RESUMO
Triboelectrification necessitates a frictional interaction between two materials, and their contact electrification is characteristically based on the polarity variance in the triboelectric series. Utilizing this fundamental advantage of the triboelectric phenomenon, different materials can be identified according to their contact electrification capability. Herein, an in-depth analysis of the amino acids present in the stratum corneum of human skin is performed and these are quantified regarding triboelectric polarization. The principal focus of this study lies in analyzing and identifying the amino acids present in copious amounts in the stratum corneum to explain their positive behavior during the contact electrification process. Thus, an augmented triboelectric series of amino acids with quantified triboelectric charging polarity by scrutinizing the transfer charge, work function, and atomic percentage is presented. Furthermore, the chirality of aspartic acid as it is most susceptible to racemization with clear consequences on the human skin is detected. The study is expected to accelerate research exploiting triboelectrification and provide valuable information on the surface properties and biological activities of these important biomolecules.
Assuntos
Aminoácidos , Ácido Aspártico , Humanos , Epiderme , Pele , Propriedades de SuperfícieRESUMO
The exploration of graphitic carbon nitride (g-C3N4), a two-dimensional (2D) metal-free polymer semiconducting material, is largely discussed due to its large specific surface area, high electrical conductivity, thermal stability, and adaptable electronic structure. The adaption of sulfur (S) and phosphorous (P) atoms into the layers of g-C3N4 increases the electrochemical performance of detecting nilutamide (NT). The aggregation severity can be decreased by integrating S/P into g-C3N4, thereby improving surface area and electrical conductance. The g-C3N4, S/gC3N4, P/g-C3N4, and S/P/g-C3N4 were studied with X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), Field emission scanning electron microscopy (FESEM), Transmission electron microscopy (TEM), Fourier transform infrared (FTIR), Ultraviolet visible spectroscopy (UV), Thermogravimetric analysis (TGA), and Brunauer-Emmett-Teller (BET). The well-assigned S/P/g-C3N4 exhibited a good crystalline structure with more active sites for improved electron transfer toward NT detection. Both differential pulse voltammetry (DPV) and amperometry (IT) was studied for NT detection. The electrochemical studies were done with a linear range of 0.019-1.17 µM to 5.36-1891.98 µM in DPV and 0.01 µM-158.3 µM in IT technique. The attained limit of detection in DPV analysis was 3.2 nM and with IT analysis 2.4 nM. The nanocomposite S/P/g-C3N4 shows good selectivity towards NT. The fabricated electrode showed excellent repeatability, reproducibility, and stability, with a significant recovery range in real sample analysis.
Assuntos
Grafite , Nitrilas , Reprodutibilidade dos Testes , Nitrilas/química , Grafite/químicaRESUMO
The ill effects of prolonged use of rifamycin antibiotics such as rifampicin accentuates its need for detection in the environment as well as in biological fluids. Antibiotics in water and soil are long-lasting, bio-accumulative, and hazardous to aquatic species as well as human health. To address this issue, a sensing platform has been developed using Molybdenum diselenide (MoSe2) embedded on reduced graphene oxide (rGO) functionalized with ß-cyclodextrin (ß-cd) polymer. The formation of hybrid composite was validated with X-ray diffraction analysis (XRD), Raman spectroscopy, fourier transform infrared spectroscopy (FT-IR), X-ray photoelectron spectroscopy (XPS), and field emission scanning electron microscopy (FE-SEM) with EDX analysis. The formation of microspheres were observed with hexagonal crystal system and P63/mmc space group. Furthermore, the composite was employed to fabricate an efficient electrochemical sensor for detecting the widely used antibiotic, rifampicin (RIF). The results reveal excellent activity of the sensor with a limit of detection (LOD) of 28 nM in a linear working range from 0.019 to 374.5 µM. The sensor also exhibited a high sensitivity of 11.64 µA µM-1 cm-2. Additionally, the sensor showed appreciable recovery range when monitored in real-samples such as human serum and urine, and industrial water, and fish samples.
