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1.
Acta Chir Orthop Traumatol Cech ; 86(4): 276-280, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31524589

RESUMO

PURPOSE OF THE STUDY Septic arthritis is an infection of joints caused by a pathogenic microorganism. Septic arthritis has a mortality rate of 11-40% when it's not treated properly. The mortality rate with methicillin-sensitive Staphylococcus aureus (MSSA)is 5-7%, while the rate with methicillin-resistant Staphylococcus aureus (MRSA)is 13-20%. The aim of this study is to evaluate the effects of intraarticular vancomycin and teicoplanin on joint cartilage in in vivo settings and its utility in routine MRSA treatment. MATERIALS AND METHODS In our study, 35 male Sprague-Dawley rats aged 28 days were used. Rats were obtained from the Regenerative and Restorative Medicine Research Center (REMER) of Istanbul Medipol University. Rats were randomly divided into 5 groups each containing 7 rats. Joint injections were administered with isoflurane analgesia every day at 6 am. Three rats (15 rats) from each group were sacrified in seventh day and evaluated immunohistologically to evaluate acute healing in articular cartilage. All remaining rats were sacrificed on day 28 and their knees were evaluated by immunohistochemical examination. RESULTS In our study, there were no complications in any rat during injection and the study period. Hematoxylin eosin (H & E) histological staining for evaluating cartilage healing and healing levels did not show statistically significant differences between the groups at first week (p > 0.05). Matrix metalloproteinase-13 (MMP-13) staining did not show any statistically significant difference between the groups. (p > 0.05). DISCUSSION MRSAseptic arthritis, diagnosed for the first time in 1960, has recently been responsible for 6-22% of all septic arthritis and is increasing day by day. The use of systemic vancomycin or teicoplanin is the first-line treatment method in MRSA septic arthritis. Serum levels reach the desired level, especially with intravenous infusion dose. On the other hand, it has been shown that intraarticular concentration does not reach a sufficient level in studies conducted. The use of intraarticular antibiotics during treatment can lead to more effective and early disease control by turning this negative situation into favor of the patient. As a result, intraarticular vancomycin and teicoplanin maximale tolerable and maintenance doses can be safely used beside surgery and intravenous antibiotics to increase efficacy of treatment, reduction of recurrence rates and reduction of mortality in MRSAseptic arthritis. CONCLUSIONS Intraarticular vancomycin and teicoplanin maximale tolerable and maintenance doses can be safely used beside surgery and intravenous antibiotics to increase efficacy of treatment, reduction of recurrence rates and reduction of mortality in MRSA septic arthritis. Key words:arthritis, infectious; methicillin-resistant Staphylococcus aureus; mortality.


Assuntos
Antibacterianos/administração & dosagem , Artrite Infecciosa/tratamento farmacológico , Staphylococcus aureus Resistente à Meticilina/isolamento & purificação , Infecções Estafilocócicas/tratamento farmacológico , Teicoplanina/administração & dosagem , Vancomicina/administração & dosagem , Animais , Artrite Infecciosa/patologia , Cartilagem Articular/efeitos dos fármacos , Cartilagem Articular/patologia , Modelos Animais de Doenças , Membro Posterior/efeitos dos fármacos , Membro Posterior/microbiologia , Injeções Intra-Articulares , Masculino , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Infecções Estafilocócicas/patologia , Cicatrização/efeitos dos fármacos
2.
Eur J Med Chem ; 181: 111562, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31377592

RESUMO

The interaction between G-Protein coupled receptor CXCR4 and its natural ligand CXCL12 has been linked to inflammation experienced by patients with Irritable Bowel Disease (IBD). Blocking this interaction could potentially reduce inflammatory symptoms in IBD patients. In this work, several thiophene-based and furan-based compounds modeled after AMD3100 and WZ811-two known antagonists that interrupt the CXCR4-CXCL12 interaction-were synthesized and analyzed. Fifteen hit compounds were identified; these compounds exhibited effective concentrations (EC) lower than 1000 nM (AMD3100) and inhibited invasion of metastatic cells by at least 45%. Selected compounds (2d, 2j, 8a) that inhibited metastatic invasion at a higher rate than WZ811 (62%) were submitted for a carrageenan inflammation test, where both 8a and 2j reduced inflammation in the same range as WZ811 (40%) but did not reduce inflammation more than 40%. Select compounds were also modeled in silico to show key residue interactions. These preliminary results with furan-based and thiophene-based analogues contribute to the new class on heterocyclic aromatic-based CXCR4 antagonists.


Assuntos
Furanos/farmacologia , Compostos Heterocíclicos/farmacologia , Inflamação/tratamento farmacológico , Receptores CXCR4/antagonistas & inibidores , Tiofenos/farmacologia , Animais , Carragenina/administração & dosagem , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Furanos/síntese química , Furanos/química , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Membro Posterior/efeitos dos fármacos , Humanos , Inflamação/induzido quimicamente , Camundongos , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Estrutura Molecular , Receptores CXCR4/metabolismo , Relação Estrutura-Atividade , Tiofenos/química
3.
J Physiol Sci ; 69(5): 757-767, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31273678

RESUMO

The effects of a combination of the antioxidant astaxanthin (AX) and electrical stimulation (ES) on muscle mass and mitochondrial oxidative capacity were investigated in the soleus muscle of hindlimb unloaded rats. Five groups of male Sprague-Dawley rats were used; control, 1-week hindlimb unloading (HU), HU + AX, HU + ES, and HU + AX + ES. Respective rats in the AX groups received 50-mg/kg AX twice daily during HU. Calf muscles of rats in the ES groups were electrically stimulated for 240 s/day during HU. One-week HU decreased muscle mass along with decreased FoxO3a phosphorylation and increased ubiquitinated proteins expressions, decreased oxidative enzymatic activity accompanied with decline in PGC-1α protein expression, and increased reactive oxygen species production. However, the combination treatment could synergistically attenuate/suppress all HU-related changes, suggesting protective effects on muscle atrophy and decreased muscle oxidative capacity due to chronic neuromuscular inactivity.


