ORCID Profile
0000-0001-5080-9164
Current Organisations
University of Technology Sydney
,
Ezequiel Dias Foundation
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Publisher: Springer Science and Business Media LLC
Date: 21-01-2022
DOI: 10.1038/S41598-022-05120-2
Abstract: Preecl sia is a cardiovascular pregnancy complication characterised by new onset hypertension and organ damage or intrauterine growth restriction. It is one of the leading causes of maternal and fetal mortality in pregnancy globally. Short of pre-term delivery of the fetus and placenta, treatment options are limited. Consequently, preecl sia leads to increased cardiovascular disease risk in both mothers and offspring later in life. Here we aim to examine the impact of the reduced uterine perfusion pressure (RUPP) rat model of preecl sia on the maternal cardiovascular system, placental and fetal heart metabolism. The surgical RUPP model was induced in pregnant rats by applying silver clips around the aorta and uterine arteries on gestational day 14, resulting in ~ 40% uterine blood flow reduction. The experiment was terminated on gestational day 19 and metabolomic profile of placentae, maternal and fetal hearts analysed using high-resolution 1 H NMR spectroscopy. Impairment of uterine perfusion in RUPP rats caused placental and cardiac hypoxia and a series of metabolic adaptations: altered energetics, carbohydrate, lipid and amino acid metabolism of placentae and maternal hearts. Comparatively, the fetal metabolic phenotype was mildly affected. Nevertheless, long-term effects of these changes in both mothers and the offspring should be investigated further in the future.
Publisher: Springer Science and Business Media LLC
Date: 14-04-2020
DOI: 10.1007/S11906-020-1034-8
Abstract: Preecl sia is a dangerous pregnancy condition affecting both the mother and offspring. It is a multifactorial disease with poorly understood pathogenesis, lacking effective treatments. Maternal immune response, inflammation and oxidative stress leading to endothelial dysfunction are the most prominent pathogenic processes implicated in preecl sia development. Here, we give a detailed overview of the therapeutic applications and mechanisms of mesenchymal stem/stromal cells (MSCs) as a potential new treatment for preecl sia. MSCs have gained growing attention due to low immunogenicity, easy cultivation and expansion in vitro. Accumulating evidence now suggests that MSCs act primarily through their secretomes facilitating paracrine signalling that leads to potent immunomodulatory, pro-angiogenic and regenerative therapeutic effects. MSCs have been studied in different animal models of preecl sia demonstrating promising result, which support further investigations into the therapeutic effects and mechanisms of MSC-based therapies in preecl sia, steering these therapies into clinical trials.
Publisher: Elsevier BV
Date: 12-2020
Publisher: Elsevier BV
Date: 04-2020
Publisher: SAGE Publications
Date: 08-12-2020
Abstract: Tacrolimus (TAC), a potent immunosuppressive macrolide, has been investigated for ocular diseases due to promising results in the treatment of anterior and posterior segments eye diseases. Mesoporous and functionalized silica nanoparticles show potential as TAC delivery platforms owing to their interesting characteristic as large surface area, uniform pore size distribution, high pore volume, and excellent biocompatibility. The purpose of this study was to incorporate TAC in functionalized silica nanoparticles with 3-aminopropyltriethoxysilane (MSNAPTES) and investigate the safety and biocompatibility of the systems. The MSNAPTES and MSNAPTES TAC nanoparticles were characterized. The in vitro cytotoxicity of MSNAPTES and MSNAPTES load with TAC (MSNAPTES-TAC) in retinal pigment epithelial cells (ARPE-19) was determined, chorioallantoic membrane (CAM) assay model was used to investigate the in vivo biocompatibility, and safety of intravitreal injection was evaluated using clinical examination (assessment of intraocular pressure and indirect fundus ophthalmoscopy), electroretinographic (ERG) and histologic studies in rats’ eyes. The elemental analysis (CHN), thermogravimetric (TGA), photon correlation spectroscopy and Fourier transform infrared (FTIR) analysis confirmed the presence of functionalized agent and TAC in the MSNAPTES nanoparticles. TAC loading was estimated at 7% for the MSNAPTES TAC nanoparticles. MSNAPTES and MSNAPTES TAC did not present in vitro cytotoxicity. The drug delivery systems showed good biocompatibility on CAM. No retinal abnormalities, vitreous hemorrhage, neovascularization, retinal detachment, and optic nerve atrophy were observed during the in vivo study. Follow-up ERGs showed no changes in the function of the retina cells after 15 days of intravitreal injection, and histopathologic observations support these findings. In conclusion, MSNAPTES TAC was successfully synthesized, and physicochemical analyses confirmed the presence of TAC in the nanoparticles. In vitro and in vivo studies indicated that MSNAPTES TAC was safe to intravitreal administration. Taking into account the enormous potential of MSNAPTES to carry TAC, this platform could be a promising strategy for TAC ocular drug delivery in the treatment of eye diseases.
