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Stroke is one of the most-devastating brain diseases causing acute death or permanent disability. Although tissue-type plasminogen activator was approved by Food and Drug Administration for early reperfusion of the occluded vessels, oxidative injury may cause extensive brain infarction. Accordingly, there is a need for effective neuroprotection during reperfusion, and stem cell-based therapeutic approaches should fulfill this requirement. We established human neural stem cells (NSCs) encoding gene of choline acetyltransferase (F3.ChAT), an acetylcholine-synthesizing enzyme, and investigated whether infusion of the F3.ChAT cells attenuate the ischemia-reperfusion brain damage in a rat model of middle cerebral artery occlusion (MCAO). F3.ChAT cells were found to produce much higher amounts of ChAT as well as neuroprotective and anti-inflammatory neurotrophins than their parental F3 NSCs. After 2-h occlusion, the artery was reperfused, along with intravenous infusion of the stem cells (1 × 106 cells/rat). Administration of the F3.ChAT cells markedly reduced the infarction volume and improved both the cognitive dysfunction and behavioural deficits of MCAO animals, in which F3.ChAT cells were superior to F3 cells. F3.ChAT cells not only restored microtubule-associated protein-2, a neuronal cytoskeletal protein, and preserved microvessels, but also suppressed lipid peroxidation, pro-inflammatory cytokines, glial fibrillary acidic protein, and intercellular adhesion molecule-1 in the brain tissues. The results demonstrate that early intravenous infusion of NSCs expressing ChAT and neurotrophins attenuate brain and capillary injuries and restore neurobehavioural functions via neuroprotective and anti-inflammatory activities, and that F3.ChAT cells could be a candidate for the neuroprotection and functional recovery of acute stroke patients.
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Encéfalo/metabolismo , Colina O-Acetiltransferasa/genética , Infarto de la Arteria Cerebral Media/terapia , Células-Madre Neurales/metabolismo , Neuroprotección/fisiología , Trasplante de Células Madre , Animales , Colina O-Acetiltransferasa/metabolismo , Modelos Animales de Enfermedad , Neuronas/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
BACKGROUND: Osteoarthritis (OA), a chronic age-related disease characterized by the slowly progressive destruction of articular cartilage, is one of the leading causes of disability. As a new strategy for treatment of OA, mesenchymal stem cells (MSCs) have the potential for articular cartilage regeneration. Meanwhile, thrombospondin 2 (TSP2) promotes the chondrogenic differentiation of MSCs. AIM: To investigate whether TSP2 induces chondrogenic differentiation of human adipose-derived MSCs (hADMSCs) and potentiates the therapeutic effects of hADMSCs in OA rabbits. METHODS: We investigated the chondrogenic potential of TSP2 in hADMSCs by analyzing the expression of chondrogenic markers as well as NOTCH signaling genes in normal and TSP2 small interfering RNA (siRNA)-treated stem cells. Anterior cruciate ligament transection surgery was performed in male New Zealand white rabbits, and 8 wk later, hADMSCs (1.7 × 106 or 1.7 × 107 cells) were injected into the injured knees alone or in combination with intra-articular injection of TSP2 (100 ng/knee) at 2-d intervals. OA progression was monitored by gross, radiological, and histological examinations. RESULTS: In hADMSC culture, treatment with TSP2 increased the expression of chondrogenic markers (SOX9 and collagen II) as well as NOTCH signaling genes (JAGGED1 and NOTCH3), which were inhibited by TSP2 siRNA treatment. In vivo, OA rabbits treated with hADMSCs or TSP2 alone exhibited lower degree of cartilage degeneration, osteophyte formation, and extracellular matrix loss 8 wk after cell transplantation. Notably, such cartilage damage was further alleviated by the combination of hADMSCs and TSP2. In addition, synovial inflammatory cytokines, especially tumor-necrosis factor-α, markedly decreased following the combination treatment. CONCLUSION: The results indicate that TSP2 enhances chondrogenic differentiation of hADMSCs via JAGGED1/NOTCH3 signaling, and that combination therapy with hADMSCs and TSP2 exerts synergistic effects in the cartilage regeneration of OA joints.
