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1.
J Sci Med Sport ; 25(8): 661-666, 2022 Aug.
Article in English | MEDLINE | ID: mdl-35715303

ABSTRACT

OBJECTIVES: The aim of this study was to analyse the association between physical activity and motor competence in primary school children using traditional and compositional data analysis approaches over time (time 1 and time 2). DESIGN: A longitudinal observational design was used to study 124 typically developed children (45.2% girls), 5-10 years old at baseline. METHODS: Children's objectively measured physical activity and sedentary behaviour, actual and perceived motor competence were assessed at two time points, one year apart. Longitudinal association of movement behaviors with actual and perceived motor competence, in locomotion, ball skills and overall motor competence was explored using structural equation models, compositional analysis, and isotemporal substitution. RESULTS: When adjusted for sex, age, and body mass index, structural equation models and the composition consistently predicted actual and perceived motor competence at time 1 and time 2 (p < 0.01). Reallocation of 10 min from sedentary to light, or to moderate-to-vigorous physical activity, was associated with changes in actual motor competence, which was consistent from time 1 to time 2. Additionally, regarding self-perception, in time 1, isotemporal substitution of sedentary to light physical activity was the only reallocation associated with increases in perceived motor competence. In time 2, however, such positive associations were only found when reallocating time from sedentary or light to moderate-to-vigorous physical activity. CONCLUSIONS: Achieving adequate levels of moderate-to-vigorous physical activity, at the expense of sedentary and light physical activity, is associated with increases of actual and perceived motor competence over time.


Subject(s)
Exercise , Sedentary Behavior , Accelerometry , Body Mass Index , Child , Child, Preschool , Cross-Sectional Studies , Female , Humans , Male , Motor Skills , Movement
2.
Clin Rehabil ; 36(8): 1016-1031, 2022 Aug.
Article in English | MEDLINE | ID: mdl-35535548

ABSTRACT

OBJECTIVE: To investigate the effects of whole body vibration on chronic ankle instability-associated sensorimotor deficits in balance, strength, joint position sense and muscle activity. DATA SOURCES: Electronic databases including Cochrane Library, PubMed, Embase, Web of Science, EBSCO, China National Knowledge Infrastructure and WanFang were searched from database inception up to 31 March 2022. METHODS: The risk of bias and methodological quality of included studies were assessed using the Cochrane tool and Physiotherapy Evidence Database (PEDro) scale respectively. Standardized mean difference (SMD) and mean differences (MD) with 95% confidence interval (CI) were calculated using the RevMan 5.3 software. Meta-regression was conducted with Stata 16. RESULTS: Eight studies, with 315 subjects were eventually included in this review with an average PEDro score of 6.1/10. Significant effects of whole body vibration on balance (SMD = 0.61, 95% CI: 0.12 to 1.09, P = 0.01), and on the posterolateral direction (MD = 5.52, 95% CI: 1.02 to 10.01, P = 0.02) and medial direction (MD = 3.90, 95% CI: 0.87 to 6.94, P = 0.01) of the star excursion balance test were found. Whole body vibration significantly improved the peak torque (SMD = 0.36, 95% CI: 0.04 to 0.69, P = 0.03), joint position sense (SMD = 0.60, 95% CI: 0.10 to 1.11, P = 0.02), and muscle activity in tibialis anterior (SMD = 0.46, 95% CI: 0.04 to 0.88, P = 0.03) and gastrocnemius (SMD = 0.68, 95% CI: 0.14 to 1.23, P = 0.01). CONCLUSIONS: The current evidence supports the use of whole body vibration to improve sensorimotor deficits involving balance, strength, joint position sense, and muscle activity in people with chronic ankle instability.


Subject(s)
Joint Instability , Vibration , Ankle , Humans , Joint Instability/etiology , Muscle, Skeletal , Physical Therapy Modalities , Vibration/therapeutic use
4.
Angew Chem Weinheim Bergstr Ger ; 128(22): 6511-6515, 2016 May 23.
Article in English | MEDLINE | ID: mdl-27397940

ABSTRACT

In spite of the recent increase in endoperoxide antimalarials under development, it remains unclear if all these chemotypes share a common mechanism of action. This is important since it will influence cross-resistance risks between the different classes. Here we investigate this proposition using novel clickable 1,2,4-trioxolane activity based protein-profiling probes (ABPPs). ABPPs with potent antimalarial activity were able to alkylate protein target(s) within the asexual erythrocytic stage of Plasmodium falciparum (3D7). Importantly, comparison of the alkylation fingerprint with that generated from an artemisinin ABPP equivalent confirms a highly conserved alkylation profile, with both endoperoxide classes targeting proteins in the glycolytic, hemoglobin degradation, antioxidant defence, protein synthesis and protein stress pathways, essential biological processes for plasmodial survival. The alkylation signatures of the two chemotypes show significant overlap (ca. 90 %) both qualitatively and semi-quantitatively, suggesting a common mechanism of action that raises concerns about potential cross-resistance liabilities.

