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1.
Sci Total Environ ; 913: 169606, 2024 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-38159744

RESUMO

Nanoplastic particles are pervasive environmental contaminants with potential health risks, while mouse intestinal organoids provide accurate in vitro models for studying these interactions. Metabolomics, especially through LC-MS, enables detailed cellular response studies, and there's a novel interest in comparing metabolic changes across nanoparticle species using gut organoids. This study used a mouse intestinal organoid combined with cell model to explore the differences in metabolites and toxicity mechanisms induced by exposure to three nanoplastics (PS, PTFE, and PMMA). The results showed that PS, PTFE, and PMMA exposure reduced mitochondrial membrane potential, intracellular ROS accumulation and oxidative stress, and inhibited the AKT/mTOR signaling pathway. Non-targeted metabolomics results confirmed that three types of nanoplastic particles regulate cellular status by regulating fatty acid metabolism, nucleotide metabolism, necroptosis and autophagy pathways. More importantly, these representative metabolites were further validated in model groups after mouse intestinal organoids and HCT116 cells were exposed to the respective NPs, indicating that organoid metabolomics results can be used to effectively predict toxicity. Untargeted metabolomics is sensitive enough to detect subtle metabolomic changes when functional cellular analysis shows no significant differences. Overall, our study reveals the underlying metabolic mechanism of NPs-induced intestinal organoid toxicity and provides new insights into the possible adverse consequences of NPs.


Assuntos
Microplásticos , Nanopartículas , Animais , Camundongos , Polimetil Metacrilato , Metabolômica/métodos , Nanopartículas/toxicidade , Organoides , Politetrafluoretileno , Poliestirenos/toxicidade
2.
Exp Mol Med ; 55(12): 2596-2607, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-38036735

RESUMO

Exposure to nanomicroplastics (nano-MPs) can induce lung damage. The gut microbiota is a critical modulator of the gut-lung axis. However, the mechanisms underlying these interactions have not been elucidated. This study explored the role of lactate, a key metabolite of the microbiota, in the development of lung damage induced by nano-MPs (LDMP). After 28 days of exposure to nano-MPs (50-100 nm), mice mainly exhibited damage to the lungs and intestinal mucosa and dysbiosis of the gut microbiota. Lactate accumulation was observed in the lungs, intestines and serum and was strongly associated with the imbalance in lactic acid bacteria in the gut. Furthermore, no lactate accumulation was observed in germ-free mice, while the depletion of the gut microbiota using a cocktail of antibiotics produced similar results, suggesting that lactate accumulation in the lungs may have been due to changes in the gut microbiota components. Mechanistically, elevated lactate triggers activation of the HIF1a/PTBP1 pathway, exacerbating nano-MP-induced lung damage through modulation of the epithelial-mesenchymal transition (EMT). Conversely, mice with conditional knockout of Ptbp1 in the lungs (Ptbp1flfl) and PTBP1-knockout (PTBP1-KO) human bronchial epithelial (HBE) cells showed reversal of the effects of lactate through modulation of the HIF1a/PTBP1 signaling pathway. These findings indicate that lactate is a potential target for preventing and treating LDMP.


Assuntos
Microbioma Gastrointestinal , Microbiota , Humanos , Animais , Camundongos , Ácido Láctico/metabolismo , Mucosa Intestinal/metabolismo , Pulmão , Camundongos Endogâmicos C57BL , Ribonucleoproteínas Nucleares Heterogêneas/metabolismo , Proteína de Ligação a Regiões Ricas em Polipirimidinas/metabolismo , Proteína de Ligação a Regiões Ricas em Polipirimidinas/farmacologia
3.
Chemosphere ; 342: 140108, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37714480

RESUMO

Nanoplastics have been widely studied as environmental pollutants, which can accumulate in the human body through the food chain or direct contact. Research has shown that nanoplastics can affect the immune system and mitochondrial function, but the underlying mechanisms are unclear. Lungs and macrophages have important immune and metabolic functions. This study explored the effects of 100 nm PS-NPs on innate immunity, mitochondrial function, and cellular metabolism-related pathways in lung (BEAS-2B) cells and macrophages (RAW264.7). The results had shown that PS-NPs exposure caused a decrease in mitochondrial membrane potential, intracellular ROS accumulation, and Ca2+ overload, and activated the cGAS-STING signaling pathway related to innate immunity. These changes had been observed at concentrations of PS-NPs as low as 60 µg/mL, which might have been comparable to environmental levels. Non-target metabolomics and Western Blotting results confirmed that PS-NPs regulated prostaglandin B1 and other metabolites to cause cell damage through the cGAS-STING pathway. Supplementation of prostaglandin B1 alleviated the immune activation and metabolic disturbance caused by PS-NPs exposure. This study identified PS-NPs-induced innate immune activation, mitochondrial dysfunction, and metabolic toxicity pathways, providing new insights into the potential for adverse outcomes of NPs in human life.