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Anti-thrombotic activity and safety of nattokinase, an enzyme produced by Bacillus subtilis during soybean fermentation, were investigated in comparison with tissue-type plasminogen activator (t-PA). Carotid arterial thrombosis was produced with a FeCl3-soaked paper, followed by intravenous injection of nattokinase or t-PA. Nattokinase and t-PA delayed thrombus formation, near-fully (> 90%) inhibiting at 75 and 8.5 mg/kg, respectively. As adverse effects, t-PA induced petechial haemorrhage at 10 mg/kg in the lungs and thymus, and extensive bleeding at 20 mg/kg. Nattokinase also caused pulmonary haemorrhage from 300 mg/kg. Collectively, the standard safety margins (SSMs) for t-PA and nattokinase were calculated to be 1.2 and 4.0, respectively. Combinational treatment with dexamethasone (2 mg/kg) increased the efficacy and safety of t-PA and nattokinase, widening their SSMs to 2.4 and 8.0, respectively. The results indicate that nattokinase delayed thrombus formation and dissolved thrombi, and that nattokinase could be a good candidate anti-thrombotic agent with relatively-low haemorrhagic risk.
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[This corrects the article DOI: 10.1155/2018/2929107.].
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The effects of human oligodendrocyte progenitor (F3.olig2) cells on improving neurobehavioral deficits were investigated in an experimental model of periventricular leukomalacia (PVL). Seven-day-old male rats were subjected to hypoxia-ischemia-lipopolysaccharide injection (HIL), and intracerebroventricularly transplanted with F3.olig2 (4 × 105 cells/rat) once at post-natal day (PND) 10 or repeatedly at PND10, 17, 27, and 37. Neurobehavioral disorders were evaluated at PND14, 20, 30, and 40 via cylinder test, locomotor activity, and rotarod performance, and cognitive function was evaluated at PND41-45 through passive avoidance and Morris water-maze performances. F3.olig2 cells recovered the rate of use of the forelimb contralateral to the injured brain, improved locomotor activity, and restored rotarod performance of PVL animals; in addition, marked improvement of learning and memory function was seen. It was confirmed that transplanted F3·olig2 cells migrated to injured areas, matured to oligodendrocytes expressing myelin basic protein (MBP), and markedly attenuated the loss of host MBP in the corpus callosum. The results indicate that the transplanted F3.olig2 cells restored neurobehavioral functions by preventing axonal demyelination, and that human oligodendrocyte progenitor cells could be a candidate for cell therapy of perinatal hypoxic-ischemic and infectious brain injuries including PVL and cerebral palsy.
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Leucomalacia Periventricular/terapia , Células Precursoras de Oligodendrocitos/trasplante , Animales , Animales Recién Nacidos , Línea Celular , Cognición , Disfunción Cognitiva/fisiopatología , Disfunción Cognitiva/terapia , Modelos Animales de Enfermedad , Femenino , Humanos , Leucomalacia Periventricular/fisiopatología , Locomoción , Aprendizaje por Laberinto , Memoria , Células Precursoras de Oligodendrocitos/citología , Embarazo , Ratas , Ratas Sprague-DawleyRESUMEN
[This corrects the article on p. 105 in vol. 33, PMID: 28747975.].
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Objective: In order to assess the effectiveness of a hop extract (HE) for postmenopausal symptoms, the effects of Lifenol on ovariectomy-induced osteoporosis, hyperlipidemia, body weight increase, and hot flash were investigated in rats. Methods: Female Sprague-Dawley rats were ovariectomized and subjected to a daily scheduled exercise training (15 min at 15 m/min) or treated with HE (30 or 100 mg/kg, oral) or 17ß-estradiol (100 µg/kg, intraperitoneal) for 12 weeks. Body and visceral fat weights, serum lipid profiles, osteoporotic parameters in serum, and femoral bones were analyzed. Separately, forced running-induced dermal and rectal temperatures and blood flow velocity were measured in ovariectomized rats. Results: Ovariectomy increased blood lipids including triglycerides, total cholesterol, and low-density lipoproteins, leading to visceral fat accumulation and overweight. Estrogen depletion caused osteoporosis, displaying decreased femoral bone weight, bone mineral density and content, and blood phosphorus level. The disturbances in lipid metabolism and bone resorption were recovered by treatment with HE in a dose-dependent manner. In addition, HE treatment shortened the duration of forced running-induced alterations in skin and rectal temperatures by reducing blood flow velocity. Conclusion: The results indicate that HE attenuated overweight, osteoporosis, and hot flash in estrogen-deficient animals by regulating blood lipid profile and fat accumulation, blood estrogen and bone resorption factors, and dermal blood flow.