Assuntos
Grafite , beta-Ciclodextrinas , Animais , Antibacterianos , Técnicas Eletroquímicas/métodos , Grafite/química , Humanos , Microesferas , Molibdênio/química , Rifampina , Solo , Espectroscopia de Infravermelho com Transformada de Fourier , ÁguaRESUMO
The modern development in the agricultural production has huge influential factors being highly beneficial and also includes some health hazards. Under the class of chlorophenols, 2,4,6-trichlorophenol is a widely used chemical which remains as a major pollutant in the environment. The detection of 2,4,6-trichlorophenol was initiated as a controlling measure to decrease the seriousness prevailing in the ecosystem. The electrochemical and UV-vis absorption sensing platform are simple and low-cost detection techniques with precise and sensitive analysis. Cadmium tin oxide integrated with the reduced graphene oxide was employed as a nanohybrid for the construction of the working electrode. The structural and morphological analysis confirmed the high degree of crystallinity of the nanocomposite with nanorod formation. The high surface area, with high charge carrier mobility, and increased electrical conductivity of the material boosted the 2,4,6-trichlorophenol detection. The active surface area was calculated to be 0.068 cm-1, 0.089 cm-1, 0.118 cm-1 and 0.146 cm-1 for all the modified electrodes. The resistance of the electrodes was about 91.4 Ω, 72.9 Ω, 48.8 Ω and 41.6 Ω. The linear range of 2,4,6-trichlorophenol was 0.019 µM-0.299 µM and 1.299 µM-1678.97 µM in electrochemical sensing and 10.99 µM-24.84 µM in UV detection. The obtained limit of detection with the formulation 3σ/SD was about 3.05 nM and 80 nM with sensitivity about 14.01 µA µM-1 cm-2. The real sample detection in environmental real samples showed good recovery results. The specific selectivity, good repeatability, reproducibility and stability analysis proves the good sensing parameters. Thus, the fabricated electrode is highly sufficient of sensing 2,4,6-trichlorophenol. These excellent features of the material can be applied for several other applications which will provide good performances.
Assuntos
Clorofenóis , Poluentes Ambientais , Grafite , Nanotubos , Cádmio , Compostos de Cádmio , Ecossistema , Técnicas Eletroquímicas/métodos , Eletrodos , Grafite/química , Nanotubos/química , Óxidos , Fenóis , Reprodutibilidade dos TestesRESUMO
Spinel structured aluminates TAl2O4 (T = Mg, Zn, and Cu) were synthesized by a facile hydrothermal method. The resultant enhancement in the electrochemical behavior was achieved due to the covalent synergism among the elements coexisting together. Structural and morphological characterizations were performed by X-ray diffraction, Fourier transform infrared spectroscopy, Raman spectroscopy, and field emission scanning electron microscopy. MgAl2O4, ZnAl2O4 and CuAl2O4 has displayed same space group Fd3m of Laue class lattice type of the cubic structure as they were synthesized at same temperature (600 °C). CuAl2O4 spinel structure displayed a nanoneedle like structure along with the small sized cylindrical particles alongside to which CuAl2O4 spinel is combined with activated carbon (CuAl/C) and was applied to develop a facile sensor for the electrochemical detection of Acetaminophen (ACAP) using cyclic voltammetry (CV) and differential pulse voltammetry (DPV), which exhibited maximum conductivity, and a substantial electroactive surface area. Finally, the defect-rich composite, CuAl/C, showed excellent sensor performance towards DPV with 21.5 nM limit of detection (LOD) in a wide linear working range of 0.199 µM-165.88 µM ACAP concentration, with a high sensitivity of 19.1221 µA µM-1cm2. Additionally, the sensor showed excellent recovery results in real-time analysis for environmental aquatic samples like industrial wastewater and Tuna Fish.
