Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 3.440
Filtrar
1.
Molecules ; 26(5)2021 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-33668340

RESUMO

Sigma-1 (σ-1) receptor agonists are considered as potential treatment for stroke. TS-157 is an alkoxyisoxazole-based σ-1 receptor agonist previously discovered in our group. The present study describes TS-157 profile in a battery of tests for cerebral ischemia. Initial evaluation demonstrated the compound's safety profile and blood-brain barrier permeability, as well as its ability to induce neurite outgrowth in vitro. The neurite outgrowth was shown to be mediated via σ-1 receptor agonism and involves upregulation of ERK phosphorylation (pERK). In particular, TS-157 also significantly accelerated the recovery of motor function in rats with transient middle cerebral artery occlusion (tMCAO). Overall, the results herein support the notion that σ-1 receptor agonists are potential therapeutics for stroke and further animal efficacy studies are warranted.


Assuntos
MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Infarto da Artéria Cerebral Média/tratamento farmacológico , Atividade Motora/efeitos dos fármacos , Crescimento Neuronal/efeitos dos fármacos , Oxazóis/farmacologia , Receptores sigma/agonistas , Recuperação de Função Fisiológica/efeitos dos fármacos , Animais , Infarto da Artéria Cerebral Média/metabolismo , Masculino , Estrutura Molecular , Oxazóis/síntese química , Oxazóis/química , Fosforilação/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
2.
Life Sci ; 272: 119234, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-33607158

RESUMO

Stroke still ranks as a most lethal disease worldwide. Angiogenesis during the chronic phase of ischemic stroke can alleviate ischemic injury and attenuate neurological deficit. XQ-1H is a new compound derived from the structure modification of ginkgolide B, which exerts anti-inflammation and neuroprotection against cerebral ischemic injury during the acute or subacute phase. However, whether XQ-1H facilitates angiogenesis and neural functional recovery during the chronic phase remains unclear. This research was designed to explore whether XQ-1H promotes angiogenesis after ischemic stroke and to preliminarily elucidate the mechanism. In vitro, XQ-1H was found to facilitate proliferation, migration and tube formation in bEnd.3 cells. In vivo, XQ-1H raised the CD31 positive microvessel number and increased focal cerebral blood flow in mice exposed to cerebral ischemic injury, and improved the neurological function. Mechanism studies revealed that XQ-1H exerted angiogenesis promoting effect via the PI3K/Akt/GSK3ß/ß-catenin/VEGF signal pathway, which was reversed by LY294002 (the specific inhibitor of PI3K/Akt). In conclusion, XQ-1H exerts angiogenetic effect both in vivo and in vitro, which is a potential agent against ischemic stroke during chronic phase.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Ginkgolídeos/metabolismo , Ginkgolídeos/farmacologia , Lactonas/metabolismo , Lactonas/farmacologia , Animais , Encéfalo/metabolismo , Isquemia Encefálica/metabolismo , Isquemia Encefálica/fisiopatologia , Circulação Cerebrovascular/efeitos dos fármacos , China , Glicogênio Sintase Quinase 3 beta/metabolismo , Infarto da Artéria Cerebral Média/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microvasos/metabolismo , Neovascularização Fisiológica/efeitos dos fármacos , Neovascularização Fisiológica/fisiologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Recuperação de Função Fisiológica/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Acidente Vascular Cerebral/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , beta Catenina/metabolismo
3.
Turk Neurosurg ; 31(1): 93-98, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33491171

RESUMO

AIM: To examine the effect of propolis on the healing process in terms of both electrophysiological and ultrastructural parameters in a rat model of experimental spinal cord injury. MATERIAL AND METHODS: Thirty rats were divided into control, spinal cord trauma, and treated trauma groups with 10 rats per group. The rats were sacrificed after 10 days. Before sacrifice, all rats were neurologically assessed by electrophysiological monitoring, and immediately after sacrifice, the spinal cord was examined ultrastructurally by transmission electron microscopy (TEM). RESULTS: According to the electrophysiological examination, the treatment group was statistically significantly different from the trauma group. However, no statistically significant difference was found between the control and treatment groups. In terms of the TEM examination, the treatment group was significantly different from the trauma group. CONCLUSION: In this study, propolis was administered just before the induction of trauma, and the findings suggest that the use of propolis has a positive effect on the healing process. This implies that in order to prevent postoperative deficits, this treatment may be preferably applied before spinal cord surgery for trauma.


Assuntos
Própole/uso terapêutico , Recuperação de Função Fisiológica/efeitos dos fármacos , Traumatismos da Medula Espinal/tratamento farmacológico , Medula Espinal/efeitos dos fármacos , Animais , Masculino , Própole/farmacologia , Ratos , Ratos Wistar , Recuperação de Função Fisiológica/fisiologia , Medula Espinal/patologia , Medula Espinal/ultraestrutura , Traumatismos da Medula Espinal/patologia , Resultado do Tratamento
4.
Turk J Med Sci ; 50(8): 1771-1780, 2020 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-33315350

