Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 39
Filtrar
2.
Nat Commun ; 14(1): 8069, 2023 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-38057316

RESUMO

CAR (CARSKNKDC) is a wound-homing peptide that recognises angiogenic neovessels. Here we discover that systemically administered CAR peptide has inherent ability to promote wound healing: wounds close and re-epithelialise faster in CAR-treated male mice. CAR promotes keratinocyte migration in vitro. The heparan sulfate proteoglycan syndecan-4 regulates cell migration and is crucial for wound healing. We report that syndecan-4 expression is restricted to epidermis and blood vessels in mice skin wounds. Syndecan-4 regulates binding and internalisation of CAR peptide and CAR-mediated cytoskeletal remodelling. CAR induces syndecan-4-dependent activation of the small GTPase ARF6, via the guanine nucleotide exchange factor cytohesin-2, and promotes syndecan-4-, ARF6- and Cytohesin-2-mediated keratinocyte migration. Finally, we show that genetic ablation of syndecan-4 in male mice eliminates CAR-induced wound re-epithelialisation following systemic administration. We propose that CAR peptide activates syndecan-4 functions to selectively promote re-epithelialisation. Thus, CAR peptide provides a therapeutic approach to enhance wound healing in mice; systemic, yet target organ- and cell-specific.


Assuntos
Sindecana-4 , Cicatrização , Masculino , Camundongos , Animais , Sindecana-4/genética , Sindecana-4/metabolismo , Cicatrização/fisiologia , Peptídeos/metabolismo , Epiderme/metabolismo , Células Epidérmicas/metabolismo , Movimento Celular
3.
Sci Rep ; 13(1): 15163, 2023 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-37704661

RESUMO

During fatiguing piano tasks, muscle fatigue develops differently between expert pianists. Differences in neuromotor strategies employed could explain a slower rate of fatigue development. The objective was to compare muscle activation and kinematic variabilities between ShortDuration (i.e., pianists with less endurance) and LongDuration groups. Results from 49 pianists showed that EMG activation variability of most shoulder and upper limbs muscles was greater for the ShortDuration group with time during two piano fatiguing tasks, namely Digital and Chord tasks. Segment acceleration variability, assessed using inertial measurement units, was also greater with time for the ShortDuration group at the right arm during the Digital task, and at the thorax and head during the Chord task. Finally, thorax lateroflexion variability increased with time for the LongDuration group (but not the ShortDuration group) during the Digital task. During the Chord task, wrist flexion variability was higher for the LongDuration group compared to the ShortDuration group. These results showed a direct effect of time on the pianists' acceleration variability and EMG activation variability. In contrast, a protective effect of fatigue development could be attributed to kinematic variability. Results also suggest a higher risk of injury among pianists in the ShortDuration group.


Assuntos
Extremidade Superior , Punho , Aceleração , Fadiga Muscular , Músculos
4.
Hum Mov Sci ; 90: 103110, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37295318

RESUMO

Repetitive movements are considered a risk factor for developing practice-related musculoskeletal disorders. Intra-participant kinematic variability might help musicians reduce the risk of injury during repetitive tasks. No research has studied the effects of proximal motion (i.e., trunk and shoulder movement) on upper-limb movement variability in pianists. The first objective was to determine the effect of proximal movement strategies and performance tempo on both intra-participant joint angle variability of upper-limb joints and endpoint variability. The second objective was to compare joint angle variability between pianist's upper-limb joints. As secondary objectives, we assessed the relationship between intra-participant joint angle variability and task range of motion (ROM) and documented inter-participant joint angle variability. The upper body kinematics of 9 expert pianists were recorded using an optoelectronic system. Participants continuously performed two right-hand chords (lateral leap motions) while changing movements based on trunk motion (with and without) and shoulder motion (counter-clockwise, back-and-forth, and clockwise) at two tempi (slow and fast). Trunk and shoulder movement strategies collectively influenced variability at the shoulder, elbow and, to a lesser extent, the wrist. Slow tempi led to greater variability at wrist and elbow flexion/extension compared to fast tempi. Endpoint variability was influenced only along the anteroposterior axis. When the trunk was static, the shoulder had the lowest joint angle variability. When trunk motion was used, elbow and shoulder variability increased, and became comparable to wrist variability. ROM was correlated with intra-participant joint angle variability, suggesting that increased task ROM might result in increased movement variability during practice. Inter-participant variability was approximately six times greater than intra-participant variability. Pianists should consider incorporating trunk motion and a variety of shoulder movements as performance strategies while performing leap motions at the piano, as they might reduce exposure to risks of injury.