5.
Angew Chem Int Ed Engl ; 55(22): 6401-5, 2016 05 23.
Article in English | MEDLINE | ID: mdl-27089538

ABSTRACT

In spite of the recent increase in endoperoxide antimalarials under development, it remains unclear if all these chemotypes share a common mechanism of action. This is important since it will influence cross-resistance risks between the different classes. Here we investigate this proposition using novel clickable 1,2,4-trioxolane activity based protein-profiling probes (ABPPs). ABPPs with potent antimalarial activity were able to alkylate protein target(s) within the asexual erythrocytic stage of Plasmodium falciparum (3D7). Importantly, comparison of the alkylation fingerprint with that generated from an artemisinin ABPP equivalent confirms a highly conserved alkylation profile, with both endoperoxide classes targeting proteins in the glycolytic, hemoglobin degradation, antioxidant defence, protein synthesis and protein stress pathways, essential biological processes for plasmodial survival. The alkylation signatures of the two chemotypes show significant overlap (ca. 90 %) both qualitatively and semi-quantitatively, suggesting a common mechanism of action that raises concerns about potential cross-resistance liabilities.


Subject(s)
Antimalarials/pharmacology , Artemisinins/pharmacology , Heterocyclic Compounds/pharmacology , Plasmodium falciparum/drug effects , Proteins/chemical synthesis , Proteomics , Alkylation , Antimalarials/chemical synthesis , Antimalarials/chemistry , Artemisinins/chemistry , Click Chemistry , Heterocyclic Compounds/chemistry , Molecular Structure , Parasitic Sensitivity Tests , Proteins/chemistry
6.
Proc Natl Acad Sci U S A ; 113(8): 2080-5, 2016 Feb 23.
Article in English | MEDLINE | ID: mdl-26858419

ABSTRACT

The artemisinin (ART)-based antimalarials have contributed significantly to reducing global malaria deaths over the past decade, but we still do not know how they kill parasites. To gain greater insight into the potential mechanisms of ART drug action, we developed a suite of ART activity-based protein profiling probes to identify parasite protein drug targets in situ. Probes were designed to retain biological activity and alkylate the molecular target(s) of Plasmodium falciparum 3D7 parasites in situ. Proteins tagged with the ART probe can then be isolated using click chemistry before identification by liquid chromatography-MS/MS. Using these probes, we define an ART proteome that shows alkylated targets in the glycolytic, hemoglobin degradation, antioxidant defense, and protein synthesis pathways, processes essential for parasite survival. This work reveals the pleiotropic nature of the biological functions targeted by this important class of antimalarial drugs.


Subject(s)
Antimalarials , Artemisinins , Lactones , Life Cycle Stages/drug effects , Molecular Probes , Plasmodium falciparum/metabolism , Protozoan Proteins , Antimalarials/chemical synthesis , Antimalarials/chemistry , Antimalarials/pharmacology , Artemisinins/chemical synthesis , Artemisinins/chemistry , Artemisinins/pharmacology , Click Chemistry , Humans , Lactones/chemical synthesis , Lactones/chemistry , Lactones/pharmacology , Molecular Probes/chemical synthesis , Molecular Probes/chemistry , Molecular Probes/pharmacology , Protozoan Proteins/antagonists & inhibitors , Protozoan Proteins/metabolism
7.
J Med Chem ; 53(22): 8202-6, 2010 Nov 25.
Article in English | MEDLINE | ID: mdl-20979352

ABSTRACT

We extend our approach of combination chemotherapy through a single prodrug entity (O'Neill et al. Angew. Chem., Int. Ed. 2004, 43, 4193) by using a 1,2,4-trioxolane as a protease inhibitor carbonyl-masking group. These molecules are designed to target the malaria parasite through two independent mechanisms of action: iron(II) decomposition releases the carbonyl protease inhibitor and potentially cytotoxic C-radical species in tandem. Using a proposed target "heme", we also demonstrate heme alkylation/carbonyl inhibitor release and quantitatively measure endoperoxide turnover in parasitized red blood cells.