RESUMO

Background/aim: Based on the antiviral and antibacterial properties of aluminum salts, we aimed to find out the influence of aluminum salts on COVID-19 infected patients. Materials and methods: We performed an observational retrospective cohort study which includes the patients diagnosed as COVID-19 and received aluminum salts in addition to actual treatments during hospitalization as the treatment group (Alum Group). Patients who received standard COVID-19 treatment protocols in the Infectious Diseases Clinics were included as the Control Group. Clinical findings, laboratory parameters, length of stay, survival, radiological follow-up, intensive care and mechanical ventilation needs, the presence of comorbidity, polymerase chain reaction (PCR) tests, symptoms, symptom recovery times, hospital stay times, treatment protocols, and clinical presence of pneumonia were examined in all patients. Advanced chemical composition analyzes of existing aluminum salts were also performed. Results: A total of 109 patients, 54 in the alum group and 55 in the control group, were included in the study. None of the patients in the aluminum group developed side effects due to the intake of aluminum salt. Survival status was significantly different between the two groups as there were 5 loss in the Control Group and none in the Alum Group (P = 0.023). The symptom recovery time was significantly shorter in the Alum Group; 2 (1­3) vs. 1 (1­2) days, P = 0.003. According to the paired samples analyses of the comparison between hospitalization and discharge, CRP levels significantly drops in the Alum Group (from 54.09 to 27, P = 0.001) but not in the Control Group. The drop was significantly same for the lactate dehydrogenase (LDH) and procalcitonin levels with P = 0.001. Conclusion: It has been observed that aluminum salts have beneficial effects in COVID-19 infected cases. Considering the low systemic toxicity of intermittent oral intake of aluminum salts as food supplements and the fact that pandemic control is still not achieved, the use of aluminum salts is promising.


Assuntos
Compostos de Alúmen , Hospitalização/estatística & dados numéricos , Recuperação de Função Fisiológica/efeitos dos fármacos , Compostos de Alúmen/administração & dosagem , Compostos de Alúmen/efeitos adversos , Antivirais/administração & dosagem , Antivirais/efeitos adversos , /tratamento farmacológico , /fisiopatologia , Cuidados Críticos/métodos , Cuidados Críticos/estatística & dados numéricos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Respiração Artificial/estatística & dados numéricos , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento , Turquia/epidemiologia
5.
Int J Nanomedicine ; 15: 10113-10125, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33363370

RESUMO

Background: The excess production of reactive oxygen species (ROS) after traumatic spinal cord injury (TSCI) has been identified as a leading cause of secondary injury, which can significantly exacerbate acute damage in the injured spinal cord. Thus, scavenging of ROS has emerged as an effective route to ameliorate secondary spinal cord injury. Purpose: Selenium-doped carbon quantum dots (Se-CQDs) with the ability to scavenge reactive oxygen species were prepared and used for efficiently ameliorating secondary injury in TSCI. Methods: Water-soluble Se-CQDs were easily synthesized via hydrothermal treatment of l-selenocystine. The chemical structure, size, and morphology of the Se-CQDs were characterized in detail. The biocompatibility and protective effects of the Se-CQDs against H2O2-induced oxidative damage were investigated in vitro. Moreover, the behavioral test, bladder function, histological observation, Western blot were used to investigate the neuroprotective effect of Se-CQDs in a rat model of contusion TSCI. Results: The obtained Se-CQDs exhibited good biocompatibility and remarkable protective effect against H2O2-induced oxidative damage in astrocytes and PC12 cells. Moreover, Se-CQDs displayed marked anti-inflammatory and anti-apoptotic activities, which thereby reduced the formation of glial scars and increased the survival of neurons with unscathed myelin sheaths in vivo. As a result, Se-CQDs were capable of largely improving locomotor function of rats with TSCI. Conclusion: This study suggests that Se-CQDs can be used as a promising therapeutic platform for ameliorating secondary injury in TSCI.


Assuntos
Carbono/química , Pontos Quânticos/química , Espécies Reativas de Oxigênio/metabolismo , Selênio/farmacologia , Traumatismos da Medula Espinal/patologia , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Astrócitos/efeitos dos fármacos , Astrócitos/patologia , Modelos Animais de Doenças , Feminino , Camundongos , Atividade Motora/efeitos dos fármacos , Neuroglia/efeitos dos fármacos , Neuroglia/patologia , Neuroproteção/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Células PC12 , Pontos Quânticos/ultraestrutura , Ratos , Ratos Sprague-Dawley , Recuperação de Função Fisiológica/efeitos dos fármacos , Medula Espinal/efeitos dos fármacos , Medula Espinal/patologia , Medula Espinal/fisiopatologia , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/fisiopatologia
6.
Cochrane Database Syst Rev ; 12: CD012467, 2020 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-33314078