Assuntos
Movimento , Extremidade Superior , Humanos , Ombro , Cotovelo , Punho , Fenômenos Biomecânicos
5.
Bioorg Med Chem Lett ; 74: 128942, 2022 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-35973549

RESUMO

The discovery of a dual MAO-B/SSAO inhibitor PXS-5131 is reported. The compound offers a compact and rigid three-dimensional structure with superior selectivity over MAO-A. Potency and selectivity are linked to both the double bond geometry and stereochemistry of the allylamine moiety, highlighting the importance of optimal set up of these features in the class of amine oxidase inhibitors. PXS-5131 possesses an attractive preclinical pharmacokinetic profile and has anti-inflammatory properties in models of acute inflammation and neuroinflammation.


Assuntos
Amina Oxidase (contendo Cobre) , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Monoaminoxidase , Inibidores da Monoaminoxidase/farmacologia
6.
Front Psychol ; 13: 838554, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35719481

RESUMO

Playing the piano at expert levels typically involves significant levels of trial-and-error learning since the majority of practice occurs in isolation. To better optimize musical outcomes, pianists might be well served by emulating some of the practices found in sports, where motor learning strategies are grounded in biomechanics and ergonomics in order to improve performance and reduce risk of performance-related injuries. The purpose of the current study is to examine trunk-hand coordination and preparatory movement strategization in piano performance, while considering the influence of anthropometry, skill level of the performer, and musical context. Using a ten-camera motion capture system, movement of C7 and right-hand distal phalanges was tracked at three different playing speeds during performance of an excerpt from Beethoven's "Appassionata" Sonata. There were three participants: two males and one female of differing anthropometric characteristics and skill levels. Motor strategization was examined. Expertise influenced starting trunk position: Initiation intervals and trunk range of motion (ROM) both suggested anthropometry to be a performance factor. For the shortest performer, trunk movement appeared to be used as an efficiency measure to compensate for a shorter arm reach. Skill level was revealed by examining right-hand velocity at the fastest tempo. The current study hypothesizes that an examination of proximal-to-distal preparatory strategies in terms of anthropometry and skill level can help to optimize motor learning for pianists. To realize piano performance as a whole-body skill and encourage healthy practice, pedagogy needs to educate learners regarding fundamental biomechanical and ergonomic principles, movement optimization, and movement strategization in the service of artful performance.

7.
Phys Ther Sport ; 55: 111-118, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35325670

RESUMO

OBJECTIVES: To investigate if maturity status was associated with injury risk in male academy soccer players. DESIGN: Prospective cohort surveillance study. SETTING: Professional soccer academies. PARTICIPANTS: 501 players (aged 9-23 years) from eight academies in England, Spain, Uruguay and Brazil. MAIN OUTCOME MEASURES: Players were grouped by maturity offset as pre-peak height velocity (PHV), circa-PHV, post-PHV or adult. Injury prevalence proportion (IPP) and days missed were recorded for one season per player, with training/match exposure recorded in a sub-sample (n = 166). RESULTS: IPP for all injuries combined increased with advancing maturity, with circa-PHV (p = 0.032), post-PHV (p < 0.001) and adult (p < 0.001) higher than pre-PHV. IPP was higher in post-PHV and adult than pre-PHV for non-contact (p = 0.001 and p = 0.012), soft-tissue (both p < 0.001), non-contact soft-tissue (p < 0.001 and p = 0.005), muscle (both p < 0.001), thigh (both p < 0.001), ankle (p = 0.035 and p = 0.007) and hamstring injuries (p = 0.041 and p = 0.017). Ligament/tendon IPP was greater in adult versus pre-PHV (p = 0.002). IPP for growth-related injuries was lower in post-PHV than pre-PHV (p = 0.039). Injury incidence rates (n = 166) exhibited similar patterns to IPP in the full cohort. CONCLUSIONS: Injury patterns were similar between post-PHV and adult academy players but, crucially, relatively more of these groups suffered injuries compared to pre- and circa-PHV (except growth-related injuries).