Subject(s)
Antimalarials/chemical synthesis , Chalcones/chemical synthesis , Cysteine Endopeptidases/metabolism , Cysteine Proteinase Inhibitors/chemical synthesis , Peroxides/chemical synthesis , Prodrugs/chemical synthesis , Antimalarials/chemistry , Antimalarials/pharmacology , Chalcones/chemistry , Chalcones/pharmacology , Cysteine Proteinase Inhibitors/chemistry , Cysteine Proteinase Inhibitors/pharmacology , Erythrocytes/drug effects , Erythrocytes/parasitology , Inhibitory Concentration 50 , Models, Molecular , Peroxides/chemistry , Peroxides/pharmacology , Plasmodium falciparum/drug effects , Prodrugs/chemistry , Prodrugs/pharmacology , Structure-Activity Relationship
9.
Curr Opin Chem Biol ; 14(4): 440-6, 2010 Aug.
Article in English | MEDLINE | ID: mdl-20570550

ABSTRACT

The cytochrome bc(1) complex is a key mitochondrial enzyme that catalyses transfer of electrons maintaining the membrane potential of mitochondria. Currently, atovaquone is the only drug in clinical use targeting the Plasmodium falciparum bc(1) complex. The rapid emergence of resistance to atovaquone resulted in a costly combination with proguanil (Malarone), limiting its widespread use in resource-poor disease-endemic areas. Cheaper alternatives that can overcome resistance are desperately required. Here we describe recent advances of bc(1)-targeted inhibitors that include hydroxynaphthoquinones (atovaquone analogues), pyridones (clodipol analogues), acridine related compounds (acridinediones and acridones) and quinolones. Significantly, many of these developmental compounds demonstrate little cross resistance with atovaquone-resistant parasite strains, and selected classes have excellent oral activity profiles in rodent models of malaria.


Subject(s)
Antimalarials/pharmacology , Electron Transport Complex III/antagonists & inhibitors , Plasmodium falciparum/enzymology , Animals , Atovaquone/pharmacology , Models, Molecular , Protein Conformation
10.
J Med Chem ; 53(11): 4555-9, 2010 Jun 10.
Article in English | MEDLINE | ID: mdl-20476788

ABSTRACT

The semisynthetic artemisinin derivatives such as artesunate and artemether, along with the fully synthetic endoperoxide antimalarials (e.g., OZ277, Nature 2004, 430, 900-904), are believed to mediate their antimalarial effects by iron-induced formation of carbon-centered radicals capable of alkylating heme and/or protein. Here, we describe the design and synthesis of a series of biotinylated endoperoxide probe molecules for use in proteomic studies. The target molecules include derivatives of the artemisinin and OZ families, and we demonstrate that these conjugates express nanomolar in vitro activity versus cultured strains of Plasmodium falciparum. We also describe the synthesis of chemically cleavable linked conjugates designed to enable mild elution of labeled proteins during target protein identification.


Subject(s)
Antimalarials/chemical synthesis , Antimalarials/pharmacology , Carbon/chemistry , Drug Design , Prodrugs/chemistry , Prodrugs/chemical synthesis , Proteomics/methods , Antimalarials/chemistry , Antimalarials/metabolism , Artemisinins/chemical synthesis , Artemisinins/chemistry , Artemisinins/metabolism , Artemisinins/pharmacology , Biotinylation , Inhibitory Concentration 50 , Plasmodium falciparum/drug effects , Prodrugs/metabolism
11.
Molecules ; 15(3): 1705-21, 2010 Mar 12.
Article in English | MEDLINE | ID: mdl-20336009