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Estrógenos/sangre , Sofocos/tratamiento farmacológico , Humulus , Metabolismo de los Lípidos/efectos de los fármacos , Obesidad/tratamiento farmacológico , Osteoporosis/tratamiento farmacológico , Fitoterapia , Animales , Densidad Ósea/efectos de los fármacos , Resorción Ósea/prevención & control , Estrógenos/deficiencia , Femenino , Fémur/efectos de los fármacos , Fémur/metabolismo , Grasa Intraabdominal/metabolismo , Obesidad/metabolismo , Osteoporosis/metabolismo , Ovariectomía , Sobrepeso/tratamiento farmacológico , Sobrepeso/metabolismo , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Posmenopausia , Ratas Sprague-DawleyRESUMEN
Since plant oils are believed to be better than animal fats for cerebrovascular and cardiovascular diseases, the effects of various plant oils and trans-fat on blood lipid profiles and ischemic stroke were investigated. Sprague-Dawley rats were fed a diet containing the oils or trans-fat, and then body weights, blood lipids, and effects on brain infarction and physical dysfunction induced by middle cerebral artery occlusion (MCAO) were analyzed. All the oils and trans-fat, except perilla oil, significantly increased body fats and body weight gain. Sesame oil and trans-fat specifically increased blood cholesterols and triglycerides, respectively, while perilla oil decreased both cholesterols and triglycerides. Perilla oil not only attenuated cerebral infarction, but also restored locomotor activity and rota-rod performances of MCAO rats. It is suggested that perilla oil among oils and fats could be the first choice to reduce the risk of metabolic syndrome and ischemic stroke.
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Ginsenosides from Panax ginseng are well known for their diverse pharmacological effects including antithrombotic activity. Since adventitious roots of mountain ginseng (ARMG) also contain various ginsenosides, blood flow-improving effects of the dried powder and extract of ARMG were investigated. Rats were orally administered with dried powder (PARMG) or ethanol extract (EARMG) of ARMG (125, 250 or 500 mg/kg) or aspirin (30 mg/kg, a reference control) for 3 weeks. Forty min after the final administration, carotid arterial thrombosis was induced by applying a 70% FeCl3-soaked filter paper outside the arterial wall for 5 min, and the blood flow was monitored with a laser Doppler probe. Both PARMG and EARMG delayed the FeCl3-induced arterial occlusion in a dose-dependent manner, doubling the occlusion time at high doses. In mechanism studies, a high concentration of EARMG inhibited platelet aggregation induced by collagen in vitro. In addition, EARMG improved the blood lipid profiles, decreasing triglyceride and cholesterol levels. Although additional action mechanisms remain to be clarified, it is suggested that ARMG containing high amount of ginsenosides such as Rg3 improves blood flow not only by inhibiting oxidative thrombosis, but also by modifying blood lipid profiles.
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This study investigated the effects of a silk peptide fraction obtained by incubating silk proteins with Protease N and Neutrase (SP-NN) on cognitive dysfunction of Alzheimer disease model rats. In order to elucidate underlying mechanisms, the effect of SP-NN on the expression of choline acetyltransferase (ChAT) mRNA was assessed in F3.ChAT neural stem cells and Neuro2a neuroblastoma cells; active amino acid sequence was identified using HPLC-MS. The expression of ChAT mRNA in F3.ChAT cells increased by 3.79-fold of the control level by treatment with SP-NN fraction. The active peptide in SP-NN was identified as tyrosine-glycine with 238.1 of molecular weight. Male rats were orally administered with SP-NN (50 or 300mg/kg) and challenged with a cholinotoxin AF64A. As a result of brain injury and decreased brain acetylcholine level, AF64A induced astrocytic activation, resulting in impairment of learning and memory function. Treatment with SP-NN exerted recovering activities on acetylcholine depletion and brain injury, as well as cognitive deficit induced by AF64A. The results indicate that, in addition to a neuroprotective activity, the SP-NN preparation restores cognitive function of Alzheimer disease model rats by increasing the release of acetylcholine.