Assuntos
Traumatismos em Atletas , Traumatismos da Perna , Futebol , Traumatismos dos Tendões , Adulto , Traumatismos em Atletas/epidemiologia , Humanos , Incidência , Masculino , Estudos Prospectivos , Futebol/lesões
8.
J Athl Train ; 57(7): 696-703, 2022 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-35142844

RESUMO

CONTEXT: Whether playing position influences injury in male academy soccer players (ASPs) is unclear. OBJECTIVE: To determine if playing position was associated with injury in ASPs. DESIGN: Descriptive epidemiology study. SETTING: English, Spanish, Uruguayan, and Brazilian soccer academies. PATIENTS OR OTHER PARTICIPANTS: A total of 369 ASPs from the under-14 to under-23 age groups, classified as post-peak height velocity using maturity offset, and grouped as goalkeepers, lateral defenders, central defenders, lateral midfielders, central midfielders, or forwards. MAIN OUTCOME MEASURE(S): Injuries were recorded prospectively over 1 season. Injury prevalence proportion (IPP), days missed, and injury incidence rate (IIR, injuries/1000 training or match hours, n = 116) were analyzed according to playing position. RESULTS: No association with playing position was observed for any injury type or location regarding IPP (P ≥ .089) or days missed (P ≥ .235). The IIR was higher in central defenders than in lateral defenders for general (9.30 versus 4.18 injuries/1000 h, P = .009), soft tissue (5.14 versus 1.95 injuries/1000 h, P = .026), and ligament or tendon injuries (2.69 versus 0.56 injuries/1000 h, P = .040). The central versus lateral or forward positions were not associated with IPP (P ≥ .051) or days missed (P ≥ .083), but general IIR was greater in the central position than the lateral or forward positions (8.67 versus 6.12 injuries/1000 h, P = .047). CONCLUSIONS: Academy soccer players' playing positions were not associated with IPP or days missed, but the higher general, soft tissue, and ligament or tendon IIRs in central defenders suggest that this position warrants specific attention regarding injury-prevention strategies. These novel findings highlight the importance of considering training or match exposure when investigating the influence of playing position on injury in ASPs.


Assuntos
Futebol , Brasil , Humanos , Incidência , Masculino , Futebol/lesões
9.
Scand J Med Sci Sports ; 32(2): 338-350, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34633711

RESUMO

It is currently unknown if injury risk is associated with genetic variation in academy soccer players (ASP). We investigated whether nine candidate single nucleotide polymorphisms were associated (individually and in combination) with injury in ASP at different stages of maturation. Saliva samples and one season's injury records were collected from 402 Caucasian male ASP from England, Spain, Uruguay, and Brazil, whose maturity status was defined as pre- or post-peak height velocity (PHV). Pre-PHV COL5A1 rs12722 CC homozygotes had relatively higher prevalence of any musculoskeletal soft tissue (22.4% vs. 3.0%, p = 0.018) and ligament (18.8% vs. 11.8%, p = 0.029) injury than T-allele carriers, while VEGFA rs2010963 CC homozygotes had greater risk of ligament/tendon injury than G-allele carriers. Post-PHV IL6 rs1800795 CC homozygotes had a relatively higher prevalence of any (67.6% vs. 40.6%, p = 0.003) and muscle (38.2% vs. 19.2%, p = 0.013) injuries than G-allele carriers. Relatively more post-PHV EMILIN1 rs2289360 CC homozygotes suffered any injury than CT and TT genotypes (56.4% vs. 40.3% and 32.8%, p = 0.007), while the "protective" EMILIN1 TT genotype was more frequent in post- than pre-PHV ASP (22.3 vs. 10.0%, p = 0.008). Regardless of maturity status, T-alleles of ACTN3 rs1815739 and EMILIN1 rs2289360 were associated with greater absence following ankle injury, while the MMP3 rs679620 T-allele and MYLK rs28497577 GT genotype were associated with greater absence following knee injury. The combination of injury-associated genotypes was greater in injured vs. non-injured ASP. This study is the first to demonstrate that a genetic association exists with injury prevalence in ASP, which differs according to maturity status.


