- Dichotomy of bisphenol A-induced expression of peroxisome proliferator-activated receptors in hepatic and testicular tissues in mice. [Journal Article]
- CChemosphere 2019 Jul 01; 236:124264
- Environmental and dietary exposure to bisphenol A (BPA) and its toxicological consequences are extensively reported. BPA has multiple cellular targets. One of the mechanisms of action of BPA involves…
Environmental and dietary exposure to bisphenol A (BPA) and its toxicological consequences are extensively reported. BPA has multiple cellular targets. One of the mechanisms of action of BPA involves interaction with and activation of nuclear receptors (NRs) including peroxisome proliferator activated-receptors (PPARs). PPARs regulate genes involved in adipogenesis, and metabolism of glucose, lipid and cholesterol. Study of tissue and dose specific PPAR expression may decipher the toxicity outcome of BPA exposure. We studied expression of three forms of PPARs in mouse liver and testes exposed to BPA for 14 days. mRNA and protein expression of all forms of PPAR increased linearly (monotonic) with the dose in the liver while non-monotonic but dose specific effects were observed in the testes showing a differential pattern of expression. However, histopathological study showed a dose-dependent pattern of changes in liver as well as testes demonstrating a monotonic effect. These findings imply that other PPAR-independent mechanisms may play a role in BPA-induced pathological changes. The present study warrants exploration of the role of PPARs in BPA-induced effects on male reproductive functions and offers an insight into the peculiar response of BPA at low subchronic levels which may be helpful in designing appropriate risk assessment framework.
- Quantifying deep grey matter atrophy using automated segmentation approaches: A systematic review of structural MRI studies. [Review]
- NNeuroimage 2019 Jul 15; :116018
- The deep grey matter (DGM) nuclei of the brain play a crucial role in learning, behaviour, cognition, movement and memory. Although automated segmentation strategies can provide insight into the impa…
The deep grey matter (DGM) nuclei of the brain play a crucial role in learning, behaviour, cognition, movement and memory. Although automated segmentation strategies can provide insight into the impact of multiple neurological conditions affecting these structures, such as Multiple Sclerosis (MS), Huntington's disease (HD), Alzheimer's disease (AD), Parkinson's disease (PD) and Cerebral Palsy (CP), there are a number of technical challenges limiting an accurate automated segmentation of the DGM. Namely, the insufficient contrast of T1 sequences to completely identify the boundaries of these structures, as well as the presence of iso-intense white matter lesions or extensive tissue loss caused by brain injury. Therefore in this systematic review, 269 eligible studies were analysed and compared to determine the optimal approaches for addressing these technical challenges. The automated approaches used among the reviewed studies fall into three broad categories, atlas-based approaches focusing on the accurate alignment of atlas priors, algorithmic approaches which utilise intensity information to a greater extent, and learning-based approaches that require an annotated training set. Studies that utilise freely available software packages such as FIRST, FreeSurfer and LesionTOADS were also eligible, and their performance compared. Overall, deep learning approaches achieved the best overall performance, however these strategies are currently hampered by the lack of large-scale annotated data. Improving model generalisability to new datasets could be achieved in future studies with data augmentation and transfer learning. Multi-atlas approaches provided the second-best performance overall, and may be utilised to construct a "silver standard" annotated training set for deep learning. To address the technical challenges, providing robustness to injury can be improved by using multiple channels, highly elastic diffeomorphic transformations such as LDDMM, and by following atlas-based approaches with an intensity driven refinement of the segmentation, which has been done with the Expectation Maximisation (EM) and level sets methods. Accounting for potential lesions should be achieved with a separate lesion segmentation approach, as in LesionTOADS. Finally, to address the issue of limited contrast, R2*, T2* and QSM sequences could be used to better highlight the DGM due to its higher iron content. Future studies could look to additionally acquire these sequences by retaining the phase information from standard structural scans, or alternatively acquiring these sequences for only a training set, allowing models to learn the "improved" segmentation from T1-sequences alone.
