ORCID Profile
0000-0002-6346-9928
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
In Research Link Australia (RLA), "Research Topics" refer to ANZSRC FOR and SEO codes. These topics are either sourced from ANZSRC FOR and SEO codes listed in researchers' related grants or generated by a large language model (LLM) based on their publications.
Nanomaterials | Biomedical Engineering not elsewhere classified | Nanotechnology | Nanotoxicology, Health and Safety
Substance Abuse | Expanding Knowledge in Engineering | Expanding Knowledge in the Biological Sciences |
Publisher: American Physiological Society
Date: 05-2016
DOI: 10.1152/AJPHEART.00949.2015
Abstract: Fenestrations are pores within the liver sinusoidal endothelial cells (LSECs) that line the sinusoids of the highly vascularized liver. Fenestrations facilitate the transfer of substrates between blood and hepatocytes. With pseudocapillarization of the hepatic sinusoid in old age, there is a loss of fenestrations. LSECs are uniquely exposed to gut-derived dietary and microbial substrates delivered by the portal circulation to the liver. Here we studied the effect of 25 diets varying in content of macronutrients and energy on LSEC fenestrations using the Geometric Framework method in a large cohort of mice aged 15 mo. Macronutrient distribution rather than total food or energy intake was associated with changes in fenestrations. Porosity and frequency were inversely associated with dietary fat intake, while fenestration diameter was inversely associated with protein or carbohydrate intake. Fenestrations were also linked to diet-induced changes in gut microbiome, with increased fenestrations associated with higher abundance of Firmicutes and reduced abundance of Bacteroidetes. Diet-induced changes in levels of several fatty acids (C16:0, C19:0, and C20:4) were also significantly inversely associated with fenestrations, suggesting a link between dietary fat and modulation of lipid rafts in the LSECs. Diet influences fenestrations and these data reflect both the key role of the LSECs in clearing gut-derived molecules from the vascular circulation and the impact these molecules have on LSEC morphology.
Publisher: Research Square Platform LLC
Date: 26-01-2023
DOI: 10.21203/RS.3.RS-2440528/V1
Abstract: Injectable insulin is an extensively used medication with potential life-threatening hypoglycaemic events. Here we evaluated silver sulfide quantum dots (QDs) with a chitosan/glucose (CS/GS) encapsulating polymer to produce an oral insulin nanocarrier (QD-INS-CS/GS). This formulation was insoluble at acidic-neutral pH, showed increased absorption in human duodenum explants and Caenorhabditis elegans and was highly sensitive to glucosidase enzymes to mediate hepatic release. In C57BL/6J mice, 50% of QD-INS-CS/GS distributed to the liver and promoted a dose-dependent reduction in blood glucose. Compared to injectable insulin, QD-INS-CS/GS had a similar effect size and time-to-onset in non-obese diabetic mice and streptozotocin-induced diabetic rats without promoting hypoglycaemia or weight gain. Non-diabetic baboons showed a dose dependent-reduction in blood glucose up to 30% with 10 IU/kg in insulin tolerance testing. No biochemical or haematological toxicity, or adverse events were observed. These studies demonstrate the successful application of this oral insulin platform with inhibited hypoglycaemia.
Publisher: Cold Spring Harbor Laboratory
Date: 29-06-2023
DOI: 10.1101/2023.06.28.546913
Abstract: Liver sinusoidal endothelial cells (LSECs) play an important role in liver development, regeneration and pathophysiology, but the differentiation process that generates their unique tissue-specific phenotype is poorly understood and difficult to study as primary cells are only available in limited quantities. To address this, we hypothesised that human induced pluripotent stem cell (hiPSC)-derived endothelial cells (iECs) can produce hiPSC-derived LSECs upon transplantation into the livers of Fah −/− /Rag2 −/− /Il2rg −/− mice, and serve as a model to study LSEC specification. Progressive and long-term repopulation of the liver vasculature was observed, as iECs expanded along the sinusoids that run between hepatocytes and increasingly produced human factor VIII, indicating differentiation into LSEC-like cells. To chart the developmental profile associated with LSEC specification, the bulk transcriptome of transplanted cells at time-points between 1 and 12 weeks were compared against primary human adult LSECs, which demonstrated a chronological increase in LSEC markers, LSEC differentiation pathways, and zonation. Bulk transcriptome analysis suggested that the transcription factors NOTCH1 , GATA4 , and FOS play a central role in LSEC specification, interacting with a network of 27 transcription factors. Novel markers associated with this process include EMCN and CLEC14A . Additionally, single cell transcriptomic analysis demonstrated that transplanted iECs at 4 weeks contain zonal subpopulations with a region-specific phenotype. Collectively, this study confirms that hiPSC can adopt LSEC-like features and provides insight into LSEC specification. This humanised xenograft system can be applied to further interrogate LSEC developmental biology and pathophysiology, bypassing current logistical obstacles associated with primary human LSECs.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 02-11-2018
Abstract: Ponatinib, a cancer drug, inhibits occurrence and growth of cerebral cavernous malformation in mouse models.
