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1.
J Mol Neurosci ; 2020 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-32529537

RESUMO

The original version of this article unfortunately contained an error in Fig. 3. The image shown for "C57S" was incorrect.

2.
Brain Behav Immun ; 2020 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-32450195

RESUMO

The transcription factor nuclear factor kappa B (NF-κB) regulates the expression of many inflammatory genes that are overexpressed in a subset of people with schizophrenia. Transcriptional reduction in one NF-κB inhibitor, Human Immunodeficiency Virus Enhancer Binding Protein 2 (HIVEP2), is found in the brain of patients, aligning with evidence of NF-κB over-activity. Cellular co-expression of HIVEP2 and cytokine transcripts is a prerequisite for a direct effect of HIVEP2 on pro-inflammatory transcription, and we do not know if changes in HIVEP2 and markers of neuroinflammation are occurring in the same brain cell type. We performed in situ hybridisation on postmortem dorsolateral prefrontal cortex tissue to map and compare the expression of HIVEP2 and Serpin Family A Member 3 (SERPINA3), one of the most consistently increased inflammatory genes in schizophrenia, between schizophrenia patients and controls. We find that HIVEP2 expression is neuronal and is decreased in almost all grey matter cortical layers in schizophrenia patients with neuroinflammation, and that SERPINA3 is increased in the dorsolateral prefrontal cortex grey matter and white matter in the same group of patients. We are the first to map the upregulation of SERPINA3 to astrocytes and to some neurons, and find evidence to suggest that blood vessel-associated astrocytes are the main cellular source of SERPINA3 in the schizophrenia cortex. We show that a lack of HIVEP2 in mice does not cause astrocytic upregulation of Serpina3n but does induce its transcription in neurons. We speculate that HIVEP2 downregulation is not a direct cause of astrocytic pro-inflammatory cytokine synthesis in schizophrenia but may contribute to neuronally-mediated neuroinflammation.

3.
J Mol Neurosci ; 2020 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-32445072

RESUMO

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the degeneration of motor neurons. Between 12 and 20% of inherited cases and approximately 1-2% of all cases are caused by mutations in the gene encoding dismutase 1 (SOD1). Mutant SOD1 A4V (alanine to valine) induces endoplasmic reticulum (ER) stress, which is increasingly implicated as a pathway to motor neuron degeneration and death in ALS. However, it remains unclear how ER stress is induced by mutant SOD1 A4V. Previous studies have established that it is induced early in pathophysiology and it precedes the formation of mutant SOD1 inclusions. SOD1 contains four cysteine residues, two of which form an intra-subunit disulphide bond involving Cys-57 and Cys-146. The remaining two cysteines, Cys-6 and Cys-111, remain unpaired and have been implicated in mutant SOD1 aggregation. In this study, we examined the relationship between the SOD1 A4V cysteine residues and aggregation, ER stress induction and toxicity. We report here that mutation of Cys-6 and Cys-111 in mutant SOD1 A4V, but not Cys-57 or Cys-146, ameliorates ER stress, inclusion formation and apoptosis in neuronal cell lines. These results imply that protein misfolding, induced by Cys-6 and Cys-111, is required for these pathological events in neuronal cells.

4.
J Proteome Res ; 19(7): 2898-2906, 2020 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-32407095

RESUMO

We describe a useful workflow for characterizing proteomics experiments incorporating many conditions and abundance data using the popular weighted gene correlation network analysis (WGCNA) approach and functional annotation with the PloGO2 R package, the latter of which we have extended and made available to Bioconductor. The approach can use quantitative data from labeled or label-free experiments and was developed to handle multiple files stemming from data partition or multiple pairwise comparisons. The WGCNA approach can similarly produce a potentially large number of clusters of interest, which can also be functionally characterized using PloGO2. Enrichment analysis will identify clusters or subsets of proteins of interest, and the WGCNA network topology scores will produce a ranking of proteins within these clusters or subsets. This can naturally lead to prioritized proteins to be considered for further analysis or as candidates of interest for validation in the context of complex experiments. We demonstrate the use of the package on two published data sets using two different biological systems (plant and human plasma) and proteomics platforms (sequential window acquisition of all theoretical fragment-ion spectra (SWATH) and tandem mass tag (TMT)): an analysis of the effect of drought on rice over time generated using TMT and a pediatric plasma sample data set generated using SWATH. In both, the automated workflow recapitulates key insights or observations of the published papers and provides additional suggestions for further investigation. These findings indicate that the data set analysis using WGCNA combined with the updated PloGO2 package is a powerful method to gain biological insights from complex multifaceted proteomics experiments.