Assuntos
Óxido de Alumínio , Técnicas Eletroquímicas , Animais , Técnicas Eletroquímicas/métodos , Eletrodos , Óxido de Magnésio , ZincoRESUMO
BACKGROUND: Long-term antiplatelet agents including the potent P2Y12 antagonist ticagrelor are indicated in patients with a previous history of acute coronary syndrome. We sought to compare the effect of ticagrelor with that of aspirin monotherapy on vascular endothelial function in patients with prior acute coronary syndrome. METHODS: This was a prospective, single center, parallel group, investigator-blinded randomized controlled trial. We randomized 200 patients on long-term aspirin monotherapy with prior acute coronary syndrome in a 1:1 fashion to receive ticagrelor 60 mg BD (n=100) or aspirin 100 mg OD (n=100). The primary end point was change from baseline in brachial artery flow-mediated dilation at 12 weeks. Secondary end points were changes to platelet activation marker (CD41_62p) and endothelial progenitor cell (CD34/133) count measured by flow cytometry, plasma level of adenosine, IL-6 (interleukin-6) and EGF (epidermal growth factor), and multi-omics profiling at 12 weeks. RESULTS: After 12 weeks, brachial flow-mediated dilation was significantly increased in the ticagrelor group compared with the aspirin group (ticagrelor: 3.48±3.48% versus aspirin: -1.26±2.85%, treatment effect 4.73 [95% CI, 3.85-5.62], P<0.001). Nevertheless ticagrelor treatment for 12 weeks had no significant effect on platelet activation markers, circulating endothelial progenitor cell count or plasma level of adenosine, IL-6, and EGF (all P>0.05). Multi-omics pathway assessment revealed that changes in the metabolism and biosynthesis of amino acids (cysteine and methionine metabolism; phenylalanine, tyrosine, and tryptophan biosynthesis) and phospholipids (glycerophosphoethanolamines and glycerophosphoserines) were associated with improved brachial artery flow-mediated dilation in the ticagrelor group. CONCLUSIONS: In patients with prior acute coronary syndrome, ticagrelor 60 mg BD monotherapy significantly improved brachial flow-mediated dilation compared with aspirin monotherapy and was associated with significant changes in metabolomic and lipidomic signatures. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03881943.
Assuntos
Síndrome Coronariana Aguda , Intervenção Coronária Percutânea , Adenosina/efeitos adversos , Aspirina/efeitos adversos , Fator de Crescimento Epidérmico , Humanos , Interleucina-6 , Inibidores da Agregação Plaquetária/efeitos adversos , Estudos Prospectivos , Ticagrelor/efeitos adversos , Resultado do TratamentoRESUMO
Transition metal chalcogenides (TMCs) have great potential in diverse electrochemical technologies owing to their unique characteristics. In the present work, we portray the design and synthesis of Vanadium selenide (V2Se9)/reduced graphene oxide (rGO) forming a two-dimensional (2D) hybrid nanocomposite via a simple hydrothermal method. The successfully synthesized nanocomposite underwent in-depth surface and morphological characterizations by XRD, Raman spectroscopy, XPS, TEM, STEM and its potential as an electro catalyst was investigated by using glassy carbon electrode (GCE) for the detection of 2,4,6-trichlorophenol (TCP). The structural features favored a high charge transfer ratio, high surface area as well as excellent conductivity and catalytic activity. The V2Se9/rGO/GCE modified electrode showed a low charge transfer resistance (Rct) of 54.057 Ω cm2, a decent detection limit (LOD) of 35.07 nM and a very high sensitivity of 22 µA µM-1 cm-2 in a working range of 0.001 µM-1150 µM. This is due to the active proton interaction, surface enhancement, and positive synergistic effect between rGO and V2Se9. The proposed sensor has good detection potential in agricultural soil, river water, fish, and beverage samples like wine and apple juice. The obtained results from our investigation would elucidate the application of the catalyst in electrochemical sensors.
Assuntos
Grafite , Nanocompostos , Animais , Eletrodos , VanádioRESUMO
The effect of annealing temperature variance on magnesium ferrites (MgFe2O4) later anchored on reduced graphene oxide (rGO) forming hybrid nanocomposite is demonstrated and its electrochemical performance investigated by using a screen-printed carbon paste electrode (SPCE) for detection of the environmental hazardous phenolic compound 4-cyanophenol (4-CY). The MgFe2O4 (MFO-600 °C) displayed an enhanced charge transfer ratio with high conductivity and electrocatalytic activity. To confirm the structural and morphological parameters of the rGO-MFO-2 hybrid micro/nanocomposite, X-ray diffraction (XRD), Raman spectroscopy, X-ray photoelectron microscopy (XPS), and field-emission electron microscopy (FE-EM) with EDX mapping have been utilized. The rGO/MFO-2/SPCE electrode displayed high catalytic performance in detecting 4-CY with good sensitivity of 6.836 µA µM-1 cm-2 in a working range 0.001 to 700 µM with a limit of detection of 0.0012 µM by using differential pulse voltammetry (DPV). This is achieved for the active interaction between rGO and MFO-2 active surface site areas resulting in good electrochemical activity and high electron transfer rate. Moreover, 4-CY detection has been performed in the presence of various interferents and through real-time analysis in samples like tap water, industrial river water, and fish which resulted in admirable recovery.Graphical abstract.