ABSTRACT

Despite international efforts to 'roll back malaria' the 2008 World Malaria Report revealed the disease still affects approximately 3 billion people in 109 countries; 45 within the WHO African region. The latest report however does provide some 'cautious optimism'; more than one third of malarious countries have documented greater than 50% reductions in malaria cases in 2008 compared to 2000. The goal of the Member States at the World Health Assembly and 'Roll Back Malaria' (RBM) partnership is to reduce the numbers of malaria cases and deaths recorded in 2000 by 50% or more by the end of 2010. Although malaria is preventable it is most prevalent in poorer countries where prevention is difficult and prophylaxis is generally not an option. The burden of disease has increased by the emergence of multi drug resistant (MDR) parasites which threatens the use of established and cost effective antimalarial agents. After a major change in treatment policies, artemisinins are now the frontline treatment to aid rapid clearance of parasitaemia and quick resolution of symptoms. Since artemisinin and its derivatives are eliminated rapidly, artemisinin combination therapies (ACT's) are now recommended to delay resistance mechanisms. In spite of these precautionary measures reduced susceptibility of parasites to the artemisinin-based component of ACT's has developed at the Thai-Cambodian border, a historical 'hot spot' for MDR parasite evolution and emergence. This development raises serious concerns for the future of the artemsinins and this is not helped by controversy related to the mode of action. Although a number of potential targets have been proposed the actual mechanism of action remains ambiguous. Interestingly, artemisinins have also shown potent and broad anticancer properties in cell lines and animal models and are becoming established as anti-schistosomal agents. In this review we will discuss the recent evidence explaining bioactivation and potential molecular targets in the chemotherapy of malaria and cancer.


Subject(s)
Antimalarials/pharmacology , Artemisinins/pharmacology , Plasmodium falciparum/drug effects , Animals , Electrophoresis, Polyacrylamide Gel
12.
Bioorg Med Chem Lett ; 19(7): 2038-43, 2009 Apr 01.
Article in English | MEDLINE | ID: mdl-19251414

ABSTRACT

A novel series of semi-synthetic trioxaquines and synthetic trioxolaquines were prepared, in moderate to good yields. Antimalarial activity was evaluated against both the chloroquine-sensitive 3D7 and resistant K1 strain of Plasmodium falciparum and both series of compounds were shown to be active in the low nanomolar range. For comparison the corresponding 9-amino acridine analogues were also prepared and shown to have low nanomolar activity like their quinoline counterparts.


Subject(s)
Antimalarials/chemical synthesis , Peroxides/chemistry , Plasmodium falciparum/drug effects , Quinolines/chemical synthesis , Aminacrine/chemical synthesis , Aminacrine/chemistry , Animals , Antimalarials/chemistry , Antimalarials/pharmacology , Artemisinins/chemical synthesis , Artemisinins/chemistry , Peroxides/chemical synthesis , Quinolines/chemistry , Quinolines/pharmacology , Structure-Activity Relationship
14.
Endocrinology ; 144(8): 3406-14, 2003 Aug.
Article in English | MEDLINE | ID: mdl-12865319

ABSTRACT

IL-11 is a member of the gp130 family of cytokines, which signal via assembly of multisubunit receptor complexes containing at least one molecule of the transmembrane signaling receptor gp130. IL-11 forms a high-affinity complex, thereby inducing gp130-dependent signaling. Previous studies have identified three distinct receptor binding sites, I, II, and III, crucial for the binding of murine IL-11 (mIL-11) to both the IL-11R and gp130. In this study, we have further characterized the role of the mIL-11 site III mutant W147A. We show that W147A is a high-affinity specific antagonist of mIL-11-mediated signaling in gp130/IL-11R-transfected Ba/F3 cells. The antagonistic action of W147A is due to its ability to competitively disrupt multimeric gp130/IL-11R signaling complex formation. We also show that W147A inhibits IL-11-mediated signaling in primary human endometrial cells, thus demonstrating the potential utility of W147A in suppressing IL-11 responses in vivo.


Subject(s)
Interleukin-11/metabolism , Receptors, Interleukin/genetics , Animals , Antigens, CD/genetics , Antigens, CD/metabolism , Binding Sites/genetics , Cell Line , Cells, Cultured , Cytokine Receptor gp130 , DNA-Binding Proteins/metabolism , Endometrium/metabolism , Female , Gene Expression , Humans , Interleukin-11/pharmacology , Interleukin-11 Receptor alpha Subunit , Membrane Glycoproteins/genetics , Membrane Glycoproteins/metabolism , Mice , Mutation , Phosphorylation , Phosphotyrosine/metabolism , Receptors, Interleukin/physiology , Receptors, Interleukin-11 , STAT3 Transcription Factor , Signal Transduction , Trans-Activators/metabolism , Transfection
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