Assuntos
Traumatismos do Joelho , Futebol , Actinina/genética , Alelos , Estatura , Humanos , Masculino , Polimorfismo de Nucleotídeo Único
10.
Front Sports Act Living ; 4: 981755, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36733958

RESUMO

Purpose: The aim of this case report was to describe the sleep responses in a male combat sport athlete, who was engaging in both chronic (CWL) and acute (AWL) weight loss practices in order to reduce body mass for a national competition. Methods: During the first seven weeks of training (Phases 1 and 2), the athlete adhered to a daily energy intake (EI) equating to their resting metabolic rate (1700 kcal·day-1) followed by a reduction in EI (915-300 kcal·day-1) in the 5 days before weighing in (Phase 3). Nocturnal sleep was monitored throughout the 8-week training period using wristwatch actigraphy and frequent measurements of body mass/composition, daily exercise energy expenditure and training load (TL) were taken. Results: The athlete was in a state of low energy availability (LEA) during the entire training period. There was a very large decrease in LEA status during phase 3 compared with phases 1 and 2 (3 vs. 20 kcal·kgFFM·day-1) and there was a small decrease in TL during phase 3 compared with phase 2 (410 vs. 523 AU). The athlete's sleep efficiency increased throughout the training period, but total sleep time displayed a small to moderate decrease in phase 3 compared with phases 1 and 2 (386 vs. 429 and 430 min). However, correlational analysis demonstrated trivial to small, non-significant relationships between sleep characteristics and the athlete's LEA status and TL. Conclusion: These findings suggest that CWL and AWL practices that cause fluctuations in LEA and TL may be implemented without compromising the sleep of combat sport athletes.

12.
Med Probl Perform Art ; 36(3): 141-149, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34464960

RESUMO

One of the greatest challenges in reducing high rates of performance injuries among musicians is in providing them usable tools to address playing-related musculoskeletal problems (PRMP) before they become disorders. Studies in biomechanics have the potential to provide such tools. In order to better understand the mechanisms through which PRMP manifest in pianists, especially in the distal segments of the upper limbs, the current study quantifies wrist internal loading (WIL) and wrist impact loading frequency. It does so while discussing pianists' motor behaviours and observed effort-reduction strategies in the wrists as a function of anthropometry. This concept has great utility for performers. A VICON 3D motion capture system documented two expert pianists performing a B major scale, hands together, at 4, 6, 8, 9, and 10 notes/sec. Biomechanical modeling quantified WIL. Changes in motor behaviour were observed at 8 notes/sec. Individualized anthropometry influenced the range of motor strategies available to each pianist. The pianist with the larger hand span employed a flexion/extension wrist strategy as a compensatory means for effort reduction, while the pianist with the smaller hand span employed a radial/ ulnar deviation strategy. The current study provides a new perspective in addressing PRMP among pianists by rationalizing anthropometric potentials in terms of ergonomic parameters and documenting the availability and utility of effort-reduction strategies in the wrists during piano performance as performers consider PRMP risk and avoidance.


Assuntos
Música , Punho , Fenômenos Biomecânicos , Mãos , Humanos , Articulação do Punho
13.
Percept Mot Skills ; 128(3): 1252-1274, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33775176

RESUMO

Piano performance motor learning research requires more "artful" methodologies if it is to meaningfully address music performance as a corporeal art. To date, research has been sparse and it has typically constrained multiple performance variables in order to isolate specific phenomena. This approach has denied the fundamental ethos of music performance which, for elite performers, is an act of interpretation, not mere reproduction. Piano performances are intentionally manipulated for artistic expression. We documented motor movements in the complex task of performance of the first six measures of Chopin's "Revolutionary" Etude by two anthropometrically different elite pianists. We then discussed their motor strategy selections as influenced by anthropometry and the composer's musical directives. To quantify the joint angles of the trunk, shoulders, elbows, and wrists, we used a VICON 3 D motion capture system and biomechanical modeling. A Kistler force plate (1 N, Swiss) quantified center of gravity (COG) shifts. Changes in COG and trunk angles had considerable influence on the distal segments of the upper limbs. The shorter pianist used an anticipatory strategy, employing larger shifts in COG and trunk angles to produce dynamic stability as compensation for a smaller stature. Both pianists took advantage of low inertial left shoulder internal rotation and adduction to accommodate large leaps in the music. For the right arm, motor strategizing was confounded by rests in the music. These two cases illustrated, in principle, that expert pianists' individualized motor behaviors can be explained as compensatory efforts to accommodate both musical goals and anthropometric constraints. Motor learning among piano students can benefit from systematic attention to motor strategies that consider both of these factors.