Assuntos
Técnicas Eletroquímicas/instrumentação , Compostos Férricos/química , Grafite/química , Compostos de Magnésio/química , Fenóis/química , Temperatura , Técnicas Eletroquímicas/métodos , Concentração de Íons de Hidrogênio , Limite de Detecção , Nanocompostos/química , OxirreduçãoRESUMO
The military is experiencing high rates of mental illness, yet service members and veterans with mental health problems often choose not to seek treatment. Based on clinical-psychology models of client-therapist matching and cultural competency, we hypothesized that willingness to seek treatment among military personnel is higher when the potential psychotherapist is a discharged veteran. Seventy-seven military personnel (73% men, 70% White, Mage = 34.2) took part in the study. As hypothesized, the majority of participants indicated that they would prefer to see a psychologist who is a veteran. When responding to vignettes, ratings of the psychotherapist's ability to understand the client (a soldier post-deployment), of his ability to help such a client, and of whether the client should seek treatment from this psychotherapist were higher when the psychotherapist was a veteran compared to when he had no military experience. There were no between-group differences in age, years of service, deployment history, or attitudes toward psychotherapy in general. Similarly, gender and education level had no effect on the results. These findings imply that having the opportunity to receive treatment by a psychotherapist who is a veteran may remove barriers for treatment and encourage more service members and veterans to seek and obtain the help that they need. This can be done by communicating these findings to the military population and by encouraging therapists who have military experience to make this fact known to their potential clients.
RESUMO
BACKGROUND: Peripheral nerve injury (PNI) can result in neurodegenerative changes leading to motor, sensory and autonomic dysfunction. Injury to the rat sciatic nerve is used to model pathophysiologic processes following PNI and assess the efficacy of therapeutic interventions. Frequently, temporal changes in the sciatic functional index (SFI), a measure of sensorimotor integration are measured in rats to assess functional recovery following sciatic nerve injury. However, multiple rat strains and behavioral endpoints have been employed to investigate pathophysiology of PNI and impact of therapeutic intervention on recovery, raising the possibility that rat strain may influence the outcome of such studies. NEW METHOD: The temporal course of recovery from sham, sciatic nerve crush or transection injury was assessed using SFI determined by two methods (footprint and DigiGait), and proprioceptive hind limb placement (a measure of proprioceptive integrity) of the sciatic nerve innervation, in male Sprague Dawley, Lewis, Fischer, Wistar and Long Evans rats. RESULTS: The SFI profile, as assessed by both inked footprint analysis and DigiGait, following sciatic nerve injury was remarkably conserved across strains. Dramatic strain-related differences were observed in the latency to place the crush- or transection-injured hind limb following proprioceptive hind limb stimulation. COMPARISON WITH EXISTING METHOD: The novelty of this study is the parallel comparison of multiple strains using existing and novel tests. CONCLUSION: These results suggest that some sensorimotor function tests may be sensitive to the choice of strain, as evidenced by the differences between SFI and proprioceptive function outcomes.