5.
BMJ Open ; 10(3): e035080, 2020 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-32198305

RESUMO

INTRODUCTION: Due to the anti-inflammatory, antioxidant and anti-apoptotic properties of minocycline, clinical trials have evaluated the potential of this drug to treat several psychiatric and neurological disorders, including major depressive disorder, schizophrenia, bipolar disorder, stroke and amyotrophic lateral sclerosis. This protocol proposes a systematic review (and potential meta-analysis) that aims to identify and critically evaluate randomised controlled trials of minocycline for treating psychiatric and neurological disorders. METHODS AND ANALYSIS: PubMed, Embase, Cochrane Central Register of Controlled Clinical Trials, PsycINFO and Cumulative Index to Nursing and Allied Health Literature (CINAHL) will be used to identify randomised controlled trials that used minocycline to treat psychiatric and neurological disorders. Double-blind, randomised, controlled, clinical trials of participants aged 18 years or older and written in English will be included in the review. Data will be extracted by two independent reviewers. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines will be followed and the Cochrane Collaboration's 'Risk of Bias' tool will be used to assess the risk of bias in all studies included in the systematic review. The Grading of Recommendations, Assessment, Development and Evaluation system will be used to access the overall quality of the level of evidence of the studies. If sufficient evidence is identified, a meta-analysis will be conducted using the standardised mean difference approach and reported with 95% CIs. Heterogeneity of evidence will be evaluated using the I2 model. ETHICS AND DISSEMINATION: This systematic review will evaluate only published data; therefore, ethical approval is not required. The systematic review will be published in a peer-reviewed journal and presented at relevant research conferences. TRIAL REGISTRATION NUMBER: CRD42020153292.

6.
J Neurol Neurosurg Psychiatry ; 91(2): 162-171, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31690696

RESUMO

OBJECTIVE: Since the first report of CHCHD10 gene mutations in amyotrophiclateral sclerosis (ALS)/frontotemporaldementia (FTD) patients, genetic variation in CHCHD10 has been inconsistently linked to disease. A pathological assessment of the CHCHD10 protein in patient neuronal tissue also remains to be reported. We sought to characterise the genetic and pathological contribution of CHCHD10 to ALS/FTD in Australia. METHODS: Whole-exome and whole-genome sequencing data from 81 familial and 635 sporadic ALS, and 108 sporadic FTD cases, were assessed for genetic variation in CHCHD10. CHCHD10 protein expression was characterised by immunohistochemistry, immunofluorescence and western blotting in control, ALS and/or FTD postmortem tissues and further in a transgenic mouse model of TAR DNA-binding protein 43 (TDP-43) pathology. RESULTS: No causal, novel or disease-associated variants in CHCHD10 were identified in Australian ALS and/or FTD patients. In human brain and spinal cord tissues, CHCHD10 was specifically expressed in neurons. A significant decrease in CHCHD10 protein level was observed in ALS patient spinal cord and FTD patient frontal cortex. In a TDP-43 mouse model with a regulatable nuclear localisation signal (rNLS TDP-43 mouse), CHCHD10 protein levels were unaltered at disease onset and early in disease, but were significantly decreased in cortex in mid-stage disease. CONCLUSIONS: Genetic variation in CHCHD10 is not a common cause of ALS/FTD in Australia. However, we showed that in humans, CHCHD10 may play a neuron-specific role and a loss of CHCHD10 function may be linked to ALS and/or FTD. Our data from the rNLS TDP-43 transgenic mice suggest that a decrease in CHCHD10 levels is a late event in aberrant TDP-43-induced ALS/FTD pathogenesis.

7.
Genome Biol Evol ; 12(1): 3550-3561, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31596481

RESUMO

DNA diversity varies across the genome of many species. Variation in diversity across a genome might arise from regional variation in the mutation rate, variation in the intensity and mode of natural selection, and regional variation in the recombination rate. We show that both noncoding and nonsynonymous diversity are positively correlated to a measure of the mutation rate and the recombination rate and negatively correlated to the density of conserved sequences in 50 kb windows across the genomes of humans and nonhuman homininae. Interestingly, we find that although noncoding diversity is equally affected by these three genomic variables, nonsynonymous diversity is mostly dominated by the density of conserved sequences. The positive correlation between diversity and our measure of the mutation rate seems to be largely a direct consequence of regions with higher mutation rates having more diversity. However, the positive correlation with recombination rate and the negative correlation with the density of conserved sequences suggest that selection at linked sites also affect levels of diversity. This is supported by the observation that the ratio of the number of nonsynonymous to noncoding polymorphisms is negatively correlated to a measure of the effective population size across the genome. We show these patterns persist even when we restrict our analysis to GC-conservative mutations, demonstrating that the patterns are not driven by GC biased gene conversion. In conclusion, our comparative analyses describe how recombination rate, gene density, and mutation rate interact to produce the patterns of DNA diversity that we observe along the hominine genomes.

8.
J Mol Evol ; 87(9-10): 317-326, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31570957

RESUMO

Rates of molecular evolution are known to vary between species and across all kingdoms of life. Here, we explore variation in the rate at which bacteria accumulate mutations (accumulation rates) in their natural environments over short periods of time. We have compiled estimates of the accumulation rate for over 34 species of bacteria, the majority of which are pathogens evolving either within an individual host or during outbreaks. Across species, we find that accumulation rates vary by over 3700-fold. We investigate whether accumulation rates are associated to a number potential correlates including genome size, GC content, measures of the natural selection and the time frame over which the accumulation rates were estimated. After controlling for phylogenetic non-independence, we find that the accumulation rate is not significantly correlated to any factor. Furthermore, contrary to previous results, we find that it is not impacted by the time frame of which the estimate was made. However, our study, with only 34 species, is likely to lack power to detect anything but large effects. We suggest that much of the rate variation may be explained by differences between species in the generation time in the wild.

9.
Neurosci Biobehav Rev ; 107: 862-882, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31545987

RESUMO

Activated immune-inflammatory, oxidative and nitrosative stress (IO&NS) pathways and consequent mitochondrial aberrations are involved in the pathophysiology of psychiatric disorders including major depression, bipolar disorder and schizophrenia. They offer independent and shared contributions to pathways underpinning medical comorbidities including insulin resistance, metabolic syndrome, obesity and cardiovascular disease - herein conceptualized as somatoprogression. This narrative review of human studies aims to summarize relationships between IO&NS pathways, neuroprogression and somatoprogression. Activated IO&NS pathways, implicated in the neuroprogression of psychiatric disorders, affect the pathogenesis of comorbidities including insulin resistance, dyslipidaemia, obesity and hypertension, and by inference, metabolic syndrome. These conditions activate IO&NS pathways, exacerbating neuroprogression in psychiatric disorders. The processes whereby proinflammatory cytokines, nitrosative and endoplasmic reticulum stress, NADPH oxidase isoforms, PPARγ inactivation, SIRT1 deficiency and intracellular signalling pathways impact lipid metabolism and storage are considered. Through associations between body mass index, chronic neuroinflammation and FTO expression, activation of IO&NS pathways arising from somatoprogression may contribute to neuroprogression. Early evidence highlights the potential of adjuvants targeting IO&NS pathways for treating somatoprogression and neuroprogression.

10.
Front Psychiatry ; 10: 605, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31551825

RESUMO

Neuropsychiatric disorders, such as depression, bipolar disorder, schizophrenia, obsessive-compulsive disorder, and neurodevelopmental disorders such as autism spectrum disorder, are associated with significant illness burden. Accumulating evidence supports an association between these disorders and inflammation. Consequently, anti-inflammatory agents, such as the cyclooxygenase-2 inhibitors, represent a novel avenue to prevent and treat neuropsychiatric illness. In this paper, we first review the role of inflammation in psychiatric pathophysiology including inflammatory cytokines' influence on neurotransmitters, the hypothalamic-pituitary-adrenal axis, and microglial mechanisms. We then discuss how cyclooxygenase-2-inhibitors influence these pathways with potential therapeutic benefit, with a focus on celecoxib, due to its superior safety profile. A search was conducted in PubMed, Embase, and PsychINFO databases, in addition to Clinicaltrials.gov and the Stanley Medical Research Institute trial registries. The results were presented as a narrative review. Currently available outcomes for randomized controlled trials up to November 2017 are also discussed. The evidence reviewed here suggests cyclooxygenase-2 inhibitors, and in particular celecoxib, may indeed assist in treating the symptoms of neuropsychiatric disorders; however, further studies are required to assess appropriate illness stage-related indication.

11.
Pharmacol Res ; 148: 104450, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31509764

RESUMO

Myalgic encephalomyelitis (ME) or chronic fatigue syndrome (CFS) is a common and disabling condition with a paucity of effective and evidence-based therapies, reflecting a major unmet need. Cognitive behavioural therapy and graded exercise are of modest benefit for only some ME/CFS patients, and many sufferers report aggravation of symptoms of fatigue with exercise. The presence of a multiplicity of pathophysiological abnormalities in at least the subgroup of people with ME/CFS diagnosed with the current international consensus "Fukuda" criteria, points to numerous potential therapeutic targets. Such abnormalities include extensive data showing that at least a subgroup has a pro-inflammatory state, increased oxidative and nitrosative stress, disruption of gut mucosal barriers and mitochondrial dysfunction together with dysregulated bioenergetics. In this paper, these pathways are summarised, and data regarding promising therapeutic options that target these pathways are highlighted; they include coenzyme Q10, melatonin, curcumin, molecular hydrogen and N-acetylcysteine. These data are promising yet preliminary, suggesting hopeful avenues to address this major unmet burden of illness.

12.
PeerJ ; 7: e7216, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31293838

RESUMO

Neisseria meningitidis and N. gonorrhoeae are closely related pathogenic bacteria. To compare their population genetics, we compiled a dataset of 1,145 genes found across 20 N. meningitidis and 15 N. gonorrhoeae genomes. We find that N. meningitidis is seven-times more diverse than N. gonorrhoeae in their combined core genome. Both species have acquired the majority of their diversity by recombination with divergent strains, however, we find that N. meningitidis has acquired more of its diversity by recombination than N. gonorrhoeae. We find that linkage disequilibrium (LD) declines rapidly across the genomes of both species. Several observations suggest that N. meningitidis has a higher effective population size than N. gonorrhoeae; it is more diverse, the ratio of non-synonymous to synonymous polymorphism is lower, and LD declines more rapidly to a lower asymptote in N. meningitidis. The two species share a modest amount of variation, half of which seems to have been acquired by lateral gene transfer and half from their common ancestor. We investigate whether diversity varies across the genome of each species and find that it does. Much of this variation is due to different levels of lateral gene transfer. However, we also find some evidence that the effective population size varies across the genome. We test for adaptive evolution in the core genome using a McDonald-Kreitman test and by considering the diversity around non-synonymous sites that are fixed for different alleles in the two species. We find some evidence for adaptive evolution using both approaches.

13.
Artigo em Inglês | MEDLINE | ID: mdl-31351160

RESUMO

Major antioxidant responses to increased levels of inflammatory, oxidative and nitrosative stress (ONS) are detailed. In response to increasing levels of nitric oxide, S-nitrosylation of cysteine thiol groups leads to post-transcriptional modification of many cellular proteins and thereby regulates their activity and allows cellular adaptation to increased levels of ONS. S-nitrosylation inhibits the function of nuclear factor kappa-light-chain-enhancer of activated B cells, toll-like receptor-mediated signalling and the activity of several mitogen-activated protein kinases, while activating nuclear translocation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2 or NFE2L2); in turn, the redox-regulated activation of Nrf2 leads to increased levels and/or activity of key enzymes and transporter systems involved in the glutathione system. The Nrf2/Kelch-like ECH-associated protein-1 axis is associated with upregulation of NAD(P)H:quinone oxidoreductase 1, which in turn has anti-inflammatory effects. Increased Nrf2 transcriptional activity also leads to activation of haem oxygenase-1, which is associated with upregulation of bilirubin, biliverdin and biliverdin reductase as well as increased carbon monoxide signalling, anti-inflammatory and antioxidant activity. Associated transcriptional responses, which may be mediated by retrograde signalling owing to elevated hydrogen peroxide, include the unfolded protein response (UPR), mitohormesis and the mitochondrial UPR; the UPR also results from increasing levels of mitochondrial and cytosolic reactive oxygen species and reactive nitrogen species leading to nitrosylation, glutathionylation, oxidation and nitration of crucial cysteine and tyrosine causing protein misfolding and the development of endoplasmic reticulum stress. It is shown how these mechanisms co-operate in forming a co-ordinated rapid and prolonged compensatory antioxidant response system.

14.
J Affect Disord ; 256: 584-593, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31299439

RESUMO

OBJECTIVE: Seasonal Affective Disorder (SAD) is a form of cyclic mood disorder that tends to manifest as winter depression. SAD has anecdotally been described as a hypocortisolemic condition. However, there are no systematic reviews on SAD and Hypothalamic-Pituitary-Adrenal (HPA) axis function. This review intends to summarize these findings. METHODS: Using the PRISMA (2009) guideline recommendations we searched for relevant articles indexed in databases including MEDLINE, EMBASE, PsycINFO, and PsychArticles. The following keywords were used: "Seasonal affective disorder", OR "Winter Depression", OR "Seasonal depression" associated with: "HPA Axis" OR "cortisol" OR "CRH" OR "ACTH". RESULTS: Thirteen papers were included for qualitative analysis. Studies used both heterogeneous methods and populations. The best evidence comes from a recent study showing that SAD patients tend to demonstrate an attenuated Cortisol Awakening Response (CAR) in winter, but not in summer, compared to controls. Dexamethasone Suppression Test (DST) studies suggest SAD patients have normal suppression of the HPA axis. CONCLUSION: There is still insufficient evidence to classify SAD as a hypocortisolemic condition when compared to controls. Heterogeneous methods and samples did not allow replication of results. We discuss the limitations of these studies and provide new methods and targets to probe HPA axis function in this population. SAD can provide a unique window of opportunity to study HPA axis in affective disorders, since it is highly predictable and can be followed before, during and after episodes subsides.

15.
16.
Front Neurosci ; 13: 548, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31244593

RESUMO

Neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are increasing in prevalence but lack targeted therapeutics. Although the pathological mechanisms behind these diseases remain unclear, both ALS and FTD are characterized pathologically by aberrant protein aggregation and inclusion formation within neurons, which correlates with neurodegeneration. Notably, aggregation of several key proteins, including TAR DNA binding protein of 43 kDa (TDP-43), superoxide dismutase 1 (SOD1), and tau, have been implicated in these diseases. Proteomics methods are being increasingly applied to better understand disease-related mechanisms and to identify biomarkers of disease, using model systems as well as human samples. Proteomics-based approaches offer unbiased, high-throughput, and quantitative results with numerous applications for investigating proteins of interest. Here, we review recent advances in the understanding of ALS and FTD pathophysiology obtained using proteomics approaches, and we assess technical and experimental limitations. We compare findings from various mass spectrometry (MS) approaches including quantitative proteomics methods such as stable isotope labeling by amino acids in cell culture (SILAC) and tandem mass tagging (TMT) to approaches such as label-free quantitation (LFQ) and sequential windowed acquisition of all theoretical fragment ion mass spectra (SWATH-MS) in studies of ALS and FTD. Similarly, we describe disease-related protein-protein interaction (PPI) studies using approaches including immunoprecipitation mass spectrometry (IP-MS) and proximity-dependent biotin identification (BioID) and discuss future application of new techniques including proximity-dependent ascorbic acid peroxidase labeling (APEX), and biotinylation by antibody recognition (BAR). Furthermore, we explore the use of MS to detect post-translational modifications (PTMs), such as ubiquitination and phosphorylation, of disease-relevant proteins in ALS and FTD. We also discuss upstream technologies that enable enrichment of proteins of interest, highlighting the contributions of new techniques to isolate disease-relevant protein inclusions including flow cytometric analysis of inclusions and trafficking (FloIT). These recently developed approaches, as well as related advances yet to be applied to studies of these neurodegenerative diseases, offer numerous opportunities for discovery of potential therapeutic targets and biomarkers for ALS and FTD.