Assuntos
Música , Humanos , Movimento , Desempenho Psicomotor
14.
Int J Sports Physiol Perform ; 16(9): 1288-1294, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-33662927

RESUMO

PURPOSE: (1) To compare the sleep of female players from a professional soccer team to nonathlete controls across an in-season week and (2) to compare the sleep of core and fringe players from the same team on the night after a match to training nights. METHODS: Using an observational design, 18 professional female soccer players and 18 female nonathlete controls were monitored for their sleep via wristwatch actigraphy across 1 week. Independent-sample t tests and Mann-Whitney U tests were performed to compare sleep between groups, while an analysis of variance compared sleep on training nights to the night after a match. RESULTS: Soccer players had significantly greater sleep duration than nonathlete controls (+38 min; P = .009; d: 0.92), which may have resulted from an earlier bedtime (-00:31 h:min; P = .047; d: 0.70). The soccer players also had less intraindividual variation in bedtime than nonathletes (-00:08 h:min; P = .023; r: .38). Despite this, sleep-onset latency was significantly longer among soccer players (+8 min; P = .032; d: 0.78). On the night after a match, sleep duration of core players was significantly lower than on training nights (-49 min; P = .010; d: 0.77). In fringe players, there was no significant difference between nights for any sleep characteristic. CONCLUSIONS: During the in-season period, sleep duration of professional female soccer players is greater than nonathlete controls. However, the night after a match challenges the sleep of players with more match involvement and warrants priority of sleep hygiene strategies.


Assuntos
Futebol , Actigrafia , Feminino , Humanos , Estações do Ano , Sono , Higiene do Sono
15.
Phys Ther Sport ; 44: 53-60, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32416582

RESUMO

OBJECTIVES: To identify the most common injury types/locations in high-level male youth soccer players (YSP). DESIGN: Prospective cohort surveillance study. SETTING: Professional soccer club academies. PARTICIPANTS: Six hundred and twenty-four high-level male YSP [Under 9 (U9) to U23 year-old age groups] from academies in England, Spain, Uruguay and Brazil. MAIN OUTCOME MEASURES: Injury type, location and severity were recorded during one season. Injury severity was compared between age groups, while injury type and location were compared between nations. RESULTS: Four hundred and forty-three training or match injuries were recorded, giving an injury rate of 0.71 per player. Non-contact injuries were most common (58.5%), with most (44.2%) resolved between 8 and 28 days. Most injuries (75.4%) occurred in the lower limbs, with muscle (29.6%) the most commonly injured tissue. U14 and U16 suffered a greater number of severe injuries relative to U12 and U19/U20/U23/Reserves. Tendon injury rate was higher in Brazil vs. Spain (p < 0.05), with low back/sacrum/pelvis injury rate highest in Spain (p < 0.05). CONCLUSIONS: The proportion of severe injuries in U14 and U16 suggests YSP injury risk is maturation-dependent. Minimal differences in type and location between high-level YSP from four different countries suggest injury rates in this population are geographically similar.


Assuntos
Traumatismos em Atletas/epidemiologia , Auditoria Clínica , Futebol/lesões , Traumatismos dos Tendões/epidemiologia , Adolescente , Brasil/epidemiologia , Criança , Inglaterra/epidemiologia , Humanos , Incidência , Masculino , Estudos Prospectivos , Espanha/epidemiologia , Uruguai/epidemiologia , Adulto Jovem
16.
Eur J Appl Physiol ; 120(2): 359-368, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31813044