Assuntos
Membro Posterior/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Atrofia Muscular/metabolismo , Atrofia Muscular/prevenção & controle , Oxirredução/efeitos dos fármacos , Animais , Antioxidantes/farmacologia , Suplementos Nutricionais , Estimulação Elétrica/métodos , Membro Posterior/metabolismo , Elevação dos Membros Posteriores/métodos , Masculino , Músculo Esquelético/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Xantofilas/farmacologia
4.
Trop Anim Health Prod ; 51(8): 2611-2617, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31240548

RESUMO

A study was conducted to determine the effects of flaxseed supplementation on performance, carcass traits, and hindleg fatty acid composition of guinea pigs. Sixty male and female weaned guinea pigs (1 month old, five animals/cage) were blocked by sex and bodyweight and randomly fed 0 (control) or 100 g/kg flaxseed concentrate diets (15 g/animal) plus ad libitum fresh alfalfa for 30 days. Results showed that flaxseed supplementation had no influence on animal performance. However, final body weight (P = 0.035), total feed intake (P = 0.019), and body weight gain (P < 0.001) were higher in male than female guinea pigs. Similar results were also observed for carcass composition (i.e., hot, chilled, and reference carcass weights). Inclusion of flaxseed reduced saturated (P < 0.001), mono-unsaturated (P = 0.004), and increased (P < 0.001) polyunsaturated (PUFA) fatty acid concentrations in hindlegs. Concentrations of linolenic acid and n-3 PUFA increased (P < 0.001) by 49.7 and 37.1%, respectively as a result of flaxseed inclusion. It was concluded that feeding flaxseed to guinea pigs at 100 g/kg of the concentrate diets improves meat PUFA concentrations with no adverse effects on performance or carcass composition.


Assuntos
Ingestão de Alimentos , Ácidos Graxos/análise , Linho/metabolismo , Cobaias/fisiologia , Membro Posterior , Carne/análise , Ganho de Peso , Ração Animal/análise , Animais , Dieta/veterinária , Suplementos Nutricionais/análise , Ingestão de Alimentos/efeitos dos fármacos , Feminino , Linho/química , Cobaias/crescimento & desenvolvimento , Membro Posterior/química , Membro Posterior/efeitos dos fármacos , Masculino , Peru , Distribuição Aleatória , Sementes/química , Ganho de Peso/efeitos dos fármacos
5.
Kaohsiung J Med Sci ; 35(7): 417-424, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30977589

RESUMO

Limb ischemia reperfusion (LIR) can activate endogenous cytoprotective mechanisms by generating specific proteins against reperfusion injury in remote organs. The present study investigated the roles of heme oxygenase-1 (HO-1) pathway and the molecular mechanisms underlying the regulation of this pathway on lung injury following LIR. LIR was induced by ischemia for 4 hours followed by reperfusion for 6 hours (LIR 6 hours) or 16 hours (LIR 16 hours) in male Sprague-Dawley rats. HO-1 inducer cobalt protoporphyrin (Copp) or HO-1 inhibitor zinc protoporphyrin (Znpp) was intravenously injected 24 hours before ischemia. The animals were randomly divided into nine groups, including normal control, LIR 6 hours, LIR 16 hours, Copp, Copp + LIR 6 hours, Copp + LIR 16 hours, and Znpp, Znpp+ LIR 6 hours, and Znpp + LIR 16 hours groups (each group included four samples). Lung injury was examined through histopathology. Quantitative real-time PCR, immunohistochemistry and Western blot were applied to detect the mRNA and protein levels of HO-1, Nrf2, and Bach1. Our study showed that LIR induced Nrf2 upregulation but Bach1 downregulation to promote HO-1 expression in lung tissues. Activation of HO-1 pathway by Copp potentially enhanced Nrf2 expression but inhibition of the pathway by Znpp promoted Bach1 expression. Inducer of HO-1 pathway, Copp injection improved the lung injury. Nevertheless, Znpp injection aggravated the lung injury following LIR. Our findings suggested that activated HO-1 pathway might exert protective effects on the lung injury following LIR.


Assuntos
Heme Oxigenase (Desciclizante)/genética , Lesão Pulmonar/genética , Traumatismo por Reperfusão/genética , Transdução de Sinais/genética , Animais , Fatores de Transcrição de Zíper de Leucina Básica/genética , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Ativadores de Enzimas/farmacologia , Inibidores Enzimáticos/farmacologia , Regulação da Expressão Gênica , Heme Oxigenase (Desciclizante)/antagonistas & inibidores , Heme Oxigenase (Desciclizante)/metabolismo , Membro Posterior/irrigação sanguínea , Membro Posterior/efeitos dos fármacos , Membro Posterior/enzimologia , Pulmão , Lesão Pulmonar/etiologia , Lesão Pulmonar/patologia , Lesão Pulmonar/prevenção & controle , Masculino , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Protoporfirinas/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/complicações , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/prevenção & controle
6.
Contrast Media Mol Imaging ; 2019: 2538909, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30863219