Assuntos
Traumatismos dos Nervos Periféricos/fisiopatologia , Ratos/fisiologia , Recuperação de Função Fisiológica/fisiologia , Nervo Isquiático/lesões , Animais , Marcha/fisiologia , Membro Posterior/fisiopatologia , Masculino , Atividade Motora/fisiologia , Músculo Esquelético/patologia , Músculo Esquelético/fisiopatologia , Tamanho do Órgão , Traumatismos dos Nervos Periféricos/patologia , Propriocepção/fisiologia , Nervo Isquiático/fisiopatologia , Neuropatia Ciática/patologia , Neuropatia Ciática/fisiopatologia , Especificidade da EspécieRESUMO
Neuregulins are important growth factors involved in cardiac development and response to stress. Certain isoforms and fragments of neuregulin have been found to be cardioprotective. The effects of a full-length neuregulin-1ß isoform, glial growth factor 2 (GGF2; USAN/INN; also called cimaglermin) were investigated in vitro. Various dosing regimens were then evaluated for their effects on left ventricular (LV) function in rats with surgically-induced myocardial infarction. In vitro, GGF2 bound with high affinity to erythroblastic leukemia viral oncogene (ErbB) 4 receptors, potently promoted Akt phosphorylation, as well as reduced cell death following doxorubicin exposure in HL1 cells. Daily GGF2 treatment beginning 7-14 days after left anterior descending coronary artery ligation produced improvements in LV ejection fraction and other measures of LV function and morphology. The improvements in LV function (e.g. 10% point increase in absolute LV ejection fraction) with GGF2 were dose-dependent. LV performance was substantially improved when GGF2 treatment was delivered infrequently, despite a serum half-life of less than 2h and could be maintained for more than 10 months with treatment once weekly or once every 2 weeks. These studies confirm previous findings that GGF2 may improve contractile performance in the failing rat heart and that infrequent exposure to GGF2 may improve LV function and impact remodeling in the failing myocardium. GGF2 is now being developed for the treatment of heart failure in humans.
Assuntos
Ventrículos do Coração/efeitos dos fármacos , Infarto do Miocárdio/fisiopatologia , Neuregulina-1/farmacologia , Disfunção Ventricular/tratamento farmacológico , Sequência de Aminoácidos , Animais , Células CHO , Cricetinae , Cricetulus , Citoproteção/efeitos dos fármacos , Doxorrubicina/efeitos adversos , Esquema de Medicação , Insuficiência Cardíaca/complicações , Humanos , Camundongos , Infarto do Miocárdio/complicações , Neuregulina-1/administração & dosagem , Neuregulina-1/química , Neuregulina-1/metabolismo , Ratos , Receptor ErbB-4/metabolismoRESUMO
BACKGROUND: Neuregulin-1ß (NRG-1ß) is a growth factor critical for cardiac development and repair with therapeutic potential for heart failure. We previously showed that the glial growth factor 2 (GGF2) isoform of NRG-1ß improves cardiac function in rodents after myocardial infarction (MI), but its efficacy in a large animal model of cardiac injury has not been examined. We therefore sought to examine the effects of GGF2 on ventricular remodeling, cardiac function, and global transcription in post-MI swine, as well as potential mechanisms for anti-remodeling effects. METHODS AND RESULTS: MI was induced in anesthetized swine (n=23) by intracoronary balloon occlusion. At 1 week post-MI, survivors (n=13) received GGF2 treatment (intravenous, biweekly for 4 weeks; n=8) or were untreated (n=5). At 5 weeks post-MI, fractional shortening was higher (32.8% versus 25.3%, P=0.019), and left ventricular (LV) end-diastolic dimension lower (4.5 versus 5.3 cm, P=0.003) in GGF2-treated animals. Treatment altered expression of 528 genes, as measured by microarrays, including collagens, basal lamina components, and matricellular proteins. GGF2-treated pigs exhibited improvements in LV cardiomyocyte mitochondria and intercalated disk structures and showed less fibrosis, altered matrix structure, and fewer myofibroblasts (myoFbs), based on trichrome staining, electron microscopy, and immunostaining. In vitro experiments with isolated murine and rat cardiac fibroblasts demonstrate that NRG-1ß reduces myoFbs, and suppresses TGFß-induced phospho-SMAD3 as well as αSMA expression. CONCLUSIONS: These results suggest that GGF2/NRG-1ß prevents adverse remodeling after injury in part via anti-fibrotic effects in the heart.