- Priority Symptoms, Causes, and Self-Management Strategies Reported by AYAs with Cancer. [Journal Article]
- JPJ Pain Symptom Manage 2019 Jul 15
- CONCLUSIONS: Supporting AYAs to identify their priority symptoms may facilitate a more personalized approach to care. Seeking the patient's perspective regarding priority symptoms could enhance patient-clinician collaboration in symptom management.
- The nuclear factor interleukin 3-regulated (NFIL3) transcription factor involved in innate immunity by activating NF-κB pathway in mud crab Scylla paramamosain. [Journal Article]
- DCDev Comp Immunol 2019 Jul 15; :103452
- NFIL3 is a transcriptional activator of the IL-3 promoter in T cells. In vertebrates, it has been characterized as an essential regulator of several cellular processes such as immunity response, apop…
NFIL3 is a transcriptional activator of the IL-3 promoter in T cells. In vertebrates, it has been characterized as an essential regulator of several cellular processes such as immunity response, apoptosis and NK cells maturation. However, the identification and functional characterization of NFIL3 still remains unclear in arthropods. In this study, the NFIL3 homologue was firstly cloned and characterized in mud crab Scylla paramamosain. The full-length of SpNFIL3 was 2, 041 bp in length with an open reading frame of 1, 509 bp, containing a conserved basic region of leucin zipper domain. The qRT-PCR analysis indicated that SpNFIL3 was significantly highly expressed in hepatopancreas and in hemocytes. Moreover, the SpNFIL3 transcription could be up-regulated after the challenge of Vibrio alginolyticus or virus-analog Poly (I:C). The dual-luciferase reporter assays revealed that SpNFIL3 could activate NF-κB pathway. The immunofluorescence assay indicated SpNFIL3 was located in nucleus. After NFIL3 was interfered in vivo and in vitro, the expressions of two NF-κB members (SpRelish and SpDorsal), six antimicrobial peptide genes (SpCrustin and SpALF2-6) and pro-inflammatory cytokine SpIL-16 were suppressed, and the bacteria clearance capacity of crabs was also markedly impaired in NFIL3 silenced crabs. These results indicated that SpNFIL3 played crucial role in the innate immunity of S. paramamosain and it also brought new insight into the origin and evolution of NFIL3 in arthropods and even in invertebrates.
- Ginsenoside Rb1 inhibits vascular calcification as a selective androgen receptor modulator. [Journal Article]
- EJEur J Pharmacol 2019 Jul 15; :172546
- Ginsenoside Rb1 (Rb1), a major component of ginseng, has a steroidal chemical structure, implying that it exerts sex hormone-like actions. Recent studies have been suggested cardioprotective actions …
Ginsenoside Rb1 (Rb1), a major component of ginseng, has a steroidal chemical structure, implying that it exerts sex hormone-like actions. Recent studies have been suggested cardioprotective actions of Rb1. However, the actions of Rb1 in vascular calcification, one of the significant pathological features associated with aging and atherosclerosis, have not been examined. In the present study, we examined the effects of Rb1 on vascular calcification, focusing on its androgen-like actions. Using inorganic phosphate (Pi)-induced calcification of vascular smooth muscle cells (VSMC), we found that Rb1, like testosterone, significantly inhibited calcium deposition in a concentration-dependent manner. Further, this inhibition of Rb1 was abolished by bicalutamide, an androgen receptor antagonist, but not by MPP or PHTPP, estrogen receptor α or β antagonists. Rb1 significantly inhibited apoptosis, one of the regulatory mechanisms of calcification, and restored growth arrest-specific gene 6 (Gas6) expression that was suppressed by Pi. Moreover, Rb1 transactivated Gas6, and proximal androgen-responsive element (ARE) of the promoter region was found to be crucial for Gas6 transactivation. In contrast, in a human prostate cancer cell line, testosterone-induced ARE activity was abrogated by Rb1. This antagonistic effect was also confirmed by the transrepression and downregulation of prostate-specific antigen in the presence of testosterone and Rb1 together. Thus, these findings provide a novel mechanistic insight into the vasculoprotective actions of Rb1 as a selective androgen receptor modulator, i.e., inhibitory effects on VSMC calcification through androgen receptor-mediated Gas6 transactivation and antagonistic effects in prostate cancer cells.
- Autophagy inhibition exerts neuroprotection on white matter ischemic damage after chronic cerebral hypoperfusion in mice. [Journal Article]
- BRBrain Res 2019 Jul 15; :146337
- Autophagy plays vital roles in the pathophysiology of many central nervous system diseases. Emerging evidence indicates that autophagy has both detrimental and protective effects in ischemic cerebral…
Autophagy plays vital roles in the pathophysiology of many central nervous system diseases. Emerging evidence indicates that autophagy has both detrimental and protective effects in ischemic cerebral injury. This study aimed to investigate the temporal pattern of autophagy activation in the white matter of bilateral common carotid artery stenosis (BCAS) mouse model by immunofluorescence and western blotting. The effect of wortmannin, an autophagy inhibitor, against hypoperfusion induced white matter injury (WMI) was studied by immunofluorescence and eight-arm radial maze test. We found that autophagy was initially activated in the white matter 3 days after BCAS, and then suppressed by day 10, and was activated again at day 30. Administration of wortmannin during the first three days after BCAS revealed protective effects on axon-glia integrity and against the cognitive injury induced by the chronic hypoperfusion. The results indicated the possible link between autophagy and white matter ischemic damage after chronic cerebral hypoperfusion. Modulation of autophagy in a time course dependent manner may broaden the insight on the treatment of WMI.
- Trapping and Characterization of Non-Toxic Aβ42 Aggregation Intermediates. [Journal Article]
- ACACS Chem Neurosci 2019 Jul 18
- Amyloid β (Aβ) 42 is an aggregation-prone peptide and the believed seminal etiological agent of Alzheimer's Disease (AD). Intermediates of Aβ42 aggregation, commonly referred to as diffusible oligome…
Amyloid β (Aβ) 42 is an aggregation-prone peptide and the believed seminal etiological agent of Alzheimer's Disease (AD). Intermediates of Aβ42 aggregation, commonly referred to as diffusible oligomers, are considered to be among the most toxic forms of the peptide. Here we studied the effect of the age-related epimerization of Ser26 (i.e. S26s chiral edit) in Aβ42, and discovered that this subtle molecular change led to reduced fibril formation propensity. Surprisingly, the resultant soluble aggregates were non-toxic. To gain insight into the structural changes that occurred in the peptide upon S26s substitution, the system was probed using an array of biophysical and biochemi-cal methods. These experiments consistently pointed to the stabilization of aggregation intermediates in the Aβ42-S26s system. To better understand the changes arising as a consequence of the S26s substitution, molecular level structural studies were performed. Using a com-bined NMR- and DFT-computational approach, we found that the S26s chiral edit induced only local structural changes in the Gly25-Ser26-Asn27 region. Interestingly, these subtle changes enabled the formation of an intramolecular Ser26-Asn27 H-bond, which disrupted the ability of Asn27 to engage in the fibrillogenic sidechain-to-sidechain H-bonding pattern. This reveals that intermolecular stabilizing interactions between Asn27 sidechains are a key element controlling Aβ42 aggregation and toxicity.
- Children with Tourette Syndrome in the United States: Parent-Reported Diagnosis, Co-Occurring Disorders, Severity, and Influence of Activities on Tics. [Journal Article]
- JDJ Dev Behav Pediatr 2019 Jul 10
- CONCLUSIONS: In this sample of children with TS, the time to diagnosis averaged less than 2 years from when tics were initially noticed. More severe TS was associated with greater functional impairment, and co-occurring disorders were common among children with TS. This study provides insight into the current experiences of children with TS in the United States and their families.