RESUMO

BACKGROUND: Acute kidney injury (AKI) is a major comorbidity in hospitalised patients. Patients with severe AKI require continuous renal replacement therapy (CRRT) when they are haemodynamically unstable. CRRT is prescribed assuming it is delivered over 24 hours. However, it is interrupted when the extracorporeal circuits clot and the replacement is required. The interruption may impair the solute clearance as it causes under dosing of CRRT. To prevent the circuit clotting, anticoagulation drugs are frequently used. OBJECTIVES: To assess the benefits and harms of pharmacological interventions for preventing clotting in the extracorporeal circuits during CRRT. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies up to 12 September 2019 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: We selected randomised controlled trials (RCTs or cluster RCTs) and quasi-RCTs of pharmacological interventions to prevent clotting of extracorporeal circuits during CRRT. DATA COLLECTION AND ANALYSIS: Data were abstracted and assessed independently by two authors. Dichotomous outcomes were calculated as risk ratio (RR) with 95% confidence intervals (CI). The primary review outcomes were major bleeding, successful prevention of clotting (no need of circuit change in the first 24 hours for any reason), and death. Evidence certainty was determined using the Grading of Recommendation Assessment, Development, and Evaluation (GRADE) approach. MAIN RESULTS: A total of 34 completed studies (1960 participants) were included in this review. We identified seven ongoing studies which we plan to assess in a future update of this review. No included studies were free from risk of bias. We rated 30 studies for performance bias and detection bias as high risk of bias. We rated 18 studies for random sequence generation,ààsix studies for the allocation concealment, three studies for performance bias, three studies for detection bias,à nine studies for attrition bias,à14 studies for selective reporting and nine studies for the other potential source of bias, as having low risk of bias. We identified eight studies (581 participants) that compared citrate with unfractionated heparin (UFH). Compared to UFH, citrate probably reduces major bleeding (RR 0.22, 95% CI 0.08 to 0.62; moderate certainty evidence) and probably increases successful prevention of clotting (RR 1.44, 95% CI 1.10 to 1.87; moderate certainty evidence). Citrate may have little or no effect on death at 28 days (RR 1.06, 95% CI 0.86 to 1.30, moderate certainty evidence). Citrate versus UFH may reduce the number of participants who drop out of treatment due to adverse events (RR 0.47, 95% CI 0.15 to 1.49; low certainty evidence). Compared to UFH, citrate may make little or no difference to the recovery of kidney function (RR 1.04, 95% CI 0.89 to 1.21; low certainty evidence). Compared to UFH, citrate may reduceàthrombocytopenia (RR 0.39, 95% CI 0.14 to 1.03; low certainty evidence). It was uncertain whether citrate reduces a cost to health care services because of inadequate data. For low molecular weight heparin (LMWH) versus UFH, six studies (250 participants) were identified. Compared to LMWH, UFH may reduce major bleeding (0.58, 95% CI 0.13 to 2.58; low certainty evidence). It is uncertain whether UFH versus LMWH reduces death at 28 days or leads to successful prevention of clotting. Compared to LMWH, UFH may reduce the number of patient dropouts from adverse events (RR 0.29, 95% CI 0.02 to 3.53; low certainty evidence). It was uncertain whether UFH versus LMWH leads to the recovery of kidney function because no included studies reported this outcome. It was uncertain whether UFH versus LMWH leads to thrombocytopenia. It was uncertain whether UFH reduces a cost to health care services because of inadequate data. For the comparison of UFH to no anticoagulation, one study (10 participants) was identified. It is uncertain whether UFH compare to no anticoagulation leads to more major bleeding. It is uncertain whether UFH improves successful prevention of clotting in the first 24 hours, death at 28 days, the number of patient dropouts due to adverse events, recovery of kidney function, thrombocytopenia, or cost to health care services because no study reported these outcomes. For the comparison ofàcitrate to no anticoagulation,àno completed study was identified. AUTHORS' CONCLUSIONS: Currently,àavailable evidence does not support the overall superiority of any anticoagulant to another. Compared to UFH, citrate probably reduces major bleeding and prevents clotting and probably has little or no effect on death at 28 days. For other pharmacological anticoagulation methods, there is no available data showing overall superiority to citrate or no pharmacological anticoagulation. Further studies are needed to identify patient populations in which CRRT should commence with no pharmacological anticoagulation or with citrate.


Assuntos
Lesão Renal Aguda/terapia , Anticoagulantes/administração & dosagem , Coagulação Sanguínea/efeitos dos fármacos , Obstrução do Cateter , Terapia de Substituição Renal Contínua/instrumentação , Lesão Renal Aguda/mortalidade , Anticoagulantes/efeitos adversos , Viés , Obstrução do Cateter/etiologia , Ácido Cítrico/administração & dosagem , Ácido Cítrico/efeitos adversos , Terapia de Substituição Renal Contínua/efeitos adversos , Terapia de Substituição Renal Contínua/mortalidade , Filtração/instrumentação , Hemorragia/induzido quimicamente , Hemorragia/prevenção & controle , Heparina/administração & dosagem , Heparina/efeitos adversos , Heparina de Baixo Peso Molecular/administração & dosagem , Heparina de Baixo Peso Molecular/efeitos adversos , Humanos , Rim/fisiologia , Pacientes Desistentes do Tratamento , Ensaios Clínicos Controlados Aleatórios como Assunto , Recuperação de Função Fisiológica/efeitos dos fármacos , Trombocitopenia/prevenção & controle
7.
J Med Life ; 13(3): 283-288, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33072197

RESUMO

Cognitive dysfunction is a significant complaint among patients after moderate to severe traumatic brain injury (TBI), with devastating consequences on functional recovery and quality of life. Prognostic models allow a better assessment and management of neurotrauma patients. The aim of the study was to demonstrate the predictive value of the Baseline Prognostic Risk Score (BPRS) in moderate to severe TBI, in a sample of patients treated with neurotrophic factors. Eighty patients with moderate-severe TBI from the CAPTAIN II study were included in secondary data analysis. Patients received active treatment with Cerebrolysin, 50 mL per day for ten days, followed by two treatment cycles with 10 mL per day for ten days. BPRS was determined on admission; the age was recorded, and patients were evaluated using the following neurocognitive tests: Mini-Mental State Essay (MMSE), Wechsler Adult Intelligence Scale-Third Edition Processing Speed Index (WAIS-III PSI) and Stroop Colour Word Test-Victoria Version at 10, 30 and 90 days. Hierarchical regression analysis was performed to investigate the unique predictive value of BPRS on cognitive evolution, independent of age. BPRS independently predicted scores on the WAIS-III PSI DSCales and the Word subscale of the Stroop Colour Word Test at 90 days. Age was a significant predictor for all the investigated scales at 10, 30, and 90 days. This study demonstrates the predictive value of a validated prognostic model (BPRS) for medium-term neurocognitive outcomes in a sample of moderate-severe traumatic brain injury treated with neurotrophic factors.