Publisher: American Physiological Society
Date: 2019
Abstract: Fenestrations are pores within liver sinusoidal endothelial cells (LSECs) that enable the transfer of substrates (particularly insulin and lipoproteins) between blood and hepatocytes. With increasing age, there are marked reductions in fenestrations, referred to as pseudocapillarization. Currently, fenestrations are thought to be regulated by vascular endothelial growth factor and nitric oxide (NO) pathways promoting remodeling of the actin cytoskeleton and cell membrane lipid rafts. We investigated the effects of drugs that act on these pathways on fenestrations in old (18–24 mo) and young mice (3–4 mo). Isolated LSECs were incubated with either cytochalasin 7-ketocholesterol, sildenafil, amlodipine, simvastatin, 2, 5-dimethoxy-4-iodo hetamine (DOI), bosentan, TNF-related apoptosis-inducing ligand (TRAIL) or nicotinamide mononucleotide (NMN). LSECs were visualized under scanning electron microscopy to quantify fenestration porosity, diameter, and frequency, as well as direct stochastic optical reconstruction microscopy to examine actin and NO synthase. In young and old LSECs, fenestration porosity, diameter and frequency were increased by 7-ketocholesterol, while porosity and/or frequency were increased with NMN, sildenafil, amlodipine, TRAIL, and cytochalasin D. In old mice only, bosentan and DOI increased fenestration porosity and/or frequency. Modification of the actin cytoskeleton was observed with all agents that increased fenestrations, while NO synthase was only increased by sildenafil, amlodipine, and TRAIL. In conclusion, agents that target NO, actin, or lipid rafts promote changes in fenestrations in mice LSECs. Regulation of fenestrations occurs via both NO-dependent and independent pathways. This work indicates that age-related defenestration can be reversed pharmacologically, which has potential translational relevance for dyslipidemia and insulin resistance. NEW & NOTEWORTHY We demonstrate the effects of multiple nitric oxide-dependent and -independent pharmaceutical agents on fenestrations of the liver sinusoidal endothelium. Fenestrations are reorganized in response to nicotinamide mononucleotide, sildenafil, amlodipine, and TNF-related apoptosis-inducing ligand. This work indicates that age-related defenestration can be reversed pharmacologically, which has potential translational relevance for dyslipidemia and insulin resistance in old age.
Publisher: American Chemical Society (ACS)
Date: 24-02-2021
Publisher: Springer Science and Business Media LLC
Date: 21-07-2020
DOI: 10.1038/S41514-020-0046-6
Abstract: There is an unmet need and urgency to find safe and effective anti-obesity interventions. Our recent study in mice fed on obesogenic diet found that treatment with the alcohol aversive drug disulfiram reduced feeding efficiency and led to a decrease in body weight and an increase in energy expenditure. The intervention with disulfiram improved glucose tolerance and insulin sensitivity, and mitigated metabolic dysfunctions in various organs through poorly defined mechanisms. Here, integrated analysis of transcriptomic and proteomic data from mouse and rat livers unveiled comparable signatures in response to disulfiram, revealing pathways associated with lipid and energy metabolism, redox, and detoxification. In cell culture, disulfiram was found to be a potent activator of autophagy, the malfunctioning of which has negative consequences on metabolic regulation. Thus, repurposing disulfiram may represent a potent strategy to combat obesity.