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Enfermedad de Alzheimer/psicología , Aziridinas/toxicidad , Colina O-Acetiltransferasa/genética , Colina/análogos & derivados , Cognición/efectos de los fármacos , Modelos Animales de Enfermedad , Proteínas de Insectos/química , Fragmentos de Péptidos/farmacología , Seda/química , Enfermedad de Alzheimer/inducido químicamente , Animales , Reacción de Prevención/efectos de los fármacos , Línea Celular Tumoral , Colina/toxicidad , Regulación Enzimológica de la Expresión Génica , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratas , Ratas Sprague-DawleyRESUMEN
Anti-atherosclerosis effects of perilla oil were investigated, in comparison with lovastatin, in rabbits fed a high-cholesterol diet (HCD). Hypercholesterolemia was induced in rabbits by feeding the HCD containing 0.5% cholesterol and 1% corn oil, and perilla oil (0.1 or 0.3%) was added to the diet containing 0.5% cholesterol for 10 weeks. HCD greatly increased blood total cholesterol and low-density lipoproteins, and caused thick atheromatous plaques, covering 74% of the aortic wall. Hyper-cholesterolemia also induced lipid accumulation in the liver and kidneys, leading to lipid peroxidation. Perilla oil not only attenuated hypercholesterolemia and atheroma formation, but also reduced fat accumulation and lipid peroxidation in hepatic and renal tissues. The results indicate that perilla oil prevents atherosclerosis and fatty liver by controlling lipid metabolism, and that it could be the first choice oil to improve diet-induced metabolic syndrome.
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Amygdala is involved in the fear memory that recognizes certain environmental cues predicting threatening events. Manipulation of neurotransmission within the amygdala affects the expression of conditioned and unconditioned emotional memories such as fear freezing behaviour. We previously demonstrated that F3.ChAT human neural stem cells (NSCs) overexpressing choline acetyltransferase (ChAT) improve cognitive function of Alzheimer's disease model rats with hippocampal or cholinergic nerve injuries by increasing acetylcholine (ACh) level. In the present study, we examined the effect of F3.ChAT cells on the deficit of unconditioned fear freezing. Rats given N-methyl-d-aspartate (NMDA) in their amygdala 2 weeks prior to cat odor exposure displayed very short resting (freezing) time compared to normal animals. NMDA induced neuronal degeneration in the amygdala, leading to a decreased ACh concentration in cerebrospinal fluid. However, intracerebroventricular transplantation of F3.ChAT cells attenuated amygdala lesions 4 weeks after transplantation. The transplanted cells were found in the NMDA-injury sites and produced ChAT protein. In addition, F3.ChAT-receiving rats recuperated freezing time staying remote from the cat odor source, according to the recovery of brain ACh concentration. The results indicate that human NSCs overexpressing ChAT may facilitate retrieval of unconditioned fear memory by increasing ACh level.
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Colina O-Acetiltransferasa/uso terapéutico , Miedo/fisiología , Acetilcolina , Enfermedad de Alzheimer , Amígdala del Cerebelo/lesiones , Animales , Conducta Animal/fisiología , Encéfalo , Colina O-Acetiltransferasa/metabolismo , Cognición , Hipocampo , Humanos , Masculino , Memoria/fisiología , Modelos Animales , Células-Madre Neurales/trasplante , Ratas , Ratas Sprague-DawleyRESUMEN
In Alzheimer disease (AD), amyloid-beta (Aß) peptides induce the degeneration of presynaptic cholinergic system, in which decreased activity of enzyme choline acetyltransferase (ChAT) responsible for acetylcholine synthesis is observed. Cereboost™, an extract of American ginseng extract, contains a high concentration of Rb1 ginsenoside which is a well-known ingredient improving human cognitive function. We investigated the effects of Cereboost™ on learning and memory function of mice challenged with an Aß1-42 peptide and the underlying mechanisms in vitro. Cereboost™ protected against Aß1-42-induced cytotoxicity in F3.ChAT stem cells, and enhanced the ChAT gene expression. Aß1-42 injection into the mouse brain impaired the cognitive function, which was recovered by oral administration of Cereboost™. In addition, Cereboost™ restored brain microtubule-associated protein 2 and synaptophysin as well as acetylcholine concentration. The results demonstrate that Cereboost™ administration recovered the cognitive function of AD model animals by enhancing acetylcholine level via ChAT gene expression and neuroprotection.