Assuntos
Insuficiência Cardíaca/tratamento farmacológico , Miocárdio/patologia , Neuregulina-1/farmacologia , Função Ventricular Esquerda/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos , Actinas/metabolismo , Animais , Células Cultivadas , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Fibrose , Regulação da Expressão Gênica/efeitos dos fármacos , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , Contração Miocárdica/efeitos dos fármacos , Miocárdio/metabolismo , Miofibroblastos/efeitos dos fármacos , Miofibroblastos/metabolismo , Miofibroblastos/patologia , Fosforilação , Ratos Sprague-Dawley , Proteína Smad3/metabolismo , Suínos , Fatores de Tempo , Transcrição Gênica/efeitos dos fármacos , Remodelação Ventricular/genéticaRESUMO
AIMS: Recombinant Neuregulin (NRG)-1ß has multiple beneficial effects on cardiac myocytes in culture, and has potential as a clinical therapy for heart failure (HF). A number of factors may influence the effect of NRG-1ß on cardiac function via ErbB receptor coupling and expression. We examined the effect of the NRG-1ß isoform, glial growth factor 2 (GGF2), in rats with myocardial infarction (MI) and determined the impact of high-fat diet as well as chronicity of disease on GGF2 induced improvement in left ventricular systolic function. Potential mechanisms for GGF2 effects on the remote myocardium were explored using microarray and proteomic analysis. METHODS AND RESULTS: Rats with MI were randomized to receive vehicle, 0.625 mg/kg, or 3.25 mg/kg GGF2 in the presence and absence of high-fat feeding beginning at day 7 post-MI and continuing for 4 weeks. Residual left ventricular (LV) function was improved in both of the GGF2 treatment groups compared with the vehicle treated MI group at 4 weeks of treatment as assessed by echocardiography. High-fat diet did not prevent the effects of high dose GGF2. In experiments where treatment was delayed until 8 weeks after MI, high but not low dose GGF2 treatment was associated with improved systolic function. mRNA and protein expression analysis of remote left ventricular tissue revealed a number of changes in myocardial gene and protein expression altered by MI that were normalized by GGF2 treatment, many of which are involved in energy production. CONCLUSIONS: This study demonstrates that in rats with MI induced systolic dysfunction, GGF2 treatment improves cardiac function. There are differences in sensitivity of the myocardium to GGF2 effects when administered early vs. late post-MI that may be important to consider in the development of GGF2 in humans.
Assuntos
Regulação da Expressão Gênica/efeitos dos fármacos , Infarto do Miocárdio/genética , Infarto do Miocárdio/fisiopatologia , Neuregulina-1/farmacologia , Neuregulina-1/uso terapêutico , Função Ventricular Esquerda/efeitos dos fármacos , Animais , Dieta Hiperlipídica , Eletrocardiografia , Fibrose , Glucose/metabolismo , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/patologia , Ventrículos do Coração/fisiopatologia , Humanos , Injeções Intravenosas , Masculino , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/tratamento farmacológico , Miocárdio/metabolismo , Miocárdio/patologia , Neuregulina-1/administração & dosagem , Neuregulina-1/metabolismo , Tamanho do Órgão/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Tomografia por Emissão de Pósitrons , Isoformas de Proteínas/metabolismo , Proteoma/metabolismo , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo Real , Receptores Proteína Tirosina Quinases/metabolismo , Sobrevivência de Tecidos/efeitos dos fármacos , UltrassonografiaRESUMO
Neuregulins are a family of growth factors essential for normal cardiac and nervous system development. The EGF-like domain of neuregulins contains the active site which binds and activates signaling cascades through ErbB receptors. A neuregulin-1 gene EGF-like fragment demonstrated neuroprotection in the transient middle cerebral artery occlusion (MCAO) stroke model and drastically reduced infarct volume (Xu et al., 2004). Here we use a permanent MCAO rat model to initially compare two products of the neuregulin-1 gene and also assess levels of recovery with acute versus delayed time to treatment. In the initial study full-length glial growth factor 2 (GGF2) and an EGF-like domain fragment were compared with acute intravenous delivery. In a second study GGF2 only was delivered starting at 24h, 3 days or 7 days after permanent ischemia was induced. In both studies daily intravenous administration continued for 10 days. Recovery of neurological function was assessed using limb placing and body swing tests. GGF2 had similar functional improvements compared to the EGF-like domain fragment at equimolar doses, and a higher dose of GGF2 demonstrated more robust functional improvements compared to a lower dose. GGF2 improved sensorimotor recovery with all treatment paradigms, even enhancing recovery of function with a delay of 7 days to treatment. Histological assessments did not show any associated reduction in infarct volume at either 48 h or 21 days post-ischemic event. Neurorestorative effects of this kind are of great potential clinical importance, given the difficulty of delivering neuroprotective therapies within a short time after an ischemic event in human patients. If confirmed by additional work including additional data on mechanism(s) of improved outcome with verification in other stroke models, one can make a compelling case to bring GGF2 to clinical trials as a neurorestorative approach to improving outcome following stroke injury.