RESUMO

Purpose: Peripheral artery disease (PAD) causes narrowing of arteries in the limbs, leading to tissue ischemia, gangrene, and eventually limb amputation. The presence of diabetes greatly exacerbates the course of PAD, accounting for the majority of lower limb amputations. Therapeutic strategies focussing on macrovascular repair are less effective in diabetic patients where smaller vessels are affected, and proangiogenic therapies offer a viable adjunct to improve vascularisation in these at risk individuals. The purpose of the current study was to assess the proangiogenic effects of drugs routinely used to treat cardiovascular disease in a diabetic murine model of hind limb ischemia longitudinally using multimodal imaging. Procedures: Diabetic mice underwent surgical intervention to induce hind limb ischemia and were treated with simvastatin, metformin, or a combination orally for 28 days and compared to diabetic and nondiabetic mice. Neovascularisation was assessed using [18F]FtRGD PET imaging, and macrovascular volume was assessed by quantitative time of flight MRI. At each imaging time point, VEGF expression and capillary vessel density were quantified using immunohistochemical analysis, and functional recovery and disease progression were assessed. Results: Combined use of simvastatin and metformin significantly increased neovascularisation above levels measured with either treatment alone. Early angiogenic events were accurately assessed using PET [18F]FtRGD, showing maximal retention in the ischemic hind limb by day 8, which translated to a sustained increase in vascular volume at later time points. Immunohistochemical analysis shows that combined therapy significantly increased VEGF expression and capillary density (CD31+) in a similar time course and also slowed disease progression while simultaneously improving functional foot use. Conclusions: Combined treatment with simvastatin and metformin led to a significant improvement in limb angiogenesis, vascular volume, and sustained functional recovery in a diabetic murine model of HLI. PET imaging with [18F]FtRGD provides a robust method for early detection of these proangiogenic effects preclinically and may be useful for the assessment of proangiogenic therapies used clinically to treat diabetic PAD patients.


Assuntos
Fármacos Cardiovasculares/uso terapêutico , Diabetes Mellitus Experimental/tratamento farmacológico , Membro Posterior/diagnóstico por imagem , Isquemia/diagnóstico por imagem , Isquemia/tratamento farmacológico , Animais , Membro Posterior/efeitos dos fármacos , Membro Posterior/patologia , Imuno-Histoquímica , Imagem por Ressonância Magnética/métodos , Masculino , Metformina/uso terapêutico , Camundongos , Camundongos Endogâmicos BALB C , Músculo Esquelético/diagnóstico por imagem , Músculo Esquelético/efeitos dos fármacos , Oligopeptídeos/química , Sinvastatina/uso terapêutico
7.
PLoS One ; 14(3): e0205477, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30889182

RESUMO

Metabolic syndrome (MS), overlapping type 2 diabetes, hyperlipidemia, and/or hypertension, owing to high-fat diet, poses risk for cardiovascular disease. A critical feature associated with such risk is the functional impairment of endothelial progenitor cells (EPCs). Dipeptidyl dipeptidase-4 inhibitors (DPP-4 i) not only inhibit degradation of incretins to control blood glucose levels, but also improve EPC bioactivity and induce anti-inflammatory effects in tissues. In the present study, we investigated the effects of such an inhibitor, MK-06266, in an ischemia model of MS using diet-induced obese (DIO) mice. EPC bioactivity was examined in MK-0626-administered DIO mice and a non-treated control group, using an EPC colony-forming assay and bone marrow cKit+ Sca-1+ lineage-cells, and peripheral blood-mononuclear cells. Our results showed that, in vitro, the effect of MK-0626 treatment on EPC bioactivities and differentiation was superior compared to the control. Furthermore, microvascular density and pericyte-recruited arteriole number increased in MK-0626-administered mice, but not in the control group. Lineage profiling of isolated cells from ischemic tissues revealed that MK-0626 administration has an inhibitory effect on unproductive inflammation. This occurred via a decrease in the influx of total blood cells and pro-inflammatory cells such as neutrophils, total macrophages, M1, total T-cells, cytotoxic T-cells, and B-cells, with a concomitant increase in number of regeneration-associated cells, such as M2/M ratio and Treg/T-helper. Laser Doppler analysis revealed that at day 14 after ischemic injury, blood perfusion in hindlimb was greater in MK-0626-treated DIO mice, but not in control. In conclusion, the DPP-4 i had a positive effect on EPC differentiation in MS model of DIO mice. Following ischemic injury, DPP-4 i sharply reduced recruitment of pro-inflammatory cells into ischemic tissue and triggered regeneration and reparation, making it a promising therapeutic agent for MS treatment.


Assuntos
Células Progenitoras Endoteliais/efeitos dos fármacos , Membro Posterior/efeitos dos fármacos , Isquemia/tratamento farmacológico , Leucócitos Mononucleares/efeitos dos fármacos , Obesidade/tratamento farmacológico , Regeneração/efeitos dos fármacos , Triazóis/farmacologia , Adulto , Animais , Dieta/efeitos adversos , Inibidores da Dipeptidil Peptidase IV/farmacologia , Células Progenitoras Endoteliais/citologia , Células Progenitoras Endoteliais/metabolismo , Voluntários Saudáveis , Humanos , Isquemia/etiologia , Isquemia/patologia , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Pessoa de Meia-Idade , Obesidade/etiologia , Obesidade/metabolismo , Adulto Jovem
8.
Am J Physiol Regul Integr Comp Physiol ; 316(5): R417-R426, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30840487

RESUMO

Recent findings have shown that muscle contraction evokes an exaggerated pressor response in type 1 diabetes mellitus (T1DM) rats; however, it is not known whether the mechanoreflex, which is commonly stimulated by stretching the Achilles tendon, contributes to this abnormal response. Furthermore, the role of mechano-gated Piezo channels, found on thin-fiber afferent endings, in evoking the mechanoreflex in T1DM is also unknown. Therefore, in male and female streptozotocin (STZ, 50 mg/kg)-induced T1DM and healthy control (CTL) rats, we examined the pressor and cardioaccelerator responses to tendon stretch during the early stage of the disease. To determine the role of Piezo channels, GsMTx-4, a selective Piezo channel inhibitor, was injected into the arterial supply of the hindlimb. At 1 wk after STZ injection in anesthetized, decerebrate rats, we stretched the Achilles tendon for 30 s and measured pressor and cardioaccelerator responses. We then compared pressor and cardioaccelerator responses to tendon stretch before and after GsMTx-4 injection (10 µg/100 ml). We found that the pressor (change in mean arterial pressure) response [41 ± 5 mmHg (n = 15) for STZ and 18 ± 3 mmHg (n = 11) for CTL (P < 0.01)] and cardioaccelerator (change in heart rate) response [18 ± 4 beats/min for STZ (n = 15) and 8 ± 2 beats/min (n = 11) for CTL (P < 0.05)] to tendon stretch were exaggerated in STZ rats. Local injection of GsMTx-4 attenuated the pressor [55 ± 7 mmHg (n = 6) before and 27 ± 9 mmHg (n = 6) after GsMTx-4 (P < 0.01)], but not the cardioaccelerator, response to tendon stretch in STZ rats and had no effect on either response in CTL rats. These data suggest that T1DM exaggerates the mechanoreflex response to tendon stretch and that Piezo channels play a role in this exaggeration.


Assuntos
Pressão Sanguínea/fisiologia , Diabetes Mellitus Experimental/fisiopatologia , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Contração Muscular/efeitos dos fármacos , Venenos de Aranha/farmacologia , Animais , Estado de Descerebração/fisiopatologia , Feminino , Membro Posterior/efeitos dos fármacos , Membro Posterior/fisiopatologia , Masculino , Contração Muscular/fisiologia , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/fisiologia , Condicionamento Físico Animal/fisiologia , Ratos Sprague-Dawley , Reflexo/fisiologia
9.
Mol Med Rep ; 19(4): 3321-3329, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30816501

RESUMO

Cuscuta chinensis Lamak (CCL) has traditionally been used in Korea to treat sexual disorders and skin problems. The aim of the present study was to investigate the effects of CCL extract on surgical injury­induced ischemia in the hind limbs of mice. Specifically, female C57BL/6 mice were ovariectomized, and their hind­limb vessels were ligated with surgical silk (6­0) and excised. CCL (150 or 450 mg/kg/BW) was then administered to the mice for 3 weeks, and the blood flow rate was evaluated using a laser Doppler system at ­7, 0, 7, 14 and 21 days following hind­limb ischemia. The serum expression profiles of angiogenic and inflammatory mediators were measured using an antibody array, and the transcript levels were reverse transcription­quantitative polymerase chain reaction. The rate of hind limb blood flow was normalized to non­ischemic lesions and revealed to be markedly elevated at 14 and 21 days following ischemia when compared with the vehicle group. The density of capillaries in the hind limbs was also significantly increased following treatment with CCL in a dose­dependent manner. In addition, the transcriptional expression of angiogenetic factors were upregulated, whereas that of inflammatory cytokines were downregulated. Finally, vascular endothelial cell migration and tube formation were evaluated in vitro using human umbilical vein endothelial cells (HUVECs) and identified to be significantly increased following treatment with CCL. Overall, the results of the present study indicate that CCL extract exhibits therapeutic potential for the treatment of hind­limb ischemia as it promotes peripheral angiogenic and anti­inflammatory effects in mice.


Assuntos
Indutores da Angiogênese/farmacologia , Anti-Inflamatórios/farmacologia , Cuscuta/química , Membro Posterior/irrigação sanguínea , Membro Posterior/patologia , Isquemia/patologia , Extratos Vegetais/farmacologia , Indutores da Angiogênese/química , Animais , Anti-Inflamatórios/química , Biomarcadores , Movimento Celular/efeitos dos fármacos , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Expressão Gênica , Membro Posterior/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Imuno-Histoquímica , Mediadores da Inflamação/metabolismo , Isquemia/tratamento farmacológico , Isquemia/etiologia , Camundongos , Extratos Vegetais/química , Cicatrização/efeitos dos fármacos
10.
Diabetes ; 68(5): 1040-1053, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30765336

RESUMO

Fenofibrate, a peroxisome proliferator-activated receptor α (PPARα) agonist, reduces lower limb amputations in patients with type 2 diabetes. The mechanism is, however, unknown. In this study, we demonstrate that fenofibrate markedly attenuates diabetes-related impairment of ischemia-mediated angiogenesis. In a murine model of hindlimb ischemia, daily oral fenofibrate treatment restored diabetes-impaired blood flow recovery, foot movement, hindlimb capillary density, vessel diameter, and vascular endothelial growth factor signaling to nondiabetic levels in both wild-type and PPARα-knockout mice, indicating that these fenofibrate effects are largely PPARα independent. In vitro, fenofibric acid (FFA) rescued high glucose-induced (25 mmol/L) impairment of endothelial cell migration, tubulogenesis, and survival in a PPARα-independent manner. Interestingly, fenofibrate in vivo and FFA in vitro reversed high glucose-induced expression of thioredoxin-interacting protein (TXNIP), an exquisitely glucose-inducible gene previously identified as a critical mediator of diabetes-related impairment in neovascularization. Conversely, adenoviral overexpression of TXNIP abrogated the restorative effects of FFA on high glucose-impaired endothelial cell function in vitro, indicating that the effects of FFA are mediated by TXNIP. We conclude that fenofibrate rescues diabetic impairment in ischemia-mediated angiogenesis, in large part, by PPARα-independent regulation of TXNIP. These findings may therefore explain the reduction in amputations seen in patients with diabetes treated with fenofibrate.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Fenofibrato/uso terapêutico , Isquemia/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/metabolismo , Animais , Proteínas de Transporte/metabolismo , Fenofibrato/análogos & derivados , Glucose/farmacologia , Membro Posterior/efeitos dos fármacos , Membro Posterior/patologia , Isquemia/metabolismo , Camundongos , Transdução de Sinais/efeitos dos fármacos
11.
J Physiol Sci ; 69(2): 223-233, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30232713