Publisher: Georg Thieme Verlag KG
Date: 14-08-2020
DOI: 10.1055/A-1223-2525
Abstract: Rosmarinic acid, a plant-derived compound with antiangiogenic activity, can be applied for the treatment of ocular diseases related to neovascularization, such as diabetic retinopathy, macular edema, and age-related macular degeneration. These diseases represent the leading causes of blindness worldwide if they are not properly treated. Intravitreal devices allow for localized drug delivery to the posterior segment, increasing the drug bioavailability and promoting extended release, thus, reducing side effects and enhancing the patientʼs compliance to the treatment. In this work, rosmarinic acid-loaded poly lactic-co-glycolic acid intraocular implants were developed with a view for the treatment of ocular neovascularization. Physical-chemical, biocompatibility, and safety studies of the implants were carried out in vitro and in vivo as well as an evaluation of the antiangiogenic activity in a chorioallantoic membrane assay. Data obtained showed that rosmarinic acid released from the implants was quantified in the vitreous for 6 weeks, while when it was in the solution formulation, after 24 h, no drug was found in the vitreous. The delivery device did not show any sign of toxicity after clinical evaluation and in electroretinographic findings. Histological analysis showed normal eye tissue. Rosmarinic acid released from implants reduced 30% of new vesselʼs formation. The intravitreal implant successfully allowed for the prolonged release of rosmarinic acid, was safe to rabbits eyes, and demonstrated activity in vessel reduction, thus demonstrating potential in preventing neovascularization in ophthalmic diseases.
Publisher: Research Square Platform LLC
Date: 30-12-2020
DOI: 10.21203/RS.3.RS-135799/V1
Abstract: Background: Preecl sia is a life-threatening cardiovascular disorder of pregnancy that leads to an increased risk of ongoing cardiovascular and metabolic disorders. Much of the pathogenesis and mechanisms involved in cardiac health are unknown. A novel anti-angiogenic protein, FKBPL, is emerging as having a potential role in both preecl sia and cardiovascular disease (CVD). Therefore, in this study we aimed to investigate the role of FKBPL in cardiac health in the rat reduced uterine perfusion pressure (RUPP) model and 3D cardiac spheroid model, of preecl sia. Methods: The RUPP model was induced in pregnant rats and histological analysis performed on the heart, kidneys, liver and placenta (n≥6). Picrosirius red staining was performed to quantify collagen I/III deposition in rat hearts, placentae and livers as an indicator of fibrosis. RT-qPCR was used to determine changes in Fkbpl , Icam1 , Vcam1, Flt1 and/or Vegfa mRNA in hearts and/or placentae and ELISA was used to evaluate cardiac brain natriuretic peptide (BNP45) and FKBPL secretion in rat hearts. Cardiac spheroids were generated using human cardiac fibroblasts (HCFs) and human coronary artery endothelial cells (HCAECs) and treated with patient plasma from normotensive controls, early-onset preecl sia (EOPE) and late-onset preecl sia (LOPE) (n=3). FKBPL and CD31 expression was quantified by immunofluorescent labelling. Results: The RUPP procedure induced significant increase in blood pressure (p .001), cardiac collagen deposition (p .001) and cardiac BNP45 (p .05). It also induced a significant increase in cardiac FKBPL mRNA expression (p .05) and protein levels (p .01). RUPP placentae also exhibited increased collagen deposition and decreased Flt1 mRNA expression (p .05). RUPP kidneys revealed an increase in average glomerular size (p .05). Cardiac spheroids showed a significant increase in FKBPL expression when treated with LOPE patient plasma (p .05) and a trend towards increased FKBPL expression following treatment with EOPE plasma (p=0.06). Conclusions: The rat RUPP model induced cardiac, renal and placental features reflective of preecl sia in humans. FKBPL was increased in the hearts of RUPP rats and in cardiac spheroids treated with plasma from women with preecl sia, reflective of restricted angiogenesis in this disorder. Elucidation of this novel FKBPL mechanism in cardiac health in preecl sia could be key in preventing future CVD.