RESUMO

PURPOSE: To investigate the effect of early evening exercise training at different intensities on nocturnal sleep and cardiac autonomic activity in endurance-trained runners. METHODS: Eight runners completed three experimental trials in a randomised, counterbalanced order. In the early evening (end of exercise 3.5 h before bedtime), participants performed either: (i) a 1 h high-intensity interval running session (HIGH, 6 × 5 min at 90% VO2peak interspersed with 5 min recovery); (ii) a 1 h low-intensity running session (LOW, 60 min at 45% VO2peak) or (iii) no exercise (CON). Subsequent nocturnal sleep was assessed using polysomnography, wristwatch actigraphy, and subjective sleep quality. A two-lead electrocardiogram recorded nocturnal cardiac autonomic activity. RESULTS: Total sleep time increased after HIGH (477.4 ± 17.7 min, p = 0.022) and LOW (479.6 ± 15.6 min, p = 0.006) compared with CON (462.9 ± 19.0 min). Time awake was lower after HIGH (31.8 ± 18.5 min, p = 0.047) and LOW (30.4 ± 15.7 min, p = 0.008) compared with CON (46.6 ± 20.0 min). There were no differences between conditions for actigraphy and subjective sleep quality (p > 0.05). Nocturnal heart rate variability was not different between conditions, but average nocturnal heart rate increased after HIGH (50 ± 5 beats min-1) compared with LOW (47 ± 5 beats min-1, p = 0.02) and CON (47 ± 5 beats min-1, p = 0.028). CONCLUSION: When performed in the early evening, high-intensity exercise does not disrupt and may even improve subsequent nocturnal sleep in endurance-trained runners, despite increased cardiac autonomic activity. Additionally, low-intensity exercise induced positive changes in sleep behaviour that are comparable to those obtained following high-intensity exercise.


Assuntos
Ritmo Circadiano/fisiologia , Exercício Físico , Resistência Física , Corrida/fisiologia , Sono/fisiologia , Esportes , Actigrafia , Adulto , Humanos , Masculino , Polissonografia , Fatores de Tempo , Adulto Jovem
17.
Int J Hematol ; 110(6): 699-708, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31637674

RESUMO

Primary myelofibrosis (PMF) is a chronic myeloproliferative neoplasm (MPN) that usually portends a poor prognosis with limited therapeutic options available. Currently, only allogeneic stem cell transplantation is curative in those who are candidates, while administration of the JAK1/2 inhibitor ruxolitinib carries a risk of worsening cytopenia. The limited therapeutic options available highlight the need for the development of novel treatments for PMF. Lysyl oxidase (LOX), an enzyme vital for collagen cross-linking and extracellular matrix stiffening, has been found to be upregulated in PMF. Herein, we evaluate two novel LOX inhibitors, PXS-LOX_1 and PXS-LOX_2, in two animal models of PMF (GATA1low and JAK2V617F-mutated mice). Specifically, PXS-LOX_1 or vehicle was given to 15- to 16-week-old GATA1low mice via intraperitoneal injection at a dose of 15 mg/kg four times a week for 9 weeks. PXS-LOX_1 was found to significantly decrease the bone marrow fibrotic burden and megakaryocyte number compared to vehicle in both male and female GATA1low mice. Given these results, PXS-LOX_1 was then tested in 15- to 17-week-old JAK2V617F-mutated mice at a dose of 30 mg/kg four times a week for 8 weeks. Again, we observed a significant decrease in bone marrow fibrotic burden. PXS-LOX_2, a LOX inhibitor with improved oral bioavailability, was next evaluated in 15- to 17-week-old JAK2V617F-mutated mice at a dose of 5 mg/kg p.o. four times a week for 8 weeks. This inhibitor also resulted in a significant decrease in bone marrow fibrosis, albeit with a more pronounced amelioration in female mice. Taking these results together, PXS-LOX_1 and PXS-LOX_2 appear to be promising new candidates for the treatment of fibrosis in PMF.


Assuntos
Inibidores Enzimáticos/farmacologia , Mielofibrose Primária/tratamento farmacológico , Proteína-Lisina 6-Oxidase/antagonistas & inibidores , Animais , Disponibilidade Biológica , Neoplasias da Medula Óssea , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/uso terapêutico , Feminino , Masculino , Camundongos , Fatores Sexuais , Resultado do Tratamento
18.
J Med Chem ; 62(21): 9874-9889, 2019 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-31580073

RESUMO

Lysyl oxidase-like 2 (LOXL2) is a secreted enzyme that catalyzes the formation of cross-links in extracellular matrix proteins, namely, collagen and elastin, and is indicated in fibrotic diseases. Herein, we report the identification and subsequent optimization of a series of indole-based fluoroallylamine inhibitors of LOXL2. The result of this medicinal chemistry campaign is PXS-5120A (12k), a potent, irreversible inhibitor that is >300-fold selective for LOXL2 over LOX. PXS-5120A also shows potent inhibition of LOXL3, an emerging therapeutic target for lung fibrosis. Key to the development of this compound was the utilization of a compound oxidation assay. PXS-5120A was optimized to show negligible substrate activity in vitro for related amine oxidase family members, leading to metabolic stability. PXS-5120A, in a pro-drug form (PXS-5129A, 12o), displayed anti-fibrotic activity in models of liver and lung fibrosis, thus confirming LOXL2 as an important target in diseases where collagen cross-linking is implicated.


