic disease of bone in England: a study of medieval and industrial samples

    Soria, Sabrina; Buckberry, Jo (2022-09)
    Objective: The increasing prevalence of malignant disease has been associated with shifts in environmental, socioeconomic, and lifestyle risk factors as well as increased adult lifespan. We examine the relationship between malignant neoplasms affecting bone, age and industrialization. Materials: Pre-existing skeletal data from 11 medieval (1066-1547, n=8,973) and 14 industrial (1700-1890, n=4,748) cemeteries (N=13,721) from England. Methods: Context number, sex, age-at-death, evidence of skeletal malignancy, and diagnosis were collated. The data were compared using chi square, Kolmogorov-Smirnov tests and logistic regression (α=0.01). Results: There was a statistically significant increase in skeletal malignancy from 0.06% in the medieval sample to 0.36) in the industrial sample (p< 0.001). Age had a strong relationship with malignancy (p = 0.003), sex did not (p = 0.464). Logistic regression revealed that time-period (p < 0.001) was a stronger predictor of skeletal malignancy than age-at-death (p = 0.002). Conclusion: Our results confirm that even with the temporal increase in adult human lifespan the increase of malignant neoplasms of bone between the medieval and industrial time periods is still statistically significant. Significance: The augmented exposure to carcinogens and pollution during the Industrial Revolution had a strong effect on an individual’s susceptibility to developing malignant disease of bone. Limitations: This meta-analysis relies upon previously gathered data and diagnosis from a large number of researchers and did not include radiographic or CT screening. Only malignant neoplasms that affected bone could be included. Suggestions for further research: Increasing excavation and analysis of post-medieval cemeteries will provide more data. Multimethod approaches (radiography, CT, Micro-CT and histology) are encouraged.
  • The Chemerin-CMKLR1 Axis is Functionally important for Central Regulation of Energy Homeostasis

    Yun, Haesung; Dumbell, R.; Hanna, Katie; Bowen, Junior; McLean, Samantha L.; Kantamneni, Sriharsha; Pors, Klaus; Wu, Q-F; Helfer, Gisela (2022-05)
    Chemerin is an adipokine involved in inflammation, adipogenesis, angiogenesis and energy metabolism, and has been hypothesized as a link between obesity and type II diabetes. In humans affected by obesity, chemerin gene expression in peripheral tissues and circulating levels are elevated. In mice, plasma levels of chemerin are upregulated by high-fat feeding and gain and loss of function studies show an association of chemerin with body weight, food intake and glucose homeostasis. Therefore, chemerin is an important blood-borne mediator that, amongst its other functions, controls appetite and body weight. Almost all studies of chemerin to date have focused on its release from adipose tissue and its effects on peripheral tissues with the central effects largely overlooked. To demonstrate a central role of chemerin, we manipulated chemerin signaling in the hypothalamus, a brain region associated with appetite regulation, using pharmacological and genetic manipulation approaches. Firstly, the selective chemerin receptor CMKLR1 antagonist α-NETA was administered i.c.v. to rats to test for an acute physiological effect. Secondly, we designed a short-hairpin-RNA (shRNA) lentivirus construct targeting expression of CMKLR1. This shRNA construct, or a control construct was injected bilaterally into the arcuate nucleus of male Sprague Dawley rats on high-fat diet (45%). After surgery, rats were maintained on high-fat diet for 2 weeks and then switched to chow diet for a further 2 weeks. We found a significant weight loss acutely and inhibition of weight gain chronically. This difference became apparent after diet switch in arcuate nucleus-CMKLR1 knockdown rats. This was not accompanied by a difference in blood glucose levels. Interestingly, appetite-regulating neuropeptides remained unaltered, however, we found a significant reduction of the inflammatory marker TNF-α suggesting reduced expression of CMKLR1 protects from high-fat diet induced neuroinflammation. In white and brown adipose tissue, mRNA expression of chemerin, its receptors and markers of adipogenesis, lipogenesis and brown adipocyte activation remained unchanged confirming that the effects are driven by the brain. Our behavioral analyses suggest that knockdown of CMKLR1 had an impact on object recognition. Our data demonstrate that CMKLR1 is functionally important for the central effects of chemerin on body weight regulation and neuroinflammation.
  • Intermittent PI3Ko inhibition sustains anti-tumor immunity and curbs irAEs

    Eschweiler, S.; Ramirez-Suastegui, C.; Li, Y.; King, E.; Chudley, L.; Thomas, J.; Wood, O.; von Witzleben, A.; Jeffrey, D.; McCann, K.; et al. (2022-05-26)
    Phosphoinositide 3-kinase δ (PI3Kδ) has a key role in lymphocytes, and inhibitors that target this PI3K have been approved for treatment of B cell malignancies1–3. Although studies in mouse models of solid tumours have demonstrated that PI3Kδ inhibitors (PI3Kδi) can induce anti-tumour immunity4,5, its effect on solid tumours in humans remains unclear. Here we assessed the effects of the PI3Kδi AMG319 in human patients with head and neck cancer in a neoadjuvant, double-blind, placebo-controlled randomized phase II trial (EudraCT no. 2014-004388-20). PI3Kδ inhibition decreased the number of tumour-infiltrating regulatory T (Treg) cells and enhanced the cytotoxic potential of tumour-infiltrating T cells. At the tested doses of AMG319, immune-related adverse events (irAEs) required treatment to be discontinued in 12 out of 21 of patients treated with AMG319, suggestive of systemic effects on Treg cells. Accordingly, in mouse models, PI3Kδi decreased the number of Treg cells systemically and caused colitis. Single-cell RNA-sequencing analysis revealed a PI3Kδi-driven loss of tissue-resident colonic ST2 Treg cells, accompanied by expansion of pathogenic T helper 17 (TH17) and type 17 CD8+ T (TC17) cells, which probably contributed to toxicity; this points towards a specific mode of action for the emergence of irAEs. A modified treatment regimen with intermittent dosing of PI3Kδi in mouse models led to a significant decrease in tumour growth without inducing pathogenic T cells in colonic tissue, indicating that alternative dosing regimens might limit toxicity.
  • Phenotypic differences between microvascular and macrovascular smooth muscle cells and their contribution to coronary microvascular dysfunction

    Riches-Suman, Kirsten (2021-06-11)
    Coronary microvascular dysfunction (CMD) is an under-diagnosed condition characterized by functional alteration of the small coronary arterioles and the cardiac capillary bed. The vessels do not dilate appropriately in response to changes in cardiac oxygen demand, leading to chest pain and symptoms of angina. These blood vessels contain two major cell types: the endothelial cells, which line the blood vessels and detect changes in oxygen demand, and smooth muscle cells (SMC) which respond to these changes by contracting or relaxing to provide an optimal blood supply to the cardiac tissue. Many CMD studies have focused on the endothelial cells as these cells secrete vasorelaxants and vasoconstrictors. However, comparably fewer studies have examined SMC despite their functional role in contracting and relaxing. A variety of health conditions and lifestyle choices, such as diabetes, hypertension and cigarette smoking, can promote the development of both CMD and macrovascular coronary artery disease; a condition where SMC have been studied extensively. This review article will consider the influence of CMD on SMC phenotype. It will discuss the structural, cellular and molecular changes in CMD, and will summarise how co-morbidities can have differing effects on micro- and macro-vascular SMC phenotype and function, which complicates the development of new therapeutic avenues for CMD.
  • Diverse roles of microRNA-145 in regulating smooth muscle (dys)function in health and disease

    Riches-Suman, Kirsten (2021-02-22)
    MicroRNAs are short, non-coding RNAs that target messenger RNAs for degradation. miR-145 is a vascular-enriched microRNA that is important for smooth muscle cell (SMC) differentiation. Under healthy circumstances, SMC exist in a contractile, differentiated phenotype promoted by miR-145. In cases of disease or injury, SMC can undergo reversible dedifferentiation into a synthetic phenotype, accompanied by inhibition of miR-145 expression. Vascular disorders such as atherosclerosis and neointimal hyperplasia are characterised by aberrant phenotypic switching in SMC. This review will summarise the physiological roles of miR-145 in vascular SMC, including the molecular regulation of differentiation, proliferation and migration. Furthermore, it will discuss the different ways in which miR-145 can be dysregulated and the downstream impact this has on the progression of vascular pathologies. Finally, it will discuss whether miR-145 may be suitable for use as a biomarker of vascular disease.
  • Preservation of Smooth Muscle Cell Integrity and Function: A Target for Limiting Abdominal Aortic Aneurysm Expansion?

    Clark, E.R.; Helliwell, R.J.; Bailey, M.A.; Hemmings, K.E.; Bridge, K.I.; Griffin, K.J.; Scott, D.J.A.; Jennings, L.M.; Riches-Suman, Kirsten; Porter, K.E. (2022-03)
    (1) Abdominal aortic aneurysm (AAA) is a silent, progressive disease with significant mortality from rupture. Whilst screening programmes are now able to detect this pathology early in its development, no therapeutic intervention has yet been identified to halt or retard aortic expansion. The inability to obtain aortic tissue from humans at early stages has created a necessity for laboratory models, yet it is essential to create a timeline of events from EARLY to END stage AAA progression. (2) We used a previously validated ex vivo porcine bioreactor model pre-treated with protease enzyme to create "aneurysm" tissue. Mechanical properties, histological changes in the intact vessel wall, and phenotype/function of vascular smooth muscle cells (SMC) cultured from the same vessels were investigated. (3) The principal finding was significant hyperproliferation of SMC from EARLY stage vessels, but without obvious histological or SMC aberrancies. END stage tissue exhibited histological loss of α-smooth muscle actin and elastin; mechanical impairment; and, in SMC, multiple indications of senescence. (4) Aortic SMC may offer a therapeutic target for intervention, although detailed studies incorporating intervening time points between EARLY and END stage are required. Such investigations may reveal mechanisms of SMC dysfunction in AAA development and hence a therapeutic window during which SMC differentiation could be preserved or reinstated.
  • Identifying and targeting the molecular signature of smooth muscle cells undergoing early vascular ageing

    Richces-Suman, Kirsten; Hussain, Alisah (2022-07-01)
    Early vascular ageing (EVA) is a pathological phenomenon whereby the vascular system ages more quickly than chronological age. This underpins many cardiovascular diseases including the complications of type 2 diabetes, aneurysm formation and hypertension. Smooth muscle cells (SMC) are the principal cell type in the vascular wall and maintain vascular tone. EVA-related phenotypic switching of these cells contributes towards disease progression. EVA is distinct from chronological ageing, and research is ongoing to identify a definitive molecular signature of EVA. This will facilitate the discovery of new clinical tests for early detection of EVA and identify therapeutic targets to halt (or prevent) EVA in SMC, thus reducing macrovascular morbidity and mortality.

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