4.
Front Pharmacol ; 13: 1056614, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36386124

RESUMO

Background: Adult neurogenesis plays an important role in repairing damaged neurons and improving cognitive impairment in Alzheimer's disease (AD). B. Papyrifera (L.) L'Hér. ex Vent. fruits (BL), a traditional Chinese medicine for tonifying the kidney, has been reported to improve cognitive function in AD mice, but the underlying mechanisms have not been clearly illuminated. This study aimed to provide an overview of the differential compounds in the brain of APP/PS1 mice after BL water extract (BLWE) treatment through metabolomics technology and to elucidate whether the therapeutic effect and mechanism are through the enhancement of neurogenesis. Methods: APP/PS1 transgenic mice were treated with different doses of BLWE. After 6 weeks of intragastric injection, the therapeutic effects of BLWE on APP/PS1 transgenic mice were determined by the Morris water maze test, immunohistochemistry, hematoxylin & eosin and Nissl staining, enzyme-linked immunosorbent assay and terminal deoxynucleotidyl transferase dUTP nick end labeling staining. Subsequently, metabolomics technology was used to analyze the regulatory effect of BLWE on differential compounds in the brain of APP/PS1 mice, and on this basis, its molecular mechanism of BLWE was screened. Finally, the protein expression of the Wnt/ß-catenin signaling pathway was detected by Western blotting. Results: After BLWE treatment, the learning and memory function of APP/PS1 mice were significantly improved, which was related to the increase in the number of Nestin+/BrdU+ and NeuN+/BrdU+ cells, and the decrease in the number of apoptotic cells in the hippocampus. BLWE treatment could also up-regulate the expression of synapse-associated proteins. Moreover, BLWE could modulate endogenous metabolic compounds in the brains of AD mice, including N-acetyl-aspartate, glutamine, etc. Furthermore, BLWE inhibited the phosphorylation of Tyr216-GSK-3ß and ß-catenin protein while increased CyclinD1 protein expression. Conclusion: We demonstrated that BLWE can enhance neural stem cells proliferation and improve neurogenesis, thereby efficiently repairing damaged neurons in the hippocampus and ameliorating cognitive impairment in APP/PS1 transgenic mice. The mechanism is at least partly through activating the Wnt/ß-catenin signaling pathway.

6.
ACS Appl Mater Interfaces ; 13(38): 45394-45405, 2021 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-34519493

RESUMO

Searching for high-quality air electrode catalysts is the long-term goal for the practical application of Zn-air batteries. Here, a series of coexistent composite materials (CoNi/NHCS-TUC-x) of cobalt-nickel supported on nitrogen-doped hollow spherical carbon and tubular carbon are obtained using a simple pyrolysis strategy. Co and Ni in the composites are mainly present in the form of alloy nanoparticles, M-Nx and M-Cx (M = Co or Ni) species, with high oxygen reduction reaction (ORR)/oxygen evolution reaction (OER) electroactivity. The materials containing different proportions of spherical carbon and tubular carbon obtained by simply adjusting the raw materials for generating tubular carbon exhibit interesting bifunctional performance: samples with an abundant tubular content have the highest ORR onset potential (0.91 V vs reversible hydrogen electrode), while those with a rich spherical content have the highest ORR current density (5.13 mA·cm-2). Furthermore, CoNi/NHCS-TUC-3 provides the lowest potential difference (ΔE = Ej=10 - E1/2) of 0.806 V. We then test the potential possibility of CoNi/NHCS-TUC-3 as an air electrode for primary and rechargeable Zn-air batteries. The primary battery delivers an open-circuit potential of 1.59 V, a peak power density of 361.8 mA·cm-2, and a specific capacity of 756.5 mA h·gZn-1. The rechargeable battery could be cycled stably for more than 55 h at 10 mA·cm-2. These characteristics make CoNi/NHCS-TUC-3 a superior electrocatalyst for both the ORR and OER, as well as a suitable bifunctional electrode applied to a rechargeable Zn-air battery.