Assuntos
Aminas/química , Aminas/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Proteína-Lisina 6-Oxidase/antagonistas & inibidores , Animais , Desenho de Fármacos , Humanos , Camundongos , Triazóis/química
19.
J Cell Mol Med ; 23(3): 1759-1770, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30536539

RESUMO

Fibrosis is characterized by the excessive deposition of extracellular matrix and crosslinked proteins, in particular collagen and elastin, leading to tissue stiffening and disrupted organ function. Lysyl oxidases are key players during this process, as they initiate collagen crosslinking through the oxidation of the ε-amino group of lysine or hydroxylysine on collagen side-chains, which subsequently dimerize to form immature, or trimerize to form mature, collagen crosslinks. The role of LOXL2 in fibrosis and cancer is well documented, however the specific enzymatic function of LOXL2 and LOXL3 during disease is less clear. Herein, we describe the development of PXS-5153A, a novel mechanism based, fast-acting, dual LOXL2/LOXL3 inhibitor, which was used to interrogate the role of these enzymes in models of collagen crosslinking and fibrosis. PXS-5153A dose-dependently reduced LOXL2-mediated collagen oxidation and collagen crosslinking in vitro. In two liver fibrosis models, carbon tetrachloride or streptozotocin/high fat diet-induced, PXS-5153A reduced disease severity and improved liver function by diminishing collagen content and collagen crosslinks. In myocardial infarction, PXS-5153A improved cardiac output. Taken together these results demonstrate that, due to their crucial role in collagen crosslinking, inhibition of the enzymatic activities of LOXL2/LOXL3 represents an innovative therapeutic approach for the treatment of fibrosis.


Assuntos
Aminoácido Oxirredutases/antagonistas & inibidores , Colágeno/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Fibrose/prevenção & controle , Infarto do Miocárdio/prevenção & controle , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Animais , Tetracloreto de Carbono/toxicidade , Colágeno/efeitos dos fármacos , Colágeno/metabolismo , Reagentes de Ligações Cruzadas/química , Elastina/antagonistas & inibidores , Elastina/efeitos dos fármacos , Elastina/metabolismo , Matriz Extracelular/efeitos dos fármacos , Fibrose/induzido quimicamente , Fibrose/enzimologia , Fibrose/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/enzimologia , Infarto do Miocárdio/patologia , Hepatopatia Gordurosa não Alcoólica/enzimologia , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/patologia , Ratos , Ratos Wistar
20.
Eur J Sport Sci ; 19(5): 576-584, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30355269

RESUMO

The current study examined how sleep may be influenced by the scheduling of training and match load within 10 youth-soccer players. Sleep was measured over a 14-day in-season period using a commercially available wireless sleep monitor. Each collected sleep variable; lights out, sleep latency, total sleep time wake after sleep onset and final awakening, was compared for the specific day within the training schedule (e.g. match day [MD], day after match [MD + 1]) and to training/match load (high-speed distance (>5.5 m/s) [HSD] and rating of perceived exertion. The data were analysed using mixed models and effect sizes, to describe the magnitude of effects that training schedule and training load may have on sleep. A reduction of sleep duration was observed on the day after the match (MD + 1) in relation to the training days preceding the match (MD-2: -65 min, ES: 0.89 ± 0.79; MD-1 -61 min, ES: 0.82 ± 0.64) and reduction on match day (+45 min; ES: 1.91 ± 1.69). This may suggest youth-soccer players actively change their sleep scheduling behaviours in relation to the imposed soccer schedule. Increased high-speed running (for every 100 m) showed a small increase to total sleep time (+9 min; ES: 0.48 ± 0.31). This may suggest that increases in training load may be associated with small increases in sleep quantity. Such observations may highlight that the type of day and the associated load within the training microcycle may have important consequences for sleep within youth-soccer players.


Assuntos
Condicionamento Físico Humano , Sono , Carga de Trabalho , Adolescente , Atletas , Humanos , Masculino , Futebol , Adulto Jovem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA