252 results on '"Eskitis Institute for Drug Discovery"'
Search Results
2. Meta-analysis of genome-wide DNA methylation identifies shared associations across neurodegenerative disorders.
- Author
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Nabais MF, Laws SM, Lin T, Vallerga CL, Armstrong NJ, Blair IP, Kwok JB, Mather KA, Mellick GD, Sachdev PS, Wallace L, Henders AK, Zwamborn RAJ, Hop PJ, Lunnon K, Pishva E, Roubroeks JAY, Soininen H, Tsolaki M, Mecocci P, Lovestone S, Kłoszewska I, Vellas B, Furlong S, Garton FC, Henderson RD, Mathers S, McCombe PA, Needham M, Ngo ST, Nicholson G, Pamphlett R, Rowe DB, Steyn FJ, Williams KL, Anderson TJ, Bentley SR, Dalrymple-Alford J, Fowder J, Gratten J, Halliday G, Hickie IB, Kennedy M, Lewis SJG, Montgomery GW, Pearson J, Pitcher TL, Silburn P, Zhang F, Visscher PM, Yang J, Stevenson AJ, Hillary RF, Marioni RE, Harris SE, Deary IJ, Jones AR, Shatunov A, Iacoangeli A, van Rheenen W, van den Berg LH, Shaw PJ, Shaw CE, Morrison KE, Al-Chalabi A, Veldink JH, Hannon E, Mill J, Wray NR, and McRae AF more...
- Subjects
- Alleles, Biomarkers, Blood Cells metabolism, Case-Control Studies, Disease Susceptibility, Gene Expression Profiling, Genetic Loci, Genetic Predisposition to Disease, Humans, Neurodegenerative Diseases metabolism, DNA Methylation, Epigenesis, Genetic, Genome-Wide Association Study, Neurodegenerative Diseases etiology
- Abstract
Background: People with neurodegenerative disorders show diverse clinical syndromes, genetic heterogeneity, and distinct brain pathological changes, but studies report overlap between these features. DNA methylation (DNAm) provides a way to explore this overlap and heterogeneity as it is determined by the combined effects of genetic variation and the environment. In this study, we aim to identify shared blood DNAm differences between controls and people with Alzheimer's disease, amyotrophic lateral sclerosis, and Parkinson's disease., Results: We use a mixed-linear model method (MOMENT) that accounts for the effect of (un)known confounders, to test for the association of each DNAm site with each disorder. While only three probes are found to be genome-wide significant in each MOMENT association analysis of amyotrophic lateral sclerosis and Parkinson's disease (and none with Alzheimer's disease), a fixed-effects meta-analysis of the three disorders results in 12 genome-wide significant differentially methylated positions. Predicted immune cell-type proportions are disrupted across all neurodegenerative disorders. Protein inflammatory markers are correlated with profile sum-scores derived from disease-associated immune cell-type proportions in a healthy aging cohort. In contrast, they are not correlated with MOMENT DNAm-derived profile sum-scores, calculated using effect sizes of the 12 differentially methylated positions as weights., Conclusions: We identify shared differentially methylated positions in whole blood between neurodegenerative disorders that point to shared pathogenic mechanisms. These shared differentially methylated positions may reflect causes or consequences of disease, but they are unlikely to reflect cell-type proportion differences. more...
- Published
- 2021
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Catalog
3. Factors related to sleep disturbances for individuals with Parkinson's disease: a regional perspective.
- Author
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Wade R, Pachana NA, Mellick G, and Dissanayaka N
- Subjects
- Aged, Aged, 80 and over, Anxiety etiology, Cross-Sectional Studies, Depression etiology, Female, Humans, Male, Middle Aged, Queensland, Severity of Illness Index, Sleep physiology, Surveys and Questionnaires, Parkinson Disease complications, Parkinson Disease psychology, Quality of Life psychology, Sleep Wake Disorders complications
- Abstract
Objectives: Sleep disturbances negatively impact the quality of life of patients with Parkinson's disease (PD). While persons living in regional areas are at higher risk of PD, PD is poorly managed in regional communities. This study examined factors associated with sleep problems in PD in a regional context., Design: A mixed-methods cross-sectional design was used., Participants: Patients with PD were recruited from the Queensland Parkinson's Project database., Measurements: Those who agreed to participate were sent a questionnaire assessing aspects of sleep, depression, anxiety, quality of life, and PD severity. Qualitative information was also gathered. Correlations between variables were examined; thematic analyses were performed for qualitative data., Results: All participants (n = 49) reported sleep disturbances, with 73% (n = 36) reporting sleep disturbance to be problematic. Global sleep dysfunction positively correlated with daytime napping (r = .34, p = .01), watching the clock when unable to sleep (r = .38, p = <.01), staying in bed when unable to sleep (r = .43, p = <.01), and going to bed hungry (r = .31, p = .03) and negatively correlated with daytime exercise (r = -.32, p = .02). Positive correlations were observed between global sleep dysfunction and depression (r = .55, p = <.01), anxiety (r = .31, p = .04), and dysfunctional sleep beliefs (r = .39, p = <.01)., Conclusion: There is a clear need for identifying factors related to sleep disturbances in PD for effective management. more...
- Published
- 2020
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4. 8-Aminoquinolines with an Aminoxyalkyl Side Chain Exert in vitro Dual-Stage Antiplasmodial Activity.
- Author
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Leven M, Held J, Duffy S, Alves Avelar LA, Meister S, Delves M, Plouffe D, Kuna K, Tschan S, Avery VM, Winzeler EA, Mordmüller B, and Kurz T
- Subjects
- Aminoquinolines chemical synthesis, Aminoquinolines pharmacology, Antimalarials chemical synthesis, Antimalarials pharmacology, Cell Survival drug effects, Hep G2 Cells, Humans, Life Cycle Stages drug effects, Plasmodium falciparum drug effects, Structure-Activity Relationship, Aminoquinolines chemistry, Antimalarials chemistry, Plasmodium falciparum growth & development
- Abstract
A series of novel 8-aminoquinolines (8-AQs) with an aminoxyalkyl side chain were synthesized and evaluated for in vitro antiplasmodial properties against asexual blood stages, liver stages, and sexual stages of Plasmodium falciparum. 8-AQs bearing 2-alkoxy and 5-phenoxy substituents on the quinoline ring system were found to be the most promising compounds under study, exhibiting potent blood schizontocidal and moderate tissue schizontocidal in vitro activity., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.) more...
- Published
- 2019
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5. Corrigendum to "Solid-phase synthesis of Biotin-S-Farnesyl-l-Cysteine, a surrogate substrate for isoprenylcysteine Carboxylmethyltransferase (ICMT)" [Bioorg. Med. Chem. Lett. 23 (2013) [5671-5673].
- Author
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Stevenson GI, Yong S, Fechner GA, Neve J, Lock A, and Avery VM
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- 2018
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6. Cell Swelling Induced by the Antimalarial KAE609 (Cipargamin) and Other PfATP4-Associated Antimalarials.
- Author
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Dennis ASM, Lehane AM, Ridgway MC, Holleran JP, and Kirk K
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- Erythrocytes parasitology, Humans, Osmotic Fragility drug effects, Antimalarials pharmacology, Biological Transport, Active drug effects, Cell Size drug effects, Indoles pharmacology, Malaria, Falciparum drug therapy, Membrane Transport Proteins drug effects, Plasmodium falciparum drug effects, Plasmodium falciparum growth & development, Spiro Compounds pharmacology
- Abstract
For an increasing number of antimalarial agents identified in high-throughput phenotypic screens, there is evidence that they target PfATP4, a putative Na
+ efflux transporter on the plasma membrane of the human malaria parasite Plasmodium falciparum For several such "PfATP4-associated" compounds, it has been noted that their addition to parasitized erythrocytes results in cell swelling. Here we show that six structurally diverse PfATP4-associated compounds, including the clinical candidate KAE609 (cipargamin), induce swelling of both isolated blood-stage parasites and intact parasitized erythrocytes. The swelling of isolated parasites is dependent on the presence of Na+ in the external environment and may be attributed to the osmotic consequences of Na+ uptake. The swelling of the parasitized erythrocyte results in an increase in its osmotic fragility. Countering cell swelling by increasing the osmolarity of the extracellular medium reduces the antiplasmodial efficacy of PfATP4-associated compounds, consistent with cell swelling playing a role in the antimalarial activity of this class of compounds., (Copyright © 2018 American Society for Microbiology.) more...- Published
- 2018
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7. Comparison of serum levels of IL-6, IL-8, TGF-β and TNF-α in coronary artery diseases, stable angina and participants with normal coronary artery.
- Author
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Sepehri ZS, Masoomi M, Ruzbehi F, Kiani Z, Nasiri AA, Kohan F, Sheikh Fathollahi M, Kazemi Arababadi M, Kennedy D, and Asadikaram GA
- Subjects
- Angina, Stable drug therapy, Angina, Stable genetics, Angina, Stable pathology, Case-Control Studies, Coronary Artery Disease drug therapy, Coronary Artery Disease genetics, Coronary Artery Disease pathology, Coronary Vessels metabolism, Coronary Vessels pathology, Cross-Sectional Studies, Exercise, Female, Gene Expression, Humans, Interleukin-6 genetics, Interleukin-8 genetics, Iran, Male, Middle Aged, Nitroglycerin therapeutic use, Risk Factors, Smoking physiopathology, Transforming Growth Factor beta genetics, Tumor Necrosis Factor-alpha genetics, Vasodilator Agents therapeutic use, Angina, Stable blood, Coronary Artery Disease blood, Interleukin-6 blood, Interleukin-8 blood, Transforming Growth Factor beta blood, Tumor Necrosis Factor-alpha blood
- Abstract
Cytokines, which typically regulate the immune responses, play a role in cardiovascular diseases such as coronary artery diseases (CAD) and ischemic heart diseases (IHD). The aims of this study were to evaluate serum levels of IL-6, IL-8, TGF-β and TNF-α in patients with or without CAD, as well as stable angina, and to assess the effects of drug administration on the serum levels of these cytokines. Serum levels of the cytokines were analyzed in the three groups: patients with acute coronary syndrome, stable angina and participants with normal coronary arteries as controls. Cohort study of the patients showed that Nitrocontin was the only drug used in a significantly different pattern between the groups where it was used less frequently in patients with stable angina compared to the acute coronary syndrome or control groups. Serum levels of the evaluated cytokines were not different neither between the studied groups nor between the groups with variable Gensini scores. However, IL-8 in controls that were not engaged in regular exercise was higher than the controls performing regular exercise. In the stable angina group, TNF-α in non-smokers was higher than the smokers. It was revealed that serum levels of pro-inflammatory cytokines are not associated with atherosclerosis and stable angina in patients from the South-East of Iran. However, suppressed expression of TGF-β, may increase the risk of CAD. Exercise can reduce the risk of CAD through downregulation of pro-inflammatory cytokines. more...
- Published
- 2018
8. Sulfotransferase 1A3/4 copy number variation is associated with neurodegenerative disease.
- Author
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Butcher NJ, Horne MK, Mellick GD, Fowler CJ, Masters CL, and Minchin RF
- Subjects
- Adult, Aged, Aged, 80 and over, Alzheimer Disease diagnosis, Female, Humans, Male, Middle Aged, Neurodegenerative Diseases diagnosis, Neurodegenerative Diseases genetics, Parkinson Disease diagnosis, Alzheimer Disease genetics, Arylsulfotransferase genetics, DNA Copy Number Variations genetics, Genetic Association Studies methods, Parkinson Disease genetics
- Abstract
The cytosolic aryl sulfotransferase genes SULT1A3 and SULT1A4 are located on chromosome 16p11.2 in a region of chromosomal instability. SULT1A3/4 are important enzymes in the metabolism of catecholamines linked to neurodegenerative diseases such as Parkinson's and Alzheimer's. In the present study, copy number variation of the SULT1A3/4 genes in healthy individuals, as well as a cohort of Parkinson's disease and Alzheimer's disease patients was examined. In all subjects, SULT1A3/4 copy number varied from 1 to 10. In Alzheimer's disease patients, there was a significantly lower copy number compared to controls, and a positive correlation between copy number and age of disease onset. By contrast, there were no differences in Parkinson's disease patients. However, when early-onset Parkinson's disease was evaluated separately, there appeared to be an association with gene copy number and risk. The current study shows that these neurodegenerative diseases may be related to SULT1A3/4 copy number. more...
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- 2018
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9. Deubiquitinating Enzyme USP9X Suppresses Tumor Growth via LATS Kinase and Core Components of the Hippo Pathway.
- Author
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Toloczko A, Guo F, Yuen HF, Wen Q, Wood SA, Ong YS, Chan PY, Shaik AA, Gunaratne J, Dunne MJ, Hong W, and Chan SW
- Subjects
- Adaptor Proteins, Signal Transducing genetics, Adaptor Proteins, Signal Transducing metabolism, Angiomotins, Animals, Apoptosis, Biomarkers, Tumor, Breast Neoplasms genetics, Breast Neoplasms metabolism, Cell Proliferation, Cells, Cultured, Embryo, Mammalian cytology, Embryo, Mammalian metabolism, Female, Fibroblasts cytology, Fibroblasts metabolism, Follow-Up Studies, Hippo Signaling Pathway, Humans, Intercellular Signaling Peptides and Proteins genetics, Intercellular Signaling Peptides and Proteins metabolism, Intracellular Signaling Peptides and Proteins genetics, Intracellular Signaling Peptides and Proteins metabolism, Male, Membrane Proteins genetics, Membrane Proteins metabolism, Mice, Mice, Knockout, Microfilament Proteins, Neoplasm Staging, Pancreatic Neoplasms genetics, Pancreatic Neoplasms metabolism, Phosphoproteins genetics, Phosphoproteins metabolism, Phosphorylation, Prognosis, Protein Serine-Threonine Kinases genetics, Signal Transduction, Survival Rate, Transcription Factors genetics, Transcription Factors metabolism, Ubiquitin Thiolesterase genetics, Ubiquitination, YAP-Signaling Proteins, Breast Neoplasms pathology, Endopeptidases physiology, Pancreatic Neoplasms pathology, Protein Serine-Threonine Kinases metabolism, Ubiquitin Thiolesterase metabolism
- Abstract
The core LATS kinases of the Hippo tumor suppressor pathway phosphorylate and inhibit the downstream transcriptional co-activators YAP and TAZ, which are implicated in various cancers. Recent studies have identified various E3 ubiquitin ligases that negatively regulate the Hippo pathway via ubiquitination, yet few deubiquitinating enzymes (DUB) have been implicated. In this study, we report the DUB USP9X is an important regulator of the core kinases of this pathway. USP9X interacted strongly with LATS kinase and to a lesser extent with WW45, KIBRA, and Angiomotin, and LATS co-migrated exclusively with USP9X during gel filtration chromatography analysis. Knockdown of USP9X significantly downregulated and destabilized LATS and resulted in enhanced nuclear translocation of YAP and TAZ, accompanied with activation of their target genes. In the absence of USP9X, cells exhibited an epithelial-to-mesenchymal transition phenotype, acquired anchorage-independent growth in soft agar, and led to enlarged, disorganized, three-dimensional acini. YAP/TAZ target gene activation in response to USP9X knockdown was suppressed by knockdown of YAP, TAZ, and TEAD2. Deletion of USP9X in mouse embryonic fibroblasts resulted in significant downregulation of LATS. Furthermore, USP9X protein expression correlated positively with LATS but negatively with YAP/TAZ in pancreatic cancer tissues as well as pancreatic and breast cancer cell lines. Overall, these results strongly indicate that USP9X potentiates LATS kinase to suppress tumor growth. Cancer Res; 77(18); 4921-33. ©2017 AACR ., (©2017 American Association for Cancer Research.) more...
- Published
- 2017
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10. N400 and emotional word processing in Parkinson's disease.
- Author
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Dissanayaka NNW, Au TR, Angwin AJ, O'Sullivan JD, Byrne GJ, Silburn PA, Marsh R, Mellick GD, and Copland DA
- Subjects
- Aged, Electroencephalography, Female, Humans, Male, Middle Aged, Emotions physiology, Evoked Potentials physiology, Language, Parkinson Disease physiopathology
- Abstract
Objective: Emotional and cognitive disturbances are common complications in Parkinson's disease (PD). N400 is an event related potential (ERP) strongly linked to lexical-semantic processing and has demonstrated alterations in amplitude and latency when PD patients performed semantic priming tasks. The present study investigated the role of N400 in an automatic affective priming paradigm in PD. Other ERP components relevant to emotion processing were also examined., Method: Twenty-two PD patients and 17 healthy adults performed an automatic affective priming task while ERPs were recorded using 128 channels. Prime-target word pairs of negative or neutral valence were presented at a stimulus onset asynchrony of 250 ms. Participants were asked to evaluate the valence of the target word by button press., Results: A larger N400 amplitude for incongruent compared with congruent neutral targets was observed at right central and parietal regions and did not differ between PD and controls. PD and controls also displayed larger P300 and late positive potential (LPP) amplitudes for negative compared with neutral targets at central parietal and right frontal regions. In contrast, whereas controls showed a larger slow negative wave (SNW) for negative targets compared with neutral targets at left frontal and left central regions, PD group demonstrated a significant reduction in SNW amplitude difference at the left central region., Conclusion: N400 is intact in PD when processing evaluative judgments of emotional words. P300 and LPP were also intact in PD. The altered left central SNW in PD suggests an ERP marker for emotional dysfunction in PD. (PsycINFO Database Record, ((c) 2017 APA, all rights reserved).) more...
- Published
- 2017
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11. Trojan horse L-selectin monocytes: A portal of Burkholderia pseudomallei entry into the brain.
- Author
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St John JA
- Subjects
- Brain, Humans, Melioidosis, Monocytes, Burkholderia pseudomallei, L-Selectin
- Published
- 2017
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12. Loss of Usp9x disrupts cell adhesion, and components of the Wnt and Notch signaling pathways in neural progenitors.
- Author
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Premarathne S, Murtaza M, Matigian N, Jolly LA, and Wood SA
- Subjects
- Animals, Cell Line, Female, HEK293 Cells, Humans, Male, Mice, Nervous System metabolism, Signal Transduction genetics, beta Catenin genetics, Cell Adhesion genetics, Receptors, Notch genetics, Ubiquitin Thiolesterase genetics, Wnt Signaling Pathway genetics
- Abstract
Development of neural progenitors depends upon the coordination of appropriate intrinsic responses to extrinsic signalling pathways. Here we show the deubiquitylating enzyme, Usp9x regulates components of both intrinsic and extrinsic fate determinants. Nestin-cre mediated ablation of Usp9x from embryonic neural progenitors in vivo resulted in a transient disruption of cell adhesion and apical-basal polarity and, an increased number and ectopic localisation of intermediate neural progenitors. In contrast to other adhesion and polarity proteins, levels of β-catenin protein, especially S33/S37/T41 phospho-β-catenin, were markedly increased in Usp9x
-/Y embryonic cortices. Loss of Usp9x altered composition of the β-catenin destruction complex possibly impeding degradation of S33/S37/T41 phospho-β-catenin. Pathway analysis of transcriptomic data identified Wnt signalling as significantly affected in Usp9x-/Y embryonic brains. Depletion of Usp9x in cultured human neural progenitors resulted in Wnt-reporter activation. Usp9x also regulated components of the Notch signalling pathway. Usp9x co-localized and associated with both Itch and Numb in embryonic neocortices. Loss of Usp9x led to decreased Itch and Numb levels, and a concomitant increase in levels of the Notch intracellular domain as well as, increased expression of the Notch target gene Hes5. Therefore Usp9x modulates and potentially coordinates multiple fate determinants in neural progenitors. more...- Published
- 2017
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13. Reply: Heterozygous PINK1 p.G411S in rapid eye movement sleep behaviour disorder.
- Author
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Puschmann A, Fiesel FC, Caulfield TR, Hudec R, Ando M, Truban D, Hou X, Ogaki K, Heckman MG, James ED, Swanberg M, Jimenez-Ferrer I, Hansson O, Opala G, Siuda J, Boczarska-Jedynak M, Friedman A, Koziorowski D, Rudzinska-Bar M, Aasly JO, Lynch T, Mellick GD, Mohan M, Silburn PA, Sanotsky Y, Vilariño-Güell C, Farrer MJ, Chen L, Dawson VL, Dawson TM, Wszolek ZK, Ross OA, and Springer W more...
- Subjects
- Heterozygote, Humans, Protein Kinases, Sleep, REM, Parkinson Disease, REM Sleep Behavior Disorder
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- 2017
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14. Actinomycete Metabolome Induction/Suppression with N-Acetylglucosamine.
- Author
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Dashti Y, Grkovic T, Abdelmohsen UR, Hentschel U, and Quinn RJ
- Subjects
- Animals, Anti-Bacterial Agents pharmacology, Indoles, Metabolome, Molecular Structure, Nuclear Magnetic Resonance, Biomolecular, Acetylglucosamine pharmacology, Actinobacteria chemistry, Actinobacteria genetics, Porifera microbiology
- Abstract
The metabolite profiles of three sponge-derived actinomycetes, namely, Micromonospora sp. RV43, Rhodococcus sp. RV157, and Actinokineospora sp. EG49 were investigated after elicitation with N-acetyl-d-glucosamine.
1 H NMR fingerprint methodology was utilized to study the differences in the metabolic profiles of the bacterial extracts before and after elicitation. Our study found that the addition of N-acetyl-d-glucosamine modified the secondary metabolite profiles of the three investigated actinomycete isolates. N-Acetyl-d-glucosamine induced the production of 3-formylindole (11) and guaymasol (12) in Micromonospora sp. RV43, the siderophore bacillibactin 16, and surfactin antibiotic 17 in Rhodococcus sp. RV157 and increased the production of minor metabolites actinosporins E-H (21-24) in Actinokineospora sp. EG49. These results highlight the use of NMR fingerprinting to detect changes in metabolism following addition of N-acetyl-d-glucosamine. N-Acetyl-d-glucosamine was shown to have multiple effects including suppression of metabolites, induction of new metabolites, and increased production of minor compounds. more...- Published
- 2017
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15. USP9X deubiquitylating enzyme maintains RAPTOR protein levels, mTORC1 signalling and proliferation in neural progenitors.
- Author
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Bridges CR, Tan MC, Premarathne S, Nanayakkara D, Bellette B, Zencak D, Domingo D, Gecz J, Murtaza M, Jolly LA, and Wood SA
- Subjects
- Animals, Cell Cycle Checkpoints, Endopeptidases metabolism, HEK293 Cells, Humans, Mice, Proteolysis, Signal Transduction, Cell Self Renewal, Mechanistic Target of Rapamycin Complex 1 metabolism, Neural Stem Cells metabolism, Regulatory-Associated Protein of mTOR metabolism, Ubiquitin Thiolesterase metabolism
- Abstract
USP9X, is highly expressed in neural progenitors and, essential for neural development in mice. In humans, mutations in USP9X are associated with neurodevelopmental disorders. To understand USP9X's role in neural progenitors, we studied the effects of altering its expression in both the human neural progenitor cell line, ReNcell VM, as well as neural stem and progenitor cells derived from Nestin-cre conditionally deleted Usp9x mice. Decreasing USP9X resulted in ReNcell VM cells arresting in G0 cell cycle phase, with a concomitant decrease in mTORC1 signalling, a major regulator of G0/G1 cell cycle progression. Decreased mTORC1 signalling was also observed in Usp9x-null neurospheres and embryonic mouse brains. Further analyses revealed, (i) the canonical mTORC1 protein, RAPTOR, physically associates with Usp9x in embryonic brains, (ii) RAPTOR protein level is directly proportional to USP9X, in both loss- and gain-of-function experiments in cultured cells and, (iii) USP9X deubiquitlyating activity opposes the proteasomal degradation of RAPTOR. EdU incorporation assays confirmed Usp9x maintains the proliferation of neural progenitors similar to Raptor-null and rapamycin-treated neurospheres. Interestingly, loss of Usp9x increased the number of sphere-forming cells consistent with enhanced neural stem cell self-renewal. To our knowledge, USP9X is the first deubiquitylating enzyme shown to stabilize RAPTOR. more...
- Published
- 2017
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16. An integrative systematic framework helps to reconstruct skeletal evolution of glass sponges (Porifera, Hexactinellida).
- Author
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Dohrmann M, Kelley C, Kelly M, Pisera A, Hooper JNA, and Reiswig HM
- Abstract
Background: Glass sponges (Class Hexactinellida) are important components of deep-sea ecosystems and are of interest from geological and materials science perspectives. The reconstruction of their phylogeny with molecular data has only recently begun and shows a better agreement with morphology-based systematics than is typical for other sponge groups, likely because of a greater number of informative morphological characters. However, inconsistencies remain that have far-reaching implications for hypotheses about the evolution of their major skeletal construction types (body plans). Furthermore, less than half of all described extant genera have been sampled for molecular systematics, and several taxa important for understanding skeletal evolution are still missing. Increased taxon sampling for molecular phylogenetics of this group is therefore urgently needed. However, due to their remote habitat and often poorly preserved museum material, sequencing all 126 currently recognized extant genera will be difficult to achieve. Utilizing morphological data to incorporate unsequenced taxa into an integrative systematics framework therefore holds great promise, but it is unclear which methodological approach best suits this task., Results: Here, we increase the taxon sampling of four previously established molecular markers (18S, 28S, and 16S ribosomal DNA, as well as cytochrome oxidase subunit I) by 12 genera, for the first time including representatives of the order Aulocalycoida and the type genus of Dactylocalycidae, taxa that are key to understanding hexactinellid body plan evolution. Phylogenetic analyses suggest that Aulocalycoida is diphyletic and provide further support for the paraphyly of order Hexactinosida; hence these orders are abolished from the Linnean classification. We further assembled morphological character matrices to integrate so far unsequenced genera into phylogenetic analyses in maximum parsimony (MP), maximum likelihood (ML), Bayesian, and morphology-based binning frameworks. We find that of these four approaches, total-evidence analysis using MP gave the most plausible results concerning congruence with existing phylogenetic and taxonomic hypotheses, whereas the other methods, especially ML and binning, performed more poorly. We use our total-evidence phylogeny of all extant glass sponge genera for ancestral state reconstruction of morphological characters in MP and ML frameworks, gaining new insights into the evolution of major hexactinellid body plans and other characters such as different spicule types., Conclusions: Our study demonstrates how a comprehensive, albeit in some parts provisional, phylogeny of a larger taxon can be achieved with an integrative approach utilizing molecular and morphological data, and how this can be used as a basis for understanding phenotypic evolution. The datasets and associated trees presented here are intended as a resource and starting point for future work on glass sponge evolution. more...
- Published
- 2017
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17. Role of the VPS35 D620N mutation in Parkinson's disease.
- Author
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Mohan M and Mellick GD
- Subjects
- Animals, Humans, Parkinson Disease physiopathology, Mutation physiology, Parkinson Disease diagnosis, Parkinson Disease genetics, Vesicular Transport Proteins physiology
- Abstract
Parkinson's disease (PD) is a neurodegenerative disorder involving the loss of dopaminergic neurons in the brain. Following the discovery of the PD-causing D620N mutation in the VPS35 (Vacuolar sorting protein 35) gene, dysfunction in the subcellular retromer complex has been strongly implicated in pathogenesis of PD. Although the function and dysfunction of the retromer has been a focus of study for some time, the role of this complex in the development of PD is not fully understood. Investigating cellular alterations that occur when the retromer is rendered dysfunctional, such as when the D620N disease-causing mutation is introduced into various model systems, shows that endosomal processing defects are major contributors to the disease phenotype. Altered trafficking of retromer cargo molecules, reduced cellular survival and altered processing of alpha-synuclein have all been observed in the presence of the D620N mutation. In addition, interactions between the retromer and the protein products of other familial Parkinsonism-related genes, has made the retromer a prime target of research in PD. This review gives an overview of the changes in retromer function, identified thus far, that may contribute to the neurodegeneration observed in PD., (Copyright © 2016. Published by Elsevier Ltd.) more...
- Published
- 2017
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18. Probing function and structure of trehalose-6-phosphate phosphatases from pathogenic organisms suggests distinct molecular groupings.
- Author
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Cross M, Lepage R, Rajan S, Biberacher S, Young ND, Kim BN, Coster MJ, Gasser RB, Kim JS, and Hofmann A
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- Animals, Aspartic Acid chemistry, Bacterial Proteins chemistry, Bacterial Proteins genetics, Bacterial Proteins metabolism, Catalytic Domain, Helminth Proteins genetics, Helminth Proteins metabolism, Mycobacterium enzymology, Phosphoric Monoester Hydrolases genetics, Phosphoric Monoester Hydrolases metabolism, Brugia malayi enzymology, Conserved Sequence, Helminth Proteins chemistry, Phosphoric Monoester Hydrolases chemistry
- Abstract
The trehalose biosynthetic pathway is of great interest for the development of novel therapeutics because trehalose is an essential disaccharide in many pathogens but is neither required nor synthesized in mammalian hosts. As such, trehalose-6-phosphate phosphatase (TPP), a key enzyme in trehalose biosynthesis, is likely an attractive target for novel chemotherapeutics. Based on a survey of genomes from a panel of parasitic nematodes and bacterial organisms and by way of a structure-based amino acid sequence alignment, we derive the topological structure of monoenzyme TPPs and classify them into 3 groups. Comparison of the functional roles of amino acid residues located in the active site for TPPs belonging to different groups reveal nuanced variations. Because current literature on this enzyme family shows a tendency to infer functional roles for individual amino acid residues, we investigated the roles of the strictly conserved aspartate tetrad in TPPs of the nematode Brugia malayi by using a conservative mutation approach. In contrast to aspartate-213, the residue inferred to carry out the nucleophilic attack on the substrate, we found that aspartate-215 and aspartate-428 of Bm TPP are involved in the chemistry steps of enzymatic hydrolysis of the substrate. Therefore, we suggest that homology-based inference of functionally important amino acids by sequence comparison for monoenzyme TPPs should only be carried out for each of the 3 groups.-Cross, M., Lepage, R., Rajan, S., Biberacher, S., Young, N. D., Kim, B.-N., Coster, M. J., Gasser, R. B., Kim, J.-S., Hofmann, A. Probing function and structure of trehalose-6-phosphate phosphatases from pathogenic organisms suggests distinct molecular groupings., (© FASEB.) more...
- Published
- 2017
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19. Multidrug-resistant cancer cells and cancer stem cells hijack cellular systems to circumvent systemic therapies, can natural products reverse this?
- Author
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Zhang Q, Feng Y, and Kennedy D
- Subjects
- Animals, Apoptosis drug effects, Humans, Neoplastic Stem Cells drug effects, Neoplastic Stem Cells metabolism, Signal Transduction drug effects, Biological Products pharmacology, Drug Resistance, Multiple drug effects, Drug Resistance, Neoplasm drug effects, Neoplastic Stem Cells pathology
- Abstract
Chemotherapy is one of the most effective and broadly used approaches for cancer management and many modern regimes can eliminate the bulk of the cancer cells. However, recurrence and metastasis still remain a major obstacle leading to the failure of systemic cancer treatments. Therefore, to improve the long-term eradication of cancer, the cellular and molecular pathways that provide targets which play crucial roles in drug resistance should be identified and characterised. Multidrug resistance (MDR) and the existence of tumor-initiating cells, also referred to as cancer stem cells (CSCs), are two major contributors to the failure of chemotherapy. MDR describes cancer cells that become resistant to structurally and functionally unrelated anti-cancer agents. CSCs are a small population of cells within cancer cells with the capacity of self-renewal, tumor metastasis, and cell differentiation. CSCs are also believed to be associated with chemoresistance. Thus, MDR and CSCs are the greatest challenges for cancer chemotherapy. A significant effort has been made to identify agents that specifically target MDR cells and CSCs. Consequently, some agents derived from nature have been developed with a view that they may overcome MDR and/or target CSCs. In this review, natural products-targeting MDR cancer cells and CSCs are summarized and clustered by their targets in different signaling pathways. more...
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- 2017
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20. Chronoinflammaging in Alzheimer; A systematic review on the roles of toll like receptor 2.
- Author
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Ravari A, Mirzaei T, Kennedy D, and Kazemi Arababadi M
- Subjects
- Chronic Disease, Humans, Alzheimer Disease complications, Inflammation complications, Toll-Like Receptor 2 physiology
- Abstract
Aging is associated with a range of chronic low-grade inflammation (Chronoinflammaging) which may play a significant role in some chronic inflammatory based diseases, such as Alzheimer disease (AD). However, the events which lead to the induction of chronoinflammaging in AD are yet to be clarified. It has been proposed that the recognition of endogenous ligands by pathogen recognition receptors (PRRs) may be involved in the induction of chronoinflammaging. Toll like receptors (TLRs) are a family of PRRs which recognize endogenous damage associated molecular patterns (DAMPs) and subsequently induce inflammation. Therefore, TLRs are worthy of investigation to elucidate their roles in chronoinflammaging associated AD. This review article explores the main roles played by TLR2 in the pathogenesis of chronoinflammaging in patients suffering from AD., (Copyright © 2017 Elsevier Inc. All rights reserved.) more...
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- 2017
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21. Synthesis, biological characterisation and structure activity relationships of aromatic bisamidines active against Plasmodium falciparum.
- Author
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Sauer B, Skinner-Adams TS, Bouchut A, Chua MJ, Pierrot C, Erdmann F, Robaa D, Schmidt M, Khalife J, Andrews KT, and Sippl W
- Subjects
- Antimalarials chemistry, Antimalarials toxicity, Caco-2 Cells, Chemistry Techniques, Synthetic, Drug Design, Furans chemistry, Furans toxicity, HEK293 Cells, Humans, Structure-Activity Relationship, Antimalarials chemical synthesis, Antimalarials pharmacology, Furans chemical synthesis, Furans pharmacology, Plasmodium falciparum drug effects
- Abstract
Malaria is one of the most significant tropical diseases and remains a major challenge due to the lack of a broadly effective vaccine and parasite resistance to current drugs. This means there is a need for new drug candidates with novel modes of action. Aromatic bisamidines, such as furamidine (DB75), were initially developed as anti-Trypanosoma agents however as clinical trials with furamidine highlighted potential side effects they were not pursued further in that setting. Despite apparent cytotoxicity liabilities the potency of furamidine against Plasmodium falciparum makes it a promising scaffold for the development of new anti-Plasmodium agents with improved selectivity. In this study a bisamidine compound series based on furamidine was synthesized by introducing modifications at the furan core structure and terminal amidine groups. The activity of the derived compounds was tested in vitro against drug sensitive and resistant P. falciparum lines and a human cell line (HEK293 cells) to generate anti-Plasmodium structure-activity relationships and to provide preliminary selectivity data., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.) more...
- Published
- 2017
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22. Discovery of new nanomolar inhibitors of GPa: Extension of 2-oxo-1,2-dihydropyridinyl-3-yl amide-based GPa inhibitors.
- Author
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Loughlin WA, Jenkins ID, Karis ND, and Healy PC
- Subjects
- Animals, Inhibitory Concentration 50, Models, Molecular, Molecular Conformation, Rabbits, Amides chemistry, Amides pharmacology, Drug Design, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacology, Glycogen Phosphorylase antagonists & inhibitors
- Abstract
Glycogen Phosphorylase (GP) is a functionally active dimeric enzyme, which is a target for inhibition of the conversion of glycogen to glucose-1-phosphate. In this study we report the design and synthesis of 14 new pyridone derivatives, and seek to extend the SAR analysis of these compounds. The SAR revealed the minor influence of the amide group, importance of the pyridone ring both spatially around the pyridine ring and for possible π-stacking, and confirmed a preference for inclusion of 3,4-dichlorobenzyl moieties, as bookends to the pyridone scaffold. Upon exploring a dimer strategy as part of the SAR analysis, the first extended 2-oxo-dihydropyridinyl-3-yl amide nanomolar based inhibitors of GPa (IC
50 = 230 and 260 nM) were identified., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.) more...- Published
- 2017
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23. Optimization of 2-Anilino 4-Amino Substituted Quinazolines into Potent Antimalarial Agents with Oral in Vivo Activity.
- Author
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Gilson PR, Tan C, Jarman KE, Lowes KN, Curtis JM, Nguyen W, Di Rago AE, Bullen HE, Prinz B, Duffy S, Baell JB, Hutton CA, Jousset Subroux H, Crabb BS, Avery VM, Cowman AF, and Sleebs BE
- Subjects
- Administration, Oral, Animals, Antimalarials administration & dosage, Antimalarials pharmacology, Disease Models, Animal, Mice, Plasmodium falciparum drug effects, Quinazolines administration & dosage, Quinazolines pharmacology, Structure-Activity Relationship, Antimalarials therapeutic use, Quinazolines therapeutic use
- Abstract
Novel antimalarial therapeutics that target multiple stages of the parasite lifecycle are urgently required to tackle the emerging problem of resistance with current drugs. Here, we describe the optimization of the 2-anilino quinazoline class as antimalarial agents. The class, identified from publicly available antimalarial screening data, was optimized to generate lead compounds that possess potent antimalarial activity against P. falciparum parasites comparable to the known antimalarials, chloroquine and mefloquine. During the optimization process, we defined the functionality necessary for activity and improved in vitro metabolism and solubility. The resultant lead compounds possess potent activity against a multidrug resistant strain of P. falciparum and arrest parasites at the ring phase of the asexual stage and also gametocytogensis. Finally, we show that the lead compounds are orally efficacious in a 4 day murine model of malaria disease burden. more...
- Published
- 2017
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24. Potential of marine natural products against drug-resistant fungal, viral, and parasitic infections.
- Author
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Abdelmohsen UR, Balasubramanian S, Oelschlaeger TA, Grkovic T, Pham NB, Quinn RJ, and Hentschel U
- Subjects
- Animals, Drug Resistance, Bacterial, Drug Resistance, Fungal, Humans, Mycoses, Parasitic Diseases, United States, Virus Diseases, Anti-Infective Agents administration & dosage, Biological Products therapeutic use, Drugs, Investigational therapeutic use, Marine Biology
- Abstract
Antibiotics have revolutionised medicine in many aspects, and their discovery is considered a turning point in human history. However, the most serious consequence of the use of antibiotics is the concomitant development of resistance against them. The marine environment has proven to be a very rich source of diverse natural products with significant antibacterial, antifungal, antiviral, antiparasitic, antitumour, anti-inflammatory, antioxidant, and immunomodulatory activities. Many marine natural products (MNPs)-for example, neoechinulin B-have been found to be promising drug candidates to alleviate the mortality and morbidity rates caused by drug-resistant infections, and several MNP-based anti-infectives have already entered phase 1, 2, and 3 clinical trials, with six approved for usage by the US Food and Drug Administration and one by the EU. In this Review, we discuss the diversity of marine natural products that have shown in-vivo efficacy or in-vitro potential against drug-resistant infections of fungal, viral, and parasitic origin, and describe their mechanism of action. We highlight the drug-like physicochemical properties of the reported natural products that have bioactivity against drug-resistant pathogens in order to assess their drug potential. Difficulty in isolation and purification procedures, toxicity associated with the active compound, ecological impacts on natural environment, and insufficient investments by pharmaceutical companies are some of the clear reasons behind market failures and a poor pipeline of MNPs available to date. However, the diverse abundance of natural products in the marine environment could serve as a ray of light for the therapy of drug-resistant infections. Development of resistance-resistant antibiotics could be achieved via the coordinated networking of clinicians, microbiologists, natural product chemists, and pharmacologists together with pharmaceutical venture capitalist companies., (Copyright © 2017 Elsevier Ltd. All rights reserved.) more...
- Published
- 2017
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25. SC83288 is a clinical development candidate for the treatment of severe malaria.
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Pegoraro S, Duffey M, Otto TD, Wang Y, Rösemann R, Baumgartner R, Fehler SK, Lucantoni L, Avery VM, Moreno-Sabater A, Mazier D, Vial HJ, Strobl S, Sanchez CP, and Lanzer M
- Subjects
- Acute Disease, Animals, Antimalarials chemical synthesis, Antimalarials pharmacokinetics, Calcium-Transporting ATPases genetics, Calcium-Transporting ATPases metabolism, Disease Models, Animal, Drug Resistance, Endoplasmic Reticulum metabolism, Gene Expression, Humans, Inhibitory Concentration 50, Ion Transport, Malaria, Falciparum parasitology, Male, Mice, Mice, Inbred NOD, Mice, SCID, Plasmodium falciparum genetics, Plasmodium falciparum growth & development, Plasmodium falciparum metabolism, Structure-Activity Relationship, Antimalarials pharmacology, Calcium-Transporting ATPases antagonists & inhibitors, Endoplasmic Reticulum drug effects, Malaria, Falciparum drug therapy, Plasmodium falciparum drug effects
- Abstract
Severe malaria is a life-threatening complication of an infection with the protozoan parasite Plasmodium falciparum, which requires immediate treatment. Safety and efficacy concerns with currently used drugs accentuate the need for new chemotherapeutic options against severe malaria. Here we describe a medicinal chemistry program starting from amicarbalide that led to two compounds with optimized pharmacological and antiparasitic properties. SC81458 and the clinical development candidate, SC83288, are fast-acting compounds that can cure a P. falciparum infection in a humanized NOD/SCID mouse model system. Detailed preclinical pharmacokinetic and toxicological studies reveal no observable drawbacks. Ultra-deep sequencing of resistant parasites identifies the sarco/endoplasmic reticulum Ca
2+ transporting PfATP6 as a putative determinant of resistance to SC81458 and SC83288. Features, such as fast parasite killing, good safety margin, a potentially novel mode of action and a distinct chemotype support the clinical development of SC83288, as an intravenous application for the treatment of severe malaria., Competing Interests: The authors declare no competing financial interests. more...- Published
- 2017
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26. Synthesis and biological evaluation of a new class of benzothiazines as neuroprotective agents.
- Author
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Mancini A, Chelini A, Di Capua A, Castelli L, Brogi S, Paolino M, Giuliani G, Cappelli A, Frosini M, Ricci L, Leonelli E, Giorgi G, Giordani A, Magistretti J, and Anzini M
- Subjects
- Animals, Brain pathology, Calcium Channels drug effects, Cell Death drug effects, Glutamic Acid deficiency, Humans, Neuroblastoma pathology, Neuroprotective Agents pharmacology, Oxygen metabolism, Reactive Oxygen Species, Thiazines chemical synthesis, Voltage-Gated Sodium Channels drug effects, Neuroprotective Agents chemical synthesis, Thiazines pharmacology
- Abstract
Neurodegenerative diseases are disorders related to the degeneration of central neurons that gradually lead to various, severe alterations of cognitive and/or motor functions. Currently, for no such diseases does any pharmacological treatment exist able to arrest its progression. Riluzole (1) is a small molecule able to interfere with multiple cellular and molecular mechanisms of neurodegeneration, and is the only approved treatment of amyotrophic lateral sclerosis (ALS), the progression of which proved to significantly slow, thus increasing somewhat average survival. Here we report the synthesis of differently functionalized 4H-3,1-benzothiazine (5-6) and 2H-1,4-benzothiazine (7) series as superior homologues of 1. Biological evaluation demonstrated that amidine 4H-3,1-benzothiazine derivatives 5b-d can reduce glutamate and LDH release in the oxygen/glucose deprivation and reperfusion model (OGD/R) applied to brain slices with a higher potency than 1. Moreover the mentioned compounds significantly reduce glutamate- and 6-hydroxydopamine (6-OHDA)-induced cytotoxicity in neuroblastoma cells. In addition, the same compounds limit ROS formation in both neuronal preparations. Finally, 5c proved effective in inhibiting neuronal voltage-dependent Na
+ and Ca2+ -channels, showing a profile comparable with that of 1., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.) more...- Published
- 2017
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27. Polyoxygenated Cyclohexenes and Other Constituents of Cleistochlamys kirkii Leaves.
- Author
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Nyandoro SS, Munissi JJ, Gruhonjic A, Duffy S, Pan F, Puttreddy R, Holleran JP, Fitzpatrick PA, Pelletier J, Avery VM, Rissanen K, and Erdélyi M
- Subjects
- Antimalarials chemistry, Antineoplastic Agents, Phytogenic chemistry, Cyclohexenes chemistry, HEK293 Cells chemistry, Humans, Inhibitory Concentration 50, Molecular Structure, X-Ray Diffraction, Antimalarials isolation & purification, Antimalarials pharmacology, Antineoplastic Agents, Phytogenic isolation & purification, Antineoplastic Agents, Phytogenic pharmacology, Breast Neoplasms chemistry, Breast Neoplasms drug therapy, Cyclohexenes isolation & purification, Cyclohexenes pharmacology, HEK293 Cells pathology, Plant Leaves chemistry, Plasmodium falciparum drug effects
- Abstract
Thirteen new metabolites, including the polyoxygenated cyclohexene derivatives cleistodiendiol (1), cleistodienol B (3), cleistenechlorohydrins A (4) and B (5), cleistenediols A-F (6-11), cleistenonal (12), and the butenolide cleistanolate (13), 2,5-dihydroxybenzyl benzoate (cleistophenolide, 14), and eight known compounds (2, 15-21) were isolated from a MeOH extract of the leaves of Cleistochlamys kirkii. The purified metabolites were identified by NMR spectroscopic and mass spectrometric analyses, whereas the absolute configurations of compounds 1, 17, and 19 were established by single-crystal X-ray diffraction. The configuration of the exocyclic double bond of compound 2 was revised based on comparison of its NMR spectroscopic features and optical rotation to those of 1, for which the configuration was determined by X-ray diffraction. Observation of the co-occurrence of cyclohexenoids and heptenolides in C. kirkii is of biogenetic and chemotaxonomic significance. Some of the isolated compounds showed activity against Plasmodium falciparum (3D7, Dd2), with IC
50 values of 0.2-40 μM, and against HEK293 mammalian cells (IC50 2.7-3.6 μM). While the crude extract was inactive at 100 μg/mL against the MDA-MB-231 triple-negative breast cancer cell line, some of its isolated constituents demonstrated cytotoxic activity with IC50 values ranging from 0.03-8.2 μM. Compound 1 showed the most potent antiplasmodial (IC50 0.2 μM) and cytotoxic (IC50 0.03 μM, MDA-MB-231 cell line) activities. None of the compounds investigated exhibited translational inhibitory activity in vitro at 20 μM. more...- Published
- 2017
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28. Peroxisomal protein PEX13 functions in selective autophagy.
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Lee MY, Sumpter R Jr, Zou Z, Sirasanagandla S, Wei Y, Mishra P, Rosewich H, Crane DI, and Levine B
- Subjects
- Animals, Cell Line, Gene Knockdown Techniques, Humans, Membrane Proteins genetics, Mice, Mice, Transgenic, Mitochondria metabolism, Mitophagy, Peroxisomes metabolism, Protein Binding, Protein Transport, RNA, Small Interfering genetics, Sindbis Virus physiology, Ubiquitin-Protein Ligases metabolism, Zellweger Syndrome genetics, Zellweger Syndrome metabolism, Autophagy, Membrane Proteins metabolism
- Abstract
PEX13 is an integral membrane protein on the peroxisome that regulates peroxisomal matrix protein import during peroxisome biogenesis. Mutations in PEX13 and other peroxin proteins are associated with Zellweger syndrome spectrum (ZSS) disorders, a subtype of peroxisome biogenesis disorder characterized by prominent neurological, hepatic, and renal abnormalities leading to neonatal death. The lack of functional peroxisomes in ZSS patients is widely accepted as the underlying cause of disease; however, our understanding of disease pathogenesis is still incomplete. Here, we demonstrate that PEX13 is required for selective autophagy of Sindbis virus (virophagy) and of damaged mitochondria (mitophagy) and that disease-associated PEX13 mutants I326T and W313G are defective in mitophagy. The mitophagy function of PEX13 is shared with another peroxin family member PEX3, but not with two other peroxins, PEX14 and PEX19, which are required for general autophagy. Together, our results demonstrate that PEX13 is required for selective autophagy, and suggest that dysregulation of PEX13-mediated mitophagy may contribute to ZSS pathogenesis., (© 2016 The Authors. Published under the terms of the CC BY NC ND 4.0 license.) more...
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- 2017
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29. A Patient-Specific Stem Cell Model to Investigate the Neurological Phenotype Observed in Ataxia-Telangiectasia.
- Author
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Stewart R, Wali G, Perry C, Lavin MF, Féron F, Mackay-Sim A, and Sutharsan R
- Subjects
- Adult Stem Cells cytology, Adult Stem Cells metabolism, Cell Differentiation genetics, Cell Differentiation physiology, Humans, Olfactory Mucosa cytology, Olfactory Mucosa metabolism, Ataxia Telangiectasia metabolism, Ataxia Telangiectasia Mutated Proteins metabolism, Stem Cells cytology, Stem Cells metabolism
- Abstract
The molecular pathogenesis of ataxia-telangiectasia (A-T) is not yet fully understood, and a versatile cellular model is required for in vitro studies. The occurrence of continuous neurogenesis and easy access make the multipotent adult stem cells from the olfactory mucosa within the nasal cavity a potential cellular model. We describe an efficient method to establish neuron-like cells from olfactory mucosa biopsies derived from A-T patients for the purpose of studying the cellular and molecular aspects of this debilitating disease. more...
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- 2017
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30. Heterozygous PINK1 p.G411S increases risk of Parkinson's disease via a dominant-negative mechanism.
- Author
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Puschmann A, Fiesel FC, Caulfield TR, Hudec R, Ando M, Truban D, Hou X, Ogaki K, Heckman MG, James ED, Swanberg M, Jimenez-Ferrer I, Hansson O, Opala G, Siuda J, Boczarska-Jedynak M, Friedman A, Koziorowski D, Rudzińska-Bar M, Aasly JO, Lynch T, Mellick GD, Mohan M, Silburn PA, Sanotsky Y, Vilariño-Güell C, Farrer MJ, Chen L, Dawson VL, Dawson TM, Wszolek ZK, Ross OA, and Springer W more...
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Case-Control Studies, Female, Fibroblasts, Heterozygote, Humans, Male, Middle Aged, Pedigree, Risk, Young Adult, Genetic Association Studies, Genetic Predisposition to Disease genetics, Models, Molecular, Parkinson Disease genetics, Protein Kinases genetics
- Abstract
SEE GANDHI AND PLUN-FAVREAU DOI101093/AWW320 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: It has been postulated that heterozygous mutations in recessive Parkinson's genes may increase the risk of developing the disease. In particular, the PTEN-induced putative kinase 1 (PINK1) p.G411S (c.1231G>A, rs45478900) mutation has been reported in families with dominant inheritance patterns of Parkinson's disease, suggesting that it might confer a sizeable disease risk when present on only one allele. We examined families with PINK1 p.G411S and conducted a genetic association study with 2560 patients with Parkinson's disease and 2145 control subjects. Heterozygous PINK1 p.G411S mutations markedly increased Parkinson's disease risk (odds ratio = 2.92, P = 0.032); significance remained when supplementing with results from previous studies on 4437 additional subjects (odds ratio = 2.89, P = 0.027). We analysed primary human skin fibroblasts and induced neurons from heterozygous PINK1 p.G411S carriers compared to PINK1 p.Q456X heterozygotes and PINK1 wild-type controls under endogenous conditions. While cells from PINK1 p.Q456X heterozygotes showed reduced levels of PINK1 protein and decreased initial kinase activity upon mitochondrial damage, stress-response was largely unaffected over time, as expected for a recessive loss-of-function mutation. By contrast, PINK1 p.G411S heterozygotes showed no decrease of PINK1 protein levels but a sustained, significant reduction in kinase activity. Molecular modelling and dynamics simulations as well as multiple functional assays revealed that the p.G411S mutation interferes with ubiquitin phosphorylation by wild-type PINK1 in a heterodimeric complex. This impairs the protective functions of the PINK1/parkin-mediated mitochondrial quality control. Based on genetic and clinical evaluation as well as functional and structural characterization, we established p.G411S as a rare genetic risk factor with a relatively large effect size conferred by a partial dominant-negative function phenotype., (© The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain.) more...
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- 2017
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31. 6α-Acetoxyanopterine: A Novel Structure Class of Mitotic Inhibitor Disrupting Microtubule Dynamics in Prostate Cancer Cells.
- Author
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Levrier C, Sadowski MC, Rockstroh A, Gabrielli B, Kavallaris M, Lehman M, Davis RA, and Nelson CC
- Subjects
- Antimitotic Agents chemistry, Antineoplastic Agents chemistry, Apoptosis drug effects, Biological Products chemistry, Cell Cycle drug effects, Cell Line, Tumor, Cell Proliferation drug effects, Cell Survival drug effects, Gene Expression Profiling, Humans, Male, Mitosis genetics, Prostatic Neoplasms metabolism, Protein Multimerization drug effects, Spindle Apparatus drug effects, Tubulin chemistry, Tubulin metabolism, Tubulin Modulators chemistry, Vinblastine pharmacology, Antimitotic Agents pharmacology, Antineoplastic Agents pharmacology, Biological Products pharmacology, Microtubules metabolism, Mitosis drug effects, Tubulin Modulators pharmacology
- Abstract
The lack of a cure for metastatic castrate-resistant prostate cancer (mCRPC) highlights the urgent need for more efficient drugs to fight this disease. Here, we report the mechanism of action of the natural product 6α-acetoxyanopterine (6-AA) in prostate cancer cells. At low nanomolar doses, this potent cytotoxic alkaloid from the Australian endemic tree Anopterus macleayanus induced a strong accumulation of LNCaP and PC-3 (prostate cancer) cells as well as HeLa (cervical cancer) cells in mitosis, severe mitotic spindle defects, and asymmetric cell divisions, ultimately leading to mitotic catastrophe accompanied by cell death through apoptosis. DNA microarray of 6-AA-treated LNCaP cells combined with pathway analysis identified very similar transcriptional changes when compared with the anticancer drug vinblastine, which included pathways involved in mitosis, microtubule spindle organization, and microtubule binding. Like vinblastine, 6-AA inhibited microtubule polymerization in a cell-free system and reduced cellular microtubule polymer mass. Yet, microtubule alterations that are associated with resistance to microtubule-destabilizing drugs like vinca alkaloids (vinblastine/vincristine) or 2-methoxyestradiol did not confer resistance to 6-AA, suggesting a different mechanism of microtubule interaction. 6-AA is a first-in-class microtubule inhibitor that features the unique anopterine scaffold. This study provides a strong rationale to further develop this novel structure class of microtubule inhibitor for the treatment of malignant disease. Mol Cancer Ther; 16(1); 3-15. ©2016 AACR., (©2016 American Association for Cancer Research.) more...
- Published
- 2017
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32. Merosesquiterpene Congeners from the Australian Sponge Hyrtios digitatus as Potential Drug Leads for Atherosclerosis Disease.
- Author
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Wahab HA, Pham NB, Muhammad TS, Hooper JN, and Quinn RJ
- Subjects
- Animals, Australia, Cardiovascular Agents chemistry, Cardiovascular Agents pharmacology, Cell Line, Tumor, Hep G2 Cells, Humans, Atherosclerosis drug therapy, Porifera chemistry, Sesquiterpenes chemistry, Sesquiterpenes pharmacology, Xanthones chemistry, Xanthones pharmacology
- Abstract
A study of the chemical constituents from the Australian Sponge Hyrtios digitatus has provided a perspective on the connection between the chemistry and biology of the puupehenones, a unique and unusual class of merosesquiterpenes. In this study, a new tetracyclic merosesquiterpene, 19-methoxy-9,15-ene-puupehenol ( 1 ) was isolated from the marine sponge Hyrtios digitatus along with the known 20-methoxy-9,15-ene-puupehenol ( 2 ). Their structures were elucidated on the basis of spectroscopic data (¹H and
13 C NMR) in combination with experimental electronic circular dichroism (ECD) data. Compounds 1 and 2 are active at 1.78 μM and 3.05 μM, respectively, on Scavenger Receptor-Class B Type 1 HepG2 (SR-B1 HepG2) stable cell lines, targeting atherosclerosis disease., Competing Interests: The authors declare no conflict of interest. more...- Published
- 2016
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33. P-glycoprotein-mediated chemoresistance is reversed by carbonic anhydrase XII inhibitors.
- Author
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Kopecka J, Rankin GM, Salaroglio IC, Poulsen SA, and Riganti C
- Subjects
- Animals, Cell Line, Tumor, Doxorubicin pharmacokinetics, Doxorubicin pharmacology, Drug Resistance, Neoplasm drug effects, Female, Humans, Hydrogen-Ion Concentration, Mice, Mice, Inbred BALB C, Neoplasms, Experimental enzymology, ATP Binding Cassette Transporter, Subfamily B, Member 1 physiology, Carbonic Anhydrase Inhibitors pharmacology, Carbonic Anhydrases physiology, Neoplasms, Experimental drug therapy
- Abstract
Carbonic anhydrase XII (CAXII) is a membrane enzyme that maintains pH homeostasis and sustains optimum P-glycoprotein (Pgp) efflux activity in cancer cells. Here, we investigated a panel of eight CAXII inhibitors (compounds 1-8), for their potential to reverse Pgp mediated tumor cell chemoresistance. Inhibitors (5 nM) were screened in human and murine cancer cells (colon, lung, breast, bone) with different expression levels of CAXII and Pgp. We identified three CAXII inhibitors (compounds 1, 2 and 4) that significantly (≥ 2 fold) increased the intracellular retention of the Pgp-substrate and chemotherapeutic doxorubicin, and restored its cytotoxic activity. The inhibitors lowered intracellular pH to indirectly impair Pgp activity. Ca12-knockout assays confirmed that the chemosensitizing property of the compounds was dependent on active CAXII. Furthermore, in a preclinical model of drug-resistant breast tumors compound 1 (1900 ng/kg) restored the efficacy of doxorubicin to the same extent as the direct Pgp inhibitor tariquidar. The expression of carbonic anhydrase IX had no effect on the intracellular doxorubicin accumulation. Our work provides strong evidence that CAXII inhibitors are effective chemosensitizer agents in CAXII-positive and Pgp-positive cancer cells. The use of CAXII inhibitors may represent a turning point in combinatorial chemotherapeutic schemes to treat multidrug-resistant tumors. more...
- Published
- 2016
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34. Meeting the Challenge: Using Cytological Profiling to Discover Chemical Probes from Traditional Chinese Medicines against Parkinson's Disease.
- Author
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Wang C, Yang X, Mellick GD, and Feng Y
- Subjects
- Animals, Antiparkinson Agents pharmacology, Cytological Techniques, Drugs, Chinese Herbal pharmacology, Humans, Phytotherapy, Antiparkinson Agents chemistry, Antiparkinson Agents therapeutic use, Drug Discovery, Drugs, Chinese Herbal chemistry, Drugs, Chinese Herbal therapeutic use, Parkinson Disease drug therapy
- Abstract
Parkinson's disease (PD) is an incurable neurodegenerative disorder with a high prevalence rate worldwide. The fact that there are currently no proven disease-modifying treatments for PD underscores the urgency for a more comprehensive understanding of the underlying disease mechanism. Chemical probes have been proven to be powerful tools for studying biological processes. Traditional Chinese medicine (TCM) contains a huge reservoir of bioactive small molecules as potential chemical probes that may hold the key to unlocking the mystery of PD biology. The TCM-sourced chemical approach to PD biology can be advanced through the use of an emerging cytological profiling (CP) technique that allows unbiased characterization of small molecules and their cellular responses. This comprehensive technique, applied to chemical probe identification from TCM and used for studying the molecular mechanisms underlying PD, may inform future therapeutic target selection and provide a new perspective to PD drug discovery. more...
- Published
- 2016
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35. In vitro and ex vivo activity of an Azadirachta indica A.Juss. seed kernel extract on early sporogonic development of Plasmodium in comparison with azadirachtin A, its most abundant constituent.
- Author
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Dahiya N, Chianese G, Abay SM, Taglialatela-Scafati O, Esposito F, Lupidi G, Bramucci M, Quassinti L, Christophides G, Habluetzel A, and Lucantoni L
- Subjects
- Animals, Anopheles, Cell Line, Female, Humans, Malaria transmission, Mice, Inbred BALB C, Seeds chemistry, Antiprotozoal Agents pharmacology, Azadirachta chemistry, Limonins pharmacology, Malaria parasitology, Plant Extracts pharmacology, Plasmodium berghei drug effects
- Abstract
Background: NeemAzal
® (NA) is a quantified extract from seed kernels of neem, Azadirachta indica A.Juss. (Meliaceae), with a wide spectrum of biological properties, classically ascribed to its limonoid content. NA contains several azadirachtins (A to L), azadirachtin A (AzaA) being its main constituent. AzaA has been shown to inhibit microgamete formation of the rodent malaria parasite Plasmodium berghei, and NA was found to completely inhibit the transmission of Plasmodium berghei to Anopheles stephensi mosquitoes when administered to gametocytemic mice at a corresponding AzaA dose of 50mg/kg before exposure to mosquitoes., Purpose: The present study was aimed at i) assessing the pharmacodynamics and duration of action of NA and AzaA against P. berghei exflagellation in systemic circulation in mice and ii) elucidating the transmission blocking activity (TBA) of the main NA constituents., Study Design: The NA and AzaA pharmacodynamics on exflagellation were assessed through ex vivo exflagellation assays, while TBA of NA constituents was evaluated through in vitro ookinete development assay., Methods: Pharmacodynamics experiments: Peripheral blood from P. berghei infected BALB/c mice with circulating mature gametocytes, were treated i.p. with 50mg/kg and 100mg/kg pure AzaA and with NeemAzal® (Trifolio-M GmbH) at the corresponding AzaA concentrations. The effect magnitude and duration of action of compounds was estimated by counting exflagellation centers, formed by microgametocytes in process of releasing flagellated gametes, at various time points after treatment in ex vivo exflagellation tests. Ookinete Development Assay: The direct effects of NeemAzal® and AzaA on ookinete development were measured by fluorescence microscopy after incubation of gametocytemic blood with various concentrations of test substances in microplates for 24h., Results: The exflagellation tests revealed an half-life of NA anti-plasmodial compounds of up to 7h at a NA dose corresponding to 100mg/kg equivalent dose of AzaA. The ookinete development assay showed an increased activity of NA against early sporogonic stages compared to that of AzaA. The IC50 value determined for NA was 6.8µg/ml (CI95 : 5.95-7.86), about half of the AzaA IC50 (12.4µg/ml; CI95 : 11.0-14.04)., Conclusion: The stronger activity of NA, when compared to AzaA, could not be explained by an additive or synergistic effect by other azadirachtins (B, D and I) present in NA. In fact, the addition of these compounds at 50µM concentration to AzaA did not evidence any decrease of the IC50 against early sporogonic stages to that obtained with AzaA alone. It is likely that other non-limonoid compounds present in NA may contribute to AzaA activity and enhanced pharmacodynamics against exflagellation both in vitro and in vivo., (Copyright © 2016. Published by Elsevier GmbH.) more...- Published
- 2016
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36. Erratum to "Profiling the anti-protozoal activity of anti-cancer HDAC inhibitors against Plasmodium and Trypanosoma parasites" [Int. J. Parasitol. Drugs Drug Res. 5 (2015) 117-126].
- Author
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Engel JA, Jones AJ, Avery VM, Sumanadasa SDM, Ng SS, Fairlie DP, Skinner-Adams T, and Andrews KT
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- 2016
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37. Library of diversely substituted 2-(quinolin-4-yl)imidazolines delivers novel non-cytotoxic antitubercular leads.
- Author
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Krasavin M, Mujumdar P, Parchinsky V, Vinogradova T, Manicheva O, and Dogonadze M
- Subjects
- Carbon-13 Magnetic Resonance Spectroscopy, Catalysis, Palladium chemistry, Proton Magnetic Resonance Spectroscopy, Spectrometry, Mass, Electrospray Ionization, Antitubercular Agents administration & dosage, Imidazolines administration & dosage
- Abstract
A novel library based on quinolin-4-ylimidazoline core was designed to incorporate a general quinoline antimicrobial pharmacophore. A synthesis of the well-characterized library of 36 compounds was achieved using the Pd-catalyzed Buchwald-Hartwig-type imidazoline arylation chemistry developed earlier. Compounds were tested for biological activity and were found to possess no antimalarial activity. However, the library delivered two promising antitubercular leads, which are non-cytotoxic and can be further optimized with respect to antimycobacterial potency. more...
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- 2016
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38. Olfactory ensheathing cells but not fibroblasts reduce the duration of autonomic dysreflexia in spinal cord injured rats.
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Cloutier F, Kalincik T, Lauschke J, Tuxworth G, Cavanagh B, Meedeniya A, Mackay-Sim A, Carrive P, and Waite P
- Subjects
- Animals, Autonomic Dysreflexia pathology, Autonomic Dysreflexia physiopathology, Blood Pressure physiology, Cell Survival, Disease Models, Animal, Fibroblasts pathology, Fibroblasts physiology, Heart Rate physiology, Male, Neuroglia pathology, Neuroglia physiology, Neurons pathology, Neurons physiology, Olfactory Mucosa pathology, Olfactory Mucosa physiology, Olfactory Mucosa transplantation, Rats, Wistar, Skin Transplantation, Sympathetic Nervous System pathology, Sympathetic Nervous System physiopathology, Autonomic Dysreflexia therapy, Fibroblasts transplantation, Neuroglia transplantation
- Abstract
Autonomic dysreflexia is a common complication after high level spinal cord injury and can be life-threatening. We have previously shown that the acute transplantation of olfactory ensheathing cells into the lesion site of rats transected at the fourth thoracic spinal cord level reduced autonomic dysreflexia up to 8weeks after spinal cord injury. This beneficial effect was correlated with changes in the morphology of sympathetic preganglionic neurons despite the olfactory cells surviving no longer than 3weeks. Thus the transitory presence of olfactory ensheathing cells at the injury site initiated long-term functional as well as morphological changes in the sympathetic preganglionic neurons. The primary aim of the present study was to evaluate whether olfactory ensheathing cells survive after transplantation within the parenchyma close to sympathetic preganglionic neurons and whether, in this position, they still reduce the duration of autonomic dysreflexia and modulate sympathetic preganglionic neuron morphology. The second aim was to quantify the density of synapses on the somata of sympathetic preganglionic neurons with the hypothesis that the reduction of autonomic dysreflexia requires synaptic changes. As a third aim, we evaluated the cell type-specificity of olfactory ensheathing cells by comparing their effects with a control group transplanted with fibroblasts. Animals transplanted with OECs had a faster recovery from hypertension induced by colorectal distension at 6 and 7weeks but not at 8weeks after T4 spinal cord transection. Olfactory ensheathing cells survived for at least 8weeks and were observed adjacent to sympathetic preganglionic neurons whose overall number of primary dendrites was reduced and the synaptic density on the somata increased, both caudal to the lesion site. Our results showed a long term cell type-specific effects of olfactory ensheathing cells on sympathetic preganglionic neurons morphology and on the synaptic density on their somata, and a transient cell type-specific reduction of autonomic dysreflexia., (Copyright © 2016 Elsevier B.V. All rights reserved.) more...
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- 2016
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39. Targeted knockdown of DJ-1 induces multiple myeloma cell death via KLF6 upregulation.
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Raninga PV, Di Trapani G, Vuckovic S, and Tonissen KF
- Subjects
- Antineoplastic Agents pharmacology, Bortezomib pharmacology, Cell Line, Tumor, Drug Resistance, Neoplasm drug effects, Gene Expression Regulation, Neoplastic, Gene Knockdown Techniques, Humans, Kruppel-Like Factor 6 metabolism, Multiple Myeloma genetics, Multiple Myeloma metabolism, Protein Deglycase DJ-1 metabolism, Up-Regulation, Apoptosis, Kruppel-Like Factor 6 genetics, Multiple Myeloma physiopathology
- Abstract
Multiple myeloma (MM) is an incurable plasma B cell malignancy. Despite recent advancements in anti-MM therapies, development of drug resistance remains a major clinical hurdle. DJ-1, a Parkinson's disease-associated protein, is upregulated in many cancers and its knockdown suppresses tumor growth and overcomes chemoresistance. However, the role of DJ-1 in MM remains unknown. Using gene expression databases we found increased DJ-1 expression in MM patient cells, which correlated with shorter overall survival and poor prognosis in MM patients. Targeted DJ-1 knockdown using siRNAs induced necroptosis in myeloma cells. We found that Krüppel-like factor 6 (KLF6) is expressed at lower levels in myeloma cells compared to PBMCs, and DJ-1 knockdown increased KLF6 expression in myeloma cells. Targeted knockdown of KLF6 expression in DJ-1 knockdown myeloma cells rescued these cells from undergoing cell death. Higher DJ-1 levels were observed in bortezomib-resistant myeloma cells compared to parent cells, and siRNA-mediated DJ-1 knockdown reversed bortezomib resistance. DJ-1 knockdown increased KLF6 expression in bortezomib-resistant myeloma cells, and subsequent siRNA-mediated KLF6 knockdown rescued bortezomib-resistant myeloma cells from undergoing cell death. We also demonstrated that specific siRNA-mediated DJ-1 knockdown reduced myeloma cell growth under a hypoxic microenvironment. DJ-1 knockdown reduced the expression of HIF-1α and its target genes in hypoxic-myeloma cells, and overcame hypoxia-induced bortezomib resistance. Our findings demonstrate that elevated DJ-1 levels correlate with myeloma cell survival and acquisition of bortezomib resistance. Thus, we propose that inhibiting DJ-1 may be an effective therapeutic strategy to treat newly diagnosed as well as relapsed/refractory MM patients. more...
- Published
- 2016
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40. Biological characterization of chemically diverse compounds targeting the Plasmodium falciparum coenzyme A synthesis pathway.
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Fletcher S, Lucantoni L, Sykes ML, Jones AJ, Holleran JP, Saliba KJ, and Avery VM
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- Cell Survival drug effects, Enzyme Inhibitors pharmacology, Inhibitory Concentration 50, Trypanosoma brucei brucei drug effects, Trypanosoma brucei brucei physiology, Trypanosoma cruzi drug effects, Trypanosoma cruzi physiology, Antimalarials pharmacology, Coenzyme A metabolism, Metabolic Networks and Pathways drug effects, Plasmodium falciparum drug effects
- Abstract
Background: In the fight against malaria, the discovery of chemical compounds with a novel mode of action and/or chemistry distinct from currently used drugs is vital to counteract the parasite's known ability to develop drug resistance. Another desirable aspect is efficacy against gametocytes, the sexual developmental stage of the parasite which enables the transmission through Anopheles vectors. Using a chemical rescue approach, we previously identified compounds targeting Plasmodium falciparum coenzyme A (CoA) synthesis or utilization, a promising target that has not yet been exploited in anti-malarial drug development., Results: We report on the outcomes of a series of biological tests that help to define the species- and stage-specificity, as well as the potential targets of these chemically diverse compounds. Compound activity against P. falciparum gametocytes was determined to assess stage-specificity and transmission-reducing potential. Against early stage gametocytes IC
50 values ranging between 60 nM and 7.5 μM were obtained. With the exception of two compounds with sub-micromolar potencies across all intra-erythrocytic stages, activity against late stage gametocytes was lower. None of the compounds were specific pantothenate kinase inhibitors. Chemical rescue profiling with CoA pathway intermediates demonstrated that most compounds acted on either of the two final P. falciparum CoA synthesis enzymes, phosphopantetheine adenylyltransferase (PPAT) or dephospho CoA kinase (DPCK). The most active compound targeted either phosphopantothenoylcysteine synthetase (PPCS) or phosphopantothenoylcysteine decarboxylase (PPCDC). Species-specificity was evaluated against Trypanosoma cruzi and Trypanosoma brucei brucei. No specific activity against T. cruzi amastigotes was observed; however three compounds inhibited the viability of trypomastigotes with sub-micromolar potencies and were confirmed to act on T. b. brucei CoA synthesis., Conclusions: Utilizing the compounds we previously identified as effective against asexual P. falciparum, we demonstrate for the first time that gametocytes, like the asexual stages, depend on CoA, with two compounds exhibiting sub-micromolar potencies across asexual forms and all gametocytes stages tested. Furthermore, three compounds inhibited the viability of T. cruzi and T. b. brucei trypomastigotes with sub-micromolar potencies and were confirmed to act on T. b. brucei CoA synthesis, indicating that the CoA synthesis pathway might represent a valuable new drug target in these parasite species. more...- Published
- 2016
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41. Hit-to-Lead Optimization of a Novel Class of Potent, Broad-Spectrum Trypanosomacides.
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Russell S, Rahmani R, Jones AJ, Newson HL, Neilde K, Cotillo I, Rahmani Khajouei M, Ferrins L, Qureishi S, Nguyen N, Martinez-Martinez MS, Weaver DF, Kaiser M, Riley J, Thomas J, De Rycker M, Read KD, Flematti GR, Ryan E, Tanghe S, Rodriguez A, Charman SA, Kessler A, Avery VM, Baell JB, and Piggott MJ more...
- Subjects
- 14-alpha Demethylase Inhibitors chemical synthesis, 14-alpha Demethylase Inhibitors chemistry, Animals, Humans, Mice, Molecular Structure, Parasitic Sensitivity Tests, Sterol 14-Demethylase metabolism, Structure-Activity Relationship, Trypanocidal Agents chemical synthesis, Trypanocidal Agents chemistry, 14-alpha Demethylase Inhibitors pharmacology, Drug Discovery, Trypanocidal Agents pharmacology, Trypanosoma brucei brucei drug effects, Trypanosoma cruzi drug effects
- Abstract
The parasitic trypanosomes Trypanosoma brucei and T. cruzi are responsible for significant human suffering in the form of human African trypanosomiasis (HAT) and Chagas disease. Drugs currently available to treat these neglected diseases leave much to be desired. Herein we report optimization of a novel class of N-(2-(2-phenylthiazol-4-yl)ethyl)amides, carbamates, and ureas, which rapidly, selectively, and potently kill both species of trypanosome. The mode of action of these compounds is unknown but does not involve CYP51 inhibition. They do, however, exhibit clear structure-activity relationships, consistent across both trypanosome species. Favorable physicochemical parameters place the best compounds in CNS drug-like chemical space but, as a class, they exhibit poor metabolic stability. One of the best compounds (64a) cleared all signs of T. cruzi infection in mice when CYP metabolism was inhibited, with sterile cure achieved in one mouse. This family of compounds thus shows significant promise for trypanosomiasis drug discovery. more...
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- 2016
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42. Increased Serum Levels of IL-17A and IL-23 Are Associated with Decreased Vitamin D3 and Increased Pain in Osteoarthritis.
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Askari A, Naghizadeh MM, Homayounfar R, Shahi A, Afsarian MH, Paknahad A, Kennedy D, and Ataollahi MR
- Subjects
- Adult, Case-Control Studies, Cross-Sectional Studies, Female, Humans, Interleukins blood, Male, Cholecalciferol blood, Interleukin-17 blood, Interleukin-23 blood, Osteoarthritis blood, Osteoarthritis complications, Pain complications
- Abstract
Introduction: Osteoarthritis (OA) is the most common type of arthritis and proinflammatory cytokines have been considered as the main etiologic factor in the pathogenesis of the disease. Serum levels of cytokines, that are associated with innate immunity and TH1 cells, have been analyzed in OA patients, however, there is limited research that profiles cytokines associated with Th17 cells and their relation to vitamin D3 and pain., Material and Methods: The sera from 131 patients with OA and 262 healthy controls were evaluated for serum levels of IL-17A, IL-21, IL-23 and vitamin D3 using ELISA., Results: Serum levels of IL-17A, and IL-23 were statistically higher in OA patients than in healthy controls, while IL-21 and vitamin D3 were significantly lower in OA patients when compared to controls. A significant positive correlation was found between the serum levels of IL-17A and IL-23 using WOMAC pain scores and vitamin D3 serum levels., Discussion: The results suggest that IL-17A plays a significant role in OA pathogenesis and the induction of pain. Decreased serum levels of vitamin D3 may reflect a positive role played by the factor in the regulation of immune responses in OA patients., Competing Interests: The authors have declared that no competing interests exist. more...
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- 2016
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43. Semi-synthesis and NMR spectral assignments of flavonoid and chalcone derivatives.
- Author
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Kumar R, Lu Y, Elliott AG, Kavanagh AM, Cooper MA, and Davis RA
- Subjects
- Anti-Bacterial Agents pharmacology, Chalcones pharmacology, Drug Resistance, Microbial, Flavonoids pharmacology, Fungi drug effects, Magnetic Resonance Spectroscopy, Mass Spectrometry, Microbial Sensitivity Tests, Staphylococcus aureus drug effects, Structure-Activity Relationship, Syzygium chemistry, Chalcones chemical synthesis, Chalcones chemistry, Flavonoids chemical synthesis, Flavonoids chemistry
- Abstract
Previous investigations of the aerial parts of the Australian plant Eremophila microtheca and Syzygium tierneyanum resulted in the isolation of the antimicrobial flavonoid jaceosidin (4) and 2',6'-dihydroxy-4'-methoxy-3',5'-dimethyl chalcone (7), respectively. In this current study, compounds 4 and 7 were derivatized by acetylation, pivaloylation, and methylation reactions. The final products, 5,7,4'-triacetoxy jaceosidin (10), 5,7,4'-tripivaloyloxy jaceosidin (11), 5,7,4'-trimethoxy jaceosidin (12), 2',6'-diacetoxy-4'-methoxy-3',5'-dimethyl chalcone (13), 2'-hydroxy-4'-methoxy-6'-pivaloyloxy-3',5'-dimethyl chalcone (14), and 2'-hydroxy-4',6'-dimethoxy-3',5'-dimethyl chalcone (15) were all fully characterized by NMR and MS. Derivatives 10 and 13 have been previously reported but were only partially characterized. This is the first reported synthesis of 11 and 14. The natural products and their derivatives were evaluated for their antibacterial and antifungal properties, and the natural product, jaceosidin (4) and the acetylated derivative, 5,7,4'-triacetoxy jaceosidin (10), showed modest antibacterial activity (32-128 µg/ml) against Staphylococcus aureus strains. Copyright © 2016 John Wiley & Sons, Ltd., (Copyright © 2016 John Wiley & Sons, Ltd.) more...
- Published
- 2016
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44. Evaluation of NLRC4, NLRP1, and NLRP3, as Components of Inflammasomes, in Chronic Hepatitis B Virus-Infected Patients.
- Author
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Askari A, Nosratabadi R, Khaleghinia M, Zainodini N, Kennedy D, Shabani Z, and Kazemi Arababadi M
- Subjects
- Adult, Alanine Transaminase blood, Aspartate Aminotransferases blood, Bilirubin blood, Biomarkers, Case-Control Studies, DNA, Viral blood, Female, Hepatitis B e Antigens blood, Hepatitis B virus isolation & purification, Hepatitis B, Chronic blood, Hepatitis B, Chronic virology, Humans, Inflammasomes blood, Inflammasomes immunology, Liver pathology, Liver Function Tests, Male, Monocytes metabolism, NLR Proteins, RNA, Messenger metabolism, Real-Time Polymerase Chain Reaction, Viral Load, Adaptor Proteins, Signal Transducing metabolism, Apoptosis Regulatory Proteins metabolism, CARD Signaling Adaptor Proteins metabolism, Calcium-Binding Proteins metabolism, Hepatitis B virus immunology, Hepatitis B, Chronic immunology, Inflammasomes metabolism, NLR Family, Pyrin Domain-Containing 3 Protein metabolism
- Abstract
Nucleotide-binding domain leucine repeats (NLRs) are required for the recognition of various molecules that are expressed within microbes and are able to actuate appropriate immune responses via activation of cytokines. The current study evaluates the expression levels of NLRP1 and NLRC4, which are components of inflammasomes, in chronic hepatitis B (CHB) virus-infected patients. This study recruited two series of CHB patients (each contained 60 patients) and 60 healthy controls. Real-time polymerase chain reaction (PCR) was employed to evaluate mRNA expression levels of NLRP1, NLRP3, and NLRC4 as well as hepatitis B virus (HBV)-DNA copy number. Serum levels of liver markers were also used to evaluate the patients. Hepatitis B envelope antigen (HBeAg) and hepatitis B surface antigen (HBsAg) were also examined in all patients to evaluate infection. The data showed that expression levels of NLRC4 and NLRP1 were not significantly different in circulating monocytes of CHB patients when compared with those of healthy controls. Furthermore, the data indicate that mRNA levels of NLRP1, NLRP3, and NLRC4 were also not altered in CHB patients regardless of HBV-DNA copy numbers/mL and HBeAg status. The data revealed that mRNA expression levels of NLRP1 and NLRC4 were not altered in CHB patients, suggesting that these genes are not responsible for the impaired immune responses against HBV observed in these patients. more...
- Published
- 2016
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45. Open Source Drug Discovery: Highly Potent Antimalarial Compounds Derived from the Tres Cantos Arylpyrroles.
- Author
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Williamson AE, Ylioja PM, Robertson MN, Antonova-Koch Y, Avery V, Baell JB, Batchu H, Batra S, Burrows JN, Bhattacharyya S, Calderon F, Charman SA, Clark J, Crespo B, Dean M, Debbert SL, Delves M, Dennis AS, Deroose F, Duffy S, Fletcher S, Giaever G, Hallyburton I, Gamo FJ, Gebbia M, Guy RK, Hungerford Z, Kirk K, Lafuente-Monasterio MJ, Lee A, Meister S, Nislow C, Overington JP, Papadatos G, Patiny L, Pham J, Ralph SA, Ruecker A, Ryan E, Southan C, Srivastava K, Swain C, Tarnowski MJ, Thomson P, Turner P, Wallace IM, Wells TN, White K, White L, Willis P, Winzeler EA, Wittlin S, and Todd MH more...
- Abstract
The development of new antimalarial compounds remains a pivotal part of the strategy for malaria elimination. Recent large-scale phenotypic screens have provided a wealth of potential starting points for hit-to-lead campaigns. One such public set is explored, employing an open source research mechanism in which all data and ideas were shared in real time, anyone was able to participate, and patents were not sought. One chemical subseries was found to exhibit oral activity but contained a labile ester that could not be replaced without loss of activity, and the original hit exhibited remarkable sensitivity to minor structural change. A second subseries displayed high potency, including activity within gametocyte and liver stage assays, but at the cost of low solubility. As an open source research project, unexplored avenues are clearly identified and may be explored further by the community; new findings may be cumulatively added to the present work. more...
- Published
- 2016
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46. Diversity-oriented synthesis yields novel multistage antimalarial inhibitors.
- Author
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Kato N, Comer E, Sakata-Kato T, Sharma A, Sharma M, Maetani M, Bastien J, Brancucci NM, Bittker JA, Corey V, Clarke D, Derbyshire ER, Dornan GL, Duffy S, Eckley S, Itoe MA, Koolen KM, Lewis TA, Lui PS, Lukens AK, Lund E, March S, Meibalan E, Meier BC, McPhail JA, Mitasev B, Moss EL, Sayes M, Van Gessel Y, Wawer MJ, Yoshinaga T, Zeeman AM, Avery VM, Bhatia SN, Burke JE, Catteruccia F, Clardy JC, Clemons PA, Dechering KJ, Duvall JR, Foley MA, Gusovsky F, Kocken CH, Marti M, Morningstar ML, Munoz B, Neafsey DE, Sharma A, Winzeler EA, Wirth DF, Scherer CA, and Schreiber SL more...
- Subjects
- Animals, Antimalarials administration & dosage, Antimalarials therapeutic use, Azabicyclo Compounds administration & dosage, Azabicyclo Compounds chemical synthesis, Azabicyclo Compounds pharmacology, Azabicyclo Compounds therapeutic use, Azetidines administration & dosage, Azetidines adverse effects, Azetidines pharmacology, Cytosol enzymology, Disease Models, Animal, Female, Liver drug effects, Liver parasitology, Macaca mulatta parasitology, Malaria, Falciparum prevention & control, Malaria, Falciparum transmission, Male, Mice, Phenylalanine-tRNA Ligase antagonists & inhibitors, Phenylurea Compounds administration & dosage, Phenylurea Compounds chemical synthesis, Phenylurea Compounds pharmacology, Phenylurea Compounds therapeutic use, Plasmodium falciparum cytology, Plasmodium falciparum enzymology, Safety, Antimalarials chemical synthesis, Antimalarials pharmacology, Azetidines therapeutic use, Drug Discovery, Life Cycle Stages drug effects, Malaria, Falciparum drug therapy, Plasmodium falciparum drug effects, Plasmodium falciparum growth & development
- Abstract
Antimalarial drugs have thus far been chiefly derived from two sources-natural products and synthetic drug-like compounds. Here we investigate whether antimalarial agents with novel mechanisms of action could be discovered using a diverse collection of synthetic compounds that have three-dimensional features reminiscent of natural products and are underrepresented in typical screening collections. We report the identification of such compounds with both previously reported and undescribed mechanisms of action, including a series of bicyclic azetidines that inhibit a new antimalarial target, phenylalanyl-tRNA synthetase. These molecules are curative in mice at a single, low dose and show activity against all parasite life stages in multiple in vivo efficacy models. Our findings identify bicyclic azetidines with the potential to both cure and prevent transmission of the disease as well as protect at-risk populations with a single oral dose, highlighting the strength of diversity-oriented synthesis in revealing promising therapeutic targets. more...
- Published
- 2016
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47. Mitochondrial changes and oxidative stress in a mouse model of Zellweger syndrome neuropathogenesis.
- Author
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Rahim RS, Chen M, Nourse CC, Meedeniya AC, and Crane DI
- Subjects
- Animals, Blotting, Western, Brain pathology, Cells, Cultured, Disease Models, Animal, Fibroblasts metabolism, Fibroblasts pathology, Fluorescent Antibody Technique, Glial Fibrillary Acidic Protein metabolism, Membrane Proteins deficiency, Membrane Proteins genetics, Mice, Inbred C57BL, Mice, Knockout, Microscopy, Fluorescence, Mitochondria pathology, Neuroglia metabolism, Neuroglia pathology, Superoxide Dismutase metabolism, Tryptophan Hydroxylase metabolism, Zellweger Syndrome pathology, Brain metabolism, Mitochondria metabolism, Oxidative Stress physiology, Zellweger Syndrome metabolism
- Abstract
Zellweger syndrome (ZS) is a peroxisome biogenesis disorder that involves significant neuropathology, the molecular basis of which is still poorly understood. Using a mouse model of ZS with brain-restricted deficiency of the peroxisome biogenesis protein PEX13, we demonstrated an expanded and morphologically modified brain mitochondrial population. Cultured fibroblasts from PEX13-deficient mouse embryo displayed similar changes, as well as increased levels of mitochondrial superoxide and membrane depolarization; this phenotype was rescued by antioxidant treatment. Significant oxidative damage to neurons in brain was indicated by products of lipid and DNA oxidation. Similar overall changes were observed for glial cells. In toto, these findings suggest that mitochondrial oxidative stress and aberrant mitochondrial dynamics are associated with the neuropathology arising from PEX13 deficiency., (Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.) more...
- Published
- 2016
- Full Text
- View/download PDF
48. Evaluation of fermentation conditions triggering increased antibacterial activity from a near-shore marine intertidal environment-associated Streptomyces species.
- Author
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English AL, Boufridi A, Quinn RJ, and Kurtböke DI
- Abstract
A near-shore marine intertidal environment-associated Streptomyces isolate (USC-633) from the Sunshine Coast Region of Queensland, Australia, cultivated under a range of chemically defined and complex media to determine optimal parameters resulting in the secretion of diverse array of secondary metabolites with antimicrobial properties against various antibiotic resistant bacteria. Following extraction, fractioning and re-testing of active metabolites resulted in persistent antibacterial activity against Escherichia coli (Migula) (ATCC 13706) and subsequent Nuclear Magnetic Resonance (NMR) analysis of the active fractions confirmed the induction of metabolites different than the ones in fractions which did not display activity against the same bacterial species. Overall findings again confirmed the value of One Strain-Many Compounds (OSMAC) approach that tests a wide range of growth parameters to trigger bioactive compound secretion increasing the likelihood of finding novel therapeutic agents. The isolate was found to be adaptable to both marine and terrestrial conditions corresponding to its original near-shore marine intertidal environment. Wide variations in its morphology, sporulation and diffusible pigment production were observed when different growth media were used. more...
- Published
- 2016
- Full Text
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49. Expression of the thioredoxin system in an in vivo-like cancer cell environment upon auranofin treatment.
- Author
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Bhatia M, Lovitt CJ, Raninga PV, Avery VM, Di Trapani G, and Tonissen KF
- Subjects
- Breast Neoplasms metabolism, Breast Neoplasms pathology, Cell Hypoxia drug effects, Cell Line, Tumor, Cell Proliferation drug effects, Doxorubicin pharmacology, Female, Humans, Lung Neoplasms metabolism, Lung Neoplasms pathology, Thioredoxin-Disulfide Reductase metabolism, Thioredoxins antagonists & inhibitors, Auranofin pharmacology, Breast Neoplasms drug therapy, Lung Neoplasms drug therapy, Thioredoxins biosynthesis
- Abstract
As essential elements of the tumor microenvironment, the variable oxygenation state of the tumor tissue, the extracellular matrix (ECM) and different cell types are important determinants of carcinogenesis. These elements may also influence how tumor cells respond to therapeutic treatments. In the present study, we assessed the anti-cancer activity of auranofin and its effect on the thioredoxin (Trx) system under conditions that closely resemble the in vivo tumor microenvironment with respect to the oxygen levels and tissue architecture. We utilised an oxygen scheme involving growth of cancer cells under normoxia (20%) and hypoxia (0.1%). We also preconditioned cells with intermittent hypoxia (IH) prior to a prolonged hypoxic incubation. This oxygen scheme did not affect the cytotoxicity of auranofin; however, IH preconditioned cells were less sensitive towards the inhibition of thioredoxin reductase (TrxR) specific activity upon treatment with auranofin. IH preconditioning also upregulated Trx protein levels in auranofin treated cells. We also compared the activity of auranofin against cancer cells cultured in 2D monolayer and 3D spheroid-based culture models. Auranofin was less potent against cells grown under a more in vivo-like 3D environment. The results presented in this paper implicate the importance of the tumor oxygen environment and tissue architecture in influencing the response of cancer cells towards auranofin., (Copyright © 2016 Elsevier GmbH. All rights reserved.) more...
- Published
- 2016
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50. Transmission blocking effects of neem (Azadirachta indica) seed kernel limonoids on Plasmodium berghei early sporogonic development.
- Author
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Tapanelli S, Chianese G, Lucantoni L, Yerbanga RS, Habluetzel A, and Taglialatela-Scafati O
- Subjects
- Animals, Antimalarials isolation & purification, Female, Limonins isolation & purification, Mice, Inbred BALB C, Molecular Structure, Antimalarials pharmacology, Azadirachta chemistry, Limonins pharmacology, Plasmodium berghei drug effects, Seeds chemistry
- Abstract
Azadirachta indica, known as neem tree and traditionally called "nature's drug store" makes part of several African pharmacopeias and is widely used for the preparation of homemade remedies and commercial preparations against various illnesses, including malaria. Employing a bio-guided fractionation approach, molecules obtained from A. indica ripe and green fruit kernels were tested for activity against early sporogonic stages of Plasmodium berghei, the parasite stages that develop in the mosquito mid gut after an infective blood meal. The limonoid deacetylnimbin (3) was identified as one the most active compounds of the extract, with a considerably higher activity compared to that of the close analogue nimbin (2). Pure deacetylnimbin (3) appeared to interfere with transmissible Plasmodium stages at a similar potency as azadirachtin A. Considering its higher thermal and chemical stability, deacetylnimbin could represent a suitable alternative to azadirachtin A for the preparation of transmission blocking antimalarials., (Copyright © 2016 Elsevier B.V. All rights reserved.) more...
- Published
- 2016
- Full Text
- View/download PDF
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