Methyl glyoxal (MG), a major precursor of advanced glycation end-products, has been identified as significant in the progression of several diseases including aging, diabetes and neurodegenerative ...diseases as well as causing hepatic damages. 7-hydroxycoumarin (7-HC), a natural-occurring derivative of coumarin from fruits and plants, has been reported to exert antioxidant and free radical-scavenging properties, protecting cells from aldehydes and oxidants. In this study, the ability of 7-HC to protect human HepG2 cells against MG-induced toxicity and oxidative stress was investigated. Results show that 7-HC pretreatment significantly attenuates MG-induced cytotoxicity, apoptotic changes and ROS accumulation and that this protection is shown to be associated with the induction of the nuclear factor erythroid 2-related factor 2 (NRF2) and its downstream detoxifying enzymes. In response to 7-HC, NRF2 protein translocates from cytosol to the nuclei. In addition, depletion of NRF2 by siRNA significantly reduces the protective effect of 7-HC against MG, suggesting that NRF2 plays an important role in the protective function of 7-HC. These findings highlight the potential for the interventional activation of the NRF2 induction via the non-toxic natural phytochemical 7-HC as a novel therapeutic approach towards the detoxification of MG, with the aim of halting the progression of diseases in which MG has been implicated.
•7-hydroxycoumarin treatment protects against methyl glyoxal -induced cytotoxicity, apoptosis and ROS accumulation.•AKR7A2, AKR1C3 and AKR7A3 enzymes are inducible by 7-hydroxycoumarin.•7-hydroxycoumarin increases NRF2 nuclear accumulation.•NRF2 contributes significantly to the protective effect of 7-HC treatment.
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•Acrylate-based hybrid polymer networks lack material design flexibility.•Diazirine-grafted polyol, a novel carbene crosslinker of hybrid networks.•Diazirine remains unreacted during ...thiol/ene crosslinking reaction.•Carbene enables high level of control over hybrid network material properties.
Thiol/ene-based resorbable elastomers display tough elongation but lack adhesion to soft tissues. Carbene-based bioadhesives (e.g. CaproGlu) allow soft tissue adhesion, but the covalent crosslinks limit extensibility after photoactivation. Herein thiol/ene resorbable elastomers are combined with a carbene bioadhesive into a 3-component hybrid network by exploiting tunable photoactivation of each macromolecule independently or simultaneously. Dual crosslinking was monitored by photorheometry, where 405 nm initiates formation of a thiol/ene elastomeric network, followed by 365 nm activation of diazirine-grafted polycaprolactone tetrol (CaproGlu). Dynamic shear moduli, gelation point, elongation at break, and lap shear stress of the hybrid polymer network are evaluated with respect to absorbed light energy dose. Surface-exposed unreacted CaproGlu enables adhesion of the hybrid network to various substrates, as well as intermolecular crosslinking within the transparent matrix. The network morphology and functional group conversion is evaluated through scanning electron microscopy and infrared spectroscopy, respectively. For the first time, we demonstrate hybrid thiol/ene/diazirine double sided bioadhesives with tunable dynamic moduli in the range of 10–800 kPa and 160 kPa lap-shear adhesion strength.
•Mouse AKR7A5 protects cells from some reactive aldehydes derived from LPO.•Mouse AKR7A5 also protects cells from the cytotoxicity of oxidants.•Mouse AKR7A5 lowers hydrogen peroxide and ...menadione-induced ROS.•Mouse AKR7A5 restores hydrogen peroxide and menadione-induced GSH depletion.•First demonstration that AKR7A5 plays a role in protecting against oxidative stress.