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Acetilcolina/metabolismo , Enfermedad de Alzheimer/prevención & control , Conducta Animal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Colina O-Acetiltransferasa/metabolismo , Cognición/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Panax/química , Extractos Vegetales/farmacología , Acetilcolinesterasa/metabolismo , Enfermedad de Alzheimer/inducido químicamente , Enfermedad de Alzheimer/enzimología , Enfermedad de Alzheimer/psicología , Péptidos beta-Amiloides , Animales , Reacción de Prevención/efectos de los fármacos , Encéfalo/enzimología , Línea Celular , Colina O-Acetiltransferasa/genética , Inhibidores de la Colinesterasa/aislamiento & purificación , Inhibidores de la Colinesterasa/farmacología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Proteínas Ligadas a GPI/antagonistas & inhibidores , Proteínas Ligadas a GPI/metabolismo , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratones Endogámicos ICR , Proteínas Asociadas a Microtúbulos/metabolismo , Fármacos Neuroprotectores/aislamiento & purificación , Fragmentos de Péptidos , Fitoterapia , Extractos Vegetales/aislamiento & purificación , Plantas Medicinales , Sinaptofisina/metabolismo , Factores de Tiempo , Transfección , Regulación hacia ArribaRESUMEN
White rose (Rosa hybrida) petals were extracted with ethanol (EtOH) or butanol (BuOH), and tested for their antimicrobial activities against two species of Gram-positive bacteria, six species of Gram-negative bacteria, and two species of fungi. On in vitro antimicrobial assays, Helicobacter pylori and Propionibacterium acnes were highly susceptible to white rose petal extract (WRPE)-EtOH and WRPE-BuOH, leading to minimal inhibitory concentrations of 100 and 10 µg/mL for H. pylori and 400 and 40 µg/mL for P. acnes, respectively. In in vivo experiments, C57BL/6 mice were infected with H. pylori by intragastric inoculation (1 × 10(8) CFU/mouse) 3 times, and orally treated twice a day for 14 days with WRPE-EtOH and WRPE-BuOH. On a CLO kit assay, 200 mg/kg of WRPE-EtOH fully eliminated the bacteria from the gastric mucosa, and the effect of 100 mg/kg of ethanol fraction was similar to pantoprazole (30 mg/kg), displaying 75% elimination. WRPE-BuOH was more effective, exhibiting 75% elimination at 20 mg/kg. The CLO test results were confirmed by bacterial identification. WRPE-EtOH and WRPE-BuOH inhibited the growth of various bacteria and fungi, and in particular, they effectively killed H. pylori and eliminated the bacteria from the mouse stomach. The results indicate that WRPE-EtOH and WRPE-BuOH could be good candidates for the elimination of H. pylori.
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Antiinfecciosos/farmacología , Butanoles/química , Etanol/química , Flores/química , Mucosa Gástrica/efectos de los fármacos , Infecciones por Helicobacter/tratamiento farmacológico , Helicobacter pylori/efectos de los fármacos , Propionibacterium acnes/efectos de los fármacos , Rosa/química , Solventes/química , Animales , Antiinfecciosos/aislamiento & purificación , Recuento de Colonia Microbiana , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Mucosa Gástrica/microbiología , Infecciones por Helicobacter/microbiología , Helicobacter pylori/crecimiento & desarrollo , Masculino , Ratones Endogámicos C57BL , Pruebas de Sensibilidad Microbiana , Fitoterapia , Plantas Medicinales , Propionibacterium acnes/crecimiento & desarrolloRESUMEN
In order to assess inhibitory potentials of white rose petal extracts (WRPE) on the activities of enzymes related to dermal aging according to the extraction conditions, three extraction methods were adopted. WRPE was prepared by extracting dried white rose (Rosa hybrida) petals with 50% ethanol (WRPE-EtOH), Pectinex® SMASH XXL enzyme (WRPE-enzyme) or high temperature-high pressure (WRPE-HTHP). In the inhibition of matrix metalloproteinase-1, although the enzyme activity was fully inhibited by all 3 extracts at 100 µg/mL in 60 min, partial inhibition (50-70%) was achieved only by WRPE-EtOH and WRPE-enzyme at 50 µg/mL. High concentrations (≥250 µg/mL) of all 3 extracts markedly inhibited the elastase activity. However, at low concentrations (15.6-125 µg/mL), only WRPE-EtOH inhibited the enzyme activity. Notably, WRPE-EtOH was superior to WRPE-enzyme and WRPE-HTHP in the inhibition of tyrosinase. WRPE-EtOH significantly inhibited the enzyme activity from 31.2 µM, reaching 80% inhibition at 125 µM. In addition to its strong antioxidative activity, the ethanol extract of white rose petals was confirmed to be effective in inhibiting skin aging-related enzymes. Therefore, it is suggested that WRPE-EtOH could be a good candidate for the improvement of skin aging such as wrinkle formation and pigmentation.