Assuntos
Aminoácidos/uso terapêutico , Lesões Encefálicas Traumáticas/tratamento farmacológico , Adulto , Aminoácidos/farmacologia , Atenção/efeitos dos fármacos , Lesões Encefálicas Traumáticas/fisiopatologia , Cognição/efeitos dos fármacos , Função Executiva/efeitos dos fármacos , Feminino , Humanos , Masculino , Testes de Estado Mental e Demência , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Qualidade de Vida , Recuperação de Função Fisiológica/efeitos dos fármacos , Fatores de Risco , Teste de Stroop , Escalas de Wechsler
8.
PLoS One ; 15(9): e0238208, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32881928

RESUMO

INTRODUCTION: Peripheral nerve injury (PNI) often leads to significant functional loss in patients and poses a challenge to physicians since treatment options for improving functional outcomes are limited. Recent studies suggest that erythropoietin and glucocoticoids have beneficial effects as mediators of neuro-regenerative processes. We hypothesized that combination treatment with erythropoietin and glucocoticoids would have a synergistic effect on functional outcome after PNI. MATERIALS AND METHODS: Sciatic nerve crush injury was simulated in ten-week-old male C57BL/6 mice. The mice were divided into four groups according to the type of drugs administered (control, erythropoietin, dexamethasone, and erythropoietin with dexamethasone). Motor functional recovery was monitored by walking track analysis at serial time points up to 28 days after injury. Morphological analysis of the nerve was performed by immunofluorescent staining for neurofilament (NF) heavy chain and myelin protein zero (P0) in cross-sectional and whole-mount nerve preparations. Additionally, morphological analysis of the muscle was performed by Hematoxylin and eosin staining. RESULTS: Combination treatment with erythropoietin and dexamethasone significantly improved the sciatic functional index at 3, 7, 14, and 28 days after injury. Fluorescence microscopy of cross sectional nerve revealed that the combination treatment increased the ratio of P0/NF-expressing axons. Furthermore, confocal microscopy of the whole-mount nerve revealed that the combination treatment increased the fluorescence intensity of P0 expression. The cross-sectional area and minimum Feret's diameter of the muscle fibers were significantly larger in the mice which received combination treatment than those in the controls. CONCLUSION: Our results demonstrated that combination treatment with erythropoietin and dexamethasone accelerates functional recovery and reduces neurogenic muscle atrophy caused by PNI in mice, which may be attributed to the preservation of myelin and Schwann cell re-myelination. These findings may provide practical therapeutic options for patients with acute PNI.


Assuntos
Dexametasona/uso terapêutico , Eritropoetina/uso terapêutico , Músculos/metabolismo , Traumatismos dos Nervos Periféricos/tratamento farmacológico , Nervo Isquiático/metabolismo , Doença Aguda , Animais , Axônios/metabolismo , Dexametasona/farmacologia , Modelos Animais de Doenças , Quimioterapia Combinada , Eritropoetina/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Confocal , Músculos/patologia , Atrofia Muscular/patologia , Atrofia Muscular/prevenção & controle , Proteína P0 da Mielina/metabolismo , Traumatismos dos Nervos Periféricos/patologia , Recuperação de Função Fisiológica/efeitos dos fármacos , Remielinização/efeitos dos fármacos , Células de Schwann/citologia , Células de Schwann/metabolismo , Nervo Isquiático/patologia
9.
PLoS One ; 15(7): e0235232, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32735618

RESUMO

The tamoxifen-dependent Cre/lox system in transgenic mice has become an important research tool across all scientific disciplines for manipulating gene expression in specific cell types. In these mouse models, Cre-recombination is not induced until tamoxifen is administered, which allows researchers to have temporal control of genetic modifications. Interestingly, tamoxifen has been identified as a potential therapy for spinal cord injury (SCI) and traumatic brain injury patients due to its neuroprotective properties. It is also reparative in that it stimulates oligodendrocyte differentiation and remyelination after toxin-induced demyelination. However, it is unknown whether tamoxifen is neuroprotective and neuroreparative when administration is delayed after SCI. To properly interpret data from transgenic mice in which tamoxifen treatment is delayed after SCI, it is necessary to identify the effects of tamoxifen alone on anatomical and functional recovery. In this study, female and male mice received a moderate mid-thoracic spinal cord contusion. Mice were then gavaged with corn oil or a high dose of tamoxifen from 19-22 days post-injury, and sacrificed 42 days post-injury. All mice underwent behavioral testing for the duration of the study, which revealed that tamoxifen treatment did not impact hindlimb motor recovery. Similarly, histological analyses revealed that tamoxifen had no effect on white matter sparing, total axon number, axon sprouting, glial reactivity, cell proliferation, oligodendrocyte number, or myelination, but tamoxifen did decrease the number of neurons in the dorsal and ventral horn. Semi-thin sections confirmed that axon demyelination and remyelination were unaffected by tamoxifen. Sex-specific responses to tamoxifen were also assessed, and there were no significant differences between female and male mice. These data suggest that delayed tamoxifen administration after SCI does not change functional recovery or improve tissue sparing in female or male mice.