Assuntos
Ataque Isquêmico Transitório/tratamento farmacológico , Neuregulina-1/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Acidente Vascular Cerebral/tratamento farmacológico , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Infarto Encefálico/tratamento farmacológico , Infarto Encefálico/patologia , Fator de Crescimento Epidérmico/genética , Humanos , Ataque Isquêmico Transitório/patologia , Ataque Isquêmico Transitório/fisiopatologia , Masculino , Neuregulina-1/genética , Estrutura Terciária de Proteína , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/genética , Proteínas Recombinantes/uso terapêutico , Acidente Vascular Cerebral/patologia , Acidente Vascular Cerebral/fisiopatologia , Fatores de TempoRESUMO
Chondroitin sulfate proteoglycans are synthesized and deposited in the spinal cord following injury. These proteoglycans may restrict regeneration and plasticity and contribute to the limited recovery seen after an injury. Chondroitinase, a bacterial enzyme that catalyzes the hydrolysis of the chondroitin chains on proteoglycans, has been shown to improve motor and sensory function following partial transection lesions of the spinal cord. To assess the effects of chondroitinase in a clinically relevant model of spinal cord injury, 128 female Long-Evans rats received either a severe, moderate, or mild contusion injury at the vertebral level T9/T10 with a forceps model and were treated for 2 weeks with chondroitinase ABCI at 0.06 Units per dose, penicillinase, or vehicle control via an intrathecal catheter placed near the injury. Motor behavior was measured by open-field testing of locomotion and bladder function monitored by measuring daily residual urine volumes. Animals treated with chondroitinase showed significant improvements in open-field locomotor activity as measured by the Basso, Beattie and Bresnahan scoring system after both severe and moderate SCI (p<0.05 and 0.01, respectively). No significant locomotor differences were observed in the mild injury group. In the moderate injury group, residual urine volumes were reduced with chondroitinase treatment by 2 weeks after injury (p<0.05) and in the severe injury group, by 6 weeks after injury (NS). These results demonstrate that chondroitinase is effective at promoting both somatic and autonomic motor recovery following a clinically relevant contusion spinal cord injury and is a candidate as a therapeutic for human spinal cord injury.
Assuntos
Fármacos do Sistema Nervoso Autônomo/uso terapêutico , Condroitina ABC Liase/uso terapêutico , Atividade Motora/efeitos dos fármacos , Traumatismos da Medula Espinal/tratamento farmacológico , Animais , Fármacos do Sistema Nervoso Autônomo/farmacologia , Condroitina ABC Liase/farmacologia , Feminino , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Ratos , Ratos Long-Evans , Recuperação de Função Fisiológica/efeitos dos fármacos , Recuperação de Função Fisiológica/fisiologia , Traumatismos da Medula Espinal/fisiopatologia , Vértebras Torácicas , Índices de Gravidade do Trauma , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/fisiopatologiaRESUMO
There is much evidence that the kinase cascade which leads to the phosphorylation of c-jun plays an important signaling role in the mediation of programmed cell death. We have previously shown that c-jun is phosphorylated in a model of induced apoptotic death in dopamine neurons of the substantia nigra in vivo. To determine the generality and functional significance of this response, we have examined c-jun phosphorylation and the effect on cell death of a novel mixed lineage kinase inhibitor, CEP11004, in the 6-hydroxydopamine model of induced apoptotic death in dopamine neurons. We found that expression of total c-jun and Ser73-phosphorylated c-jun is increased in this model and both colocalize with apoptotic morphology. CEP11004 suppresses apoptotic death to levels of 44 and 58% of control values at doses of 1.0 and 3.0 mg/kg, respectively. It also suppresses, to approximately equal levels, the number of profiles positive for the activated form of capase 9. CEP11004 markedly suppresses striatal dopaminergic fiber loss in these models, to only 22% of control levels. We conclude that c-jun phosphorylation is a general feature of apoptosis in living dopamine neurons and that the mixed lineage kinases play a functional role as up-stream mediators of cell death in these neurons.