Publisher: Elsevier BV
Date: 03-2017
DOI: 10.1016/J.JFO.2016.10.010
Abstract: To evaluate the antiangiogenic activity of bevacizumab-loaded polyurethane using two animal models of neovascularization. The percentage of blood vessels was evaluated in a chicken chorioallantoic membrane model (n=42) and in the rabbit cornea (n=24) with neovascularization induced by alkali injury. In each model, the animals were randomly ided into the groups treated with the bevacizumab-loaded polyurethane device, phosphate-buffered-saline (negative control) and bevacizumab commercial solution (positive control). Clinical examination, as well as histopathological and immunohistochemical evaluation, were performed in the rabbit eyes. Microvascular density in hot spot areas was determined in semi-thin sections of corneal tissue by hematoxylin-eosin staining and factor VIII immunohistochemistry. Immunohistochemical analysis was also performed to evaluate VEGF expression. In the evaluated models, the use of bevacizumab (Avastin The present study shows that the bevacizumab-loaded polyurethane device may release bevacizumab and inhibit neovascularization similarly to commercial bevacizumab solution in the short-term.
Publisher: Elsevier BV
Date: 10-2016
Publisher: Springer Science and Business Media LLC
Date: 18-01-2023
DOI: 10.1007/S00018-022-04648-W
Abstract: Preecl sia is a pregnancy-specific cardiovascular disorder, involving significant maternal endothelial dysfunction. Although inappropriate placentation due to aberrant angiogenesis, inflammation and shallow trophoblast invasion are the root causes of preecl sia, pathogenic mechanisms are poorly understood, particularly in early pregnancy. Here, we first confirm the abnormal expression of important vascular and inflammatory proteins, FK506-binding protein-like (FKBPL) and galectin-3 (Gal-3), in human plasma and placental tissues from women with preecl sia and normotensive controls. We then employ a three-dimensional microfluidic placental model incorporating human umbilical vein endothelial cells (HUVECs) and a first trimester trophoblast cell line (ACH-3P) to investigate FKBPL and Gal-3 signaling in inflammatory conditions. In human s les, both circulating ( n = 17 controls n = 30 preecl sia) and placental ( n ≥ 6) FKBPL and Gal-3 levels were increased in preecl sia compared to controls (plasma: FKBPL, p 0.0001 Gal-3, p 0.01 placenta: FKBPL, p 0.05 Gal-3, p 0.01), indicative of vascular dysfunction in preecl sia. In our placenta-on-a-chip model, we show that endothelial cells are critical for trophoblast-mediated migration and that trophoblasts effectively remodel endothelial vascular networks. Inflammatory cytokine tumour necrosis factor-α (10 ng/mL) modulates both FKBPL and Gal-3 signaling in conjunction with trophoblast migration and impairs vascular network formation ( p 0.005). Our placenta-on-a-chip recapitulates aspects of inappropriate placental development and vascular dysfunction in preecl sia.
Publisher: Elsevier BV
Date: 11-2021
DOI: 10.1016/J.BIOPHA.2021.112145
Abstract: Lupeol is a pentacyclic triterpene with known anti-inflammatory effects. However, its role in the treatment of noninfectious uveitis has not been explored. This work investigated anti-inflammatory activity of lupeol in ocular tissues with in vitro and in vivo models. First, we evaluated the effect of lupeol (100 µM) on inflammatory response induced by lipopolysaccharide (LPS) in retinal pigment epithelium cells (ARPE-19) by measuring levels of released interleukins (IL-6 and IL-8). Then, we investigated the anti-inflammatory action of intravitreal lupeol in a rodent model of panuveitis induced by Mycobacterium bovis Calmette-Guérin Bacillus (BCG). Rats were submitted to electroretinography and clinical analyses on days 3, 7, and 15 after uveitis induction. In addition, histopathological analysis, and indirect quantification of myeloperoxidase (MPO) and N-acetylglucosaminidase (NAG) in the posterior segment were performed. Treatment with lupeol (100 µM) significantly decreased IL-6 and IL-8 levels in comparison to untreated LPS-activated ARPE-19 cells. This reduction was similar to that detected in ARPE-19 cells treated with dexamethasone. The results of the in vivo assay demonstrated that intravitreal lupeol is able to modulate inflammation in the anterior and posterior segment of the rat eyes, indicating that it should be further investigated as a novel potential candidate for management of uveitis.
Publisher: Springer Science and Business Media LLC
Date: 27-06-2018
No related grants have been discovered for Claire Richards.