- Design Principles, Sensing Mechanisms, and Applications of Highly Specific Fluorescent Probes for HOCl/OCl. [Journal Article]
- ACAcc Chem Res 2019 Jul 18
- Hypochlorous acid/hypochlorite (HOCl/OCl-), one of the most important reactive oxygen species (ROS), plays vital roles in various physiological and pathological processes. At normal concentrations, O…
Hypochlorous acid/hypochlorite (HOCl/OCl-), one of the most important reactive oxygen species (ROS), plays vital roles in various physiological and pathological processes. At normal concentrations, OCl- acts as part of an immune defense system by destroying invasive bacteria and pathogens. However, nonproperly located or excessive amounts of OCl- are related to many diseases, including cancers. Thus, detection of OCl- has great importance. Owing to their high sensitivities, selectivities, fast response times, technical simplicities, and high temporal and spatial resolution, fluorescent probes are powerful tools for in vitro and in vivo sensing of target substances. This Account focuses on the development of new chemosensors for detection of OCl-, which operate by undergoing a chemical reaction with this ROS in conjunction with a change in emission properties. As part of the presentation, we first introduce several important factors that need to be considered in the design of fluorescent chemosensors for OCl-, including fluorophores, reaction groups, cosolvents, and buffers. Discussion here revolves around the need to select fluorophores that resist oxidation by OCl-. As well, attention is given to the sensitivities and selectivities of groups in the sensors that react with OCl- to trigger a fluorescence response. Moreover, well-known reaction groups, which react with highly reactive ROS (hROS), have been redesigned to be specific for OCl-. In addition, it is pointed out that several cosolvents and buffers such as DMSO and HEPES are not suitable for use in systems for the detection of OCl- because they are readily oxidized by this ROS. We further discuss recent investigations carried out by us and others aimed at the development of fluorescent probes for in vitro and in vivo detection of OCl-. These efforts led to the new "dual lock" strategy for designing OCl- chemosensors as well as several new specific reaction groups such as imidazoline-2-thiones and imidazoline-2-boranes. Probes created using this strategy and the new reacting groups have been successfully applied to imaging exogenous and endogenous OCl- in live cells and/or tissues. The design concepts and strategies emanating from our studies of fluorescent OCl- probes have provided insight into the general field of fluorescent probes. Despite the progress made thus far, challenges still remain in developing and applying fluorescent OCl- probes. For example, more highly specific and sensitive fluorescent OCl- probes are still in great demand for studies of the biological roles played by OCl-. Thus, interdisciplinary collaborations of chemists, biologists, and medical practitioners are needed to drive future developments of OCl- probes for disease diagnosis and drug screening.
New Search Next
- Phenylalanine meta-hydroxylase: a single residue mediates mechanistic control of aromatic amino acid hydroxylation. [Journal Article]
- CChembiochem 2019 Jul 18
- The rare non-proteinogenic amino acid, meta- L-tyrosine is biosynthetically intriguing. Whilst the biogenesis of tyrosine from phenylalanine is well characterised, the mechanistic basis for meta-hydr…
The rare non-proteinogenic amino acid, meta- L-tyrosine is biosynthetically intriguing. Whilst the biogenesis of tyrosine from phenylalanine is well characterised, the mechanistic basis for meta-hydroxylation is unknown. Herein, we report the analysis of 3-hydroxylase (Phe3H) from Streptomyces coeruleorbidus. Insight from kinetic analyses, of both the wild-type enzyme and key mutants, of the biocatalytic conversion of synthetic isotopically labelled substrates and fluorinated substrate analogues advances understanding of the process by which meta-hydroxylation is mediated, revealing T202 to play an important role. In contrast to the established mechanism of tyrosine biogenesis, which proceeds via NIH shift, our data support direct, enzyme catalysed deprotonation following electrophilic aromatic substitution. We demonstrate that T202 is responsible for this shift in mechanism, with mutation to alanine resulting in a switch to the NIH shift mechanism and loss of regiospecificity. Furthermore, our kinetic parameters for Phe3H show efficient regiospecific generation of meta-L-tyrosine from phenylalanine and demonstrate the enzyme's ability to regiospecifically hydroxylate unnatural fluorinated substrates.