RESUMO

The protective effects of Brazilian propolis on capillary regression induced by chronically neuromuscular inactivity were investigated in rat soleus muscle. Four groups of male Wistar rat were used in this study; control (CON), control plus Brazilian propolis supplementation (CON + PP), 2-week hindlimb unloading (HU), and 2-week hindlimb unloading plus Brazilian propolis supplementation (HU + PP). The rats in the CON + PP and HU + PP groups received two oral doses of 500 mg/kg Brazilian propolis daily (total daily dose 1000 mg/kg) for 2 weeks. Unloading resulted in a decrease in capillary number, luminal diameter, and capillary volume, and an increase in the expression of anti-angiogenic factors, such as p53 and TSP-1, within the soleus muscle. Brazilian propolis supplementation, however, prevented these changes in capillary structure due to unloading through the stimulation of pro-angiogenic factors and suppression of anti-angiogenic factors. These results suggest that Brazilian propolis is a potential non-drug therapeutic agent against capillary regression induced by chronic unloading.


Assuntos
Capilares/efeitos dos fármacos , Membro Posterior/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Própole/farmacologia , Substâncias Protetoras/farmacologia , Indutores da Angiogênese/metabolismo , Animais , Brasil , Capilares/metabolismo , Suplementos Nutricionais , Elevação dos Membros Posteriores/métodos , Masculino , Músculo Esquelético/metabolismo , Ratos , Ratos Wistar
12.
Cell Prolif ; 52(2): e12545, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30430685

RESUMO

OBJECT: The purpose of this study was to explore whether melatonin could protect mesenchymal stem cells (MSCs) against ischaemic injury, by inhibiting endoplasmic reticulum (ER) stress and autophagy both in vivo and in vitro. MATERIALS AND METHODS: To confirm the protective effect of melatonin against ER stress in MSCs, markers of cell viability, apoptosis and autophagy were analysed. To further investigate the regenerative effect of melatonin-treated MSCs in ischaemic tissues, a murine hindlimb ischaemic model was established. RESULTS: Under oxidative stress conditions, treatment with melatonin suppressed the activation of ER stress-associated proteins and autophagy-associated proteins acting through upregulation of cellular prion protein (PrPC ) expression. Consequently, inhibition of apoptotic cell death occurred. Melatonin also promoted the activation of MnSOD and catalase activities in MSCs. In a murine hindlimb ischaemia model, melatonin-treated MSCs also enhanced the functional limb recovery as well as neovascularization. These beneficial effects of melatonin were all blocked by knock-down of PrPC expression. CONCLUSION: Melatonin protects against ER stress/autophagy-induced apoptotic cell death by augmenting PrPC expression. Thus, melatonin-treated MSCs could be a potential cell-based therapeutic agent for ER stress-induced ischaemic diseases, and melatonin-induced PrPC might be a key molecule in ameliorating ER stress and autophagy.


Assuntos
Antioxidantes/uso terapêutico , Autofagia/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Isquemia/tratamento farmacológico , Melatonina/uso terapêutico , Células-Tronco Mesenquimais/efeitos dos fármacos , Proteínas Priônicas/metabolismo , Animais , Antioxidantes/farmacologia , Células Cultivadas , Membro Posterior/irrigação sanguínea , Membro Posterior/efeitos dos fármacos , Membro Posterior/metabolismo , Membro Posterior/patologia , Isquemia/metabolismo , Isquemia/patologia , Masculino , Melatonina/farmacologia , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/patologia , Camundongos Endogâmicos BALB C , Camundongos Nus , Estresse Oxidativo/efeitos dos fármacos , Proteínas Priônicas/análise
13.
J Cardiothorac Vasc Anesth ; 33(4): 1003-1011, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30195965

RESUMO

OBJECTIVES: Spinal cord ischemia secondary to trauma or a vascular occlusive event is a threatening phenomenon. The neuroprotective properties of minocycline have been shown in several models of central nervous system diseases and after spinal cord ischemia; however, the benefit of using the drug requires additional confirmation in different animal models. Astrocytes are essential as regulators of neuronal functions and for providing nutrients. The authors hypothesized that astrocytes in the spinal cord may be an important target for minocycline action after ischemia and thus in the prevention of secondary spreading damage. DESIGN: A prospective, randomized animal study. SETTING: University research laboratory, single institution. PARTICIPANTS: Adult male Sprague Dawley rats, weighing between 400 and 450 g. INTERVENTIONS: A model of spinal cord ischemia in the rat was used for this study to determine whether a single, high-dose (10 mg/kg) of minocycline protects against damage to the neuronal cytoskeleton, both in the white and gray matter, and whether it reduces glial fibrillary acidic protein levels, which is an index for prevention of astrocyte activation during ischemia. Thirty minutes before thoracic aorta occlusion, minocycline was administered for 18 minutes using a 2 F Fogarty catheter. MEASUREMENTS AND MAIN RESULTS: Minocycline given prophylactically significantly mitigated severe hindlimb motor impairment and reduced glial fibrillary acidic protein plus astrocytosis in both the white and gray matter of the spinal cord, caudal to the occlusion. Neuronal histologic cytoarchitecture, which was severely and significantly compromised in control animals, was preserved in the minocycline-treated animals. CONCLUSIONS: This study's data imply that minocycline may attenuate reactive astrocytosis in response to injury with better neurologic outcome in a model of spinal cord ischemia in rats. The data suggest that future use of minocycline, clinically, might be advantageous in surgeries with a potential risk for paraplegia due to spinal cord ischemia.


Assuntos
Arteriopatias Oclusivas/prevenção & controle , Gliose/tratamento farmacológico , Membro Posterior/irrigação sanguínea , Minociclina/administração & dosagem , Paraplegia/tratamento farmacológico , Isquemia do Cordão Espinal/tratamento farmacológico , Animais , Arteriopatias Oclusivas/patologia , Gliose/patologia , Membro Posterior/efeitos dos fármacos , Membro Posterior/patologia , Masculino , Neurônios/efeitos dos fármacos , Neurônios/patologia , Paraplegia/patologia , Profilaxia Pré-Exposição/métodos , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Isquemia do Cordão Espinal/patologia
14.
Congenit Anom (Kyoto) ; 59(2): 39-42, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29653020

RESUMO

To investigate the abnormalities that are specific to administration of flucytosine at one time point during embryonic organogenesis, flucytosine was administered orally to pregnant Sprague Dawley (SD) rats in a single dose on day 11 of pregnancy at 25 or 35 mg/kg. Fetuses on day 20 of pregnancy were externally, viscerally, and skeletally examined. Maternal body weight gain and food consumption were suppressed the day after administration of a 35 mg/kg. Fetal examinations revealed various alterations in both dose groups: externally preaxial polydactyly in the hind limb; skeletally fused lumbar centrum, absent sacral centrum, supernumerary sacral vertebra, and absent ribs. Our findings indicated that specific types of external and skeletal anomalies were induced following flucytosine administration on day 11 of pregnancy.


Assuntos
Anormalidades Induzidas por Medicamentos/patologia , Ectromelia/patologia , Desenvolvimento Fetal/efeitos dos fármacos , Flucitosina/toxicidade , Polidactilia/patologia , Teratogênios/toxicidade , Anormalidades Induzidas por Medicamentos/etiologia , Administração Oral , Animais , Esquema de Medicação , Ingestão de Alimentos/efeitos dos fármacos , Ectromelia/induzido quimicamente , Feminino , Feto , Membro Posterior/anormalidades , Membro Posterior/efeitos dos fármacos , Região Lombossacral/anormalidades , Masculino , Exposição Materna/efeitos adversos , Organogênese/efeitos dos fármacos , Polidactilia/induzido quimicamente , Gravidez , Ratos , Ratos Sprague-Dawley , Costelas/anormalidades , Costelas/efeitos dos fármacos , Ganho de Peso/efeitos dos fármacos
15.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 35(5): 438-442, 2019 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-31894677

RESUMO

OBJECTIVE: To observe the effects of different doses of acetyl-L-carnitine (ALC) on hindlimb motor function and spinal cord tissue structure in rats with spinal cord injury. The study will provide theoretical and experimental evidences for acetyl-L-carnitine's clinical treatment. METHODS: Fifty-five SD rats aged 8-10 weeks were randomly divided into high, medium and low-dose drug intervention (SCI + ALC) group, injury group (SCI) and sham group for behavioral evaluation, MAD and SOD detection, as well as HPLC detection and HE staining. BBB scores and Rivlin experiments were performed to evaluate hindlimb motor function in each group. The morphology and structure of spinal cord tissue was detected by HE staining. Another 9 rats were randomly divided into Sham group, SCI group and ALC group for TUMEL detection of apoptosis. RESULTS: The BBB scores of the high, medium, and low dose SCI+ALC groups were significantly higher than those in the SCI group. The medium and high-dose ALC groups had significant differences (P<0.01), and the hindlimb motor function was significantly improved in rats. The maximum tilt angle of the Rivlin experiment was observed. The SCI+ALC group had a significantly increased angle compared with the SCI group (P<0.05), the medium and high-dose ALC group had a significant difference (P<0.01). Compared with the SCI group, the tissue structure of ALC high-dose group was improved significantly, the number of inflammatory cells and red blood cells was decreased, and the nucleolus of the nerve cells was unclear. The SOD activity of the SCI+ALC group was significantly higher than that of the SCI group, while the MDA content was significantly decreased(P<0.05), the middle and high dose ALC groups were significantly different (P<0.01). HPLC chromatogram showed that the SCI+ALC fresh serum sample and the ALC standard solution had the same absorption spectrum at 260 nm, while the Sham group and SCI group serum samples did not show spectral values there, which indicated that the same substance as the standard existed in the sample of SCI+ALC group. TUNEL staining showed that the apoptosis signal was occasionally seen in the sham group, and the apoptosis signal was significantly decreased in the ALC high-dose group compared with the SCI group(P<0.05). CONCLUSION: ALC can promote the recovery of hindlimb motor function in rats with spinal cord injury, inhibit oxidative stress and apoptosis, and repair the damaged spinal cord tissue.