Assuntos
Neurônios/efeitos dos fármacos , Remielinização/efeitos dos fármacos , Traumatismos da Medula Espinal/tratamento farmacológico , Tamoxifeno/administração & dosagem , Tempo para o Tratamento , Administração Oral , Animais , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Membro Posterior/inervação , Membro Posterior/fisiologia , Humanos , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Oligodendroglia/efeitos dos fármacos , Recuperação de Função Fisiológica/efeitos dos fármacos , Fatores Sexuais , Corno Dorsal da Medula Espinal/citologia , Corno Dorsal da Medula Espinal/efeitos dos fármacos , Corno Ventral da Medula Espinal/citologia , Corno Ventral da Medula Espinal/efeitos dos fármacos
10.
Life Sci ; 258: 118214, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32768585

RESUMO

Large numbers of rodents are often used in the study of disease progression and in the evaluation of its potential treatments. To avoid subjective observation and to minimize home cage interference, we developed a computerized home cage monitoring system (HCMS100) based on a standard cage rack adapted with a single laser beam and a detector mounted on each cage, enabling to monitor mice movements based on laser beam interruptions. This retrofit system provided continuous and uninterrupted monitoring of spontaneous movement of a group of mice in a home cage. Validity was evaluated using disease state induced by LPS modelling bacterial infection and by influenza virus. RESULTS: Spontaneous activity of different number of mice (2-8) per cage showed the expected circadian rhythm with increased activity during the night, and its extent dependent on the number of mice in the cage. Females and males show similar circadian rhythm. Intranasal LPS administration and pulmonary infection with live influenza virus resulted in major reduction of mice activity along disease progression. Increase in activity over time was a good indicator of the recovery process from both LPS exposure and the flu infection. CONCLUSIONS: HCMS100 was shown to be a reliable, inexpensive, easy to use system that requires no changes in the common housing of various experimental animals (mice, hamsters, rats etc.). With minimal intervention, HCMS100 provides a continuous record of group activity with clear pattern of circadian rhythm, allowing long term recording of home cage activity even in restricted access environments.


Assuntos
Progressão da Doença , Abrigo para Animais , Lipopolissacarídeos/toxicidade , Infecções por Orthomyxoviridae/fisiopatologia , Orthomyxoviridae , Recuperação de Função Fisiológica/fisiologia , Animais , Ritmo Circadiano/fisiologia , Feminino , Abrigo para Animais/tendências , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Infecções por Orthomyxoviridae/psicologia , Recuperação de Função Fisiológica/efeitos dos fármacos
11.
Int J Nanomedicine ; 15: 4393-4405, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32606684

RESUMO

Aim: The effects of polyamidoamine (PAMAM) dendrimers on the mammalian heart are not completely understood. In this study, we have investigated the effects of a sixth-generation cationic dendrimer (G6 PAMAM) on cardiac function in control and diabetic rat hearts following ischemia-reperfusion (I/R) injury. Methods: Isolated hearts from healthy non-diabetic (Ctr) male Wistar rats were subjected to ischemia and reperfusion (I/R). LV contractility and hemodynamics data were computed digitally whereas cardiac damage following I/R injury was assessed by measuring cardiac enzymes. For ex vivo acute exposure experiments, G6 PAMAM was administered during the first 10 mins of reperfusion in Ctr animals. In chronic in vivo studies, nondiabetic rats (Ctr) received either vehicle or daily i.p. injections of G6 PAMAM (40 mg/kg) for 4 weeks. Diabetic (D) animals received either vehicle or daily i.p. injections of G6 PAMAM (10, 20 or 40 mg/kg) for 4 weeks. The impact of G6 PAMAM on pacing-postconditioning (PPC) was also studied in Ctr and D rats. Results: In ex vivo studies, acute administration of G6 PAMAM to isolated Ctr hearts during reperfusion dose-dependently impaired recovery of cardiac hemodynamics and vascular dynamics parameters following I/R injury. Chronic daily i.p. injections of G6 PAMAM significantly (P<0.01) impaired recovery of cardiac function following I/R injury in nondiabetic animals but this was not generally observed in diabetic animals except for CF which was impaired by about 50%. G6 PAMAM treatment completely blocked the protective effects of PPC in the Ctr animals. Conclusion: Acute ex vivo or chronic in vivo treatment with naked G6 PAMAM dendrimer can significantly compromise recovery of non-diabetic hearts from I/R injury and can further negate the beneficial effects of PPC. Our findings are therefore extremely important in the nanotoxicological evaluation of G6 PAMAM dendrimers for potential clinical applications in physiological and pathological settings.


Assuntos
Dendrímeros/toxicidade , Coração/fisiopatologia , Mamíferos/fisiologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Nanopartículas/toxicidade , Poliaminas/administração & dosagem , Recuperação de Função Fisiológica/efeitos dos fármacos , Animais , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Experimental/fisiopatologia , Coração/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Pós-Condicionamento Isquêmico , Masculino , Contração Miocárdica/efeitos dos fármacos , Miocárdio/enzimologia , Ratos Wistar
12.
Medicine (Baltimore) ; 99(28): e20934, 2020 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-32664090

RESUMO

This study aimed to investigate the myocardial protective effect of liquid sodium phosphocreatine cardiac arrest in extracorporeal circulation surgery treating infants with atrial septal defects.Eighty-four infants with atrial septal defects who required extracorporeal circulation surgery treatment at our hospital from January 2016 to June 2018 were divided into an observation group and a control group through a digitally randomized method, with 42 cases in each group. The control group adopted the conventional modified St Thomas II high potassium cold liquid crystal cardiac arrest, while the observation group adopted the liquid sodium phosphocreatine cardiac arrest.The myocardial enzyme indexes of the 2 groups 3, 6, 12, and 24 hours postoperatively were higher than before establishing the cardiopulmonary bypass and the enzyme indexes of the control group at the same time were higher than that of the observation group; adenosine triphosphate, adenosine diphosphate, and other energy levels and the postoperative recovery rate energy levels of the observation group were higher than those in the control group, the difference was statistically significant (P < .05).Liquid sodium phosphocreatine cardiac arrest used in extracorporeal circulation surgery treating infants with atrial septal defects can reduce myocardial ischemia-reperfusion injury, maintain energy supply during ischemia, strengthen the St Thomas II effect, and aid postoperative cardiac function recovery of high potassium cold liquid crystal cardiac arrest used in infants with atrial septal defects and treated with extracorporeal circulation surgery.