Publisher: Springer Science and Business Media LLC
Date: 29-04-2019
Publisher: The American Association of Immunologists
Date: 08-2016
Abstract: C-type lectin receptors play important roles in immune cell interactions with the environment. We described CD302 as the simplest, single domain, type I C-type lectin receptor and showed it was expressed mainly on the myeloid phagocytes in human blood. CD302 colocalized with podosomes and lamellopodia structures, so we hypothesized that it played a role in cell adhesion or migration. In this study, we used mouse models to obtain further insights into CD302 expression and its potential immunological function. Mouse CD302 transcripts were, as in humans, highest in the liver, followed by lungs, lymph nodes (LN), spleen, and bone marrow. In liver, CD302 was expressed by hepatocytes, liver sinusoidal endothelial cells, and Kupffer cells. A detailed analysis of CD302 transcription in mouse immune cells revealed highest expression by myeloid cells, particularly macrophages, granulocytes, and myeloid dendritic cells (mDC). Interestingly, 2.5-fold more CD302 was found in migratory compared with resident mDC populations and higher CD302 expression in mouse M1 versus M2 macrophages was also noteworthy. CD302 knockout (CD302KO) mice were generated. Studies on the relevant immune cell populations revealed a decrease in the frequency and numbers of migratory mDC within CD302KO LN compared with wild-type LN. In vitro studies showed CD302KO and wild-type DC had an equivalent capacity to undergo maturation, prime T cells, uptake Ags, and migrate toward the CCL19/CCL21 chemokines. Nevertheless, CD302KO migratory DC exhibited reduced in vivo migration into LN, confirming a functional role for CD302 in mDC migration.
Publisher: American Chemical Society (ACS)
Date: 24-01-2020
Abstract: Quantum dots (QDs) are used for imaging and transport of therapeutics. Here we demonstrate rapid absorption across the small intestine and targeted delivery of QDs with bound materials to the liver sinusoidal endothelial cells (LSECs) or hepatocytes
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 27-04-2020
DOI: 10.1002/HEP4.1517
Abstract: This is a meeting report of the 2019 Liver Sinusoid Meeting, 20th International Symposium on Cells of the Hepatic Sinusoid, held in Sydney, Australia, in September 2019. The meeting, which was organized by the International Society for Hepatic Sinusoidal Research, provided an update on the recent advances in the field of hepatic sinusoid cells in relation to cell biology, aging, and liver disease, with particular focus on the molecular and cellular targets involved in hepatic fibrosis, nonalcoholic hepatic steatohepatitis, alcoholic liver disease, hepatocellular carcinoma, and cirrhosis. In addition, the meeting highlighted the recent advances in regenerative medicine, targeted nanotechnologies, therapeutics, and novel methodologies.
Publisher: Springer Science and Business Media LLC
Date: 08-06-2021
DOI: 10.1038/S42255-021-00393-9
Abstract: Reduced protein intake, through dilution with carbohydrate, extends lifespan and improves mid-life metabolic health in animal models. However, with transition to industrialised food systems, reduced dietary protein is associated with poor health outcomes in humans. Here we systematically interrogate the impact of carbohydrate quality in diets with varying carbohydrate and protein content. Studying 700 male mice on 33 isocaloric diets, we find that the type of carbohydrate and its digestibility profoundly shape the behavioural and physiological responses to protein dilution, modulate nutrient processing in the liver and alter the gut microbiota. Low (10%)-protein, high (70%)-carbohydrate diets promote the healthiest metabolic outcomes when carbohydrate comprises resistant starch (RS), yet the worst outcomes were with a 50:50 mixture of monosaccharides fructose and glucose. Our findings could explain the disparity between healthy, high-carbohydrate diets and the obesogenic impact of protein dilution by glucose-fructose mixtures associated with highly processed diets.
Publisher: The Royal Society
Date: 05-2019
Abstract: Protein and calorie restrictions extend median lifespan in many organisms. However, studies suggest that among-in idual variation in the age at death is also affected. Ultimately, both of these outcomes must be caused by effects of nutrition on underlying patterns of age-specific mortality (ASM). Using model life tables , we tested for effects of dietary macronutrients on ASM in mice ( Mus musculus ). High concentrations of protein and fat relative to carbohydrates were associated with low life expectancy and high variation in the age at death, a result caused predominantly by high mortality prior to middle age. A lifelong diet comprising the ratio of macronutrients self-selected by mouse (in early adulthood) was associated with low mortality up until middle age, but higher late-life mortality. This pattern results in reasonably high life expectancy, but very low variation in the age at death. Our analyses also indicate that it may be possible to minimize ASM across life by altering the ratio of dietary protein to carbohydrate in the approach to old age. Mortality in early and middle life was minimized at around one-part protein to two-parts carbohydrate, whereas in later life slightly greater than equal parts protein to carbohydrate reduced mortality.
No related organisations have been discovered for Victoria Cogger.
Start Date: 2017
End Date: 12-2020
Amount: $325,000.00
Funder: Australian Research Council
View Funded Activity