Aldo–keto reductase (AKR) enzymes are critical in the detoxification of endogenous and exogenous aldehydes. In previous studies, we have shown that AKR7A5 enzyme is catalytically active towards aldehydes arising from lipid peroxidation (LPO) and that it can significantly protect against 4-hydroxynonenal-induced apoptosis, suggesting a protective role against the consequences of oxidative stress. The aim of this study was to elucidate the cytoprotective effect of AKR7A5 against oxidative stress using a transgenic mammalian cell line expressing AKR7A5. Results show that expression of AKR7A5 in V79-4 cells provides significant protection against the cytotoxicity of H2O2 and menadione, with its expression altering the IC50 of H2O2 from 1.1 to 2.3mM and the IC50 of menadione from 8.6 to 9.6μM, thus providing direct evidence for its anti-oxidant activity. Cells expressing AKR7A5 were also found to be more resistant to several LPO-derived aldehydes – trans-2-nonenal, hexanal and methylglyoxal. In addition the ability of AKR7A5 to enable the cells to cope with ROS accumulation and glutathione depletion was assessed. V79-4 cells overexpressing AKR7A5 were able to lower cellular ROS levels following treatment with H2O2 and menadione. AKR7A5 was also able to maintain cellular glutathione homeostasis in the presence of H2O2 and menadione. These findings indicate the importance of AKR7A5 in protecting cells from the damaging effects of oxidative stress, and that this cytoprotective function is carried out through multiple pathways.
Recent neuroimaging studies have reported alterations in brain activation during cognitive tasks in cancer patients who have undergone chemotherapy treatment. However, the location of these altered ...brain activation patterns after chemotherapy varies considerably across studies. The aim of the present meta-analysis was to quantitatively synthesise this body of evidence using Activation Likelihood Estimation to identify reliable regions of altered brain activation in cancer patients treated with chemotherapy, compared to healthy controls and no chemotherapy controls. Our systematic search identified 12 studies that adopted task-related fMRI on non-central nervous system cancer patients who received chemotherapy relative to controls. All studies were included in the analyses and were grouped into four contrasts. Cancer patients treated with chemotherapy showed reduced activation in the left superior parietal lobe/precuneus (family-wise error corrected
p
< .05) compared to no chemotherapy controls. No significant clusters were found in three of our contrasts. The majority of studies did not support an association between altered brain activation and cognitive performance after chemotherapy. Findings point towards a possible chemotherapy-induced alteration, which could inform targeted treatment strategies. With continued work in this field using homogenous task-related protocols and cancer populations, fMRI may be used as a biomarker of cognitive deficits in the future.
Early in the pandemic, Aboriginal Community Controlled Health Organisations (ACCHOs) and Aboriginal communities mobilised rapidly to reduce the risk of local COVID-19 outbreaks, and this is a key ...reason for the success to date in keeping Aboriginal people safe from COVID-19.4,5 Supporting these efforts in New South Wales is a comprehensive partnership approach to COVID-19 from the government health agency and the Aboriginal Community Controlled Health sector.
Epidemiological studies of occupational, medical, and environmental exposures have provided important information on lung cancer risk and how those risks might depend on the type of exposure, dose ...rate, and other potential modifying factors such as sex and age of the exposed. Analyses of data from underground miner cohorts and residential case-control studies provide convincing evidence that radon is a leading cause of lung cancer. For low-LET radiation, risk models derived from results from the Lifespan Study of Japanese atomic bomb survivors suggest that for acute exposures, lifetime attributable risks for lung cancer are greater than for other specific cancer sites and are substantially larger for females than males. However, for protracted and fractionated exposures other than from radon, results from epidemiological studies are seemingly often contradictory.This report includes summaries of oral presentations during a symposium on radiogenic lung cancer risk given by a panel of experts on October 5 during the Radiation Research Society’s 67th annual meeting. This session included presentations on: 1) the largest pooled study of male uranium miners (PUMA) exposed to radon; 2) the most recent analysis of the Canadian Fluoroscopy cohort featuring state-of-the-art dosimetry for radiation exposures associated with frequent medical diagnostic procedures; 3) an update from the Million Person Study on risks from fractionated occupational exposures, and 4) studies of second primary malignancies – including lung cancer – in patients who had been treated for thyroid cancer.