Assuntos
Acetilcarnitina , Traumatismos da Medula Espinal , Medula Espinal , Acetilcarnitina/farmacologia , Acetilcarnitina/uso terapêutico , Animais , Membro Posterior/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Medula Espinal/efeitos dos fármacos , Traumatismos da Medula Espinal/tratamento farmacológico , Resultado do Tratamento
16.
J Neuroinflammation ; 15(1): 335, 2018 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-30509328

RESUMO

OBJECTIVE: The regulatory role of capsaicin-sensitive peptidergic sensory nerves has been shown in acute inflammation, but little is known about their involvement in T/B-cell driven autoimmune arthritis. This study integratively characterized the function of these nerve endings in the proteoglycan-induced chronic arthritis (PGIA), a translational model of rheumatoid arthritis. METHODS: Peptidergic afferents were defunctionalized by resiniferatoxin (RTX) pretreatment in BALB/c mice, PGIA was induced by repeated antigen challenges. Hind paw volume, arthritis severity, grasping ability and the mechanonociceptive threshold were monitored during the 17-week experiment. Myeloperoxidase activity, vascular leakage and bone turnover were evaluated by in vivo optical imaging. Bone morphology was assessed using micro-CT, the intertarsal small joints were processed for histopathological analysis. RESULTS: Following desensitization of the capsaicin-sensitive afferents, ankle edema, arthritis severity and mechanical hyperalgesia were markedly diminished. Myeloperoxidase activity was lower in the early, but increased in the late phase, whilst plasma leakage and bone turnover were not altered. Desensitized mice displayed similar bone spurs and erosions, but increased trabecular thickness of the tibia and bony ankylosis of the spine. Intertarsal cartilage thickness was not altered in the model, but desensitization increased this parameter in both the non-arthritic and arthritic groups. CONCLUSION: This is the first integrative in vivo functional and morphological characterization of the PGIA mouse model, wherein peptidergic afferents have an important regulatory function. Their overall effect is proinflammatory by increasing acute inflammation, immune cell activity and pain. Meanwhile, their activation decreases spinal ankylosis, arthritis-induced altered trabecularity, and cartilage thickness in small joints.


Assuntos
Artrite Reumatoide/induzido quimicamente , Artrite Reumatoide/patologia , Capsaicina/farmacologia , Proteoglicanas/toxicidade , Fármacos do Sistema Sensorial/farmacologia , Limiar Sensorial/efeitos dos fármacos , Animais , Tornozelo/diagnóstico por imagem , Cartilagem/patologia , Modelos Animais de Doenças , Diterpenos/farmacologia , Feminino , Membro Posterior/efeitos dos fármacos , Membro Posterior/fisiopatologia , Camundongos , Camundongos Endogâmicos BALB C , Neurotoxinas/farmacologia , Peptídeos/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Índice de Gravidade de Doença , Coluna Vertebral/diagnóstico por imagem
17.
Cell Rep ; 25(6): 1593-1609.e7, 2018 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-30404012

RESUMO

The induction of limb repair in adult vertebrates is a pressing, unsolved problem. Here, we characterize the effects of an integrated device that delivers drugs to severed hindlimbs of adult Xenopus laevis, which normally regenerate cartilaginous spikes after amputation. A wearable bioreactor containing a silk protein-based hydrogel that delivered progesterone to the wound site immediately after hindlimb amputation for only 24 hr induced the regeneration of paddle-like structures in adult frogs. Molecular markers, morphometric analysis, X-ray imaging, immunofluorescence, and behavioral assays were used to characterize the differences between the paddle-like structures of successful regenerates and hypomorphic spikes that grew in untreated animals. Our experiments establish a model for testing therapeutic cocktails in vertebrate hindlimb regeneration, identify pro-regenerative activities of progesterone-containing bioreactors, and provide proof of principle of brief use of integrated device-based delivery of small-molecule drugs as a viable strategy to induce and maintain a long-term regenerative response.


Assuntos
Reatores Biológicos , Membro Posterior/efeitos dos fármacos , Progesterona/administração & dosagem , Progesterona/farmacologia , Dispositivos Eletrônicos Vestíveis , Xenopus laevis/fisiologia , Potenciais de Ação/efeitos dos fármacos , Animais , Remodelação Óssea/efeitos dos fármacos , Redes Reguladoras de Genes/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Receptores de Progesterona/metabolismo , Regeneração/efeitos dos fármacos , Natação , Transcriptoma/genética , Cicatrização/efeitos dos fármacos , Xenopus laevis/genética
18.
J Ethnopharmacol ; 227: 121-130, 2018 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-30170078

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Naoxintong (NXT) is a compound preparation that is widely used in patients with cardiovascular and cerebrovascular diseases. AIM OF STUDY: The aim of this study is to investigate the protective mechanism of NXT on the mice model of peripheral vascular disease (PAD). MATERIALS AND METHODS: In the study, hindlimb ischemia was induced by ligation of femoral artery on the right leg of mice. After surgery, the mice were administrated with saline solution, 10 mg/kg/d simvastatin and 700 mg/kg/d NXT for 4 weeks. The blood flow perfusion was measured by laser Doppler perfusion imaging system. Histological and immunofluorescent staining was used to determine muscle recovery, capillary density, tissue vascular endothelial growth factor (VEGF), phosphorylated-Akt (p-Akt) and phosphorylated-endothelial nitric oxide synthase (p-eNOS) expression. Terminal deoxynucleotidyl transferased UTP nick end labeling (TUNEL) was performed to detect the apoptosis of myocytes in hindlimb. The autophagy-associated gene expression and peroxisome proliferator-activated receptors (PPARs) expression were measured by Quantitative Real-Time Reverse Transcription Polymerase Chain Reaction (qRT-PCR). Western blotting was performed to detect the expressions of light-chain 3 (LC3), VEGF, p-Akt, p-eNOS and PPARs. The EMSA experiment was performed to figure out whether PPARδ could directly bind to the predicted PPRE motif of VEGF. RESULTS: NXT treatment significantly accelerated perfusion recovery and reduced tissue injury in mice muscle. Apoptosis and autophagy were decreased within the ischemic muscle of NXT-treated mice. Quantification of vessels in hindlimb muscles provided evidences that NXT promoted angiogenesis in peripheral ischemia. In addition, results from western blotting and immunofluorescent staining suggested NXT induced angiogenesis via VEGF/Akt/eNOS signaling pathway. More interestingly, NXT specifically increased the expression of PPARδ in both mRNA and protein levels. EMSA results showed that PPARδ associated with PPRE site of VEGF promoter, suggesting that NXT-induced VEGF expression is mediated, at least in part, by PPARδ. CONCLUSION: In conclusion, the present study implicated that the restoration of hindlimb blood perfusion and recovery of limb functions were improved in NXT-treated mice with significant improvement of angiogenesis mediated by PPARδ-VEGF-Akt-eNOS axis as well as attenuation of autophagy and apoptosis. These results expand knowledge about the beneficial effects of NXT in angiogenesis and blood flow recovery. It might provide insight into the PPARδ regulating neovascularization in hindlimb ischemia and identify NXT as a potent new compound used for the treatment of peripheral vascular disease.


Assuntos
Indutores da Angiogênese/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Isquemia/metabolismo , PPAR delta/metabolismo , Indutores da Angiogênese/uso terapêutico , Animais , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/uso terapêutico , Membro Posterior/irrigação sanguínea , Membro Posterior/efeitos dos fármacos , Isquemia/tratamento farmacológico , Isquemia/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , PPAR delta/genética , RNA Mensageiro/metabolismo , Fluxo Sanguíneo Regional/efeitos dos fármacos
19.
Toxicology ; 409: 103-111, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30096436

RESUMO

The present study aimed to investigate the protective effect and mechanism of calpeptin (CP) on acrylamide (ACR)-induced microtubule (MT) injury in the sciatic nerve of rats. All rats were divided into four groups (control, CP, ACR, and ACR + CP):1 ml/kg saline, 200 µg/kg CP, 30 mg/kg ACR, and 30 mg/kg ACR plus 200 µg/kg CP were administered to the corresponding rats for 4 weeks through intraperitoneal injection. Body weight and neurobehavioral indicators were measured weekly and α-tubulin, ß-tubulin, and other concerned proteins were estimated by western blotting and immunohistochemistry. At 4 weeks, decreased body weight, increased gait scores, increased hindlimb splay, and decreased time of fall of ACR rats were observed compared with those of control rats. All these mentioned changes were restored in the ACR + CP group compared with the ACR group. After 4 weeks of administration, western blotting and immunohistochemistry revealed significant increase in the protein levels of ß-tubulin, calpain I, calpain II, Tau, microtubule-associated protein 2 (MAP2), protein kinase C, and cyclin-dependent kinase 5 in the ACR group compared with the control group; these increases were significantly lower in the ACR + CP group than in the ACR group. Furthermore, histopathological examination revealed loose arrangement, disorganised structure, uneven density, and exfoliated perineurium in the ACR group, and CP administration improved these changes significantly. The present results suggest that CP has an intervening effect on ACR-induced MT injury. A possible mechanism is that calpain maintains the stability of MTs by regulating the metabolism of Tau and MAP2.


Assuntos
Acrilamida/toxicidade , Dipeptídeos/farmacologia , Microtúbulos/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Nervo Isquiático/lesões , Animais , Feminino , Marcha/efeitos dos fármacos , Membro Posterior/efeitos dos fármacos , Ratos Wistar , Teste de Desempenho do Rota-Rod , Nervo Isquiático/metabolismo , Nervo Isquiático/patologia
20.
ACS Appl Mater Interfaces ; 10(36): 30081-30091, 2018 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-30118197

RESUMO

Mesenchymal stem cell (MSC)-derived exosomes have been recognized as new candidates for cell-free treatment of various diseases. However, maintaining the retention and stability of exosomes over time in vivo after transplantation is a major challenge in the clinical application of MSC-derived exosomes. Here, we investigated if human placenta-derived MSC-derived exosomes incorporated with chitosan hydrogel could boost the retention and stability of exosomes and further enhance their therapeutic effects. Our results demonstrated that chitosan hydrogel notably increased the stability of proteins and microRNAs in exosomes, as well as augmented the retention of exosomes in vivo as confirmed by Gaussia luciferase imaging. In addition, we assessed endothelium-protective and proangiogenesis abilities of hydrogel-incorporated exosomes in vitro. Meanwhile, we evaluated the therapeutic function of hydrogel-incorporated exosomes in a murine model of hindlimb ischemia. Our data demonstrated that chitosan hydrogel could enhance the retention and stability of exosomes and further augment the therapeutic effects for hindlimb ischemia as revealed by firefly luciferase imaging of angiogenesis. The strategy used in this study may facilitate the development of easy and effective approaches for assessing and enhancing the therapeutic effects of stem cell-derived exosomes.


Assuntos
Exossomos/transplante , Hidrogéis/química , Hidrogéis/farmacologia , Isquemia/terapia , Células-Tronco Mesenquimais/metabolismo , Neovascularização Fisiológica/efeitos dos fármacos , Animais , Exossomos/química , Membro Posterior/efeitos dos fármacos , Membro Posterior/patologia , Isquemia/tratamento farmacológico , Camundongos
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