Assuntos
Ponte Cardiopulmonar/métodos , Cardiotônicos/farmacologia , Parada Cardíaca Induzida/métodos , Comunicação Interatrial/cirurgia , Fosfocreatina/farmacologia , Difosfato de Adenosina/metabolismo , Trifosfato de Adenosina/metabolismo , Cardiotônicos/administração & dosagem , Estudos de Casos e Controles , Pré-Escolar , Circulação Extracorpórea/métodos , Feminino , Parada Cardíaca/induzido quimicamente , Comunicação Interatrial/diagnóstico , Comunicação Interatrial/tratamento farmacológico , Humanos , Lactente , Masculino , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miocárdio/química , Miocárdio/enzimologia , Preservação de Órgãos/métodos , Fosfocreatina/administração & dosagem , Período Pós-Operatório , Cloreto de Potássio/administração & dosagem , Cloreto de Potássio/farmacologia , Substâncias Protetoras/administração & dosagem , Recuperação de Função Fisiológica/efeitos dos fármacos
13.
Nat Commun ; 11(1): 3420, 2020 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-32647127

RESUMO

Remyelination of the peripheral and central nervous systems (PNS and CNS, respectively) is a prerequisite for functional recovery after lesion. However, this process is not always optimal and becomes inefficient in the course of multiple sclerosis. Here we show that, when acetylated, eukaryotic elongation factor 1A1 (eEF1A1) negatively regulates PNS and CNS remyelination. Acetylated eEF1A1 (Ac-eEF1A1) translocates into the nucleus of myelinating cells where it binds to Sox10, a key transcription factor for PNS and CNS myelination and remyelination, to drag Sox10 out of the nucleus. We show that the lysine acetyltransferase Tip60 acetylates eEF1A1, whereas the histone deacetylase HDAC2 deacetylates eEF1A1. Promoting eEF1A1 deacetylation maintains the activation of Sox10 target genes and increases PNS and CNS remyelination efficiency. Taken together, these data identify a major mechanism of Sox10 regulation, which appears promising for future translational studies on PNS and CNS remyelination.


Assuntos
Fator 1 de Elongação de Peptídeos/metabolismo , Remielinização/genética , Ativação Transcricional/genética , Acetilação , Envelhecimento/metabolismo , Animais , Desdiferenciação Celular/efeitos dos fármacos , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Histona Desacetilase 1/metabolismo , Histona Desacetilase 2/metabolismo , Lisina Acetiltransferase 5/metabolismo , Camundongos , Modelos Biológicos , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/metabolismo , Sistema Nervoso Periférico/efeitos dos fármacos , Sistema Nervoso Periférico/fisiologia , Recuperação de Função Fisiológica/efeitos dos fármacos , Remielinização/efeitos dos fármacos , Fatores de Transcrição SOXE/metabolismo , Fator de Transcrição STAT3/metabolismo , Células de Schwann/efeitos dos fármacos , Células de Schwann/metabolismo , Teofilina/farmacologia , Transativadores/metabolismo , Ativação Transcricional/efeitos dos fármacos
14.
J Antimicrob Chemother ; 75(10): 2977-2980, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32607555

RESUMO

BACKGROUND: Remdesivir is a prodrug of the nucleoside analogue GS-441524 and is under evaluation for treatment of SARS-CoV-2-infected patients. OBJECTIVES: To evaluate the pharmacokinetics of remdesivir and GS-441524 in plasma, bronchoalveolar aspirate (BAS) and CSF in two critically ill COVID-19 patients. METHODS: Remdesivir was administered at 200 mg loading dose on the first day followed by 12 days of 100 mg in two critically ill patients. Blood samples were collected immediately after (C0) and at 1 (C1) and 24 h (C24) after intravenous administration on day 3 until day 9. BAS samples were collected on Days 4, 7 and 9 from both patients while one CSF on Day 7 was obtained in one patient. Remdesivir and GS-441524 concentrations were measured in these samples using a validated UHPLC-MS/MS method. RESULTS: We observed higher concentrations of remdesivir at C0 (6- to 7-fold higher than EC50 from in vitro studies) and a notable decay at C1. GS-441524 plasma concentrations reached a peak at C1 and persisted until the next administration. Higher concentrations of GS-441524 were observed in the patient with mild renal dysfunction. Mean BAS/plasma concentration ratios of GS-441524 were 2.3% and 6.4% in Patient 1 and Patient 2, respectively. The CSF concentration found in Patient 2 was 25.7% with respect to plasma. GS-441524 levels in lung and CNS suggest compartmental differences in drug exposure. CONCLUSIONS: We report the first pharmacokinetic evaluation of remdesivir and GS-441524 in recovered COVID-19 patients. Further study of the pharmacokinetic profile of remdesivir, GS-441524 and the intracellular triphosphate form are required.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Trifosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/farmacocinética , Betacoronavirus , Infecções por Coronavirus/metabolismo , Estado Terminal/terapia , Pneumonia Viral/metabolismo , Monofosfato de Adenosina/farmacocinética , Monofosfato de Adenosina/uso terapêutico , Trifosfato de Adenosina/farmacocinética , Trifosfato de Adenosina/uso terapêutico , Idoso , Alanina/farmacocinética , Alanina/uso terapêutico , Antivirais/uso terapêutico , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/tratamento farmacológico , Feminino , Humanos , Masculino , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/tratamento farmacológico , Recuperação de Função Fisiológica/efeitos dos fármacos , Recuperação de Função Fisiológica/fisiologia
15.
Neurology ; 95(4): e362-e373, 2020 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-32601121