The well-known thickness-dependent (111)-to-(100) texture transformation in thin FCC films is usually attributed to a competition between interface and strain energies. In this model, thin films ...retain their (111) texture due to the lower energy of the (111) interface, while thick films transform to (100) due to the lower stiffness and thus strain energy of a (100) film. However, recent work has called this model into question, suggesting that neither the stress nor the interface energy play a dominant role in texture transformation. We investigated the driving forces involved in this transformation by using a bulge test apparatus to induce different stresses in thin Ag films under identical annealing conditions. In situ synchrotron XRD measurements show the change in texture during annealing, and reveal that applied stresses have no effect on the transformation. Stress analysis shows that differences in driving forces for texture transformation due to applied bulge pressure were significant (≈200 kJ/m3), suggesting that a different, much larger driving force must be responsible. Reduction in defect energy has been proposed as an alternative. However, vacancy and dislocation densities must be exceptionally high to significantly exceed the strain energy and do not provide obvious orientation selection mechanisms. Nanotwins in reported densities are shown to provide greater driving force (≈1000 kJ/m3) and may account for orientation selection. The large difference between the calculated strain and defect energies and the driving force for grain growth (21,100 kJ/m3) casts doubt on the applicability of a simple thermodynamic model of texture transformation.
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► AKR7A2 is responsible for protecting SH-SY5Y cells from methyl glyoxal toxicity. ► AKR1C3 is responsible for protecting SH-SY5Y cells from 4-hydroxynonenal toxicity. ► Expression of AKR1C and AKR1B ...is inducible by methyl glyoxal and 4-hydroxynonenal. ► Tert-butyl hydroquinone induces expression of AKR1B and AKR1C.
Reactive aldehydes including methyl glyoxal, acrolein and 4-hydroxy-2-nonenal (4-HNE) have been implicated in the progression of neurodegenerative diseases. The reduction of aldehydes to alcohols by the aldo–keto reductase (AKR) family of enzymes may represent an important detoxication route within neuronal cells. In this study, the ability of AKR enzymes to protect human neuroblastoma SH-SY5Y cells against reactive aldehydes was assessed. Using gene-specific RNA interference (RNAi), we report that AKR7A2 makes a significant contribution to the reduction of methyl glyoxal in SH-SY5Y cells, with its knockdown altering the IC50 from 410 to 25.8μM, and that AKR1C3 contributes to 4-HNE reduction, with its knockdown lowering the IC50 from 1.25 to 0.58μM. In addition, we have shown that pretreatment of cells with sub-lethal concentrations of 4-HNE or methyl glyoxal leads to a significant increase in IC50 when cells are exposed to higher concentrations of the toxic aldehyde. The IC50 for methyl glyoxal increased from 410μM to 1.9mM, and the IC50 for 4-HNE increased from 120 to 690nM. To investigate this protection, we show that pretreatment of cells with the AKR inhibitor sorbinil lead to decreased resistance to aldehydes. We show that AKR1C can be induced 8-fold in SH-SY5Y cells by treatment with sub-lethal concentrations of methyl glyoxal, and 5-fold by 4-HNE treatment. AKR1B is not induced by methyl glyoxal but is induced 10-fold by 4-HNE treatment. Furthermore, we have shown that this adaptive response can also be induced using the chemoprotective agent tert-butyl hydroquinone (t-BHQ), and that this also evokes an increase in the expression and activity of AKR1B and AKR1C. These findings highlight the potential for the interventional upregulation of AKR via non-toxic derivatives or natural compounds as a novel therapeutic approach towards the detoxication of aldehydes, with the aim of halting the progression of aldehyde-dependent neurodegenerative diseases.
Parents who are plurilingual have a portfolio of assets they can use to support the language development of their children. This portfolio of assets is positioned as a strength that parents bring ...into their partnership with early childhood educators. However, not all parents who are plurilingual have the same assets in their language portfolios. Our study, using case studies of parents who have multiple languages and a desire to raise their children with more than one language, demonstrates that previous parental experiences with multiple languages, and intra-familial support for multiple languages combine to impact on parental language strengths and the expectations parents have of early childhood professionals. To build effective partnerships with parents, early childhood professionals need to understand the assets in parental language portfolios.
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