7.
J Ethnopharmacol ; 267: 113612, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33249246

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: According to the theory of traditional Chinese medicine (TCM), Alzheimer's disease (AD) is identified as "forgetfulness" or "dementia", and it can be caused by spleen deficiency. Longan Aril (the aril of Dimocarpus longan Lour., LA) is a kind of Chinese medicine, and it can improve intelligence attributed to entering the spleen-meridian. This study aimed to explore the therapeutic effects of LA on AD mice with spleen deficiency, and to understand anti-AD mechanism of LA. MATERIAL AND METHODS: A mouse model of AD with spleen deficiency was established by D-gal (140 mg/kg, intraperitoneal injection) and AlCl3 (20 mg/kg, intragastrical administration) in combination with an irregular diet for 60 days, in which mice in LA group were daily given LA (0.5, 1.0 or 2.0 g/kg). The anti-AD effects of LA were evaluated by the Morris water maze, enzyme-linked immunosorbent assay (ELISA), hematoxylin and eosin (H&E), Nissl, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays. The anti-AD mechanism of LA was studied by using metabolomics, and the expressions of RAS/MEK/extracellular signal-regulated kinase (ERK) signaling pathway-related proteins were detected by Western blotting. RESULTS: LA improved learning and memory abilities, superoxide dismutase (SOD) level, and form and number of Nissl bodies, while reduced the levels of Aß42, phosphorylated-tau (p-tau), reactive oxygen species (ROS), malondialdehyde (MDA), monoamine oxidase-B (MAO-B), histological injury, and apoptosis rate in AD group (P < 0.05, P < 0.01 or P < 0.001). The anti-AD mechanism of LA may be related to RAS/MEK/ERK and other signaling pathways, in which the expressions of RAS/MEK/ERK signaling pathway-related proteins significantly reduced (P < 0.05 or P < 0.01). CONCLUSIONS: LA could improve the cognitive ability and reduce the pathologic impairment in AD mice, which might be partly mediated via inhibition of RAS/MEK/ERK singling pathway.


Assuntos
Doença de Alzheimer/prevenção & controle , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Cognição/efeitos dos fármacos , Disfunção Cognitiva/prevenção & controle , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Nootrópicos/farmacologia , Extratos Vegetais/farmacologia , Sapindaceae , Proteínas ras/metabolismo , Cloreto de Alumínio , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/enzimologia , Doença de Alzheimer/psicologia , Animais , Apoptose/efeitos dos fármacos , Encéfalo/enzimologia , Encéfalo/fisiopatologia , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/enzimologia , Disfunção Cognitiva/psicologia , Modelos Animais de Doenças , Feminino , Galactosamina , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Nootrópicos/isolamento & purificação , Estresse Oxidativo/efeitos dos fármacos , Fosforilação , Extratos Vegetais/isolamento & purificação , Sapindaceae/química , Transdução de Sinais
8.
Bioorg Chem ; 99: 103844, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32325336

RESUMO

Alzheimer's disease (AD) is a complex neurodegenerative disease with multiple pathological features. Multifunctional compounds able to simultaneously interact with several pathological components have been considered as a solution to treat the complex pathologies of neurodegenerative diseases. ß-carboline and cinnamic acid have been extensively studied for their widespread biological effects in treatment of AD, further application is limited due to its poor solubility and high toxicity. Herein, a series of carboline-cinnamic acid hybrids was designed and synthesized to obtain new multifunctional molecules with low toxicity and good physicochemical properties. In particular, e3 and e12 exhibited significant inhibition of Aß aggregation (inhibitory rate at 25 µM: 65% and 72% respectively), moderate BuChE inhibition, excellent neuroprotective effects and low neurotoxicity. Furthermore, in the AD mice model, e3 and e12 could restore learning and memory function to a comparable level to that of the control and did not exhibit any acute toxicity in vivo at a relatively high dose of 600 mg/kg. Thus, these new compounds can be further studied as multifunctional molecules for AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/antagonistas & inibidores , Carbolinas/farmacologia , Cinamatos/farmacologia , Desenho de Fármacos , Fármacos Neuroprotetores/farmacologia , Fragmentos de Peptídeos/antagonistas & inibidores , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Carbolinas/química , Sobrevivência Celular/efeitos dos fármacos , Cinamatos/química , Relação Dose-Resposta a Droga , Humanos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos ICR , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Fragmentos de Peptídeos/metabolismo , Agregados Proteicos/efeitos dos fármacos , Ratos , Relação Estrutura-Atividade , Células Tumorais Cultivadas
9.
Brain Behav Immun ; 67: 118-129, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28823624