RESUMO

OBJECTIVE: To evaluate whether pretreatment with metformin (MET) is associated with less stroke severity and better outcome after IV thrombolysis (IVT), we analyzed a cohort of 1,919 patients with stroke with type 2 diabetes mellitus in a multicenter exploratory analysis. METHODS: Data from patients with diabetes and ischemic stroke treated with IVT were collected within the European Thrombolysis in Ischemic Stroke Patients (TRISP) collaboration. We applied propensity score matching (PSM) to obtain balanced baseline characteristics of patients treated with and without MET. RESULTS: Of 1,919 patients with stroke with type 2 diabetes who underwent IVT, 757 (39%) had received MET before stroke (MET+), whereas 1,162 (61%) had not (MET-). MET+ patients were younger with a male preponderance. Hypercholesterolemia and pretreatment with statins, antiplatelets, or antihypertensives were more common in the MET+ group. After PSM, the 2 groups were well balanced with respect to demographic and clinical aspects. Stroke severity on admission (NIH Stroke Scale 10.0 ± 6.7 vs 11.3 ± 6.5), 3-month degree of independence on modified Rankin Scale (2 [interquartile range (IQR) 1.0-4.0] vs 3 [IQR 1.0-4.0]), as well as mortality (12.5% vs 18%) were significantly lower in the MET+ group. The frequency of symptomatic intracerebral hemorrhages did not differ between groups. HbA1c levels were well-balanced between the groups. CONCLUSIONS: Patients with stroke and diabetes on treatment with MET receiving IVT had less severe strokes on admission and a better functional outcome at 3 months. This suggests a protective effect of MET resulting in less severe strokes as well as beneficial thrombolysis outcome.


Assuntos
Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico , Recuperação de Função Fisiológica/efeitos dos fármacos , Acidente Vascular Cerebral , Idoso , Diabetes Mellitus Tipo 2/tratamento farmacológico , Feminino , Fibrinolíticos/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/mortalidade , Acidente Vascular Cerebral/fisiopatologia , Terapia Trombolítica/métodos
16.
PLoS One ; 15(7): e0236050, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32678832

RESUMO

Neurotrophic factors have been regarded having promising potentials for neuronal protection and regeneration, and thus promoting beneficial effects of kinesiological functions. They can be suspected to play important roles in cell/tissue grafting for various neural diseases. The clinical applications of such trophic factors to the central nervous system (CNS), however, have caused problematic side effects on account of the distinctive bioactive properties. In the course of developing synthetic compounds reflecting beneficial properties of basic fibroblast growth factor (bFGF), we conducted screening candidates that stimulate to trigger the intracellular tyrosine phosphorylation of FGF receptor and lead to the subsequent intracellular signaling in neurons. A small synthetic molecule SUN13837 was characterized by mimicking the beneficial properties of bFGF, which have been known as its specific activities when applied to CNS. What is more remarkable is that SUN13837 is eliminated the bioactivity to induce cell proliferation of non-neuronal somatic cells. On the bases of studies of pharmacology, behavior, physiology and histology, the present study reports that SUN13837 is characterized as a promising synthetic compound for treatment of devastating damages onto the rat spinal cord.


Assuntos
Materiais Biomiméticos/farmacologia , Fator 2 de Crescimento de Fibroblastos/metabolismo , Recuperação de Função Fisiológica/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/farmacologia , Traumatismos da Medula Espinal/fisiopatologia , Animais , Axônios/efeitos dos fármacos , Axônios/fisiologia , Feminino , Crescimento Neuronal/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Regeneração/efeitos dos fármacos , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/patologia
17.
Muscle Nerve ; 62(3): 404-412, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32497302

RESUMO

BACKGROUND: After facial nerve injury and surgical repair in rats, recovery of vibrissal whisking is associated with a high proportion of mono-innervated neuro-muscular junctions (NMJs). Our earlier work with Sprague Dawley (SD)/Royal College of Surgeons (RCS) rats, which are blind and spontaneously restore NMJ-monoinnervation and whisking, showed correlations between functional recovery and increase of fibroblast growth factor-2 (FGF2) and brain-derived neurotrophic factor (BDNF) in denervated vibrissal muscles. METHODS: We used normally sighted rats (Wistar), in which NMJ-polyinnervation is highly correlated with poor whisking recovery, and injected the vibrissal muscle levator labii superioris (LLS) with combinations of BDNF, anti-BDNF, and FGF2 at different postoperative periods after facial nerve injury. RESULTS: Rats receiving anti-BDNF+FGF2 showed low NMJ-polyinnervation and best recovery of whisking amplitude. CONCLUSIONS: Restoration of target reinnervation after peripheral nerve injury requires a complex mixture of trophic factors with a specific time course of availability for each of them.


Assuntos
Anticorpos Neutralizantes/uso terapêutico , Fator Neurotrófico Derivado do Encéfalo/imunologia , Traumatismos do Nervo Facial/tratamento farmacológico , Fator 2 de Crescimento de Fibroblastos/uso terapêutico , Regeneração Nervosa/fisiologia , Recuperação de Função Fisiológica/fisiologia , Vibrissas/fisiologia , Animais , Fator Neurotrófico Derivado do Encéfalo/farmacologia , Denervação , Músculos Faciais/efeitos dos fármacos , Músculos Faciais/inervação , Músculos Faciais/fisiopatologia , Traumatismos do Nervo Facial/fisiopatologia , Feminino , Fator 2 de Crescimento de Fibroblastos/farmacologia , Regeneração Nervosa/efeitos dos fármacos , Ratos , Ratos Wistar , Recuperação de Função Fisiológica/efeitos dos fármacos
18.
PLoS One ; 15(6): e0234039, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32555710

RESUMO

Sepsis is characterized by organ dysfunction due to a dysregulated immune response to infection. Currently, no effective treatment for sepsis exists. Platelets are recognized as mediators of the immune response and may be a potential therapeutic target for the treatment of sepsis. We previously demonstrated that NLRP3 inflammasome activation in sepsis-induced activated platelets was associated with multi-organ injury in the cecal-ligation puncture (CLP) rat model of sepsis. In this study, we tested the hypothesis that inhibition of NLRP3 would inhibit platelet activation and attenuate multi-organ injury in the CLP rat. CLP (n = 10) or Sham (n = 10) surgery were performed in male and female Sprague-Dawley rats. A subset of CLP rats were treated with MCC950 (50mg/kg/d), a specific NLRP3 inhibitor (CLP+MCC950, n = 10). At 72 hrs. post-CLP, blood and organs were harvested for analysis of platelet activation, NLRP3 activation, inflammation and end organ damage. Platelet activation increased from 8±0.8% in Sham to 16±1% in CLP, and was reduced to 9±1% in CLP+M rats (p<0.05). NLRP3 activation was also increased in platelets of CLP vs Sham. NLRP3 expression was unchanged in kidney and lung after CLP, but Caspase 1 expression and IL-1ß were increased. MCC950 treatment attenuated NLRP3 activation in platelets. Plasma, kidney, and lung levels of NLRP3 inflammasome associated cytokines, IL-1ß and IL-18, were significantly increased in CLP compared to Sham rats. Inhibition of NLRP3 normalized cytokine levels. Glomerular injury, pulmonary edema, and endothelial dysfunction markers were increased in CLP rats vs Sham. MCC950 treatment significantly decreased renal and pulmonary injury and endothelial dysfunction in CLP+M. Our results demonstrate a role for NLRP3 in contributing to platelet activation and multi-organ injury in sepsis.


Assuntos
Ceco/cirurgia , Inflamassomos/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Ativação Plaquetária/efeitos dos fármacos , Punções/efeitos adversos , Sepse/tratamento farmacológico , Sepse/fisiopatologia , Animais , Caspase 1/metabolismo , Citocinas/metabolismo , Endotélio/efeitos dos fármacos , Endotélio/metabolismo , Feminino , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Rim/efeitos dos fármacos , Rim/fisiopatologia , Ligadura/efeitos adversos , Masculino , Permeabilidade/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Recuperação de Função Fisiológica/efeitos dos fármacos , Sepse/metabolismo
19.
Neurology ; 95(8): e1091-e1104, 2020 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-32591475

RESUMO

OBJECTIVE: We evaluated the effect of 2 doses of natalizumab on functional outcomes in patients with acute ischemic stroke (AIS). METHODS: In this double-blind phase 2b trial, patients with AIS aged 18-80 years with NIH Stroke Scale scores of 5-23 from 53 US and European sites were randomized 1:1:1 to receive a single dose of 300 or 600 mg IV natalizumab or placebo, with randomization stratified by treatment window (≤9 or >9 to ≤24 hours from patient's last known normal state). The primary endpoint was a composite measure of excellent outcome (modified Rankin Scale score ≤1 and Barthel Index score ≥95) at day 90 assessed in all patients receiving a full dose. Sample size was estimated from a Bayesian model; p values were not used for hypothesis testing. RESULTS: An excellent outcome was less likely with natalizumab than with placebo (natalizumab 300 or 600 mg odds ratio 0.60; 95% confidence interval 0.39-0.93). There was no effect modification by time to treatment or use of thrombolysis/thrombectomy. For natalizumab 300 mg, 600 mg, or placebo, there were no differences in incidence of adverse events (90.0%, 92.1%, and 92.3%, respectively), serious adverse events (25.6%, 32.6%, and 20.9%, respectively), or deaths (6.7%, 4.5%, and 5.5%, respectively). CONCLUSIONS: Natalizumab administered ≤24 hours after AIS did not improve patient outcomes. CLINICALTRIALSGOV IDENTIFIER: NCT02730455 CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for patients with AIS, an excellent outcome was less likely in patients treated with natalizumab than with placebo.


Assuntos
Fatores Imunológicos/administração & dosagem , Natalizumab/administração & dosagem , Recuperação de Função Fisiológica/efeitos dos fármacos , Acidente Vascular Cerebral/tratamento farmacológico , Idoso , Isquemia Encefálica/complicações , Isquemia Encefálica/tratamento farmacológico , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Acidente Vascular Cerebral/etiologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...