18.
J Appl Ecol ; 56(3): 688-698, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30983625

RESUMO

The mass release of transgenic insects carrying female lethal self-limiting genes can reduce pest insect populations. Substantial releases are also a novel resistance management tool, since wild type alleles conferring susceptibility to pesticides can dilute resistance alleles in target populations. However, a potential barrier is the need for large-scale area-wide releases. Here, we address whether localized releases of transgenic insects could provide an alternative means of population suppression and resistance management, without serious loss of efficacy.We used experimental mesocosms constituting insect metapopulations to explore the evolution of resistance to the Bacillus thuringiensis toxin Cry1Ac in a high-dose/refugia landscape in the insect Plutella xylostella. We ran two selection experiments, the first compared the efficacy of "everywhere" releases and negative controls to a spatially density-dependent or "whack-a-mole" strategy that concentrated release of transgenic insects in subpopulations with elevated resistance. The second experiment tested the relative efficacy of whack-a-mole and everywhere releases under spatially homogenous and heterogeneous selection pressure.The whack-a-mole releases were less effective than everywhere releases in terms of slowing the evolution of resistance, which, in the first experiment, largely prevented the evolution of resistance. In contrast to predictions, heterogeneous whack-a-mole releases were no more effective under heterogeneous selection pressure. Heterogeneous selection pressure did, however, reduce total insect population sizes.Whack-a-mole releases provided early population suppression, indistinguishable from homogeneous everywhere releases. However, insect population densities tracked the evolution of resistance in this system, as phenotypic resistance provides access to additional diet containing the toxin Cry1Ac. Thus, as resistance levels diverged between treatments, carrying capacities and population sizes increased under the whack-a-mole approach. Synthesis and applications. Spatially density-dependent releases of transgenic insects, particularly those targeting source populations at a landscape level, could suppress pest populations in the absence of blanket area-wide releases. The benefits of self-limiting transgenic insects were reduced in spatially localized releases, suggesting that they are not ideal for "spot" treatment of resistance problems. Nevertheless, spatially homogeneous or heterogeneous releases could be used to support other resistance management interventions.

19.
Biomacromolecules ; 20(5): 2148-2158, 2019 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-30995832

RESUMO

Poly(amidoamine) dendrimer (PAMAM) is well-known for its high efficiency as a drug delivery vehicle. However, the intrinsic cytotoxicity and lack of a detectable signal to facilitate tracking have impeded its practical applications. Herein, we have developed a novel label-free fluorescent and biocompatible PAMAM derivative by simple surface modification of PAMAM using acetaldehyde. The modified PAMAM possessed a strong green fluorescence, which was generated by the C=N bonds of the resulting Schiff Bases via n-π* transition, while the intrinsic cytotoxicity of PAMAM was simultaneously ameliorated. Through further PEGylation, the fluorescent PAMAM demonstrated excellent intracellular tracking in human melanoma SKMEL28 cells. In addition, our PEGylated fluorescent PAMAM derivative achieved enhanced loading and delivery efficiency of the anticancer drug doxorubicin (DOX) compared to the original PAMAM. Importantly, the accelerated kinetics of DOX-encapsulated fluorescent PAMAM nanocomposites in an acidic environment facilitated intracellular drug release, which demonstrated comparable cytotoxicity to that of the free-form doxorubicin hydrochloride (DOX·HCl) against melanoma cells. Overall, our label free fluorescent PAMAM derivative offers a new opportunity of traceable and controlled delivery for DOX and other drugs of potential clinical importance.

20.
Front Neurosci ; 13: 335, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31031584

RESUMO

During neurodegenerative disease, the multifunctional RNA-binding protein TDP-43 undergoes a vast array of post-translational modifications, including phosphorylation, acetylation, and cleavage. Many of these alterations may directly contribute to the pathogenesis of TDP-43 proteinopathies, which include most forms of amyotrophic lateral sclerosis (ALS) and approximately half of all frontotemporal dementia, pathologically identified as frontotemporal lobar degeneration (FTLD) with TDP-43 pathology. However, the relative contributions of the various TDP-43 post-translational modifications to disease remain unclear, and indeed some may be secondary epiphenomena rather than disease-causative. It is therefore critical to determine the involvement of each modification in disease processes to allow the design of targeted treatments. In particular, TDP-43 C-terminal fragments (CTFs) accumulate in the brains of people with ALS and FTLD and are therefore described as a neuropathological signature of these diseases. Remarkably, these TDP-43 CTFs are rarely observed in the spinal cord, even in ALS which involves dramatic degeneration of spinal motor neurons. Therefore, TDP-43 CTFs are not produced non-specifically in the course of all forms of TDP-43-related neurodegeneration, but rather variably arise due to additional factors influenced by regional heterogeneity in the central nervous system. In this review, we summarize how TDP-43 CTFs are generated and degraded by cells, and critique evidence from studies of TDP-43 CTF pathology in human disease tissues, as well as cell and animal models, to analyze the pathophysiological relevance of TDP-43 CTFs to ALS and FTLD. Numerous studies now indicate that, although TDP-43 CTFs are prevalent in ALS and FTLD brains, disease-related pathology is only variably reproduced in TDP-43 CTF cell culture models. Furthermore, TDP-43 CTF expression in both transgenic and viral-mediated in vivo models largely fails to induce motor or behavioral dysfunction reminiscent of human disease. We therefore conclude that although TDP-43 CTFs are a hallmark of TDP-43-related neurodegeneration in the brain, they are not a primary cause of ALS or FTLD.

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