RESUMO

Mechanical brain injury (MBI) is a common neurotrosis disorder of the central nervous system (CNS), which has a higher mortality and disability. In the case of MBI, neurons death leads to loss of nerve function. To date, there was no satisfactory way to restore neural deficits caused by MBI. Endogenous neural stem cells (NSCs) can proliferate, differentiate and migrate to the lesions after brain injury, to replace and repair the damaged neural cells in the subventricular zone (SVZ), hippocampus and the regions of brain injury. In the present study, we first prepared a mouse model of cortical stab wound brain injury. Using the immunohistochemical and hematoxylin-eosin (H&E) staining method, we demonstrated that osthole (Ost), a natural coumarin derivative, was capable of promoting the proliferation of endogenous NSCs and improving neuronal restoration. Then, using the Morris water maze (MWM) test, we revealed that Ost significantly improved the learning and memory function in the MBI mice, increased the number of neurons in the regions of brain injury, hippocampus DG and CA3 regions. Additionally, we found that Ost up-regulated the expression of self-renewal genes Notch 1 and Hes 1. However, when Notch activity was blocked by the γ-secretase inhibitor DAPT, the expression of Notch 1 and Hes 1 mRNA was down-regulated, augmentation of NICD and Hes 1 protein was ameliorated, the proliferation-inducing effect of Ost was abolished. These results suggested that the effects of Ost were at least in part mediated by activation of Notch signaling pathway. Our findings support that Ost is a potential drug for treating MBI due to its neuronal restoration.


Assuntos
Lesões Encefálicas/metabolismo , Proliferação de Células/efeitos dos fármacos , Cumarínicos/administração & dosagem , Células-Tronco Neurais/fisiologia , Receptor Notch1/metabolismo , Fatores de Transcrição HES-1/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Lesões Encefálicas/complicações , Sobrevivência Celular , Disfunção Cognitiva/complicações , Aprendizagem em Labirinto , Camundongos Endogâmicos C57BL , Células-Tronco Neurais/efeitos dos fármacos , RNA Mensageiro/metabolismo , Transdução de Sinais , Regulação para Cima
10.
Biol Pharm Bull ; 40(7): 1043-1054, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28674247

RESUMO

Neuroendoscopy processes can cause severe traumatic brain injury. Existing therapeutic methods, such as neural stem cell transplantation and osthole have not been proven effective. Therefore, there is an emerging need on the development of new techniques for the treatment of brain injuries. In this study we propose to combine the above stem cell based methods and then evaluate the efficiency and accuracy of the new method. Mice were randomly divided into four groups: group 1 (brain injury alone); group 2 (osthole); group 3 (stem cell transplantation); and group 4 (osthole combined with stem cell transplantation). We carried out water maze task to exam spatial memory. Immunocytochemistry was used to test the inflammatory condition of each group, and the differentiation of stem cells. To evaluate the condition of the damaged blood brain barrier restore, we detect the Evans blue (EB) extravasation across the blood brain barrier. The result shows that osthole and stem cell transplantation combined therapeutic method has a potent effect on improving the spatial memory. This combined method was more effective on inhibiting inflammation and preventing neuronal degeneration than the single treated ones. In addition, there was a distinct decline of EB extravasation in the combined treatment groups, which was not observed in single treatment groups. Most importantly, the combined usage of osthole and stem cell transplantation provide a better treatment for the traumatic brain injury caused by neuroendoscopy. The collective evidence indicates osthole combined with neural stem cell transplantation is superior than either method alone for the treatment of traumatic brain injury caused by neuroendoscopy.


Assuntos
Lesões Encefálicas Traumáticas/terapia , Cumarínicos/uso terapêutico , Neuroendoscopia/efeitos adversos , Transplante de Células-Tronco , Animais , Lesões Encefálicas Traumáticas/tratamento farmacológico , Lesões Encefálicas Traumáticas/etiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células-Tronco Neurais/transplante
11.
Front Neurosci ; 11: 340, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28659755

RESUMO

Alzheimer's disease (AD) is the most serious neurodegenerative disease worldwide and is characterized by progressive cognitive impairment and multiple neurological changes, including neuronal loss in the brain. However, there are no available drugs to delay or cure this disease. Consequently, neuronal replacement therapy may be a strategy to treat AD. Osthole (Ost), a natural coumarin derivative, crosses the blood-brain barrier and exerts strong neuroprotective effects against AD in vitro and in vivo. Recently, microRNAs (miRNAs) have demonstrated a crucial role in pathological processes of AD, implying that targeting miRNAs could be a therapeutic approach to AD. In the present study, we investigated whether Ost could enhance cell viability and prevent cell death in amyloid precursor protein (APP)-expressing neural stem cells (NSCs) as well as promote APP-expressing NSCs differentiation into more neurons by upregulating microRNA (miR)-9 and inhibiting the Notch signaling pathway in vitro. In addition, Ost treatment in APP/PS1 double transgenic (Tg) mice markedly restored cognitive functions, reduced Aß plague production and rescued functional impairment of hippocampal neurons. The results of the present study provides evidence of the neurogenesis effects and neurobiological mechanisms of Ost against AD, suggesting that Ost is a promising drug for treatment of AD or other neurodegenerative diseases.

12.
J Neurosci Res ; 95(12): 2493-2499, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28467619

RESUMO

Although several donor nerves can be chosen to repair avulsed brachial plexus nerve injury, available nerves are still limited. The purpose of this study is to validate whether the vagus nerve (VN) can be used as a donor. Eighteen Sprague-Dawley male rats were divided into three groups (n = 6). The right musculocutaneous nerve (McN) was transected with differing subsequent repair. (1) HS-VN group: a saphenous nerve (SN) graft-end was helicoidally wrapped round the VN side (epi-and perineurium was opened) with a 30 ° angle, distal SN end was coapted to the McN with end-to-end repair. (2) EE-PN group: a SN was interpositionally grafted between the transected phrenic nerve (PN) and the McN by end-to-end coaptation. (3) Sham control group: McN was transected and not repaired and postoperative vital signs were checked daily. At three months, electrophysiology, tetanic force, wet biceps muscle weight, and histology were evaluated. Every tested mean value in HS-VN group was significantly greater than the EE-PN or the sham control groups (p < 0.05 or p < 0.005). The mean recovery ratio of regenerated nerve fibers was 96% and, in HS-VN group, the mean recovery ratio of CMAP was 79%. No vital signs changed in any group. There was no statistical difference (p > 0.5) between the mean VN nerve-fiber numbers of the segments proximal (2237 ± 134) and distal (2150 ± 156) to the VN graft-attachment site. Histological analysis revealed no axon injury or intraneural scarring at any point along the VN. This study demonstrated that VN is a practical and reliable donor nerve for end-to-side nerve transfer. © 2017 Wiley Periodicals, Inc.


Assuntos
Nervo Musculocutâneo/cirurgia , Transferência de Nervo/métodos , Nervo Vago/transplante , Animais , Regeneração Nervosa/fisiologia , Ratos , Ratos Sprague-Dawley
13.
J Reconstr Microsurg ; 33(6): 435-440, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28293917

RESUMO

Background After peripheral nerve injury, there is an increase in calcium concentration in the injured nerves. Our previous publications have shown that increase in calcium concentration correlated well with degree of nerve injury and that local infusion of calcitonin has a beneficial effect on nerve recovery. Schwann cells play a pivotal role in regeneration and recovery. We aim to examine cultured Schwann cell survivals in various concentrations of calcium-containing growth media and the effect of calcitonin in such media. Methods To establish baseline in postinjury state, crush injury was induced in male Sprague-Dawley rats' sciatic nerves. Extra- and intraneural calcium concentrations were measured. To study Schwann cell survival, uninjured sciatic nerve segment was harvested and cultured in media containing various amounts of calcium. To study the effect of calcitonin, nerve harvest and culture were done in four additional media: (1) normal control, (2) normal control with calcitonin, (3) high calcium medium, and (4) high calcium medium with calcitonin. Schwann cells were studied and analyzed under fluorescent conditions. Results With increasing calcium concentration, there was a significant decrease in the number of Schwann cells. For the experimental groups, in which calcitonin had been added to the growth medium, there were similar amounts of Schwann cells present in both high and low calcium-containing medium. Conclusion Schwann cells are sensitive to increasing calcium concentration. Calcitonin counteracts the detrimental effects of high calcium on Schwann cell survival. This can have significant future clinical implications for patients with peripheral nerve injuries.


Assuntos
Cálcio/metabolismo , Regeneração Nervosa/efeitos dos fármacos , Células de Schwann/citologia , Células de Schwann/efeitos dos fármacos , Nervo Isquiático/lesões , Nervo Isquiático/metabolismo , Animais , Conservadores da Densidade Óssea/farmacologia , Calcitonina/farmacologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Masculino , Compressão Nervosa , Regeneração Nervosa/fisiologia , Ratos , Ratos Sprague-Dawley , Recuperação de Função Fisiológica , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/fisiopatologia
14.
J Neurosci Res ; 95(9): 1786-1795, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28052373

RESUMO

Peripheral nerve injury can have a devastating effect on daily life. Calcium concentrations in nerve fibers drastically increase after nerve injury, and this activates downstream processes leading to neuron death. Our previous studies showed that calcium-modulating agents decrease calcium accumulation, which aids in regeneration of injured peripheral nerves; however, the optimal therapeutic window for this application has not yet been identified. In this study, we show that calcium clearance after nerve injury is positively correlated with functional recovery in rats suffering from a crushed sciatic nerve injury. After the nerve injury, calcium accumulation increased. Peak volume is from 2 to 8 weeks post injury; calcium accumulation then gradually decreased over the following 24-week period. The compound muscle action potential (CMAP) measurement from the extensor digitorum longus muscle recovered to nearly normal levels in 24 weeks. Simultaneously, real-time polymerase chain reaction results showed that upregulation of calcium-ATPase (a membrane protein that transports calcium out of nerve fibers) mRNA peaked at 12 weeks. These results suggest that without intervention, the peak in calcium-ATPase mRNA expression in the injured nerve occurs after the peak in calcium accumulation, and CMAP recovery continues beyond 24 weeks. Immediately using calcium-modulating agents after crushed nerve injury improved functional recovery. These studies suggest that a crucial time frame in which to initiate effective clinical approaches to accelerate calcium clearance and nerve regeneration would be prior to 2 weeks post injury. © 2017 Wiley Periodicals, Inc.


Assuntos
Calcitonina/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Cálcio/metabolismo , Nifedipino/farmacologia , Traumatismos dos Nervos Periféricos/metabolismo , Recuperação de Função Fisiológica/fisiologia , Animais , Masculino , Compressão Nervosa , Regeneração Nervosa/efeitos dos fármacos , Regeneração Nervosa/fisiologia , Ratos , Ratos Sprague-Dawley
15.
Phytother Res ; 31(2): 284-295, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27981642

RESUMO

Ginseng (Panax ginseng C.A. Meyer) is one of the most widely used herbal medicines worldwide. The present study evaluated the neuroprotective effects of ginseng protein (GP) and its possible mechanisms in a cellular and animal model of AD. The results demonstrated that GP (10-100 µg/mL) significantly improved the survival rate of neurons and reduced the cells' apoptosis and the mRNA expression of caspase-3 and Bax/Bcl-2. In addition, GP (0.1 g/kg) significantly shortened the escape latency, prolonged the crossing times and the percentage of residence time; reduced the level of Aß1-42 and p-tau, the activity of T-NOS and iNOS, and the content of MDA and NO, improved the activity of SOD, the concentration of cAMP and the protein expression of p-PKA/PKA and -CREB/CREB. The results demonstrated that GP significantly inhibited Alzheimer-like pathophysiological changes induced by Aß25-35 or H2 O2 in cells or those induced by D-gal/ Al in animals. These neuroprotective effects of GP may be associated with the cAMP/PKA/CREB pathway. Also, in combination with our previous studies, these results indicate that the anti-AD mechanism of GP was likely to activate the CREB pathway through multiple channels. Copyright © 2016 John Wiley & Sons, Ltd.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Disfunção Cognitiva/tratamento farmacológico , Panax/química , Compostos de Alumínio , Animais , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Transtornos Cognitivos/tratamento farmacológico , Modelos Animais de Doenças , Feminino , Fármacos Neuroprotetores/farmacologia , Ratos , Ratos Wistar
16.
Muscle Nerve ; 56(4): 768-772, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27997687

RESUMO

INTRODUCTION: After nerve injury, calcium concentrations in intranerve fibers quickly increase. We have shown that functional recovery of injured nerves correlates with calcium absorption. A slight increase in calcium reduces the number of Schwann cells present. Calcitonin therapy greatly improves regeneration by accelerating calcium absorption. We examined the effect of adding calcitonin to higher concentration calcium media on cultured Schwann cells. METHODS: The cells, isolated from intact sciatic nerves, were cultured with normal or higher concentration calcium media with or without calcitonin. Schwann cells were incubated with anti-S-100, goat-anti-mouse, and propidium iodide and then viewed through fluorescent light and phase-contrast microscopy for observation and analysis. RESULTS: The cells in each calcitonin-containing medium showed many Schwann cells, however, the cells in the higher concentration calcium media showed fewer and more defective Schwann cells. CONCLUSION: These results show that calcitonin protects against the harmful effects of excessive calcium encountered in peripheral nerve injury. Muscle Nerve 56: 768-772, 2017.


Assuntos
Calcitonina/farmacologia , Cálcio/metabolismo , Células de Schwann/efeitos dos fármacos , Células de Schwann/metabolismo , Animais , Conservadores da Densidade Óssea/farmacologia , Cálcio/farmacologia , Células Cultivadas , Masculino , Ratos , Ratos Sprague-Dawley
17.
Neurochem Res ; 42(2): 398-405, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27734182

RESUMO

In recent years, neural stem cell (NSC) transplantation has been widely explored as a treatment for neurodegenerative diseases. NSCs are special cells that have some capacity for self-renewal and the potential to differentiate into multiple cell types. However, the inflammatory environment of diseased tissue is not conducive to the survival of transplanted cells. Osthole (Ost) is a principal bioactive component of Fructus Cnidii, Radix Angelicae Pubescentis and other traditional Chinese medicines. Ost has a wide range of pharmacological activities, such as anti-inflammation, immunomodulation, and neuroprotection. In the present study, we assessed the protective effects of Ost on bone marrow-derived-NSCs (BM-NSCs) against injury induced by hydrogen peroxide (H2O2). BM-NSCs were pre-treated with different doses of Ost and treated with H2O2. The cell counting kit-8 (CCK-8) method and lactate dehydrogenase (LDH) leakage assay were used to determine cell viability. Using the TUNEL assay and RT-PCR, we evaluated the effect of Ost on cell apoptosis. The results showed that Ost had protective effects against H2O2-induced cell damage, and the number of apoptotic cells was significantly decreased in the Ost pre-treated groups compared to the H2O2 group. The expression ratio of Bax/Bcl-2 mRNA was also decreased. Furthermore, western blotting was used to analyze levels of proteins related to PI3K/Akt-1 signaling pathway, and results indicated that ost can increase p-Akt and PI3K. Our findings suggested that Ost protects BM-NSCs against oxidative stress injury, and it can be used to improve the inflammatory environment of neurodegenerative diseases so and promote the survival rate of transplanted NSCs.


Assuntos
Cumarínicos/farmacologia , Citoproteção/fisiologia , Células-Tronco Neurais/metabolismo , Estresse Oxidativo/fisiologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Medula Óssea/efeitos dos fármacos , Medula Óssea/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Células Cultivadas , Citoproteção/efeitos dos fármacos , Relação Dose-Resposta a Droga , Peróxido de Hidrogênio/toxicidade , Camundongos , Camundongos Endogâmicos C57BL , Células-Tronco Neurais/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
18.
Life Sci ; 166: 131-138, 2016 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-27720999

RESUMO

AIMS: Recently, the potential for neural stem cells (NSCs) to be used in the treatment of Alzheimer's disease (AD) has been reported; however, the therapeutic effects are modest by virtue of the low neural differentiation rate. In our study, we transfected bone marrow-derived NSCs (BM-NSCs) with Neurotrophin-3 (NT-3), a superactive neurotrophic factor that promotes neuronal survival, differentiation, and migration of neuronal cells, to investigate the effects of NT-3 gene overexpression on the proliferation and differentiation into cholinergic neuron of BM-NSCs in vitro and its possible molecular mechanism. MAIN METHODS: BM-NSCs were generated from BM mesenchymal cells of adult C57BL/6 mice and cultured in vitro. After transfected with NT-3 gene, immunofluorescence and RT-PCR method were used to determine the ability of BM-NSCs on proliferation and differentiation into cholinergic neuron; Acetylcholine Assay Kit was used for acetylcholine (Ach). RT-PCR and WB analysis were used to characterize mRNA and protein level related to the Notch signaling pathway. KEY FINDINGS: We found that NT-3 can promote the proliferation and differentiation of BM-NSCs into cholinergic neurons and elevate the levels of acetylcholine (ACh) in the supernatant. Furthermore, NT-3 gene overexpression increase the expression of Hes1, decreased the expression of Mash1 and Ngn1 during proliferation of BM-NSCs. Whereas, the expression of Hes1 was down-regulated, and Mash1 and Ngn1 expression were up-regulated during differentiation of BM-NSCs. SIGNIFICANCE: Our findings support the prospect of using NT-3-transduced BM-NSCs in developing therapies for AD due to their equivalent therapeutic potential as subventricular zone-derived NSCs (SVZ-NSCs), greater accessibility, and autogenous attributes.


Assuntos
Células da Medula Óssea/citologia , Neurônios Colinérgicos/citologia , Células-Tronco Neurais/citologia , Neurogênese , Neurotrofina 3/metabolismo , Receptores Notch/metabolismo , Transdução de Sinais , Animais , Células da Medula Óssea/metabolismo , Proliferação de Células , Células Cultivadas , Neurônios Colinérgicos/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Células-Tronco Neurais/metabolismo , Neurotrofina 3/genética , Transdução Genética , Regulação para Cima
19.
Front Pharmacol ; 7: 182, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27445818

RESUMO

UNLABELLED: Convection enhanced delivery (CED) infuses drugs directly into brain tissue. Needle insertion is required and results in a stab wound injury (SWI). Subsequent secondary injury involves the release of inflammatory and apoptotic cytokines, which have dramatic consequences on the integrity of damaged tissue, leading to the evolution of a pericontusional-damaged area minutes to days after in the initial injury. The present study investigated the capacity for arctigenin (ARC) to prevent secondary brain injury and the determination of the underlying mechanism of action in a mouse model of SWI that mimics the process of CED. After CED, mice received a gavage of ARC from 30 min to 14 days. Neurological severity scores (NSS) and wound closure degree were assessed after the injury. Histological analysis and immunocytochemistry were used to evaluated the extent of brain damage and neuroinflammation. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) was used to detect universal apoptosis. Enzyme-linked immunosorbent assays (ELISA) was used to test the inflammatory cytokines (tumor necrosis factor (TNF)-α, interleukin (IL)-6 and IL-10) and lactate dehydrogenase (LDH) content. Gene levels of inflammation (TNF-α, IL-6, and IL-10) and apoptosis (Caspase-3, Bax and Bcl-2) were detected by reverse transcription-polymerase chain reaction (RT-PCR). Using these, we analyzed ARC's efficacy and mechanism of action. RESULTS: ARC treatment improved neurological function by reducing brain water content and hematoma and accelerating wound closure relative to untreated mice. ARC treatment reduced the levels of TNF-α and IL-6 and the number of allograft inflammatory factor (IBA)- and myeloperoxidase (MPO)-positive cells and increased the levels of IL-10. ARC-treated mice had fewer TUNEL+ apoptotic neurons and activated caspase-3-positive neurons surrounding the lesion than controls, indicating increased neuronal survival. CONCLUSIONS: ARC treatment confers neuroprotection of brain tissue through anti-inflammatory and anti-apoptotic effects in a mouse model of SWI. These results suggest a new strategy for promoting neuronal survival and function after CED to improve long-term patient outcome.

20.
J Mol Neurosci ; 60(1): 71-81, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27394443

RESUMO

Accumulation of ß-amyloid peptide (Aß) in the brain plays an important role in the pathogenesis of Alzheimer's disease (AD). It has been reported that osthole exerts its neuroprotective effect on neuronal synapses, but its exact mechanism is obscure. Recently, microRNAs have been demonstrated to play a crucial role in inducing synaptotoxicity by Aß, implying that targeting microRNAs could be a therapeutic approach of AD. In the present study, we investigated the neuroprotective effects of osthole on a cell model of AD by transducing APP695 Swedish mutant (APP695swe, APP) into mouse cortical neurons and human SH-SY5Y cells. In this study, the cell counting kit CCK-8, apoptosis assay, immunofluorescence analysis, enzyme-linked immunosorbent assay (ELISA), quantitative real-time polymerase chain reaction, and Western blot assay were used. We found that osthole could enhance cell viability, prevent cell death, and reverse the reduction of synaptic proteins (synapsin-1, synaptophysin, and postsynaptic density-95) in APP-overexpressed cells, which was attributed to increases in microRNA-9 (miR-9) expression and subsequent decreases in CAMKK2 and p-AMPKα expressions. These results demonstrated that osthole plays a neuroprotective activity role in part through upregulating miR-9 in AD.


Assuntos
Doença de Alzheimer/metabolismo , Cumarínicos/farmacologia , MicroRNAs/genética , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Sinapses/efeitos dos fármacos , Quinases Proteína-Quinases Ativadas por AMP , Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Animais , Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/genética , Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/metabolismo , Linhagem Celular Tumoral , Células Cultivadas , Fatores de Troca do Nucleotídeo Guanina/genética , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/metabolismo , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Sinapses/metabolismo , Sinapsinas/genética , Sinapsinas/metabolismo , Sinaptofisina/genética , Sinaptofisina/metabolismo
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